Atlas Of Diseases Of Kidney

Diseases of Water Metabolism Sumit Kumar Tomas Berl

T

he maintenance of the tonicity of body fluids within a very narrow physiologic range is made possible by homeostatic mechanisms that control the intake and excretion of water. Critical to this process are the osmoreceptors in the hypothalamus that control the secretion of antidiuretic hormone (ADH) in response to changes in tonicity. In turn, ADH governs the excretion of water by its end-organ effect on the various segments of the renal collecting system. The unique anatomic and physiologic arrangement of the nephrons brings about either urinary concentration or dilution, depending on prevailing physiologic needs. In the first section of this chapter, the physiology of urine formation and water balance is described. The kidney plays a pivotal role in the maintenance of normal water homeostasis, as it conserves water in states of water deprivation, and excretes water in states of water excess. When water homeostasis is deranged, alterations in serum sodium ensue. Disorders of urine dilution cause hyponatremia. The pathogenesis, causes, and management strategies are described in the second part of this chapter. When any of the components of the urinary concentration mechanism is disrupted, hypernatremia may ensue, which is universally characterized by a hyperosmolar state. In the third section of this chapter, the pathogenesis, causes, and clinical settings for hypernatremia and management strategies are described.

CHAPTER

1

1.2

Disorders of Water, Electrolytes, and Acid-Base

Normal water intake (1.0–1.5 L/d)

Water of cellular metabolism (350–500 mL/d) Extracellular compartment (15 L)

Total body water 42L (60% body weight in a 70-kg man)

Variable water excretion

Fixed water excretion

Filtrate/d 180L Stool 0.1 L/d

Sweat 0.1 L/d

Total insensible losses ~0.5 L/d

Pulmonary 0.3 L/d

Total urine output 1.0–1.5 L/d

Water excretion

Intracellular compartment (27 L)

Water intake and distribution

Physiology of the Renal Diluting and Concentrating Mechanisms FIGURE 1-1 Principles of normal water balance. In most steady-state situations, human water intake matches water losses through all sources. Water intake is determined by thirst (see Fig. 1-12) and by cultural and social behaviors. Water intake is finely balanced by the need to maintain physiologic serum osmolality between 285 to 290 mOsm/kg. Both water that is drunk and that is generated through metabolism are distributed in the extracellular and intracellular compartments that are in constant equilibrium. Total body water equals approximately 60% of total body weight in young men, about 50% in young women, and less in older persons. Infants’ total body water is between 65% and 75%. In a 70-kg man, in temperate conditions, total body water equals 42 L, 65% of which (22 L) is in the intracellular compartment and 35% (19 L) in the extracellular compartment. Assuming normal glomerular filtration rate to be about 125 mL/min, the total volume of blood filtered by the kidney is about 180 L/24 hr. Only about 1 to 1.5 L is excreted as urine, however, on account of the complex interplay of the urine concentrating and diluting mechanism and the effect of antidiuretic hormone to different segments of the nephron, as depicted in the following figures.

Diseases of Water Metabolism

Generation of medullary hypertonicity Normal function of the thick ascending limb of loop of Henle Urea delivery Normal medullary blood flow

;;;;;;;;;;; ;;;; ;;;;;;;;;;; ;;;; ;;;;;;;;;;;;;;; ;;;;;;;;;;; ;;;; ;;;;;;;;;;; ;;;; ;;;;;;;;;;;;;;; ;;;;;;;;;;; ;;;;;;;;;;;;;;; ;;;; ;;;;;;;;;;; ;;;; ;;;;;;;;;;; ;;;; ;;;; ;;;;;;;;;;; ;;;; ;;;;;;;;;;; ;;;; ;;; ;;;;;;;;;;; ;;;; ;;; ;;;;;;;;;;; ;;;; ;;; ;;;;;;;;;;; ;;;; ;;; ;;;; ;;; ;;; NaCl

H 2O

GFR

ADH

H 2O

ADH

NaCl

H 2O

NaCl

Determinants of delivery of NaCl to distal tubule: GFR Proximal tubular fluid and solute (NaCl) reabsorption

NaCl

NaCl

H 2O

ADH

NaCl

H 2O

NaCl

H 2O

H 2O

H 2O

;; ;;

Water delivery NaCl movement Solute concentration

Collecting system water permeability determined by Presence of arginine vasopressin Normal collecting system

FIGURE 1-2 Determinants of the renal concentrating mechanism. Human kidneys have two populations of nephrons, superficial and juxtamedullary. This anatomic arrangement has important bearing on the formation of urine by the countercurrent mechanism. The unique anatomy of the nephron [1] lays the groundwork for a complex yet logical physiologic arrangement that facilitates the urine concentration and dilution mechanism, leading to the formation of either concentrated or dilute urine, as appropriate to the person’s needs and dictated by the plasma osmolality. After two thirds of the filtered load (180 L/d) is isotonically reabsorbed in the proximal convoluted tubule, water is handled by three interrelated processes: 1) the delivery of fluid to the diluting segments; 2) the separation of solute and water (H2O) in the diluting segment; and 3) variable reabsorption of water in the collecting duct. These processes participate in the renal concentrating mechanism [2]. 1. Delivery of sodium chloride (NaCl) to the diluting segments of the nephron (thick ascending limb of the loop of Henle and the distal convoluted tubule) is determined by glomerular filtration rate (GFR) and proximal tubule function. 2. Generation of medullary interstitial hypertonicity, is determined by normal functioning of the thick ascending limb of the loop of Henle, urea delivery from the medullary collecting duct, and medullary blood flow. 3. Collecting duct permeability is determined by the presence of antidiuretic hormone (ADH) and normal anatomy of the collecting system, leading to the formation of a concentrated urine.

1.3

1.4

Disorders of Water, Electrolytes, and Acid-Base

Normal functioning of Thick ascending limb of loop of Henle Cortical diluting segment

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H 2O

GFR

H 2O

NaCl NaCl

Determinants of delivery of H2O to distal parts of the nephron GFR Proximal tubular H2O and NaCl reabsorption

Impermeable collecting duct

FIGURE 1-3 Determinants of the urinary dilution mechanism include 1) delivery of water to the thick ascending limb of the loop of Henle, distal convoluted tubule, and collecting system of the nephron; 2) generation of maximally hypotonic fluid in the diluting segments (ie, normal thick ascending limb of the loop of Henle and cortical diluting segment); 3) maintenance of water impermeability of the collecting system as determined by the absence of antidiuretic hormone (ADH) or its action and other antidiuretic substances. GFR—glomerular filtration rate; NaCl—sodium chloride; H2O—water.

H 2O

NaCl

H 2O

NaCl

H 2O

H 2O

Collecting duct impermeability depends on Absence of ADH Absence of other antidiuretic substances

Distal tubule Urea H 2O

Cortex Na+ K+ 2Cl2– NaCl

Outer medulla

Na+ K+ 2Cl2–

2 H 2O

Na+ 1 K+ 2Cl2– Urea

Outer medullary collecting duct

Na+ K+ 2Cl2– Urea

H 2O

H 2O

Inner medullary collecting duct

4 3 H 2O Urea NaCl

NaCl

Urea

5 NaCl Inner medulla

Loop of Henle

Collecting tubule

FIGURE 1-4 Mechanism of urine concentration: overview of the passive model. Several models of urine concentration have been put forth by investigators. The passive model of urine concentration described by Kokko and Rector [3] is based on permeability characteristics of different parts of the nephron to solute and water and on the fact that the active transport is limited to the thick ascending limb. 1) Through the Na+, K+, 2 Cl cotransporter, the thick ascending limb actively transports sodium chloride (NaCl), increasing the interstitial tonicity, resulting in tubular fluid dilution with no net movement of water and urea on account of their low permeability. 2) The hypotonic fluid under antidiuretic hormone action undergoes osmotic equilibration with the interstitium in the late distal tubule and cortical and outer medullary collecting duct, resulting in water removal. Urea concentration in the tubular fluid rises on account of low urea permeability. 3) At the inner medullary collecting duct, which is highly permeable to urea and water, especially in response to antidiuretic hormone, the urea enters the interstitium down its concentration gradient, preserving interstitial hypertonicity and generating high urea concentration in the interstitium. (Legend continued on next page)

Diseases of Water Metabolism FIGURE 1-4 (continued) 4) The hypertonic interstitium causes abstraction of water from the descending thin limb of loop of Henle, which is relatively impermeable to NaCl and urea, making the tubular fluid hypertonic with high NaCl concentration as it arrives at the bend of the loop of

Henle. 5) In the thin ascending limb of the loop of Henle, NaCl moves passively down its concentration gradient into the interstitium, making tubular fluid less concentrated with little or no movement of water. H2O—water. FIGURE 1-5 Pathways for urea recycling. Urea plays an important role in the generation of medullary interstitial hypertonicity. A recycling mechanism operates to minimize urea loss. The urea that is reabsorbed into the inner medullary stripe from the terminal inner medullary collecting duct (step 3 in Fig. 1-4) is carried out of this region by the ascending vasa recta, which deposits urea into the adjacent descending thin limbs of a short loop of Henle, thus recycling the urea to the inner medullary collecting tubule (pathway A). Some of the urea enters the descending limb of the loop of Henle and the thin ascending limb of the loop of Henle. It is then carried through to the thick ascending limb of the loop of Henle, the distal collecting tubule, and the collecting duct, before it reaches the inner medullary collecting duct (pathway B). This process is facilitated by the close anatomic relationship that the hairpin loop of Henle and the vasa recta share [4].

Cortex Urea

Urea

Urea

Urea Outer stripe

Outer medulla

Urea

Inner stripe

Urea

1.5

Collecting duct

Urea Urea Ascending vasa recta

Pathway B Pathway A

Inner medulla

Urea

1500 20 mL

0.3 mL

Osmolality, mOsm/kg H2O

1200

900

600

Maximal ADH

300 100 mL

2.0 mL

30 mL 20 mL

no ADH

16 mL

0 Proximal tubule

Loop of Henle

Distal tubule and cortical collecting tubule

Outer and inner medullary collecting ducts

FIGURE 1-6 Changes in the volume and osmolality of tubular fluid along the nephron in diuresis and antidiuresis. The osmolality of the tubular fluid undergoes several changes as it passes through different segments of the tubules. Tubular fluid undergoes marked reduction in its volume in the proximal tubule; however, this occurs iso-osmotically with the glomerular filtrate. In the loop of Henle, because of the aforementioned countercurrent mechanism, the osmolality of the tubular fluid rises sharply but falls again to as low as 100 mOsm/kg as it reaches the thick ascending limb and the distal convoluted tubule. Thereafter, in the late distal tubule and the collecting duct, the osmolality depends on the presence or absence of antidiuretic hormone (ADH). In the absence of ADH, very little water is reabsorbed and dilute urine results. On the other hand, in the presence of ADH, the collecting duct, and in some species, the distal convoluted tubule, become highly permeable to water, causing reabsorption of water into the interstitium, resulting in concentrated urine [5].

1.6

Disorders of Water, Electrolytes, and Acid-Base Paraventricular neurons

Osmoreceptors Pineal

Baroreceptors

Third ventricle VP,NP

Supraoptic neuron

Tanycyte SON Optic chiasm Superior hypophysial artery Portal capillaries in zona externa of median eminence

Mammilary body

VP,NP

FIGURE 1-7 Pathways of antidiuretic hormone release. Antidiuretic hormone is responsible for augmenting the water permeability of the cortical and medullary collecting tubules, thus promoting water reabsorption via osmotic equilibration with the isotonic and hypertonic interstitium, respecively. The hormone is formed in the supraoptic and paraventricular nuclei, under the stimulus of osmoreceptors and baroreceptors (see Fig. 1-11), transported along their axons and secreted at three sites: the posterior pituitary gland, the portal capillaries of the median eminence, and the cerebrospinal fluid of the third ventricle. It is from the posterior pituitary that the antidiuretic hormone is released into the systemic circulation [6]. SON—supraoptic nucleus; VP—vasopressin; NP—neurophysin.

Posterior pituitary Long portal vein Systemic venous system Anterior pituitary Short portal vein

VP,NP

Exon 1

Pre-pro-vasopressin (164 AA)

AVP

Gly

Exon 3

Exon 2

Lys

Arg

Neurophysin II

Arg

Glycopeptide

Neurophysin II

Arg

Glycopeptide

Neurophysin II

+

Glycopeptide

(Cleavage site) Signal peptide

Pro-vasopressin

AVP

Gly

Products of pro-vasopressin

AVP

NH2

Lys

Arg

+

FIGURE 1-8 Structure of the human arginine vasopressin (AVP/antidiuretic hormone) gene and the prohormone. Antidiuretic hormone (ADH) is a cyclic hexapeptide (mol. wt. 1099) with a tail of three amino acids. The biologically inactive macromolecule, pre-pro-vasopressin is cleaved into the smaller, biologically active protein. The protein of vasopressin is translated through a series of signal transduction pathways and intracellular cleaving. Vasopressin, along with its binding protein, neurophysin II, and the glycoprotein, are secreted in the form of neurosecretory granules down the axons and stored in nerve terminals of the posterior lobe of the pituitary [7]. ADH has a short half-life of about 15 to 20 minutes and is rapidly metabolized in the liver and kidneys. Gly—glycine; Lys—lysine; Arg—arginine.

Diseases of Water Metabolism

AQP-3 Recycling vesicle Endocytic retrieval AQP-2

cAMP ATP AQP-2 PKA

H 2O

Gαs

AQP-2

Gαs

Exocytic insertion Recycling vesicle

AVP

AQP-4 Basolateral

Luminal

1.7

FIGURE 1-9 Intracellular action of antidiuretic hormone. The multiple actions of vasopressin can be accounted for by its interaction with the V2 receptor found in the kidney. After stimulation, vasopressin binds to the V2 receptor on the basolateral membrane of the collecting duct cell. This interaction of vasopressin with the V2 receptor leads to increased adenylate cyclase activity via the stimulatory G protein (Gs), which catalyzes the formation of cyclic adenosine 3’, 5’monophosphate (cAMP) from adenosine triphosphate (ATP). In turn, cAMP activates a serine threonine kinase, protein kinase A (PKA). Cytoplasmic vesicles carrying the water channel proteins migrate through the cell in response to this phosphorylation process and fuse with the apical membrane in response to increasing vasopressin binding, thus increasing water permeability of the collecting duct cells. These water channels are recyled by endocytosis once the vasopressin is removed. The water channel responsible for the high water permeability of the luminal membrane in response to vasopressin has recently been cloned and designated as aquaporin-2 (AQP-2) [8]. The other members of the aquaporin family, AQP-3 and AQP-4 are located on the basolateral membranes and are probably involved in water exit from the cell. The molecular biology of these channels and of receptors responsible for vasopressin action have contributed to the understanding of the syndromes of genetically transmitted and acquired forms of vasopressin resistance. AVP—arginine vasopressin.

AQUAPORINS AND THEIR CHARACTERISTICS

Size (amino acids) Permeability to small solutes Regulation by antidiurectic hormone Site Cellular localization Mutant phenotype

AQP-1

AQP-2

AQP-3

AQP-4

269 No No Proximal tubules; descending thin limb Apical and basolateral membrane Normal

271 No Yes Collecting duct; principal cells

285 Urea glycerol No Medullary collecting duct; colon Basolateral membrane

301 No No Hypothalamic—supraoptic, paraventricular nuclei; ependymal, granular, and Purkinje cells Basolateral membrane of the prinicpal cells

Unknown

Unknown

Apical membrane and intracellular vesicles Nephrogenic diabetes insipidus

FIGURE 1-10 Aquaporins and their characteristics. An ever growing family of aquaporin (AQP) channels are being described. So far, about seven

different channels have been cloned and characterized; however, only four have been found to have any definite physiologic role.

1.8

Disorders of Water, Electrolytes, and Acid-Base

50

Isotonic volume depletion Isovolemic osmotic increase

45 Plasma AVP, pg/mL

40 35 30 25 20 15 10 5 0 0

5

10 15 Change, %

20

FIGURE 1-11 Osmotic and nonosmotic regulation of antidiuretic hormone (ADH) secretion. ADH is secreted in response to changes in osmolality and in circulating arterial volume. The “osmoreceptor” cells are located in the anterior hypothalamus close to the supraoptic nuclei. Aquaporin-4 (AQP-4), a candidate osmoreceptor, is a member of the water channel family that was recently cloned and characterized and is found in abundance in these neurons. The osmoreceptors are sensitive to changes in plasma osmolality of as little as 1%. In humans, the osmotic threshold for ADH release is 280 to 290 mOsm/kg. This system is so efficient that the plasma osmolality usually does not vary by more than 1% to 2% despite wide fluctuations in water intake [9]. There are several other nonosmotic stimuli for ADH secretion. In conditions of decreased arterial circulating volume (eg, heart failure, cirrhosis, vomiting), decrease in inhibitory parasympathetic afferents in the carotid sinus baroreceptors affects ADH secretion. Other nonosmotic stimuli include nausea, which can lead to a 500-fold rise in circulating ADH levels, postoperative pain, and pregnancy. Much higher ADH levels can be achieved with hypovolemia than with hyperosmolarity, although a large fall in blood volume is required before this response is initiated. In the maintenance of tonicity the interplay of these homeostatic mechanisms also involves the thirst mechanism, that under normal conditions, causes either intake or exclusion of water in an effort to restore serum osmolality to normal.

Control of Water Balance and Serum Sodium Concentration Increased plasma osmolality or decreased arterial circulating volume

Decreased plasma osmolality or increased arterial circulating blood volume

Increased thirst

Increased ADH release

Decreased thirst

Decreased ADH release

Increased water intake

Decreased water excretion

Decreased water intake

Decreased water excretion

A

Water retention

Water excretion

Decreased plasma osmolality or increased arterial circulating volume

Increased plasma osmolality and decreased arterial circulating volume

Decreased ADH release and thirst

FIGURE 1-12 Pathways of water balance (conservation, A, and excretion, B). In humans and other terrestrial animals, the thirst mechanism plays an important role in water (H2O) balance. Hypertonicity is the most potent stimulus for thirst: only 2% to 3 % changes in plasma osmolality produce a strong desire to drink water. This absolute level of osmolality at which the sensation of thirst arises in healthy persons, called the osmotic threshold for thirst, usually averages about 290 to 295 mOsm/kg H2O (approximately 10 mOsm/kg H2O above that of antidiuretic hormone [ADH] release). The socalled thirst center is located close to the osmoreceptors but is

B

Increased ADH release and thirst

anatomically distinct. Between the limits imposed by the osmotic thresholds for thirst and ADH release, plasma osmolality may be regulated still more precisely by small osmoregulated adjustments in urine flow and water intake. The exact level at which balance occurs depends on various factors such as insensible losses through skin and lungs, and the gains incurred from eating, normal drinking, and fat metabolism. In general, overall intake and output come into balance at a plasma osmolality of 288 mOsm/kg, roughly halfway between the thresholds for ADH release and thirst [10].

Diseases of Water Metabolism

Plasma osmolality 280 to 290 mOsm/kg H2O Decrease Supression of thirst

Supression of ADH release

Increase Stimulation of thirst

Stimulation of ADH release

Dilute urine

Concentrated urine

Disorder involving urine dilution with H2O intake

Disorder involving urine concentration with inadequate H2O intake

Hyponatremia

Hypernatremia

1.9

FIGURE 1-13 Pathogenesis of dysnatremias. The countercurrent mechanism of the kidneys in concert with the hypothalamic osmoreceptors via antidiuretic hormone (ADH) secretion maintain a very finely tuned balance of water (H2O). A defect in the urine-diluting capacity with continued H2O intake results in hyponatremia. Conversely, a defect in urine concentration with inadequate H2O intake culminates in hypernatremia. Hyponatremia reflects a disturbance in homeostatic mechanisms characterized by excess total body H2O relative to total body sodium, and hypernatremia reflects a deficiency of total body H2O relative to total body sodium [11]. (From Halterman and Berl [12]; with permission.)

Approach to the Hyponatremic Patient EFFECTS OF OSMOTICALLY ACTIVE SUBSTANCES ON SERUM SODIUM

Substances the increase osmolality without changing serum sodium Urea Ethanol Ethylene glycol Isopropyl alcohol Methanol

Substances that increase osmolality and decrease serum sodium (translocational hyponatremia) Glucose Mannitol Glycine Maltose

FIGURE 1-14 Evaluation of a hyponatremic patient: effects of osmotically active substances on serum sodium. In the evaluation of a hyponatremic patient, a determination should be made about whether hyponatremia is truly hypo-osmotic and not a consequence of translocational or

pseudohyponatremia, since, in most but not all situations, hyponatremia reflects hypo-osmolality. The nature of the solute plays an important role in determining whether or not there is an increase in measured osmolality or an actual increase in effective osmolality. Solutes that are permeable across cell membranes (eg, urea, methanol, ethanol, and ethylene glycol) do not cause water movement and cause hypertonicity without causing cell dehydration. Typical examples are an uremic patient with a high blood urea nitrogen value and an ethanolintoxicated person. On the other hand, in a patient with diabetic ketoacidosis who is insulinopenic the glucose is not permeant across cell membranes and, by its presence in the extracellular fluid, causes water to move from the cells to extracellular space, thus leading to cell dehydration and lowering serum sodium. This can be viewed as translocational at the cellular level, as the serum sodium level does not reflect changes in total body water but rather movement of water from intracellular to extracellular space. Glycine is used as an irrigant solution during transurethral resection of the prostate and in endometrial surgery. Pseudohyponatremia occurs when the solid phase of plasma (usually 6% to 8%) is much increased by large increments of either lipids or proteins (eg, in hypertriglyceridemia or paraproteinemias).

1.10

Disorders of Water, Electrolytes, and Acid-Base FIGURE 1-15 Pathogenesis of hyponatremia. The normal components of the renal diluting mechanism are depicted in Figure 1-3. Hyponatremia results from disorders of this diluting capacity of the kidney in the following situations:

↓ Reabsorption of sodium chloride in distal convoluted tubule Thiazide diuretics

↓ Reabsorption of sodium chloride in thick ascending limb of loop of Henle Loop diuretics Osmotic diuretics Interstitial disease

GFR diminished Age Renal disease Congestive heart failure Cirrhosis Nephrotic syndrome Volume depletion

NaCl

↑ ADH release or action Drugs Syndrome of inappropriate antidiuretic hormone secretion, etc.

1. Intrarenal factors such as a diminished glomerular filtration rate (GFR), or an increase in proximal tubule fluid and sodium reabsorption, or both, which decrease distal delivery to the diluting segments of the nephron, as in volume depletion, congestive heart failure, cirrhosis, or nephrotic syndrome. 2. A defect in sodium chloride transport out of the water-impermeable segments of the nephrons (ie, in the thick ascending limb of the loop of Henle). This may occur in patients with interstitial renal disease and administration of thiazide or loop diuretics. 3. Continued secretion of antidiuretic hormone (ADH) despite the presence of serum hypo-osmolality mostly stimulated by nonosmotic mechanisms [12].

NaCl—sodium chloride.

Assessment of volume status

Hypovolemia •Total body water ↓ •Total body sodium ↓↓

Hypervolemia •Total body water ↑↑ •Total body sodium ↑

Euvolemia (no edema) •Total body water ↑ •Total body sodium ←→

UNa >20

UNa <20

UNa >20

UNa >20

UNa <20

Renal losses Diuretic excess Mineralcorticoid deficiency Salt-losing deficiency Bicarbonaturia with renal tubal acidosis and metabolic alkalosis Ketonuria Osmotic diuresis

Extrarenal losses Vomiting Diarrhea Third spacing of fluids Burns Pancreatitis Trauma

Glucocorticoid deficiency Hypothyroidism Stress Drugs Syndrome of inappropriate antidiuretic hormone secretion

Acute or chronic renal failure

Nephrotic syndrome Cirrhosis Cardiac failure

FIGURE 1-16 Diagnostic algorithm for hyponatremia. The next step in the evaluation of a hyponatremic patient is to assess volume status and identify it as hypovolemic, euvolemic or hypervolemic. The patient with hypovolemic hyponatremia has both total body sodium and water deficits, with the sodium deficit exceeding the water deficit. This occurs with large gastrointestinal and renal losses of water and solute when accompanied by free water or hypotonic fluid intake. In patients with hypervolemic hyponatremia, total body sodium is

increased but total body water is increased even more than sodium, causing hyponatremia. These syndromes include congestive heart failure, nephrotic syndrome, and cirrhosis. They are all associated with impaired water excretion. Euvolemic hyponatremia is the most common dysnatremia in hospitalized patients. In these patients, by definition, no physical signs of increased total body sodium are detected. They may have a slight excess of volume but no edema [12]. (Modified from Halterman and Berl [12]; with permission.)

Diseases of Water Metabolism

DRUGS ASSOCIATED WITH HYPONATREMIA Antidiuretic hormone analogues Deamino-D-arginine vasopressin (DDAVP) Oxytocin Drugs that enhance release of antidiuretic hormone Chlorpropamide Clofibrate Carbamazepine-oxycarbazepine Vincristine Nicotine Narcotics Antipsychotics Antidepressants Ifosfamide Drugs that potentiate renal action of antidiuretic hormone Chlorpropamide Cyclophosphamide Nonsteroidal anti-inflammatory drugs Acetaminophen Drugs that cause hyponatremia by unknown mechanisms Haloperidol Fluphenazine Amitriptyline Thioradazine Fluoxetine

FIGURE 1-17 Drugs that cause hyponatremia. Drug-induced hyponatremia is mediated by antidiuretic hormone analogues like deamino-D-arginine-vasopressin (DDAVP), or antidiuretic hormone release, or by potentiating the action of antidiuretic hormone. Some drugs cause hyponatremia by unknown mechanisms [13]. (From Veis and Berl [13]; with permission.)

DIAGNOSTIC CRITERIA FOR THE SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION Essential Decreased extracellular fluid effective osmolality (< 270 mOsm/kg H2O) Inappropriate urinary concentration (> 100 mOsm/kg H2O) Clinical euvolemia Elevated urinary sodium concentration (U[Na]), with normal salt and H2O intake Absence of adrenal, thyroid, pituitary, or renal insufficiency or diuretic use Supplemental Abnormal H2O load test (inability to excrete at least 90% of a 20–mL/kg H2O load in 4 hrs or failure to dilute urinary osmolality to < 100 mOsm/kg) Plasma antidiuretic hormone level inappropriately elevated relative to plasma osmolality No significant correction of plasma sodium with volume expansion, but improvement after fluid restriction

1.11

CAUSES OF THE SYNDROME OF INAPPROPRIATE DIURETIC HORMONE SECRETION

Carcinomas Bronchogenic Duodenal Pancreatic Thymoma Gastric Lymphoma Ewing’s sarcoma Bladder Carcinoma of the ureter Prostatic Oropharyngeal

Pulmonary Disorders Viral pneumonia Bacterial pneumonia Pulmonary abscess Tuberculosis Aspergillosis Positive-pressure breathing Asthma Pneumothorax Mesothelioma Cystic fibrosis

Central Nervous System Disorders Encephalitis (viral or bacterial) Meningitis (viral, bacterial, tuberculous, fungal) Head trauma Brain abscess Brain tumor Guillain-Barré syndrome Acute intermittent porphyria Subarachnoid hemorrhage or subdural hematoma Cerebellar and cerebral atrophy Cavernous sinus thrombosis Neonatal hypoxia Hydrocephalus Shy-Drager syndrome Rocky Mountain spotted fever Delirium tremens Cerebrovascular accident (cerebral thrombosis or hemorrhage) Acute psychosis Multiple sclerosis

FIGURE 1-18 Causes of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Though SIADH is the commonest cause of hyponatremia in hospitalized patients, it is a diagnosis of exclusion. It is characterized by a defect in osmoregulation of ADH in which plasma ADH levels are not appropriately suppressed for the degree of hypotonicity, leading to urine concentration by a variety of mechanisms. Most of these fall into one of three categories (ie, malignancies, pulmonary diseases, central nervous system disorders) [14]. FIGURE 1-19 Diagnostic criteria for the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Clinically, SIADH is characterized by a decrease in the effective extracellular fluid osmolality, with inappropriately concentrated urine. Patients with SIADH are clinically euvolemic and are consuming normal amounts of sodium and water (H2O). They have elevated urinary sodium excretion. In the evaluation of these patients, it is important to exclude adrenal, thyroid, pituitary, and renal disease and diuretic use. Patients with clinically suspected SIADH can be tested with a water load. Upon administration of 20 mL/kg of H2O, patients with SIADH are unable to excrete 90% of the H2O load and are unable to dilute their urine to an osmolality less than 100 mOsm/kg [15]. (Modified from Verbalis [15]; with permission.)

1.12

Disorders of Water, Electrolytes, and Acid-Base

SIGNS AND SYMPTOMS OF HYPONATREMIA Central Nervous System

Gastrointestinal System

Mild Apathy Headache Lethargy Moderate Agitation Ataxia Confusion Disorientation Psychosis Severe Stupor Coma Pseudobulbar palsy Tentorial herniation Cheyne-Stokes respiration Death

Anorexia Nausea Vomiting

Musculoskeletal System Cramps Diminished deep tendon reflexes

FIGURE 1-20 Signs and symptoms of hyponatremia. In evaluating hyponatremic patients, it is important to assess whether or not the patient is symptomatic, because symptoms are a better determinant of therapy than the absolute value itself. Most patients with serum sodium values above 125 mEq/L are asymptomatic. The rapidity with which hyponatremia develops is critical in the initial evaluation of such patients. In the range of 125 to 130 mEq/L, the predominant symptoms are gastrointestinal ones, including nausea and vomiting. Neuropsychiatric symptoms dominate the picture once the serum sodium level drops below 125 mEq/L, mostly because of cerebral edema secondary to hypotonicity. These include headache, lethargy, reversible ataxia, psychosis, seizures, and coma. Severe manifestations of cerebral edema include increased intracerebral pressure, tentorial herniation, respiratory depression and death. Hyponatremia-induced cerebral edema occurs principally with rapid development of hyponatremia, typically in patients managed with hypotonic fluids in the postoperative setting or those receiving diuretics, as discussed previously. The mortality rate can be as great as 50%. Fortunately, this rarely occurs. Nevertheless, neurologic symptoms in a hyponatremic patient call for prompt and immediate attention and treatment [16,17].

FIGURE 1-21 Cerebral adaptation to hyponatremia. 3 Na+/H2O ↓Na+/↑H2O ↓Na+/↑H2O A, Decreases in extracellular osmolality 2 cause movement of water (H2O) into the cells, increasing intracellular volume and K+, Na+ ↓K+, ↓Na+ K+, Na+ thus causing tissue edema. This cellular H 2O ↑H2O H 2O osmolytes osmolytes ↓osmolytes edema within the fixed confines of the cranium causes increased intracranial pressure, leading to neurologic symptoms. To prevent this from happening, mechanisms geared toward volume regulation come into operaNormonatremia Acute hyponatremia Chronic hyponatremia A tion, to prevent cerebral edema from developing in the vast majority of patients with hyponatremia. After induction of extracellular fluid hypo-osmolality, H2O moves into the brain in response to osmotic gradients, producing cerebral edema (middle panel, 1). However, within 1 to 3 hours, a decrease in cerebral extracellular volume occurs by movement of K+ fluid into the cerebrospinal fluid, which is then shunted back into the systemic circulation. Glutamate This happens very promptly and is evident by the loss of extracellular and intracellular solutes (sodium and chloride ions) as early as 30 minutes after the onset of hyponatremia. Na+ As H2O losses accompany the losses of brain solute (middle panel, 2), the expanded brain Urea volume decreases back toward normal (middle panel, 3) [15]. B, Relative decreases in individual osmolytes during adaptation to chronic hyponatremia. Thereafter, if hyponatremia persists, other organic osmolytes such as phosphocreatine, myoinositol, and amino acids Inositol like glutamine, and taurine are lost. The loss of these solutes markedly decreases cerebral Cl– swelling. Patients who have had a slower onset of hyponatremia (over 72 to 96 hours or Taurine longer), the risk for osmotic demyelination rises if hyponatremia is corrected too rapidly Other B [18,19]. Na+—sodium; K+—potassium; Cl-—chloride. 1

Diseases of Water Metabolism

HYPONATREMIC PATIENTS AT RISK FOR NEUROLOGIC COMPLICATIONS Complication

Persons at Risk

Acute cerebral edema

Postoperative menstruant females Elderly women taking thiazides Children Psychiatric polydipsic patients Hypoxemic patients

Osmotic demyelination syndrome

Alcoholics Malnourished patients Hypokalemic patients Burn victims Elderly women taking thiazide diuretics

FIGURE 1-22 Hyponatremic patients at risk for neurologic complications. Those at risk for cerebral edema include postoperative menstruant women, elderly women taking thiazide diuretics, children, psychiatric patients with polydipsia, and hypoxic patients. In women, and, in particular, menstruant ones, the risk for developing neurologic complications is 25 times greater than that for nonmenstruant women or men. The increased risk was independent of the rate of development, or the magnitude of the hyponatremia [21]. The osmotic demyelination syndrome or central pontine myelinolysis seems to occur when there is rapid correction of low osmolality (hyponatremia) in a brain already chronically adapted (more than 72 to 96 hours). It is rarely seen in patients with a serum sodium value greater than 120 mEq/L or in those who have hyponatremia of less than 48 hours’ duration [20,21]. (Adapted from Lauriat and Berl [21]; with permission.)

A

1.13

SYMPTOMS OF CENTRAL PONTINE MYELINOLYSIS Initial symptoms Mutism Dysarthria Lethargy and affective changes Classic symptoms Spastic quadriparesis Pseudobulbar palsy Lesions in the midbrain, medulla oblongata, and pontine tegmentum Pupillary and oculomotor abnormalities Altered sensorium Cranial neuropathies Extrapontine myelinolysis Ataxia Behavioral abnormalities Parkinsonism Dystonia

FIGURE 1-23 Symptoms of central pontine myelinolysis. This condition has been described all over the world, in all age groups, and can follow correction of hyponatremia of any cause. The risk for development of central pontine myelinolysis is related to the severity and chronicity of the hyponatremia. Initial symptoms include mutism and dysarthria. More than 90% of patients exhibit the classic symptoms of myelinolysis (ie, spastic quadriparesis and pseudobulbar palsy), reflecting damage to the corticospinal and corticobulbar tracts in the basis pontis. Other symptoms occur on account of extension of the lesion to other parts of the midbrain. This syndrome follows a biphasic course. Initially, a generalized encephalopathy, associated with a rapid rise in serum sodium, occurs. This is followed by the classic symptoms 2 to 3 days after correction of hyponatremia, however, this pattern does not always occur [22]. (Adapted from Laureno and Karp [22]; with permission.)

B

FIGURE 1-24 A, Imaging of central pontine myelinolysis. Brain imaging is the most useful diagnostic technique for central pontine myelinolysis. Magnetic resonance imaging (MRI) is more sensitive than computed tomography (CT). On CT, central pontine and extrapontine lesions appear as symmetric areas of hypodensity (not shown). On T2 images of MRI, the lesions appear as hyperintense and on T1

images, hypointense. These lesions do not enhance with gadolinium. They may not be apparent on imaging until 2 weeks into the illness. Other diagnostic tests are brainstem auditory evoked potentials, electroencephalography, and cerebrospinal fluid protein and myelin basic proteins [22]. B, Gross appearance of the pons in central pontine myelinolysis. (From Laureno and Karp [22]; with permission.)

1.14

Disorders of Water, Electrolytes, and Acid-Base

Severe hyponatremia (<125 mmol/L) Symptomatic

Asymptomatic

Acute Duration <48 h

Chronic Duration >48 h

Chronic Rarely <48 h

Emergency correction needed Hypertonic saline 1–2 mL/kg/h Coadministration of furosemide

Some immediate correction needed Hypertonic saline 1–2 mL/kg/h Coadministration of furosemide Change to water restriction upon 10% increase of sodium or if symptoms resolve Perform frequent measurement of serum and urine electrolytes Do not exceed 1.5 mmol/L/hr or 20 mmol/d

No immediate correction needed

Long-term management Identification and treatment of reversible causes Water restriction Demeclocycline, 300–600 mg bid Urea, 15–60 g/d V2 receptor antagonists

A. GENERAL GUIDELINES FOR THE TREATMENT OF SYMPTOMATIC HYPONATREMIA* Acute hyponatremia (duration < 48 hrs) Increase serum sodium rapidly by approximately 2 mmol/L/h until symptoms resolve Full correction probably safe but not necessary Chronic hyponatremia (duration > 48 hrs) Initial increase in serum sodium by 10% or 10 mmol/L Perform frequent neurologic evaluations; correction rate may be reduced with improvement in symptoms At no time should correction exceed rate of 1.5 mmol/L/h, or increments of 15 mmol/d Measure serum and urine electrolytes every 1–2 h *The sum of urinary cations (UNa + UK) should be less than the concentration of infused sodium, to ensure excretion of electrolyte-free water.

FIGURE 1-26 General guidelines for the treatment of symptomatic hyponatremia, A. Included herein are general guidelines for treatment of patients with acute and chronic symptomatic hyponatremia. In the treatment of chronic symptomatic hyponatremia, since cerebral water is increased by approximately 10%, a prompt increase in serum sodium by 10% or 10 mEq/L is permissible. Thereafter, the patient’s fluids should be restricted. The total correction rate should not

FIGURE 1-25 Treatment of severe euvolemic hyponatremia (<125 mmol/L). The evaluation of a hyponatremic patient involves an assessment of whether the patient is symptomatic, and if so, the duration of hyponatremia should be ascertained. The therapeutic approach to the hyponatremic patient is determined more by the presence or absence of symptoms than by the absolute level of serum sodium. Acutely hyponatremic patients are at great risk for permanent neurologic sequelae from cerebral edema if the hyponatremia is not promptly corrected. On the other hand, chronic hyponatremia carries the risk of osmotic demyelination syndrome if corrected too rapidly. The next step involves a determination of whether the patient has any risk factors for development of neurologic complications. The commonest setting for acute, symptomatic hyponatremia is hospitalized, postoperative patients who are receiving hypotonic fluids. In these patients, the risk of cerebral edema outweighs the risk for osmotic demyelination. In the presence of seizures, obtundation, and coma, rapid infusion of 3% sodium chloride (4 to 6 mL/kg/h) or even 50 mL of 29.2% sodium chloride has been used safely. Ongoing careful neurologic monitoring is imperative [20].

B. TREATMENT OF CHRONIC SYMPTOMATIC HYPONATREMIA Calculate the net water loss needed to raise the serum sodium (SNa) from 110 mEq/L to 120 mEq/L in a 50 kg person. Example Current SNa  Total body water (TBW) = Desired SNa  New TBW Assume that TBW = 60% of body weight Therefore TBW of patient = 50  0.6 = 30 L 110 mEq/L  30 L New TBW = = 27.5 L 120 mEq/L Thus the electrolyte-free water loss needed to raise the SNa to 120 mEq/L = Present TBW  New TBW = 2.5 L

Calculate the time course in which to achieve the desired correction (1 mEq/h)—in this case, 250 mL/h Administer furosemide, monitor urine output, and replace sodium, potassium, and excess free water lost in the urine Continue to monitor urine output and replace sodium, potassium, and excess free water lost in the urine

exceed 1.0 to 1.5 mEq/L/h, and the total increment in 24 hours should not exceed 15 mmol/d [12]. A specific example as to how to increase a patient’s serum sodium is illustrated in B.

Diseases of Water Metabolism

1.15

MANAGEMENT OPTIONS FOR CHRONIC ASYMPTOMATIC HYPONATREMIA Treatment

Mechanism of Action

Dose

Advantages

Limitations

Fluid restriction

Decreases availability of free water

Variable

Effective and inexpensive

Noncompliance

Inhibits the kidney’s response to antidiuretic hormone Inhibits the kidney’s response to antidiurectic hormone Antagonizes vasopressin action

900–1200 mg/d

Unrestricted water intake

1200 mg/d initially; then, 300–900 mg/d

Effective; unrestricted water intake Ongoing trials

Polyuria, narrow therapeutic range, neurotoxicity Neurotoxicity, polyuria, photosensitivity, nephrotoxicity

Increases free water clearance

Titrate to optimal dose; coadminister 2–3 g sodium chloride 30–60 g/d

Effective

Ototoxicity, K+ and Mg2+ depletion

Effective; unrestricted water intake

Polyuria, unpalatable gastrointestinal symptoms

Pharmacologic inhibition of antidiuretic hormone action Lithium Demeclocycline V2-receptor antagonist Increased solute intake Furosemide Urea

Osmotic diuresis

FIGURE 1-27 Management options for patients with chronic asymptomatic hyponatremia. If the patient has chronic hyponatremia and is asymptomatic, treatment need not be intensive or emergent. Careful scrutiny of likely causes should be followed by treatment. If the cause is determined to be the syndrome of inappropriate

MANAGEMENT OF NONEUVOLEMIC HYPONATREMIA Hypovolemic hyponatremia Volume restoration with isotonic saline Identify and correct causes of water and sodium losses Hypervolemic hyponatremia Water restriction Sodium restriction Substitiute loop diuretics for thiazide diurectics Treatment of timulus for sodium and water retention V2-receptor antagonist

antidiuretic hormone (ADH) secretion, it must be treated as a chronic disorder. As summarized here, the treatment strategies involve fluid restriction, pharmacologic inhibition of ADH action, and increased solute intake. Fluid restriction is frequently successful in normalizing serum sodium and preventing symptoms [23]. FIGURE 1-28 Management of noneuvolemic hyponatremia. Hypovolemic hyponatremia results from the loss of both water and solute, with relatively greater loss of solute. The nonosmotic release of antidiuretic hormone stimulated by decreased arterial circulating blood volume causes antidiuresis and perpetuates the hyponatremia. Most of these patients are asymptomatic. The keystone of therapy is isotonic saline administration, which corrects the hypovolemia and removes the stimulus of antidiuretic hormone to retain fluid. Hypervolemic hyponatremia occurs when both solute and water are increased, but water more than solute. This occurs with heart failure, cirrhosis and nephrotic syndrome. The cornerstones of treatment include fluid restriction, salt restriction, and loop diuretics [20]. (Adapted from Lauriat and Berl [20]; with permission.)

1.16

Disorders of Water, Electrolytes, and Acid-Base

Approach to the Hypernatremic Patient ↓ ADH release or action Nephrogenic DI Central DI (see Fig. 1-)

↓ Reabsorption of sodium chloride in thick ascending limb of loop of Henle Loop diuretics Osmotic diuretics Interstitial disease

GFR diminished Age Renal disease

Urea NaCl

↓ Urea in the medulla Water diuresis Decreased dietary protein intake

FIGURE 1-29 Pathogenesis of hypernatremia. The renal concentrating mechanism is the first line of defense against water depletion and hyperosmolality. When renal concentration is impaired, thirst becomes a very effective mechanism for preventing further increases in serum osmolality. The components of the normal urine concentrating mechanism are shown in Figure 1-2. Hypernatremia results from disturbances in the renal concentrating mechanism. This occurs in interstitial renal disease, with administration of loop and osmotic diuretics, and with protein malnutrition, in which less urea is available to generate the medullary interstitial tonicity. Hypernatremia usually occurs only when hypotonic fluid losses occur in combination with a disturbance in water intake, typically in elders with altered consciousness, in infants with inadequate access to water, and, rarely, with primary disturbances of thirst [24]. GFR—glomerular filtration rate; ADH—antidiuretic hormone; DI—diabetes insipidus.

Assessment of volume status Hypovolemia •Total body water ↓↓ •Total body sodium ↓ UNa>20

UNa<20

Renal losses Osmotic or loop diuretic Postobstruction Intrinsic renal disease

Extrarenal losses Excessive sweating Burns Diarrhea Fistulas

Euvolemia (no edema) •Total body water ↓ •Total body sodium ←→

Hypervolemia •Total body water ↑ •Total body sodium ↑↑

UNa variable

UNa>20

Renal losses Diabetes insipidus Hypodipsia

FIGURE 1-30 Diagnostic algorithm for hypernatremia. As for hyponatremia, the initial evaluation of the patient with hypernatremia involves assessment of volume status. Patients with hypovolemic hypernatremia lose both sodium and water, but relatively more water. On physical examination, they exhibit signs of hypovolemia. The causes listed reflect principally hypotonic water losses from the kidneys or the gastrointestinal tract. Euvolemic hyponatremia reflects water losses accompanied by inadequate water intake. Since such hypodipsia is uncommon, hypernatremia usually supervenes in persons who have no access to water or who have a neurologic deficit that impairs thirst perception—the very young and the very old. Extrarenal water loss occurs from the skin

Extrarenal losses Insensible losses Respiratory Dermal

Sodium gains Primary Hyperaldosteronism Cushing's sydrome Hypertonic dialysis Hypertonic sodium bicarbonate Sodium chloride tablets

and respiratory tract, in febrile or other hypermetabolic states. Very high urine osmolality reflects an intact osmoreceptor–antidiuretic hormone–renal response. Thus, the defense against the development of hyperosmolality requires appropriate stimulation of thirst and the ability to respond by drinking water. The urine sodium (UNa) value varies with the sodium intake. The renal water losses that lead to euvolemic hypernatremia are a consequence of either a defect in vasopressin production or release (central diabetes insipidus) or failure of the collecting duct to respond to the hormone (nephrogenic diabetes insipidus) [23]. (Modified from Halterman and Berl [12]; with permission.)

Diseases of Water Metabolism

Urine volume = CH2O + COsm

COsm Isotonic or hypertonic urine

CH2O Hypotonic urine

Polyuria due to increased solute excretion Sodium chloride Diuretics Renal sodium wasting Excessive salt intake Bicarbonate Vomiting/metabolic alkalosis Alkali administration Mannitol Diuretics Bladder lavage Treatment of cerebral edema

Polyuria due to increased free water clearance Excessive water intake Psychogenic polydipsia Defect in thirst Hyper-reninemia Potassium depletion Renal vascular disease Renal tumors Renal hypoperfusion Increased renal water excretion Impaired renal water concentrating mechanism Decreased ADH secretion Increased ADH degradation Resistance to ADH action

FIGURE 1-31 Physiologic approach to polyuric disorders. Among euvolemic hypernatremic patients, those affected by polyuric disorders are an important subcategory. Polyuria is arbitrarily defined as urine output of more than 3 L/d. Urine volume can be conceived of as having two components: the volume needed to excrete solutes at the concentration of solutes in plasma (called the osmolar clearance) and the other being the free water clearance, which is the volume of solute-free water that has been added to (positive free water clearance [CH2O]) or subtracted (negative CH2O) from the isotonic portion of the urine osmolar clearance (Cosm) to create either a hypotonic or hypertonic urine. Consumption of an average American diet requires the kidneys to excrete 600 to 800 mOsm of solute each day. The urine volume in which this solute is excreted is determined by fluid intake. If the urine is maximally diluted to 60 mOsm/kg of water, the 600 mOsm will need 10 L of urine for effective osmotic clearance. If the concentrating mechanism is maximally stimulated to 1200 mOsm/kg of water, osmotic clearance will occur in a minimum of 500 mL of urine. This flexibility is affected when drugs or diseases alter the renal concentrating mechanism. Polyuric disorders can be secondary to an increase in solute clearance, free water clearance, or a combination of both. ADH—antidiuretic hormone.

WATER DEPRIVATION TEST

Diagnosis Normal Complete central diabetes insipidus Partial central diabetes insipidus Nephrogenic diabetes insipidus Primary polydipsia

Urine Osmolality with Water Deprivation (mOsm/kg H2O)

CLINICAL FEATURES OF DIABETES INSIPIDUS Plasma Arginine Vasopressin (AVP) after Dehydration

Increase in Urine Osmolality with Exogenous AVP

> 800 < 300

> 2 pg/mL Indetectable

Little or none Substantial

300–800

< 1.5 pg/mL > 5 pg/mL

> 10% of urine osmolality after water deprivation Little or none

< 5 pg/mL

Little or none

< 300–500 > 500

1.17

* Water intake is restricted until the patient loses 3%–5% of weight or until three consecutive hourly determinations of urinary osmolality are within 10% of each other. (Caution must be exercised to ensure that the patient does not become excessively dehydrated.) Aqueous AVP (5 U subcutaneous) is given, and urine osmolality is measured after 60 minutes. The expected responses are given above.

FIGURE 1-32 Water deprivation test. Along with nephrogenic diabetes insipidus and primary polydipsia, patients with central diabetes insipius present with polyuria and polydipsia. Differentiating between these entities can be accomplished by measuring vasopressin levels and determining the response to water deprivation followed by vasopressin administration [25]. (From Lanese and Teitelbaum [26]; with permission.)

Abrupt onset Equal frequency in both sexes Rare in infancy, usual in second decade of life Predilection for cold water Polydipsia Urine output of 3 to 15 L/d Marked nocturia but no diurnal variation Sleep deprivation leads to fatigue and irritability Severe life-threatening hypernatremia can be associated with illness or water deprivation

FIGURE 1-33 Clinical features of diabetes insipidus. Other clinical features can distinguish compulsive water drinkers from patients with central diabetes insipidus. The latter usually has abrupt onset, whereas compulsive water drinkers may give a vague history of the onset. Unlike compulsive water drinkers, patients with central diabetes insipidus have a constant need for water. Compulsive water drinkers exhibit large variations in water intake and urine output. Nocturia is common with central diabetes insipidus and unusual in compulsive water drinkers. Finally, patients with central diabetes insipidus have a predilection for drinking cold water. Plasma osmolality above 295 mOsm/kg suggests central diabetes insipidus and below 270 mOsm/kg suggests compulsive water drinking [23].

1.18

Disorders of Water, Electrolytes, and Acid-Base FIGURE 1-34 Causes of diabetes insipidus. The causes of diabetes insipidus can be divided into central and nephrogenic. Most (about 50%) of the central causes are idiopathic; the rest are caused by central nervous system involvement with infection, tumors, granuloma, or trauma. The nephrogenic causes can be congenital or acquired [23].

CAUSES OF DIABETES INSIPIDUS Central diabetes insipidus

Nephrogenic diabetes insipidus

Congenital Autosomal-dominant Autosomal-recessive Acquired Post-traumatic Iatrogenic Tumors (metastatic from breast, craniopharyngioma, pinealoma) Cysts Histiocytosis Granuloma (tuberculosis, sarcoid) Aneurysms Meningitis Encephalitis Guillain-Barré syndrome Idiopathic

Congenital X-linked Autosomal-recessive Acquired Renal diseases (medullary cystic disease, polycystic disease, analgesic nephropathy, sickle cell nephropathy, obstructive uropathy, chronic pyelonephritis, multiple myeloma, amyloidosis, sarcoidosis) Hypercalcemia Hypokalemia Drugs (lithium compounds, demeclocycline, methoxyflurane, amphotericin, foscarnet)

SP

VP

NP

NP

Exon 1

NP

CP

Exon 2

Exon 3 83

–19..–16

47 79

50

87

14 17 57

20 24

–3 –1

61 62

67 65

Missense mutation

Stop codon

Deletion

FIGURE 1-35 Congenital central diabetes insipidus (DI), autosomal-dominant form. This condition has been described in many families in Europe and North America. It is an autosomal dominant inherited disease associated with marked loss of cells in the supraoptic nuclei. Molecular biology techniques have revealed multiple point mutations in the vasopressin-neurophysin II gene. This condition usually presents early in life [25]. A rare autosomal-recessive form of central DI has been described that is characterized by DI, diabetes mellitus (DM), optic atrophy (OA), and deafness (DIDMOAD or Wolfram’s syndrome). This has been linked to a defect in chromosome-4 and involves abnormalities in mitochondrial DNA [27]. SP—signal peptide; VP—vasopressin; NP—neurophysin; GP—glycoprotein.

Diseases of Water Metabolism

FIGURE 1-36 Treatment of central diabetes insipidus (DI). Central DI may be treated with hormone replacement or drugs. In acute settings when renal water losses are extensive, aqueous vasopressin (pitressin) is useful. It has a short duration of action that allows for careful monitoring and avoiding complications like water intoxication. This drug should be used with caution in patients with underlying coronary artery disease and peripheral vascular disease, as it can cause vascular spasm and prolonged vasoconstriction. For the patient with established central DI, desmopressin acetate (dDAVP) is the agent of choice. It has a long half-life and does not have significant vasoconstrictive effects like those of aqueous vasopressin. It can be conveniently administered intranasally every 12 to 24 hours. It is usually tolerated well. It is safe to use in pregnancy and resists degradation by circulating vasopressinase. In patients with partial DI, agents that potentiate release of antidiuretic hormone can be used. These include chlorpropamide, clofibrate, and carbamazepine. They work effectively only if combined with hormone therapy, decreased solute intake, or diuretic administration [23].

TREATMENT OF CENTRAL DIABETES INSIPIDUS Condition

Drug

Dose

Complete central DI

dDAVP

10–20 (g intranasally q 12–24 h

Partial central DI

Vasopressin tannate Aqueous vasopressin Chlorpropamide Clofibrate Carbamazepine

2–5 U IM q 24–48 h 5–10 U SC q 4–6 h 250–500 mg/d 500 mg tid–qid 400–600 mg/d

S N S S

Q

P

S L

S P

E R

L

L P

A R

D

R T

P L D

A E L * L A F S I L A V A V L G S V A L V N A L L * * A R R G R R G

Intracellular

V A D L F

P

L

D T A K W A L Q L P Q L F V L A A C L H I G H V

I P A W H

H

* G

P

V

A

S

T T S A M L M 1

Extracellular

–NH2

R F

R G P A E P W F G D C R A S G G A R G E W L T V C V C Y * D T N R V R A T W A Q F V K I A L Y I L Q M V L F P Q M F V V L G M A P S Y T L A L L S S G I S L A F Y A A M W I L C Q A A V V L M T I F L V L P D E R R I H R H R N A A W S I H V L C H A V R A G * P P G S M G L E G P A Y R H G S E R * P G G R R

P E D W A W A Q L L V F F A P C W V L V Y V V V I L M T R V T K A S A V A

A P L E G A L L N N

V S

P F L M A S S C P W Y A

V L * L T I S F S S S S E L R

S

L L

C C

C S E D Q P G L P S

R G

G

S

A R G R T P P

T T T R

R

1.19

A

S

S S 371 L A K D T S S –COOH

FIGURE 1-37 Congenital nephrogenic diabetes insipidus, X-linked–recessive form. This is a rare disease of male patients who do not concentrate their urine after administration of antidiuretic hormone. The pedigrees of affected families have been linked to a group of Ulster Scots who emigrated to Halifax, Nova Scotia in 1761 aboard the ship called “Hopewell.” According to the Hopewell hypothesis, most North American patients with this disease are descendants of a common ancestor with a single gene defect. Recent studies, however, disproved this hypothesis [28]. The gene defect has now been traced to 87 different mutations in the gene for the vasopressin receptor (AVP-R2) in 106 presumably unrelated families [29]. (From Bichet, et al. [29]; with permission.)

1.20

Disorders of Water, Electrolytes, and Acid-Base

Urinary lumen

L A P A S 11 V 9,12 R V L A V N A D T A G G 8 P R L K N I S F M D N D S S A D 13 C P T H G T 6 T W T I A V Y E Q A L P S G H F H Q I W L V G I A P V L L L G T W L A P A G 4 E V I Q M A N L G H L V A L A L A G A V S F G G F V A A G L L I S L G L F L L T L F F I G T G G G V Q Q A I F L S 12 S L A V L 13 V L L L L V Q T L Y C A Y F A A N P T A I Y G F A G L F L V A P E L R 7 H S N A F L I T F E P D G V S V P E R R S 1 G A A A V R K S H S H F L I C Q P S A S S L 2 N H P G E I 11 R L R P V G S M L E T W E L R A L K A V C 3 V A V T V A S L Q R K R G V E Principal cell R E L E W D T D P E -intracellular

FIGURE 1-38 Congenital nephrogenic diabetes insipidus (NDI), autosomalrecessive form. In the autosomal recessive form of NDI, mutations have been found in the gene for the antiiuretic hormone (ADH)– sensitive water channel, AQP-2. This form of NDI is exceedingly rare as compared with the X-linked form of NDI [30]. Thus far, a total of 15 AQP-2 mutations have been described in total of 13 families [31]. The acquired form of NDI occurs in various kidney diseases and in association with various drugs, such as lithium and amphotericin B. (From Canfield et al. [31]; with permission.)

ACQUIRED NEPHROGENIC DIABETES INSIPIDUS: CAUSES AND MECHANISMS

Disease State

PATIENT GROUPS AT INCREASED RISK FOR SEVERE HYPERNATREMIA

Defect in Generation of Medullary Defect in cAMP Downregulation Interstitial Tonicity Generation of AQP-2 Other

Chronic renal failure

✔

✔

✔

Hypokalemia Hypercalcemia Sickle cell disease Protein malnutrition Demeclocycline Lithium Pregnancy

✔ ✔ ✔ ✔

✔ ✔

✔

Downregulation of V2 receptor message

✔ ✔ ✔

✔

Elders and infants Hospitalized patients receiving Hypertonic infusions Tube feedings Osmotic diuretics Lactulose Mechanical ventilation Altered mental status Uncontrolled diabetes mellitus Underlying polyuria

Placental secretion of vasopressinase

FIGURE 1-39 Causes and mechanisms of acquired nephrogenic diabetes insidpidus. Acquired nephrogenic diabetes insipidus occurs in chronic renal failure, electrolyte imbalances, with certain drugs, in sickle cell disease and pregnancy. The exact mechanism involved has been the subject of extensive investigation over the past decade and has now been carefully elucidated for most of the etiologies.

FIGURE 1-40 Patient groups at increased risk for severe hypernatremia. Hypernatremia always reflects a hyperosmolar state. It usually occurs in a hospital setting (reported incidence 0.65% to 2.23% of all hospitalized patients) with very high morbidity and mortality (estimates of 42% to over 70%) [12].

Diseases of Water Metabolism

Hypovolemic hypernatremia

Euvolemic hypernatremia

Hypervolemic hypernatremia

Correction of volume deficit Administer isotonic saline until hypovolemia improves Treat causes of losses (insulin, relief of urinary tract obstruction, removal of osmotic diuretics)

Correction of water deficit Calculate water deficit Administer 0.45% saline, 5% dextrose or oral water to replace the deficit and ongoing losses In central diabetes insipidus with severe losses, aqueous vasopressin (pitressin) 5 U SC q 6 hr Follow serum sodium concentration carefully to avoid water intoxication

Removal of sodium Discontinue offending agents Administer furosemide Provide hemodialysis, as needed, for renal failure

SIGNS AND SYMPTOMS OF HYPERNATREMIA Central Nervous System Mild Restlessness Lethargy Altered mental status Irritability Moderate Disorientation Confusion Severe Stupor Coma Seizures Death

Correction of water deficit Calculate water deficit Administer 0.45% saline, 5% dextrose or oral water replacing deficit and ongoing losses

Long term therapy Central diabetes insipidus (see Table 1–12) Nephrogenic diabetes insipidus Correct plasma potassium and calcium concentration Remove offending drugs Low-sodium diet Thiazide diuretics Amiloride (for lithium-induced nephrogenic diabetes insipidus)

Respiratory System Labored respiration

Gastrointestinal System Intense thirst Nausea Vomiting

Musculoskeletal System Muscle twitching Spasticity Hyperreflexia

FIGURE 1-41 Signs and symptoms of hypernatremia. Hypernatremia always reflects a hyperosmolar state; thus, central nervous system symptoms are prominent in affected patients [12].

1.21

FIGURE 1-42 Management options for patients with hypernatremia. The primary goal in the treatment of hypernatremia is restoration of serum tonicity. Hypovolemic hypernatremia in the context of low total body sodium and orthostatic blood pressure changes should be managed with isotonic saline until blood pressure normalizes. Thereafter, fluid management generally involves administration of 0.45% sodium chloride or 5% dextrose solution. The goal of therapy for hypervolemic hypernatremias is to remove the excess sodium, which is achieved with diuretics plus 5% dextrose. Patients who have renal impairment may need dialysis. In euvolemic hypernatremic patients, water losses far exceed solute losses, and the mainstay of therapy is 5% dextrose. To correct the hypernatremia, the total body water deficit must be estimated. This is based on the serum sodium concentration and on the assumption that 60% of the body weight is water [24]. (Modified from Halterman and Berl [12]; with permission.)

GUIDELINES FOR THE TREATMENT OF SYMPTOMATIC HYPERNATREMIA* Correct at a rate of 2 mmol/L/h Replace half of the calculated water deficit over the first 12–24 hrs Replace the remaining deficit over the next 24–36 hrs Perform serial neurologic examinations (prescribed rate of correction can be decreased as symptoms improve) Measure serum and urine electrolytes every 1–2 hrs *If UNa + U K is less than the concentration of PNa, then water loss is ongoing and needs to be replaced.

FIGURE 1-43 Guidelines for the treatment of symptomatic hypernatremia. Patients with severe symptomatic hypernatremia are at high risk of dying and should be treated aggressively. An initial step is estimating the total body free water deficit, based on the weight (in kilograms) and the serum sodium. During correction of the water deficit, it is important to perform serial neurologic examinations.

1.22

Disorders of Water, Electrolytes, and Acid-Base

References 1. Jacobson HR: Functional segmentation of the mammalian nephron. Am J Physiol 1981, 241:F203. 2. Goldberg M: Water control and the dysnatremias. In The Sea Within Us. Edited by Bricker NS. New York: Science and Medicine Publishing Co., 1975:20. 3. Kokko J, Rector F: Countercurrent multiplication system without active transport in inner medulla. Kidney Int 1972, 114. 4. Knepper MA, Roch-Ramel F: Pathways of urea transport in the mammalian kidney. Kidney Int 1987, 31:629. 5. Vander A: In Renal Physiology. New York: McGraw Hill, 1980:89. 6. Zimmerman E, Robertson AG: Hypothalamic neurons secreting vasopressin and neurophysin. Kidney Int 1976, 10(1):12. 7. Bichet DG: Nephrogenic and central diabetes insipidus. In Diseases of the Kidney, edn. 6. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown, and Co., 1997:2430 8. Bichet DG : Vasopressin receptors in health and disease. Kidney Int 1996, 49:1706. 9. Dunn FL, Brennan TJ, Nelson AE, Robertson GL: The role of blood osmolality and volume in regulating vasopressin secretion in the rat. J Clin Invest 1973, 52:3212. 10. Rose BD: Antidiuretic hormone and water balance. In Clinical Physiology of Acid Base and Electrolyte Disorders, edn. 4. New York: McGraw Hill, 1994. 11. Cogan MG: Normal water homeostasis. In Fluid & Electrolytes, Physiology and Pathophysiology. Edited by Cogan MG. Norwalk: Appleton & Lange, 1991:98. 12. Halterman R, Berl T: Therapy of dysnatremic disorders. In Therapy in Nephrology and Hypertension. Edited by Brady H, Wilcox C. Philadelphia: WB Saunders, 1998, in press. 13. Veis JH, Berl T, Hyponatremia: In The Principles and Practice of Nephrology, edn. 2. Edited by Jacobson HR, Striker GE, Klahr S. St.Louis: Mosby, 1995:890. 14. Berl T, Schrier RW: Disorders of water metabolism. In Renal and Electrolyte Disorders, edn 4. Philadelphia: Lippincott-Raven, 1997:52. 15. Verbalis JG: The syndrome of ianappropriate diuretic hormone secretion and other hypoosmolar disorders. In Diseases of the Kidney, edn. 6. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown, and Co., 1997:2393.

16. Berl T, Schrier RW: Disorders of water metabolism. In Renal and Electrolyte Disorders, edn. 4. Edited by Schrier RW. Philadelphia: Lippincott-Raven, 1997:54. 17. Berl T, Anderson RJ, McDonald KM, Schreir RW: Clinical Disorders of water metabolism. Kidney Int 1976, 10:117. 18. Gullans SR, Verbalis JG: Control of brain volume during hyperosmolar and hypoosmolar conditions. Annu Rev Med 1993, 44:289. 19. Zarinetchi F, Berl T: Evaluation and management of severe hyponatremia. Adv Intern Med 1996, 41:251. 20. Lauriat SM, Berl T: The Hyponatremic Patient: Practical focus on therapy. J Am Soc Nephrol 1997, 8(11):1599. 21. Ayus JC, Wheeler JM, Arieff AI: Postoperative hyponatremic encephalopathy in menstruant women. Ann Intern Med 1992,117:891. 22. Laureno R, Karp BI: Myelinolysis after correction of hyponatremia. Ann Intern Med 1997, 126:57. 23. Kumar S, Berl T: Disorders of serum sodium concentration. Lancet 1998. in press. 24. Cogan MG: Normal water homeostasis. In Fluid & Electrolytes, Physiology and Pathophysiology. Edited by Cogan MG. Norwalk: Appleton & Lange, 1991:94. 25. Rittig S, Robertson G, Siggaard C, et al.: Identification of 13 new mutations in the vasopressin-neurophysin II gene in 17 kindreds with familial autosomal dominant neurohypophyseal diabetes insipidus. Am J Hum Genet 1996, 58:107. 26. Lanese D, Teitelbaum I: Hypernatremia. In The Principles and Practice of Nephrology, edn. 2. Edited by Jacobson HR, Striker GE, Klahr S. St. Louis: Mosby, 1995:895. 27. Barrett T, Bundey S: Wolfram (DIDMOAD) syndrome. J Med Genet 1997, 29:1237. 28. Holtzman EJ, Ausiello DA: Nephrogenic Diabetes insipidus: Causes revealed. Hosp Pract 1994, Mar 15:89–104. 29. Bichet D, Oksche A, Rosenthal W: Congential Nephrogenic Diabetes Insipidus. J Am Soc Nephrol 1997, 8:1951. 30. Lieburg van, Verdjik M, Knoers N, et al.: Patients with autosomal nephrogenic diabetes insipidus homozygous for mutations in the aquaporin 2 water channel. Am J Hum Genet 1994, 55:648. 31. Canfield MC, Tamarappoo BK, Moses AM, et al.: Identification and characterization of aquaporin-2 water channel mutations causing nephrogenic diabetes insipidus with partial vasopressin response. Hum Mol Genet 1997, 6(11):1865.

Disorders of Sodium Balance David H. Ellison

S

odium is the predominant cation in extracellular fluid (ECF); the volume of ECF is directly proportional to the content of sodium in the body. Disorders of sodium balance, therefore, may be viewed as disorders of ECF volume. The body must maintain ECF volume within acceptable limits to maintain tissue perfusion because plasma volume is directly proportional to ECF volume. The plasma volume is a crucial component of the blood volume that determines rates of organ perfusion. Many authors suggest that ECF volume is maintained within narrow limits despite wide variations in dietary sodium intake. However, ECF volume may increase as much as 18% when dietary sodium intake is increased from very low to moderately high levels [1,2]. Such variation in ECF volume usually is well tolerated and leads to few short-term consequences. In contrast, the same change in dietary sodium intake causes only a 1% change in mean arterial pressure (MAP) in normal persons [3]. The body behaves as if the MAP, rather than the ECF volume, is tightly regulated. Under chronic conditions, the effect of MAP on urinary sodium excretion displays a remarkable gain; an increase in MAP of 1 mm Hg is associated with increases in daily sodium excretion of 200 mmol [4]. Guyton [4] demonstrated the importance of the kidney in control of arterial pressure. Endogenous regulators of vascular tone, hormonal vasoconstrictors, neural inputs, and other nonrenal mechanisms are important participants in short-term pressure homeostasis. Over the long term, blood pressure is controlled by renal volume excretion, which is adjusted to a set point. Increases in arterial pressure lead to natriuresis (called pressure natriuresis), which reduces blood volume. A decrease in blood volume reduces venous return to the heart and cardiac output. Urinary volume excretion exceeds dietary intake until the blood volume decreases sufficiently to return the blood pressure to the set point. Disorders of sodium balance resulting from primary renal sodium retention lead only to modest volume expansion without edema because increases in MAP quickly return sodium excretion to baseline

CHAPTER

2

2.2

Disorders of Water, Electrolytes, and Acid-Base

levels. Examples of these disorders include chronic renal failure and states of mineralocorticoid excess. In this case, the price of a return to sodium balance is hypertension. Disorders of sodium balance that result from secondary renal sodium retention, as in congestive heart failure, lead to more profound volume expansion owing to hypotension. In mild to moderates cases, volume expansion eventually returns the MAP to its set point; the price of sodium balance in this case is edema. In more severe cases, volume expansion never returns blood pressure to normal, and renal sodium retention is unremitting. In still other situations, such as nephrotic syndrome, volume expansion results from changes in both the renal set point and body volume distribution. In this case, the price of sodium balance may be both edema and hypertension. In each of these cases, renal sodium (and chloride) retention results from a discrepancy between the existing MAP and the renal set point. The examples listed previously emphasize that disorders of sodium balance do not necessarily abrogate the ability to achieve sodium balance. When balance is defined as the equation of sodium intake and output, most patients with ECF expansion (and edema or hypertension) or ECF volume depletion achieve sodium balance. They do so, however, at the expense of expanded or contracted ECF volume. The failure to achieve sodium balance at normal ECF volumes characterizes these disorders. Frequently, distinguishing disorders of sodium balance from disorders of water balance is useful. According to this scheme, disorders of water balance are disorders of body osmolality and usually are manifested by alterations in serum sodium concentration

(see Chapter 1). Disorders of sodium balance are disorders of ECF volume. This construct has a physiologic basis because water balance and sodium balance can be controlled separately and by distinct hormonal systems. It should be emphasized, however, that disorders of sodium balance frequently lead to or are associated with disorders of water balance. This is evident from Figure 2-24 in which hyponatremia is noted to be a sign of either ECF volume expansion or contraction. Thus, the distinction between disorders of sodium and water balance is useful in constructing differential diagnoses; however, the close interrelationships between factors that control sodium and water balance should be kept in mind. The figures herein describe characteristics of sodium homeostasis in normal persons and also describe several of the regulatory systems that are important participants in controlling renal sodium excretion. Next, mechanisms of sodium transport along the nephron are presented, followed by examples of disorders of sodium balance that illuminate current understanding of their pathophysiology. Recently, rapid progress has been made in unraveling mechanisms of renal volume homeostasis. Most of the hormones that regulate sodium balance have been cloned and sequenced. Intracellular signaling mechanisms responsible for their effects have been characterized. The renal transport proteins that mediate sodium reabsorption also have been cloned and sequenced. The remaining challenges are to integrate this information into models that describe systemic volume homeostasis and to determine how alterations in one or more of the well-characterized systems lead to volume expansion or contraction.

Normal Extracellular Fluid Volume Homeostasis Adult male Extravascular (15%) Plasma (5%) Blood volume (9%)

RBC (4%)

Adult female ECF volume (20%)

Extravascular (11%) Plasma (4%)

Blood volume (7%)

RBC (3%)

ICF volume (40%)

A

ECF volume (15%)

ICF volume (35%)

B

FIGURE 2-1 Fluid volumes in typical adult men and women, given as percentages of body weight. In men (A), total body water typically is 60% of body weight (Total body water = Extracellular fluid [ECF] volume + Intracellular fluid [ICF] volume). The ECF volume comprises the plasma volume and the extravascular volume. The ICF volume comprises the water inside erythrocytes (RBCs) and inside other cells. The blood volume comprises the plasma volume plus the RBC volume. Thus, the RBC volume is a unique component of ICF volume that contributes directly to cardiac output and blood pressure. Typically, water comprises a smaller percentage of the body weight in a woman (B) than in a man; thus, when expressed as a percentage of body weight, fluid volumes are smaller. Note, however, that the percentage of total body water that is intracellular is approximately 70% in both men and women [5].

2.3

Disorders of Sodium Balance

ECF volume, L

10 9 8 7 6 5 4 3 2 1 0

13 12 11 10 0

5

0

10 15 Days

1

20

Dietary sodium intake, g

14

25

FIGURE 2-2 Effects of changes in dietary sodium (Na) intake on extracellular fluid (ECF) volume. The dietary intake of Na was increased from 2 to 5 g, and then returned to 2 g. The relationship between dietary Na intake (dashed line) and ECF volume (solid line) is derived from the model of Walser [1]. In this model the rate of Na excretion is assumed to be proportional to the content of Na in the body (At) above a zero point (A0) at which Na excretion ceases. This relation can be expressed as dAt/dt = I - k(At - A0), where I is the dietary Na intake and t is time. The ECF volume is approximated as the total body Na content divided by the plasma Na concentration. (This assumption is strictly incorrect because approximately 25% of Na is tightly bound in bone; however, this amount is nearly invariant and can be ignored in the current analysis.) According to this construct, when dietary Na intake changes from level 1 to level 2, the ECF volume approaches a new steady state exponentially with a time constant of k according to the following equation: I I I A2  A1 = 2 + 1 2 ekt k k

Urinary sodium excretion, g/d 2 3 4

5

6

18

100

17

98 Mean arterial pressure, mmHg

15 14 13 12

∆≈ 18%

Urinary sodium excretion, g/d 2 3 4

5

6

5

6

94 92 90 88 86 ∆≈ 1%

84

11

82

10

80 0

A

1

96

16 ECF volume, L

0

1

2

3 4 Sodium intake, g/d

5

6

FIGURE 2-3 Relation between dietary sodium (Na), extracellular fluid (ECF) volume, and mean arterial pressure (MAP). A, Relation between the dietary intake of Na, ECF volume, and urinary Na excretion at steady state in a normal person. Note that 1 g of Na equals 43 mmol (43 mEq) of Na. At steady state, urinary Na excretion essentially is identical to the dietary intake of Na. As discussed in Figure 2-2, ECF volume increases linearly as the dietary intake of Na increases. At an ECF volume of under about 12 L, urinary Na excretion ceases. The gray bar indicates a normal dietary intake of Na when consuming a typical Western diet. The dark blue bar indicates the range of Na

0

B

1

2

3 4 Sodium intake, g/d

intake when consuming a “no added salt” diet. The light blue bar indicates that a “low-salt” diet generally contains about 2 g/d of Na. Note that increasing the dietary intake of Na from very low to normal levels leads to an 18% increase in ECF volume. B, Relation between the dietary intake of Na and MAP in normal persons. MAP is linearly dependent on Na intake; however, increasing dietary Na intake from very low to normal levels increases the MAP by only 1%. Thus, arterial pressure is regulated much more tightly than is ECF volume. (A, Data from Walser [1]; B, Data from Luft and coworkers [3].)

2.4

Disorders of Water, Electrolytes, and Acid-Base

UNaV, X normal

6 5 4 3 2 1 0

+

Nonrenal fluid loss

–

+ 0

50 100 150 200 MAP, mm Hg

+

Arterial pressure

NaCl and fluid intake

Net volume intake

Rate of change of extracellular fluid volume

–

Kidney volume output

+

Extracellular fluid volume +

+

Total peripheral resistance

+

Blood volume +

+

Autoregulation + Cardiac output

+

Mean circulatory filling pressure

Venous return

FIGURE 2-4 Schema for the kidney blood volume pressure feedback mechanism adapted from the work of Guyton and colleagues [6]. Positive relations are indicated by a plus sign; inverse relations are indicated by a minus sign. The block diagram shows that increases

Lumen Na

Blood

DCT 5-7%

Cl

CD 3-5% PROX 60%

–

+

Na Lumen Lumen Na HCO3 H2CO3 CA H 2O

H 2O H

Blood

Blood K

H+ OH

Lumen + Na K Cl

CO2

HCO3

Blood –

K

CO2 Na

LOH 25%

in extracellular fluid (ECF) volume result from increases in sodium chloride (NaCl) and fluid intake or decreases in kidney volume output. An increase in ECF volume increases the blood volume, thereby increasing the venous return to the heart and cardiac output. Increases in cardiac output increase arterial pressure both directly and by increasing peripheral vascular resistance (autoregulation). Increased arterial pressure is sensed by the kidney, leading to increased kidney volume output (pressure diuresis and pressure natriuresis), and thus returning the ECF volume to normal. The inset shows this relation between mean arterial pressure (MAP), renal volume, and sodium excretion [4]. The effects of acute increases in arterial pressure on urinary excretion are shown by the solid curve. The chronic effects are shown by the dotted curve; note that the dotted line is identical to the curve in Figure 2-3. Thus, when the MAP increases, urinary output increases, leading to decreased ECF volume and return to the original pressure set point. UNaV—urinary sodium excretion volume.

FIGURE 2-5 Sodium (Na) reabsorption along the mammalian nephron. About 25 moles of Na in 180 L of fluid daily is delivered into the glomerular filtrate of a normal person. About 60% of this load is reabsorbed along the proximal tubule (PROX), indicated in dark blue; about 25% along the loop of Henle (LOH), including the thick ascending limb indicated in light blue; about 5% to 7% along the distal convoluted tubule (DCT), indicated in dark gray; and 3% to 5% along the collecting duct (CD) system, indicated in light gray. All Na transporting cells along the nephron express the ouabain-inhibitable sodium-potassium adenosine triphosphatase (Na-K ATPase) pump at their basolateral (blood) cell surface. (The pump is not shown here for clarity.) Unique pathways are expressed at the luminal membrane that permit Na to enter cells. The most quantitatively important of these luminal Na entry pathways are shown here. These pathways are discussed in more detail in Figures 2-15 to 2-19. CA—carbonic anhydrase; Cl—chloride; CO2—carbon dioxide; H—hydrogen; H2CO3—carbonic acid; HCO3—bicarbonate; K—potassium; OH—hydroxyl ion.

Disorders of Sodium Balance

2.5

Mechanisms of Extracellular Fluid Volume Control ↑ Renal tubular sodium reabsoption ↑ ERSNA

↑ Angiotensin II

↑ Activation of baroreceptors

↑ Renin

↑ Aldosterone

↑ FF

↓ Arterial pressure

ECFV contraction

Normal ECF volume

FIGURE 2-6 Integrated response of the kidneys to changes in extracellular fluid (ECF) volume. This composite figure illustrates natriuretic and antinatriuretic mechanisms. For simplicity, the systems are shown operating only in one direction and not all pathways are shown. The major antinatriuretic systems are the renin-angiotensin-aldosterone axis and increased efferent renal sympathetic nerve activity (ERSNA). The most important natriuretic mechanism is pressure natriuresis, because the level of renal perfusion pressure (RPP) determines the magnitude of the response to all other natriuretic systems. Renal interstitial hydrostatic pressure (RIHP) is a link between the circulation and renal tubular sodium reabsorption. Atrial natriuretic peptide (ANP) is the major systemic natriuretic hormone. Within the kidney, kinins and renomedullary prostaglandins are important modulators of the natriuretic response of the kidney. AVP—arginine vasopressin; FF—filtration fraction. (Modified from Gonzalez-Campoy and Knox [7].)

ECFV expansion ↑ ANP

↑ Arterial pressure

↑ Kinins

↑ RIHP

↑ Prostaglandins

↓ Renal tubular sodium reabsoption

ACE

SVR + Angiotensinogen

+

DRVYIHPFHL

DRVYIHPF

Angiotensin I

Angiotensin II +

+ Aldo

Renin

– –

UNaV

FIGURE 2-7 Overview of the renin-angiotensin-aldosterone system [8,9]. Angiotensinogen (or renin substrate) is a 56-kD glycoprotein produced and secreted by the liver. Renin is produced by the juxtaglomerular apparatus of the kidney, as shown in Figures 2-8 and 2-9. Renin cleaves the 10 N-terminal amino acids from angiotensinogen. This decapeptide (angiotensin I) is cleaved by angiotensin converting enzyme (ACE). The resulting angiotensin II comprises the 8 N-terminal amino acids of angiotensin I. The primary amino acid structures of angiotensins I and II are shown in single letter codes. Angiotensin II increases systemic vascular resistance (SVR), stimulates aldosterone secretion from the adrenal gland (indicated in gray), and increases sodium (Na) absorption by renal tubules, as shown in Figures 2-15 and 2-17. These effects decrease urinary Na (and chloride excretion; UNaV).

2.6

Disorders of Water, Electrolytes, and Acid-Base FIGURE 2-8 The juxtaglomerular (JG) apparatus. This apparatus brings into close apposition the afferent (A) and efferent (E) arterioles with the macula densa (MD), a specialized region of the thick ascending limb (TAL). The extraglomerular mesangium (EM), or lacis “Goormaghtigh apparatus (cells),” forms at the interface of these components. MD cells express the Na-K-2Cl (sodium-potassium-chloride) cotransporter (NKCC2) at the apical membrane [10,11]. By way of the action of this transporter, MD cells sense the sodium chloride concentration of luminal fluid. By way of mechanisms that are unclear, this message is communicated to JG cells located in and near the arterioles (especially the afferent arteriole). These JG cells increase renin secretion when the NaCl concentration in the lumen is low [12]. Cells in the afferent arteriole also sense vascular pressure directly, by way of the mechanisms discussed in Figure 2-9. Both the vascular and tubular components are innervated by sympathetic nerves (N). B—Bowman’s space, G—glomerular capillary; IM—intraglomerular mesangium. (From Barajas [13]; with permission.)

B N JG

N

A

IM

G

MD

E

JG

G

N

ANP Prorenin

–

β1

Renin

Sympathetic nerves

AC

Renin ↑cAMP

+

–

–

AT1

All

+

NO

↑Ca PGE2 PGI2

–

↑Ca +

+

Membrane depolarization

+

Membrane stretch

+ Arterial pressure

MD NaCl

FIGURE 2-9 Schematic view of a (granular) juxtaglomerular cell showing secretion mechanisms of renin [8]. Renin is generated from prorenin. Renin secretion is inhibited by increases in and stimulated by decreases in intracellular calcium (Ca) concentrations. Voltage-sensitive Ca channels in the plasma membrane are activated by membrane stretch, which correlates with arterial pressure and is assumed to mediate baroreceptor-sensitive renin secretion. Renin secretion is also stimulated when the concentration of sodium (Na) and chloride (Cl) at the macula densa (MD) decreases [12,14]. The mediators of this effect are less well characterized; however, some studies suggest that the effect of Na and Cl in the lumen is more potent than is the baroreceptor mechanism [15]. Many other factors affect rates of renin release and contribute to the physiologic regulation of renin. Renal nerves, by way of  receptors coupled to adenylyl cyclase (AC), stimulate renin release by increasing the production of cyclic adenosine monophosphate (cAMP), which reduces Ca release. Angiotensin II (AII) receptors (AT1 receptors) inhibit renin release, as least in vitro. Prostaglandins E2 and I2 (PGE2 and PGI2, respectively) strongly stimulate renin release through mechanisms that remain unclear. Atrial natriuretic peptide (ANP) strongly inhibits renin secretion. Constitutive nitric oxide (NO) synthase is expressed by macula densa (MD) cells [16]. NO appears to stimulate renin secretion, an effect that may counteract inhibition of the renin gene by AII [17,18].

Disorders of Sodium Balance AME or Licorice Basolateral

FIGURE 2-10 Mechanism of aldosterone action in the distal nephron [19]. Aldosterone, the predominant human mineralocorticoid hormone, enters distal nephron cells through the plasma membrane and interacts with its receptor (the mineralocorticoid receptor [MR], or Type I receptor). Interaction between aldosterone and this receptor initiates induction of new proteins that, by way of mechanisms that remain unclear, increase the number of sodium channels (ENaC) and sodium-potassium adenosine triphosphatase (Na-K ATPase) pumps at the cell surface. This increases transepithelial Na (and potassium) transport. Cortisol, the predominant human glucocorticoid hormone, also enters cells through the plasma membrane and interacts with its receptor (the glucocorticoid receptor [GR]). Cortisol, however, also interacts with mineralocorticoid receptors; the affinity of cortisol and aldosterone for mineralocorticoid receptors is approximately equal. In distal nephron cells, this interaction also stimulates electrogenic Na transport [20]. Cortisol normally circulates at concentrations 100 to 1000 times higher than the circulating concentration of aldosterone. In aldosterone-responsive tissues, such as the distal nephron, expression of the enzyme 11-hydroxysteroid dehydrogenase (11-HSD) permits rapid metabolism of cortisol so that only aldosterone can stimulate Na transport in these cells. An inherited deficiency of the enzyme 11-HSD (the syndrome of apparent mineralocorticoid excess, AME), or inhibition of the enzyme by ingestion of licorice, leads to hypertension owing to chronic stimulation of distal Na transport by endogenous glucocorticoids [21].

Apical

Cortisone 11β HSD Cortisol

Cortisol

GR ↑ ENaC ↑ Na/K ATPase

Cortisone 11β HSD Cortisol

MR Aldo

Aldo MR

Distal nephron cell

↑ Preload SLRRSSCFGGRLDRIGAQSGLGCNSFRY

+

Plasma ANP +

+

Vagal afferent activity

Capillary permeability

–

+

Renal NaCl reabsoption

Fluid shift into interstitium –

Cardiac output +

Renin secretion

Arteriolar contraction

+

+ +

Sympathetic efferent activity +

–

–

–

+

Angiotensin II + Aldosterone +

+

– Vascular volume

Peripheral vascular resistance

+ ↓ Preload + Blood pressure

2.7

+

FIGURE 2-11 Control of systemic hemodynamics by the atrial natriuretic peptide (ANP) system. Increases in atrial stretch (PRELOAD) increase ANP secretion by cardiac atria. The primary amino acid sequence of ANP is shown in single letter code with its disulfide bond indicated by the lines. The amino acids highlighted in blue are conserved between ANP, brain natriuretic peptide, and C-type natriuretic peptide. ANP has diverse functions that include but are not limited to the following: stimulating vagal afferent activity, increasing capillary permeability, inhibiting renal sodium (Na) and water reabsorption, inhibiting renin release, and inhibiting arteriolar contraction. These effects reduce sympathetic nervous activity, reduce angiotensin II generation, reduce aldosterone secretion, reduce total peripheral resistance, and shift fluid out of the vasculature into the interstitium. The net effect of these actions is to decrease cardiac output, vascular volume, and peripheral resistance, thereby returning preload toward baseline. Many effects of ANP (indicated by solid arrows) are diminished in patients with edematous disorders (there is an apparent resistance to ANP). Effects indicated by dashed arrows may not be diminished in edematous disorders; these effects contribute to shifting fluid from vascular to extravascular tissue, leading to edema. This observation may help explain the association between elevated right-sided filling pressures and the tendency for Na retention [22]. (Modified from Brenner and coworkers [23].)

2.8

Disorders of Water, Electrolytes, and Acid-Base Afferent

20 Knockout

Cerebral cortex

Carotid sinus

16

Hypothalamus

ANP infusion

14

Medulla

IX

X

12 Carotid bodies

10

X

8 6 Thoracic

UNAV, mmol/min/g body wt

Efferent

Wild type

18

4 2 0 30

45

60

75 90 105 120 135 150 165 180 Time, min

Blood vessel Lumbar

15

FIGURE 2-12 Mechanism of atrial natriuretic peptide (ANP) action on the kidney. Animals with disruption of the particulate form of guanylyl cyclase (GC) manifest increased mean arterial pressure that is independent of dietary intake of sodium chloride. To test whether ANP mediates its renal effects by way of the action of GC, ANP was infused into wild-type and GC-A–deficient mice. In wild-type animals, ANP led to prompt natriuresis. In GC-A–deficient mice, no effect was observed. UNaV—urinary sodium excretion volume. (Modified from Kishimoto [24].)

Adrenal

Kidney

Sacral

Other somatic (eg, muscle, splanchnic viscera, joint receptors) Spinal cord

Splanchnic viscera

FIGURE 2-13 Schematic diagram of neural connections important in circulatory control. Although the system is bilaterally symmetric, afferent fibers are shown to the left and efferent fibers to the right. Sympathetic fibers are shown as solid lines and parasympathetic fibers as dashed lines. The heart receives both sympathetic and parasympathetic innervation. Sympathetic fibers lead to vasoconstriction and renal sodium chloride retention. X indicates the vagus nerve; IX indicates glossopharyngeal. (From Korner [25]; with permission.)

Normal effective arterial volume

Low effective arterial volume

GFR =Filtration fraction RPF

↓GFR =↑Filtration fraction ↓↓RPF Filtration

A

E

Filtration A

E

onc

onc

Reabsorption

Reabsorption Pt

A

Pt

Pi

Backleak

B

Pi

↓ Backleak

FIGURE 2-14 Cellular mechanisms of increased solute and water reabsorption by the proximal tubule in patients with “effective” arterial volume depletion. A, Normal effective arterial volume in normal persons. B, Low effective arterial volume in patients with both decreased glomerular filtration rates (GFR) and renal plasma flow (RPF). In contrast to normal persons, patients with low effective arterial volume have decreased GFR and RPF, yet the filtration fraction is increased because the RPF decreases more than does the GFR. The increased filtration fraction concentrates the plasma protein (indicated by the dots) in the peritubular capillaries leading to increased plasma oncotic pressure (onc). Increased plasma oncotic pressure reduces the amount of backleak from the peritubular capillaries. Simultaneously, the increase in filtration fraction reduces volume delivery to the (Legend continued on next page)

Disorders of Sodium Balance FIGURE 2-14 (continued) peritubular capillary, decreasing its hydrostatic pressure, and thereby reducing the renal interstitial hydrostatic pressure (Pi). Even though the proximal tubule hydrostatic pressure (Pt) may be

2.9

reduced, owing to diminished GFR, the hydrostatic gradient from tubule to interstitium is increased, favoring increased volume reabsorption. A—afferent arteriole; E—efferent arteriole.

Mechanisms of Sodium and Chloride Transport along the Nephron Lumen α

+

Na+ H+

Renal nerves See figure 2-13

+ AT1

–

+

All See figure 2-7

DA1

Dopamine

– H 2O

↑FF ~

3Na+

See figure 2-14

2K+ +

Na+ Cl-

↓Pi +

Interstitum

↑onc

FIGURE 2-15 Cellular mechanisms and regulation of sodium chloride (NaCl) and volume reabsorption along the proximal tubule. The sodium-potassium adenosine triphosphate (Na-K ATPase) pump (shown as white circle with light blue outline) at the basolateral cell membrane keeps the intracellular Na concentration low; the K concentration high; and the cell membrane voltage oriented with the cell interior negative, relative to the exterior. Many pathways participate in Na entry across the luminal membrane. Only the sodiumhydrogen (Na-H) exchanger is shown because its regulation in states of volume excess and depletion has been characterized extensively. Activity of the Na-H exchanger is increased by stimulation of renal nerves, acting by way of  receptors and by increased levels of circulating angiotensin II (AII), as shown in Figures 2-7 and 2-13 [25–28]. Increased levels of dopamine (DA1) act to inhibit activity of the Na-H exchanger [29,30]. Dopamine also acts to inhibit activity of the Na-K ATPase pump at the basolateral cell membrane [30]. As described in Figure 2-14, increases in the filtration fraction (FF) lead to increases in oncotic pressure (onc) in peritubular capillaries and decreases in peritubular and interstitial hydrostatic pressure (Pi). These changes increase solute and volume absorption and decrease solute backflux. Water flows through water channels (Aquaporin-1) Na and Cl also traverse the paracellular pathway.

2.10

Disorders of Water, Electrolytes, and Acid-Base

Lumen cAMP

+

Na

? V2

2Cl

–

–

K

AVP

PGE2

PR

– K

Cl

20-HETE 20-COOH-AA

c-P450 Arachidonic acid

~ 2K+

3Na+

+

–

Na Interstitum

A

0.16 mol NaCl

H 2O

kD 199-

FIGURE 2-16 Cellular mechanisms and regulation of sodium (Na) and chloride (Cl) transport by thick ascending limb (TAL) cells. Na, Cl, and potassium (K) enter cells by way of the bumetanide-sensitive Na-K2Cl cotransporter (NKCC2) at the apical membrane. K recycles back through apical membrane K channels (ROMK) to permit continued operation of the transporter. In this nephron segment, the asymmetric operations of the luminal K channel and the basolateral chloride channel generate a transepithelial voltage, oriented with the lumen positive. This voltage drives paracellular Na absorption. Although arginine vasopressin (AVP) is known to stimulate Na reabsorption by TAL cells in some species, data from studies in human subjects suggest AVP has minimal or no effect [31,32]. The effect of AVP is mediated by way of production of cyclic adenosine monophosphate (cAMP). Prostaglandin E2 (PGE2) and cytochrome P450 (c-P450) metabolites of arachidonic acid (20-HETE [hydroxy-eicosatetraenoic acid] and 20-COOH-AA) inhibit transepithelial NaCl transport, at least in part by inhibiting the Na-K-2Cl cotransporter [33–35]. PGE2 also inhibits vasopressin-stimulated Na transport, in part by activating Gi and inhibiting adenylyl cyclase [36]. Increases in medullary NaCl concentration may activate transepithelial Na transport by increasing production of PGE2. Inset A, Regulation of NKCC2 by chronic Na delivery. Animals were treated with 0.16 mol NaCl or water as drinking fluid for 2 weeks. The Western blot shows upregulation of NKCC2 in the group treated with saline [37]. Gi—inhibitory G protein; PR—prostaglandin receptor; V2— AVP receptors. (Modified from Ecelbarger [37].)

1208748-

Lumen +

+

Aldo receptor

Aldo

Na

See figure Y

+

Cl

α

+ ~

+

2K+

3Na+ AT1

All See figure 2-7

DCT –

+

Interstitum

FIGURE 2-17 Mechanisms and regulation of sodium (Na) and chloride (Cl) transport by the distal nephron. As in other nephron segments, intracellular Na concentration is maintained low by the action of the Na-K ATPase (sodium-potassium adenosine triphosphatase) pump at the basolateral cell membrane. Na enters distal convoluted tubule (DCT) cells across the luminal membrane coupled directly to chloride by way of the thiazide-sensitive Na-Cl cotransporter. Activity of the Na-Cl cotransporter appears to be stimulated by both aldosterone and angiotensin II (AII) [38–40]. Transepithelial Na transport in this segment is also stimulated by sympathetic nerves acting by way of  receptors [41,42]. The DCT is impermeable to water.

2.11

Disorders of Sodium Balance

Lumen –

Na

Interstitum

+

+

Aldo receptor

+

Aldo

+ ~ K

cAMP

R

+

Na Na Na Na Na Na Na

cGMP

AR

–

ANP

GC

2K+

3Na+

+

↑GFR

Gi

PGE2 α

– Lumen

PGE2

~ 2K+

3Na+

AC

H 2O

Gs V2

ATP CCT

AVP

H 2O

+

V2

AVP

– MCT +

FIGURE 2-18 Principal cortical collecting tubule (CCT) cells. In these cells, sodium (Na) enters across the luminal membrane through Na channels (ENaC). The movement of cationic Na from lumen to cell depolarizes the luminal membrane, generating a transepithelial electrical gradient oriented with the lumen negative with respect to interstitium. This electrical gradient permits cationic potassium (K) to diffuse preferentially from cell to lumen through K channels (ROMK). Na transport is stimulated when aldosterone interacts with its intracellular receptor [43]. This effect involves both increases in the number of Na channels at the luminal membrane and increases in the number of Na-K ATPase (Sodium-potassium adenosine triphosphatase) pumps at the basolateral cell membrane. Arginine vasopressin (AVP) stimulates both Na absorption (by interacting with V2 receptors and, perhaps, V1 receptors) and water transport (by interacting with V2 receptors) [44–46]. V2 receptor stimulation leads to insertion of water channels (aquaporin 2) into the luminal membrane [47]. V2 receptor stimulation is modified by PGE2 and 2 agonists that interact with a receptor that stimulates Gi [48]. AC—adenylyl cyclase; ATP—adenosine triphosphate; cAMP—cyclic adenosine monophosphate; CCT—cortical collecting tubule; Gi—inhibitory G protein; Gs—stimulatory G protein; R—Ri receptor.

FIGURE 2-19 Cellular mechanism of the medullary collecting tubule (MCT). Sodium (Na) and water are reabsorbed along the MCT. Atrial natriuretic peptide (ANP) is the best-characterized hormone that affects Na absorption along this segment [22]. Data on the effects of arginine vasopressin (AVP) and aldosterone are not as consistent [46,49]. Prostaglandin E2 (PGE2) inhibits Na transport by inner medullary collecting duct cells and may be an important intracellular mediator for the actions of endothelin and interleukin-1 [50,51]. ANP inhibits medullary Na transport by interacting with a G-protein–coupled receptor that generates cyclic guanosine monophosphate (cGMP). This second messenger inhibits a luminal Na channel that is distinct from the Na channel expressed by the principal cells of the cortical collecting tubule, as shown in Figure 2-18 [52,53]. Under normal circumstances, ANP also increases the glomerular filtration rate (GFR) and inhibits Na transport by way of the effects on the renin-angiotensin-aldosterone axis, as shown in Figures 2-7 to 2-10. These effects increase Na delivery to the MCT. The combination of increased distal Na delivery and inhibited distal reabsorption leads to natriuresis. In patients with congestive heart failure, distal Na delivery remains depressed despite high levels of circulating ANP. Thus, inhibition of apical Na entry does not lead to natriuresis, despite high levels of MCT cGMP. AR—ANP receptor; GC—guanylyl cyclase; K—potassium; V2—receptors.

2.12

Disorders of Water, Electrolytes, and Acid-Base

Causes, Signs, and Symptoms of Extracellular Fluid Volume Expansion and Contraction CAUSES OF VOLUME EXPANSION Primary renal sodium retention (with hypertension but without edema) Hyperaldosteronism (Conn’s syndrome) Cushing’s syndrome Inherited hypertension (Liddle’s syndrome, glucocorticoid remediable hyperaldosteronism, pseudohypoaldosteronism Type II, others) Renal failure Nephrotic syndrome (mixed disorder) Secondary renal sodium retention Hypoproteinemia Nephrotic syndrome Protein-losing enteropathy Cirrhosis with ascites Low cardiac output Hemodynamically significant pericardial effusion Constrictive pericarditis Valvular heart disease with congestive heart failure Severe pulmonary disease Cardiomyopathies Peripheral vasodilation Pregnancy Gram-negative sepsis Anaphylaxis Arteriovenous fistula Trauma Cirrhosis Idiopathic edema (?) Drugs: minoxidil, diazoxide, calcium channel blockers (?) Increased capillary permeability Idiopathic edema (?) Burns Allergic reactions, including certain forms of angioedema Adult respiratory distress syndrome Interleukin-2 therapy Malignant ascites Sequestration of fluid (“3rd spacing,” urine sodium concentration low) Peritonitis Pancreatitis Small bowel obstruction Rhabdomyolysis, crush injury Bleeding into tissues Venous occlusion

FIGURE 2-20 In volume expansion, total body sodium (Na) content is increased. In primary renal Na retention, volume expansion is modest and edema does not develop because blood pressure increases until Na excretion matches intake. In secondary Na retention, blood pressure may not increase sufficiently to increase urinary Na excretion until edema develops.

CAUSES OF VOLUME DEPLETION Extrarenal losses (urine sodium concentration low) Gastrointestinal salt losses Vomiting Diarrhea Nasogastric or small bowel aspiration Intestinal fistulae or ostomies Gastrointestinal bleeding Skin and respiratory tract losses Burns Heat exposure Adrenal insufficiency Extensive dermatologic lesions Cystic fibrosis Pulmonary bronchorrhea Drainage of large pleural effusion Renal losses (urine sodium concentration normal or elevated) Extrinsic Solute diuresis (glucose, bicarbonate, urea, mannitol, dextran, contrast dye) Diuretic agents Adrenal insufficiency Selective aldosterone deficiency Intrinsic Diuretic phase of oliguric acute renal failure Postobstructive diuresis Nonoliguric acute renal failure Salt-wasting nephropathy Medullary cystic disease Tubulointerstitial disease Nephrocalcinosis

FIGURE 2-21 In volume depletion, total body sodium is decreased.

Disorders of Sodium Balance

CLINICAL SIGNS OF VOLUME EXPANSION

CLINICAL SIGNS OF VOLUME DEPLETION

Edema Pulmonary crackles Ascites Jugular venous distention Hepatojugular reflux Hypertension

Orthostatic decrease in blood pressure and increase in pulse rate Decreased pulse volume Decreased venous pressure Loss of axillary sweating Decreased skin turgor Dry mucous membranes

FIGURE 2-22 Clinical signs of volume expansion.

FIGURE 2-23 Clinical signs of volume depletion.

2.13

LABORATORY SIGNS OF VOLUME DEPLETION OR EXPANSION Hypernatremia Hyponatremia Acid-base disturbances Abnormal plasma potassium Decrease in glomerular filtration rate Elevated blood urea nitrogen–creatinine ratio Low functional excretion of sodium (FENa)

FIGURE 2-24 Note that laboratory test results for volume expansion and contraction are similar. Serum sodium (Na) concentration may be increased or decreased in either volume expansion or contraction, depending on the cause and intake of free water (see Chapter 1). Acid-base disturbances, such as metabolic alkalosis, and hypokalemia are common in both conditions. The similarity of the laboratory test results of volume depletion and expansion results from the fact that the “effective” arterial volume is depleted in both states despite dramatic expansion of the extracellular fluid volume in one.

Unifying Hypothesis of Renal Sodium Excretion Myocardial dysfunction –

↓ Extracellular fluid volume –

AV fistula –

Cardiac output

×

High output failure –

Cirrhosis

Pregnancy

–

Systemic vascular resistance

–

=

Mean arterial pressure + Sodium excretion (pressure natriuresis)

FIGURE 2-25 Summary of mechanisms of sodium (Na) retention in volume contraction and in depletion of the “effective” arterial volume. In secondary Na retention, Na retention results primarily

from a reduction in mean arterial pressure (MAP). Some disorders decrease cardiac output, such as congestive heart failure owing to myocardial dysfunction; others decrease systemic vascular resistance, such as high-output cardiac failure, atriovenous fistulas, and cirrhosis. Because MAP is the product of systemic vascular resistance and cardiac output, all causes lead to the same result. As shown in Figures 2-3 and 2-4, small changes in MAP lead to large changes in urinary Na excretion. Although edematous disorders usually are characterized as resulting from contraction of the effective arterial volume, the MAP, as a determinant of renal perfusion pressure, may be the crucial variable (Figs. 2-26 and 2-28 provide supportive data). The mechanisms of edema in nephrotic syndrome are more complex and are discussed in Figures 2-36 to 2-39.

2.14

Disorders of Water, Electrolytes, and Acid-Base

Mechanisms of Extracellular Fluid Volume Expansion in Congestive Heart Failure 130

130 MI

120 115 110 105 100 95

Am J Physiol 1977

120 115 110 105 100 95 90

90 Control

Small MI

Large MI AVF

A

Control

B

FIGURE 2-26 Role of renal perfusion pressure in sodium (Na) retention. A, Results from studies in rats that had undergone myocardial infarction (MI) or placement of an arteriovenous fistula (AVF) [54]. Rats with small and large MIs were identified. Both small and large MIs induced significant Na retention when challenged with Na loads. Renal Na retention occurred in the setting of mild hypotension. AVF also induced significant Na retention, which was associated with a decrease in mean arterial pressure (MAP) [55,56]. Figure 2-3 has shown that Na excretion decreases greatly for each mm Hg decrease in MAP. B, Results of two groups of experiments performed by Levy and Allotey [57,58] in

600

10

UNaV ANP MAP PRA

500

8

400 6 300 4 200 2

100

0

0 -5

0

5

10

15 20 Days

25

30

35

40

PRA, ng ANG I mL-1•h-1

UNaV, mmol/d or plasma ANP, pg/mL or MAP, mmHg;

J Lab Clin Med 1978

125

AVF

Mean arterial pressure, mmHg

Mean arterial pressure, mmHg

125

Balance

Na Ret. Cirrhosis

Ascites

which experimental cirrhosis was induced in dogs by sporadic feeding with dimethylnitrosamine. Three cirrhotic stages were identified based on the pattern of Na retention. In the first, dietary Na intake was balanced by Na excretion. In the second, renal Na retention began, but still without evidence of ascites or edema. In the last, ascites were detected. Because Na was retained before the appearance of ascites, “primary” renal Na retention was inferred. An alternative interpretation of these data suggests that the modest decrease in MAP is responsible for Na retention in this model. Note that in both heart failure and cirrhosis, Na retention correlates with a decline in MAP. FIGURE 2-27 Mechanism of sodium (Na) retention in high-output cardiac failure. Effects of high-output heart failure induced in dogs by arteriovenous (AV) fistula [59]. After induction of an AV fistula (day 0), plasma renin activity (PRA; thick solid line) increased greatly, correlating temporally with a reduction in urinary Na excretion (UNaV; thin solid line). During this period, mean arterial pressure (MAP; dotted line) declined modestly. After day 5, the plasma atrial natriuretic peptide concentration (ANP; dashed line) increased because of volume expansion, returning urinary Na excretion to baseline levels. Thus, Na retention, mediated in part by the renin-angiotensin-aldosterone system, led to volume expansion. The volume expansion suppressed the renin-angiotensin-aldosterone system and stimulated ANP secretion, thereby returning Na excretion to normal. These experiments suggest that ANP secretion plays an important role in maintaining Na excretion in compensated congestive heart failure. This effect of ANP has been confirmed directly in experiments using anti-ANP antibodies [60]. AI—angiotensin I.

Disorders of Sodium Balance

UNaV, µmol/min

400

FIGURE 2-28 Mechanism of renal resistance to atrial natriuretic peptide (ANP) in experimental low-output heart failure. Low-output heart failure was induced in dogs by thoracic inferior vena caval constriction (TIVCC), which also led to a significant decrease in renal perfusion pressure (RPP) (from 127 to 120 mm Hg). ANP infusion into dogs with TIVCC did not increase urinary sodium (Na) excretion (UNaV, ANP group). In contrast, when the RPP was returned to baseline by infusing angiotensin II (AII), urinary Na excretion increased greatly (ANP + AII). To exclude a direct effect of AII on urinary Na excretion, intrarenal saralasin (SAR) was infused to block renal AII receptors. SAR did not significantly affect the natriuresis induced by ANP plus AII. An independent effect of SAR on urinary Na excretion was excluded by infusing ANP plus SAR and AII plus SAR. These treatments were without effect. These results were interpreted as indicating that the predominant cause of resistance to ANP in dogs with low-output congestive heart failure is a reduction in RPP. (Data from Redfield and coworkers [61].)

ANP

300

ANP & SAR ANP & AII

200

ANP & AII & SAR AII & SAR

100 0 Baseline

TIVCC

Infusion

Net volume intake

Nonrenal fluid loss

– +

Blood volume, L

+

30 20

20

10

10

0

0 0

Arterial pressure

+

Kidney volume output

–

Rate of change of extracellular fluid volume

+

10 20 ECF volume, L Extracellular fluid volume +

+

Total peripheral resistance Autoregulation + Cardiac output

Blood volume +

+

+ Venous return

Mean circulatory filling pressure

30

Intersititial volume, L

30 Fluid intake

2.15

FIGURE 2-29 Mechanism of extracellular fluid (ECF) volume expansion in congestive heart failure. A primary decrease in cardiac output (indicated by dark blue arrow) leads to a decrease in arterial pressure, which decreases pressure natriuresis and volume excretion. These decreases expand the ECF volume. The inset graph shows that the ratio of interstitial volume (solid line) to plasma volume (dotted line) increases as the ECF volume expands because the interstitial compliance increases [62]. Thus, although expansion of the ECF volume increases blood volume and venous return, thereby restoring cardiac output toward normal, this occurs at the expense of a disproportionate expansion of interstitial volume, often manifested as edema.

2.16

Disorders of Water, Electrolytes, and Acid-Base

Mechanisms of Extracellular Fluid Volume Expansion in Cirrhosis Vasodilation theory

Underfill theory Hepatic venous outflow obstruction

Overflow theory –

SVR

Hepatic venous outflow obstruction

+

Transudation

Transudation

+ –

? +

Renin

↑ ECF volume

↓ Blood volume ?

–

–

FIGURE 2-30 Three theories of ascites formation in hepatic cirrhosis. Hepatic venous outflow obstruction leads to portal hypertension. According to the underfill theory, transudation from the liver leads to reduction of the blood volume, thereby stimulating sodium (Na) retention by the kidney. As indicated by the question mark near the term blood volume, a low blood volume is rarely detected in clinical or experimental cirrhosis. Furthermore, this theory predicts that ascites would develop before renal Na retention, when the reverse generally occurs. According to the overflow theory, increased portal pressure stimulates renal Na retention through incompletely defined mechanisms. As indicated by the question mark near the arrow from hepatic venous outflow obstruction to UNaV, the nature of the portal hypertension–induced signals for renal Na retention remains unclear. The vasodilation theory suggests that portal hypertension leads to vasodilation and relative arterial hypotension. Evidence for vasodilation in cirrhosis that precedes renal Na retention is now convincing, as shown in Figures 2-31 and 2-33 [63].

UNaV

Vasodilators Nitric oxide Glucagon CGRP ANP VIP Substance P Prostaglandin E2 Encephalins TNF Andrenomedullin

Vasoconstrictors

SNS RAAS Vasopressin ET-1

C.O.=5.22 L/min

C.O.=6.41 L/min

3.64 L

4.34 L

1.81 L

1.31 L Central blood volume

Central blood volume

A

Noncentral blood volume

B

Noncentral blood volume

Control subjects, n=16 Cirrhotic patients, n=60

FIGURE 2-31 Alterations in cardiovascular hemodynamics in hepatic cirrhosis. Hepatic dysfunction and portal hypertension increase the production and impair the metabolism of several vasoactive substances. The overall balance of vasoconstriction and vasodilation shifts in favor of dilation. Vasodilation may also shift blood away from the central circulation toward the periphery and away from the kidneys. Some of the vasoactive substances postulated to participate in the hemodynamic disturbances of cirrhosis include those shown here. ANP—atrial natrivretic peptide; ET-1—endothelin-1; CGRP—calcitonin gene related peptide; RAAS—renin/angiotensin/aldosterone system; TNF—tumor necrosis factor; VIP— vasoactive intestinal peptide. (Data from Møller and Henriksen [64].)

FIGURE 2-32 Effects of cirrhosis on central and noncentral blood volumes. The central blood volume is defined as the blood volume in the heart, lungs, and central arterial tree. Compared with control subjects (A), patients with cirrhosis (B) have decreased central and increased noncentral blood volumes. The higher cardiac output (CO) results from peripheral vasodilation. Perfusion of the kidney is reduced significantly in patients with cirrhosis. (Data from Hillarp and coworkers [65].)

Disorders of Sodium Balance

FIGURE 2-33 Contribution of nitric oxide to vasodilation and sodium (Na) retention in cirrhosis. Compared with control rats, rats having cirrhosis induced by carbon tetrachloride and phenobarbital exhibited increased plasma renin activity (PRA) and plasma arginine vasopressin (AVP) concentrations. At steady state, the urinary Na excretion (UNaV) was similar in both groups. After treatment with LNAME for 7 days, plasma renin activity decreased to normal levels, AVP concentrations decreased toward normal levels, and urinary Na excretion increased by threefold. These changes were associated with a normalization of mean arterial pressure and cardiac output. (Data compiled from Niederberger and coworkers [66,67] and Martin and Schrier [68].)

15

Control Cirrhosis Cirrhosis & L-name

10

10

5

5

UNaV, mmol/d

PRA, ng/min/h or AVP, pg/mL

15

2.17

0

0 PRA

AVP

UNaV

Blood volume, L

+

Fluid intake

Net volume intake

Nonrenal fluid loss

–

30 20

20

10

10

+

0

0 0

Arterial pressure

+

Kidney volume output

Rate of change of extracellular fluid volume

–

Total peripheral resistance

+

30

Extracellular fluid volume +

Central blood volume

Peripheral blood volume +

+ Cardiac output

+

10 20 ECF volume, L

Intersititial volume, L (with low albumin)

30

+ Venous return

Mean circulatory filling pressure

FIGURE 2-34 Mechanisms of sodium (Na) retention in cirrhosis. A primary decrease in systemic vascular resistance (indicated by dark blue arrow), induced by mediators shown in Figure 2-31, leads to a decrease in arterial pressure. The reduction in systemic vascular resistance, however, is not uniform and favors movement of blood from the central (“effective”) circulation into the peripheral circulation, as shown in Figure 2-32. Hypoalbuminemia shifts the interstitial to blood volume ratio upward (compare the interstitial volume with normal [dashed line], and low [solid line], protein levels in the inset graph). Because cardiac output increases and venous return must equal cardiac output, dramatic expansion of the extracellular fluid (ECF) volume occurs.

Mechanisms of Extracellular Fluid Volume Expansion in Nephrotic Syndrome FIGURE 2-35 Changes in plasma protein concentration affect the net oncotic pressure difference across capillaries (c - i) in humans. Note that moderate reductions in plasma protein concentration have little effect on differences in transcapillary oncotic pressure. Only when plasma protein concentration decreases below 5 g/dL do changes become significant. (Data from Fadnes and coworkers [69].)

14

C - i, mmHg

12 10 8 6 4 2 0

2 4 6 8 Plasma protein concentration, g/dL

2.18

Disorders of Water, Electrolytes, and Acid-Base

300

20

35

30

30 15

10

150 100

5

ANP

25

25

20

20 15 15 10

10

50

5

5 0

0 -6

-5

-4 -3

-2

-1 0 Days

1

2

3

4

5

6

20 mEq 300 mEq Controls

100

100 Control PAN

80

60

60

40

40

20

20

0

0 Proximal

Loop

Distal

CD (*)

Fractional absorption, %

80

GFR

0

0

FIGURE 2-36 Time course of recovery from minimal change nephrotic syndrome in five children. Note that urinary Na excretion (squares) increases before serum albumin concentration increases. The data suggest that the natriuresis reflects a change in intrinsic renal Na retention. The data also emphasize that factors other than hypoalbuminemia must contribute to the Na retention that occurs in nephrosis. UNaV—urinary Na excretion volume. (Data from Oliver and Owings [70].)

GFR, % of control

ANP, fmol/mL

200

PRA, ng/L × sec

250 Albumin, g/L ( )

UNaV, mmol/24 hrs ( )

PRA

AGN

NS

FIGURE 2-37 Plasma renin activity (PRA) and atrial natriuretic peptide (ANP) concentration in the nephrotic syndrome. Shown are PRA and ANP concentration (standard error) in normal persons ingesting diets high (300 mEq/d) and low (20 mEq/d) in sodium (Na) and in patients with acute glomerulonephritis (AGN), predominantly poststreptococcal, or nephrotic syndrome (NS). Note that PRA is suppressed in patients with AGN to levels below those in normal persons on diets high in Na. PRA suppression suggests that primary renal NaCl retention plays an important role in the pathogenesis of volume expansion in AGN. Although plasma renin activity in patients with nephrotic syndrome is not suppressed to the same degree, the absence of PRA elevation in these patients suggests that primary renal Na retention plays a significant role in the pathogenesis of Na retention in NS as well. (Data from Rodrígeuez-Iturbe and coworkers [71].) FIGURE 2-38 Sites of sodium (Na) reabsorption along the nephron in control and nephrotic rats (induced by puromycin aminonucleoside [PAN]). The glomerular filtration rates (GFR) in normal and nephrotic rats are shown by the hatched bars. Note the modest reduction in GFR in the nephrotic group, a finding that is common in human nephrosis. Fractional reabsorption rates along the proximal tubule, the loop of Henle, and the superficial distal tubule are indicated. The fractional reabsorption along the collecting duct (CD) is estimated from the difference between the end distal and urine deliveries. The data suggest that the predominant site of increased reabsorption is the collecting duct. Because superficial and deep nephrons may differ in reabsorptive rates, these data would also be consistent with enhanced reabsorption by deep nephrons. Asterisk—data inferred from the difference between distal and urine samples. (Data from Ichikawa and coworkers [72].)

Disorders of Sodium Balance

Blood volume, L

+

Fluid intake

Net volume intake

Nonrenal fluid loss

– +

30 20

20

10

10

0

0 0

+

Arterial pressure

Kidney volume output

–

Rate of change of extracellular fluid volume

+

10 20 ECF volume, L Extracellular fluid volume +

Total peripheral resistance

+

Blood volume +

+ Cardiac output

+ Venous return

Mean circulatory filling pressure

30

Intersititial volume, L

30

2.19

FIGURE 2-39 Mechanisms of extracellular fluid (ECF) volume expansion in nephrotic syndrome. Nephrotic syndrome is characterized by hypoalbuminemia, which shifts the relation between blood and interstitial volume upward (dashed to solid lines in inset). As discussed in Figure 2-35, these effects of hypoalbuminemia are evident when serum albumin concentrations decrease by more than half. In addition, however, hypoalbuminemia may induce vasodilation and arterial hypotension that lead to sodium (Na) retention, independent of transudation of fluid into the interstitium [73,74]. Unlike other states of hypoproteinemia and vasodilation, however, nephrotic syndrome usually is associated with normotension or hypertension. Coupled with the observation made in Figure 2-36 that natriuresis may take place before increases in serum albumin concentration in patients with nephrotic syndrome, these data implicate an important role for primary renal Na retention in this disorder (dark blue arrow). As suggested by Figure 237, the decrease in urinary Na excretion may play a larger role in patients with acute glomerulonephritis than in patients with minimal change nephropathy [71].

Extracellular Fluid Volume Homeostasis in Chronic Renal Failure FIGURE 2-40 Relation between glomerular filtration rate (GFR) and fractional sodium (Na) excretion (FENa). The normal FENa is less than 1%. Adaptations in chronic renal failure maintain urinary Na excretion equal to dietary intake until end-stage renal disease is reached. To achieve this, the FENa must increase as the GFR decreases.

35 30 FENA, %

25 20 15 10 5 0 0

20

40 60 80 GFR, mL/min

100 120

2.20

Disorders of Water, Electrolytes, and Acid-Base

18

15

Normal

14

Mild CRF Severe CRF

17

13 12 11 10

15

9 8

14

7 13

6

Dietary sodium intake, g

ECF volume, L

16

5

12

4

FIGURE 2-41 Effects of dietary sodium (Na) intake on extracellular fluid (ECF) volume in chronic renal failure (CRF) [75]. Compared with normal persons, patients with CRF have expanded ECF volume at normal Na intake. Furthermore, the time necessary to return to neutral balance on shifting from one to another level of Na intake is increased. Thus, whereas urinary Na excretion equals dietary intake of Na within 3 to 5 days in normal persons, this process may take up to 2 weeks in patients with CRF. This time delay means that not only are these patients susceptible to volume overload, but also to volume depletion. This phenomenon can be modeled simply by reducing the time constant (k) given in the equation in Figure 2-2, and leaving the set point (A0) unchanged. The curves here represent time constants of 0.79 ±0.05 day-1 (normal), 0.5 day-1 (mild CRF), and 0.25 day-1 (severe CRF).

3 2

11

1

10 0

5

10

15

20

25

Days

References 1.

Walser M: Phenomenological analysis of renal regulation of sodium and potassium balance. Kidney Int 1985, 27:837–841.

12. Briggs JP: Whys and the wherefores of juxtaglomerular apparatus functions.Kidney Int 1996, 49:1724–1726.

2.

Simpson FO: Sodium intake, body sodium, and sodium excretion. Lancet 1990, 2:25–29.

3.

Luft FC, Weinberger MH, Grim CE: Sodium sensitivity and resistance in normotensive humans. Am J Med 1982, 72:726–736.

13. Barajas L: Architecture of the juxtaglomerular apparatus. In Hypertension: Pathophysiology, Diagnosis and Treatment. Edited by Laragh JH, Brenner BM. New York: Raven Press; 1990:XX–XX.

4.

Guyton AC: Blood pressure control: special role of the kidneys and body fluids. Science 1991, 252:1813–1816.

5.

Lassiter WE: Regulation of sodium chloride distribution within the extracellular space. In The Regulation of Sodium and Chloride Balance. Edited by Seldin DW, Giebisch G. New York: Raven Press; 1990:23–58.

6.

Hall JE, Jackson TE: The basic kidney-blood volume-pressure regulatory system: the pressure diuresis and natriuresis phenomena. In Arterial Pressure and Hypertension. Edited by Guyton AC. Philadelphia: WB Saunders Co, 1998:87–99.

7.

Gonzalez-Campoy JM, Knox FG: Integrated responses of the kidney to alterations in extracellular fluid volume. In The Kidney: Physiology and Pathophysiology, edn 2. Edited by Seldin DW, Giebisch G. New York: Raven Press; 1992:2041–2097.

14. Skott O, Briggs JP: Direct demonstration of macula densa mediated renin secretion. Science 1987, 237:1618–1620. 15. Hall JE, Guyton AC: Changes in renal hemodynamics and renin release caused by increased plasma oncotic pressure. Am J Physiol 1976, 231:1550. 16. Bachmann S, Bosse HM, Mundel P: Topography of nitric oxide synthesis by localizing constitutive NO synthetases in mammalian kidney. Am J Physiol 1995, 268:F885–F898. 17. Johnson RA, Freeman RH: Renin release in rats during blockade of nitric oxide synthesis. Am J Physiol 1994, 266:R1723–R1729. 18. Schricker K, Hegyi I, Hamann M, et al.: Tonic stimulation of renin gene expression by nitric oxide is counteracted by tonic inhibition through angiotensin II. Proc Natl Acad Sci USA 1995, 92:8006–8010. 19. Funder JW: Mineralocorticoids, glucocorticoids, receptors and response elements. Science 1993, 259:1132–1133.

8.

Hall JE, Brands MW: The renin-angiotensin-aldosterone systems. In The Kidney: Physiology and Pathophysiology, edn 2. Edited by Seldin DW, Giebisch G. New York: Raven Press; 1992:1455–1504.

20. Náray-Fejes-Tóth A, Fejes-Tóth G: Glucocorticoid receptors mediate mineralocorticoid-like effects in cultured collecting duct cells. Am J Physiol Renal Fluid Electrolyte Physiol 1990, 259:F672–F678.

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Laragh JH, Sealey JE: The intergrated regulation of electrolyte balance and blood pressure by the renin system. In The Regulation of Sodium and Chloride Balance. Edited by Seldin DW, Giebisch G. New York: Raven Press, 1990:133–193.

21. Mune T, Rogerson FM, Nikkila H, et al.: Human hypertension caused by mutations in the kidney isozyme of 11*beta*-hydroxysteroid dehydrogenase. Nature Genet 1995, 10:394–399.

10. Obermüller N, Kunchaparty S, Ellison DH, Bachmann S: Expression of the Na-K-2Cl cotransporter by macula densa and thick ascending limb cells of rat and rabbit nephron. J Clin Invest 1996, 98:635–640.

22. Hollander W, Judson WE: The relationship of cardiovascular and renal hemodynamic function to sodium excretion in patients with severe heart disease but without edema. J Clin Invest 1956, 35:970–979.

11. Lapointe J-Y, Bell PD, Cardinal J: Direct evidence for apical Na+:2Cl:K+ cotransport in macula densa cells. Am J Physiol 1990, 258:F1466–F1469.

23. Brenner BM, Ballermann BJ, Gunning ME, Zeidel ML: Diverse biological actions of atrial natriuretic peptide. Physiol Rev 1990, 70:665–700.

Disorders of Sodium Balance 24. Kishimoto I, Dubois SK, Garbers DL: The heart communicates with the kidney exclusively through the guanylyl cyclase-A receptor: Acute handling of sodium and water in response to volume expansion. Proc Natl Acad Sci USA 1996, 93:6215–6219. 25. Korner PI: Integrative neural cardiovascular control. Physiol Rev 1971, 51:312–367. 26. Cogan MG: Neurogenic regulation of proximal bicarbonate and chloride reabsorption. Am J Physiol 1986, 250:F22–F26. 27. Geibel J, Giebisch G, Boron WF: Angiotensin II stimulates both Na+H+ exchange and Na+/HCO-3 cotransport in the rabbit proximal tubule. Proc Natl Acad Sci USA 1990, 87:7917–7920. 28. Block RD, Zikos D, Fisher KA, et al.: Peterson DR: Activation of proximal tubular Na+-H+ exchanger by angiotensin II. Am J Physiol 1992, 263:F135–F143. 29. Bertorello A, Aperia A: Regulation of Na+-K+-ATPase activity in kidney proximal tubules: involvement of GTP binding proteins. Am J Physiol 1989, 256:F57–F62. 30. Aperia AC: Regulation of sodium transport. Curr Opinion Nephrol Hypertens 1995, 4:416–420. 31. Bouby N, Bankir L, Trinh-Trang-Tan MM, et al.: Selective ADHinduced hypertrophy of the medullary thick ascending limb in Brattleboro rats. Kidney Int 1985, 28:456–466. 32. Chabardès D, Gagnan-Brunette M, Imbert-Tébol M: Adenylate cyclase responsiveness to hormones in various portions of the human nephron. J Clin Invest 1980, 65:439–448. 33. Stokes JB: Effects of prostaglandin E2 on chloride transport across the rabbit thick ascending limb of Henle. J Clin Invest 1979, 64:495–502. 34. Escalante B, Erlij D, Falck JR, McGiff JC: Effect of cytochrome P450 arachidonate metabolites on ion transport in rabbit kidney loop of Henle. Science 1991, 251:799–802. 35. Amlal H, Legoff C, Vernimmen C, et al.: Na(+)-K+(NH4+)-2Clcotransport in medullary thick ascending limb: control by PKA, PKC, and 20-HETE. Am J Physiol 1996, 271:C455–C463. 36. Culpepper RM, Adreoli TE: Interactions among prostaglandin E2, antidiuretic hormone and cyclic adenosine monophosphate in modulating Cl- absorption in single mouse medullary thick ascending limbs of Henle. J Clin Invest 1983, 71:1588–1601. 37. Ecelbarger CA, Terris J, Hoyer JR, et al.: Localization and regulation of the rat renal Na+-K+-2Cl-, cotransporter, BSC-1. Am J Physiol Renal Fluid Electrolyte Physiol 1996, 271:F619–F628. 38. Chen Z, Vaughn DA, Blakeley P, Fanestil DD: Adrenocortical steroids increase renal thiazide diuretic receptor density and response. J Am Soc Nephrol 1994, 5:1361–1368. 39. Velázquez H, Bartiss A, Bernstein PL, Ellison DH: Adrenal steroids stimulate thiazide-sensitive NaCl transport by the rat renal distal tubule. Am J Physiol 1996, 39:F211–F219. 40. Wang T, Giebisch G: Effects of angiotensin II on electrolyte transport in the early and late distal tubule in rat kidney. Am J Physiol Renal Fluid Electrolyte Physiol 1996, 271:F143–F149. 41. Wang T, Chan YL: Neural control of distal tubular bicarbonate and fluid transport. Am J Physiol 1989, 257:F72–F76. 42. Bencsáth P, Szénási G, Takács L: Water and electrolyte transport in Henle’s loop and distal tubule after renal sympathectomy in the rat. Am J Physiol 1985, 249:F308–F314. 43. Rossier BC, Palmer LG: Mechanisms of aldosterone action on sodium and potassium transport. In The Kidney: Physiology and Pathophysiology, edn 2. Edited by Seldin DW, Giebisch G. New York: Raven Press, 1992:1373–1409. 44. Breyer MD, Ando Y: Hormonal signalling and regulation of salt and water transport in the collecting duct. Ann Rev Physiol 1994, 56:711–739. 45. Schafer JA, Hawk CT: Regulation of Na+ channels in the cortical collecting duct by AVP and mineralocorticoids. Int Kidney 1992, 41:255–268.

2.21

46. Kudo LH, Van Baak AA, Rocha AS: Effects of vasopressin on sodium transport across inner medullary collecting duct. Am J Physiol 1990, 258:F1438–F1447. 47. Nielsen S, Chou C-L, Marples D, et al.: Vasopressin increases water permeability of kidney collecting duct by inducing translocation of aquaporin: CD water channels to plasma membrane. Proc Natl Acad Sci USA 1995, 92:1013–1017. 48. Schafer JA: Salt and water homeostasis: Is it just a matter of good bookkeeping? J Am Soc Nephrol 1994, 4:1933–1950. 49. Husted RF, Laplace JR, Stokes JB: Enhancement of electrogenic Na+ transport across rat inner medullary collecting duct cells in culture. J Clin Invest 1990, 86:498–506. 50. Zeidel ML, Jabs K, Kikeri D, Silva P: Kinins inhibit conductive Na+ uptake by rabbit inner medullary collecting duct cells. Am J Physiol Renal Fluid Electrolyte Physiol 1990, 258:F1584–F1591. 51. Zeidel ML: Hormonal regulation of inner medullary collecting duct sodium transport. Am J Physiol Renal Fluid Electrolyte Physiol 1993, 265:F159–F173. 52. Light DB, Ausiello DA, Stanton BA: Guanine nucleotide-binding protein, i  3, directly activates a cation channel in rat renal inner medullary collecting duct cells. J Clin Invest 1989, 84:352–356. 53. Light DB, Schwiebert EM, Karlson KH, Stanton BA: Atrial natriuretic peptide inhibits a cation channel in renal inner medullary collecting duct cells. Science 1989, 243:383–385. 54. Hostetter TH, Pfeffer JM, Pfeffer MA, et al.: Cardiorenal hemodynamics and sodium excretion in rats with myocardial dysfunction. Am J Physiol 1983, 245:H98–H103. 55. Villarreal D, Freeman RH, Brands MW: DOCA administration and atrial natriuretic factor in dogs with chronic heart failure. Am J Physiol 1989, 257:H739–H745. 56. Villarreal D, Freeman RH, Davis JO, et al.: Atrial natriuretic factor secretion in dogs with experimental high-output heart failure. Am J Physiol 1987, 252:H692–H696. 57. Levy M, Allotey JBK: Temporal relationsips between urinary salt retention and altered systemic hemodynamics in dogs with experimental cirrhosis. J Lab Clin Med 1978, 92:560–569. 58. Levy M: Sodium retention and ascites formation in dogs with experimental portal cirrhosis. Am J Physiol 1977, 233:F572–F585. 59. Villarreal D, Freeman RH, Johnson RA: Neurohumoral modulators and sodium balance in experimental heart failure. Am J Physiol Heart Circ Physiol 1993, 264:H1187–H1193. 60. Awazu M, Ichikawa I: Alterations in renal function in experimental congestive heart failure. Sem Nephrology 1994, 14:401–411. 61. Redfield MM, Edwards BS, Heublein DM, Burnett JC Jr: Restoration of renal response to atrial natriuretic factor in experimental low-output heart failure. Am J Physiol 1989, 257:R917–R923. 62. Manning RD Jr, Coleman TG, Samar RE: Autoregulation, cardiac output, total peripheral resistance and the “quantitative cascade” of the kidney-blood volume system for pressure control. In Arterial Pressure and Hypertension. Edited by Guyton AC. Philadelphia: WB Saunders Co; 1980:139–155. 63. Albillos A, Colombato LA, Groszmann RJ: Vasodilation and sodium retention in prehepatic portal hypertension. Gastroenterology 1992, 102:931–935. 64. Møller S, Henriksen JH: Circulatory abnormalities in cirrhosis with focus on neurohumoral aspects. Sem Nephrol 1997, 17:505–519. 65. Hillarp A, Zöller B, Dahlbäck M: Activated protein C resistance as a basis for venous thrombosis. Am J Med 1996, 101:534–540. 66. Niederberger M, Martin P-Y, Ginès P, et al.: Normalization of nitric oxide production corrects arterial vasodilation and hyperdynamic circulation in cirrhotic rats. Gastroenterology 1995, 109:1624–1630.

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67. Niederberger M, Ginès P, Tsai P, et al.: Increased aortic cyclic guanosine monophosphate concentration in experimental cirrhosis in rats: evidence for a role of nitric oxide in the pathogenesis of arterial vasodilation in cirrhosis. Hepatology 1995, 21:1625–1631. 68. Martin P-Y, Schrier RW: Pathogenesis of water and sodium retention in cirrhosis. Kidney Int 1997, 51(suppl 59):S-43–S-49. 69. Fadnes HO, Pape JF, Sundsfjord JA: A study on oedema mechanism in nephrotic syndrome. Scand J Clin Lab Invest 1986, 46:533–538. 70. Oliver WJ, Owings CL: Sodium excretion in the nephrotic syndrome: relation to serum albumin concentration, glomerular filtration rate, and aldosterone secretion rate. Am J Dis Child 1967, 113:352–362.

71. Rodrígeuez-Iturbe B, Colic D, Parra G, Gutkowska J: Atrial natriuretic factor in the acute nephritic and nephrotic syndromes. Kidney Int 1990, 38:512–517. 72. Ichikawa I, Rennke HG, Hoyer JR, et al.: Role for intrarenal mechanisms in the impaired salt excretion of experimental nephrotic syndrome. J Clin Invest 1983, 71:91–103. 73. Manning RD Jr: Effects of hypoproteinemia on renal hemodynamics, arterial pressure, and fluid volume. Am J Physiol 1997, 252:F91–F98. 74. Manning RD Jr, Guyton AC: Effects of hypoproteinemia on fluid volumes and arterial pressure. Am J Physiol 1983, 245:H284–H293. 75. Mitch WE, Wilcox CS: Disorders of body fluids, sodium and potassium in chronic renal failure. Am J Med 1982, 72:536–550.

Disorders of Potassium Metabolism Fredrick V. Osorio Stuart L. Linas

P

otassium, the most abundant cation in the human body, regulates intracellular enzyme function and neuromuscular tissue excitability. Serum potassium is normally maintained within the narrow range of 3.5 to 5.5 mEq/L. The intracellular-extracellular potassium ratio (Ki/Ke) largely determines neuromuscular tissue excitability [1]. Because only a small portion of potassium is extracellular, neuromuscular tissue excitability is markedly affected by small changes in extracellular potassium. Thus, the body has developed elaborate regulatory mechanisms to maintain potassium homeostasis. Because dietary potassium intake is sporadic and it cannot be rapidly excreted renally, short-term potassium homeostasis occurs via transcellular potassium shifts [2]. Ultimately, long-term maintenance of potassium balance depends on renal excretion of ingested potassium. The illustrations in this chapter review normal transcellular potassium homeostasis as well as mechanisms of renal potassium excretion. With an understanding of normal potassium balance, disorders of potassium metabolism can be grouped into those that are due to altered intake, altered excretion, and abnormal transcellular distribution. The diagnostic algorithms that follow allow the reader to limit the potential causes of hyperkalemia and hypokalemia and to reach a diagnosis as efficiently as possible. Finally, clinical manifestations of disorders of potassium metabolism are reviewed, and treatment algorithms for hypokalemia and hyperkalemia are offered. Recently, the molecular defects responsible for a variety of diseases associated with disordered potassium metabolism have been discovered [3–8]. Hypokalemia and Liddle’s syndrome [3] and hyperkalemia and pseudohypoaldosteronism type I [4] result from mutations at different sites on the epithelial sodium channel in the distal tubules. The hypokalemia of Bartter’s syndrome can be accounted for by two separate ion transporter defects in the thick ascending limb of Henle’s loop [5]. Gitelman’s syndrome, a clinical variant of Bartter’s

CHAPTER

3

3.2

Disorders of Water, Electrolytes, and Acid-Base

syndrome, is caused by a mutation in an ion cotransporter in a completely different segment of the renal tubule [6]. The genetic mutations responsible for hypokalemia in the syndrome of

apparent mineralocorticoid excess [7] and glucocorticoidremediable aldosteronism [8] have recently been elucidated and are illustrated below.

Overview of Potassium Physiology PHYSIOLOGY OF POTASSIUM BALANCE: DISTRIBUTION OF POTASSIUM ECF 350 mEq (10%)

ICF 3150 mEq (90%)

Plasma 15 mEq (0.4%) Interstitial fluid 35 mEq (1%) Bone 300 mEq (8.6%) [K+] = 3.5–5.0 mEq/L Urine 90–95 mEq/d Stool 5–10mEq/d Sweat < 5 mEq/d

Muscle 2650 mEq (76%) Liver 250 mEq (7%) Erythrocytes 250 mEq (7%) [K+] = 140–150 mEq/L Urine 90–95 mEq/d Stool 5–10mEq/d Sweat < 5 mEq/d

FIGURE 3-2 Factors that cause transcellular potassium shifts.

FACTORS CAUSING TRANSCELLULAR POTASSIUM SHIFTS Factor Acid-base status Metabolic acidosis Hyperchloremic acidosis Organic acidosis Respiratory acidosis Metabolic alkalosis Respiratory alkalosis Pancreatic hormones Insulin Glucagon Catecholamines -Adrenergic -Adrenergic Hyperosmolarity Aldosterone Exercise

FIGURE 3-1 External balance and distribution of potassium. The usual Western diet contains approximately 100 mEq of potassium per day. Under normal circumstances, renal excretion accounts for approximately 90% of daily potassium elimination, the remainder being excreted in stool and (a negligible amount) in sweat. About 90% of total body potassium is located in the intracellular fluid (ICF), the majority in muscle. Although the extracellular fluid (ECF) contains about 10% of total body potassium, less than 1% is located in the plasma [9]. Thus, disorders of potassium metabolism can be classified as those that are due 1) to altered intake, 2) to altered elimination, or 3) to deranged transcellular potassium shifts.

 Plasma K+

↑↑ ↔ ↑ ↓ ↓ ↓↓ ↑ ↓ ↑ ↑ ↓, ↔ ↑

Diseases of Potassium Metabolism

3.3

FIGURE 3-3 Extrarenal potassium homeostasis: insulin and catecholamines. Schematic representation of the cellular mechanisms by which insulin and -adrenergic stimulation promote potassium uptake by extrarenal tissues. Insulin binding to its receptor results in hyperpolarization of cell membranes (1), which facilitates potassium uptake. After binding to its receptor, insulin also activates Na+-K+-ATPase pumps, resulting in cellular uptake of potassium (2). The second messenger that mediates this effect has not yet been identified. Catecholamines stimulate cellular potassium uptake via the 2 adrenergic receptor (2R). The generation of cyclic adenosine monophosphate (3, 5 cAMP) activates Na+-K+-ATPase pumps (3), causing an influx of potassium in exchange for sodium [10]. By inhibiting the degradation of cyclic AMP, theophylline potentiates catecholaminestimulated potassium uptake, resulting in hypokalemia (4).

FIGURE 3-4 Renal potassium handling. More than half of filtered potassium is passively reabsorbed by the end of the proximal convolted tubule (PCT). Potassium is then added to tubular fluid in the descending limb of Henle’s loop (see below). The major site of active potassium reabsorption is the thick ascending limb of the loop of Henle (TAL), so that, by the end of the distal convoluted tubule (DCT), only 10% to 15% of filtered potassium remains in the tubule lumen. Potassium is secreted mainly by the principal cells of the cortical collecting duct (CCD) and outer medullary collecting duct (OMCD). Potassium reabsorption occurs via the intercalated cells of the medullary collecting duct (MCD). Urinary potassium represents the difference between potassium secreted and potassium reabsorbed [11]. During states of total body potassium depletion, potassium reabsorption is enhanced. Reabsorbed potassium initially enters the medullary interstitium, but then it is secreted into the pars recta (PR) and descending limb of the loop of Henle (TDL). The physiologic role of medullary potassium recycling may be to minimize potassium “backleak” out of the collecting tubule lumen or to enhance renal potassium secretion during states of excess total body potassium [12]. The percentage of filtered potassium remaining in the tubule lumen is indicated in the corresponding nephron segment.

3.4

Disorders of Water, Electrolytes, and Acid-Base

FIGURE 3-5 Cellular mechanisms of renal potassium transport: proximal tubule and thick ascending limb. A, Proximal tubule potassium reabsorption is closely coupled to proximal sodium and water transport. Potassium is reabsorbed through both paracellular and cellular pathways. Proximal apical potassium channels are normally almost completely closed. The lumen of the proximal tubule is negative in the early proximal tubule and positive in late proximal tubule segments. Potassium transport is not specifically regulated in this portion of the nephron, but net potassium reabsorption is closely coupled to sodium and water reabsorption. B, In the thick ascending limb of Henle’s loop, potassium reabsorption proceeds by electroneutral Na+-K+-2Cl- cotransport in the thick ascending limb, the low intracellular sodium and chloride concentrations providing the driving force for transport. In addition, the positive lumen potential allows some portion of luminal potassium to be reabsorbed via paracellular pathways [11]. The apical potassium channel allows potassium recycling and provides substrate to the apical Na+-K+-2Cl- cotransporter [12]. Loop diuretics act by competing for the Cl- site on this carrier.

FIGURE 3-6 Cellular mechanisms of renal potassium transport: cortical collecting tubule. A, Principal cells of the cortical collecting duct: apical sodium channels play a key role in potassium secretion by increasing the intracellular sodium available to Na+-K+-ATPase pumps and by creating a favorable electrical potential for potassium secretion. Basolateral Na+-K+-ATPase creates a favorable concentration gradient for passive diffusion of potassium from cell to lumen through potassium-selective channels. B, Intercalated cells. Under conditions of potassium depletion, the cortical collecting duct becomes a site for net potassium reabsorption. The H+-K+-ATPase pump is regulated by potassium intake. Decreases in total body potassium increase pump activity, resulting in enhanced potassium reabsorption. This pump may be partly responsible for the maintenance of metabolic alkalosis in conditions of potassium depletion [11].

Diseases of Potassium Metabolism

3.5

Hypokalemia: Diagnostic Approach

FIGURE 3-7 Overview of diagnostic approach to hypokalemia: hypokalemia without total body potassium depletion. Hypokalemia can result from transcellular shifts of potassium into cells without total body potassium depletion or from decreases in total body potassium. Perhaps the most dramatic examples occur in catecholamine excess states, as after administration of 2adreneric receptor (2AR) agonists or during “stress.” It is important to note

that, during some conditions (eg, ketoacidosis), transcellular shifts and potassium depletion exist simultaneously. Spurious hypokalemia results when blood specimens from leukemia patients are allowed to stand at room temperature; this results in leukocyte uptake of potassium from serum and artifactual hypokalemia. Patients with spurious hypokalemia do not have clinical manifestations of hypokalemia, as their in vivo serum potassium values are normal. Theophylline poisoning prevents cAMP breakdown (see Fig. 3-3). Barium poisoning from the ingestion of soluble barium salts results in severe hypokalemia by blocking channels for exit of potassium from cells. Episodes of hypokalemic periodic paralysis can be precipitated by rest after exercise, carbohydrate meal, stress, or administration of insulin. Hypokalemic periodic paralysis can be inherited as an autosomal-dominant disease or acquired by patients with thyrotoxicosis, especially Chinese males. Therapy of megaloblastic anemia is associated with potassium uptake by newly formed cells, which is occasionally of sufficient magnitude to cause hypokalemia [13].

FIGURE 3-8 Diagnostic approach to hypokalemia: hypokalemia with total body potassium depletion secondary to extrarenal losses. In the absence of redistribution, measurement of urinary potassium is helpful in determining whether hypokalemia is due to renal or to extrarenal potassium losses. The normal kidney responds to several (3 to 5) days of potassium depletion with appropriate renal potassium conservation. In the absence of severe polyuria, a “spot” urinary potassium

concentration of less than 20 mEq/L indicates renal potassium conservation. In certain circumstances (eg, diuretics abuse), renal potassium losses may not be evident once the stimulus for renal potassium wasting is removed. In this circumstance, urinary potassium concentrations may be deceptively low despite renal potassium losses. Hypokalemia due to colonic villous adenoma or laxative abuse may be associated with metabolic acidosis, alkalosis, or no acid-base disturbance. Stool has a relatively high potassium content, and fecal potassium losses could exceed 100 mEq per day with severe diarrhea. Habitual ingestion of clay (pica), encountered in some parts of the rural southeastern United States, can result in potassium depletion by binding potassium in the gut, much as a cation exchange resin does. Inadequate dietary intake of potassium, like that associated ith anorexia or a “tea and toast” diet, can lead to hypokalemia, owing to delayed renal conservation of potassium; however, progressive potassium depletion does not occur unless intake is well below 15 mEq of potassium per day.

3.6

Disorders of Water, Electrolytes, and Acid-Base

FIGURE 3-9 Diagnostic approach to hypokalemia: hypokalemia due to renal losses with normal acidbase status or metabolic acidosis. Hypokalemia is occasionally observed during the diuretic recovery phase of acute tubular necrosis (ATN) or after relief of acute obstructive

uropathy, presumably secondary to increased delivery of sodium and water to the distal nephrons. Patients with acute monocytic and myelomonocytic leukemias occasionally excrete large amounts of lysozyme in their urine. Lysozyme appears to have a direct kaliuretic effect on the kidneys (by an undefined mechanism). Penicillin in large doses acts as a poorly reabsorbable anion, resulting in obligate renal potassium wasting. Mechanisms for renal potassium wasting associated with aminoglycosides and cisplatin are illdefined. Hypokalemia in type I renal tubular acidosis is due in part to secondary hyperaldosteronism, whereas type II renal tubular acidosis can result in a defect in potassium reabsorption in the proximal nephrons. Carbonic anhydrase inhibitors result in an acquired form of renal tubular acidosis. Ureterosigmoidostomy results in hypokalemia in 10% to 35% of patients, owing to the sigmoid colon’s capacity for net potassium secretion. The osmotic diuresis associated with diabetic ketoacidosis results in potassium depletion, although patients may initially present with a normal serum potassium value, owing to altered transcellular potassium distribution.

FIGURE 3-10 Hypokalemia and magnesium depletion. Hypokalemia and magnesium depletion can occur concurrently in a variety of clinical settings, including diuretic therapy, ketoacidosis, aminoglycoside therapy, and prolonged osmotic diuresis (as with poorly controlled diabetes mellitus). Hypokalemia is also a common finding in patients with congenital magnesium-losing kidney disease. The patient depicted was treated with cisplatin 2 months before presentation. Attempts at oral and intravenous potassium replacement of up to 80 mEq/day were unsuccessful in correcting the hypokalemia. Once serum magnesium was corrected, however, serum potassium quickly normalized [14].

Diseases of Potassium Metabolism

3.7

FIGURE 3-11 Diagnostic approach to hypokalemia: hypokalemia due to renal losses with metabolic alkalosis. The urine chloride value is helpful in distinguishing the causes of hypokalemia. Diuretics are a common cause of hypokalemia; however, after discontinuing diuretics, urinary potassium and chloride may be appropriately low. Urine diuretic screens are warranted for patients suspected of surreptious diuretic abuse. Vomiting results in chloride and sodium depletion, hyperaldosteronism, and renal potassium wasting. Posthypercapnic states are often associated with chloride depletion (from diuretics) and sodium avidity. If hypercapnia is corrected without replacing chloride, patients develop chloride-depletion alkalosis and hypokalemia.

FIGURE 3-12 Mechanisms of hypokalemia in Bartter’s syndrome and Gitelman’s syndrome. A, A defective Na+-K+-2Cl- cotransporter in the thick ascending limb (TAL) of Henle’s loop can account for virtually all features of Bartter’s syndrome. Since approximately 30% of filtered sodium is reabsorbed by this segment of the nephron, defective sodium reabsorption

results in salt wasting and elevated renin and aldosterone levels. The hyperaldosteronism and increased distal sodium delivery account for the characteristic hypokalemic metabolic alkalosis. Moreover, impaired sodium reabsorption in the TAL results in the hypercalciuria seen in these patients, as approximately 25% of filtered calcium is reabsorbed in this segment in a process coupled to sodium reabsorption. Since potassium levels in the TAL are much lower than levels of sodium or chloride, luminal potassium concentrations are rate limiting for Na+-K+-2Cl- co-transporter activity. Defects in ATP-sensitive potassium channels would be predicted to alter potassium recycling and diminish Na+-K+-2Cl- cotransporter activity. Recently, mutations in the gene that encodes for the Na+-K+-2Clcotransporter and the ATP-sensitive potassium channel have been described in kindreds with Bartter’s syndrome. Because loop diuretics interfere with the Na+-K+-2Clcotransporter, surrepititious diuretic abusers have a clinical presentation that is virtually indistinguishable from that of Bartter’s syndrome. B, Gitelman’s syndrome, which typically presents later in life and is associated with hypomagnesemia and hypocalciuria, is due to a defect in the gene encoding for the thiazide-sensitive Na+-Cl- cotransporter. The mild volume depletion results in more avid sodium and calcium reabsorption by the proximal nephrons.

3.8

Disorders of Water, Electrolytes, and Acid-Base

FIGURE 3-13 Diagnostic approach to hypokalemia: hypokalemia due to renal losses with hypertension and metabolic alkalosis. FIGURE 3-14 Distinguishing characteristics of hypokalemia associated with hypertension and metabolic alkalosis.

CHARACTERISTICS OF HYPOKALEMIA WITH HYPERTENSION AND METABOLIC ALKALOSIS

Primary aldosteronism 11 -hydroxysteroid dehydrogenase deficiency Glucocorticoid remediable aldosteronism Liddle’s syndrome

Aldosterone

Renin

Response to Dexamethasone

↑ ↓

↓ ↓

— +

↑

↓

+

↓→

↓

—

Diseases of Potassium Metabolism

3.9

FIGURE 3-15 Mechanism of hypokalemia in Liddle’s syndrome. The amiloridesensitive sodium channel on the apical membrane of the distal tubule consists of homologous , , and  subunits. Each subunit is composed of two transmembrane-spanning domains, an extracellular loop, and intracellular amino and carboxyl terminals. Truncation mutations of either the  or  subunit carboxyl terminal result in greatly increased sodium conductance, which creates a favorable electrochemical gradient for potassium secretion. Although patients with Liddle’s syndrome are not universally hypokalemic, they may exhibit severe potassium wasting with thiazide diuretics. The hypokalemia, hypertension, and metabolic alkalosis that typify Liddle’s syndrome can be corrected with amiloride or triamterene or restriction of sodium.

FIGURE 3-16 Mechanism of hypokalemia in the syndrome of apparent mineralocorticoid excess (AME). Cortisol and aldosterone have equal affinity for the intracellular mineralocorticoid receptor (MR); however, in aldosterone-sensitive tissues such as the kidney, the enzyme 11 -hydroxysteroid dehydrogenase (11 -HSD) converts cortisol to cortisone. Since cortisone has a low affinity for the MR, the enzyme 11 -HSD serves to protect the kidney from the effects of glucocorticoids. In hereditary or acquired AME, 11 -HSD is defective or is inactiveted (by licorice or carbenoxalone). Cortisol, which is present at concentrations approximately 1000-fold that of aldosterone, becomes a mineralocorticoid. The hypermineralocorticoid state results in increased transcription of subunits of the sodium channel and the Na+-K+-ATPase pump. The favorable electrochemical gradient then favors potassium secretion [7,15].

3.10

Disorders of Water, Electrolytes, and Acid-Base

FIGURE 3-17 Genetics of glucocorticoid-remediable aldosteronism (GRA): schematic representation of unequal crossover in GRA. The genes for aldosterone synthase (Aldo S) and 11 -hydroxylase (11 -OHase) are normally expressed in separate zones of the adrenal cortex. Aldosterone is

produced in the zona glomerulosa and cortisol, in the zona fasciculata. These enzymes have identical intron-extron structures and are closely linked on chromosome 8. If unequal crossover occurs, a new hybrid gene is produced that includes the 5’ segment of the 11 -OHase gene (ACTH-response element and the 11 -OHase segment) plus the 3’ segment of the Aldo S gene (aldosterone synthase segment). The chimeric gene is now under the contol of ACTH, and aldosterone secretion is enhanced, thus causing hypokalemia and hypertension. By inhibiting pituitary release of ACTH, glucocorticoid administration leads to a fall in aldosterone levels and correction of the clinical and biochemical abnormalities of GRA. The presence of Aldo S activity in the zona fasciculata gives rise to characteristic elevations in 18-oxidation products of cortisol (18-hydroxycortisol and 18-oxocortisol), which are diagnostic for GRA [8].

Hypokalemia: Clinical Manifestations CLINICAL MANIFESTATIONS OF HYPOKALEMIA Cardiovascular Abnormal electrocardiogram Predisposition for digitalis toxicity Atrial ventricular arrhythmias Hypertension Neuromuscular Smooth muscle Constipation/ileus Bladder dysfunction Skeletal muscle Weakness/cramps Tetany Paralysis Myalgias/rhabdomyolysis

Renal/electrolyte Functional alterations Decreased glomerular filtration rate Decreased renal blood flow Renal concentrating defect Increased renal ammonia production Chloride wasting Metabolic alkalosis Hypercalciuria Phosphaturia Structural alterations Dilation and vacuolization of proximal tubules Medullary cyst formation Interstitial nephritis Endocrine/metabolic Decreased insulin secretion Carbohydrate intolerance Increased renin Decreased aldosterone Altered prostaglandin synthesis Growth retardation

FIGURE 3-18 Clinical manifestations of hypokalemia.

FIGURE 3-19 Electrocardiographic changes associated with hypokalemia. A, The U wave may be a normal finding and is not specific for hypokalemia. B, When the amplitude of the U wave exceeds that of the T wave, hypokalemia may be present. The QT interval may appear to be prolonged; however, this is often due to mistaking the QU interval for the QT interval, as the latter does not change in duration with hypokalemia. C, Sagging of the ST segment, flattening of the T wave, and a prominent U wave are seen with progressive hypokalemia. D, The QRS complex may widen slightly, and the PR interval is often prolonged with severe hypokalemia. Hypokalemia promotes the appearance of supraventricular and ventricular ectopic rhythms, especially in patients taking digitalis [16].

Diseases of Potassium Metabolism

3.11

FIGURE 3-20 Renal lesions associated with hypokalemia. The predominant pathologic finding accompanying potassium depletion in humans is vacuolization of the epithelium of the proximal convoluted tubules. The vacoules are large and coarse, and staining for lipids is usually negative. The tubular vacuolation is reversible with sustained correction of the hypokalemia; however, in patients with long-standing hypokalemia, lymphocytic infiltration, interstitial scarring, and tubule atrophy have been described. Increased renal ammonia production may promote complement activation via the alternate pathway and can contribute to the interstitial nephritis [17,18].

Hypokalemia: Treatment FIGURE 3-21 Treatment of hypokalemia: estimation of potassium deficit. In the absence of stimuli that alter intracellular-extracellular potassium distribution, a decrease in the serum potassium concentration from 3.5 to 3.0 mEq/L corresponds to a 5% reduction (~175 mEq) in total body potassium stores. A decline from 3.0 to 2.0 mEq/L signifies an additional 200 to 400-mEq deficit. Factors such as the rapidity of the fall in serum potassium and the presence or absence of symptoms dictate the aggressiveness of replacement therapy. In general, hypokalemia due to intracellular shifts can be managed by treating the underlying condition (hyperinsulinemia, theophylline intoxication). Hypokalemic periodic paralysis and hypokalemia associated with myocardial infarction (secondary to endogenous -adrenergic agonist release) are best managed by potassium supplementation [19].

3.12

Disorders of Water, Electrolytes, and Acid-Base FIGURE 3-22 Treatment of hypokalemia.

Hyperkalemia: Diagnostic Approach

FIGURE 3-23 Approach to hyperkalemia: hyperkalemia without total body potassium excess. Spurious hyperkalemia is suggested by the absence of electrocardiographic (ECG) findings in patients with elevated serum potassium. The most common cause of spurious hyperkalemia is hemolysis, which may be apparent on visual inspection of serum. For patients with extreme leukocytosis or thrombocytosis, potassium levels should be measured in plasma samples that have been promptly separated from the cellular components since extreme elevations in

either leukocytes or platelets results in leakage of potassium from these cells. Familial pseudohyperkalemia is a rare condition of increased potassium efflux from red blood cells in vitro. Ischemia due to tight or prolonged tourniquet application or fist clenching increases serum potassium concentrations by as much as 1.0 to 1.6 mEq/L. Hyperkalemia can also result from decreases in K movement into cells or increases in potassium movement from cells. Hyperchloremic metabolic acidosis (in contrast to organic acid, anion-gap metabolic acidosis) causes potassium ions to flow out of cells. Hypertonic states induced by mannitol, hypertonic saline, or poor blood sugar control promote movement of water and potassium out of cells. Depolarizing muscle relaxants such as succinylcholine increase permeability of muscle cells and should be avoided by hyperkalemic patients. The mechanism of hyperkalemia with -adrenergic blockade is illustrated in Figure 3-3. Digitalis impairs function of the Na+-K+-ATPase pumps and blocks entry of potassium into cells. Acute fluoride intoxication can be treated with cation-exchange resins or dialysis, as attempts at shifting potassium back into cells may not be successful.

Diseases of Potassium Metabolism

3.13

FIGURE 3-24 Approach to hyperkalemia: hyperkalemia with reduced glomerular filtration rate (GFR). Normokalemia can be maintained in patients who consume normal quantities of potassium until GFR decreases to less than 10 mL/min; however, diminished GFR predisposes patients to hyperkalemia from excessive exogenous or endogenous potassium loads. Hidden sources of endogenous and exogenous potassium—and drugs that predispose to hyperkalemia—are listed.

FIGURE 3-25 Approach to hyperkalemia: hyporeninemic hypoaldosteronism. Hyporeninemic hypoaldosteronism accounts for the majority of cases of unexplained hyperkalemia in patients with reduced glomerular filtration rate (GFR) whose level of renal insufficiency is not what would be expected to cause hyperkalemia. Interstitial renal disease is a feature of most of the diseases listed. The transtubular potassium gradient (see Fig. 3-26) can be used to distinguish between primary tubule defects and hyporeninemic hypoaldosteronism. Although the transtubular potassium gradient should be low in both disorders, exogenous mineralocorticoid would normalize transtubular potassium gradient in hyporeninemic hypoaldosteronism.

3.14

Disorders of Water, Electrolytes, and Acid-Base FIGURE 3-26 Physiologic basis of the transtubular potassium concentration gradient (TTKG). Secretion of potassium in the cortical collecting duct and outer medullary collecting duct accounts for the vast majority of potassium excreted in the urine. Potassium secretion in these segments is influenced mainly by aldosterone, plasma potassium concentrations, and the anion composition of the fluid in the lumen. Use of the TTKG assumes that negligible amounts of potassium are secreted or reabsorbed distal to these sites. The final urinary potassium concentration then depends on water reabsorption in the medullary collecting ducts, which results in a rise in the final urinary potassium concentration without addition of significant amounts of potassium to the urine. The TTKG is calculated as follows: TTKG = ([K+]urine/(U/P)osm)/[K+]plasma The ratio of (U/P)osm allows for “correction” of the final urinary potassium concentration for the amount of water reabsorbed in the medullary collecting duct. In effect, the TTKG is an index of the gradient of potassium achieved at potassium secretory sites, independent of urine flow rate. The urine must at least be iso-osmolal with respect to serum if the TTKG is to be meaningful [20].

CAUSES FOR HYPERKALEMIA WITH AN INAPPROPRIATELY LOW TTKG THAT IS UNRESPONSIVE TO MINERALOCORTICOID CHALLENGE Potassium-sparing diuretics Amiloride Triamterene Spironolactone Tubular resistance to aldosterone Interstitial nephritis Sickle cell disease Urinary tract obstruction Pseudohypoaldosteronism type I Drugs Trimethoprim Pentamidine

Increased distal nephron potassium reabsorption Pseudohypoaldosteronism type II Urinary tract obstruction

FIGURE 3-27 Clinical application of the transtubular potassium gradient (TTKG). The TTKG in normal persons varies much but is genarally within the the range of 6 to 12. Hypokalemia from extrarenal causes results in renal potassium conservation and a TTKG less than 2. A higher value suggests renal potassium losses, as through hyperaldosteronism. The expected TTKG during hyperkalemia is greater than 10. An inappropriately low TTKG in a hyperkalemic patient suggests hypoaldosteronism or a renal tubule defect. Administration of the mineralocorticoid 9 -fludrocortisone (0.05 mg) should cause TTKG to rise above 7 in cases of hypoaldosteronism. Circumstances are listed in which the TTKG would not increase after mineralocorticoid challenge, because of tubular resistance to aldosterone [21].

Diseases of Potassium Metabolism

3.15

FIGURE 3-28 Approach to hyperkalemia: low aldosterone with normal to increased plasma renin. Heparin impairs aldosterone synthesis by inhibiting the enzyme 18-hydroxylase. Despite its frequent use, heparin is rarely associated with overt hyperkalemia; this suggests that other mechanisms (eg, reduced renal potassium secretion) must be present simultaneously for hyperkalemia to manifest itself. Both angiotensin-converting enzyme inhibitors and the angiotensin type 1 receptor blockers (AT1) receptor blockers interfere with adrenal aldosterone synthesis. Generalized impairment of adrenal cortical function manifested by combined glucocorticoid and mineralocorticoid deficiencies are seen in Addison’s disease and in defects of aldosterone biosynthesis.

FIGURE 3-29 Approach to hyperkalemia: pseudohypoaldosteronism. The mechanism of decreased potassium excretion is caused either by failure to secrete potassium in the cortical collecting tubule or enhanced reabsorption of potassium in the medullary or papillary collecting tubules. Decreased secretion of potassium in the cortical and medullary collecting duct results from decreases in either apical sodium or potassium channel function or diminished basolateral Na+-K+-ATPase activity. Alternatively, potassium may be secreted normally but hyperkalemia can develop because potassium reabsorption is enhanced in the intercalated cells of the medullary collecting duct (see Fig. 3-4). The transtubule potassium gradient (TTKG) in both situations is inappropriately low and fails to normalize in response to mineralocorticoid replacement.

3.16

Disorders of Water, Electrolytes, and Acid-Base FIGURE 3-30 Mechanism of hyperkalemia in pseudohypoaldosteronism type I (PHA I). This rare autosomally transmitted disease is characterized by neonatal dehydration, failure to thrive, hyponatremia, hyperkalemia, and metabolic acidosis. Kidney and adrenal function are normal, and patients do not respond to exogenous mineralocorticoids. Genetic mutations responsible for PHA I occur in the  and  subunits of the amiloride-sensitive sodium channel of the collecting tubule. Frameshift or premature stop codon mutations in the cytoplasmic amino terminal or extracellular loop of either subunit disrupt the integrity of the sodium channel and result in loss of channel activity. Failure to reabsorb sodium results in volume depletion and activation of the renin-aldosterone axis. Furthermore, since sodium reabsorption is indirectly coupled to potassium and hydrogen ion secretion, hyperkalemia and metabolic acidosis ensue. Interestingly, when mutations are introduced into the cytoplasmic carboxyl terminal, sodium channel activity is increased and Liddle’s syndrome is observed [4].

Hyperkalemia: Clinical Manifestations CLINICAL MANIFESTATIONS OF HYPERKALEMIA

Cardiac Abnormal electrocardiogram Atrial/ventricular arrhythmias Pacemaker dysfunction Neuromuscular Paresthesias Weakness Paralysis

Renal electrolyte Decreased renal NH4+ production Natriuresis Endocrine Increased aldosterone secretion Increased insulin secretion

FIGURE 3-31 Clinical manifestations of hyperkalemia.

Diseases of Potassium Metabolism

3.17

FIGURE 3-32 Electrocardiographic (ECG) changes associated with hyperkalemia. A, Normal ECG pattern. B, Peaked, narrow-based T waves are the earliest sign of hyperkalemia. C, The P wave broadens and the QRS complex widens when the plamsa potassium level is above 7 mEq/L. D, With higher elevations in potassium, the P wave becomes difficult to identify. E, Eventually, an undulating sinusoidal pattern is evident. Although the ECG changes are depicted here as correlating to the severity of hyperkalemia, patients with even mild ECG changes may abruptly progress to terminal rhythm disturbances. Thus, hyperkalemia with any ECG changes should be treated as an emergency.

Hyperkalemia: Treatment FIGURE 3-33 Treatment of hyperkalemia.

References 1. 2. 3.

MacNight ADC: Epithelial transport of potassium. Kidney Int 1977, 11:391–397. Bia MJ, DeFronzo RA: Extrarenal potassium homeostasis. Am J Physiol 1981, 240:F257–262. Hansson JH, Nelson-Williams C, Suzuki H, et al.: Hypertension caused by a truncated epithelial sodium channel gamma subunit: Genetic heterogeneity of Liddle’s syndrome. Nature Genetics 1995, 11:76–82.

4.

Chang SS, Grunder S, Hanukoglu A, et al.: Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalemic acidosis, pseudohypoaldosteronism type I. Nature Genetics 1996, 12:248–253.

5.

Simon DB, Karet FE, Rodriguez-Soriano J, et al.: Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the K+ channel, ROMK. Nature Genetics 1996, 14:152–156.

3.18 6.

7.

8.

9. 10.

11. 12. 13.

Disorders of Water, Electrolytes, and Acid-Base

Pollack MR, Delaney VB, Graham RM, Hebert SC. Gitelman’s syndrome (Bartter’s variant) maps to the thiazide-sensitive co-transporter gene locus on chromosome 16q13 in a large kindred. J Am Soc Nephrol 1996, 7:2244–2248. Sterwart PM, Krozowski ZS, Gupta A, et al.: Hypertension in the syndrome of apparent mineralocorticoid excess due to a mutation of the 11 (-hydroxysteroid dehydrogenase type 2 gene. Lancet 1996, 347:88–91. Pascoe L, Curnow KM, Slutsker L, et al.: Glucocorticoid suppressable hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2. Proc Natl Acad Sci USA 1992, 89:8237–8331. Welt LG, Blyth WB. Potassium in clinical medicine. In A Primer on Potassium Metabolism. Chicago: Searle & Co.; 1973. DeFronzo RA: Regulation of extrarenal potassium homeostasis by insulin and catecholamines. In Current Topics in Membranes and Transport, vol. 28. Edited by Giebisch G. San Diego: Academic Press; 1987:299–329. Giebisch G, Wang W: Potassium transport: from clearance to channels and pumps. Kidney Int 1996, 49:1642–1631. Jamison RL: Potassium recycling. Kidney Int 1987, 31:695–703. Nora NA, Berns AS: Hypokalemic, hypophosphatemic thyrotoxic periodic paralysis. Am J Kidney Dis 1989, 13:247–251.

14. Whang R, Flink EB, Dyckner T, et al.: Magnesium depletion as a cause of refractory potassium repletion. Arch Int Med 1985, 145:1686–1689. 15. Funder JW: Corticosteroid receptors and renal 11 -hydroxysteroid dehydrogenase activity. Semin Nephrol 1990, 10:311–319. 16. Marriott HJL: Miscellaneous conditions: Hypokalemia. In Practical Electrocardiography, edn 8. Baltimore: Williams and Wilkins; 1988. 17. Riemanschneider TH, Bohle A: Morphologic aspects of low-potassium and low-sodium nephropathy. Clin Nephrol 1983, 19:271–279. 18. Tolins JP, Hostetter MK, Hostetter TH: Hypokalemic nephropathy in the rat: Role of ammonia in chronic tubular injury. J Clin Invest 1987, 79:1447–1458. 19. Sterns RH, Cox M, Fieg PU, et al.: Internal potassium balance and the control of the plasma potassium concentration. Medicine 1981, 60:339–344. 20. Kamel KS, Quaggin S, Scheich A, Halperin ML: Disorders of potassium homeostasis: an approach based on pathophysiology. Am J Kidney Dis 1994, 24:597–613. 21. Ethier JH, Kamel SK, Magner PO, et al.: The transtubular potassium concentration gradient in patients with hypokalemia and hyperkalemia. Am J Kidney Dis 1990, 15:309–315.

Divalent Cation Metabolism: Magnesium James T. McCarthy Rajiv Kumar

M

agnesium is an essential intracellular cation. Nearly 99% of the total body magnesium is located in bone or the intracellular space. Magnesium is a critical cation and cofactor in numerous intracellular processes. It is a cofactor for adenosine triphosphate; an important membrane stabilizing agent; required for the structural integrity of numerous intracellular proteins and nucleic acids; a substrate or cofactor for important enzymes such as adenosine triphosphatase, guanosine triphosphatase, phospholipase C, adenylate cyclase, and guanylate cyclase; a required cofactor for the activity of over 300 other enzymes; a regulator of ion channels; an important intracellular signaling molecule; and a modulator of oxidative phosphorylation. Finally, magnesium is intimately involved in nerve conduction, muscle contraction, potassium transport, and calcium channels. Because turnover of magnesium in bone is so low, the short-term body requirements are met by a balance of gastrointestinal absorption and renal excretion. Therefore, the kidney occupies a central role in magnesium balance. Factors that modulate and affect renal magnesium excretion can have profound effects on magnesium balance. In turn, magnesium balance affects numerous intracellular and systemic processes [1–12]. In the presence of normal renal function, magnesium retention and hypermagnesemia are relatively uncommon. Hypermagnesemia inhibits magnesium reabsorption in both the proximal tubule and the loop of Henle. This inhibition of reabsorption leads to an increase in magnesium excretion and prevents the development of dangerous levels of serum magnesium, even in the presence of above-normal intake. However, in familial hypocalciuric hypercalcemia, there appears to be an abnormality of the thick ascending limb of the loop of Henle that prevents excretion of calcium. This abnormality may also extend to Mg. In familial hypocalciuric hypercalcemia, mild hypermagnesemia does not increase the renal excretion of magnesium. A similar abnormality may be caused by lithium [1,2,6,10]. The renal excretion of magnesium also is below normal in states of hypomagnesemia, decreased dietary magnesium, dehydration and volume depletion, hypocalcemia, hypothyroidism, and hyperparathyroidism [1,2,6,10].

CHAPTER

4

4.2

Disorders of Water, Electrolytes, and Acid-Base

Magnesium Distribution TOTAL BODY MAGNESIUM (MG) DISTRIBUTION Location

Percent of Total

Mg Content, mmol*

Bone Muscle Soft tissue Erythrocyte Serum

53 27 19.2 0.5 0.3

530 270 192 5 3

12720 6480 4608 120 72

1000

24000

Total

Mg Content, mg*

FIGURE 4-1 Total distribution of magnesium (Mg) in the body. Mg (molecular weight, 24.305 D) is predominantly distributed in bone, muscle, and soft tissue. Total body Mg content is about 24 g (1 mol) per 70 kg. Mg in bone is adsorbed to the surface of hydroxyapatite crystals, and only about one third is readily available as an exchangeable pool. Only about 1% of the total body Mg is in the serum and interstitial fluid [1,2,8,9,11,12].

*data typical for a 70 kg adult

Intracellular magnesium (Mg)

Proteins, enzymes, citrate, ATP, ADP – –

Endoplasmic reticulum

Membrane proteins

–

Mg2+ DNA Mg2+

Ca • Mg • ATPase

RNA

Mitochondria

FIGURE 4-2 Intracellular distribution of magnesium (Mg). Only 1% to 3% of the total intracellular Mg exists as the free ionized form of Mg, which has a closely regulated concentration of 0.5 to 1.0 mmol. Total cellular Mg concentration can vary from 5 to 20 mmol, depending on the type of tissue studied, with the highest Mg concentrations being found in skeletal and cardiac muscle cells. Our understanding of the concentration and distribution of intracellular Mg has been facilitated by the development of electron microprobe analysis techniques and fluorescent dyes using microfluorescence spectrometry. Intracellular Mg is predominantly complexed to organic molecules (eg, adenosine triphosphatase [ATPase], cell and nuclear membrane-associated proteins, DNA and RNA, enzymes, proteins, and citrates) or sequestered within subcellular organelles (mitochondria and endoplasmic reticulum). A heterogeneous distribution of Mg occurs within cells, with the highest concentrations being found in the perinuclear areas, which is the predominant site of endoplasmic reticulum. The concentration of intracellular free ionized Mg is tightly regulated by intracellular sequestration and complexation. Very little change occurs in the concentration of intracellular free Mg, even with large variations in the concentrations of total intracellular or extracellular Mg [1,3,11]. ADP— adenosine diphosphate; ATP—adenosine triphosphate; Ca+—ionized calcium.

Divalent Cation Metabolism: Magnesium

4.3

Intracellular Magnesium Metabolism Extracellular Mg2+

ß-Adrenergic receptor

[Mg2+] = 0.7-1.2mmol Na+ (Ca2+?) Plasma membrane

? +?

Cellular

+ Mg

Adenylyl cyclase

2+

ATP+Mg2+

Mitochondrion

Nucleus

Mg2+

cAMP

ADP

Plasma membrane

Mg2+? E.R. or S.R.

[Mg2+] = 0.5mmol

Ca2+ Mg2+?

Ca2+

Mg2+ +? ?

Ca2+ Pi + +

ATP•Mg

? Mg2+?

+?

pK C

D.G. + IP3 Muscarinic receptor or vasopressin receptor

Na+ (Ca2+?) Extracellular

FIGURE 4-3 Regulation of intracellular magnesium (Mg2+) in the mammalian cell. Shown is an example of Mg2+ movement between intracellular and extracellular spaces and within intracellular compartments. The stimulation of adenylate cyclase activity (eg, through stimulation of -adrenergic receptors) increases cyclic adenosine monophosphate (cAMP). The increase in cAMP induces extrusion of Mg from mitochondria by way of mitochondrial adenine nucleotide translocase, which exchanges 1 Mg2+-adenosine triphosphate (ATP) for adenosine diphosphate (ADP). This slight increase in cytosolic Mg2+ can then be extruded through the plasma membrane by way of a Mg-cation exchange mechanism, which may be activated by either cAMP or Mg. Activation of other cell receptors (eg, muscarinic receptor or vasopressin receptor) may alter cAMP levels or produce diacyl-

glycerol (DAG). DAG activates Mg influx by way of protein kinase C (pK C) activity. Mitochondria may accumulate Mg by the exchange of a cytosolic Mg2+-ATP for a mitochondrial matrix Pi molecule. This exchange mechanism is Ca2+-activated and bidirectional, depending on the concentrations of Mg2+-ATP and Pi in the cytosol and mitochondria. Inositol 1,4,5-trisphosphate (IP3) may also increase the release of Mg from endoplasmic reticulum or sarcoplasmic reticulum (ER or SR, respectively), which also has a positive effect on this Mg2+-ATP-Pi exchanger. Other potential mechanisms affecting cytosolic Mg include a hypothetical Ca2+-Mg2+ exchanger located in the ER and transport proteins that can allow the accumulation of Mg within the nucleus or ER. A balance must exist between passive entry of Mg into the cell and an active efflux mechanism because the concentration gradient favors the movement of extracellular Mg (0.7–1.2 mmol) into the cell (free Mg, 0.5 mmol). This Mg extrusion process may be energyrequiring or may be coupled to the movement of other cations. The cellular movement of Mg generally is not involved in the transepithelial transport of Mg, which is primarily passive and occurs between cells [1–3,7]. (From Romani and coworkers [3]; with permission.)

4.4

Disorders of Water, Electrolytes, and Acid-Base Mg2+

Extracellular

Outer membrane Mg

Mg2+

N

2+

Periplasm

Mg2+

Mg2+

CorA ATP

MgtB

MgtA

1 2

N

3

4

Periplasm

Cytosol

6 7

8 9 10

Cytoplasm

ATP Mg2+

5

Periplasm

12

Cytoplasm C

3

C

ADP Mg2+

Mg2+

A

ADP

B

37 kDa?

FIGURE 4-4 A, Transport systems of magnesium (Mg). Specific membraneassociated Mg transport proteins only have been described in bacteria such as Salmonella. Although similar transport proteins are believed to be present in mammalian cells based on nucleotide sequence analysis, they have not yet been demonstrated. Both MgtA and MgtB (molecular weight, 91 and 101 kDa, respectively) are members of the adenosine triphosphatase (ATPase) family of transport proteins. B, Both of these transport proteins have six C-terminal and four N-terminal membrane-spanning segments, with both the N- and C-terminals within the cytoplasm. Both proteins transport Mg with its electrochemical gradient, in contrast to other known ATPase proteins that usually transport ions

MgtA and MgtB

CorA

against their chemical gradient. Low levels of extracellular Mg are capable of increasing transcription of these transport proteins, which increases transport of Mg into Salmonella. The CorA system has three membrane-spanning segments. This system mediates Mg influx; however, at extremely high extracellular Mg concentrations, this protein can also mediate Mg efflux. Another cell membrane Mg transport protein exists in erythrocytes (RBCs). This RBC Na+-Mg2+ antiporter (not shown here) facilitates the outward movement of Mg from erythrocytes in the presence of extracellular Na+ and intracellular adenosine triphosphate (ATP) [4,5]. ADP—adenosine diphosphate; C—carbon; N—nitrogen. (From Smith and Maguire [4]).

Gastrointestinal Absorption of Magnesium

Gastrointestinal absorption of dietary magnesium (Mg)

Site

Mg absorption % of intake mmol/day mg/day absorption

Stomach Duodenum Jejunum Proximal Ileum Distal Ileum Colon

0 0.63 1.25 1.88

0 15 30 45

0 5 10 15

1.25

30

10

0.63

15

5

Total*

5.6

135

45

*Normal dietary Mg intake = 300 mg (12.5 mmol) per day

FIGURE 4-5 Gastrointestinal absorption of dietary intake of magnesium (Mg). The normal adult dietary intake of Mg is 300 to 360 mg/d (12.5–15 mmol/d). A Mg intake of about 3.6 mg/kg/d is necessary to maintain Mg balance. Foods high in Mg content include green leafy vegetables (rich in Mg-containing chlorophyll), legumes, nuts, seafoods, and meats. Hard water contains about 30 mg/L of Mg. Dietary intake is the only source by which the body can replete Mg stores. Net intestinal Mg absorption is affected by the fractional Mg absorption within a specific segment of intestine, the length of that intestinal segment, and transit time of the food bolus. Approximately 40% to 50% of dietary Mg is absorbed. Both the duodenum and jejunum have a high fractional absorption of Mg. These segments of intestine are relatively short, however, and the transit time is rapid. Therefore, their relative contribution to total Mg absorption is less than that of the ileum. In the intact animal, most of the Mg absorption occurs in the ileum and colon. 1,25-dihydroxy-vitamin D3 may mildly increase the intestinal absorption of Mg; however, this effect may be an indirect result of increased calcium absorption induced by the vitamin. Secretions of the upper intestinal tract contain approximately 1 mEq/L of Mg, whereas secretions from the lower intestinal tract contain 15 mEq/L of Mg. In states of nausea, vomiting, or nasogastric suction, mild to moderate losses of Mg occur. In diarrheal states, Mg depletion can occur rapidly owing to both high intestinal secretion and lack of Mg absorption [2,6,8–13].

4.5

Divalent Cation Metabolism: Magnesium 10

7

Physiological Mg-intake, mmol/d

Mg transported, µEq/h

8

6

7 6 3

5 4

3

3 22

2 1

13

3

Magnesium absorbed M Mg , mmol

9

5 4 3 2 1

12

0

0 0

3

6

A

9

12

15

18

21

24

0

B

[Mg] in bicarbonate saline, mEq/L

10

20

30

40

Oral magnesium dose m, mmol

FIGURE 4-6 Intestinal magnesium (Mg) absorption. In rats, the intestinal Mg absorption is related to the luminal Mg concentration in a curvilinear fashion (A). This same phenomenon has been observed in humans (B and C). The hyperbolic curve (dotted line in B and C) seen at low doses and concentrations may reflect a saturable transcellular process; whereas the linear function (dashed line in B and C) at higher Mg intake may be a concentration-dependent passive intercellular Mg absorption. Alternatively, an intercellular process that can vary its permeability to Mg, depending on the luminal Mg concentration, could explain these findings (see Fig. 4-7) [13–15]. (A, From Kayne and Lee [13]; B, from Roth and Wermer [14]; C, from Fine and coworkers [15]; with permission.)

10 Net Mg absorption, mEq/10 hrs

6

8 6 4 2 0 0

20

40 Mg intake, mEq/meal

C

Mechanism of intestinal magnesium absorption Nucleus Lumen Mg2+ A Mg2+ B

Mg2+

Mg2+ K+

Na+ ATPase

60

80

FIGURE 4-7 Proposed pathways for movement of magnesium (Mg) across the intestinal epithelium. Two possible routes exist for the absorption of Mg across intestinal epithelial cells: the transcellular route and the intercellular pathway. Although a transcellular route has not yet been demonstrated, its existence is inferred from several observations. No large chemical gradient exists for Mg movement across the cell membrane; however, a significant uphill electrical gradient exists for the exit of Mg from cells. This finding suggests the existence and participation of an energy-dependent mechanism for extrusion of Mg from intestinal cells. If such a system exists, it is believed it would consist of two stages. 1) Mg would enter the apical membrane of intestinal cells by way of a passive carrier or facilitated diffusion. 2) An active Mg pump in the basolateral section of the cell would extrude Mg. The intercellular movement of Mg has been demonstrated to occur by both gradient-driven and solvent-drag mechanisms. This intercellular path may be the only means by which Mg moves across the intestinal epithelium. The change in transport rates at low Mg concentrations would reflect changes in the “openness” of this pathway. High concentrations of luminal Mg (eg, after a meal) are capable of altering the morphology of the tight junction complex. High local Mg concentrations near the intercellular junction also can affect the activities of local membrane-associated proteins (eg, sodium-potassium adenosine triphosphate [Na-K ATPase]) near the tight junction and affect its permeability (see Fig. 4-6) [13–15].

4.6

Disorders of Water, Electrolytes, and Acid-Base

Renal Handling of Magnesium Afferent arteriole

Efferent arteriole

Glomerular capillary

Bowman's space

Mg2+-protein Mg2+ionized

FIGURE 4-8 The glomerular filtration of magnesium (Mg). Total serum Mg consists of ionized, complexed, and protein bound fractions, 60%, 7%, and 33% of total, respectively. The complexed Mg is bound to molecules such as citrate, oxalate, and phosphate. The ultrafilterable Mg is the total of the ionized and complexed fractions. Normal total serum Mg is approximately 1.7 to 2.1 mg/dL (about 0.70–0.90 mmol/L) [1,2,7–9,11,12].

Mg2+complexed

Mg2+-ultrafilterable % of total serum Mg2+ Mg2+ Ionized Mg 60% Protein-bound Mg 33% Complexed Mg 7%

Proximal tubule

*Normal total serum Mg = 1.7–2.1 mg/dL (0.70–0.9 mmol/L)

Juxtamedullary nephron

Superficial cortical nephron 5–10%

0–5%

Filtered Mg2+ (100%)

Filtered Mg2+ (100%) 20% 65% 65%

20%

Excreted (5%)

FIGURE 4-9 The renal handling of magnesium (Mg2+). Mg is filtered at the glomerulus, with the ultrafilterable fraction of plasma Mg entering the proximal convoluted tubule (PCT). At the end of the PCT, the Mg concentration is approximately 1.7 times the initial concentra-

tion of Mg and about 20% of the filtered Mg has been reabsorbed. Mg reabsorption occurs passively through paracellular pathways. Hydrated Mg has a very large radius that decreases its intercellular permeability in the PCT when compared with sodium. The smaller hydrated radius of sodium is 50% to 60% reabsorbed in the PCT. No clear evidence exists of transcellular reabsorption or secretion of Mg within the mammalian PCT. In the pars recta of the proximal straight tubule (PST), Mg reabsorption can continue to occur by way of passive forces in the concentrating kidney. In states of normal hydration, however, very little Mg reabsorption occurs in the PST. Within the thin descending limb of the loop of Henle, juxtamedullary nephrons are capable of a small amount of Mg reabsorption in a state of antidiuresis or Mg depletion. This reabsorption does not occur in superficial cortical nephrons. No data exist regarding Mg reabsorption in the thin ascending limb of the loop of Henle. No Mg reabsorption occurs in the medullary portion of the thick ascending limb of the loop of Henle; whereas nearly 65% of the filtered load is absorbed in the cortical thick ascending limb of the loop of Henle in both juxtamedullary and superficial cortical nephrons. A small amount of Mg is absorbed in the distal convoluted tubule. Mg transport in the connecting tubule has not been well quantified. Little reabsorption occurs and no evidence exists of Mg secretion within the collecting duct. Normally, 95% of the filtered Mg is reabsorbed by the nephron. In states of Mg depletion the fractional excretion of Mg can decrease to less than 1%; whereas Mg excretion can increase in states of above-normal Mg intake, provided no evidence of renal failure exists [1,2,6–9,11,12].

Divalent Cation Metabolism: Magnesium

FIGURE 4-10 Magnesium (Mg) reabsorption in the cortical thick ascending limb (cTAL) of the loop of Henle. Most Mg reabsorption within the nephron occurs in the cTAL owing primarily to voltage-dependent Mg flux through the intercellular tight junction. Transcellular Mg movement occurs only in response to cellular metabolic needs. The sequence of events necessary to generate the lumen-positive electrochemical gradient that drives Mg reabsorption is as follows: 1) A basolateral sodium-potassium-adenosine triphosphatase (Na+-K+ATPase) decreases intracellular sodium, generating an inside-negative electrical potential difference; 2) Intracellular K is extruded by an electroneutral K-Cl (chloride) cotransporter; 3) Cl is extruded by way of conductive pathways in the basolateral membrane; 4) The apical-luminal Na-2Cl-K (furosemide-sensitive) cotransport mechanism is driven by the inside-negative potential difference and decrease in intracellular Na; 5) Potassium is recycled back into the lumen by way of an apical K conductive channel; 6) Passage of approximately 2 Na molecules for every Cl molecule is allowed by the paracellular pathway (intercellular tight junction), which is cation permselective; 7) Mg reabsorption occurs passively, by way of intercellular channels, as it moves down its electrical gradient [1,2,6,7]. (Adapted from de Rouffignac and Quamme [1].)

Mg absorption in cTAL –78mV

+8mV

0mV

6

2Na+

1Cl– 4

3Na+ 6Cl– 3K+

2K+

1

3Na+

2

2K+ 2Cl– 4Cl–

3

3K+

4.7

5 Mg Mg ~1.0mmol Mg ~1.0mmol

A Mg 0.5mmol

FIGURE 4-11 Voltage-dependent net magnesium (Mg) flux in the cortical thick ascending limb (cTAL). Within the isolated mouse cTAL, Mg flux (JMg) occurs in response to voltage-dependent mechanisms. With a relative lumen-positive transepithelial potential difference (Vt), Mg reabsorption increases (positive JMg). Mg reabsorption equals zero when no voltage-dependent difference exists, and Mg is capable of moving into the tubular lumen (negative JMg) when a lumen-negative voltage difference exists [1,16]. (From di Stefano and coworkers [16]).

JMg, pmol.min–1.mm–1 0.8 0.6 0.4 (7) 0.2 Vt, mV –18 –15 –12 –9 –6 –3 –0.2 –0.4 (8)

–0.6 –0.8

3 6 (15)

9

12

15 18

4.8

Disorders of Water, Electrolytes, and Acid-Base

Net fluxes, pmol • min–1• mm–1

JMg2+ 1.0

AVP

GLU

*

*

HCT

PTH

ISO

INS

*

*

*

0.8 * 0.6 0.4 0.2 0

C

C

C

C

C

C

C

C

C

C

C

C

FIGURE 4-12 Effect of hormones on magnesium (Mg) transport in the cortical thick ascending limb (cTAL). In the presence of arginine vasopressin (AVP), glucagon (GLU), human calcitonin (HCT), parathyroid hormone (PTH), 1,4,5-isoproteronol (ISO), and insulin (INS), increases occur in Mg reabsorption from isolated segments of mouse cTALs. These hormones have no effect on medullary TAL segments. As already has been shown in Figure 4-3, these hormones affect intracellular “second messengers” and cellular Mg movement. These hormone-induced alterations can affect the paracellular permeability of the intercellular tight junction. These changes may also affect the transepithelial voltage across the cTAL. Both of these forces favor net Mg reabsorption in the cTAL [1,2,7,8]. Asterisk—significant change from preceding period; JMg—Mg flux; C—control, absence of hormone. (Adapted from de Rouffignac and Quamme [1].)

Magnesium Depletion CAUSES OF MAGNESIUM (Mg) DEPLETION

Poor Mg intake Starvation Anorexia Protein calorie malnutrition No Mg in intravenous fluids Renal losses see Fig. 4-14 Increased gastrointestinal Mg losses Nasogastric suction Vomiting Intestinal bypass for obesity Short-bowel syndrome Inflammatory bowel disease Pancreatitis Diarrhea Laxative abuse Villous adenoma

Other Lactation Extensive burns Exchange transfusions

FIGURE 4-13 The causes of magnesium (Mg) depletion. Depletion of Mg can develop as a result of low intake or increased losses by way of the gastrointestinal tract, the kidneys, or other routes [1,2,8–13].

Divalent Cation Metabolism: Magnesium Renal magnesium (Mg) wasting Thiazides(?) Volume expansion • Osmotic diuresis Glucose Mannitol Urea • Diuretic phase acute renal failure* • Post obstructive diuresis* • Hypercalcemia* • Phosphate depletion* • Chronic renal disease* • ? Aminoglycosides* • Renal transplant* • Interstitial nephritis*

Tubular defects Bartter's syndrome Gitelman's syndrome Renal tubular acidosis Medullary calcinosis Drugs/toxins Cis-platinum Amphotericin B Cyclosporine Pentamidine ? Aminoglycosides* Foscarnet (?ATN) Ticarcillin/carbenicillin ? Digoxin Electrolyte imbalances Hypercalcemia* Phosphate depletion* Metabolic acidosis Starvation Ketoacidosis Alcoholism

4.9

FIGURE 4-14 Renal magnesium (Mg) wasting. Mg is normally reabsorbed in the proximal tubule (PT), cortical thick ascending limb (cTAL), and distal convoluted tubule (DCT) (see Fig. 4-9). Volume expansion and osmotic diuretics inhibit PT reabsorption of Mg. Several renal diseases and electrolyte disturbances (asterisks) inhibit Mg reabsorption in both the PT and cTAL owing to damage to the epithelial cells and the intercellular tight junctions, plus disruption of the electrochemical forces that normally favor Mg reabsorption. Many drugs and toxins directly damage the cTAL. Thiazides have little direct effect on Mg reabsorption; however, the secondary hyperaldosteronism and hypercalcemia effect Mg reabsorption in CD and/or cTAL. Aminoglycosides accumulate in the PT, which affects sodium reabsorption, also leading to an increase in aldosterone. Aldosterone leads to volume expansion, decreasing Mg reabsorption. Parathyroid hormone has the direct effect of increasing Mg reabsorption in cTAL; however, hypercalcemia offsets this tendency. Thyroid hormone increases Mg loss. Diabetes mellitus increases Mg loss by way of both hyperglycemic osmotic diuresis and insulin abnormalities (deficiency and resistance), which decrease Mg reabsorption in the proximal convoluted tubule and cTAL, respectively. Cisplatin causes a Gitelman-like syndrome, which often can be permanent [1,2,8–12].

Hormonal changes Hyperaldosteronism Primary hyperparathyroidism Hyperthyroidism Uncontrolled diabetes mellitus

SIGNS AND SYMPTOMS OF HYPOMAGNESEMIA

Cardiovascular Electrocardiographic results Prolonged P-R and Q-T intervals, U waves Angina pectoris ?Congestive heart failure Atrial and ventricular arrhythmias ?Hypertension Digoxin toxicity Atherogenesis Neuromuscular Central nervous system Seizures Obtundation Depression Psychosis Coma Ataxia Nystagmus Choreiform and athetoid movements

Muscular Cramps Weakness Carpopedal spasm Chvostek’s sign Trousseau’s sign Fasciculations Tremulous Hyperactive reflexes Myoclonus Dysphagia Skeletal Osteoporosis Osteomalacia

FIGURE 4-15 Signs and symptoms of hypomagnesemia. Symptoms of hypomagnesemia can develop when the serum magnesium (Mg) level falls below 1.2 mg/dL. Mg is a critical cation in nerves and muscles and is intimately involved with potassium and calcium. Therefore, neuromuscular symptoms predominate and are similar to those seen in hypocalcemia and hypokalemia. Electrocardiographic changes of hypomagnesemia include an increased P-R interval, increased Q-T duration, and development of U waves. Mg deficiency increases the mortality of patients with acute myocardial infarction and congestive heart failure. Mg depletion hastens atherogenesis by increasing total cholesterol and triglyceride levels and by decreasing high-density lipoprotein cholesterol levels. Hypomagnesemia also increases hypertensive tendencies and impairs insulin release, which favor atherogenesis. Low levels of Mg impair parathyroid hormone (PTH) release, block PTH action on bone, and decrease the activity of renal 1--hydroxylase, which converts 25-hydroxy-vitamin D3 into 1,25-dihydroxy-vitamin D3, all of which contribute to hypocalcemia. Mg is an integral cofactor in cellular sodium-potassium-adenosine triphosphatase activity, and a deficiency of Mg impairs the intracellular transport of K and contributes to renal wasting of K, causing hypokalemia [6,8–12].

4.10

Disorders of Water, Electrolytes, and Acid-Base

Total serum Mg (On normal diet of 250–350 mg/d of Mg)

Magnesium deficiency

Insulin resistance

Altered synthesis of eicosanoids

Enhanced AII action

(↓PGI2 , : ↑TXA2 , and 12-HETE) ↑Platelet aggregation

↑Aldosterone

Increased vasomotor tone

↑Na+ reabsorption

Normal (1.7–2.1 mg/dL)

Low (<1.7 mg/dL)

24 hour urine Mg

24 hour urine Mg

Normal (> 24 mg/24 hrs)

Low (< 24 mg/24 hrs)

No Mg deficiency

Tolerance Mg test (see Figure 4–18)

MAGNESIUM (Mg) TOLERANCE TEST FOR PATIENTS WITH NORMAL SERUM MAGNESIUM

Time

Action

0 (baseline) 0–4 h

Urine (spot or timed) for molar Mg:Cr ratio IV infusion of 2.4 mg (0.1 mmol) of Mg/kg lean body wt in 50 mL of 50% dextrose Collect urine (staring with Mg infusion) for Mg and Cr Calculate % Mg retained (%M)

0–24 h End %M=1

(24-h urine Mg)  ([Preinfusion urine Mg:Cr]  [24-h urine Cr])  100 Total Mg infused

Mg retained, %

Mg deficiency

>50 20–50 <20

Definite Probable None

Cr—creatinine; IV—intravenous; Mg—magnesium.

High (> 24 mg/24 hrs)

Mg deficiency present

Hypertension

FIGURE 4-16 Mechanism whereby magnesium (Mg) deficiency could lead to hypertension. Mg deficiency does the following: increases angiotensin II (AII) action, decreases levels of vasodilatory prostaglandins (PGs), increases levels of vasoconstrictive PGs and growth factors, increases vascular smooth muscle cytosolic calcium, impairs insulin release, produces insulin resistance, and alters lipid profile. All of these results of Mg deficiency favor the development of hypertension and atherosclerosis [10,11]. Na+—ionized sodium; 12-HETE—hydroxy-eicosatetraenoic [acid]; TXA2—thromboxane A2. (From Nadler and coworkers [17].)

Low (< 24 mg/24 hrs)

Check for nonrenal causes

Mg deficiency present Renal Mg wasting

Normal Mg retention

Mg retention

No Mg deficiency Normal

Mg deficiency present Check for nonrenal causes

FIGURE 4-17 Evaluation in suspected magnesium (Mg) deficiency. Serum Mg levels may not always indicate total body stores. More refined tools used to assess the status of Mg in erythrocytes, muscle, lymphocytes, bone, isotope studies, and indicators of intracellular Mg, are not routinely available. Screening for Mg deficiency relies on the fact that urinary Mg decreases rapidly in the face of Mg depletion in the presence of normal renal function [2,6,8–15,18]. (Adapted from Al-Ghamdi and coworkers [11].) FIGURE 4-18 The magnesium (Mg) tolerance test, in various forms [2,6,8–12,18], has been advocated to diagnose Mg depletion in patients with normal or near-normal serum Mg levels. All such tests are predicated on the fact that patients with normal Mg status rapidly excrete over 50% of an acute Mg load; whereas patients with depleted Mg retain Mg in an effort to replenish Mg stores. (From Ryzen and coworkers [18].)

4.11

Divalent Cation Metabolism: Magnesium

MAGNESIUM SALTS USED IN MAGNESIUM REPLACEMENT THERAPY Magnesium salt

Chemical formula

Mg content, mg/g

Examples*

Mg content

Diarrhea

27-mg tablet 54 mg/5 mL

±

Gluconate

Cl2H22MgO14

58

Magonate®

Chloride

MgCl2 . (H2O)6

120

Mag-L-100

100-mg capsule

+

Lactate

C6H10MgO6

120

MagTab SR*

84-mg caplet

+

Citrate

C12H10Mg3O14

Multiple

47–56 mg/5 mL

++

Hydroxide

Mg(OH)2

410

Maalox®, Mylanta®, Gelusil® Riopan®

83 mg/ 5 mL and 63-mg tablet 96 mg/5 mL

++

Oxide

MgO

600

Mag-Ox 400® Uro-Mag® Beelith®

241-mg tablet 84.5-mg tablet 362-mg tablet

++

Sulfate

MgSO4 . (H2O)7

100

IV IV Oral epsom salt

10%—9.9 mg/mL 50%—49.3 mg/mL 97 mg/g

++

Phillips’ Milk of Magnesia®

168 mg/ 5 mL

++

53

Milk of Magnesia

++

Data from McLean [9], Al-Ghamdi and coworkers [11], Oster and Epstein [19], and Physicians’ Desk Reference [20]. *Magonate®, Fleming & Co, Fenton, MD; MagTab Sr®, Niche Pharmaceuticals, Roanoke, TX; Maalox®, Rhone-Poulenc Rorer Pharmaceutical, Collegeville, PA; Mylanta®, J & J-Merck Consumer Pharm, Ft Washinton, PA; Riopan®, Whitehall Robbins Laboratories, Madison, NJ; Mag-Ox 400® and Uro-Mag®, Blaine, Erlanger, KY; Beelith®, Beach Pharmaceuticals, Conestee, SC; Phillips’ Milk of Magnesia, Bayer Corp, Parsippany, NJ.

FIGURE 4-19 Magnesium (Mg) salts that may be used in Mg replacement therapy.

GUIDELINES FOR MAGNESIUM (Mg) REPLACEMENT Life-threatening event, eg, seizures and cardiac arrhythmia I. 2–4 g MgSO4 IV or IM stat (2–4 vials [2 mL each] of 50% MgSO4) Provides 200–400 mg of Mg (8.3–16.7 mmol Mg) Closely monitor: Deep tendon reflexes Heart rate Blood pressure Respiratory rate Serum Mg (<2.5 mmol/L [6.0 mg/dL]) Serum K

Subacute and chronic Mg replacement I. 400–600 mg (16.7–25 mmol Mg daily for 2–5 d) IV: continuous infusion IM: painful Oral: use divided doses to minimize diarrhea

II. IV drip over first 24 h to provide no more than 1200 mg (50 mmol) Mg/24 h

FIGURE 4-20 Acute Mg replacement for life-threatening events such as seizures or potentially lethal cardiac arrhythmias has been described [8–12,19]. Acute increases in the level of serum Mg can cause nausea, vomiting, cutaneous flushing, muscular weakness, and hyporeflexia. As Mg levels increase above 6 mg/dL (2.5 mmol/L), electrocardiographic changes are followed, in sequence, by hyporeflexia, respiratory paralysis, and cardiac arrest. Mg should be administered with caution in patients with renal failure. In the event of an emergency the acute Mg load should be followed by an intravenous (IV) infusion, providing no more than 1200 mg (50 mmol) of Mg on the first day. This treatment can be followed by another 2 to 5 days of Mg repletion in the same dosage, which is used in less urgent situations. Continuous IV infusion of Mg is preferred to both intramuscular (which is painful) and oral (which causes diarrhea) administration. A continuous infusion avoids the higher urinary fractional excretion of Mg seen with intermittent administration of Mg. Patients with mild Mg deficiency may be treated with oral Mg salts rather than parenteral Mg and may be equally efficacious [8]. Administration of Mg sulfate may cause kaliuresis owing to excretion of the nonreabsorbable sulfate anion; Mg oxide administration has been reported to cause significant acidosis and hyperkalemia [19]. Parenteral Mg also is administered (often in a manner different from that shown here) to patients with preeclampsia, asthma, acute myocardial infarction, and congestive heart failure.

4.12

Disorders of Water, Electrolytes, and Acid-Base

References 1. de Rouffignac C, Quamme G: Renal magnesium handling and its hormonal control. Physiol Rev 1994, 74:305–322. 2. Quamme GA: Magnesium homeostasis and renal magnesium handling. Miner Electrolyte Metab 1993, 19:218–225. 3. Romani A, Marfella C, Scarpa A: Cell magnesium transport and homeostasis: role of intracellular compartments. Miner Electrolyte Metab 1993, 19:282–289. 4. Smith DL, Maguire ME: Molecular aspects of Mg2+ transport systems. Miner Electrolyte Metab 1993, 19:266–276. 5. Roof SK, Maguire ME: Magnesium transport systems: genetics and protein structure (a review). J Am Coll Nutr 1994, 13:424–428. 6. Sutton RAL, Domrongkitchaiporn S: Abnormal renal magnesium handling. Miner Electrolyte Metab 1993, 19:232–240. 7. de Rouffignac C, Mandon B, Wittner M, di Stefano A: Hormonal control of magnesium handling. Miner Electrolyte Metab 1993, 19:226–231. 8. Whang R, Hampton EM, Whang DD: Magnesium homeostasis and clinical disorders of magnesium deficiency. Ann Pharmacother 1994, 28:220–226. 9. McLean RM: Magnesium and its therapeutic uses: a review. Am J Med 1994, 96:63–76. 10. Abbott LG, Rude RK: Clinical manifestations of magnesium deficiency. Miner Electrolyte Metab 1993, 19:314–322. 11. Al-Ghamdi SMG, Cameron EC, Sutton RAL: Magnesium deficiency: pathophysiologic and clinical overview. Am J Kid Dis 1994, 24:737–752.

12. Nadler JL, Rude RK: Disorders of magnesium metabolism. Endocrinol Metab Clin North Am 1995, 24:623–641. 13. Kayne LH, Lee DBN: Intestinal magnesium absorption. Miner Electrolyte Metab 1993, 19:210–217. 14. Roth P, Werner E: Intestinal absorption of magnesium in man. Int J Appl Radiat Isotopes 1979, 30:523–526. 15. Fine KD, Santa Ana CA, Porter JL, Fordtran JS: Intestinal absorption of magnesium from food and supplements. J Clin Invest 1991, 88:396–402. 16. di Stefano A, Roinel N, de Rouffignac C, Wittner M: Transepithelial Ca+ and Mg+ transport in the cortical thick ascending limb of Henle’s loop of the mouse is a voltage-dependent process. Renal Physiol Biochem 1993, 16:157–166. 17. Nadler JL, Buchanan T, Natarajan R, et al.: Magnesium deficiency produces insulin resistance and increased thromboxane synthesis. Hypertension 1993, 21:1024–1029. 18. Ryzen E, Elbaum N, Singer FR, Rude RK: Parenteral magnesium tolerance testing in the evaluation of magnesium deficiency. Magnesium 1985, 4:137–147. 19. Oster JR, Epstein M: Management of magnesium depletion. Am J Nephrol 1988, 8:349–354. 20. Physicians’ Desk Reference (PDR). Montvale, NJ: Medical Economics Company; 1996.

Divalent Cation Metabolism: Calcium James T. McCarthy Rajiv Kumar

C

alcium is an essential element in the human body. Although over 99% of the total body calcium is located in bone, calcium is a critical cation in both the extracellular and intracellular spaces. Its concentration is held in a very narrow range in both spaces. In addition to its important role in the bone mineral matrix, calcium serves a vital role in nerve impulse transmission, muscular contraction, blood coagulation, hormone secretion, and intercellular adhesion. Calcium also is an important intracellular second messenger for processes such as exocytosis, chemotaxis, hormone secretion, enzymatic activity, and fertilization. Calcium balance is tightly regulated by the interplay between gastrointestinal absorption, renal excretion, bone resorption, and the vitamin D–parathyroid hormone (PTH) system [1–7].

CHAPTER

5

5.2

Disorders of Water, Electrolytes, and Acid-Base

Calcium Distribution TOTAL DISTRIBUTION OF CALCIUM IN THE BODY Ca Content* Location

Concentration

mmol

mg

99% 2.4 mmol 0.1 mol

~31.4  103 35 <1

~1255  103 ~1400 <40

~31.5  103

~1260  103

Bone Extracellular fluid Intracellular fluid Total

FIGURE 5-1 Total distribution of calcium (Ca) in the body. Ca (molecular weight, 40.08 D) is predominantly incorporated into bone. Total body Ca content is about 1250 g (31 mol) in a person weighing 70 kg. Bone Ca is incorporated into the hydroxyapatite crystals of bone, and about 1% of bone Ca is available as an exchangeable pool. Only 1% of the total body calcium exists outside of the skeleton.

*data for a 70 kg person

Intracellular Calcium Metabolism [Ca2+]o≈1-3mM

Ca2+o

+8-0mV -50mV Ca2+-binding proteins; phosphate, citrate, etc. complexes

VOC ROC SOC

Ca2+i

[Ca2+]i<10-3mM

Mitochondria

Nucleus

~ 2+ SRCa Ca s ATPase

InsP3 receptor

Ca2+ Plasma membrane ATPase

Sarcoplasmic or endoplasmic reticulum

Na+ 3Na+: Ca2+exchanger

~ Ca2+

Ca2+

FIGURE 5-2 General scheme of the distribution and movement of intracellular calcium (Ca). In contrast to magnesium, Ca has a particularly

adaptable coordination sphere that facilitates its binding to the irregular geometry of proteins, a binding that is readily reversible. Low intracellular Ca concentrations can function as either a first or second messenger. The extremely low concentrations of intracellular Ca are necessary to avoid Ca-phosphate microprecipitation and make Ca an extremely sensitive cellular messenger. Less than 1% of the total intracellular Ca exists in the free ionized form, with a concentration of approximately 0.1 µmol/L. Technical methods available to investigate intracellular free Ca concentration include Ca-selective microelectrodes, bioluminescent indicators, metallochromic dyes, Ca-sensitive fluorescent indicators, electron-probe radiographic microanalysis, and fluorine-19 nuclear magnetic resonance imaging. Intracellular Ca is predominantly sequestered within the endoplasmic reticulum (ER) and sarcoplasmic reticulum (SR). Some sequestration of Ca occurs within mitochondria and the nucleus. Ca can be bound to proteins such as calmodulin and calbindin, and Ca can be complexed to phosphate, citrate, and other anions. Intracellular Ca is closely regulated by balancing Ca entry by way of voltage-operated channels (VOC), receptoroperated channels (ROC), and store-operated channels (SOC), with active Ca efflux by way of plasma membrane–associated Ca-adenosine triphosphatase (ATPase) and a Na-Ca exchanger. Intracellular Ca also is closely regulated by balancing Ca movement into the SR (SR Ca-ATPase) and efflux from the SR by an inositol 1,4,5-trisphosphate (InsP3) receptor [1–7]. The highest concentration of intracellular Ca is found in the brush border of epithelial cells, where there is also the highest concentration of Ca-binding proteins such as actin-myosin and calbindin. Intracellular Ca messages are closely modulated by the phospholipase C-InsP3 pathway and also the phospholipase A2–arachidonic acid pathway, along with intracellular Ca, which itself modulates the InsP3 receptor.

Divalent Cation Metabolism: Calcium

5.3

Vitamin D and Parathyroid Hormone Actions

7-dehydrocholesterol HO UV light

Skin

Vitamin D3

Liver 25-hydroxylase HO OH + PTH PTHrP Hypophosphatemia Hypocalcemia 24R, 25(OH)2D3 IGF-1

25-hydroxyvitamin D3

– Hypercalcemia Hyperphosphatemia 1, 25(OH)2D3 Acidosis HO Kidney

1-alphahydroxylase

24-hydroxylase

+ 1, 25(OH)2D3 Hypercalcemia Hyperphosphatemia Kidney, intestine, other tissue

OH

OH

OH 24, 25-hydroxyvitamin D3

1, 25-hydroxyvitamin D3

HO

HO

OH Various tissue enzymes

Hydroxylated and conjugated polar metabolites

FIGURE 5-4 Calcium (Ca) flux between body compartments. Ca balance is a complex process involving bone, intestinal absorption of dietary Ca, and renal excretion of Ca. The parathyroid glands, by their production of parathyroid hormone, and the liver, through its participation in vitamin D metabolism, also are integral organs in the maintenance of Ca balance. (From Kumar [1]; with permission.)

Soft tissue and intracellular calcium

Oral calcium intake ~1000 mg/d Intestine 400 mg 200 mg

Extracellular fluid and plasma 10,000 mg

500 mg 500 mg

9800 mg Bone

Feces 800 mg

Kidney

Urine 200 mg

FIGURE 5-3 Metabolism of vitamin D. The compound 7dehydrocholesterol, through the effects of heat (37°C) and (UV) light (wavelength 280–305 nm), is converted into vitamin D3 in the skin. Vitamin D3 is then transported on vitamin D binding proteins (VDBP) to the liver. In the liver, vitamin D3 is converted to 25-hydroxyvitamin D3 by the hepatic microsomal and mitochondrial cytochrome P450–containing vitamin D3 25-hydroxylase enzyme. The 25hydroxy-vitamin D3 is transported on VDBP to the proximal tubular cells of the kidney, where it is converted to 1,25-dihydroxy-vitamin D3 by a 1--hydroxylase enzyme, which also is a cytochrome P450–containing enzyme. The genetic information for this enzyme is encoded on the 12q14 chromosome. Alternatively, 25-hydroxy-vitamin D3 can be converted to 24R,25-dihydroxy-vitamin D3, a relatively inactive vitamin D metabolite. 1,25dihydroxy-vitamin D3 can then be transported by VDBP to its most important target tissues in the distal tubular cells of the kidney, intestinal epithelial cells, parathyroid cells, and bone cells. VDBP is a 58 kD -globulin that is a member of the albumin and -fetoprotein gene family. The DNA sequence that encodes for this protein is on chromosome 4q11-13. 1,25dihydroxy-vitamin D3 is eventually metabolized to hydroxylated and conjugated polar metabolites in the enterohepatic circulation. Occasionally, 1,25-dihydroxy-vitamin D3 also may be produced in extrarenal sites, such as monocyte-derived cells, and may have an antiproliferative effect in certain lymphocytes and keratinocytes [1,7–9]. (Adapted from Kumar [1].)

5.4

Disorders of Water, Electrolytes, and Acid-Base FIGURE 5-5 Effects of 1,25-dihydroxy-vitamin D3 (calcitriol) on bone. In addition to the effects on parathyroid cells, the kidney, and intestinal epithelium, calcitriol has direct effects on bone metabolism. Calcitriol can promote osteoclast differentiation and activity from monocyte precursor cells. Calcitriol also promotes osteoblast differentiation into mature cells. (From Holick [8]; with permission.)

1,25(OH)2D3

??? Osteoblast precusor

T-lymphocyte

Monoblast

Osteoclast

Osteoblast Cytokines Osteocalcin Osteopontin Alkaline Phosphatase

Bone

DNA binding gly→asp 30 his→gln 32

Hinge region

arg→gln 70

arg→gln 42

NH2

18

Calcitiriol binding

cys→trp 187

arg→gln 77

42 44 lys→glu phe→ile

149 gln→stop

tyr→stop 292

271 arg→leu

424

COOH

ZN Mutant amino acid

FIGURE 5-6 The vitamin D receptor (VDR). Within its target tissues, calcitriol binds to the VDR. The VDR is a 424 amino acid polypeptide. Its genomic information is encoded on the

VDBP VDR-D3 complex

1,25 (OH)2D3

VDRE

VDR RAF Pi

Regulation mRNA transcription

Nucleus

CaBP 24-OHase PTH Osteocalcin Osteopontin Alkaline phosphatase

12q12-14 chromosome, near the gene for the 1--hydroxylase enzyme. The VDR is found in the intestinal epithelium, parathyroid cells, kidney cells, osteoblasts, and thyroid cells. VDR also can be detected in keratinocytes, monocyte precursor cells, muscle cells, and numerous other tissues. The allele variations for the vitamin D receptor. Two allele variations exist for the vitamin D receptor (VDR): the b allele and the B allele. In general, normal persons with the b allele seem to have a higher bone mineral density [9]. Among patients on dialysis, those with the b allele may have higher levels of circulating parathyroid hormone (PTH) [7,9,10,11]. COOH—carboxy terminal; NH2—amino terminal. (From Root [7]; with permission.)

FIGURE 5-7 Mechanism of action of 1-25-dihydroxy-vitamin D3 (1,25(OH)2D3). 1,25(OH)2D3 is transported to the target cell bound to the vitamin D–binding protein (VDBP). The free form of 1,25(OH)2D3 enters the target cell and interacts with the vitamin D receptor (VDR) at the nucleus. This complex is phosphorylated and combined with the nuclear accessory factor (RAF). This forms a heterodimer, which then interacts with the vitamin D responsive element (VDRE). The VDRE then either promotes or inhibits the transcription of messenger RNA (mRNA) for proteins regulated by 1,25(OH)2D3, such as Ca-binding proteins, the 25-hydroxy-vitamin D3 24-hydroxylase enzyme, and parathyroid hormone. Pi—inorganic phosphate. (Adapted from Holick [8].)

Divalent Cation Metabolism: Calcium

Parathyroid cell Cell membrane Ca2+ Sensing receptor DNA

Ca2+

G-protein

VDRE

VDR

Nucleus OH

HO

PTH mRNA

PTH mRNA

OH

Degradation

1,25 (OH)2D3 or Calcitriol

PTH

PTH

proPTH

Secretory granules

preproPTH

Rough endoplasmic reticulum Golgi apparatus

1 PTH (mw 9600)

N

PTH-like peptide (mw 16,000)

N

34

84 C

1

-2

-1

1

2

141 C

3

4

5

PTH LYS ARG SER VAL SER GLU ILE

6

7

8

9

10

11

12

13

GLN LEU MET HIS ASN LEU GLY LYS

PTH-like peptide LYS ARG ALA VAL SER GLU HIS GLN LEU LEU HIS ASP LYS GLY LYS

5.5

FIGURE 5-8 Metabolism of parathyroid hormone (PTH). The PTH gene is located on chromosome 11p15. PTH messenger RNA (mRNA) is transcribed from the DNA fragment and then translated into a 115 amino acid– containing molecule of prepro-PTH. In the rough endoplasmic reticulum, this undergoes hydrolysis to a 90 amino acid–containing molecule, pro-PTH, which undergoes further hydrolysis to the 84 amino acid–containing PTH molecule. PTH is then stored within secretory granules in the cytoplasm for release. PTH is metabolized by hepatic Kupffer cells and renal tubular cells. Transcription of the PTH gene is inhibited by 1,25-dihydroxy-vitamin D3, calcitonin, and hypercalcemia. PTH gene transcription is increased by hypocalcemia, glucocorticoids, and estrogen. Hypercalcemia also can increase the intracellular degradation of PTH. PTH release is increased by hypocalcemia, -adrenergic agonists, dopamine, and prostaglandin E2. Hypomagnesemia blocks the secretion of PTH [7,12]. VDR— vitamin D receptor; VDRE—vitamin D responsive element. (Adapted from Tanaka and coworkers [12].) FIGURE 5-9 Parathyroid-hormone–related protein (PTHrP). PTHrP was initially described as the causative circulating factor in the humoral hypercalcemia of malignancy, particularly in breast cancer, squamous cell cancers of the lung, renal cell cancer, and other tumors. It is now clear that PTHrP can be expressed not only in cancer but also in many normal tissues. It may play an important role in the regulation of smooth muscle tone, transepithelial Ca transport (eg, in the mammary gland), and the differentiation of tissue and organ development [7,13]. Note the high degree of homology between PTHrP and PTH at the amino end of the polypeptides. MW—molecular weight; N—amino terminal; C—carboxy terminal. (From Root [7]; with permission.)

5.6

Disorders of Water, Electrolytes, and Acid-Base 50

SP 100

NH2

X

HS Inactivating Arg186Gln Asp216Glu Tyr219Glu Glu298Lys Ser608Stop Ser658Tyr Gly670Arg Pro749Arg Arg796Trp Val818Ile Stop Activating Glu128Ala

X

500

600

550

450

350

400

250

X

300

X

200

X

*

S *

S X 614

671

684

746

771

829

829 Cell membrane

636

651

701

726

793

808

863

P P

X

P

P Cysteline Conserved Acidic P PKC phosphorylation site N-glycosylation

HOOC

FIGURE 5-10 The calcium-ion sensing receptor (CaSR). The CaSR is a guanosine triphosphate (GTP) or G-protein–coupled polypeptide receptor. The human CaSR has approximately 1084 amino acid residues. The CaSR mediates the effects of Ca on parathyroid and renal tissues. CaSR also can be found in thyroidal C cells, brain cells, and in the gastrointestinal tract. The CaSR allows Ca to act as a first messenger on target tissues and then act by way of other secondmessenger systems (eg, phospholipase enzymes and cyclic adenosine monophosphate). Within parathyroid cells, hypercalcemia

increases CaSR-Ca binding, which activates the G-protein. The Gprotein then activates the phospholipase C--1–phosphatidylinositol-4,5-biphosphate pathway to increase intracellular Ca, which then decreases translation of parathyroid hormone (PTH), decreases PTH secretion, and increases PTH degradation. The CaSR also is an integral part of Ca homeostasis within the kidney. The gene for CaSR is located on human chromosome 3q13 [3,4,7,14–16]. PKC—protein kinase C; HS—hydrophobic segment; NH2—amino terminal. (From Hebert and Brown [4]; with permission.)

Divalent Cation Metabolism: Calcium

5.7

Gastrointestinal Absorption of Calcium

Gastrointestinal absorption of dietary calcium (Ca) Net Ca absorption mmol/d mg/d

Site Stomach

% of intake absorbed

0

0

0

Duodenum

0.75

30

3

Jejunum

1.0

40

4

Ileum

3.25

130

13

Colon

0

0

0

Total*

5

200

20

*Normal dietary Ca intake =1000 mg (25 mmol) per day

Lumen Ca2+ Microvilli

1

Ca2+ 2

Ca2+ 3

Ca2+ 4

Actin Myosin-I Calmodulin

Ca2+ Calbindin-Ca2+ complex

Ca2+

Free Ca2+ Micro- diffusion vesicular transport

Calbindinsynthesis

Calcitriol Nucleus

Ca2+

Exocytosis

Na Na/Ca exchange

Ca2+

~ Ca2+

Ca2+-ATPase Ca2+

Lamina propria

FIGURE 5-11 Gastrointestinal absorption of dietary calcium (Ca). The normal recommended dietary intake of Ca for an adult is 800 to 1200 mg/d (20–30 mmol/d). Foods high in Ca content include milk, dairy products, meat, fish with bones, oysters, and many leafy green vegetables (eg, spinach and collard greens). Although serum Ca levels can be maintained in the normal range by bone resorption, dietary intake is the only source by which the body can replenish stores of Ca in bone. Ca is absorbed almost exclusively within the duodenum, jejunum, and ileum. Each of these intestinal segments has a high absorptive capacity for Ca, with their relative Ca absorption being dependent on the length of each respective intestinal segment and the transit time of the food bolus. Approximately 400 mg of the usual 1000 mg dietary Ca intake is absorbed by the intestine, and Ca loss by way of intestinal secretions is approximately 200 mg/d. Therefore, a net absorption of Ca is approximately 200 mg/d (20%). Biliary and pancreatic secretions are extremely rich in Ca. 1,25-dihydroxyvitamin D3 is an extremely important regulatory hormone for intestinal absorption of Ca [1,2,17,18].

FIGURE 5-12 Proposed pathways for calcium (Ca) absorption across the intestinal epithelium. Two routes exist for the absorption of Ca across the intestinal epithelium: the paracellular pathway and the transcellular route. The paracellular pathway is passive, and it is the predominant means of Ca absorption when the luminal concentration of Ca is high. This is a nonsaturable pathway and can account for one half to two thirds of total intestinal Ca absorption. The paracellular absorptive route may be indirectly influenced by 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) because it may be capable of altering the structure of intercellular tight junctions by way of activation of protein kinase C, making the tight junction more permeable to the movement of Ca. However, 1,25(OH)2D3 primarily controls the active absorption of Ca. (1) Ca moves down its concentration gradient through a Ca channel or Ca transporter into the apical section of the microvillae. Because the intestinal concentration of Ca usually is 10-3 mol and the intracellular Ca concentration is 10-6 mol, a large concentration gradient favors the passive movement of Ca. Ca is rapidly and reversibly bound to the calmodulin-actin-myosin I complex. Ca may then move to the basolateral area of the cell by way of microvesicular transport, or ionized Ca may diffuse to this area of the cell. (2) As the calmodulin complex becomes saturated with Ca, the concentration gradient for the movement of Ca into the microvillae is not as favorable, which slows Ca absorption. (3) Under the influence of calcitriol, intestinal epithelial cells increase their synthesis of calbindin. (4) Ca binds to calbindin, thereby unloading the Ca-calmodulin complexes, which then remove Ca from the microvillae region. This decrease in Ca concentration again favors the movement of Ca into the microvillae. As the calbindin-Ca complex dissociates, the free intracellular Ca is actively extruded from the cell by either the Ca-adenosine triphosphatase (ATPase) or Na-Ca exchanger. Calcitriol may also increase the synthesis of the plasma membrane Ca-ATPase, thereby aiding in the active extrusion of Ca into the lamina propria [2,7,9,17,18].

5.8

Disorders of Water, Electrolytes, and Acid-Base

Renal Handling of Calcium Afferent arteriole

Efferent arteriole

Glomerular capillary

Bowman's space

Ca2+-Protein Ca2+ ionized

Ca2+ complexed

FIGURE 5-13 Glomerular filtration of calcium (Ca). Total serum Ca consists of ionized, protein bound, and complexed fractions (47.5%, 46.0%, and 6.5%, respectively). The complexed Ca is bound to molecules such as phosphate and citrate. The ultrafilterable Ca equals the total of the ionized and complexed fractions. Normal total serum Ca is approximately 8.9 to 10.1 mg/dL (about 2.2–2.5 mmol/L). Ca can be bound to albumin and globulins. For each 1.0 gm/dL decrease in serum albumin, total serum Ca decreases by 0.8 mg/dL; for each 1.0 gm/dL decrease in serum globulin fraction, total serum Ca decreases by 0.12 mg/dL. Ionized Ca is also affected by pH. For every 0.1 change in pH, ionized Ca changes by 0.12 mg/dL. Alkalosis decreases the ionized Ca [1,6,7].

Ca2+-ultrafilterable

Proximal tubule

Ca2+ ATPase, VDR, CaBP-D, Na+/Ca2+ exchanger colocalized here

Parathyroid hormone and 1,25(OH)2D3 Calcitonin Thiazides

CNT DCT PCT Cortex

CTAL

Medulla

MAL

Papilla

PT

Ca remaining in tubular fluid, %

100

DT

Urine

100 80 60 40 20 0

(40) (20) (10)

(2)

FIGURE 5-14 Renal handling of calcium (Ca). Ca is filtered at the glomerulus, with the ultrafilterable fraction (UFCa) of plasma Ca entering the proximal tubule (PT). Within the proximal convoluted tubule (PCT) and the proximal straight tubule (PST), isosmotic reabsorption of Ca occurs such that at the end of the PST the UFCa to TFCa ratio is about 1.1 and 60% to 70% of the filtered Ca has been reabsorbed. Passive paracellular pathways account for about 80% of Ca reabsorption in this segment of the nephron, with the remaining 20% dependent on active transcellular Ca movement. No reabsorption of Ca occurs within the thin segment of the loop of Henle. Ca is reabsorbed in small amounts within the medullary segment of the thick ascending limb (MAL) of the loop of Henle and calcitonin (CT) stimulates Ca reabsorption here. However, the cortical segments (cTAL) reabsorb about 20% of the initially filtered load of Ca. Under normal conditions, most of the Ca reabsorption in the cTAL is passive and paracellular, owing to the favorable electrochemical gradient. Active transcellular Ca transport can be stimulated by both parathyroid hormone (PTH) and 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) in the cTAL. In the early distal convoluted tubule (DCT), thiazide-activated Ca transport occurs. The DCT is the primary site in the nephron at which Ca reabsorption is regulated by PTH and 1,25(OH)2D3. Active transcellular Ca transport must account for Ca reabsorption in the DCT, because the transepithelial voltage becomes negative, which would not favor passive movement of Ca out of the tubular lumen. About 10% of the filtered Ca is reabsorbed in the DCT, with another 3% to 10% of filtered Ca reabsorbed in the connecting tubule (CNT) by way of mechanisms similar to those in the DCT [1,2,6, 7,18]. ATPase—adenosine triphosphatase; CaBP-D—Cabinding protein D; DT—distal tubule; VDR—vitamin D receptor. (Adapted from Kumar [1].)

Divalent Cation Metabolism: Calcium Cortical thick ascending limb

5 Ca2+,

+

Mg2+

– +

Na 2Cl–

↑Ca2+

+

K

2 – PK-C PLA2 3 AA P-450 system 4 20-HETE

Urinary space –

K+

Ca2+

G-protein

IP3

cAMP

1 CaSR

– ATP Hormone recptor

5 Ca2+, Mg2+

–

Hormone

+

DHP sensitive channel Ca2+

+

Thiazide sensitive channel Ca2+

Ca2+

Tubular lumen

Distal convoluted tubule cell

Ca2+

CaBP28

CaBP9 Ca2+

cAMP ATP PTH

+

Nucleus +

?+

VDR

Na+ ~ PMCA Ca2+ Ca2+

Calcitriol

5.9

FIGURE 5-15 Effects of hypercalcemia on calcium (Ca) reabsorption in the cortical thick ascending limb (cTAL) of the loop of Henle and urinary concentration. (1) Hypercalcemia stimulates the Ca-sensing receptor (CaSR) of cells in the cTAL. (2) Activation of the G-protein increases intracellular free ionized Ca (Ca2+) by way of the inositol 1,4,5-trisphosphate (IP3) pathway, which increases the activity of the P450 enzyme system. The G-protein also increases activity of phospholipase A2 (PLAA), which increases the concentration of arachidonic acid (AA). (3) The P450 enzyme system increases production of 20-hydroxy-eicosatetraenoic acid (20HETE) from AA. (4) 20-HETE inhibits hormone-stimulated production of cyclic adenosine monophosphate (cAMP), blocks sodium reabsorption by the sodium-potassium-chloride (Na-K-2Cl) cotransporter, and inhibits movement of K out of K-channels. (5) These changes alter the electrochemical forces that would normally favor the paracellular movement of Ca (and Mg) such that Ca (and Mg) is not passively reabsorbed. Both the lack of movement of Na into the renal interstitium and inhibition of hormonal (eg, vasopressin) effects impair the ability of the nephron to generate maximally concentrated urine [3,4,14]. ATP—adenosine triphosphate; PK-C—protein kinase C. FIGURE 5-16 Postulated mechanism of the Ca transport pathway shared by PTH and 1,25(OH)2D3. Cyclic adenosine monophosphate (cAMP) generated by PTH stimulation leads to increased influx of Ca into the apical dihydropyridine-sensitive Ca channel. There also is increased activity of the basolateral Na-Ca exchanger and, perhaps, of the plasma membrane–associated Ca-adenosine triphosphatase (PMCA), which can rapidly extrude the increased intracellular free Ca (Ca2+). Calcitriol (1,25(OH)2D3), by way of the vitamin D receptor (VDR), stimulates transcription of calbindin D28k (CaBP28) and calbindin D9k (CaBP9). CaBP28 increases apical uptake of Ca by both the dihydropyridine- and thiazide-sensitive Ca channels by decreasing the concentration of unbound free Ca2+ and facilitates Ca movement to the basolateral membrane. CaBP9 stimulates PMCA activity, which increases extrusion of Ca by the cell. Similar hormonally induced mechanisms of Ca transport are believed to exist throughout the cortical thick ascending limb, the DCT, and the connecting tubule (CNT) [6]. ATP—adenosine triphosphate; Na+—ionized sodium.

5.10

Disorders of Water, Electrolytes, and Acid-Base

Disturbances of Serum Calcium Hypocalcemia Parathyroid glands

Kidney

+ + PTH↑

Gastrointestinal tract

+ PT

DCT

+ PTH

Parathyroid cell

Nucleus

FIGURE 5-17 Physiologic response to hypocalcemia. Hypocalcemia stimulates both parathyroid hormone (PTH) release and PTH synthesis. Both hypocalcemia and PTH increase the activity of the 1--hydroxylase enzyme in the proximal tubular (PT) cells of the nephron, which increases the synthesis of 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3). PTH increases bone resorption by osteoclasts. PTH and 1,25(OH)2D3 stimulate Ca reabsorption in the distal convoluted tubule (DCT). 1,25(OH)2D3 increases the fractional absorption of dietary Ca by the gastrointestinal (GI) tract. All these mechanisms aid in returning the serum Ca to normal levels [1].

+

Bone

+ 1,25(OH)2D3↑

↑Intestinal Ca2+ absorption

↓Renal Ca2+ excretion

↑Bone resorption

Normocalcemia

FIGURE 5-18 Causes of hypocalcemia (decrease in ionized plasma calcium).

CAUSES OF HYPOCALCEMIA Lack of parathyroid hormone (PTH)

Increased calcium complexation

After thyroidectomy or parathyroidectomy Hereditary (congenital) hypoparathyroidism Pseudohypoparathyroidism (lack of effective PTH) Hypomagnesemia (blocks PTH secretion)

“Bone hunger” after parathyroidectomy Rhabdomyolysis Acute pancreatitis Tumor lysis syndrome (hyperphosphatemia) Malignancy (increased osteoblastic activity)

Lack of Vitamin D Dietary deficiency or malabsorption (osteomalacia) Inadequate sunlight Defective metabolism Anticonvulsant therapy Liver disease Renal disease Vitamin D–resistant rickets

Divalent Cation Metabolism: Calcium

Hypercalcemia

Thyroid and parathyroid glands

+

Kidney

–

C-cells

↑CT –

+

PTH↑

Gastrointestinal tract

–

– PT

DCT

– PTH

Parathyroid cell Nucleus

– –

–

–

Bone

1,25(OH)2D3↓

↓Intestinal Ca2+ absorption

↑Renal Ca2+ excretion

FIGURE 5-19 Physiologic response to hypercalcemia. Hypercalcemia directly inhibits both parathyroid hormone (PTH) release and synthesis. The decrease in PTH and hypercalcemia decrease the activity of the 1--hydroxylase enzyme located in the proximal tubular (PT) cells of the nephron, which in turn, decreases the synthesis of 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3). Hypercalcemia stimulates the C cells in the thyroid gland to increase synthesis of calcitonin (CT). Bone resorption by osteoclasts is blocked by the increased CT and decreased PTH. Decreased levels of PTH and 1,25(OH)2D3 inhibit Ca reabsorption in the distal convoluted tubules (DCT) of the nephrons and overwhelm the effects of CT, which augment Ca reabsorption in the medullary thick ascending limb leading to an increase in renal Ca excretion. The decrease in 1,25(OH)2D3 decreases gastrointestinal (GI) tract absorption of dietary Ca. All of these effects tend to return serum Ca to normal levels [1].

↓Bone resorption

Normocalcemia

FIGURE 5-20 Causes of hypercalcemia (increase in ionized plasma calcium).

CAUSES OF HYPERCALCEMIA Excess parathyroid hormone (PTH) production

Increased intestinal absorption of calcium

Primary hyperparathyroidism “Tertiary” hyperparathyroidism*

Vitamin D intoxication Milk-alkali syndrome*

Excess 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3)

Decreased renal excretion of calcium

Vitamin D intoxication Sarcoidosis and granulomatous diseases Severe hypophosphatemia Neoplastic production of 1,25(OH)2D3 (lymphoma)

Familial hypocalciuric hypercalcemia Thiazides

Increased bone resorption

Aluminum intoxication* Adynamic (“low-turnover”) bone disease* Corticosteroids

Metastatic (osteolytic) tumors (eg, breast, colon, prostate) Humoral hypercalcemia PTH-related protein (eg, squamous cell lung, renal cell cancer) Osteoclastic activating factor (myeloma) 1,25 (OH)2D3 (lymphoma) Prostaglandins Hyperthyroidism Immobilization Paget disease Vitamin A intoxication *Occurs in renal failure.

Impaired bone formation and incorporation of calcium

5.11

5.12

Disorders of Water, Electrolytes, and Acid-Base FIGURE 5-21 Therapy available for the treatment of hypercalcemia.

AVAILABLE THERAPY FOR HYPERCALCEMIA* Agent

Mechanism of action

Saline and loop diuretics Corticosteroids

Increase renal excretion of calcium Block 1,25-dihydroxy-vitamin D3 synthesis and bone resorption Blocks P450 system, decreases 1, 25-dihydroxy-vitamin D3 Complexes calcium Inhibits bone resorption Inhibits bone resorption Inhibit bone resorption

Ketoconazole Oral or intravenous phosphate Calcitonin Mithramycin Bisphosphonates

*Always identify and treat the primary cause of hypercalcemia.

Secondary Hyperparathyroidism Renal failure

↓Number of nephrons

–

PT

–

↓H+ excretion ↓P excretion 1,25(OH)2D3↓

Hyperphosphatemia

↓Ca absorption

Gastrointestinal tract

Hypocalcemia

↓Activity

↓Activity

VDR

↓Degradation of PTH ↑PTH

CaSR Increased transcription

Release PTH

Hyperparathyroidism

ProPTH Pre-proPTH Parathyroid cell

↑Proliferation Nucleus

FIGURE 5-22 Pathogenesis of secondary hyperparathyroidism (HPT) in chronic renal failure (CRF). Decreased numbers of proximal tubular (PT) cells, owing to loss of renal mass, cause a quantitative decrease in synthesis of 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3). Loss of renal mass also impairs renal phosphate (P) and acid (H+) excretion. These impairments further decrease the activity of the 1--hydroxylase enzyme in the remaining PT cells, further contributing to the decrease in levels of 1,25(OH)2D3. 1,25(OH)2D3 deficiency decreases intestinal absorption of calcium (Ca), leading to hypocalcemia, which is augmented by the direct effect of hyperphosphatemia. Hypocalcemia and hyperphosphatemia stimulate PTH release and synthesis and can recruit inactive parathyroid cells into activity and PTH production. Hypocalcemia also may decrease intracellular degradation of PTH. The lack of 1,25(OH)2D3, which would ordinarily feed back to inhibit the transcription of prepro-PTH and exert an antiproliferative effect on parathyroid cells, allows the increased PTH production to continue. In CRF there may be decreased expression of the Ca-sensing receptor (CaSR) in parathyroid cells, making them less sensitive to levels of plasma Ca. Patients with the b allele or the bb genotype vitamin D receptor (VDR) may be more susceptible to HPT, because the VDR1,25(OH)2D3 complex is less effective at suppressing PTH production and cell proliferation. The deficiency of 1,25(OH)2D3 may also decrease VDR synthesis, making parathyroid cells less sensitive to 1,25(OH)2D3. Although the PTH receptor in bone cells is downregulated in CRF (ie, for any level of PTH, bone cell activity is lower in CRF patients than in normal persons), the increased plasma levels of PTH may have harmful effects on other systems (eg, cardiovascular system, nervous system, and integument) by way of alterations of intracellular Ca. Current therapeutic methods used to decrease PTH release in CRF include correction of hyperphosphatemia, maintenance of normal to high-normal levels of plasma Ca, administration of 1,25(OH)2D3 orally or intravenously, and administration of a Ca-ion sensing receptor (CaSR) agonist [14–16,19–22].

Divalent Cation Metabolism: Calcium

5.13

Calcium and Vitamin D Preparations FIGURE 5-23 Calcium (Ca) content of oral Ca preparations.

CALCIUM CONTENT OF ORAL CALCIUM PREPARATIONS

Calcium (Ca) salt Carbonate Acetate Citrate Lactate Gluconate

Tablet size, mg

Elemental Ca, mg, %

1250 667 950 325 500

500 (40) 169 (25) 200 (21) 42 (13) 4.5 (9)

Fractional intestinal absorption of Ca may differ between Ca salts. Data from McCarthy and Kumar [19] and Physicians’ Desk Reference [23].

VITAMIN D PREPARATIONS AVAILABLE IN THE UNITED STATES

Ergocalciferol (Vitamin D2)

Calcifediol (25-hydroxy-vitamin D3)

Dihydrotachysterol

Commercial name

Calciferol

Calderol® (Organon, Inc, West Orange, NJ)

DHT Intensol® (Roxane Laboratories, Columbus, OH)

Oral preparations

50,000 IU tablets

20- and 50-µg capsules

0.125-, 0.2-, 0.4-mg tablets

Rocaltrol® (Roche Laboratories, Nutley, NJ) Calcijex® (Abbott Laboratories, Abbott Park, NJ) 0.25- and 0.50-µg capsules

50,000–500,000 IU Not used 4–8 wk

20–200 µg 20–40 µg* 2–4 wk

0.2–1.0 mg 0.2-0.4 mg* 1–2 wk

0.25–5.0 µg 0.25–0.50 µg 4–7 d

17–60 d

7–30 d

3–14 d

2–10 d

Usual daily dose Hypoparathyroidism Renal failure Time until increase in serum calcium† Time for reversal of toxic effects

*Not currently advised in patients with chronic renal failure. †In patients with hypoparathyroidism who have normal renal function.

Data from McCarthy and Kumar [19] and Physicians’ Desk Reference [23].

FIGURE 5-24 Vitamin D preparations.

Calcitriol (1,25-dihydroxy-vitamin D3)

5.14

Disorders of Water, Electrolytes, and Acid-Base

References 1. Kumar R: Calcium metabolism. In The Principles and Practice of Nephrology. Edited by Jacobson HR, Striker GE, Klahr S. St. Louis: Mosby-Year Book; 1995, 964–971. 2. Johnson JA, Kumar R: Renal and intestinal calcium transport: roles of vitamin D and vitamin D-dependent calcium binding proteins. Semin Nephrol 1994, 14:119–128. 3. Hebert SC, Brown EM, Harris HW: Role of the Ca2+-sensing receptor in divalent mineral ion homeostasis. J Exp Biol 1997, 200:295–302. 4. Hebert SC, Brown EM: The scent of an ion: calcium-sensing and its roles in health and disease. Curr Opinion Nephrol Hypertens 1996, 5:45–53. 5. Berridge MJ: Elementary and global aspects of calcium signalling. J Exp Biol 1997, 200:315–319. 6. Friedman PA, Gesek FA: Cellular calcium transport in renal epithelia: measurement, mechanisms, and regulation. Physiol Rev 1995, 75:429–471. 7. Root AW: Recent advances in the genetics of disorders of calcium homeostasis. Adv Pediatr 1996, 43:77–125. 8. Holick MF: Defects in the synthesis and metabolism of vitamin D. Exp Clin Endocrinol 1995, 103:219–227. 9. Kumar R: Calcium transport in epithelial cells of the intestine and kidney. J Cell Biochem 1995, 57:392–398. 10. White CP, Morrison NA, Gardiner EM, Eisman JA: Vitamin D receptor alleles and bone physiology. J Cell Biochem 1994, 56:307–314. 11. Fernandez E, Fibla J, Betriu A, et al.: Association between vitamin D receptor gene polymorphism and relative hypoparathyroidism in patients with chronic renal failure. J Am Soc Nephrol 1997, 8:1546–1552. 12. Tanaka Y, Funahashi J, Imai T, et al.: Parathyroid function and bone metabolic markers in primary and secondary hyperparathyroidism. Sem Surg Oncol 1997, 13:125–133.

13. Philbrick WM, Wysolmerski JJ, Galbraith S, et al.: Defining the roles of parathyroid hormone-related protein in normal physiology. Physiol Rev 1996, 76:127–173. 14. Goodman WG, Belin TR, Salusky IB: In vivo> assessments of calcium-regulated parathyroid hormone release in secondary hyperparathyroidism [editorial review]. Kidney Int 1996, 50:1834–1844. 15. Chattopadhyay N, Mithal A, Brown EM: The calcium-sensing receptor: a window into the physiology and pathophysiology of mineral ion metabolism. Endocrine Rev 1996, 17:289–307. 16. Nemeth EF, Steffey ME, Fox J: The parathyroid calcium receptor: a novel therapeutic target for treating hyperparathyroidism. Pediatr Nephrol 1996, 10:275–279. 17. Wasserman RH, Fullmer CS: Vitamin D and intestinal calcium transport: facts, speculations and hypotheses. J Nutr 1995, 125:1971S–1979S. 18. Johnson JA, Kumar R: Vitamin D and renal calcium transport. Curr Opinion Nephrol Hypertens 1994, 3:424–429. 19. McCarthy JT, Kumar R: Renal osteodystrophy. In The Principles and Practice of Nephrology. Edited by Jacobson HR, Striker GE, Klahr S. St. Louis: Mosby-Year Book; 1995, 1032–1045. 20. Felsenfeld AJ: Considerations for the treatment of secondary hyperparathyroidism in renal failure. J Am Soc Nephrol 1997, 8:993–1004. 21. Parfitt AM. The hyperparathyroidism of chronic renal failure: a disorder of growth. Kidney Int 1997, 52:3–9. 22. Salusky IB, Goodman WG: Parathyroid gland function in secondary hyperparathyroidism. Pediatr Nephrol 1996, 10:359–363. 23. Physicians’ Desk Reference (PDR). Montvale NJ: Medical Economics Company; 1996.

Disorders of Acid-Base Balance Horacio J. Adrogué Nicolaos E. Madias

M

aintenance of acid-base homeostasis is a vital function of the living organism. Deviations of systemic acidity in either direction can impose adverse consequences and when severe can threaten life itself. Acid-base disorders frequently are encountered in the outpatient and especially in the inpatient setting. Effective management of acid-base disturbances, commonly a challenging task, rests with accurate diagnosis, sound understanding of the underlying pathophysiology and impact on organ function, and familiarity with treatment and attendant complications [1]. Clinical acid-base disorders are conventionally defined from the vantage point of their impact on the carbonic acid-bicarbonate buffer system. This approach is justified by the abundance of this buffer pair in body fluids; its physiologic preeminence; and the validity of the isohydric principle in the living organism, which specifies that all the other buffer systems are in equilibrium with the carbonic acid-bicarbonate buffer pair. Thus, as indicated by the Henderson equation, [H+] = 24  PaCO2/[HCO3] (the equilibrium relationship of the carbonic acid-bicarbonate system), the hydrogen ion concentration of blood ([H+], expressed in nEq/L) at any moment is a function of the prevailing ratio of the arterial carbon dioxide tension (PaCO2, expressed in mm Hg) and the plasma bicarbonate concentration ([HCO3], expressed in mEq/L). As a corollary, changes in systemic acidity can occur only through changes in the values of its two determinants, PaCO2 and the plasma bicarbonate concentration. Those acid-base disorders initiated by a change in PaCO2 are referred to as respiratory disorders; those initiated by a change in plasma bicarbonate concentration are known as metabolic disorders. There are four cardinal acid-base disturbances: respiratory acidosis, respiratory alkalosis, metabolic acidosis, and metabolic alkalosis. Each can be encountered alone, as a simple disorder, or can be a part of a mixeddisorder, defined as the simultaneous presence of two or more simple

CHAPTER

6

6.2

Disorders of Water, Electrolytes, and Acid-Base

acid-base disturbances. Mixed acid-base disorders are frequently observed in hospitalized patients, especially in the critically ill. The clinical aspects of the four cardinal acid-base disorders are depicted. For each disorder the following are

illustrated: the underlying pathophysiology, secondary adjustments in acid-base equilibrium in response to the initiating disturbance, clinical manifestations, causes, and therapeutic principles.

Respiratory Acidosis Arterial blood [H+], nEq/L 150 125

100

80 70 60

PaCO2 mm Hg

50

40

30

120 100 90 80 70

20 60

50 40

iratory ic resp Chron acidosis

Arterial plasma [HCO–3], mEq/L

50

40

30

30

Acute respira tory acidosis Normal

20

20 10

10

6.8

6.9

7.0

7.1

7.2

7.3

7.4

7.5

7.6

7.7

Arterial blood pH Steady-state relationships in respiratory acidosis: average increase per mm Hg rise in PaCO2 [HCO–3] mEq/L

[H+] nEq/L

Acute adaptation

0.1

0.75

Chronic adaptation

0.3

0.3

FIGURE 6-1 Quantitative aspects of adaptation to respiratory acidosis. Respiratory acidosis, or primary hypercapnia, is the acid-base disturbance initiated by an increase in arterial carbon dioxide tension (PaCO2) and entails acidification of body fluids. Hypercapnia elicits adaptive increments in plasma bicarbonate concentration that should be viewed as an integral part of respiratory acidosis. An immediate increment in plasma bicarbonate occurs in response to hypercapnia. This acute adaptation is complete within 5 to 10 minutes from the onset of hypercapnia and originates exclusively from acidic titration of the nonbicarbonate buffers of the body (hemoglobin, intracellular proteins and phosphates, and to a lesser extent plasma proteins). When hypercapnia is sustained, renal adjustments markedly amplify the secondary increase in plasma bicarbonate, further ameliorating the resulting acidemia. This chronic adaptation requires 3 to 5 days for completion and reflects generation of new bicarbonate by the kidneys as a result of upregulation of renal acidification [2]. Average increases in plasma bicarbonate and hydrogen ion concentrations per mm Hg increase in PaCO2 after completion of the acute or chronic adaptation to respiratory acidosis are shown. Empiric observations on these adaptations have been used for construction of 95% confidence intervals for graded degrees of acute or chronic respiratory acidosis represented by the areas in color in the acid-base template. The black ellipse near the center of the figure indicates the normal range for the acid-base parameters [3]. Note that for the same level of PaCO2, the degree of acidemia is considerably lower in chronic respiratory acidosis than it is in acute respiratory acidosis. Assuming a steady state is present, values falling within the areas in color are consistent with but not diagnostic of the corresponding simple disorders. Acid-base values falling outside the areas in color denote the presence of a mixed acid-base disturbance [4].

Eucapnia

Stable Hypercapnia

Bicarbonate reabsorption

Chloride excretion

Net acid excretion

Disorders of Acid-Base Balance

0

1

2 Days

3

4

5

FIGURE 6-2 Renal acidification response to chronic hypercapnia. Sustained hypercapnia entails a persistent increase in the secretory rate of the renal tubule for hydrogen ions (H+) and a persistent decrease in the reabsorption rate of chloride ions (Cl-). Consequently, net acid excretion (largely in the form of ammonium) transiently exceeds endogenous

6.3

acid production, leading to generation of new bicarbonate ions (HCO3) for the body fluids. Conservation of these new bicarbonate ions is ensured by the gradual augmentation in the rate of renal bicarbonate reabsorption, itself a reflection of the hypercapnia-induced increase in the hydrogen ion secretory rate. A new steady state emerges when two things occur: the augmented filtered load of bicarbonate is precisely balanced by the accelerated rate of bicarbonate reabsorption and net acid excretion returns to the level required to offset daily endogenous acid production. The transient increase in net acid excretion is accompanied by a transient increase in chloride excretion. Thus, the resultant ammonium chloride (NH4Cl) loss generates the hypochloremic hyperbicarbonatemia characteristic of chronic respiratory acidosis. Hypochloremia is sustained by the persistently depressed chloride reabsorption rate. The specific cellular mechanisms mediating the renal acidification response to chronic hypercapnia are under active investigation. Available evidence supports a parallel increase in the rates of the luminal sodium ion– hydrogen ion (Na+-H+) exchanger and the basolateral Na+-3HCO3 cotransporter in the proximal tubule. However, the nature of these adaptations remains unknown [5]. The quantity of the H+-adenosine triphosphatase (ATPase) pumps does not change in either cortex or medulla. However, hypercapnia induces exocytotic insertion of H+ATPase–containing subapical vesicles to the luminal membrane of proximal tubule cells as well as type A intercalated cells of the cortical and medullary collecting ducts. New H+-ATPase pumps thereby are recruited to the luminal membrane for augmented acidification [6,7]. Furthermore, chronic hypercapnia increases the steady-state abundance of mRNA coding for the basolateral Cl—HCO3 exchanger (band 3 protein) of type A intercalated cells in rat renal cortex and medulla, likely indicating increased band 3 protein levels and therefore augmented basolateral anion exchanger activity [8].

SIGNS AND SYMPTOMS OF RESPIRATORY ACIDOSIS

Central Nervous System

Respiratory System

Cardiovascular System

Mild to moderate hypercapnia Cerebral vasodilation Increased intracranial pressure Headache Confusion Combativeness Hallucinations Transient psychosis Myoclonic jerks Flapping tremor Severe hypercapnia Manifestations of pseudotumor cerebri Stupor Coma Constricted pupils Depressed tendon reflexes Extensor plantar response Seizures Papilledema

Breathlessness Central and peripheral cyanosis (especially when breathing room air) Pulmonary hypertension

Mild to moderate hypercapnia Warm and flushed skin Bounding pulse Well maintained cardiac output and blood pressure Diaphoresis Severe hypercapnia Cor pulmonale Decreased cardiac output Systemic hypotension Cardiac arrhythmias Prerenal azotemia Peripheral edema

FIGURE 6-3 Signs and symptoms of respiratory acidosis. The effects of respiratory acidosis on the central nervous system are collectively known as hypercapnic encephalopathy. Factors responsible for

its development include the magnitude and time course of the hypercapnia, severity of the acidemia, and degree of attendant hypoxemia. Progressive narcosis and coma may occur in patients receiving uncontrolled oxygen therapy in whom levels of arterial carbon dioxide tension (PaCO2) may reach or exceed 100 mm Hg. The hemodynamic consequences of carbon dioxide retention reflect several mechanisms, including direct impairment of myocardial contractility, systemic vasodilation caused by direct relaxation of vascular smooth muscle, sympathetic stimulation, and acidosis-induced blunting of receptor responsiveness to catecholamines. The net effect is dilation of systemic vessels, including the cerebral circulation; whereas vasoconstriction might develop in the pulmonary and renal circulations. Salt and water retention commonly occur in chronic hypercapnia, especially in the presence of cor pulmonale. Mechanisms at play include hypercapnia-induced stimulation of the renin-angiotensin-aldosterone axis and the sympathetic nervous system, elevated levels of cortisol and antidiuretic hormone, and increased renal vascular resistance. Of course, coexisting heart failure amplifies most of these mechanisms [1,2].

6.4

Disorders of Water, Electrolytes, and Acid-Base

Load

Pump Cerebrum Voluntary control Controller

Ventilatory requirement (CO2 production, O2 consumption)

Brain stem Automatic control Spinal cord Airway resistance Phrenic and intercostal nerves Lung elastic recoil

Effectors Muscles of respiration

∆V

∆V Ppl

Pabd

Chest wall elastic recoil Diaphragm

Abdominal cavity

FIGURE 6-4 Main components of the ventilatory system. The ventilatory system is responsible for maintaining the arterial carbon dioxide tension (PaCO2) within normal limits by adjusting minute ventilation • (V) to match the rate of carbon dioxide production. The main elements of ventilation are the respiratory pump, which generates a pressure gradient responsible for air flow, and the loads that oppose such action. The machinery of the respiratory pump includes the cerebrum, brain stem, spinal cord, phrenic and intercostal nerves, and the muscles of respiration. Inspiratory muscle contraction lowers pleural pressure (Ppl) thereby inflating the lungs (V). The diaphragm, the most important inspiratory muscle, moves downward as a piston at the floor of the thorax, raising abdominal pressure (Pabd). The inspiratory decrease in Ppl by the respiratory pump must be sufficient to counterbalance the opposing effect of the combined loads, including the airway flow resistance, and the elastic recoil of the lungs and chest wall. The ventilatory requirement influences the load by altering the frequency and depth of the ventilatory cycle. The strength of the respiratory pump is evaluated by the pressure generated (P = Ppl - Pabd).

Disorders of Acid-Base Balance

6.5

DETERMINANTS AND CAUSES OF CARBON DIOXIDE RETENTION Respiratory Pump Depressed Central Drive Acute General anesthesia Sedative overdose Head trauma Cerebrovascular accident Central sleep apnea Cerebral edema Brain tumor Encephalitis Brainstem lesion Chronic Sedative overdose Methadone or heroin addiction Sleep disordered breathing Brain tumor Bulbar poliomyelitis Hypothyroidism

Abnormal Neuromuscular Transmission Acute High spinal cord injury Guillain-Barré syndrome Status epilepticus Botulism Tetanus Crisis in myasthenia gravis Hypokalemic myopathy Familial periodic paralysis Drugs or toxic agents eg, curare, succinylcholine, aminoglycosides, organophosphorus Chronic Poliomyelitis Multiple sclerosis Muscular dystrophy Amyotrophic lateral sclerosis Diaphragmatic paralysis Myopathic disease eg, polymyositis Muscle Dysfunction Acute Fatigue Hyperkalemia Hypokalemia Hypoperfusion state Hypoxemia Malnutrition Chronic Myopathic disease eg, polymyositis

FIGURE 6-5 Determinants and causes of carbon dioxide retention. When the respiratory pump is unable to balance the opposing load, respiratory acidosis develops. Decreases in respiratory pump strength, increases in load, or a combination of the two, can result in carbon dioxide retention. Respiratory pump failure can occur because of depressed central drive, abnormal neuromuscular transmission, or respiratory

Load Increased Ventilatory Demand High carbohydrate diet Sorbent-regenerative hemodialysis Pulmonary thromboembolism Fat, air pulmonary embolism Sepsis Hypovolemia Augmented Airway Flow Resistance Acute Upper airway obstruction Coma-induced hypopharyngeal obstruction Aspiration of foreign body or vomitus Laryngospasm Angioedema Obstructive sleep apnea Inadequate laryngeal intubation Laryngeal obstruction after intubation Lower airway obstruction Generalized bronchospasm Airway edema and secretions Severe episode of spasmodic asthma Bronchiolitis of infants and adults Chronic Upper airway obstruction Tonsillar and peritonsillar hypertrophy Paralysis of vocal cords Tumor of the cords or larynx Airway stenosis after prolonged intubation Thymoma, aortic aneurysm Lower airway obstruction Airway scarring Chronic obstructive lung disease eg, bronchitis, bronchiolitis, bronchiectasis, emphysema

Lung Stiffness Acute Severe bilateral pneumonia or bronchopneumonia Acute respiratory distress syndrome Severe pulmonary edema Atelectasis Chronic Severe chronic pneumonitis Diffuse infiltrative disease eg, alveolar proteinosis Interstitial fibrosis Chest Wall Stiffness Acute Rib fractures with flail chest Pneumothorax Hemothorax Abdominal distention Ascites Peritoneal dialysis Chronic Kyphoscoliosis, spinal arthritis Obesity Fibrothorax Hydrothorax Chest wall tumor

muscle dysfunction. A higher load can be caused by increased ventilatory demand, augmented airway flow resistance, and stiffness of the lungs or chest wall. In most cases, causes of the various determinants of carbon dioxide retention, and thus respiratory acidosis, are categorized into acute and chronic subgroups, taking into consideration their usual mode of onset and duration [2].

6.6

Disorders of Water, Electrolytes, and Acid-Base Spontaneous breathing

FIGURE 6-6 Posthypercapnic metabolic alkalosis. Development of posthypercapnic metabolic alkalosis is shown after abrupt normalization of the arterial carbon dioxide tension (PaCO2) by way of mechanical ventilation in a 70-year-old man with respiratory decompensation who has chronic obstructive pulmonary disease and chronic hypercapnia. The acute decrease in plasma bicarbonate concentration ([HCO3]) over the first few minutes after the decrease in PaCO2 originates from alkaline titration of the nonbicarbonate buffers of the body. When a diet rich in chloride (Cl-) is provided, the excess bicarbonate is excreted by the kidneys over the next 2 to 3 days, and acidbase equilibrium is normalized. In contrast, a low-chloride diet sustains the hyperbicarbonatemia and perpetuates the posthypercapnic metabolic alkalosis. Abrupt correction of severe hypercapnia by way of mechanical ventilation generally is not recommended. Rather, gradual return toward the patient’s baseline PaCO2 level should be pursued [1,2]. [H+]—hydrogen ion concentration.

Mechanical ventilation

PaCO2, mm Hg

80

60

40

[HCO–3], mEq/L

40 Low-Cl– diet – Cl - rich diet

30

Cl–- rich diet

20

pH

7.50

30

7.40

40

7.30

50

7.20

60 0

2

4

6

[H+], nEq/L

7.60

8

Days

Airway patency secured?

No

Remove dentures, foreign bodies, or food particles; Heimlich maneuver (subdiaphragmatic abdominal thrust); tracheal intubation; tracheotomy

ent pat y a w Air

Yes Oxygen-rich mixture delivered

Mental status and blood gases evaluated

Alert, blood pH > 7.10, or PaCO2 <60 mm Hg

Obtunded, blood pH < 7.10, or PaCO2 > 60 mm Hg

• Administer O2 via nasal mask or prongs to maintain PaO2 > 60 mm Hg. • Correct reversible causes of pulmonary dysfunction with antibiotics, bronchodilators, and corticosteroids as needed. • Monitor patient with arterial blood gases initially at intervals of 20 to 30 minutes and less frequently thereafter. • If PaO2 does not increase to > 60 mm Hg or PaCO2 rises to > 60 mm Hg proceed to steps described in the box below. • Consider intubation and initiation of mechanical ventilation. • If blood pH is below 7.10 during mechanical ventilation, consider administration of sodium bicarbonate, to maintain blood pH between 7.10 and 7.20, while monitoring arterial blood gases closely. • Correct reversible causes of pulmonary dysfunction as in box above.

FIGURE 6-7 Acute respiratory acidosis management. Securing airway patency and delivering an oxygen-rich mixture are critical initial steps in management. Subsequent measures must be directed at identifying and correcting the underlying cause, whenever possible [1,9]. PaCO2—arterial carbon dioxide tension.

Disorders of Acid-Base Balance

Yes

PaO2 > 60 mm Hg on room air

PaO2 < 55 mm Hg

PaO2 ≥ 55 mm Hg, patient stable

• Consider intubation and use of standard ventilator support. • Correct reversible causes of pulmonary dysfunction with antibiotics, bronchodilators, and corticosteroids as needed.

Mental status deteriorates

• Administer O2 via nasal cannula or Venti mask • Correct reversible causes of pulmonary dysfuntion with antibiotics, bronchodilators, and corticosteroids as needed.

No

Yes

Observation, routine care.

Hemodynamic instability

No

CO2 retention worsens

Severe hypercapnic encephalopathy or hemodynamic instability

• Consider use of noninvasive nasal mask ventilation (NMV) or intubation and standard ventilator support.

6.7

FIGURE 6-8 Chronic respiratory acidosis management. Therapeutic measures are guided by the presence or absence of severe hypercapnic encephalopathy or hemodynamic instability. An aggressive approach that favors the early use of ventilator assistance is most appropriate for patients with acute respiratory acidosis. In contrast, a more conservative approach is advisable in patients with chronic hypercapnia because of the great difficulty often encountered in weaning these patients from ventilators. As a rule, the lowest possible inspired fraction of oxygen that achieves adequate oxygenation (PaO2 on the order of 60 mm Hg) is used. Contrary to acute respiratory acidosis, the underlying cause of chronic respiratory acidosis only rarely can be resolved [1,9].

• Continue same measures.

Respiratory Alkalosis Arterial blood [H+], nEq/L 150 125

100

80 70 60

PaCO2 mm Hg

50

40

30

120 100 90 80 70

20 60

50 40

40

30

30 Normal

20 Acut e resp alkalo iratory sis

ato pir res osis nic al ro alk

Ch

Arterial plasma [HCO–3], mEq/L

50

20

10

ry

10

6.8

6.9

7.0

7.1

7.2

7.3

7.4

7.5

7.6

7.7

Arterial blood pH Steady-state relationships in respiratory alkalosis: average decrease per mm Hg fall in PaCO2 Acute adaptation Chronic adaptation

[HCO–3] mEq/L 0.2

[H+] nEq/L 0.75

0.4

0.4

FIGURE 6-9 Adaptation to respiratory alkalosis. Respiratory alkalosis, or primary hypocapnia, is the acid-base disturbance initiated by a decrease in arterial carbon dioxide tension (PaCO2) and entails alkalinization of body fluids. Hypocapnia elicits adaptive decrements in plasma bicarbonate concentration that should be viewed as an integral part of respiratory alkalosis. An immediate decrement in plasma bicarbonate occurs in response to hypocapnia. This acute adaptation is complete within 5 to 10 minutes from the onset of hypocapnia and is accounted for principally by alkaline titration of the nonbicarbonate buffers of the body. To a lesser extent, this acute adaptation reflects increased production of organic acids, notably lactic acid. When hypocapnia is sustained, renal adjustments cause an additional decrease in plasma bicarbonate, further ameliorating the resulting alkalemia. This chronic adaptation requires 2 to 3 days for completion and reflects retention of hydrogen ions by the kidneys as a result of downregulation of renal acidification [2,10]. Shown are the average decreases in plasma bicarbonate and hydrogen ion concentrations per mm Hg decrease in PaCO2after completion of the acute or chronic adaptation to respiratory alkalosis. Empiric observations on these adaptations have been used for constructing 95% confidence intervals for graded degrees of acute or chronic respiratory alkalosis, which are represented by the areas in color in the acid-base template. The black ellipse near the center of the figure indicates the normal range for the acid-base parameters. Note that for the same level of PaCO2, the degree of alkalemia is considerably lower in chronic than it is in acute respiratory alkalosis. Assuming that a steady state is present, values falling within the areas in color are consistent with but not diagnostic of the corresponding simple disorders. Acid-base values falling outside the areas in color denote the presence of a mixed acid-base disturbance [4].

6.8

Disorders of Water, Electrolytes, and Acid-Base

Stable Hypocapnia

Bicarbonate reabsorption

Sodium excretion

Net acid excretion

Eucapnia

0

1

2

3

Days Km

Vmax

NS

P<0.01

1000 nmol/mg protein × min

mmol/L

10

5

Control

Chronic hypocapnia (9% O2)

500

Control

Chronic hypocapnia (9% O2)

FIGURE 6-10 Renal acidification response to chronic hypocapnia. A, Sustained hypocapnia entails a persistent decrease in the renal tubular secretory rate of hydrogen ions and a persistent increase in the chloride reabsorption rate. As a result, transient suppression of net acid excretion occurs. This suppression is largely manifested by a decrease in ammonium excretion and, early on, by an increase in bicarbonate excretion. The transient discrepancy between net acid excretion and endogenous acid production, in turn, leads to positive hydrogen ion balance and a reduction in the bicarbonate stores of the body. Maintenance of the resulting hypobicarbonatemia is ensured by the gradual suppression in the rate of renal bicarbonate reabsorption. This suppression itself is a reflection of the hypocapnia-induced decrease in the hydrogen ion secretory rate. A new steady state emerges when two things occur: the reduced filtered load of bicarbonate is precisely balanced by the dampened rate of bicarbonate reabsorption and net acid excretion returns to the level required to offset daily endogenous acid production. The transient retention of acid during sustained hypocapnia is normally accompanied by a loss of sodium in the urine (and not by a retention of chloride as analogy with chronic respiratory acidosis would dictate). The resulting extracellular fluid loss is responsible for the hyperchloremia that typically accompanies chronic respiratory alkalosis. Hyperchloremia is sustained by the persistently enhanced chloride reabsorption rate. If dietary sodium is restricted, acid retention is achieved in the company of increased potassium excretion. The specific cellular mechanisms mediating the renal acidification response to chronic hypocapnia are under investigation. Available evidence indicates a parallel decrease in the rates of the luminal sodium ion–hydrogen ion (Na+-H+) exchanger and the basolateral sodium ion–3 bicarbonate ion (Na+-3HCO3) cotransporter in the proximal tubule. This parallel decrease reflects a decrease in the maximum velocity (Vmax) of each transporter but no change in the substrate concentration at halfmaximal velocity (Km) for sodium (as shown in B for the Na+-H+ exchanger in rabbit renal cortical brush-border membrane vesicles) [11]. Moreover, hypocapnia induces endocytotic retrieval of H+adenosine triphosphatase (ATPase) pumps from the luminal membrane of the proximal tubule cells as well as type A intercalated cells of the cortical and medullary collecting ducts. It remains unknown whether chronic hypocapnia alters the quantity of the H+-ATPase pumps as well as the kinetics or quantity of other acidification transporters in the renal cortex or medulla [6]. NS—not significant. (B, From Hilden and coworkers [11]; with permission.)

SIGNS AND SYMPTOMS OF RESPIRATORY ALKALOSIS Central Nervous System

Cardiovascular System

Neuromuscular System

Cerebral vasoconstriction Reduction in intracranial pressure Light-headedness Confusion Increased deep tendon reflexes Generalized seizures

Chest oppression Angina pectoris Ischemic electrocardiographic changes Normal or decreased blood pressure Cardiac arrhythmias Peripheral vasoconstriction

Numbness and paresthesias of the extremities Circumoral numbness Laryngeal spasm Manifestations of tetany Muscle cramps Carpopedal spasm Trousseau’s sign Chvostek’s sign

FIGURE 6-11 Signs and symptoms of respiratory alkalosis. The manifestations of primary hypocapnia frequently occur in the acute phase, but seldom are evident in chronic respiratory alkalosis. Several mechanisms mediate these clinical manifestations, including cerebral hypoperfusion, alkalemia, hypocalcemia, hypokalemia, and decreased release of oxygen to the tissues by hemoglobin. The cardiovascular effects of respiratory alkalosis are more prominent in patients undergoing mechanical ventilation and those with ischemic heart disease [2].

Disorders of Acid-Base Balance

6.9

CAUSES OF RESPIRATORY ALKALOSIS

Hypoxemia or Tissue Hypoxia Decreased inspired oxygen tension High altitude Bacterial or viral pneumonia Aspiration of food, foreign object, or vomitus Laryngospasm Drowning Cyanotic heart disease Severe anemia Left shift deviation of oxyhemoglobin curve Hypotension Severe circulatory failure Pulmonary edema

Central Nervous System Stimulation

Drugs or Hormones

Stimulation of Chest Receptors

Miscellaneous

Voluntary Pain Anxiety syndromehyperventilation syndrome Psychosis Fever Subarachnoid hemorrhage Cerebrovascular accident Meningoencephalitis Tumor Trauma

Nikethamide, ethamivan Doxapram Xanthines Salicylates Catecholamines Angiotensin II Vasopressor agents Progesterone Medroxyprogesterone Dinitrophenol Nicotine

Pneumonia Asthma Pneumothorax Hemothorax Flail chest Acute respiratory distress syndrome Cardiogenic and noncardiogenic pulmonary edema Pulmonary embolism Pulmonary fibrosis

Pregnancy Gram-positive septicemia Gram-negative septicemia Hepatic failure Mechanical hyperventilation Heat exposure Recovery from metabolic acidosis

FIGURE 6-12 Respiratory alkalosis is the most frequent acid-base disorder encountered because it occurs in normal pregnancy and highaltitude residence. Pathologic causes of respiratory alkalosis include various hypoxemic conditions, pulmonary disorders, central nervous system diseases, pharmacologic or hormonal stimulation of ventilation, hepatic failure, sepsis, the anxiety-hyperventilation syndrome, and other entities. Most of these causes are associated with the abrupt occurrence of hypocapnia; however, in many instances, the process might be sufficiently prolonged

Respiratory alkalosis

Acute

Blood pH ≥ 7.55

Chronic No

Manage underlying disorder. No specific measures indicated.

Yes Hemodynamic instability, altered mental status, or cardiac arrhythmias

No

• Consider having patient rebreathe into a closed system. • Manage underlying disorder.

Yes Consider measures to correct blood pH ≤ 7.50 by: • Reducing [HCO–3]: acetazolamide, ultrafiltration and normal saline replacement, hemodialysis using a low bicarbonate bath. • Increasing PaCO2: rebreathing into a closed system, controlled hypoventilation by ventilator with or without skeletal muscle paralysis.

to permit full chronic adaptation to occur. Consequently, no attempt has been made to separate these conditions into acute and chronic categories. Some of the major causes of respiratory alkalosis are benign, whereas others are life-threatening. Primary hypocapnia is particularly common among the critically ill, occurring either as the simple disorder or as a component of mixed disturbances. Its presence constitutes an ominous prognostic sign, with mortality increasing in direct proportion to the severity of the hypocapnia [2]. FIGURE 6-13 Respiratory alkalosis management. Because chronic respiratory alkalosis poses a low risk to health and produces few or no symptoms, measures for treating the acid-base disorder itself are not required. In contrast, severe alkalemia caused by acute primary hypocapnia requires corrective measures that depend on whether serious clinical manifestations are present. Such measures can be directed at reducing plasma bicarbonate concentration ([HCO3]), increasing the arterial carbon dioxide tension (PaCO2), or both. Even if the baseline plasma bicarbonate is moderately decreased, reducing it further can be particularly rewarding in this setting. In addition, this maneuver combines effectiveness with relatively little risk [1,2].

6.10

Disorders of Water, Electrolytes, and Acid-Base

Lungs

Normal

pH 7.40 PCO2 40 – 24 [HCO3 ] 95 PO2 0.21 FiO2

LV

Peripheral tissues

Arterial compartment

Venous compartment

Circulatory

Failure

7.42 pH 35 PCO2 – 22 [HCO3 ] 80 PO2 0.35 FiO2

LV

7.29 pH 60 PCO2 – 28 [HCO3 ] 30 PO2

RV

Cardiac

7.37 pH 27 PCO2 15 [HCO3– ] 116 PO2 1.00 FiO2

pH 7.38 PCO2 46 – [HCO3 ] 26 PO2 40

RV

Arrest

LV

RV

pH 7.00 PCO2 75 [HCO–3 ] 18 PO2 17

FIGURE 6-14 Pseudorespiratory alkalosis. This entity develops in patients with profound depression of cardiac function and pulmonary perfusion but relative preservation of alveolar ventilation. Patients include those with advanced circulatory failure and those undergoing cardiopulmonary resuscitation. The severely reduced pulmonary blood flow limits the amount of carbon dioxide delivered to the lungs for excretion, thereby increasing the venous carbon dioxide tension (PCO2). In contrast, the increased ventilation-to-perfusion ratio causes a larger than normal removal of carbon dioxide per unit of blood traversing the pulmonary circulation, thereby giving rise to arterial hypocapnia [12,13]. Note a progressive widening of the arteriovenous difference in pH and PCO2 in the two settings of cardiac dysfunction. The hypobicarbonatemia in the setting of cardiac arrest represents a complicating element of lactic acidosis. Despite the presence of arterial hypocapnia, pseudorespiratory alkalosis represents a special case of respiratory acidosis, as absolute carbon dioxide excretion is decreased and body carbon dioxide balance is positive. Furthermore, the extreme oxygen deprivation prevailing in the tissues might be completely disguised by the reasonably preserved arterial oxygen values. Appropriate monitoring of acid-base composition and oxygenation in patients with advanced cardiac dysfunction requires mixed (or central) venous blood sampling in addition to arterial blood sampling. Management of pseudorespiratory alkalosis must be directed at optimizing systemic hemodynamics [1,13].

Disorders of Acid-Base Balance

6.11

Metabolic Acidosis Arterial blood [H+], nEq/L 150 125

100

80 70 60

PaCO2 mm Hg

50

40

30

120 100 90 80 70

20 60

50 40

40

30

30 20

Normal

20

M e ac tab ido oli sis c

Arterial plasma [HCO–3], mEq/L

50

10

10

6.8

6.9

7.0

7.1

7.2

7.3

7.4

7.5

7.6

7.7

FIGURE 6-15 Ninety-five percent confidence intervals for metabolic acidosis. Metabolic acidosis is the acid-base disturbance initiated by a decrease in plasma bicarbonate concentration ([HCO3]). The resultant acidemia stimulates alveolar ventilation and leads to the secondary hypocapnia characteristic of the disorder. Extensive observations in humans encompassing a wide range of stable metabolic acidosis indicate a roughly linear relationship between the steadystate decrease in plasma bicarbonate concentration and the associated decrement in arterial carbon dioxide tension (PaCO2). The slope of the steady state PaCO2 versus [HCO3] relationship has been estimated as approximately 1.2 mm Hg per mEq/L decrease in plasma bicarbonate concentration. Such empiric observations have been used for construction of 95% confidence intervals for graded degrees of metabolic acidosis, represented by the area in color in the acid-base template. The black ellipse near the center of the figure indicates the normal range for the acid-base parameters [3]. Assuming a steady state is present, values falling within the area in color are consistent with but not diagnostic of simple metabolic acidosis. Acid-base values falling outside the area in color denote the presence of a mixed acid-base disturbance [4]. [H+]— hydrogen ion concentration.

Arterial blood pH

SIGNS AND SYMPTOMS OF METABOLIC ACIDOSIS Respiratory System Hyperventilation Respiratory distress and dyspnea Decreased strength of respiratory muscles and promotion of muscle fatigue

Cardiovascular System

Metabolism

Impairment of cardiac contractility, arteriolar dilation, venoconstriction, and centralization of blood volume Reductions in cardiac output, arterial blood pressure, and hepatic and renal blood flow Sensitization to reentrant arrhythmias and reduction in threshold for ventricular fibrillation Increased sympathetic discharge but attenuation of cardiovascular responsiveness to catecholamines

Increased metabolic demands Insulin resistance Inhibition of anaerobic glycolysis Reduction in adenosine triphosphate synthesis Hyperkalemia Increased protein degradation

Central Nervous System

Skeleton

Impaired metabolism Osteomalacia Inhibition of cell Fractures volume regulation Progressive obtundation Coma

FIGURE 6-16 Signs and symptoms of metabolic acidosis. Among the various clinical manifestations, particularly pernicious are the effects of severe acidemia (blood pH < 7.20) on the cardiovascular system. Reductions in cardiac output, arterial blood pressure, and hepatic and renal blood flow can occur and lifethreatening arrhythmias can develop. Chronic acidemia, as it occurs in untreated renal tubular acidosis and uremic acidosis, can cause calcium dissolution from the bone mineral and consequent skeletal abnormalities.

6.12

Disorders of Water, Electrolytes, and Acid-Base

Normal A– 10 HCO3– 24 Na+ 140

Metabolic acidosis Normal anion gap High anion gap (hyperchloremic) (normochloremic) – A 10 A– 30 HCO3– 4 HCO3– 4

Cl– 106

Na+ 140

Cl– 126

Na+ 140

Cl– 106

Causes Causes Renal acidification defects Endogenous acid load Proximal renal tubular acidosis Ketoacidosis Classic distal tubular acidosis Diabetes mellitus Hyperkalemic distal tubular acidosis Alcoholism Early renal failure Starvation Gastrointestinal loss of bicarbonate Uremia Diarrhea Lactic acidosis Small bowel losses Exogenous toxins Ureteral diversions Osmolar gap present Anion exchange resins Methanol Ingestion of CaCl2 Ethylene glycol Osmolar gap absent Acid infusion Salicylates HCl Paraldehyde Arginine HCl Lysine HCl

FIGURE 6-17 Causes of metabolic acidosis tabulated according to the prevailing pattern of plasma electrolyte composition. Assessment of the plasma unmeasured anion concentration (anion gap) is a very useful first step in approaching the differential diagnosis of unexplained metabolic acidosis. The plasma anion gap is calculated as the difference between the sodium concentration and the sum of chloride and bicarbonate concentrations. Under normal circumstances, the plasma anion gap is primarily composed of the net negative charges of plasma proteins, predominantly albumin, with a smaller contribution from many other organic and inorganic anions. The normal value of the plasma anion gap is 12 ± 4 (mean ± 2 SD) mEq/L, where SD is the standard deviation. However, recent introduction of ion-specific electrodes has shifted the normal anion gap to the range of about 6 ± 3 mEq/L. In one pattern of metabolic acidosis, the decrease in bicarbonate concentration is offset by an increase in the concentration of chloride, with the plasma anion gap remaining normal. In the other pattern, the decrease in bicarbonate is balanced by an increase in the concentration of unmeasured anions (ie, anions not measured routinely), with the plasma chloride concentration remaining normal.

Lactic acidosis Glucose Gluconeogenesis

Cori cycle

Muscle

Brain

Skin

RBC

Liver

Kidney cortex

Anaerobic glycolysis H+ + Lactate Overproduction

Lactic acidosis

Underutilization

FIGURE 6-18 Lactate-producing and lactate-consuming tissues under basal conditions and pathogenesis of lactic acidosis. Although all tissues pro-

duce lactate during the course of glycolysis, those listed contribute substantial quantities of lactate to the extracellular fluid under normal aerobic conditions. In turn, lactate is extracted by the liver and to a lesser degree by the renal cortex and primarily is reconverted to glucose by way of gluconeogenesis (a smaller portion of lactate is oxidized to carbon dioxide and water). This cyclical relationship between glucose and lactate is known as the Cori cycle. The basal turnover rate of lactate in humans is enormous, on the order of 15 to 25 mEq/kg/d. Precise equivalence between lactate production and its use ensures the stability of plasma lactate concentration, normally ranging from 1 to 2 mEq/L. Hydrogen ions (H+) released during lactate generation are quantitatively consumed during the use of lactate such that acid-base balance remains undisturbed. Accumulation of lactate in the circulation, and consequent lactic acidosis, is generated whenever the rate of production of lactate is higher than the rate of utilization. The pathogenesis of this imbalance reflects overproduction of lactate, underutilization, or both. Most cases of persistent lactic acidosis actually involve both overproduction and underutilization of lactate. During hypoxia, almost all tissues can release lactate into the circulation; indeed, even the liver can be converted from the premier consumer of lactate to a net producer [1,14].

Disorders of Acid-Base Balance Glucose

Glycolysis

PFK

low ATP ADP

+

NAD+

NADH Pyruvate

LDH

Gluconeogenesis

–

PD – H NAD+ NADH

PC

low ATP ADP

Oxaloacetate

Lactate + NADH high Cytosol NAD+ Mitochondrial membrane Mitochondria

high NADH+ NAD Acetyl-CoA TCA – cycle

FIGURE 6-19 Hypoxia-induced lactic acidosis. Accumulation of lactate during hypoxia, by far the most common clinical setting of the disorder, originates from impaired mitochondrial oxidative function that

reduces the availability of adenosine triphosphate (ATP) and NAD+ (oxidized nicotinamide adenine dinucleotide) within the cytosol. In turn, these changes cause cytosolic accumulation of pyruvate as a consequence of both increased production and decreased utilization. Increased production of pyruvate occurs because the reduced cytosolic supply of ATP stimulates the activity of 6-phosphofructokinase (PFK), thereby accelerating glycolysis. Decreased utilization of pyruvate reflects the fact that both pathways of its consumption depend on mitochondrial oxidative reactions: oxidative decarboxylation to acetyl coenzyme A (acetyl-CoA), a reaction catalyzed by pyruvate dehydrogenase (PDH), requires a continuous supply of NAD+; and carboxylation of pyruvate to oxaloacetate, a reaction catalyzed by pyruvate carboxylase (PC), requires ATP. The increased [NADH]/[NAD+] ratio (NADH refers to the reduced form of the dinucleotide) shifts the equilibrium of the lactate dehydrogenase (LDH) reaction (that catalyzes the interconversion of pyruvate and lactate) to the right. In turn, this change coupled with the accumulation of pyruvate in the cytosol results in increased accumulation of lactate. Despite the prevailing mitochondrial dysfunction, continuation of glycolysis is assured by the cytosolic regeneration of NAD+ during the conversion of pyruvate to lactate. Provision of NAD+ is required for the oxidation of glyceraldehyde 3-phosphate, a key step in glycolysis. Thus, lactate accumulation can be viewed as the toll paid by the organism to maintain energy production during anaerobiosis (hypoxia) [14]. ADP—adenosine diphosphate; TCA cycle—tricarboxylic acid cycle.

CAUSES OF LACTIC ACIDOSIS Type A: Impaired Tissue Oxygenation Shock Severe hypoxemia Generalized convulsions Vigorous exercise Exertional heat stroke Hypothermic shivering Massive pulmonary emboli Severe heart failure Profound anemia Mesenteric ischemia Carbon monoxide poisoning Cyanide poisoning

Type B: Preserved Tissue Oxygenation Diseases and conditions Diabetes mellitus Hypoglycemia Renal failure Hepatic failure Severe infections Alkaloses Malignancies (lymphoma, leukemia, sarcoma) Thiamine deficiency Acquired immunodeficiency syndrome Pheochromocytoma Iron deficiency D-Lactic acidosis Congenital enzymatic defects

6.13

Drugs and toxins Epinephrine, norepinephrine, vasoconstrictor agents Salicylates Ethanol Methanol Ethylene glycol Biguanides Acetaminophen Zidovudine Fructose, sorbitol, and xylitol Streptozotocin Isoniazid Nitroprusside Papaverine Nalidixic acid

FIGURE 6-20 Conventionally, two broad types of lactic acidosis are recognized. In type A, clinical evidence exists of impaired tissue oxygenation. In type B, no such evidence is apparent. Occasionally, the distinction between the two types may be less than obvious. Thus, inadequate tissue oxygenation can at times defy clinical detection, and tissue hypoxia can be a part of the pathogenesis of certain causes of type B lactic acidosis. Most cases of lactic acidosis are caused by tissue hypoxia arising from circulatory failure [14,15].

6.14

Disorders of Water, Electrolytes, and Acid-Base

Inadequate tissue oxygenation?

No Cause-specific measures

Yes Oxygen-rich mixture and ventilator support, if needed

No

• Antibiotics (sepsis) • Dialysis (toxins) • Discontinuation of incriminated drugs • Insulin (diabetes) • Glucose (hypoglycemia, alcoholism) • Operative intervention (trauma, tissue ischemia) • Thiamine (thiamine deficiency) • Low carbohydrate diet and antibiotics (D-lactic acidosis)

Circulatory failure? Yes • Volume repletion • Preload and afterload reducing agents • Myocardial stimulants (dobutamine, dopamine) • Avoid vasoconstrictors

Severe/Worsening metabolic acidemia?

No

• Continue therapy • Manage predisposing conditions

Yes Alkali administration to maintain blood pH ≥ 7.20

FIGURE 6-21 Lactic acidosis management. Management of lactic acidosis should focus primarily on securing adequate tissue oxygenation and on aggressively identifying and treating the underlying cause or predisposing condition. Monitoring of the patient’s hemodynamics, oxygenation, and acid-base status should be used to guide therapy. In the presence of severe or worsening metabolic acidemia, these measures should be supplemented by judicious administration of sodium bicarbonate, given as an infusion rather than a bolus. Alkali administration should be regarded as a temporizing maneuver adjunctive to cause-specific measures. Given the ominous prognosis of lactic acidosis, clinicians should strive to prevent its development by maintaining adequate fluid balance, optimizing cardiorespiratory function, managing infection, and using drugs that predispose to the disorder cautiously. Preventing the development of lactic acidosis is all the more important in patients at special risk for developing it, such as those with diabetes mellitus or advanced cardiac, respiratory, renal, or hepatic disease [1,14–16].

Diabetic ketoacidosis and nonketotic hyperglycemia A

Increased hepatic glucose production Glucagon Insulin deficiency

B Triglycerides Increased lipolysis

Increased hepatic ketogenesis Increased lipolysis in adipocytes Decreased glucose utilization in skeletal muscle

Increased ketogenesis Ketonemia (metabolic acidosis) Increased gluconeogenesis Increased glycogenolysis Decreased glucose uptake

Increased protein breakdown Decreased amino acid uptake

Growth hormone Norepinephrine

Cortisol Counterregulation Epinephrine

Decreased ketone uptake

Decreased glucose excretion Hyperglycemia (hyperosmolality)

Decreased glucose uptake

FIGURE 6-22 Role of insulin deficiency and the counterregulatory hormones, and their respective sites of action, in the pathogenesis of hyperglycemia and ketosis in diabetic ketoacidosis (DKA).A, Metabolic processes affected by insulin deficiency, on the one hand, and excess of glucagon, cortisol, epinephrine, norepinephrine, and growth hormone, on the other. B, The roles of the adipose tissue, liver, skeletal muscle, and kidney in the pathogenesis of hyperglycemia and ketonemia. Impairment of glucose oxidation in most tissues and excessive hepatic production of glucose are the main determinants of hyperglycemia. Excessive counterregulation and the prevailing hypertonicity, metabolic acidosis, and electrolyte imbalance superimpose a state of insulin resistance. Prerenal azotemia caused by volume depletion can contribute significantly to severe hyperglycemia. Increased hepatic production of ketones and their reduced utilization by peripheral tissues account for the ketonemia typically observed in DKA.

Disorders of Acid-Base Balance

Insulin deficiency/resistance Severe

Mild

Pure DKA profound ketosis

Mixed forms DKA + NKH

Pure NKH profound hyperglycemia

Mild

Severe Excessive counterregulation

Feature

Pure DKA

Incidence Mortality Onset Age of patient Type I diabetes Type II diabetes First indication of diabetes Volume depletion Renal failure (most commonly of prerenal nature) Severe neurologic abnormalities Subsequent therapy with insulin Glucose Ketone bodies Effective osmolality pH [HCO–3] [Na+] [K+]

5–10 times higher 5–10% Rapid (<2 days) Usually < 40 years Common Rare Often Mild/moderate Mild, inconstant

Mixed forms Pure NKH 5–10 times lower 10–60% Slow (> 5 days) Usually > 40 years Rare Common Often Severe Always present

Rare Always

Frequent (coma in 25–50%) Not always

< 800 mg/dL ≥ 2 + in 1:1 dilution < 340 mOsm/kg Decreased Decreased Normal or low Variable

> 800 mg/dL < 2+ in 1:1 dilution > 340 mOsm/kg Normal Normal Normal or high Variable

6.15

FIGURE 6-23 Clinical features of diabetic ketoacidosis (DKA) and nonketotic hyperglycemia (NKH). DKA and NKH are the most important acute metabolic complications of patients with uncontrolled diabetes mellitus. These disorders share the same overall pathogenesis that includes insulin deficiency and resistance and excessive counterregulation; however, the importance of each of these endocrine abnormalities differs significantly in DKA and NKH. As depicted here, pure NKH is characterized by profound hyperglycemia, the result of mild insulin deficiency and severe counterregulation (eg, high glucagon levels). In contrast, pure DKA is characterized by profound ketosis that largely is due to severe insulin deficiency, with counterregulation being generally of lesser importance. These pure forms define a continuum that includes mixed forms incorporating clinical and biochemical features of both DKA and NKH. Dyspnea and Kussmaul’s respiration result from the metabolic acidosis of DKA, which is generally absent in NKH. Sodium and water deficits and secondary renal dysfunction are more severe in NKH than in DKA. These deficits also play a pathogenetic role in the profound hypertonicity characteristic of NKH. The severe hyperglycemia of NKH, often coupled with hypernatremia, increases serum osmolality, thereby causing the characteristic functional abnormalities of the central nervous system. Depression of the sensorium, somnolence, obtundation, and coma, are prominent manifestations of NKH. The degree of obtundation correlates with the severity of serum hypertonicity [17].

MANAGEMENT OF DIABETIC KETOACIDOSIS AND NONKETOTIC HYPERGLYCEMIA

Insulin

Fluid Administration

Potassium repletion

Alkali

1. Give initial IV bolus of 0.2 U/kg actual body weight. 2. Add 100 U of regular insulin to 1 L of normal saline (0.1 U/mL), and follow with continuous IV drip of 0.1 U/kg actual body weight per h until correction of ketosis. 3. Give double rate of infusion if the blood glucose level does not decrease in a 2-h interval (expected decrease is 40–80 mg/dL/h or 10% of the initial value.) 4. Give SQ dose (10–30 U) of regular insulin when ketosis is corrected and the blood glucose level decreases to 300 mg/dL, and continue with SQ insulin injection every 4 h on a sliding scale (ie, 5 U if below 150, 10 U if 150–200, 15 U if 200–250, and 20 U if 250–300 mg/dL).

Shock absent: Normal saline (0.9% NaCl) at 7 mL/kg/h for 4 h, and half this rate thereafter Shock present: Normal saline and plasma expanders (ie,albumin, low molecular weight dextran) at maximal possible rate Start a glucose-containing solution (eg, 5% dextrose in water) when blood glucose level decreases to 250 mg/dL.

Potassium chloride should be added to the third liter of IV infusion and subsequently if urinary output is at least 30–60 mL/h and plasma [K+] < 5 mEq/L. Add K+ to the initial 2 L of IV fluids if initial plasma [K+] < 4 mEq/L and adequate diuresis is secured.

Half-normal saline (0.45% NaCl) plus 1–2 ampules (44-88 mEq) NaHCO3 per liter when blood pH < 7.0 or total CO2 < 5 mmol/L; in hyperchloremic acidosis, add NaHCO3 when pH < 7.20; discontinue NaHCO3 in IV infusion when total CO2>8–10 mmol/L.

CO2—carbon dioxide; IV—intravenous; K+—potassium ion; NaCl—sodium chloride; NaHCO3—sodium bicarbonate; SQ—subcutaneous.

FIGURE 6-24 Diabetic ketoacidosis (DKA) and nonketotic hyperglycemia (NKH) management. Administration of insulin is the cornerstone of management for both DKA and NKH. Replacement of the prevailing water, sodium, and potassium deficits is also required. Alkali are administered only under certain circumstances in DKA and virtually never in

NKH, in which ketoacidosis is generally absent. Because the fluid deficit is generally severe in patients with NKH, many of whom have preexisting heart disease and are relatively old, safe fluid replacement may require monitoring of central venous pressure, pulmonary capillary wedge pressure, or both [1,17,18].

6.16

Disorders of Water, Electrolytes, and Acid-Base

Renal tubular acidosis FEATURES OF THE RENAL TUBULAR ACIDOSIS (RTA) SYNDROMES Feature

Proximal RTA

Classic Distal RTA

Hyperkalemic Distal RTA

Plasma bicarbonate ion concentration Plasma chloride ion concentration Plasma potassium ion concentration Plasma anion gap Glomerular filtration rate

14–18 mEq/L

Variable, may be < 10 mEq/L Increased

15–20 mEq/L

Mildly to severely increased

Normal Normal or slightly decreased ≤5.5 ≤5.5 Normal >15%

Mildly to severely decreased Normal Normal or slightly decreased >6.0 >6.0 Decreased <5%

Decreased Absent Absent Present Usually present High dose

Normal Present Present Present Absent Low dose

Normal Absent Absent Absent Absent Low dose

Urine pH during acidosis Urine pH after acid loading U-B PCO2 in alkaline urine Fractional excretion of HCO3 at normal [HCO3]p Tm HCO3 Nephrolithiasis Nephrocalcinosis Osteomalacia Fanconi’s syndrome* Alkali therapy -

Increased Mildly decreased

Increased

Normal Normal to moderately decreased ≤5.5 ≤5.5 Decreased <5%

Tm HCO3—maximum reabsorption of bicarbonate; U-B PCO2—difference between partial pressure of carbon dioxide values in urine and arterial blood. *This syndrome signifies generalized proximal tubule dysfunction and is characterized by impaired reabsorption of glucose, amino acids, phosphate, and urate.

FIGURE 6-25 Renal tubular acidosis (RTA) defines a group of disorders in which tubular hydrogen ion secretion is impaired out of proportion to any reduction in the glomerular filtration rate. These disorders are characterized by normal anion gap (hyperchloremic) metabolic acidosis. The defects responsible for impaired acidification give rise to three distinct syndromes known as proximal RTA (type 2), classic distal RTA (type 1), and hyperkalemic distal RTA (type 4).

Disorders of Acid-Base Balance

Lumen

CA

HCO–3 + H+ + Na

CO2 + OH

–

HCO–3

H 2O

3HCO–3 1Na+

H+ Na+ Na+

Glucose Amino acids Phosphate

A

Blood

B. CAUSES OF PROXIMAL RENAL TUBULAR ACIDOSIS

CA

CO2 H2CO3

Proximal tubule cell

6.17

3Na

+

2K+

Indicates possible cellular mechanisms responsible for Type 2 proximal RTA

FIGURE 6-26 A and B, Potential defects and causes of proximal renal tubular acidosis (RTA) (type 2). Excluding the case of carbonic anhydrase inhibitors, the nature of the acidification defect responsible for bicarbonate (HCO3) wastage remains unknown. It might represent defects in the luminal sodium ion– hydrogen ion (Na+-H+) exchanger, basolateral Na+-3HCO3 cotransporter, or carbonic anhydrase activity. Most patients with proximal RTA have additional defects in proximal tubule function (Fanconi’s syndrome); this generalized proximal tubule dysfunction might reflect a defect in the basolateral Na+-K+ adenosine triphosphatase. K+—potassium ion; CA—carbonic anhydrase. Causes of proximal renal tubular acidosis (RTA) (type 2). An idiopathic form and cystinosis are the most common causes of proximal RTA in children. In adults, multiple myeloma and carbonic anhydrase inhibitors (eg, acetazolamide) are the major causes. Ifosfamide is an increasingly common cause of the disorder in both age groups.

Selective defect (isolated bicarbonate wasting) Primary (no obvious associated disease) Genetically transmitted Transient (infants) Due to altered carbonic anhydrase activity Acetazolamide Sulfanilamide Mafenide acetate Genetically transmitted Idiopathic Osteopetrosis with carbonic anhydrase II deficiency York-Yendt syndrome Generalized defect (associated with multiple dysfunctions of the proximal tubule) Primary (no obvious associated disease) Sporadic Genetically transmitted Genetically transmitted systemic disease Tyrosinemia Wilson’s disease Lowe syndrome Hereditary fructose intolerance (during administration of fructose) Cystinosis Pyruvate carboxylate deficiency Metachromatic leukodystrophy Methylmalonic acidemia Conditions associated with chronic hypocalcemia and secondary hyperparathyroidism Vitamin D deficiency or resistance Vitamin D dependence

Dysproteinemic states Multiple myeloma Monoclonal gammopathy Drug- or toxin-induced Outdated tetracycline 3-Methylchromone Streptozotocin Lead Mercury Arginine Valproic acid Gentamicin Ifosfamide Tubulointerstitial diseases Renal transplantation Sjögren’s syndrome Medullary cystic disease Other renal diseases Nephrotic syndrome Amyloidosis Miscellaneous Paroxysmal nocturnal hemoglobinuria Hyperparathyroidism

6.18

Disorders of Water, Electrolytes, and Acid-Base

B. CAUSES OF CLASSIC DISTAL RENAL TUBULAR ACIDOSIS Lumen

α Intercalated cell (CCT & MCT)

H

CA

Cl–

OH– H+

Primary (no obvious associated disease) Sporadic Genetically transmitted

HCO–3

CO2 +

Blood

H2 O

K+

Cl–

Cl–

A

Indicates possible cellular mechanisms responsible for Type 1 distal RTA

FIGURE 6-27 A and B, Potential defects and causes of classic distal renal tubular acidosis (RTA) (type 1). Potential cellular defects underlying classic distal RTA include a faulty luminal hydrogen ion–adenosine triphosphatase (H+ pump failure or secretory defect), an abnormality in the basolateral bicarbonate ion–chloride ion exchanger, inadequacy of carbonic anhydrase activity, or an increase in the luminal membrane permeability for hydrogen ions (backleak of protons or permeability defect). Most of the causes of classic distal RTA likely reflect a secretory defect, whereas amphotericin B is the only established cause of a permeability defect. The hereditary form is the most common cause of this disorder in children. Major causes in adults include autoimmune disorders (eg, Sjögren’s syndrome) and hypercalciuria [19]. CA—carbonic anhydrase.

Autoimmune disorders Hypergammaglobulinemia Hyperglobulinemic purpura Cryoglobulinemia Familial Sjögren’s syndrome Thyroiditis Pulmonary fibrosis Chronic active hepatitis Primary biliary cirrhosis Systemic lupus erythematosus Vasculitis Genetically transmitted systemic disease Ehlers-Danlos syndrome Hereditary elliptocytosis Sickle cell anemia Marfan syndrome Carbonic anhydrase I deficiency or alteration Osteopetrosis with carbonic anhydrase II deficiency Medullary cystic disease Neuroaxonal dystrophy

Disorders associated with nephrocalcinosis Primary or familial hyperparathyroidism Vitamin D intoxication Milk-alkali syndrome Hyperthyroidism Idiopathic hypercalciuria Genetically transmitted Sporadic Hereditary fructose intolerance (after chronic fructose ingestion) Medullary sponge kidney Fabry’s disease Wilson’s disease Drug- or toxin-induced Amphotericin B Toluene Analgesics Lithium Cyclamate Balkan nephropathy Tubulointerstitial diseases Chronic pyelonephritis Obstructive uropathy Renal transplantation Leprosy Hyperoxaluria

Disorders of Acid-Base Balance

Principal cell

Lumen

6.19

B. CAUSES OF HYPERKALEMIC DISTAL RENAL TUBULAR ACIDOSIS

Blood

Na+ 3Na+ –

2K+

Potential difference Aldosterone

K+

receptor

Cl– α Intercalated cell Aldosterone receptor HCO–3

CO2 CA

H+

Cl–

OH– H+ K+

H2 O Cl–

Cl–

A

Indicates possible cellular mechanisms in aldosterone deficiency Indicates defects related to aldosterone resistance

FIGURE 6-28 A and B, Potential defects and causes of hyperkalemic distal renal tubular acidosis (RTA) (type 4). This syndrome represents the most common type of RTA encountered in adults. The characteristic hyperchloremic metabolic acidosis in the company of hyperkalemia emerges as a consequence of generalized dysfunction of the collecting tubule, including diminished sodium reabsorption and impaired hydrogen ion and potassium secretion. The resultant hyperkalemia causes impaired ammonium excretion that is an important contribution to the generation of the metabolic acidosis. The causes of this syndrome are broadly classified into disorders resulting in aldosterone deficiency and those that impose resistance to the action of aldosterone. Aldosterone deficiency can arise from

Deficiency of aldosterone Associated with glucocorticoid deficiency Addison’s disease Bilateral adrenalectomy Enzymatic defects 21-Hydroxylase deficiency 3--ol-Dehydrogenase deficiency Desmolase deficiency Acquired immunodeficiency syndrome Isolated aldosterone deficiency Genetically transmitted Corticosterone methyl oxidase deficiency Transient (infants) Sporadic Heparin Deficient renin secretion Diabetic nephropathy Tubulointerstitial renal disease Nonsteroidal antiinflammatory drugs -adrenergic blockers Acquired immunodeficiency syndrome Renal transplantation Angiotensin I-converting enzyme inhibition Endogenous Captopril and related drugs Angiotensin AT, receptor blockers

Resistance to aldosterone action Pseudohypoaldosteronism type I (with salt wasting) Childhood forms with obstructive uropathy Adult forms with renal insufficiency Spironolactone Pseudohypoaldosteronism type II (without salt wasting) Combined aldosterone deficiency and resistance Deficient renin secretion Cyclosporine nephrotoxicity Uncertain renin status Voltage-mediated defects Obstructive uropathy Sickle cell anemia Lithium Triamterene Amiloride Trimethoprim, pentamidine Renal transplantation

hyporeninemia, impaired conversion of angiotensin I to angiotensin II, or abnormal aldosterone synthesis. Aldosterone resistance can reflect the following: blockade of the mineralocorticoid receptor; destruction of the target cells in the collecting tubule (tubulointerstitial nephropathies); interference with the sodium channel of the principal cell, thereby decreasing the lumen-negative potential difference and thus the secretion of potassium and hydrogen ions (voltage-mediated defect); inhibition of the basolateral sodium ion, potassium ion–adenosine triphosphatase; and enhanced chloride ion permeability in the collecting tubule, with consequent shunting of the transepithelial potential difference. Some disorders cause combined aldosterone deficiency and resistance [20].

6.20

Disorders of Water, Electrolytes, and Acid-Base FIGURE 6-29 Treatment of acute metabolic acidosis. Whenever possible, causespecific measures should be at the center of treatment of metabolic acidosis. In the presence of severe acidemia, such measures should be supplemented by judicious administration of sodium bicarbonate. The goal of alkali therapy is to return the blood pH to a safer level of about 7.20. Anticipated benefits and potential risks of alkali therapy are depicted here [1].

Management of acute metabolic acidosis

Alkali therapy for severe acidemia (blood pH<7.20)

Cause-specific measures

Benefits • Prevents or reverses acidemiarelated hemodynamic compromise. • Reinstates cardiovascular responsiveness to catecholamines. • "Buys time," thus allowing causespecific measures and endogenous reparatory processes to take effect. • Provides a measure of safety against additional acidifying stresses.

Risks • Hypernatremia/ hyperosmolality • Volume overload • "Overshoot" alkalosis • Hypokalemia • Decreased plasma ionized calcium concentration • Stimulation of organic acid production • Hypercapnia

Metabolic Alkalosis Arterial blood [H+], nEq/L 150 125

100

80 70 60

PaCO2 mm Hg

50

40

30

120 100 90 80 70

20 60

50 40

Arterial plasma [HCO–3], mEq/L

50

40

30

30 20

Normal

20 10

10

6.8

6.9

7.0

7.1

7.2

7.3

7.4

Arterial blood pH

7.5

7.6

7.7

FIGURE 6-30 Ninety-five percent confidence intervals for metabolic alkalosis. Metabolic alkalosis is the acid-base disturbance initiated by an increase in plasma bicarbonate concentration ([HCO3]). The resultant alkalemia dampens alveolar ventilation and leads to the secondary hypercapnia characteristic of the disorder. Available observations in humans suggest a roughly linear relationship between the steady-state increase in bicarbonate concentration and the associated increment in the arterial carbon dioxide tension (PaCO2). Although data are limited, the slope of the steadystate PaCO2 versus [HCO3] relationship has been estimated as about a 0.7 mm Hg per mEq/L increase in plasma bicarbonate concentration. The value of this slope is virtually identical to that in dogs that has been derived from rigorously controlled observations [21]. Empiric observations in humans have been used for construction of 95% confidence intervals for graded degrees of metabolic alkalosis represented by the area in color in the acid-base template. The black ellipse near the center of the figure indicates the normal range for the acid-base parameters [3]. Assuming a steady state is present, values falling within the area in color are consistent with but not diagnostic of simple metabolic alkalosis. Acid-base values falling outside the area in color denote the presence of a mixed acid-base disturbance [4]. [H+]—hydrogen ion concentration.

Disorders of Acid-Base Balance

Excess alkali

Alkali gain

Enteral

Source? Parenteral

Gastric

H+ loss

Intestinal

Renal H+ shift

Milk alkali syndrome Calcium supplements Absorbable alkali Nonabsorbable alkali plus K+ exchange resins Ringer's solution Bicarbonate Blood products Nutrition Dialysis Vomiting Suction Villous adenoma Congenital chloridorrhea

6.21

FIGURE 6-31 Pathogenesis of metabolic alkalosis. Two crucial questions must be answered when evaluating the pathogenesis of a case of metabolic alkalosis. 1) What is the source of the excess alkali? Answering this question addresses the primary event responsible for generating the hyperbicarbonatemia. 2) What factors perpetuate the hyperbicarbonatemia? Answering this question addresses the pathophysiologic events that maintain the metabolic alkalosis.

Chloruretic diuretics Inherited transport defects Mineralocorticoid excess Posthypercapnia

K+ depletion

Reduced GFR Mode of perpetuation? Increased renal acidification

Cl– responsive defect Cl– resistant defect

Baseline

Vomiting Maintenance Low NaCl and KCl intake

[HCO3– ], mEq/L

45

Correction High NaCl and KCl intake

40 35 30 25

[Cl– ], mEq/L

105 100 95

0 Cl–

–200

Cumulative balance, mEq Na+

–400

0

–100 0

K+

–200 –400 –2

0

2

4

6

8 Days

10

12

14

16

18

FIGURE 6-32 Changes in plasma anionic pattern and body electrolyte balance during development, maintenance, and correction of metabolic alkalosis induced by vomiting. Loss of hydrochloric acid from the stomach as a result of vomiting (or gastric drainage) generates the hypochloremic hyperbicarbonatemia characteristic of this disorder. During the generation phase, renal sodium and potassium excretion increases, yielding the deficits depicted here. Renal potassium losses continue in the early days of the maintenance phase. Subsequently, and as long as the low-chloride diet is continued, a new steady state is achieved in which plasma bicarbonate concentration ([HCO3]) stabilizes at an elevated level, and renal excretion of electrolytes matches intake. Addition of sodium chloride (NaCl) and potassium chloride (KCl) in the correction phase repairs the electrolyte deficits incurred and normalizes the plasma bicarbonate and chloride concentration ([Cl-]) levels [22,23].

6.22

Disorders of Water, Electrolytes, and Acid-Base

Baseline

Vomiting Maintenance Low NaCl and KCl intake

Urine pH

8.0

Baseline

Correction High NaCl and KCl intake

6.0

Maintenance Low NaCl intake

Correction

Low KCl intake

[HCO3– ], mEq/L

7.0

Diuresis

5.0

High KCl intake

40 35 30

75 105 [Cl– ], mEq/L

50 25

100 Urine net acid excretion, mEq/d

100 95

0 Urine net acid excretion, mEq/d

Urine HCO–3 excretion, mEq/d

25

75 50

125 100 75 50

25 0

–25

–200

Cl–

0

–2

0

2

4

6

8

10

12

14

16

18

Days

FIGURE 6-33 Changes in urine acid-base composition during development, maintenance, and correction of vomiting-induced metabolic alkalosis. During acid removal from the stomach as well as early in the phase after vomiting (maintenance), an alkaline urine is excreted as acid excretion is suppressed, and bicarbonate excretion (in the company of sodium and, especially potassium; see Fig. 6-32) is increased, with the net acid excretion being negative (net alkali excretion). This acid-base profile moderates the steady-state level of the resulting alkalosis. In the steady state (late maintenance phase), as all filtered bicarbonate is reclaimed the pH of urine becomes acidic, and the net acid excretion returns to baseline. Provision of sodium chloride (NaCl) and potassium chloride (KCl) in the correction phase alkalinizes the urine and suppresses the net acid excretion, as bicarbonaturia in the company of exogenous cations (sodium and potassium) supervenes [22,23]. HCO3—bicarbonate ion.

Cumulative balance, mEq K+ Na+

–400

–50

0

–100 0

–100 –2

0

2

4

6

8

10

12

Days

FIGURE 6-34 Changes in plasma anionic pattern, net acid excretion, and body electrolyte balance during development, maintenance, and correction of diuretic-induced metabolic alkalosis. Administration of a loop diuretic, such as furosemide, increases urine net acid excretion (largely in the form of ammonium) as well as the renal losses of chloride (Cl-), sodium (Na+), and potassium (K+). The resulting hyperbicarbonatemia reflects both loss of excess ammonium chloride in the urine and an element of contraction (consequent to diuretic-induced sodium chloride [NaCl] losses) that limits the space of distribution of bicarbonate. During the phase after diuresis (maintenance), and as long as the low-chloride diet is continued, a new steady state is attained in which the plasma bicarbonate concentration ([HCO3]) remains elevated, urine net acid excretion returns to baseline, and renal excretion of electrolytes matches intake. Addition of potassium chloride (KCl) in the correction phase repairs the chloride and potassium deficits, suppresses net acid excretion, and normalizes the plasma bicarbonate and chloride concentration ([Cl-]) levels [23,24]. If extracellular fluid volume has become subnormal folllowing diuresis, administration of NaCl is also required for repair of the metabolic alkalosis.

Disorders of Acid-Base Balance

6.23

Maintenance of Cl–-responsive metabolic alkalosis ↓GFR

↑HCO3– reabsorption

Mediating factors

Cl– depletion

Na+ Cl–

Na+

Na+ H+, NH+4

↓GFR

K+ depletion

ECF volume depletion

Na+ 3HCO–3 HCO–3 Cl–

Basic mechanisms

P-cell + K + K

Hypercapnia

+

K Na

↑Na+ reabsorption and consequent ↑H+ and K+ secretion –

K+

Cl α-cell

H+

+

NH4 K+

↑HCO3 reabsorption –

+

+

NH4 , K Na+ 2Cl–

↑NH4+ synthesis and luminal entry H 2O

Na+ HCO–3 + K Cl–

H

+

Cl–

ß-cell

NH4+ NH3

NH3 NH3

HCO3 Cl

Cl

↑H+ secretion

H+ K+

H+

Cl

HCO3

↑H+ secretion coupled to K+ reabsorption

HCO3– secretion

NH3

↑NH4+ entry in medulla and secretion in medullary collecting duct

NH4+

Net acid excretion maintained at control

FIGURE 6-35 Maintenance of chloride-responsive metabolic alkalosis. Increased renal bicarbonate reabsorption frequently coupled with a reduced glomerular filtration rate are the basic mechanisms that maintain chloride-responsive metabolic alkalosis. These mechanisms have been ascribed to three mediating factors: chloride depletion itself, extracellular fluid (ECF) volume depletion, and potassium depletion. Assigning particular roles to

each of these factors is a vexing task. Notwithstanding, here depicted is our current understanding of the participation of each of these factors in the nephronal processes that maintain chloride-responsive metabolic alkalosis [22–24]. In addition to these factors, the secondary hypercapnia of metabolic alkalosis contributes importantly to the maintenance of the prevailing hyperbicarbonatemia [25].

6.24

Disorders of Water, Electrolytes, and Acid-Base Maintenance of Cl–-resistant metabolic alkalosis ↑HCO3– reabsorption

Basic mechanism

K+ depletion

Mineralocorticoid excess

Na+ 3HCO–3 HCO–3 Cl–

Mediating factors

P-cell Na+

Na+ H+, NH+4

Na+ Cl–

K K

+

NH+4, K Na+ 2Cl–

↑NH4+ synthesis and luminal entry H 2O

H

NH+4 K+

↑HCO3 reabsorption

H

Cl–

Na+ HCO–3 + K Cl–

NH+4 NH3

NH3 NH3

Virtually absent (< 10 mEq/L)

Abundant (> 20 mEq/L)

↑NH4+entry in medulla and secretion in medullary collecting duct

• Vomiting, gastric suction • Postdiuretic phase of loop and distal agents • Posthypercapnic state • Villous adenoma of the colon • Congenital chloridorrhea • Post alkali loading

Urinary [K+] Low (< 20 mEq/L)

+

+

FIGURE 6-36 Maintenance of chloride-resistant metabolic alkalosis. Increased renal bicarbonate reabsorption is the sole basic mechanism that maintains chloride-resistant metabolic alkalosis. As its name implies, factors independent of chloride intake mediate the height-

Abundant (> 30 mEq/L)

↑Na+ reabsorption and consequent ↑H+ and K+ secretion

Cl

+

α-cell

–

Urinary [Cl–]

+

K Na

• Laxative abuse • Other causes of profound K+ depletion

• Diuretic phase of loop and distal agents • Bartter's and Gitelman's syndromes • Primary aldosteronism • Cushing's syndrome • Exogenous mineralocorticoid agents • Secondary aldosteronism malignant hypertension renovascular hypertension primary reninism • Liddle's syndrome

Cl–

HCO–3 Cl– H+ K+ ß-cell HCO

↑H+ secretion coupled to K+ reabsorption

↑H+ secretion

H+

– –Cl 3

NH3

NH+4

ened bicarbonate reabsorption and include mineralocorticoid excess and potassium depletion. The participation of these factors in the nephronal processes that maintain chloride-resistant metabolic alkalosis is depicted [22–24, 26]. FIGURE 6-37 Urinary composition in the diagnostic evaluation of metabolic alkalosis. Assessing the urinary composition can be an important aid in the diagnostic evaluation of metabolic alkalosis. Measurement of urinary chloride ion concentration ([Cl-]) can help distinguish between chloride-responsive and chloride-resistant metabolic alkalosis. The virtual absence of chloride (urine [Cl-] < 10 mEq/L) indicates significant chloride depletion. Note, however, that this test loses its diagnostic significance if performed within several hours of administration of chloruretic diuretics, because these agents promote urinary chloride excretion. Measurement of urinary potassium ion concentration ([K+]) provides further diagnostic differentiation. With the exception of the diuretic phase of chloruretic agents, abundance of both urinary chloride and potassium signifies a state of mineralocorticoid excess [22].

Disorders of Acid-Base Balance

6.25

SIGNS AND SYMPTOMS OF METABOLIC ALKALOSIS Central Nervous System Headache Lethargy Stupor Delirium Tetany Seizures Potentiation of hepatic encephalopathy

Cardiovascular System

Respiratory System

Neuromuscular System

Metabolic Effects

Supraventricular and ventricular arrhythmias Potentiation of digitalis toxicity Positive inotropic ventricular effect

Hypoventilation with attendant hypercapnia and hypoxemia

Chvostek’s sign Trousseau’s sign Weakness (severity depends on degree of potassium depletion)

Increased organic acid and ammonia production Hypokalemia Hypocalcemia Hypomagnesemia Hypophosphatemia

FIGURE 6-38 Signs and symptoms of metabolic alkalosis. Mild to moderate metabolic alkalosis usually is accompanied by few if any symptoms, unless potassium depletion is substantial. In contrast, severe metabolic alkalosis ([HCO3] > 40 mEq/L) is usually a symptomatic disorder. Alkalemia, hypokalemia, hypoxemia, hypercapnia, and decreased plasma ionized calcium concentration all contribute to

Ingestion of large amounts of calcium

Augmented body content of calcium

Urine alkalinization

Augmented body bicarbonate stores

Nephrocalcinosis

Hypercalcemia

Renal vasoconstriction

Renal insufficiency

Reduced renal bicarbonate excretion

Decreased urine calcium excretion

Polyuria Polydipsia Urinary concentration defect Cortical and medullary renal cysts

these clinical manifestations. The arrhythmogenic potential of alkalemia is more pronounced in patients with underlying heart disease and is heightened by the almost constant presence of hypokalemia, especially in those patients taking digitalis. Even mild alkalemia can frustrate efforts to wean patients from mechanical ventilation [23,24].

Ingestion of large amounts of absorbable alkali

Increased urine calcium excretion (early phase)

Renal (Associated Potassium Depletion)

Metabolic alkalosis

Increased renal reabsorption of calcium

Increased renal H+ secretion

FIGURE 6-39 Pathophysiology of the milk-alkali syndrome. The milk-alkali syndrome comprises the triad of hypercalcemia, renal insufficiency, and metabolic alkalosis and is caused by the ingestion of large amounts of calcium and absorbable alkali. Although large amounts of milk and absorbable alkali were the culprits in the classic form of the syndrome, its modern version is usually the result of large doses of calcium carbonate alone. Because of recent emphasis on prevention and treatment of osteoporosis with calcium carbonate and the availability of this preparation over the counter, milk-alkali syndrome is currently the third leading cause

of hypercalcemia after primary hyperparathyroidism and malignancy. Another common presentation of the syndrome originates from the current use of calcium carbonate in preference to aluminum as a phosphate binder in patients with chronic renal insufficiency. The critical element in the pathogenesis of the syndrome is the development of hypercalcemia that, in turn, results in renal dysfunction. Generation and maintenance of metabolic alkalosis reflect the combined effects of the large bicarbonate load, renal insufficiency, and hypercalcemia. Metabolic alkalosis contributes to the maintenance of hypercalcemia by increasing tubular calcium reabsorption. Superimposition of an element of volume contraction caused by vomiting, diuretics, or hypercalcemia-induced natriuresis can worsen each one of the three main components of the syndrome. Discontinuation of calcium carbonate coupled with a diet high in sodium chloride or the use of normal saline and furosemide therapy (depending on the severity of the syndrome) results in rapid resolution of hypercalcemia and metabolic alkalosis. Although renal function also improves, in a considerable fraction of patients with the chronic form of the syndrome serum creatinine fails to return to baseline as a result of irreversible structural changes in the kidneys [27].

6.26

Disorders of Water, Electrolytes, and Acid-Base

Clinical syndrome

Affected gene

Affected chromosome

Localization of tubular defect TAL

Bartter's syndrome Type 1

NKCC2

15q15-q21 TAL CCD

Type 2

ROMK

11q24

TSC

16q13

Gitelman's syndrome

Tubular lumen Na+ K+,NH+4 Cl– Loop diuretics H+

DCT

Peritubular space

Cell

3Na

+

2K+ ATPase

+

K 3HCO–3 Na+

Tubular lumen Na

+

Cl– Thiazides

Peritubular space

Cell 3Na+ +

2K+ ATPase

Tubular lumen

Peritubular space

Cell

Na+

Cl– 3Na

K Cl–

K+

+

ATPase + 2K

+

K Cl–

K+

3Na+ 2+

Ca

2+

Ca

Ca2+ Mg2+ Thick ascending limb (TAL)

Distal convoluted tuble (DCT)

Cortical collecting duct (CCD)

FIGURE 6-40 Clinical features and molecular basis of tubular defects of Bartter’s and Gitelman’s syndromes. These rare disorders are characterized by chloride-resistant metabolic alkalosis, renal potassium wasting and hypokalemia, hyperreninemia and hyperplasia of the juxtaglomerular apparatus, hyperaldosteronism, and normotension. Regarding differentiating features, Bartter’s syndrome presents early in life, frequently in association with growth and mental retardation. In this syndrome, urinary concentrating ability is usually decreased, polyuria and polydipsia are present, the serum magnesium level is normal,

and hypercalciuria and nephrocalcinosis are present. In contrast, Gitelman’s syndrome is a milder disease presenting later in life. Patients often are asymptomatic, or they might have intermittent muscle spasms, cramps, or tetany. Urinary concentrating ability is maintained; hypocalciuria, renal magnesium wasting, and hypomagnesemia are almost constant features. On the basis of certain of these clinical features, it had been hypothesized that the primary tubular defects in Bartter’s and Gitelman’s syndromes reflect impairment in sodium reabsorption in the thick ascending limb (TAL) of the loop of Henle and the distal tubule, respectively. This hypothesis has been validated by recent genetic studies [28-31]. As illustrated here, Bartter’s syndrome now has been shown to be caused by loss-of-function mutations in the loop diuretic–sensitive sodium-potassium-2chloride cotransporter (NKCC2) of the TAL (type 1 Bartter’s syndrome) [28] or the apical potassium channel ROMK of the TAL (where it recycles reabsorbed potassium into the lumen for continued operation of the NKCC2 cotransporter) and the cortical collecting duct (where it mediates secretion of potassium by the principal cell) (type 2 Bartter’s syndrome) [29,30]. On the other hand, Gitelman’s syndrome is caused by mutations in the thiazide-sensitive Na-Cl cotransporter (TSC) of the distal tubule [31]. Note that the distal tubule is the major site of active calcium reabsorption. Stimulation of calcium reabsorption at this site is responsible for the hypocalciuric effect of thiazide diuretics.

Disorders of Acid-Base Balance

Management of metabolic alkalosis

For alkali gain

For H+ loss Eliminate source of excess alkali

For H+ shift

Discontinue administrationof bicarbonate or its precursors. via gastric route Administer antiemetics; discontinue gastric suction; administer H2 blockers or H+-K+ ATPase inhibitors. via renal route Discontinue or decrease loop and distal diuretics; substitute with amiloride, triamterene, or spironolactone; discontinue or limit drugs with mineralocorticoid activity. Potassium repletion

For decreased GFR

Interrupt perpetuating mechanisms

For Cl– responsive acidification defect

For Cl– resistant acidification defect

ECF volume repletion; renal replacement therapy

6.27

FIGURE 6-41 Metabolic alkalosis management. Effective management of metabolic alkalosis requires sound understanding of the underlying pathophysiology. Therapeutic efforts should focus on eliminating or moderating the processes that generate the alkali excess and on interrupting the mechanisms that perpetuate the hyperbicarbonatemia. Rarely, when the pace of correction of metabolic alkalosis must be accelerated, acetazolamide or an infusion of hydrochloric acid can be used. Treatment of severe metabolic alkalosis can be particularly challenging in patients with advanced cardiac or renal dysfunction. In such patients, hemodialysis or continuous hemofiltration might be required [1].

Administer NaCl and KCl

Adrenalectomy or other surgery, potassiuim repletion, administration of amiloride, triamterene, or spironolactone.

References 1. Adrogué HJ, Madias NE: Management of life-threatening acid-base disorders. N Engl J Med, 1998, 338:26–34, 107–111. 2. Madias NE, Adrogué HJ: Acid-base disturbances in pulmonary medicine. In Fluid, Electrolyte, and Acid-Base Disorders. Edited by Arieff Al, DeFronzo RA. New York: Churchill Livingstone; 1995:223–253. 3. Madias NE, Adrogué HJ, Horowitz GL, et al.: A redefinition of normal acid-base equilibrium in man: carbon dioxide tension as a key determinant of plasma bicarbonate concentration. Kidney Int 1979, 16:612–618. 4. Adrogué HJ, Madias NE: Mixed acid-base disorders. In The Principles and Practice of Nephrology. Edited by Jacobson HR, Striker GE, Klahr S. St. Louis: Mosby-Year Book; 1995:953–962. 5. Krapf R: Mechanisms of adaptation to chronic respiratory acidosis in the rabbit proximal tubule. J Clin Invest 1989, 83:890–896. 6. Al-Awqati Q: The cellular renal response to respiratory acid-base disorders. Kidney Int 1985, 28:845–855. 7. Bastani B: Immunocytochemical localization of the vacuolar H+ATPase pump in the kidney. Histol Histopathol 1997, 12:769–779. 8. Teixeira da Silva JC Jr, Perrone RD, Johns CA, Madias NE: Rat kidney band 3 mRNA modulation in chronic respiratory acidosis. Am J Physiol 1991, 260:F204–F209. 9. Respiratory pump failure: primary hypercapnia (respiratory acidosis). In Respiratory Failure. Edited by Adrogué HJ, Tobin MJ. Cambridge, MA: Blackwell Science; 1997:125–134. 10. Krapf R, Beeler I, Hertner D, Hulter HN: Chronic respiratory alkalosis: the effect of sustained hyperventilation on renal regulation of acidbase equilibrium. N Engl J Med 1991, 324:1394–1401. 11. Hilden SA, Johns CA, Madias NE: Adaptation of rabbit renal cortical Na+-H+-exchange activity in chronic hypocapnia. Am J Physiol 1989, 257:F615–F622.

12. Adrogué HJ, Rashad MN, Gorin AB, et al.: Arteriovenous acid-base disparity in circulatory failure: studies on mechanism. Am J Physiol 1989, 257:F1087–F1093. 13. Adrogué HJ, Rashad MN, Gorin AB, et al.: Assessing acid-base status in circulatory failure: differences between arterial and central venous blood. N Engl J Med 1989, 320:1312–1316. 14. Madias NE: Lactic acidosis. Kidney Int 1986, 29:752–774. 15. Kraut JA, Madias NE: Lactic acidosis. In Textbook of Nephrology. Edited by Massry SG, Glassock RJ. Baltimore: Williams and Wilkins; 1995:449–457. 16. Hindman BJ: Sodium bicarbonate in the treatment of subtypes of acute lactic acidosis: physiologic considerations. Anesthesiology 1990, 72:1064–1076. 17. AdroguÈ HJ: Diabetic ketoacidosis and hyperosmolar nonketotic syndrome. In Therapy of Renal Diseases and Related Disorders. Edited by Suki WN, Massry SG. Boston: Kluwer Academic Publishers; 1997:233–251. 18. Adrogué HJ, Barrero J, Eknoyan G: Salutary effects of modest fluid replacement in the treatment of adults with diabetic ketoacidosis. JAMA 1989, 262:2108–2113. 19. Bastani B, Gluck SL: New insights into the pathogenesis of distal renal tubular acidosis. Miner Electrolyte Metab 1996, 22:396–409. 20. DuBose TD Jr: Hyperkalemic hyperchloremic metabolic acidosis: pathophysiologic insights. Kidney Int 1997, 51:591–602. 21. Madias NE, Bossert WH, Adrogué HJ: Ventilatory response to chronic metabolic acidosis and alkalosis in the dog. J Appl Physiol 1984, 56:1640–1646. 22. Gennari FJ: Metabolic alkalosis. In The Principles and Practice of Nephrology. Edited by Jacobson HR, Striker GE, Klahr S. St Louis: Mosby-Year Book; 1995:932–942.

6.28

Disorders of Water, Electrolytes, and Acid-Base

23. Sabatini S, Kurtzman NA: Metabolic alkalosis: biochemical mechanisms, pathophysiology, and treatment. In Therapy of Renal Diseases and Related Disorders Edited by Suki WN, Massry SG. Boston: Kluwer Academic Publishers; 1997:189–210. 24. Galla JH, Luke RG: Metabolic alkalosis. In Textbook of Nephrology. Edited by Massry SG, Glassock RJ. Baltimore: Williams & Wilkins; 1995:469–477. 25. Madias NE, Adrogué HJ, Cohen JJ: Maladaptive renal response to secondary hypercapnia in chronic metabolic alkalosis. Am J Physiol 1980, 238:F283–289. 26. Harrington JT, Hulter HN, Cohen JJ, Madias NE: Mineralocorticoidstimulated renal acidification in the dog: the critical role of dietary sodium. Kidney Int 1986, 30:43–48. 27. Beall DP, Scofield RH: Milk-alkali syndrome associated with calcium carbonate consumption. Medicine 1995, 74:89–96.

28. Simon DB, Karet FE, Hamdan JM, et al.: Bartter’s syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet 1996, 13:183–188. 29. Simon DB, Karet FE, Rodriguez-Soriano J, et al.: Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet 1996, 14:152–156. 30. International Collaborative Study Group for Bartter-like Syndromes. Mutations in the gene encoding the inwardly-rectifying renal potassium channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence for genetic heterogeneity. Hum Mol Genet 1997, 6:17–26. 31. Simon DB, Nelson-Williams C, et al.: Gitelman’s variant of Bartter’s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet 1996, 12:24–30.

Disorders of Phosphate Balance Moshe Levi Mordecai Popovtzer

T

he physiologic concentration of serum phosphorus (phosphate) in normal adults ranges from 2.5 to 4.5 mg/dL (0.80–1.44 mmol/L). A diurnal variation occurs in serum phosphorus of 0.6 to 1.0 mg/dL, the lowest concentration occurring between 8 AM and 11 AM. A seasonal variation also occurs; the highest serum phosphorus concentration is in the summer and the lowest in the winter. Serum phosphorus concentration is markedly higher in growing children and adolescents than in adults, and it is also increased during pregnancy [1,2]. Of the phosphorus in the body, 80% to 85% is found in the skeleton. The rest is widely distributed throughout the body in the form of organic phosphate compounds. In the extracellular fluid, including in serum, phosphorous is present mostly in the inorganic form. In serum, more than 85% of phosphorus is present as the free ion and less than 15% is protein-bound. Phosphorus plays an important role in several aspects of cellular metabolism, including adenosine triphosphate synthesis, which is the source of energy for many cellular reactions, and 2,3-diphosphoglycerate concentration, which regulates the dissociation of oxygen from hemoglobin. Phosphorus also is an important component of phospholipids in cell membranes. Changes in phosphorus content, concentration, or both, modulate the activity of a number of metabolic pathways. Major determinants of serum phosphorus concentration are dietary intake and gastrointestinal absorption of phosphorus, urinary excretion of phosphorus, and shifts between the intracellular and extracellular spaces. Abnormalities in any of these steps can result either in hypophosphatemia or hyperphosphatemia [3–7]. The kidney plays a major role in the regulation of phosphorus homeostasis. Most of the inorganic phosphorus in serum is ultrafilterable at the level of the glomerulus. At physiologic levels of serum phosphorus and during a normal dietary phosphorus intake, approximately 6 to 7 g/d of phosphorous is filtered by the kidney. Of that

CHAPTER

7

7.2

Disorders of Water, Electrolytes, and Acid-Base

amount, 80% to 90% is reabsorbed by the renal tubules and the rest is excreted in the urine. Most of the filtered phosphorus is reabsorbed in the proximal tubule by way of a sodium gradient-dependent process (Na-Pi cotransport) located on the apical brush border membrane [8–10]. Recently two distinct Na-Pi cotransport proteins have been cloned from the kidney

(type I and type II Na-Pi cotransport proteins). Most of the hormonal and metabolic factors that regulate renal tubular phosphate reabsorption, including alterations in dietary phosphate content and parathyroid hormone, have been shown to modulate the proximal tubular apical membrane expression of the type II Na-Pi cotransport protein [11–16]. FIGURE 7-1 Summary of phosphate metabolism for a normal adult in neutral phosphate balance. Approximately 1400 mg of phosphate is ingested daily, of which 490 mg is excreted in the stool and 910 mg in the urine. The kidney, gastrointestinal (GI) tract, and bone are the major organs involved in phosphorus homeostasis.

Bone

GI intake 1400 mg/d

Digestive juice phosphorus 210 mg/d

Formation 210 mg/d

Resorption 210 mg/d

Extracellular fluid Total absorbed intestinal phosphorus 1120 mg/d

Urine 910 mg/d Stool 490 mg/d

FIGURE 7-2 Major determinants of extracellular fluid or serum inorganic phosphate (Pi) concentration include dietary Pi intake, intestinal Pi absorption, urinary Pi excretion and shift into the cells.

Major determinants of ECF or serum inorganic phosphate (Pi) concentration Dietary intake Intestinal absorption

Serum Pi Urinary excretion

Cells

Disorders of Phosphate Balance

7.3

Renal Tubular Phosphate Reabsorption 100% PCT 55-75%

DCT 5-10%

PST 10-20%

FIGURE 7-3 Renal tubular reabsorption of phosphorus. Most of the inorganic phosphorus in serum is ultrafilterable at the level of the glomerulus. At physiologic levels of serum phosphorus and during a normal dietary phosphorus intake, most of the filtered phosphorous is reabsorbed in the proximal convoluted tubule (PCT) and proximal straight tubule (PST). A significant amount of filtered phosphorus is also reabsorbed in distal segments of the nephron [7,9,10]. CCT—cortical collecting tubule; IMCD—inner medullary collecting duct or tubule; PST—proximal straight tubule.

CCT 2-5%

IMCD <1%

0.2%-20% Urine

Lumen

Blood Pi

Na+ Na

3 Na+

+

?An Na+

Pi

Pi

Pi Gluconeogenesis [HPO4=

Glycolysis H2PO4– ]

Pi+ADP ATP P +ADP ATP

Na-K ATPase

i

Respiratory chain Oxidative phosphorylation

–65mV

–65mV

FIGURE 7-4 Cellular model for renal tubular reabsorption of phosphorus in the proximal tubule. Phosphate reabsorption from the tubular fluid is sodium gradient–dependent and is mediated by the sodium gradient– dependent phosphate transport (Na-Pi cotransport) protein located on the apical brush border membrane. The sodium gradient for phosphate reabsorption is generated by then sodium-potassium adenosine triphosphatase (Na-K ATPase) pump located on the basolateral membrane. Recent studies indicate that the Na-Pi cotransport system is electrogenic [8,11]. ADP—adenosine diphosphate; An—anion.

7.4

Disorders of Water, Electrolytes, and Acid-Base

FACTORS REGULATING RENAL PROXIMAL TUBULAR PHOSPHATE REABSORPTION

Cellular model of proximal tubule Pi-reabsorption Lumen

Parathyroid hormone dietary Pi content

Blood

HPO42– 3Na

HPO42–

Na+ A–

+

FIGURE 7-5 Celluar model of proximal tubular phosphate reabsorption. Major physiologic determinants of renal tubular phosphate reabsorption are alterations in parathyroid hormone activity and alterations in dietary phosphate content. The regulation of renal tubular phosphate reabsorption occurs by way of alterations in apical membrane sodiumphosphate (Na-Pi) cotransport 3Na+-HPO24 activity [11–14].

Decreased transport

Increased transport

High phosphate diet Parathyroid hormone and parathyroidhormone–related protein Glucocorticoids Chronic metabolic acidosis Acute respiratory acidosis Aging Calcitonin Atrial natriuretic peptide Fasting Hypokalemia Hypercalcemia Diuretics Phosphatonin

Low phosphate diet Growth hormone Insulin Thyroid hormone 1,25-dihydroxy-vitamin D3 Chronic metabolic alkalosis High calcium diet High potassium diet Stanniocalcin

FIGURE 7-6 Factors regulating renal proximal tubular phosphate reabsorption.

A

B

C

D

FIGURE 7-7 (see Color Plate) Effects of a diet low in phosphate on renal tubular phosphate reabsorption in rats. A, Chronic high Pi diet. B, Acute low Pi diet. C, Colchicine and high Pi diet. D, Colchicine and low Pi diet. In response to a low phosphate diet, a rapid adaptive increase occurs in the sodium-phosphate (Na-Pi) cotransport activity of the proximal tubular apical membrane (A, B). The increase in Na-Pi cotransport activity is mediated by rapid upregulation of the type II Na-Pi cotransport protein, in the absence of changes in Na-Pi messenger RNA (mRNA) levels. This rapid upregulation is dependent on an intact microtubular network because pretreatment with colchicine prevents the upregulation of Na-Pi cotransport activity and Na-Pi protein expression (C, D). In this immunofluorescence micrograph, the Na-Pi protein is stained green (fluorescein) and the actin cytoskeleton is stained red (rhodamine). Colocalization of green and red at the level of the apical membrane results in yellow color [14].

7.5

Disorders of Phosphate Balance

FIGURE 7-8 (see Color Plate) Effects of parathyroid hormone (PTH) on renal tubular phosphate reabsorption in rats. In response to PTH administration to parathyroidectomized rats, a rapid decrease occurs in the sodium-phosphate (Na-Pi) cotransport activity of the proximal tubular apical membrane. The decrease in Na-Pi cotransport activity is mediated by rapid downregulation of the type II Na-Pi cotransport protein. In this immunofluorescence micrograph, the Na-Pi protein is stained green (fluorescein) and the actin cytoskeleton is stained red (rhodamine). Colocalization of green and red at the level of the apical membrane results in yellow color [13]. A, parathyroidectomized (PTX) effects. B, effects of PTX and PTH.

A

B

A

600

GlcCer, ng/mg

Cholesterol, nmol/mg

490

440

390

A

B

PDMP

Control

DEX

PDMP

Control

DEX

1600

1100

600

0

Low Pi diet and/or young

Control

High Pi diet and/or aged

FIGURE 7-9 Renal cholesterol content modulates renal tubular phosphate reabsorption. In aged rats versus young rats and rats fed a diet high in phosphate versus a diet low in phosphate, an inverse correlation exists between the brush border membrane (BBM) cholesterol content (A) and Na-Pi cotransport activity (B). Studies in isolated BBM vesicles and recent studies in opossum kidney cells grown in culture indicate that direct alterations in cholesterol content per se modulate Na-Pi cotransport activity [15]. CON—controls.

Na-Pi, pmol/5s/mg

Na-Pi, pmol/5s/mg

1600

B

0

FIGURE 7-10 Renal glycosphingolipid content modulates renal tubular phosphate reabsorption. In rats treated with dexamethasone (DEX) and in rats fed a potassium-deficient diet, an inverse correlation exists between brush border membrane (BBM) glucosylceramide (GluCer)—and ganglioside GM3, content and Na-Pi cotransport activity. Treatment of rats with a glucosylceramide synthase inhibitor PDMP lowers BBM glucosylceramide content (A) and increases Na-Pi cotransport activity (B) [16].

7.6

Disorders of Water, Electrolytes, and Acid-Base

Hypophosphatemia/Hyperphosphatemia FIGURE 7-11 Major causes of hypophosphatemia. (From Angus [1]; with permission.)

MAJOR CAUSES OF HYPOPHOSPHATEMIA Internal redistribution

Decreased intestinal absorption

Increased urinary excretion

Increased insulin, particularly during refeeding Acute respiratory alkalosis Hungry bone syndrome

Inadequate intake Antacids containing aluminum or magnesium Steatorrhea and chronic diarrhea

Primary and secondary hyperparathyroidism Vitamin D deficiency or resistance Fanconi’s syndrome Miscellaneous: osmotic diuresis, proximally acting diuretics, acute volume expansion

CAUSES OF MODERATE HYPOPHOSPHATEMIA Pseudohypophosphatemia Mannitol Bilirubin Acute leukemia Decreased dietary intake Decreased intestinal absorption Vitamin D deficiency Malabsorption Steatorrhea Secretory diarrhea Vomiting PO34-binding antacids Shift from serum into cells Respiratory alkalosis Sepsis Heat stroke Neuroleptic malignant syndrome Hepatic coma Salicylate poisoning Gout Panic attacks Psychiatric depression

Hormonal effects Insulin Glucagon Epinephrine Androgens Cortisol Anovulatory hormones Nutrient effects Glucose Fructose Glycerol Lactate Amino acids Xylitol

FIGURE 7-12 Causes of moderate hypophosphatemia. (From Popovtzer, et al. [6]; with permission.)

Cellular uptake syndromes Recovery from hypothermia Burkitt’s lymphoma Histiocytic lymphoma Acute myelomonocytic leukemia Acute myelogenous leukemia Chronic myelogenous leukemia in blast crisis Treatment of pernicious anemia Erythropoietin therapy Erythrodermic psoriasis Hungry bone syndrome After parathyroidectomy Acute leukemia

Increased excretion into urine Hyperparathyroidism Renal tubule defects Fanconi’s syndrome X-linked hypophosphatemic rickets Hereditary hypophosphatemic rickets with hypercalciuria Polyostotic fibrous dysphasia Panostotic fibrous dysphasia Neurofibromatosis Kidney transplantation Oncogenic osteomalacia Recovery from hemolytic-uremic syndrome Aldosteronism Licorice ingestion Volume expansion Inappropriate secretion of antidiuretic hormone Mineralocorticoid administration Corticosteroid therapy Diuretics Aminophylline therapy

Disorders of Phosphate Balance

CAUSES OF SEVERE HYPOPHOSPHATEMIA Acute renal failure: excessive P binders Chronic alcoholism and alcohol withdrawal Dietary deficiency and PO34-binding antacids Hyperalimentation Neuroleptic malignant syndrome Recovery from diabetic ketoacidosis Recovery from exhaustive exercise Kidney transplantation Respiratory alkalosis Severe thermal burns Therapeutic hypothermia

Reye’s syndrome After major surgery Periodic paralysis Acute malaria Drug therapy Ifosfamide Cisplatin Acetaminophen intoxication Cytokine infusions Tumor necrosis factor Interleukin-2

7.7

CAUSES OF HYPOPHOSPHATEMIA IN PATIENTS WITH NONKETOTIC HYPERGLYCEMIA OR DIABETIC KETOACIDOSIS Decreased net intestinal phosphate absorption Decreased phosphate intake

Increased urinary phosphate excretion Glucosuria-induced osmotic diuresis Acidosis

Acute movement of extracellular phosphate into the cells Insulin therapy

FIGURE 7-14 Causes of hypophosphatemia in patients with nonketotic hyperglycemia or diabetic ketoacidosis.

FIGURE 7-13 Causes of severe hypophosphatemia. (From Popovtzer, et al. [6]; with permission.)

CAUSES OF HYPOPHOSPHATEMIA IN PATIENTS WITH ALCOHOLISM Decreased net intestinal phosphate absorption Poor dietary intake of phosphate and vitamin D Use of phosphate binders to treat recurring gastritis Chronic diarrhea

Increased urinary phosphate excretion Alcohol-induced reversible proximal tubular defect Secondary hyperparathyroidism induced by vitamin D deficiency

CAUSES OF HYPOPHOSPHATEMIA IN PATIENTS WITH RENAL TRANSPLANTATION Acute movement of extracellular phosphate into the cells Insulin release induced by intravenous solutions containing dextrose Acute respiratory alkalosis caused by alcohol withdrawal, sepsis, or hepatic cirrhosis Refeeding of the patient who is malnourished

Increased urinary phosphate excretion Persistent hyperparathyroidism (hyperplasia or adenoma) Proximal tubular defect (possibly induced by glucocorticoids, cyclosporine, or both)

FIGURE 7-16 Causes of hypophosphatemia in patients with renal transplantation.

FIGURE 7-15 Causes of hypophosphatemia in patients with alcoholism.

MAJOR CONSEQUENCES OF HYPOPHOSPHATEMIA Decreased erythrocyte 2,3-diphosphoglycerate levels, which result in increased affinity of hemoglobin for oxygen and reduced oxygen release at the tissue level Decreased intracellular adenosine triphosphate levels, which result in impairment of cell functions dependent on energy-rich phosphate compounds

FIGURE 7-17 Major consequences of hypophosphatemia.

7.8

Disorders of Water, Electrolytes, and Acid-Base

SIGNS AND SYMPTOMS OF HYPOPHOSPHATEMIA Central nervous system dysfunction Metabolic encephalopathy owing to tissue ischemia Irritability Paresthesias Confusion Delirium Coma

Cardiac dysfunction

Pulmonary dysfunction

Skeletal and smooth muscle dysfunction

Impaired myocardial contractility Congestive heart failure

Weakness of the diaphragm Respiratory failure

Proximal myopathy Dysphagia and ileus Rhabdomyolysis

Hematologic dysfunction

Bone disease

Erythrocytes Increased bone resorption Increased erythrocyte Rickets and osteorigidity malacia caused by decreased bone Hemolysis mineralization Leukocytes Impaired phagocytosis Decreased granulocyte chemotaxis Platelets Defective clot retraction Thrombocytopenia

Renal effects Decreased glomerular filtration rate Decreased tubular transport maximum for bicarbonate Decreased renal gluconeogenesis Decreased titratable acid excretion Hypercalciuria Hypermagnesuria

Metabolic effects Low parathyroid hormone levels Increased 1,25-dihydroxy-vitamin D3 levels Increased creatinine phosphokinase levels Increased aldolase levels

FIGURE 7-18 Signs and symptoms of hypophosphatemia. (Adapted from Hruska and Slatopolsky [2] and Hruska and Gupta [7].) FIGURE 7-19 Pseudofractures (Looser’s transformation zones) at the margins of the scapula in a patient with oncogenic osteomalacia. Similar to the genetic X-linked hypophosphatemic rickets, a circulating phosphaturic factor is believed to be released by the tumor, causing phosphate wasting and reduced calcitriol formation by the kidney. Note the radiolucent ribbonlike decalcification extending into bone at a right angle to its axillary margin. Pseudofractures are pathognomonic of osteomalacia with a low remodeling rate.

FIGURE 7-20 (see Color Plate) Histologic appearance of trabecular bone from a patient with oncogenic osteomalacia. Undecalcified bone section with impaired mineralization and a wide osteoid (organic matrix) seam stained with von Kossa’s stain is illustrated. Note the wide bands of osteoid around the mineralized bone. Absence of osteoblasts on the circumference of the trabecular bone portion indicates a low remodeling rate.

Disorders of Phosphate Balance

7.9

FIGURE 7-21(see Color Plate) Microscopic appearance of bone section from a patient with vitamin D deficiency caused by malabsorption. The bone section was stained with Masson trichrome stain. Hypophosphatemia and hypocalcemia were present. Note the trabecular bone consisting of very wide osteoid areas (red) characteristic of osteomalacia.

FIGURE 7-22 Usual dosages for phosphorus repletion.

USUAL DOSAGES FOR PHOSPHORUS REPLETION Severe symptomatic hypophosphatemia (plasma phosphate concentration < 1 mg/dL) 10 mg/kg/d, intravenously, until the plasma phosphate concentration reaches 2 mg/dL

Phosphate depletion

Hypophosphatemic rickets

2–4 g/d (64 to 128 mmol/d), orally, in 3 to 4 divided doses

1–4 g/d (32 to 128 mmol/d), orally, in 3 to 4 divided doses

FIGURE 7-23 Phosphate preparations for oral use.

PHOSPHATE PREPARATIONS FOR ORAL USE Preparation

Phosphate, mg

Sodium, mEq

Potassium, mEq

250

13

1.1

K-Phos Neutral®, tablet (Beach Pharmaceuticals, Conestee, SC) Neutra-Phos®, capsule or 75-mL solution (Baker Norton Pharmaceuticals, Miami, FL) Neutra-Phos K®, capsule or 75-mL solution (Baker Norton Pharmaceuticals, Miami, FL)

250

7.1

7.1

250

0

14.2

FIGURE 7-24 Phosphate preparations for intravenous use. (From Popovtzer, et al. [6]; with permission.)

PHOSPHATE PREPARATIONS FOR INTRAVENOUS USE

Phosphate preparation

Composition, mg/mL

Potassium

236 mg K2HPO4 224 mg KH2PO4 142 mg Na2HPO4 276 mg NaH2HPO4.H2O 10.0 mg Na2HPO 2.7 mg NaH2PO4.H2O 11.5 mg Na2HPO4 2.6 mg KH2PO4

Sodium Neutral sodium Neutral sodium, potassium

Phosphate, mmol/mL

3 mmol/mL of phosphate corresponds to 93 mg of phosphorus.

Sodium, mEq/mL

Potassium, mEq/mL

3.0

0

4.4

3.0

4.0

0

0.09

0.2

0

1.10

0.2

0.02

7.10

Disorders of Water, Electrolytes, and Acid-Base

CAUSES OF HYPERPHOSPHATEMIA Pseudohyperphosphatemia

Increased endogenous loads

Reduced urinary excretion

Miscellaneous

Multiple myeloma Extreme hypertriglyceridemia In vitro hemolysis

Tumor lysis syndrome Rhabdomyolysis Bowel infarction Malignant hyperthermia Heat stroke Acid-base disorders Organic acidosis Lactic acidosis Ketoacidosis Respiratory acidosis Chronic respiratory alkalosis

Renal failure Hypoparathyroidism Hereditary Acquired Pseudohypoparathyroidism Vitamin D intoxication Growth hormone Insulin-like growth factor-1 Glucocorticoid withdrawal Mg2+ deficiency Tumoral calcinosis Diphosphonate therapy Hyopophosphatasia

Fluoride poisoning -Blocker therapy Verapamil Hemorrhagic shock Sleep deprivation

Increased exogenous phosphorus load or absorption Phosphorus-rich cow’s milk in premature neonates Vitamin D intoxication PO34-containing enemas Intravenous phosphorus supplements White phosphorus burns Acute phosphorus poisoning

FIGURE 7-25 Causes of hyperphosphatemia. (From Knochel and Agarwal [5]; with permission.)

CLINICAL MANIFESTATIONS OF HYPERPHOSPHATEMIA Consequences of secondary changes in calcium, parathyroid hormone, vitamin D metabolism and hypocalcemia: Neuromuscular irritability Tetany Hypotension Increased QT interval

Consequences of ectopic calcification: Periarticular and soft tissue calcification Vascular calcification Ocular calcification Conduction abnormalities Pruritus

FIGURE 7-26 Clinical manifestations of hyperphosphatemia.

TREATMENT OF HYPERPHOSPHATEMIA Acute hyperphosphatemia in patients with adequate renal function

Chronic hyperphosphatemia in patients with end-stage renal disease

Saline diuresis that causes phosphaturia

Dietary phosphate restriction Phosphate binders to decrease gastrointestinal phosphate reabsorption

FIGURE 7-27 Treatment of hyperphosphatemia.

Disorders of Phosphate Balance

A FIGURE 7-28 Periarticular calcium phosphate deposits in a patient with endstage renal disease who has severe hyperphosphatemia and a high level of the product of calcium and phosphorus. Note the partial

A FIGURE 7-29 Resolution of soft tissue calcifications. The palms of the hands of the patient in Figure 7-28 with end-stage renal disease are shown before (A) and after (B) treatment of hyperphosphatemia. The

7.11

B resolution of calcific masses after dietary phosphate restriction and oral phosphate binders. Left shoulder joint before (A) and after (B) treatment. (From Pinggera and Popovtzer [17]; with permission.)

B patient has a high level of the product of calcium and phosphorus. (From Pinggera and Popovtzer [17]; with permission.)

7.12

Disorders of Water, Electrolytes, and Acid-Base

A

B

FIGURE 7-30 A, B, Bone sections from the same patient as in Figures 7-28 and 7-29, illustrating osteitis fibrosa cystica caused by renal secondary hyperparathyroidism with hyperphosphatemia.

FIGURE 7-31 Roentgenographic appearance of femoral arterial vascular calcification in a patient on dialysis who has severe hyperphosphatemia. The patient has a high level of the product of calcium and phosphorus.

FIGURE 7-32 (see Color Plate) Microscopic appearance of a cross section of a calcified artery in a patient with end-stage renal disease undergoing chronic dialysis. The patient has severe hyperphosphatemia and a high level of the product of calcium and phosphorus. Note the intimal calcium phosphate deposit with a secondary occlusion of the arterial lumen.

FIGURE 7-33 Massive periarticular calcium phosphate deposit (around the hip joint) in a patient with genetic tumoral calcinosis. The patient exhibits hyperphosphatemia and increased renal tubular phosphate reabsorption. Normal parathyroid hormone levels and elevated calcitriol levels are present. The same disease affects two of the patient’s brothers.

Disorders of Phosphate Balance

7.13

FIGURE 7-34 Massive periarticular calcium phosphate deposit in the plantar joints in the same patient in Figure 7-33 who has genetic tumoral calcinosis.

FIGURE 7-35 (see Color Plate) Complications of the use of aluminum-based phosphate binders to control hyperphosphatemia. Appearance of bone section from a patient with end-stage renal disease who was treated with oral aluminum gels to control severe hyperphosphatemia. A bone biopsy was obtained 6 months after a parathyroidectomy was performed. Note the wide areas of osteoid filling previously resorbed bone.

FIGURE 7-36 (see Color Plate) The same bone section as in Figure 7-35 but under polarizing lenses, illustrating the partially woven appearance of osteoid typical of chronic renal failure.

FIGURE 7-37 (see Color Plate) The same bone section as in Figure 7-35 with positive aluminum stain of the trabecular surface. These findings are consistent with aluminum-related osteomalacia.

Acknowledgments The authors thank Sandra Nickerson and Teresa Autrey for secretarial assistance and the Medical Media Department at the Dallas VA Medical Center for the illustrations.

7.14

Disorders of Water, Electrolytes, and Acid-Base

References 1.

Agus ZS: Phosphate metabolism. In UpToDate, Inc.. Edited by Burton D. Rose, 1998.

2.

Hruska KA, Slatopolsky E: Disorders of phosphorus, calcium, and magnesium metabolism. In Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little and Brown; 1997.

10. Suki WN, Rouse D: Renal Transport of calcium, magnesium, and phosphate. In The Kidney, edn 5. Edited by Brenner BM. Philadelphia: WB Saunders; 1996. 11. Levi M, Kempson, SA, Lõtscher M, et al.: Molecular regulation of renal phosphate transport. J Membrane Biol 1996, 154:1–9.

3.

Levi M, Knochel JP: The management of disorders of phosphate metabolism. In Therapy of Renal Diseases and Related Disorders. Edited by Massry SG, Suki WN. Boston, Martinus Nijhoff; 1990.

12. Levi M, Lõtscher M, Sorribas V, et al.: Cellular mechanisms of acute and chronic adaptation of rat renal phosphate transporter to alterations in dietary phosphate. Am J Physiol 1994, 267:F900–F908.

4.

Levi M, Cronin RE, Knochel JP: Disorders of phosphate and magnesium metabolism. In Disorders of Bone and Mineral Metabolism. Edited by Coe FL, Favus MJ. New York: Raven Press; 1992.

13. Kempson SA, Lõtscher M, Kaissling B, et al.: Effect of parathyroid hormone on phosphate transporter mRNA and protein in rat renal proximal tubules. Am J Physiol 1995, 268:F784–F791.

5.

Knochel JP, Agarwal R: Hypophosphatemia and hyperphosphatemia. In The Kidney, edn 5. Edited by Brenner BM. Philadelphia: WB Saunders; 1996.

6.

Popovtzer M, Knochel JP, Kumar R: Disorders of calcium, phosphorus, vitamin D, and parathyroid hormone activity. In Renal Electrolyte Disorders, edn 5. Edited by Schrier RW. Philadelphia: LippincottRaven; 1997.

14. Lõtscher M, Biber J, Murer H, et al.: Role of microtubules in the rapid upregulation of rat renal proximal tubular Na-Pi cotransport following dietary P restriction. J Clin Invest 1997, 99:1302–1312. 15. Levi M, Baird B, Wilson P: Cholesterol modulates rat renal brush border membrane phosphate transport. J Clin Invest 1990, 85:231–237.

7.

Hruska K, Gupta A: Disorders of phosphate homeostasis. In Metabolic Bone Disease, edn 3. Edited by Avioli LV, SM Krane. New York: Academic Press; 1998.

8.

Murer H, Biber J: Renal tubular phosphate transport: cellular mechanisms. In The Kidney: Physiology and Pathophysiology, edn 2. Edited by Seldin DW, Giebisch G. New York: Raven Press; 1997.

9.

Berndt TJ, Knox FG: Renal regulation of phosphate excretion. In The Kidney: Physiology and Pathophysiology, edn 2. Edited by Seldin DW, Giebisch G. New York: Raven Press; 1992.

16. Levi M, Shayman J, Abe A, et al.: Dexamethasone modulates rat renal brush border membrane phosphate transporter mRNA and protein abundance and glycosphingolipid composition. J Clin Invest 1995, 96:207–216. 17. Pinggera WF, Popovtzer MM: Uremic osteodystrophy: the therapeutic consequences of effective control of serum phosphorus. JAMA 1972, 222:1640–1642.

Acute Renal Failure: Causes and Prognosis Fernando Liaño Julio Pascual

T

here are many causes—more than fifty are given within this present chapter—that can trigger pathophysiological mechanisms leading to acute renal failure (ARF). This syndrome is characterized by a sudden decrease in kidney function, with a consequence of loss of the hemostatic equilibrium of the internal medium. The primary marker is an increase in the concentration of the nitrogenous components of blood. A second marker, oliguria, is seen in 50% to 70% of cases. In general, the causes of ARF have a dynamic behavior as they change as a function of the economical and medical development of the community. Economic differences justify the different spectrum in the causes of ARF in developed and developing countries. The setting where ARF appears (community versus hospital), or the place where ARF is treated (intensive care units [ICU] versus other hospital areas) also show differences in the causes of ARF. While functional outcome after ARF is usually good among the surviving patients, mortality rate is high: around 45% in general series and close to 70% in ICU series. Although it is unfortunate that these mortality rates have remained fairly constant over the past decades, it should be noted that today’s patients are generally much older and display a generally much more severe condition than was true in the past. These age and severity factors, together with the more aggressive therapeutical possibilities presently available, could account for this apparent paradox. As is true for any severe clinical condition, a prognostic estimation of ARF is of great utility for both the patients and their families, the medical specialists (for analysis of therapeutical maneuvers and options), and for society in general (demonstrating the monetary costs of treatment). This chapter also contains a brief review of the prognostic tools available for application to ARF.

CHAPTER

8

8.2

Acute Renal Failure

Causes of Acute Renal Failure Sudden causes affecting

Induce

Prerenal

Renal perfusion

Parenchymal structures

Urine output

Called

GFR

Parenchymatous

Obstructive

A c u t e r e n a l f a i l u r e

FIGURE 8-1 Characteristics of acute renal failure. Acute renal failure is a syndrome characterized by a sudden decrease of the glomerular filtration rate (GFR) and consequently an increase in blood nitrogen products (blood urea nitrogen and creatinine). It is associated with oliguria in about two thirds of cases. Depending on the localization or the nature of the renal insult, ARF is classified as prerenal, parenchymatous, or obstructive (postrenal).

CAUSES OF PARENCHYMATOUS ACUTE RENAL FAILURE Acute tubular necrosis Hemodynamic: cardiovascular surgery,* sepsis,* prerenal causes* Toxic: antimicrobials,* iodide contrast agents,* anesthesics, immunosuppressive or antineoplastic agents,* Chinese herbs, Opiaceous, Extasis, mercurials, organic solvents, venoms, heavy metals, mannitol, radiation Intratubular deposits: acute uric acid nephropathy, myeloma, severe hypercalcemia, primary oxalosis, sulfadiazine, fluoride anesthesics Organic pigments (endogenous nephrotoxins): Myoglobin rhabdomyolisis: muscle trauma; infections; dermatopolymyositis; metabolic alterations; hyperosmolar coma; diabetic ketoacidosis; severe hypokalemia; hyper- or hyponatremia; hypophosphatemia; severe hypothyroidism; malignant hyperthermia; toxins such as ethylene glycol, carbon monoxide, mercurial chloride, stings; drugs such as fibrates, statins, opioids and amphetamines; hereditary diseases such as muscular dystrophy, metabolopathies, McArdle disease and carnitine deficit Hemoglobinuria: malaria; mechanical destruction of erythrocytes with extracorporeal circulation or metallic prosthesis, transfusion reactions, or other hemolysis; heat stroke; burns; glucose-6-phosphate dehydrogenase; nocturnal paroxystic hemoglobinuria; chemicals such as aniline, quinine, glycerol, benzene, phenol, hydralazine; insect venoms Acute tubulointerstitial nephritis (see Fig. 8-4)

CAUSES OF PRERENAL ACUTE RENAL FAILURE Decreased effective extracellular volume Renal losses: hemorrhage, vomiting, diarrhea, burns, diuretics Redistribution: hepatopathy, nephrotic syndrome, intestinal obstruction, pancreatitis, peritonitis, malnutrition Decreased cardiac output: cardiogenic shock, valvulopathy, myocarditis, myocardial infarction, arrhythmia, congestive heart failure, pulmonary emboli, cardiac tamponade Peripheral vasodilation: hypotension, sepsis, hypoxemia, anaphylactic shock, treatment with interleukin L2 or interferons, ovarian hyperstimulation syndrome Renal vasoconstriction: prostaglandin synthesis inhibition, -adrenergics, sepsis, hepatorenal syndrome, hypercalcemia Efferent arteriole vasodilation: converting-enzyme inhibitors

FIGURE 8-2 Causes of prerenal acute renal failure (ARF). Prerenal ARF, also known as prerenal uremia, supervenes when glomerular filtration rate falls as a consequence of decreased effective renal blood supply. The condition is reversible if the underlying disease is resolved.

Vascular occlusion Principal vessels: bilateral (unilateral in solitary functioning kidney) renal artery thrombosis or embolism, bilateral renal vein thrombosis Small vessels: atheroembolic disease, thrombotic microangiopathy, hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura, postpartum acute renal failure, antiphospholipid syndrome, disseminated intravascular coagulation, scleroderma, malignant arterial hypertension, radiation nephritis, vasculitis Acute glomerulonephritis Postinfectious: streptococcal or other pathogen associated with visceral abscess, endocarditis, or shunt Henoch-Schonlein purpura Essential mixed cryoglobulinemia Systemic lupus erythematosus ImmunoglobulinA nephropathy Mesangiocapillary With antiglomerular basement membrane antibodies with lung disease (Goodpasture is syndrome) or without it Idiopathic, rapidly progressive, without immune deposits Cortical necrosis, abruptio placentae, septic abortion, disseminated intravascular coagulation

FIGURE 8-3 Causes of parenchymal acute renal failure (ARF). When the sudden decrease in glomerular filtration rate that characterizes ARF is secondary to intrinsic renal damage mainly affecting tubules, interstitium, glomeruli and/or vessels, we are facing a parenchymatous ARF. Multiple causes have been described, some of them constituting the most frequent ones are marked with an asterisk.

8.3

Acute Renal Failure: Causes and Prognosis

MOST FREQUENT CAUSES OF ACUTE TUBULOINTERSTITIAL NEPHRITIS

Antimicrobials Penicillin Ampicillin Rifampicin Sulfonamides Analgesics, anti-inflammatories Fenoprofen Ibuprofen Naproxen Amidopyrine Glafenine Other drugs Cimetidine Allopurinol

CAUSES OF OBSTRUCTIVE ACUTE RENAL FAILURE

Congenital anomalies Ureterocele Bladder diverticula Posterior urethral valves Neurogenic bladder Acquired uropathies Benign prostatic hypertrophy Urolithiasis Papillary necrosis Iatrogenic ureteral ligation Malignant diseases Prostate Bladder Urethra Cervix Colon Breast (metastasis)

Immunological Systemic lupus erythematosus Rejection Infections (at present quite rare) Neoplasia Myeloma Lymphoma Acute leukemia Idiopathic Isolated Associated with uveitis

FIGURE 8-4 Most common causes of tubulointerstitial nephritis. During the last years, acute tubulointerstitial nephritis is increasing in importance as a cause of acute renal failure. For decades infections were the most important cause. At present, antimicrobials and other drugs are the most common causes.

ATN 43.1%

Prerenal 40.6%

ATN 45%

Other parenchymal 6.4%

Obstructive 10%

Obstructive 3.4%

ATIN 1.6% Arterial disease 1%

Prerenal 21% Acute-on-chronic 13%

A

n = 202 1977–1980

n = 748 1991

B

FINDINGS OF THE MADRID STUDY

Condition Acute tubular necrosis Prerenal acute renal failure Acute on chronic renal failure Obstructive acute renal failure Glomerulonephritis (primary or secondary) Acute tubulointerstitial nephritis Vasculitis Other vascular acute renal failure Total

Incidence (per million persons per year)

95% CI

88 46 29 23 6.3 3.5 3.5 2.1

79–97 40–52 24–34 19–27 4.8–8.3 1.7–5.3 1.7–5.3 0.8–3.4

209

Infections Schistosomiasis Tuberculosis Candidiasis Aspergillosis Actinomycosis Other Accidental urethral catheter occlusion

FIGURE 8-5 Causes of obstructive acute renal failure. Obstruction at any level of the urinary tract frequently leads to acute renal failure. These are the most frequent causes.

Other parenchymal 4.5%

Arterial disease 2.5%

Retroperitoneal fibrosis Idiopathic Associated with aortic aneurysm Trauma Iatrogenic Drug-induced Gynecologic non-neoplastic Pregnancy-related Uterine prolapse Endometriosis Acute uric acid nephropathy Drugs -Aminocaproic acid Sulfonamides

195–223

FIGURE 8-6 This figure shows a comparison of the percentages of the different types of acute renal failure (ARF) in a western European country in 1977–1980 and 1991: A, distribution in a typical Madrid hospital; B, the Madrid ARF Study [1]. There are two main differences: 1) the appearance of a new group in 1991, “acute on chronic ARF,” in which only mild forms (serum creatinine concentrations between 1.5 and 3.0 mg/dL) were considered, for methodological reasons; 2) the decrease in prerenal ARF suggests improved medical care. This low rate of prerenal ARF has been observed by other workers in an intensive care setting [2]. The other types of ARF remain unchanged. FIGURE 8-7 Incidences of different forms of acute renal failure (ARF) in the Madrid ARF Study [1]. Figures express cases per million persons per year with 95% confidence intervals (CI).

8.4

Acute Renal Failure

Sclerodermal crisis 1 Tumoral obstruction 1 Secondary glomerulonephritis 1 Vasculitis 1

ATN 43% Other 15% Prerenal 27%

Malignant hypertension 2.1 Myeloma 2.1 Acute tubulointerstitial nephritis 2.1

Not recorded 15%

Atheroembolic disease 4.2

FIGURE 8-9 Discovering the cause of acute renal failure (ARF). This is a great challenge for clinicians. This algorithm could help to determine the cause of the increase in blood urea nitrogen (BUN) or serum creatinine (SCr) in a given patient.

Bun/SCr increase Normal or big kidneys (excluding amiloidosis and polycystic kidney disease

Small kidneys

↑ SCr < 0.5 mg/dL/d Previous SCr increased

and/or

and/or

and/or

and/or

↑ SCr > 0.5 mg/dL/d Previous SCr normal

ARF

CRF

+

Urinary tract dilatation

Echography ↑ SCr < 0.5 mg/dL/d Normal Flare of previous disease

Acute-on-chronic renal failure

Repeat echograph after 24 h

Normal No Data indicating glomerular or systemic disease?

Prerenal factors?

Parenchymatous glomerular or systemic ARF

Yes

Vascular ARF

Yes

Great or small vessel disease?

No

Acute tubulointerstitial nephritis

Yes

Data indicating interstitial disease?

No

Yes

Crystals or tubular deposits?

No

Tumor lysis Sulfonamides Amyloidosis Other

FIGURE 8-8 The most frequent causes of acute renal failure (ARF) in patients with preexisting chronic renal failure are acute tubular necrosis (ATN) and prerenal failure. The distribution of causes of ARF in these patients is similar to that observed in patients without previous kidney diseases. (Data from Liaño et al. [1])

No

Yes

Obstructive ARF

Improvement with specific treatment? Yes Prerenal ARF

No

Acute tubular necrosis

Acute Renal Failure: Causes and Prognosis

BIOPSY RESULTS IN THE MADRID STUDY Disease

Patients, n

Primary GN Extracapillary Acute proliferative Endocapillary and extracapillary Focal sclerosing Secondary GN Antiglomerular basement membrane Acute postinfectious Diffuse proliferative (systemic lupus erythematosus) Vasculitis Necrotizing Wegener’s granulomatosis Not specified Acute tubular necrosis Acute tubulointerstitial nephritis Atheroembolic disease Kidney myeloma Cortical necrosis Malignant hypertension ImmunoglobulinA GN + ATN Hemolytic-uremic syndrome Not recorded

12 6 3 2 1 6 3 2 1* 10 5* 3 2 4* 4 2 2* 1 1 1 1 2

8.5

FIGURE 8-10 Biopsy results in the Madrid acute renal failure (ARF) study. Kidney biopsy has had fluctuating roles in the diagnostic work-up of ARF. After extrarenal causes of ARF are excluded, the most common cause is acute tubular necrosis (ATN). Patients with well-established clinical and laboratory features of ATN receive no benefit from renal biopsy. This histologic tool should be reserved for parenchymatous ARF cases when there is no improvement of renal function after 3 weeks’ evolution of ARF. By that time, most cases of ATN have resolved, so other causes could be influencing the poor evolution. Biopsy is mandatory when a potentially treatable cause is suspected, such as vasculitis, systemic disease, or glomerulonephritis (GN) in adults. Some types of parenchymatous non-ATN ARF might have histologic confirmation; however kidney biopsy is not strictly necessary in cases with an adequate clinical diagnosis such as myeloma, uric acid nephropathy, or some types of acute tubulointerstitial nephritis . Other parenchymatous forms of ARF can be accurately diagnosed without a kidney biopsy. This is true of acute post-streptococcal GN and of hemolytic-uremic syndrome in children. Kidney biopsy was performed in only one of every 16 ARF cases in the Madrid ARF Study [1]. All patients with primary GN, 90% with vasculitis and 50% with secondary GN were diagnosed by biopsy at the time of ARF. As many as 15 patients were diagnosed as having acute tubulointerstitial nephritis, but only four (27%) were biopsied. Only four of 337 patients with ATN (1.2%) underwent biopsy. (Data from Liaño et al. [1].)

* One patient with acute-on-chronic renal failure.

Predisposing Factors for Acute Renal Failure Renal insult Advanced age

Very elderly

Elderly

Young

11%

12%

17%

11%

7%

Proteinuria 20% Volume depletion

29%

Other Obstructive Prerenal Acute tubular necrosis

21%

30% Myeloma

Diuretic use

39% Diabetes mellitus

Previous cardiac or renal insufficiency

Higher probability for ARF

FIGURE 8-11 Factors that predispose to acute renal failure (ARF). Some of them act synergistically when they occur in the same patient. Advanced age and volume depletion are particularly important.

(n=103)

48%

(n=256)

56%

(n=389)

FIGURE 8-12 Causes of acute renal failure (ARF) relative to age. Although the cause of ARF is usually multifactorial, one can define the cause of each case as the most likely contributor to impairment of renal function. One interesting approach is to distribute the causes of ARF according to age. This

figure shows the main causes of ARF, dividing a population diagnosed with ARF into the very elderly (at least 80 years), elderly (65 to 79), and young (younger than 65). Essentially, acute tubular necrosis (ATN) is less frequent (P=0.004) and obstructive ARF more frequent (P<0.001) in the very old than in the youngest patients. Prerenal diseases appear with similar frequency in the three age groups. (Data from Pascual et al. [3].)

8.6

Acute Renal Failure

Epidemiology of Acute Renal Failure EPIDEMIOLOGY OF ACUTE RENAL FAILURE

Investigator, Year

Country (City)

Eliahou et al., 1973 [4] Abraham et al., 1989 [5] McGregor et al., 1992 [6]

Israel Kuwait United Kingdom (Glasgow) Spain (Cuenca) United Kingdom (Bristol and Devon) Spain (Madrid)

Sanchez et al., 1992 [7] Feest et al., 1993 [8] Madrid ARF Study Group, 1996 [1]

Study Period (Study Length)

Study Population (millions)

Incidence (pmp/y)

1965–1966 (2 yrs) 1984–1986 (2 yrs) 1986–1988 (2 yrs)

2.2 0.4 0.94

52 95 185

1988–1989 (2 yrs) 1986–1987 (2 yrs)

0.21 0.44

254 175

1991–1992 (9 mo)

4.23

209

FIGURE 8-14 Number of patients needing dialysis for acute renal failure (ARF), expressed as cases per million population per year (pmp/y). This has been another way of assessing the incidence of the most severe cases of ARF. Local situations, mainly economics, have an effect on dialysis facilities for ARF management. In 1973 Israeli figures showed a lower rate of dialysis than other countries at the same time. The very limited access to dialysis in developing countries supports this hypothesis. At present, the need for dialysis in a given area depends on the level of health care offered there. In two different countries (eg, the United Kingdom and Spain) the need for dialysis for ARF was very much lower when only secondary care facilities were available. At this level of health care, both countries had the same rate of dialysis. The Spanish data of the EDTA-ERA Registry in 1982 gave a rate of dialysis for ARF of 59 pmp/y. This rate was similar to that found in the Madrid ARF Study 10 years later. These data suggest that, when a certain economical level is achieved, the need of ARF patients for dialysis tends to stabilize.

EPIDEMIOLOGY OF ACUTE RENAL FAILURE: NEED OF DIALYSIS

Investigator, Year

Country

Lunding et al., 1964 [9] Eliahou et al., 1973 [4] Lachhein et al., 1978 [10] Wing et al., 1983 [11]

Scandinavia Israel West Germany European Dialysis and Transplant Association Spain Kuwait Spain United Kingdom United Kingdom United Kingdom Spain

Wing et al., 1983 [11] Abraham et al., 1989 [5] Sanchez et al., 1992 [7] McGregor et al., 1992 [6] Gerrard et al., 1992 [12] Feest et al., 1993 [8] Madrid ARF Study Group [1]

FIGURE 8-13 Prospective studies. Prospective epidemiologic studies of acute renal failure (ARF) in large populations have not often been published . The first study reported by Eliahou and colleagues [4] was developed in Israel in the 1960s and included only Jewish patients. This summary of available data suggests a progressive increase in ARF incidence that at present seems to have stabilized around 200 cases per million population per year (pmp/y). No data about ARF incidence are available from undeveloped countries.

Cases (pmp/y) 28 17* 30 29 59 31 21† 31 71 22† 57

* Very restrictive criteria. † Only secondary care facilities.

HISTORICAL PATTERNS OF ACUTE RENAL FAILURE Proportion of Cases, %

Surgical Medical Obstetric

France 1973

India 1965–1974

France 1981–1986

India 1981–1986

South Africa 1986–1988

46 30 24

11 67 22

30 70 2

30 61 9

8 77 15

FIGURE 8-15 Historical perspective of acute renal failure (ARF) patterns in France, India, and South Africa. In the 1960s and 1970s, obstetrical causes were a great problem in both France and India and overall incidences of ARF were similar. Surgical cases were almost negligible in India at that time, probably because of the relative unavailability of hospital facilities. During the 1980s surgical and medical causes were similar in both countries. In India, the increase in surgical cases may be explained by advances in health care, so that more surgical procedures could be done. The decrease in surgical cases in France, despite the fact that surgery had become very sophisticated, could be explained by better management of surgical patients. (Legend continued on next page)

8.7

Acute Renal Failure: Causes and Prognosis FIGURE 8-15 (Continued) Changes in classification criteria—inclusion of a larger percentage of medical cases than a decade before—could be an alternative explanation. In addition, obstetric cases had almost disappeared in France in the 1980s, but they were still an important cause of ARF in India. In a South African study that excluded the white population the distribution of ARF causes was almost identical to that observed in India 20 years earlier. In conclusion, 1) the economic

level of a country determines the spectrum of ARF causes observed; 2) when a developing country improves its economic situation, the spectrum moves toward that observed in developed countries; and 3) great differences can be detected in ARF causes among developing countries, depending on their individual economic power. (Data from Kleinknecht [13]; Chugh et al. [14]; Seedat et al. [15].)

Percentage of total ARF cases

25 HD 68%

20 15

Diarrhea

Hemolysis

Obstetric

10

CRRT 1%

5

HD 60%

CRRT 33%

PD 31% EDTA (1982)

A

0 1965–1974

1975–1980 Years

2221 patients

UF 1% PD 5%

Madrid study (1992)

B

270 patients

1981–1986

FIGURE 8-16 Changing trends in the causes of acute renal failure (ARF) in the Third-World countries. Trends can be identified from the analysis of medical and obstetric causes by the Chandigarh Study [14]. Chugh and colleagues showed how obstetric (septic abortion) and hemolytic (mainly herbicide toxicity) causes tended to decrease as economic power and availability of hospitalization improved with time. These causes of ARF, however, did not completely disappear. By contrast, diarrheal causes of ARF, such as cholera and other gastrointestinal diseases, remained constant. In conclusion, gastrointestinal causes of ARF will remain important in ARF until structural and sanitary measures (eg, water treatment) are implemented. Educational programs and changes in gynecological attention, focused on controlled medical abortion and contraceptive measures, should be promoted to eradicate other forms of ARF that constitute a plague in Third World countries.

FIGURE 8-17 Evolution of dialysis techniques for acute renal failure (ARF) in Spain. A, The percentages of different modalities of dialysis performed in Spain in the early 1980s. B, The same information obtained a decade. At this latter time, 90% of conventional hemodialysis (HD) was performed using bicarbonate as a buffer. These rates are those of a developed country. In developing countries, dialysis should be performed according to the available facilities and each individual doctor’s experience in the different techniques. PD—peritoneal dialysis; CRRT—continuous renal replacement technique; UF—isolated ultrafiltration. (A, Data from the EDTA-ERA Registry [11]; B data from the Madrid ARF Study [1].)

Hospital-Related Epidemiologic Data FIGURE 8-18 Serum creatinine (SCr) at hospital admission has diagnostic and prognostic implications for acute renal failure (ARF). A, Of the patients included in an ARF epidemiologic study 39% had a normal SCr concentration (less than 1.5 mg/dL) at hospital admission. It is worth noting that only 22% of the patients had clearly established ARF (SCr greater than 3 mg/dL) when admitted (no acute-on-chronic case was included). Mortality was significantly higher in patients with normal SCr at admission.

P<0.001

60 50 %

40 30 20 10 0

A

(Continued on next page) SCr<1.5 mg/dL

Mortality

SCr>3.0 mg/dL

Mortality

8.8

Acute Renal Failure

ARF

Community-acquired (SCr at admission>3 mg/dL)

Hospital-acquired (SCr at admission<1.5 mg/dL)

ATN Prerenal Obstructive

41.8 47.5 77.3

58.2 52.5 22.7

Total

49.7

50.3

FIGURE 8-18 (Continued) B, With the same two groups, acute tubular necrosis (ATN) predominated among the hospital-induced ARF group, whereas the obstructive form was the main cause of community-acquired ARF. In conclusion, the hospital could be considered an ARF generator, particularly of the most severe forms. Nonetheless, these iatrogenic ARF cases are usually “innocent,” and are an unavoidable consequence of diagnostic and therapeutic maneuvers. (Data from Liaño et al. [1].)

Medical dept. 34% ICUs 27%

Trauma 2% Nephrology 13% Surgical dept. 23%

A

Gynecology 1%

FIGURE 8-19 Acute renal failure: initial hospital location and mortality. A, Initial departmental location of ARF patients in a hospital in a Western country. The majority of the cases initially were seen in medical, surgical, and intensive care units (ICUs). The cases initially treated in nephrology departments were community acquired, whereas the ARF patients in the other settings generally acquired ARF in those settings. Obstetric-gynecologic ARF cases have almost disappeared. ARF of traumatic origin is also rare, for

EPIDEMIOLOGIC VARIABLES

Investigator, Year Hou et al., 1983* Shusterman et al., 1987* Lauzurica et al., 1989* First period Second period Abraham et al., 1989 Madrid Study, 1992 * Case-control studies.

Acute Renal Failure in Hospitalized Patients (per 1000 admissions) 49.0 19.0 16.0 6.5 1.3 1.5

Mortality, %

B

80 70 60 50 40 30 20 10 0

* All cases

B

ICUs Medical Surgical *P<0.001 respect to all cases

Nephrol

two reasons: 1) polytrauma patients are now treated in the ICU and 2) early and effective treatments applied today to trauma patients at the accident scene, and quick transfer to hospital, have decreased this cause of ARF. B, Mortality was greater for patients initially treated in the ICU and lower in the nephrology setting than rates observed in other departments. These figures were obtained from 748 ARF patients admitted to 13 different adult hospitals. (Data from Liaño et al. [1].) FIGURE 8-20 Epidemiologic variable. The incidence of hospital-acquired acute renal failure (ARF) depends on what epidemiologic method is used. In case-control studies the incidence varied between 49 and 19 per thousand. When the real occurrence was measured in large populations over longer intervals, the incidence of hospital-acquired ARF decreased to 1.5 per thousand admissions. (Data from [1,5,16,17,18].)

8.9

Acute Renal Failure: Causes and Prognosis

Prognosis HISTORICAL PERSPECTIVE OF MEDICAL PROGNOSIS APPLIED IN ACUTE RENAL FAILURE Criteria

Derivation

Applications

Advantages

Drawbacks

Classical

Doctor’s experience

Individual prognosis

Easy

Traditional Present

Univariate statistical analysis Multivariate statistical analysis Computing facilities

Risk stratification Risk stratification Individual prognosis?

Future

Multivariate analysis Computing facilities

Risk stratification Individual prognosis Patient’s quality of life evaluation Functional prediction

Easy Measurable Theoretically, “all” factors influencing outcome are considered Measurable “All” factors considered

Doctor’s inexperience Unmeasurable Only one determinant of prognosis is considered Complexity (variable, depending on model)

FIGURE 8-21 Estimating prognosis. The criteria for estimating prognosis in acute renal failure can be classified into four periods. The Classical or heuristic way is similar to that used since the Hippocratic aphorisms. The Traditional one based on simple statistical procedures, is not useful for individual prognosis. The Present form is more or less complex, depending on what method is used, and it is possible, thanks to computing facilities and the

Renal insult

Ideally, none

development of multivariable analysis. Theoretically, few of these methods can give an individual prognosis [19]. They have not been used for triage. The next step will need a great deal of work to design and implement adequate tools to stratify risks and individual prognosis. In addition, the estimate of residual renal function and survivors’ quality of life, mainly for older people, are future challenges.

100

Cumulative trend Mean

ARF

Outcome

Mortality, %

80 60 40 20 0 Prognosis

FIGURE 8-22 Ideally, prognosis should be established as the problem, the episode of acute renal failure (ARF), starts. Correct prognostic estimation gives the real outcome for a patient or group of patients as precisely as possible. In this ideal scenario, this fact is illustrated by giving the same surface area for the concepts of outcome and prognosis.

11 10 2 3 3 1

1951 55

6

34

5

60

2

7

11

16 57

65

8

5

9

20 13 11 131110 10 8 Number 9 6 55 478 6 5 64 5 of 3 2 publications

70 Year

75

80

85

1990

FIGURE 8-23 Mortality trends in acute renal failure (ARF). This figure shows the evolution of mortality during a 40-year period, starting in 1951. The graphic was elaborated after reviewing the outcome of 32,996 ARF patients reported in 258 published papers. As can be appreciated, mortality rate increases slowly but constantly during this follow-up, despite theoretically better availability of therapeutic armamentarium (mainly antibiotics and vasoactive drugs), deeper knowledge of dialysis techniques, and wider access to intensive care facilities. This improvement in supporting measures allows the physician to keep alive, for longer periods of time patients who otherwise would have died. A complementary explanation could be that the patients treated now are usually older, sicker, and more likely to be treated more aggressively. (From Kierdorf et al. [20]; with permission.)

8.10

Acute Renal Failure

Prognostic systems used in ARF

Specific ARF methods

ICU methods

Apache system

APACHE II

SAPS

APACHE III

SAPS I

OSF

MPM

MPM I

SAPS II

MPM II

OSF

MODS

Liano

SOFA

Rasmussen

Lohr

Schaefer

Brivet

Sensitivity, %

FIGURE 8-24 Ways of estimating prognosis in acute renal failure (ARF). This can be done using either general intensive care unit (ICU) score systems or methods developed specifically for ARF patients. ICU systems include Acute Physiological and Chronic Health Evaluation (APACHE) [21,22], Simplified Physiologic Score (SAPS)[23,24], Mortality Prediction Model (MPM) [25,26], and Organ System Failure scores (OSF) [27]. Multiple Organ Dysfunction Score (MODS) [28] and

100

100

80

80

60

60 APACHE II APACHE III SAPS SAPS-R SAPS-E SS MPM

40 20

40 Rasmussen Liaño Lohr Schaefer

20

0

0 0

A

Sepsis-Related Organ Failure Assessment Score (SOFA) [29] are those that seem most suitable for this purpose. APACHE II used to be most used. Other systems (white boxes) have been used in ARF. On the other hand, at least 17 specific ARF prognostic methods have been developed [20,30]. The figure shows only those that have been used after their publication [31], plus one recently published system which is not yet in general use [2].

20

40 60 1- Specificity, %

80

100

0

B

20

40 60 80 1- Specificity, %

100

FIGURE 8-25 Comparison of prognostic methods for acute renal failure (ARF) by ROC curve analysis [31]. A method is better when its ROC-curve moves to the upper left square determined by the sensitivity and the reciprocal of the specificity. A, ROC curves of seven

prognostic methods usually employed in the ICU setting. The best curve comes from the APACHE III method, which has an area under the ROC curve of 0.74 ± 0.04 (SE). B, Four ROC curves corresponding to prognostic methods specifically developed for ARF patients are depicted. The best curve in this panel comes from the Liaño method for ARF prognosis. Its area under the curve is 0.78 ± 0.03 (SE). APACHE—Acute Physiology and Chronic Health Evaluation, (II second version [21]; III third version [22]); SAPS—Simplified Acute Physiology Score [23]; SAPS-R— SAPS-reduced [33]; SAPS-E—SAPSExtended [32]; SS—Sickness Score [33]; MPM—Mortality Prediction Model [25]; ROC curve—Receiving Operating Characteristic curve; SE—Standard Error. (From Douma [31]; with permission.)

8.11

Acute Renal Failure: Causes and Prognosis

Hypotension Catabolism Hemolysis Hepatic disease Kind of surgery Hyperkalemia Need for dialysis Assisted respiration Site of war injuries Disseminated intravascular coagulopathy Pancreatitis Antibiotics Timing of treatment

FIGURE 8-26 Individual factors that have been associated with acute renal failure (ARF) outcome. Most of these innumerable variables have been related to an adverse outcome, whereas few (nephrotoxicity as a cause of ARF and early treatment) have been associated with more favorable prognosis. For a deep review of variables studied with univariate statistical analysis [34, 35]. NSAID—nonsteroidal antiinflammatory drugs; BUN—blood urea nitrogen.

40 20 0

100

40

Survivors

5

10

15

20 25 30 35 40 Days of ARF evolution

80

Persistent hypotension

69

60

P<0.001

40

33

100

20

20

60

Mortality, %

Assisted repiration 80

60 P<0.001

40

32

Yes

Jaundice

100 80

80

No

67

60

P<0.001 40

40 20

No

Oliguria

100 Mortality, %

Co ma

n A res ssis pir ted ati on Jau nd ice co No nsc rm iou al sne ss Sed ati on

ten sio

ria

Hy

po

igu

55

0 Yes

Ol

50

20

0 0

FIGURE 8-28 Precipitating condition of acute renal failure (ARF). The initial clinical condition observed in ARF patients is shown. Oliguria: urine output of less than 400 mL per day; hypotension: systolic blood pressure lower than 100 mm Hg for at least 10 hours per day independent of the use of vasoactive drugs; jaundice: serum bilirubin level higher than 2 mg/dL; coma: Glasgow coma score of 5 or less. The presence of these factors is associated with poorer outcome (see Fig. 8-29). (Data from Liaño et al. [1].)

45

FIGURE 8-27 Duration and resolution of acute renal failure (ARF). Most of the episodes of ARF resolved in the first month of evolution. Mean duration of ARF was 14 days. Seventy-eight percent of the patients with ARF who died did so within 2 weeks after the renal insult. Similarly, 60% of survivors had recovered renal function at that time. After 30 days, 90% of the patients had had a final resolution of the ARF episode, one way or the other. Patients who finally lost renal function and needed to be included in a chronic periodic dialysis program usually had severe forms of glomerulonephritis, vasculitis, or systemic disease. (From Liaño et al. [1]; with permission.)

Mortality, %

ARF patients, %

60

1

80 60

8 patients to chronic hemodialysis

Nonsurvivors

80

Mortality, %

Age Jaundice Sepsis Burns Trauma NSAIDs BUN increments Coma Oliguria Obstetric origin Malignancies Cardiovascular disease X-ray contrast agents Acidosis

Cumulative frequencies of resolved cases, %

100

ACUTE RENAL FAILURE: VARIABLES STUDIED WITH UNIVARIATE ANALYSIS

80 60

52

40

P<0.02

36

20

0

0 Yes

No

Yes

No

FIGURE 8-29 Mortality associated with the presence or absence of oliguria, persistent hypotension, assisted respiration and jaundice (as defined in Fig. 8-28). The presence of an unfavorable factor was significantly associated with higher mortality. (Data from Liaño et al. [1].)

8.12

Acute Renal Failure

100 77

80 Mortality rate, %

FIGURE 8-30 Consciousness level and mortality. Coma patients had a Glasgow coma score of 5 or lower. Sedation refers to the use of this kind of treatment, primarily in patients with assisted respiration. Both situations are associated with significantly higher mortality (P<0.001) than that observed in either patients with a normal consciousness level or the total population. (Data from Liaño et al. [1].)

92

60 45

40

30

20 0 Normal

Sedation

2

Coma

All cases

Original disease

1

3 Previous health condition

Kind and severity of kidney insult

S

SIR

Depending on 2 and 3 No SIR S Isolated ARF

ARF in a MODS complex

Death

Recovery

Depending on: *2,3, & 1 *No. of failing organs *Recovery process

Recovery

FIGURE 8-31 Outcome of acute renal failure (ARF). Two groups of factors play a role on ARF outcome. The first includes factors that affect the patient: 1) previous health condition; 2) initial disease—usually, the direct or indirect (eg, treatments) cause of kidney failure; 3) the kind and severity of kidney injury. While 1 is a conditioning element, 2 and 3 trigger the second group of factors: the response of the patient to the insult. If this response includes a systemic inflammatory response syndrome (SIRS) like that usually seen in intensive care patients (eg, sepsis, pancreatitis, burns), a multiple organ dysfunction syndrome (MODS) frequently appears and consequently outcome is associated with a higher fatality rate (thick line). On the contrary, if SIRS does not develop and isolated ARF predominates, death (thin line, right) is less frequent than survival (thick line).

Acute Renal Failure: Causes and Prognosis

FIGURE 8-32 Individual severity index (ISI). The ISI was published in its second version in 1993 [36]. The ISI estimates the probability of death. Nephrotoxic indicates an ARF of that origin; the other variables have been defined in preceding figures. The numbers preceding these keys denote the contribution of each one to the prognosis and are the factor for multiplying the clinical variables; 0.210 is the equation constant. Each clinical variable takes a value of 1 or 0, depending, respectively, on its presence or absence (with the exception of the age, which takes the value of the patient’s decade). The parameters are recorded when the nephrologist sees the patient the first time. Calculation is easy: only a card with the equation values, a pen, and paper are necessary. A real example is given.

INDIVIDUAL SEVERITY INDEX ISI=0.032 (age-decade)  0.086 (male)  0.109 (nephrotoxic)  0.109 (oliguria)  0.116 (hypotension)  0.122 (jaundice)  0.150 (coma)  0.154 (consciousness)  0.182 (assisted respiration)  0.210 Case example A 55-year-old man was seen because of oliguria following pancreatic surgery. At that moment he was hypotensive and connected to a respirator, and jaundice was evident. He was diagnosed with acute tubular necrosis. His ISI was calculated as follows: ISI=0.032(6)  0.086  0.109  0.116  0.122  0.182  0.210 = 0.845

Acute GN

ATN 66

No recovery

11 11

31 31

Partial recovery

32 32

24

No recovery 47

35 Partial recovery 63 63

Total recovery

1 yr

5 yr

25

29 5 yr

HUS/ACN 8 25 63

75

Total recovery

1 yr

Acute TIN No recovery Partial recovery

24

57 57 41

No recovery 91

Total recovery

5 yr

Dead 174

FIGURE 8-33 Outcome of acute renal failure (ARF). Long-term outcome of ARF has been studied only in some series of intrinsic or parenchymatous ARF. The figure shows the different long-term prognoses for intrinsic ARF of various causes. Left, The percentages of recovery rate of renal function 1 year after the acute episode of renal failure. Right, The situation of renal function 5 years after the ARF episode. Acute tubulointerstitial nephritis (TIN) carries the better prognosis: the vast majority of patients had recovered renal function after 1 and 5 years. Two thirds of the patients with acute tubule necrosis (ATN) recovered normal renal function, 31% showed partial recovery, and 6% experienced no functional recovery. Some patients with ATN lost renal function over the years. Patients with ARF due to glomerular lesions have a poorer prognosis; 24% at 1 year and 47% at 5 years show terminal renal failure. The poorest evolution is observed with severe forms of acute cortical necrosis or hemolytic-uremic syndrome. GN—glomerulonephritis; HUS— hemolytic-uremic syndrome; ACN—acute cortical necrosis. (Data from Bonomini et al. [37].)

67 27

1 yr

8.13

Partial recovery

1 yr

Dead 113

Dead 50

Alive 225

Alive 143

Alive 53

< 65 yr (n = 399)

65–79 yr (n = 256)

> 80 yr (n = 103)

9 5 yr

FIGURE 8-34 Age as a prognostic factor in acute renal failure (ARF). There is a tendency to treat elders with ARF less aggressively because of the presumed worse outcomes; however, prognosis may be similar to that found in the younger population. In the multicenter prospective longitudinal study in Madrid, relative risk for mortality in patients older than 80 years was not significantly different (1.09 as compared with 1 for the group younger than 65 years). Age probably is not a poor prognostic sign, and outcome seems to be within acceptable limits for elderly patients with ARF. Dialysis should not be withheld from patients purely because of their age.

8.14

Acute Renal Failure

VARIABLES ASSOCIATED WITH PROGNOSIS: MULTIVARIATE ANALYSIS (16 STUDIES)

PROGNOSIS IN ACUTE RENAL FAILURE 1960–1969

Assisted respiration Hypotension or inotropic support Age Cardiac failure/complications Jaundice Diuresis volume Coma Male sex Sepsis Chronic disease Neoplastic disease Other organ failures Serum creatinine Other conditions Summary Clinical variables Laboratory variables

11 10 8 6 6 5 5 4 3 3 2 2 2 12

No. Mortality (%) Mean age (y) Median APACHE II score Range

119 51 50.9 32 (22–45)

P

1980–1989 124 63 63 35 (25–49)

NS < 0.0001 < 0.0001

FIGURE 8-36 Prognosis in acute renal failure (ARF). This figure shows the utility of a prognostic system for evaluating the severity of ARF over time, using the experience of Turney [38]. He compared the age, mortality, and APACHE II score of ARF patients treated at one hospital between 1960 and 1969 and 1980 and 1989. In the latter period there were significant increases in both the severity of the illness as measured by APACHE II and age. Although there was a tendency to a higher mortality rate in the second period, this tendency was not great enough to be statistically significant.

20 6

FIGURE 8-35 Outcome of acute renal failure (ARF). A great number of variables have been associated with outcome in ARF by multivariate analysis. This figure gives the frequency with which these variables appear in 16 ARF studies performed with multivariable analysis (all cited in [30]).

70

68

Time

60 Mortality, %

50 42

40 30 20 10

22 ± 6

Apache II score

Admission in ICU Before dialysis 24 h after dialysis 48 h after dialysis

Nonsurvivors 24 22 25 24

Survivors 22 22 22 22

22 ± 6

0

A

Dialysis patients

Nondialysis patients

FIGURE 8-37 APACHE score. The APACHE II score is not a good method for estimating prognosis in acute renal failure (ARF) patients. A, Data from Verde and coworkers show how mortality was higher in their ICU patients with ARF needing dialysis than in those without need of dialysis, despite the fact that the APACHE II score before dialysis was equal in both groups [39]. B, Similar data were observed by Schaefer’s group [40], who found that the

B

median APACHE II score was similar in both the surviving or nonsurviving ARF patients treated in an intensive care unit. Recently Brivet and associates have found that APACHE II score influences ARF prognosis when included as a factor in a more complex logistic equation [2]. Although not useful for prognostic estimations, APACHE II score has been used in ARF for risk stratification.

Acute Renal Failure: Causes and Prognosis

Mortality, % Severity index

P<0.001

0.8

P<0.001

66 0.57

0.6

%

60 40

33

0.35

0.4

Severity index

80

0.2

20

Dialysis

No dialysis

200 Number of cases

FIGURE 8-38 Analysis of the severity and mortality in acute renal failure (ARF) patients needing dialysis. This figure is an example of the uses of a severity index for analyzing the effect of treatment on the outcome of ARF. Looking at the mortality rate, it is clear that it is higher in patients who need dialysis than in those who do not. It could lead to the sophism that dialysis is not a good treatment; however, it is also clear that the severity index score for ARF was higher in patients who needed dialysis. Severity index is the mean of the individual severity index of each of the patients in each group [36]. (Data from Liaño et al. [1].)

0

0

150 100 50

Ot he r

US ICT

C DI

Inf ec t ion Re spi r dis ato eas ry Ca e rdi ac dis eas Ga e str o ble inte ed sti ing na l

Sh

oc k

0

Or igin al d ise a se

8.15

FIGURE 8-39 Causes of death. The causes of death from acute renal failure (ARF) were analyzed in 337 patients in the Madrid ARF Study [1]. In this work all the potential causes of death were recorded; thus, more than one cause could be present in a given patient. In fact, each dead patient averaged two causes, suggesting multifactorial origin. This could be the expression of a high presence of multiple organ dysfunction syndrome (MODS) among the nonsurviving patients. The main cause of death was the original disease, which was present in 55% of nonsurviving patients. Infection and shock were the next most common causes of death, usually concurrent in septic patients. It is worth noting that, if we exclude from the mortality analysis patients who died as a result of the original disease, the corrected mortality due to the ARF episode itself and its complications, drops to 27%. GI—gastrointestinal; DIC—disseminated intravascular coagulation.

References 1. Liaño F, Pascual J the Madrid ARF Study Group: Epidemiology of acute renal failure: A prospective, multicenter, community-based study. Kidney Int 1996, 50:811–818. 2. Brivet FG, Kleinknecht DJ, Loirat P, et al.: Acute renal failure in intensive care units—causes, outcome and prognostic factors of hospital mortality: A prospective, multicenter study. Crit Care Med 1995, 24:192–197. 3. Pascual J, Liaño F, the Madrid ARF Study Group: Causes and prognosis of acute renal failure in the very old. J Am Geriatr Soc 1998, 46:1–5. 4. Eliahou HE, Modan B, Leslau V, et al.: Acute renal failure in the community: An epidemiological study. Acute Renal Failure Conference, Proceedings. New York 1973. 5. Abraham G, Gupta RK, Senthilselvan A, et al.: Cause and prognosis of acute renal failure in Kuwait: A 2-year prospective study. J Trop Med Hyg 1989, 92:325–329. 6. McGregor E, Brown I, Campbell H, et al.: Acute renal failure. A prospective study on incidence and outcome (Abstract). XXIX Congress of EDTA-ERA, Paris, 1992, p 54. 7. Sanchez Rodrìguez L, MartÌn Escobar E, Lozano L, et al.: Aspectos epidemiolûgicos del fracaso renal agudo en el ·rea sanitaria de Cuenca. Nefrologìa 1992, 12(Suppl 4):87–91. 8. Feest TG, Round A, Hamad S: Incidence of severe acute renal failure in adults: Results of a community based study. Br Med J 1993, 306:481–483.

9. Lunding M, Steiness I, Thaysen JH: Acute renal failure due to tubular necrosis. Immediate prognosis and complications. Acta Med Scand 1964, 176:103–119. 10. Lachhein L, Kielstein R, Sauer K, et al.: Evaluation of 433 cases of acute renal failure. Proc EDTA 1978, 14:628–629. 11. Wing AJ, Broyer M, Brunner FP, et al.: Combined report on regular dialysis and transplantation in Europe XIII-1982. Proc EDTA 1983, 20:5–78. 12. Gerrard JM, Catto GRD, Jones MC: Acute renal failure: An iceberg revisited (Abstract). Nephrol Dial Transplant 1992, 7:458. 13. Kleinknecht D: Epidemiology of acute renal failure in France today. In Acute Renal Failure in the Intensive Therapy Unit. Edited by Bihari D, Neild G. London:Springer-Verlag; 1990:13–21. 14. Chugh S, Sakhuja V, Malhotra HS, Pereira BJG: Changing trends in acute renal failure in Third-World countries—Chandigarh study. Q J Med 1989, 272:1117–1123. 15. Seedat YK, Nathoo BC: Acute renal failure in blacks and Indians in South Africa—Comparison after 10 years. Nephron 1993, 64:198–201. 16. Hou SH, Bushinsky DA, Wish JB, et al.: Hospital-acquired renal insufficiency: A prospective study. Am J Med 1983, 74:243–248. 17. Shusterman N, Strom BL, Murray TG, et al.: Risk factors and outcome of hospital-acquired acute renal failure. Am J Med 1987, 83:65–71.

8.16

Acute Renal Failure

18. Lauzurica R, Caralps A: Insuficiencia renal aguda producida en el hospital: Estudio prospectivo y prevenciûn de la misma. Med ClÌn (Barc) 1989, 92:331–334.

29. Vincent JL, Moreno R, Takala J, et al.: The SOFA (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. Intensive Care Med 1996, 22:707–710.

19. Liaño F, Solez K, Kleinknecht D: Scoring the patient with ARF. In Critical Care Nephrology. Edited by Ronco C, Bellomo R. Dordrecht:Kluwer Academic; 1998; Section 23.1: 1535–1545.

30. Liaño F, Pascual J: Acute renal failure, critical illness and the artificial kidney: Can we predict outcome? Blood Purif 1997, 15:346–353.

20. Kierdorf H, Sieberth HG: Continuous treatment modalities in acute renal failure. Nephrol Dial Transplant 1995; 10:2001–2008.

31. Douma CE, Redekop WK, Van der Meulen JHP, et al.: Predicting mortality in intensive care patients with acute renal failure treated with dialysis. J Am Soc Nephrol 1997, 8:111–117.

21. Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: A severity of disease classification system. Crit Care Med 1985, 13:818–829.

32. Viviand X, Gouvernet J, Granthil C, Francois G: Simplification of the SAPS by selecting independent variables. Intensive Care Med 1991, 17:164–168.

22. Knaus WA, Wagner DP, Draper EA, et al.: The APACHE III prognostic system: Risk prediction of hospital mortality for critically ill hospitalized adults. Chest 1991, 100:1619–1636.

33. Bion JF, Aitchison TC, Edlin SA, Ledingham IM: Sickness scoring and response to treatment as predictors of outcome from critical illness. Intensive Care Med 1988, 14:167–172.

23. Le Gall JR, Loirat P, Alperovitch A, et al.: A simplified acute physiology score for ICU patients. Crit Care Med 1984, 12:975–977.

34. Chew SL, Lins RL, Daelemans R, De Broe ME: Outcome in acute renal failure. Nephrol Dial Transplant 1993, 8:101–107.

24. Le Gall, Lemeshow S, Saulnier F: A new Simplified Acute Phisiology Score (SAPS II) based on a European/North American multicenter study. JAMA 1993, 270:2957–2963. 25. Lemeshow S, Teres D, Pastides H, et al.: A method for predicting survival and mortality of ICU patients using objectively derived weights. Crit Care Med 1985, 13:519–525. 26. Lemeshow S, Teres D, Klar J, et al.: Mortality probability models (MPM II) based on an international cohort of intensive care unit patients. JAMA 1993, 270:2478–2486.

35. Liaño F: Severity of acute renal failure: The need of measurement. Nephrol Dial Transplant 1994, 9(Suppl. 4):229–238. 36. Liaño F, Gallego A, Pascual J, et al.: Prognosis of acute tubular necrosis: An extended prospectively contrasted study. Nephron 1993, 63:21–23. 37. Bonomini V, Stefoni S, Vangelista A: Long-term patient and renal prognosis in acute renal failure. Nephron 1984, 36:169–172. 38. Turney JH: Why is mortality persistently high in acute renal failure? Lancet 1990, 335:971.

27. Knaus WA, Draper EA, Wagner DP, Zimmerman JE: Prognosis in acute organ-system failure. Ann Surg 1985, 202:685–693.

39. Verde E, Ruiz F, Vozmediano MC, et al.: Valor predictivo del APACHE II en el fracaso renal agudo de las unidades de cuidados intensivos (Abstract). Nefrologìa 1996, 16(Suppl. 19):32.

28. Marshall JC, Cook DJ, Christou NV, et al.: Multiple organ dysfunction score: A reliable descriptor of a complex clinical outcome. Crit Care Med 1995, 23:1638–1652.

40. Schaefer JH, Jochimsen F, Keller F, et al.: Outcome prediction of acute renal failure in medical intensive care. Intensive Care Med 1991, 17:19–24.

Renal Histopathology, Urine Cytology, and Cytopathology of Acute Renal Failure Lorraine C. Racusen Cynthia C. Nast

C

auses of acute renal failure can be divided into three categories: 1) prerenal, due to inadequate perfusion; 2) postrenal, due to obstruction of outflow; and 3) intrinsic, due to injury to renal parenchyma. Among the latter, diseases of, or injury to, glomeruli, vessels, interstitium, or tubules may lead to a decrease in glomerular filtration rate (GFR). Glomerular diseases that lead to acute renal failure are the proliferative glomerulonephritides, including postinfectious and membranoproliferative glomerulonephritis secondary to glomerular deposition of immune complexes. If glomerular injury is severe enough to damage the glomerular basement membrane, leakage of fibrin and other plasma proteins stimulates formation of cellular extracapillary “crescents” composed of epithelial cells and monocytes and macrophages. Crescents may form as a result of an inflammatory reaction to immune complexes formed to nonglomerular antigens; antibody reaction to intrinsic glomerular antigens, as in anti–glomerular basement membrane disease; and, in the absence of immune complexes, the pauci-immune processes, which include the small vessel vasculitides, including Wegener’s granulomatosis and microscopic polyarteritis. Immunohistologic examination and electron microscopy play important roles in the diagnosis of these processes. Extensive crescent formation is accompanied by rapidly progressive acute renal failure. The urine sediment in these diseases often contains red blood cells and red cell casts. Vascular diseases (involving veins, arteries, or arterioles and capillaries) can lead to hypoperfusion and acute renal failure. Venous thrombosis, most often due to trauma or a nephrotic state, and arterial thrombosis due to trauma or vasculitis, cause parenchymal ischemia and

CHAPTER

9

9.2

Acute Renal Failure

infarction. Small vessel vasculitides involve small arteries, arterioles, and glomerular capillaries, causing injury and necrosis in the glomerular tuft, which may result in crescent formation. Thrombotic microangiopathies result from endothelial injury damage in small arteries and arterioles, producing thrombosis, obstruction to blood flow, and glomerular hypoperfusion. Urine sediment in these diseases often shows hematuria or cellular casts, reflecting ischemia. Interstitial inflammatory processes lead to acute renal failure via compression of peritubular capillaries or injury to tubules. Causes of acute interstitial nephritis include infection, and immune-mediated reactions. With infection, polymorphonuclear leukocytes may be seen in tubules as well as in interstitium. Inflammatory infiltrates in hypersensitivity reactions, often due to drug exposure, feature eosinophils. Immunohistologic studies may reveal the presence of immune complexes; immune complex deposition around tubules occurs as a primary

process or associated with immune glomerular injury. Tubulitis is seen when the inflammatory reaction extends into the tubular epithelium. Epithelial cell injury is often produced by such inflammatory processes. The urine sediment reveals white blood cells and white cell casts, which may include numerous polymorphonuclear leukocytes or eosinophils. The most common cause of acute renal failure is injury to tubule epithelium. Primary tubule cell injury typically results from ischemia, toxic injury, or both. Cell injury results in disruption of the epithelium and its normal reabsorptive functions, and may lead to obstruction of tubule lumens. Cell exfoliation often occurs, and intact cells and cell fragments and debris can be seen in the urine sediment; these may be in the form of casts. Necrotic cells may be seen in situ along the tubule epithelium or in the tubule lumen, but often overt cell necrosis is not prominent. Apoptosis of tubule cells is seen after injury as well.

Glomerular Diseases

FIGURE 9-1 (see Color Plate) Early postinfectious glomerulonephritis. Numerous polymorphonuclear leukocytes in glomerular capillary loops contribute to the hypercellular appearance of the glomerulus. There is also a segmental increase in mesangial cells (hematoxylin and eosin, original magnification  400). This reactive inflammatory process occurs in response to glomerular deposition of immune complexes, including the large subepithelial “hump-like” deposits which are typical of post-infectious glomerulonephritis. The glomerulonephritis is usually selflimited and reversible, and especially with appropriate treatment of the underlying infection, long-term prognosis is excellent [1].

FIGURE 9-2 (see Color Plate) A large epithelial crescent fills Bowman’s space and compresses the capillary loops in the glomerular tuft. This silver stain highlights the glomerular mesangium and the basement membrane of the glomerular capillaries (silver stain, original magnification  400). The patient presented with hematuria and acute renal failure. Immunostains were negative in this case, a finding consistent with a pauci-immune process. The differential diagnosis includes small vessel vasculitis, and anti-neutrophil cytoplasmic antibody may be positive. Crescentic glomerulonephritis may also occur with anti-glomerular basement membrane antibody disease, or as a complication of immune complex glomerulonephritis [2].

Renal Histopathology, Urine Cytology, and Cytopathology of Acute Renal Failure

9.3

FIGURE 9-3 (see Color Plate) Urine sediment of a patient with acute renal failure revealing red blood cells and some red blood cell casts (original magnification  600). Biopsy in this case revealed crescentic glomerulonephritis. However, hematuria may be seen in any proliferative glomerulonephritis or with parenchymal infarcts. The “casts” assume the cylindrical shape of the renal tubules, and confirm an intrarenal source of the blood in the urine. Fragmented or dysmorphic red blood cells may be seen when the red cells have traversed through damaged glomerular capillaries.

Vascular Diseases FIGURE 9-4 (see Color Plate) An early thrombus is seen in a small renal artery in a patient with patchy cortical infarction (original magnification  250). The patient presented with acute renal failure. The thrombosis may be due to a hypercoaggulable state (eg, disseminated intravascular coaggulation) or endothelial injury (eg, hemolytic uremic syndrome). If the cortical necrosis is patchy, recovery of adequate renal function may occur [3].

FIGURE 9-5 (see Color Plate) A parenchymal infarct in a patient with renal vein thrombosis (hematoxylin and eosin, original magnification  200). A few surviving tubules and a rim of inflammatory cells are seen at the periphery of the infarct. Infarcts may also be seen with arterial thromboses, and with severe injury to the microvasculature, as occurs in thrombotic microangiopathies [3]. If the process is extensive, acute cortical necrosis may occur, often leading to irreversible renal failure.

9.4

Acute Renal Failure

A FIGURE 9-6 (see Color Plate) A fine-needle aspirate in renal infarction. A, Low magnification shows many degenerating cells with a “dirty background” containing cellular debris and scattered neutrophils. Compare to acute tubular necrosis, which has only scattered degenerated or necrotic cells without the extensive necrosis and cell debris. Neutrophils may be numerous if the

B edge of an infarct is aspirated (May-Grunwald Giemsa, original magnification  40). B, Diffusely degenerated and necrotic cells with condensed and disrupted cytoplasm and pyknotic nuclei, and an adjacent neutrophil. No significant numbers of viable tubule epithelial cells remain (May-Grunwald Giemsa, original magnification  160). FIGURE 9-7 (see Color Plate) A small artery with severe inflammation in a patient with a small vessel vasculitis. The wall of the vessel is infiltrated by lymphocytes, plasma cells, and eosinophils (hematoxylin and eosin, original magnification  250). The patient was p-ANCA positive. ANCA may play a pathogenic role in the vasculitis process [4]. Vasculitis in the kidney is often part of a systemic syndrome, but may occur as an apparently renal-limited process.

FIGURE 9-8 (see Color Plate) Microangiopathic changes in a small artery, with endothelial activation, evidenced by the large endothelial cells with hyperchromatic nuclei and vacuolization. There is intimal edema with some cell proliferation, and a prominent band of fibrinoid necrosis is seen; the latter appears dark red-pink on this hematoxylin-eosin stain, and represents insudation of fibrin and plasma proteins into the wall of the injured vessel (original magnification  250). The differential diagnosis includes hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, malignant hypertension, scleroderma, and drug toxicity, the latter due most commonly to mitomycin C or cyclosporine/FK506 [5].

Renal Histopathology, Urine Cytology, and Cytopathology of Acute Renal Failure

9.5

FIGURE 9-9 (see Color Plate) A cast of necrotic tubular cells in urine sediment (Papanicolaou stain, original magnification  400). The most likely causes of damage to the renal tubules with such findings in the urinary sediment are severe ischemia/infarction, or tubular necrosis due to exposure to toxins which injure the renal tubules. The latter include antibiotics, including aminoglycosides and cephalosporins, and chemotherapeutic agents.

Interstitial Disease

FIGURE 9-10 (see Color Plate) Interstitial nephritis with edema and a mononuclear inflammatory infiltrate. Eosinophils in the infiltrate suggest a possible hypersensitivity reaction (hematoxylin and eosin, original magnification 400). Drugs are the most common cause of such a reaction, which often presents with acute renal failure [6]. Inflammatory cells and cell casts may be seen in the urine sediment in these cases, as inflammatory cells infiltrate the tubular epithelium.

FIGURE 9-11 (see Color Plate) Tubulitis, with infiltration of mononuclear cells into the tubular epithelium (hematoxylin and eosin, original magnification  400). There is a mononuclear infiltrate and edema in the surrounding interstitium. Tubule cells may show evidence of lethal or sublethal injury as the inflammatory cells release damaging enzymes. Tubulitis is often seen in interstitial nephritis especially if the targets of the inflammatory reaction are tubular cell antigens or antigens deposited around the tubules. Immunofluorescence may reveal granular or linear deposits of immunoglobulin and complement around the tubules.

9.6

Acute Renal Failure FIGURE 9-12 (see Color Plate) Polymorphonuclear leukocytes forming a cast in a cortical tubule (hematoxylin and eosin, original magnification  400). Note edema and inflammation in adjacent interstitium. These intratubular cells are highly suggestive of acute infection, and may be seen in distal as well as proximal nephron as part of an ascending infection. Intratubular PML may also be seen in vasculitis and other necrotizing glomerular processes, in which these cells escape across damaged areas of the inflamed glomerular tuft.

A FIGURE 9-13 (see Color Plate) Fine-needle aspirate of acute infectious interstitial nephritis (acute pyelonephritis). A 25-gauge needle attached to a 10-cc syringe was utilized to withdraw the aspirate into 4 cc of RPMI-based medium. The specimen was then cytocentrifuged and stained with May-Grunwald Giemsa. A, The renal aspirate contains large numbers of intrarenal neutrophils, which are focally undergoing degenerative changes with cytoplasmic vacuolization and nuclear

B breakdown. In bacterial infection there are many infiltrating neutrophils and there may be associated necrosis of tubule epithelial cells (original magnification  80). B, A neutrophil contains phagocytosed bacteria within the cytoplasm; bacteria stain with Giemsa, so are readily detectable in this setting. Adjacent tubule epithelial cells have cytoplasmic granules but do not phagocytize bacteria (original magnification  160). FIGURE 9-14 (see Color Plate) Numerous polymorphonuclear leukocytes (PML) in the urine sediment of a patient with acute pyelonephritis (hematoxylin and eosin, original magnification  400). Some red blood cells and tubular cells are seen in the background of this cytospin preparation. PML may be found in the urine with acute infection of the lower urinary tract as well, or as a contaminant from vaginal secretions in females. PML casts, on the other hand, are evidence that the cells are from the kidney.

Renal Histopathology, Urine Cytology, and Cytopathology of Acute Renal Failure

A FIGURE 9-15 (see Color Plate) Fine-needle aspirate from patient with intrarenal cytomegalovirus (CMV) infection. A, There are activated and transformed lymphocytes with immature nuclear chromatin and abundant blue cytoplasm that infiltrate the kidney in response to the infection; large granular lymphocytes (NK cells) may be seen as well, but few neutrophils. Similar activated lymphocytes, NK cells, and atypical monocytes can be observed within the peripheral blood. The tubule epithelial cells are virtually never seen to contain CMV inclusions in aspirate material, in contrast to core biopsy specimens. All intrarenal

9.7

B viral infections have a similar appearance, and immunostaining or in situ hybridization is required to identify specific viruses (MayGrunwald Giemsa, original magnification  80). B, Tubular epithelial cells stained with antibody to CMV immediate and early nuclear proteins in active intrarenal CMV infection. With an immunoalkaline phosphatase method, cytoplasmic and prominent nuclear staining for these early proteins are observed in the tubular epithelium. In very early infection, neutrophils also may have cytoplasmic staining for these proteins (original magnification  240). FIGURE 9-16 (see Color Plate) Numerous eosinophils in an interstitial inflammatory infiltrate. Eosinophils may be diffuse within the infiltrate, but may also be clustered, forming “eosinophilic abscesses,” as in this area (hematoxylin and eosin, original magnification  400). Eosinophils may also be demonstrated in the urine sediment. Drugs most commonly producing acute interstitial nephritis as part of a hypersensitivity reaction include: penicillins, sulfonamides, and nonsteroidal antiinflammatory drugs [6]. The patient had recently undergone a course of therapy with methicillin. The interstitial nephritis may be part of a systemic reaction which includes fever, rash, and eosinophilia.

9.8

Acute Renal Failure

A FIGURE 9-17 (see Color Plate) Fine-needle aspirate of acute allergic interstitial nephritis. A, The aspirate contains numerous lymphocytes, occasional activated lymphocytes, and eosinophils without fully transformed lymphocytes, corresponding to the inflammatory component within the tubulointerstitium observed on routine renal biopsy. Monocytes often are

B present (May-Grunwald Giemsa, original magnification  80). B, Higher magnification showing the typical infiltrating cells, including a monocyte, activated lymphocyte, and an eosinophil. A neutrophil is present, likely owing to blood contamination (May-Grunwald Giemsa, original magnification  160).

Tubular Diseases

FIGURE 9-18 (see Color Plate) Severe vacuolization of tubular cells in injured tubular epithelium (hematoxylin and eosin, original magnification  400). The vacuoles reflect cell injury and derangement of homeostatic mechanisms that maintain the normal intracellular milieu. In this case, the vacuoles developed on exposure to intravenous immunoglobulin in a sucrose vehicle; the morphology is reminiscent of the severe changes produced by osmotic agents. While generally a nonspecific marker of cell injury, a distinctive pattern of “isometric” vacuolization, in which there are numerous intracellular vacuoles of uniform size (not shown here) is very typical of cyclosporine/FK506 effect [6].

FIGURE 9-19 (see Color Plate) Necrotic tubular cells and cell debris in tubular lumina. One tubule shows extensive cell loss, with tubular epithelium lined only by a very flattened layer of cytoplasm. The dilated lumen contains numerous necrotic tubular cells with pyknotic nuclei. Several tubules contain cell debris and one contains red blood cells (hematoxylin and eosin, original magnification  250). Such changes are more often seen with toxic than with ischemic injury [6], unless the latter is very severe.

Renal Histopathology, Urine Cytology, and Cytopathology of Acute Renal Failure

FIGURE 9-20 (see Color Plate) This micrograph shows sites of cell exfoliation, attenuation of remaining cells, and reactive and regenerative changes (hematoxylin and eosin, original magnification  400). Exfoliation occurs with disruption of cell-cell and cell-substrate adhesion, and may involve viable as well as non-viable cells [7]. Reactive and regenerative changes may include basophilia of cell cytoplasm, increased nuclear:cytoplasmic ratio, heterogeneity of nuclear size and appearance, hyperchromatic nuclei and mitotic figures.

A FIGURE 9-22 (see Color Plate) Fine-needle aspirate showing acute tubular cell injury and necrosis. A, The aspirate shows scattered tubular epithelial cells with swelling and focal degenerative changes, and a minimal associated inflammatory infiltrate. There is no significant background cell debris (MayGrunwald Giemsa, original magnification  40). B, One tubular cell is degenerated with reduction in cell size, condensed gray-blue

9.9

FIGURE 9-21 (see Color Plate) Outer medulla shows in situ cell necrosis and loss in medullary thick ascending limb (hematoxylin and eosin, original magnification  250). Tubules contain cells and cell debris. Changes reflect ischemic injury. Impaction of cells and cast material may lead to tubular obstruction, especially in narrow regions of the nephron. Adhesion molecules on the surface of exfoliated cells may contribute to aggregation of cells within the tubule and adhesion of detached cells to in situ tubular cells [8].

B cytoplasm, and a pyknotic nucleus. Another cell has more advanced necrosis with additional cytoplasmic disruption and a very small pyknotic nucleus. Compare the adjacent swollen damaged tubular cell which has not yet undergone necrosis (May-Grunwald Giemsa, original magnification  160).

9.10

Acute Renal Failure FIGURE 9-23 (see Color Plate) Urine sediment from a patient with acute tubular injury showing tubular cells and cell casts (Papanicolaou stain, original magnification  250). Many of these cells are morphologically intact, even by electron microscopy. Studies have shown that a significant percentage of the cells shed into the urine may exclude vital dyes, and may even grow when placed in culture, indicating that they remain viable. Such cells clearly detached from tubular basement membrane as a manifestation of sub-lethal injury [7].

A FIGURE 9-24 (see Color Plate) Myoglobin casts in the tubules of a patient who abused cocaine. A, Hematoxylin and eosin stained casts have a dark red, coarsely granular appearance (original magnification  250). B, Immunoperoxidase stain for myoglobin confirms positive staining in the casts

B (original magnification  250). These casts may obstruct the nephron, especially with dehydration and low tubular fluid flow rates. Rhabdomyolysis with formation of intrarenal myoglobin casts may also occur with severe trauma, crush injury, or extreme exercise.

Renal Histopathology, Urine Cytology, and Cytopathology of Acute Renal Failure

9.11

FIGURE 9-25 (see Color Plate) Apoptosis of tubular cells following tubular cell injury. Note the shrunken cells with condensed nuclei and cytoplasm in the central tubule. The patient had presumed ischemic injury (hematoxylin and eosin, original magnification  400). The role of apoptosis in injury to the renal tubule remains to be defined. The process may be difficult to quantitate, since apoptotic cells may rapidly disintegrate. In experimental models, the degree of apoptosis versus coaggulative necrosis occurring following injury is related to the severity and duration of injury, with milder injury showing more apoptosis [9].

Disintegrating fragments Shrunken cell with peripheral condensed nuclear chromatin and intact organelles

Phagocytosed apoptic cell fragments

FIGURE 9-26 Apoptosis-schematic of histologic changes in tubular epithelium. The process begins with condensation of the cytoplasm and of the nucleus, a process which involves endonucleases, which digest the DNA into ladder-like fragments characteristic of this process. The cell disintegrates into discrete membrane-bound fragments, so-called “apoptotic bodies.” These fragments may be rapidly extruded into the tubular lumen or phagocytosed by neighboring epithelial cells or inflammatory cells. (Modified from Arends, et al. [10]; with permission.)

9.12

Acute Renal Failure

Ischemia

Vascular endothelial injury

Altered permeability

Toxins

Inflammatory infiltrate

Tubular cell injury

Sublethal

Upregulation of adhesion molecules Interstitial edema

Tubular cell swelling Compression of peritubular capillaries

Loss of surface area and cell polarity

Apoptosis

Altered adhesion

Lethal

Changes of repair and regeneration

Increased epithelial permeability Loss of tubular integrity

Exfoliation

Loss of normal transport function

Vacuolization of smooth muscle cells

Arteriolar vasoconstriction

Impaction in the tubules

Loss of distal flow Glomerular collapse

"Backleak" of filtrate

Increased renal vascular resistance Aggregation of erythrocytes,fibrin and/or leukocytes in peritubular capillaries

In situ necrosis

Obstruction

Cast formation

Increased intratubular pressure

Tubular dilatation

Decrease in glomerular filtration rate Reduced renal blood flow

FIGURE 9-27 A schematic showing the relationship between morphologic and functional changes with injury to the renal tubule due to ischemia or nephrotoxins. Morphologic changes are shown in italics.

Histology reflects the altered hemodynamics, epithelial derangements, and obstruction which contribute to loss of renal function. (Modified from Racusen [11]; with permission.)

References 1.

2.

3.

4. 5. 6.

Popovic-Rolovic M, Kostic M, Antic-Peco A, et al.: Medium and long-term prognosis of patients with acute post-streptococcal glomerulonephritis. Nephron 1991, 58:393–399. Jennette JC: Crescentic glomerulonephritis. In Heptinstall’s Pathology of the Kidney, edn. 5. Edited by Jennette JC, JL Olson, M Schwarz, FG Silva. New York:Lippincott-Raven, 1998. Racusen LC, Solez K: Renal cortical necrosis, infarction and atheroembolic disease. In Renal Pathology. Edited by Tisher C, B Brenner. Philadelphia:Lippincott-Raven, 1993:811. Evert BH, Jennette JC, Falk RJ: The pathogenic role of antineutrophil cytoplasmic autoantibodies. Am J Kidney Dis 1991, 8:188–195. Remuzzi G, Ruggenenti P: The hemolytic uremic syndrome. Kidney Int 1995, 47:2–19. Nadasdy T, Racusen LC: Renal injury caused by therapeutic and diagnostic agents, and abuse of analgesics and narcotics. In Heptinstalls Pathology of the Kidney, edn. 5. Edited by Jennette JC, JL Olson, MM Schwartz, FG Silva. New York:Lippincott-Raven, 1998.

7. Racusen LC, Fivush BA, Li Y-L, et al.: Dissociation of tubular detachment and tubular cell death in clinical and experimental “acute tubular necrosis.” Lab Invest 1991, 64:546–556. 8. Goligorsky MS, Lieberthal W, Racusen L, Simon EE: Integrin receptors in renal tubular epithelium: New insights into pathophysiology of acute renal failure. Am J Physiol 1993, 264:F1–F8. 9. Schumer KM, Olsson CA, Wise GJ, Buttyan R: Morphologic, biochemical and molecular evidence of apoptosis during the reperfusion phase after brief periods of renal ischemia. Am J Pathol 1992, 140:831–838. 10. Arends MJ, Wyllie AH: Apoptosis: Mechanisms and role in pathology. Int Rev Exp Pathol 1991, 32:225–254. 11. Racusen LC: Pathology of acute renal failure: Structure/function correlations. Advances in Renal Replacement Therapy, 1997 4(Suppl. 2): 3–16.

Acute Renal Failure in the Transplanted Kidney Kim Solez Lorraine C. Racusen

A

cute renal failure (ARF) in the transplanted kidney represents a high-stakes area of nephrology and of transplantation practice. A correct diagnosis can lead to rapid return of renal function; an incorrect diagnosis can lead to loss of the graft and severe sequelae for the patient. The diagnostic possibilities are many (Fig. 10-1) and treatments quite different, although the clinical presentations of newonset functional renal impairment and of persistent nonfunctioning after transplant may be identical. In transplant-related ARF percutaneous kidney allograft biopsy is crucial in differentiating such diverse entities as acute rejection (Figs. 10-2 to 10-9), acute tubular necrosis (Figs. 10-10 to 10-14), cyclosporine toxicity (Figs. 10-15 and 10-16), posttransplant lymphoproliferative disorder (Fig. 10-17), and other, rarer, conditions. In the case of acute rejection, standardization of transplant biopsy interpretation and reporting is necessary to guide therapy and to establish an objective endpoint for clinical trials of new immunosuppressive agents. The Banff Classification of Renal Allograft Pathology [1] is an internationally accepted standard for the assessment of renal allograft biopsies sponsored by the International Society of Nephrology Commission of Acute Renal Failure. The classification had its origins in a meeting held in Banff, Alberta, in the Canadian Rockies, in August, 1991, where subsequent meetings have been held every 2 years. Hot topics likely to influence the Banff Classification of Renal Allograft Pathology in 1999 and beyond are shown in Figs. 10-17 to 10-19.

CHAPTER

10

10.2

Acute Renal Failure

Acute Rejection FIGURE 10-1 Diagnostic possibilities in transplant-related acute renal failure.

DIAGNOSTIC POSSIBILITIES IN TRANSPLANTRELATED ACUTE RENAL FAILURE

M ild i –m (w ntim od it a er of h an l ar ate, tu y ter se bu de it ve lit gr is re is) ee M tu ode bu ra lit te is

re ve itis Se bul tu

None

Borderline M ild tu bu lit is

Lesions-tubulitis, intimal arteritis

1. Acute (cell-mediated) rejection 2. Delayed-appearing antibody-mediated rejection 3. Acute tubular necrosis 4. Cyclosporine or FK506 toxicity 5. Urine leak 6. Obstruction 7. Viral infection 8. Post-transplant lymphoproliferative disorder 9. Vascular thrombosis 10. Prerenal azotemia

Mild

Moderate

Severe

Rejection

FIGURE 10-2 Diagnosis of rejection in the Banff classification makes use of two basic lesions, tubulitis and intimal arteritis. The 1993–1995 Banff classification depicted in this figure is the standard in use in virtually all current clinical trials and in many individual transplant units. In this construct, rejection is regarded as a continuum of mild, moderate, and severe forms. The 1997 Banff classification is similar, having the same threshold for rejection diagnosis, but it recognizes three different histologic types of acute rejection: tubulointersititial, vascular, and transmural. The quotation marks emphasize the possible overlap of features of the various types (eg, the finding of tubulitis should not dissuade the pathologist from conducting a thorough search for intimal arteritis).

No tubulitis

FIGURE 10-3 Tubulitis is not absolutely specific for acute rejection. It can be found in mild forms in acute tubular necrosis, normally functioning kidneys, and in cyclosporine toxicity and in conditions not related to rejection. Therefore, quantitation is necessary. The number of lymphocytes situated between and beneath tubular epithelial cells is compared with the number of tubular cells to determine the severity of tubulitis. Four lymphocytes per most inflamed tubule cross section or per ten tubular cells is required to reach the threshold for diagnosing rejection. In this figure, the two tubule cross sections in the center have eight mononuclear cells each. Rejection with intimal arteritis or transmural arteritis can occur without any tubulitis whatsoever, although usually in well-established rejection both tubulitis and intimal arteritis are observed.

Acute Renal Failure in the Transplanted Kidney

10.3

FIGURE 10-4 (see Color Plate) In this figure the tubules with lymphocytic invasion are atrophic with thickened tubular basement membranes. There are 13 or 14 lymphocytes per tubular cross section. This is an example of how a properly performed periodic acid-Schiff (PAS) stain should look. The Banff classification is critically dependent on proper performance of PAS staining. The invading lymphocytes are readily apparent and countable in the tubules. In the Banff 1997 classification one avoids counting lymphocytes in atrophic tubules, as tubulitis there is more “nonspecific” than in nonatrophed tubules. (From Solez et al. [1]; with permission.)

FIGURE 10-5 Intimal arteritis in a case of acute rejection. Note that more than 20 lymphocytes are present in the thickened intima. With this lesion, however, even a single lymphocyte in this site is sufficient to make the diagnosis. Thus, the pathologist must search for subtle intimal arteritis lesions, which are highly reliable and specific for rejection. (From Solez et al. [1]; with permission.)

FIGURE 10-6 Artery in longitudinal section shows a more florid intimal arteritis than that in Figure 10-5. Aggregation of lymphocytes is also seen in the lumen, but this is a nonspecific change. The reporting for some clinical trials has involved counting lymphocytes in the most inflamed artery, but this has not been shown to correlate with clinical severity or outcome, whereas the presence or absence of the lesion has been shown to have such a correlation. (From Solez et al. [1]; with permission.)

FIGURE 10-7 Transmural arteritis with fibrinoid change. In addition to the influx of inflammatory cells there has been proliferation of modified smooth muscle cells migrated from the media to the greatly thickened intima. Note the fibrinoid change at lower left and the penetration of the media by inflammatory cells at the upper right. Patients with these types of lesions have a less favorable prognosis, greater graft loss, and poorer long-term function as compared with patients with intimal arteritis alone. These sorts of lesions are also common in antibodymediated rejection (see Fig. 10-9).

10.4

Acute Renal Failure

Arterial lesions in acute rejection 1

8

7

Adventitia 3

10

Media 2 11

Endothelium 6

Lumen 4

5

9

FIGURE 10-8 Diagram of arterial lesions of acute rejection. The initial changes (1–5) before intimal arteritis (6) occurs are completely nonspecific. These early changes are probably mechanistically related to the diagnostic lesions but can occur as a completely self-limiting phenomenon unrelated to clinical rejection. Lesions 7 to 10 are those characteristic of “transmural” rejection. Lesion 1 is perivascular inflammation; lesion 2, myocyte vacuolization; lesion 3, apoptosis; lesion 4, endothelial activation and prominence; lesion 5, leukocyte adherence to the endothelium; lesion 6 (specific), penetration of inflammatory cells under the endothelium (intimal arteritis); lesion 7, inflammatory cell penetration of the media; lesion 8, necrosis of medial smooth muscle cells; lesion 9, platelet aggregation; lesion 10, fibrinoid change; and lesion 11 is thrombosis.

FIGURE 10-9 (see Color Plate) Antibody-mediated rejection with aggregates of polymorphonuclear leukocytes (polymorphs) in peritubular capillaries. This lesion is a feature of both classic hyperacute rejection and of later appearing antibody-mediated rejection, which is by far the more common entity. Antibody- and cell-mediated rejection can coexist, so one may find both tubulitis and intimal arteritis along with this lesion; however many cases of antibody-mediated rejection have a paucity of tubulitis [2]. The polymorph aggregates can be subtle, another reason for looking with care at the biopsy that appears to show “nothing.”

Acute Tubular Necrosis FIGURE 10-10 (see Color Plate) Acute tubular necrosis in the allograft. Unlike “acute tubule necrosis” in native kidney, in this condition actual necrosis appears in the transplanted kidney but in a very small proportion of tubules, often less than one in 300 tubule cross sections. Where the necrosis does occur it tends to affect the entire tubule cross section, as in the center of this field [3].

Acute Renal Failure in the Transplanted Kidney

FIGURE 10-11 (see Color Plate) A completely necrotic tubule in the center of the picture in a case of acute tubular necrosis (ATN) in an allograft. The tubule is difficult to identify because, in contrast to the appearance in native kidney ATN, no residual tubular cells survive; the epithelium is 100% necrotic.

10.5

FIGURE 10-12 (see Color Plate) Calcium oxalate crystals seen under polarized light. These are very characteristic of transplant acute tubular necrosis (ATN), probably because they relate to some degree to the duration of uremia, which is often much longer in transplant ATN (counting the period of uremia before transplantation) than in native ATN. With prolonged uremia elevation of plasma oxalate is greater and more persistent and consequently tissue deposition is greater [4].

FEATURES OF TRANSPLANT ACUTE TUBULAR NECROSIS (ATN) WHICH DIFFERENTIATE IT FROM NATIVE KIDNEY ATN 1. Apparently intact proximal tubular brush border 2. Occasional foci of necrosis of entire tubular cross sections 3. More extensive calcium oxalate deposition 4. Significantly fewer tubular casts 5. Significantly more interstitial inflammation 6. Less cell-to-cell variation in size and shape (“tubular cell unrest”)

FIGURE 10-13 Calcium oxalate crystals seen by electron microscopy in transplant acute tubular necrosis.

FIGURE 10-14 Features of transplant acute tubular necrosis that differentiate it from the same condition in native kidney [3].

10.6

Acute Renal Failure

Cyclosporine Toxicity

FIGURE 10-15 Cyclosporine nephrotoxicity with new-onset hyaline arteriolar thickening in the renin-producing portion of the afferent arteriole [5]. This lesion can be highly variable in extent and severity from section to section of the biopsy specimen, and it represents one of the strong arguments for examining multiple sections. The lesion is reversible if cyclosporine levels are reduced. Tacrolimus (FK506) produces an identical picture.

FIGURE 10-16 (see Color Plate) Bland hyaline arteriolar thickening of donor origin in a renal allograft recipient never treated with cyclosporine. This phenomenon provides a strong argument for doing implantation biopsies; otherwise, donor changes can be mistaken for cyclosporine toxicity.

Posttransplant Lymphoproliferative Disorder FIGURE 10-17 Posttransplant lymphoproliferative disorder (PTLD). The least satisfying facet of the 1997 Fourth Banff Conference on Allograft Pathology was the continued lack of good tools for the renal pathologist trying to distinguish the more subtle forms of PTLD from rejection. PTLD is rare, but, if misdiagnosed and treated with increased (rather than decreased) immunosuppression, it can quickly lead to death. The fact that both rejection and PTLD can occur simultaneously makes the challenge even greater [6]. It is hoped that newer techniques will make the diagnosis of this important condition more accurate in the future [7–9]. This figure shows an expansile plasmacytic infiltrate in a case of PTLD. However, most cases of PTLD are the result of Epstein-Barr virus–induced lymphoid proliferation.

Acute Renal Failure in the Transplanted Kidney

10.7

Subclinical Rejection FIGURE 10-18 (see Color Plate) Subclinical rejection. Subclinical rejection characterized by moderate to severe tubulitis may be found in as many as 35% of normally functioning grafts. Far from representing false-positive readings, such findings now appear to represent bona fide smoldering rejection that, if left untreated, is associated with increased incidence of chronic renal functional impairment and graft loss [10,11]. The important debate for the future is when to perform protocol biopsies to identify subclinical rejection and how best to treat it. This picture shows severe tubulitis in a normally functioning graft 15 months after transplantation. In the tubule in the center are 30 lymphocytes (versus 14 tubule cells). A year and a half later the patient developed renal functional impairment.

Thrombotic Microangiopathy FIGURE 10-19 Thrombotic microangiopathy in renal allografts. A host of different conditions and influences can lead to arteriolar and capillary thrombosis in renal allografts and these are as various as the first dose reaction to OKT3, HIV infection, episodes of cyclosporine toxicity, and antibody-mediated rejection [2, 12, 13]. It is hoped that further study will allow for more accurate diagnosis in patients manifesting this lesion. The figure shows arteriolar thrombosis and ischemic capillary collapse in a case of transplant thrombotic microangiopathy.

10.8

Acute Renal Failure

Peritubular Capillary Basement Membrane Changes in Chronic Rejection

A FIGURE 10-20 (see Color Plate) Peritubular capillary basement membrane ultrastructural changes, A, and staining for VCAM-1 as specific markers for chronic rejection, B [14–16]. Splitting and multilayering of peritubular capillary basement membranes by electron microscopy holds promise as a relatively specific marker for chronic rejection [14,15]. VCAM-1 staining by immunohistology in these same structures may also be

B of diagnostic utility [16]. Ongoing studies of large numbers of patients using these parameters will test the value of these parameters which may eventually be added to the Banff classification. A, Multilayering of peritubular capillary basement membrane in a case of chronic rejection; B, shows staining of peritubular capillaries for VCAM-1 by immunoperoxidase in chronic rejection.

References 1. Solez K, Axelsen RA, Benediktsson H, et al.: International standardization of criteria for the histologic diagnosis of renal allograft rejection: The Banff working classification of kidney transplant pathology. Kidney Int 1993, 44:411–422. 2. Trpkov K, Campbell P, Pazderka F, et al.: Pathologic features of acute renal allograft rejection associated with donor-specific antibody, analysis using the Banff grading schema. Transplantation 1996, 61(11):1586–1592. 3. Solez K, Racusen LC, Marcussen N, et al.: Morphology of ischemic acute renal failure, normal function, and cyclosporine toxicity in cyclosporine-treated renal allograft recipients. Kidney Int 1993, 43(5):1058–1067. 4. Salyer WR, Keren D:Oxalosis as a complication of chronic renal failure. Kidney Int 1973, 4(1):61–66. 5. Strom EH, Epper R, Mihatsch MJ: Cyclosporin-associated arteriolopathy: The renin producing vascular smooth muscle cells are more sensitive to cyclosporin toxicity. Clin Nephrol 1995, 43(4):226–231. 6. Trpkov K, Marcussen N, Rayner D, et al.: Kidney allograft with a lymphocytic infiltrate: Acute rejection, post-transplantation lymphoproliferative disorder, neither, or both entities? Am J Kidney Dis 1997, 30(3):449–454. 7. Sasaki TM, Pirsch JD, D’Alessandro AM, et al.: Increased  2-microglobulin (B2M) is useful in the detection of post-transplant lymphoproliferative disease (PTLD). Clin Transplant 1997, 11(1):29–33. 8. Chetty R, Biddolph S, Kaklamanis L, et al.: bcl-2 protein is strongly expressed in post-transplant lymphoproliferative disorders. J Pathol 1996, 180(3):254–258.

9. Wood A, Angus B, Kestevan P, et al.: Alpha interferon gene deletions in post-transplant lymphoma. Br J Haematol 1997, 98(4):1002–1003. 10. Nickerson P, Jeffrey J, McKenna R, et al.: Do renal allograft function and histology at 6 months posttransplant predict graft function at 2 years? Transplant Proc 1997, 29(6):2589–2590. 11. Rush D: Subclinical rejection. Presentation at Fourth Banff Conference on Allograft Pathology, March 7–12, 1997. 12. Wiener Y, Nakhleh RE, Lee MW, et al.: Prognostic factors and early resumption of cyclosporin A in renal allograft recipients with thrombotic microangiopathy and hemolytic uremic syndrome. Clin Transplant 1997, 11(3):157–162. 13. Frem GJ, Rennke HG, Sayegh MH: Late renal allograft failure secondary to thrombotic microangiopathy—human immunodeficiency virus nephropathy. J Am Soc Nephrol 1994, 4(9):1643–1648. 14. Monga G, Mazzucco G, Messina M, et al.: Intertubular capillary changes in kidney allografts: A morphologic investigation on 61 renal specimens. Mod Pathol 1992, 5(2):125–130. 15. Mazzucco G, Motta M, Segoloni G, Monga G: Intertubular capillary changes in the cortex and medulla of transplanted kidneys and their relationship with transplant glomerulopathy: An ultrastructural study of 12 transplantectomies. Ultrastruct Pathol 1994, 18(6):533–537. 16. Solez K, Racusen LC, Abdulkareem F, et al.: Adhesion molecules and rejection of renal allografts. Kidney Int 1997, 51(5):1476–1480.

Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents Marc E. De Broe

T

he kidneys are susceptible to toxic or ischemic injury for several reasons. Thus, it is not surprising that an impressive list of exogenous drugs and chemicals can cause clinical acute renal failure (ARF) [1]. On the contrary, the contribution of environmental toxins to ARF is rather limited. In this chapter, some of the most common drugs and exogenous toxins encountered by the nephrologist in clinical practice are discussed in detail. The clinical expression of the nephrotoxicity of drugs and chemicals is highly variable and is influenced by several factors. Among these is the direct toxic effect of drugs and chemicals on a particular type of nephron cell, the pharmacologic activity of some substances and their effects on renal function, the high metabolic activity (ie, vulnerability) of particular segments of the nephron, the multiple transport systems, which can result in intracellular accumulation of drugs and chemicals, and the high intratubule concentrations with possible precipitation and crystallization of particular drugs.

CHAPTER

11

11.2

Acute Renal Failure

General Nephrotoxic Factors FIGURE 11-1 Sites of renal damage, including factors that contribute to the kidney’s susceptibility to damage. ACE—angiotensin-converting enzyme; NSAID—nonsteroidal anti-inflammatory drugs; HgCl2—mercuric chloride.

The nephron

S1

Cortex

Sites of renal damage

Medullary ray

S1

Outer stripe

Inner stripe

Inner medula

ACE inhibitors NSAIDs Aminoglycosides Acyclovir Cisplatinum HgCl2

S3

S2

Outer medulla

S2

Lithium S3

Ischemia

Vulnerability of the kidney Important blood flow (1/4 cardiac output) High metabolic activity Largest endothelial surface by weight Multiple enzyme systems Transcellular transport Concentration of substances Protein unbinding High O2 consumption/delivery ratio in outer medulla

Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents

11.3

DRUGS AND CHEMICALS ASSOCIATED WITH ACUTE RENAL FAILURE Mechanisms M1 Reduction in renal perfusion through alteration of intrarenal hemodynamics M2 Direct tubular toxicity M3 Heme pigment–induced toxicity (rhabdomyolysis)

M1

M2

✓ ✓ ✓ ✓ ✓

✓ ✓

M3

M4

M5*

M6

Drugs

✓

Cyclosporine, tacrolimus Amphotericin B, radiocontrast agents Nonsteroidal anti-inflammatory drugs Angiotensin-converting enzyme inhibitors, interleukin-2† Methotrexate§ Aminoglycosides, cisplatin, foscarnet, heavy metals, intravenous immunoglobulin¶, organic solvents, pentamidine Cocaine Ethanol, lovastatin** Sulfonamides Acyclovir, Indinavir, chemotherapeutic agents, ethylene glycol*** Allopurinol, cephalosporins, cimetidine, ciprofloxacin, furosemide, penicillins, phenytoin, rifampin, thiazide diuretics Conjugated estrogens, mitomycin, quinine

✓ ✓

✓ ✓

✓

✓ ✓ ✓ ✓

M4 Intratubular obstruction by precipitation of the agents or its metabolites or byproducts M5 Allergic interstitial nephritis M6 Hemolytic-uremic syndrome

✓ ✓ ✓

* Many other drugs in addition to the ones listed can cause renal failure by this mechanism. † Interleukin-2 produces a capillary leak syndrome with volume contractions. § Uric acid crystals form as a result of tumor lysis. ¶ The mechanism of this agent is unclear but may be due to additives. ** Acute renal failure is most likely to occur when lovastatin is given in combination with cyclosporine. *** Ethylene glycol–induced toxicity can cause calcium oxalate crystals.

FIGURE 11-2 Drugs and chemicals associated with acute renal failure. (Apapted from Thadhani, et al. [2].)

11.4

Acute Renal Failure

Aminoglycosides 1. Filtration

2. Binding

Glomerulus

-

3. Adsorptive pinocytosis

Proximal tubule

4. Lysosomal trapping and storage

+ +

-

Lysosomal phospholipidosis ABOVE threshold: lysosomal swelling, disruption or leakage

* *

BELOW threshold: exocytosis shuttle

* * * Cell necrosis regeneration

FIGURE 11-3 Renal handling of aminoglycosides: 1) glomerular filtration; 2) binding to the brush border membranes of the proximal tubule; 3) pinocytosis; and 4) storage in the lysosomes [3]. Nephrotoxicity and otovestibular toxicity remain frequent side effects that seriously limit the use of aminoglycosides, a still important class of antibiotics. Aminoglycosides are highly charged, polycationic, hydrophilic drugs that cross biologic membranes little, if at all [4,5]. They are not metabolized but are eliminated unchanged almost entirely by the kidneys. Aminoglycosides are filtered by the glomerulus at a rate almost equal to that of water. After entering the luminal fluid of proximal renal tubule, a small but toxicologically important portion of the filtered drug is reabsorbed and stored in the proximal tubule cells. The major transport of aminoglycosides into proximal tubule cells involves interaction with acidic, negatively charged phospholipid-binding sites at the level of the brush border membrane.

*

Regression of drug-induced changes Aminoglycoside

* Hydrolase Toxins

After charge-mediated binding, the drug is taken up into the cell in small invaginations of the cell membrane, a process in which megalin seems to play a role [6]. Within 1 hour of injection, the drug is located at the apical cytoplasmic vacuoles, called endocytotic vesicles. These vesicles fuse with lysosomes, sequestering the unchanged aminoglycosides inside those organelles. Once trapped in the lysosomes of proximal tubule cells, aminoglycosides electrostatically attached to anionic membrane phospholipids interfere with the normal action of some enzymes (ie, phospholipases and sphingomyelinase). In parallel with enzyme inhibition, undigested phospholipids originating from the turnover of cell membranes accumulate in lysosomes, where they are normally digested. The overall result is lysosomal phospholipidosis due to nonspecific accumulation of polar phospholipids as “myeloid bodies,” so called for their typical electron microscopic appearance. (Adapted from De Broe [3].)

B FIGURE 11-4 Ultrastructural appearance of proximal tubule cells in aminoglycoside-treated patients (4 days of therapeutic doses). Lysosomes (large arrow) contain dense lamellar and concentric structures. Brush border, mitochondria (small arrows) and peroxisomes are unaltered. At higher magnification the structures in lysosomes show a periodic pattern. The bar in A represents 1 µm, in part B, 0.1 µm [7].

A

Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents

A

B FIGURE 11-5 (see Color Plate) Administration of aminoglycosides for days induces progression of lysosomal phospholipidosis. The overloaded lysosomes continue to swell, even if the drug is then withdrawn. In vivo this overload may result in loss of integrity of the membranes of lysosomes and release of large amounts of lysosomal enzymes, phospholipids, and aminoglycosides into the cytosol, but this has not been proven. Thus, these aminoglycosides can gain access to and injure other organelles, such as mitochondria, and disturb their functional integrity, which leads rapidly to cell death. As a consequence of cell necrosis, A, intratubular obstruction by cell debris increased intratubule pressure, a decrease in the glomerular filtration rate and cellular infiltration, B, may ensue. In parallel with these lethal processes in the kidney, a striking regeneration process is observed that is characterized by a dramatic increase in tubule cell turnover and proliferation, C, in the cortical interstitial compartment.

C

FIGURE 11-6 A, Relationship between constant serum levels and concomitant renal cortical accumulation of gentamicin after a 6 hour intravenous infusion in rats. The rate of accumulation is expressed in micrograms of aminoglycoside per gram of wet kidney cortex per hour, due to the linear accumulation in function of time. Each point represents one rat whose aminoglycosides were measured in both kidneys at the end of the infusion and the serum levels assayed twice during the infusion [8].

Vmax= 149.83 + 9.08 µg/g/h Km= 15.01+1.55 µ g/ml

150

(Continued on next page) 100 Renal cortical gentamicin accumulation rate, µ g/g/h

Renal cortical gentamicin accumulation rate, µg/g/h

200

50

60 40 20

V= 6.44 + 4.88 C r= 0.96

0

0 5 10 15 Serum gentamicin concentration, µg/ml

0 0

A

11.5

10

20

30 40 50 60 70 80 Serum gentamicin concentration, µg/ml

90

100

11.6

Acute Renal Failure

One injection a day Three injections a day

800

**

Continuous infusion Total daily dose: 10 mg/kg i.p.

600 400

**

**

**

**

200

0 1

2 4 Days of administration

B

40

6

40 Gentamicin

35

Netilmicin

35

Serum levels, µg/ml

4.5 mg/kg/d

5 mg/kg/d

30

30

25

25

20

20

Single injection

15

Single injection

15

10

10

Continuous infusion

Continuous infusion

5

5

B

0

4

8

12

16 20

40

24

0

4

8

12

16

20 24

90 Tobramycin

35

Amikacin

80

15 mg/kg/d

4.5 mg/kg/d

70

30 Serum levels, µg/ml

One injection a day

250

Continuous infusion (n–6)

P< 0.025

P< 0.025

N.S.

P< 0.05

Gentamicin 4.5 mg/kg

Netilmicin 5 mg/kg

Tobramycin 4.5 mg/kg/d

Amikacin 15 mg/kg/d

200 150 100 50 0

0

0

60

25

50 20 40 Single injection

15

Single injection

30

10

20

Continuous infusion

Continuous infusion

5

10

0 0

A

8

FIGURE 11-6 (Continued) B, Kidney cortical concentrations of gentamicin in rats given equal daily amounts of aminoglycoside in single injections, three injections, or by continuous infusion over 8 days. Each block represents the mean of seven rats ±SD. Significance is shown only between cortical levels achieved after continuous infusion and single injections (asterisk—P < 0.05; double asterisk—P < 0.01) [9]. In rats, nephrotoxicity of gentamicin is more pronounced when the total daily dose is administered by continuous infusion rather than as a single injection. Thus, a given daily drug does not produce the same degree of toxicity when it is given by different routes. Indeed, renal cortical uptake is “less efficient” at high serum concentration than at low ones. A single injection results in high peak serum levels that overcome the saturation limits of the renal uptake mechanism. The high plasma concentrations are followed by fast elimination and, finally, absence of the drug for a while. This contrasts with the continuous low serum levels obtained with more frequent dosing when the uptake at the level of the renal cortex is not only more efficient but remains available throughout the treatment period. Vmax—maximum velocity.

Renal cortical concentration after one day, µ g/g

Renal cortical gentamicin accumulation, µ g/g

1000

4

8

12

16 20

0 0 24 Time, hrs

4

8

12 16 20 24

FIGURE 11-7 Course of serum concentrations, A, and of renal cortical concentrations, B, of gentamicin, netilmicin, tobramycin, and amikacin after dosing by a 30-minute intravenous injection or continuous infusion over 24 hours [10,11]. Two trials in humans found that the dosage schedule had a critical effect on renal uptake of gentamicin, netilmicin [10], amikacin, and tobramycin [11]. Subjects were patients with normal renal function (serum creatinine concentration between 0.9 and 1.2 mg/dL, proteinuria lower than 300 mg/24 h) who had renal cancer and submitted to nephrectomy. Before surgery, patients received gentamicin (4.5 mg/kg/d), netilmicin (5 mg/kg/d), amikacin (15 mg/kg/d), or tobramycin (4.5 mg/kg/d) as a single injection or as a continuous intravenous infusion over 24 hours. The single-injection schedule resulted in 30% to 50% lower cortical drug concentrations of netilmicin, gentamicin, and amikacin as compared with continuous infusion. For tobramycin, no difference in renal accumulation could be found, indicating the linear cortical uptake of this particular aminoglycoside [8]. These data, which supported decreased nephrotoxic potential of single-dose regimens, coincided with new insights in the antibacterial action of aminoglycosides (concentration-dependent killing of gram-negative bacteria and prolonged postantibiotic effect) [12]. N.S.—not significant.

Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents

RISK FACTORS FOR AMINOGLYCOSIDE NEPHROTOXICITY Patient-Related Factors

Aminoglycoside-Related Factors

Other Drugs

Older age* Preexisting renal disease Female gender Magnesium, potassium, or calcium deficiency* Intravascular volume depletion* Hypotension* Hepatorenal syndrome Sepsis syndrome

Recent aminoglycoside therapy

Amphotericin B Cephalosporins Cisplatin Clindamycin

Larger doses* Treatment for 3 days or more*

Dose regimen*

* Similar to experimental data.

PREVENTION OF AMINOGLYCOSIDE NEPHROTOXICITY Identify risk factor Patient related Drug related Other drugs Give single daily dose of gentamicin, netilmicin, or amikacin Reduce the treatment course as much as possible Avoid giving nephrotoxic drugs concurrently Make interval between aminoglycoside courses as long as possible Calculate glomerular filtration rate out of serum creatinine concentration

Cyclosporine Foscarnet Furosemide Piperacillin Radiocontrast agents Thyroid hormone

11.7

FIGURE 11-8 Risk factors for aminoglycoside nephrotoxicity. Several risk factors have been identified and classified as patient related, aminoglycoside related, or related to concurrent administration of certain drugs. The usual recommended aminoglycoside dose may be excessive for older patients because of decreased renal function and decreased regenerative capacity of a damaged kidney. Preexisting renal disease clearly can expose patients to inadvertent overdosing if careful dose adjustment is not performed. Hypomagnesemia, hypokalemia, and calcium deficiency may be predisposing risk factors for consequences of aminoglycoside-induced damage [13]. Liver disease is an important clinical risk factor for aminoglycoside nephrotoxicity, particularly in patients with cholestasis [13]. Acute or chronic endotoxemia amplifies the nephrotoxic potential of the aminoglycosides [14].

FIGURE 11-9 Prevention of aminoglycoside nephrotoxicity. Coadministration of other potentially nephrotoxic drugs enhances or accelerates the nephrotoxicity of aminoglycosides. Comprehension of the pharmacokinetics and renal cell biologic effects of aminoglycosides, allows identification of aminoglycoside-related nephrotoxicity risk factors and makes possible secondary prevention of this important clinical nephrotoxicity.

11.8

Acute Renal Failure

Amphotericin B Water

Lipid Phospholipid

Cholesterol

C20-C33 heptaene segment

Amphotericin B

Pore

C O N H

FIGURE 11-10 Proposed partial model for the amphotericin B (AmB)–induced pore in the cell membrane. AmB is an amphipathic molecule: its structure enhances the drug’s binding to sterols in the cell membranes and induces formation of aqueous pores that result in weakening of barrier function and loss of protons and cations from the cell. The drug acts as a counterfeit phospholipid, with the C15 hydroxyl, C16 carboxyl, and C19 mycosamine groups situated at the membrane-water interface, and the C1 to C14 and C20 to C33 chains aligned in parallel within the membrane. The heptaene chain seeks a hydrophobic environment, and the hydroxyl groups seek a hydrophilic environment. Thus, a cylindrical pore is formed, the inner wall of which consists of the hydroxyl-substituted carbon chains of the AmB molecules and the outer wall of which is formed by the heptaene chains of the molecules and by sterol nuclei [15].

Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents

FIGURE 11-11 Risk factors for development of amphotericin B (AmB) nephrotoxicity. Nephrotoxicity of AmB is a major problem associated with clinical use of this important drug. Disturbances in both glomerular and tubule function are well described. The nephrotoxic effect of AmB is initially a distal tubule phenomenon, characterized by a loss of urine concentration, distal renal tubule acidosis, and wasting of potassium and magnesium, but it also causes renal vasoconstriction leading to renal ischemia. Initially, the drug binds to membrane sterols in the renal vasculature and epithelial cells, altering its membrane permeability. AmB-induced vasoconstriction and ischemia to very vulnerable sections of the nephron, such as medullary thick ascending limb, enhance the cell death produced by direct toxic action of AmB on those cells. This explains the salutary effect on AmB nephrotoxicity of salt loading, furosemide, theophylline, or calcium channel blockers, all of which improve renal blood flow or inhibit transport in the medullary thick ascending limb.

RISK FACTORS IN THE DEVELOPMENT OF AMPHOTERICIN NEPHROTOXICITY Age Concurrent use of diuretics Abnormal baseline renal function Larger daily doses Hypokalemia Hypomagnesemia Other nephrotoxic drugs (aminoglycosides, cyclosporine)

Indication for amphotericin B therapy Clinical evaluation: Is patient salt depleted? yes

Correction: Correct salt depletion Avoid diuretics Liberalize dietary sodium

Will salt loading exacerbate underlying disease?

yes

Weigh risk-benefit ratio Seek alternatives

Does patient require concommitant antibiotics?

yes

Select drug with high salt content

Is potassium (K) or magnesium (Mg) depleted?

yes

Correct abnormalities

No

Begin amphotericin B with sodium supplement, 150 mEq/d

Begin amphotericin B therapy

Routine Monitoring: Clinical evaluation (cardiovascular/respiratory status; body weight; fluid intake and excretion) Laboratory tests (renal function; serum electrolyte levels; 24 -hours urinary electrolyte excretion) Clinical evaluation: Is patient vomiting?

yes

Increase salt load

No

Correction:

Laboratory evaluation: Is serum creatinine creratinine>3 >3mg/dL mg/dLor orisisrenal renaldeterioration deteriorationrapid? rapid? Is K level ,3.5 mEq/L or Mg level <1.6 mEq/L? No

Continue amphotericin B therapy and routine monitoring Close follow-up of serum electrolytes

11.9

yes

Interrupt amphotericin B therapy, resume on improvement

yes

Use oral or intravenous supplementation

FIGURE 11-12 Proposed approach for management of amphotericin B (AmB) therapy. Several new formulations of amphotericin have been developed either by incorporating amphotericin into liposomes or by forming complexes to phospholipid. In early studies, nephrotoxicity was reduced, allowing an increase of the cumulative dose. Few studies have established a therapeutic index between antifungal and nephrotoxic effects of amphotericin. To date, the only clinically proven intervention that reduces the incidence and severity of nephrotoxicity is salt supplementation, which should probably be given prophylactically to all patients who can tolerate it. (From Bernardo JF, et al. [16]; with permission.)

11.10

Acute Renal Failure

Cyclosporine

FIGURE 11-13 (see Color Plate) Intravascular coagulation in a cyclosporine-treated renal transplant recipient. Cyclosporine produces a dose-related decrease in renal function in experimental animals and humans [17] that is attributed to the drug’s hemodynamic action to produce vasoconstriction of the afferent arteriole entering the glomerulus. When severe enough, this can decrease glomerular filtration rate. Although the precise pathogenesis of the renal hemodynamic effects of cyclosporine are unclear, endothelin, inhibition of nitric oxide,

release of vasoconstrictor prostaglandins such as thromboxane A2, and activation of the sympathetic nervous system, are among the candidates for cyclosporine-induced vasoconstriction [18]. The diagnosis of cyclosporine-induced acute renal dysfunction is not difficult when the patient has no other reason for reduced renal function (eg, psoriasis, rheumatoid arthritis). In renal transplant recipients, however, the situation is completely different. In this clinical setting, the clinician must differentiate between cyclosporine injury and acute rejection. The incidence of this acute cyclosporine renal injury can be enhanced by extended graft preservation, preexisting histologic lesions, donor hypotension, or preoperative complications. The gold standard for this important distinction remains renal biopsy. In addition, cyclosporine has been associated with hemolytic-uremic syndrome with thrombocytopenia, red blood cell fragmentation, and intravascular (intraglomerular) coagulation. Again, this drug-related intravascular coagulation has to be differentiated from that of acute rejection. The absence of clinical signs and of rejection-related interstitial edema and cellular infiltrates can be helpful. Vanrenterghem and coworkers [19] found a high incidence of venous thromboembolism shortly after (several of them within days) cadaveric kidney transplantation in patients treated with cyclosporine, in contrast to those treated with azathioprine. Recent studies [20] have shown that impaired fibrinolysis, due mainly to excess plasminogen activator inhibitor (PAI-1), may also contribute to this imbalance in coagulation and anticoagulation during cyclosporine treatment.

Lithium-Induced Acute Renal Failure SIGNS AND SYMPTOMS OF TOXIC EFFECTS OF LITHIUM Toxic Effect Mild

Moderate

Severe

Plasma Lithium Level 1–1.5 mmol/L

1.6–2.5 mmol/L

>2.5 mmol/L

Signs and Symptoms Impaired concentration, lethargy, irritability, muscle weakness, tremor, slurred speech, nausea Disorientation, confusion, drowsiness, restlessness, unsteady gait, coarse tremor, dysarthria, muscle fasciculation, vomiting Impaired consciousness (with progression to coma), delirium, ataxia, generalized fasciculations, extrapyramidal symptoms, convulsions, impaired renal function

FIGURE 11-14 Symptoms and signs of toxic effects of lithium. Lithium can cause acute functional and histologic (usually reversible) renal injury. Within 24 hours of administration of lithium to humans or animals, sodium diuresis occurs and impairment in the renal concentrating capacity becomes apparent. The defective concentrating capacity is caused by vasopressin-resistant (exogenous and endogenous) diabetes insipidus. This is in part related to lithium’s inhibition of adenylate cyclase and impairment of vasopressin-induced generation of cyclic adenosine monophosphatase. Lithium-induced impairment of distal urinary acidification has also been defined. Acute lithium intoxication in humans and animals can cause acute renal failure. The clinical picture features nonspecific signs of degenerative changes and necrosis of tubule cells [21]. The most distinctive and specific acute lesions lie at the level of the distal tubule [22]. They consist of swelling and vacuolization of the cytoplasm of the distal nephron cells plus periodic acid-Schiff–positive granular material in the cytoplasm (shown to be glycogen) [23]. Most patients receiving lithium have side effects, reflecting the drug’s narrow therapeutic index.

Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents

FIGURE 11-15 Drug interactions with lithium [24]. Acute renal failure, with or without oliguria, can be associated with lithium treatment, and with severe dehydration. In this case, acute renal failure can be considered a prerenal type; consequently, it resolves rapidly with appropriate fluid therapy. Indeed, the histologic appearance in such cases is remarkable for its lack of significant abnormalities. Conditions that stimulate sodium retention and consequently lithium reabsorption, such as low salt intake and loss of body fluid by way of vomiting, diarrhea, or diuretics, decreasing lithium clearance should be avoided. With any acute illness, particularly one associated with gastrointestinal symptoms such as diarrhea, lithium blood levels should be closely monitored and the dose adjusted when necessary. Indeed, most episodes of acute lithium intoxication are largely predictable, and thus avoidable, provided that precautions are taken [25]. Removing lithium from the body as soon as possible the is the mainstay of treating lithium intoxication. With preserved renal function, excretion can be increased by use of furosemide, up to 40 mg/h, obviously under close monitoring for excessive losses of sodium and water induced by this loop diuretic. When renal function is impaired in association with severe toxicity, extracorporeal extraction is the most efficient way to decrease serum lithium levels. One should, however, remember that lithium leaves the cells slowly and that plasma levels rebound after hemodialysis is stopped, so that longer dialysis treatment or treatment at more frequent intervals is required.

DRUG INTERACTIONS WITH LITHIUM

Salt depletion strongly impairs renal elimination of lithium. Salt loading increases absolute and fractional lithium clearance. Diuretics Acetazolamide Thiazides

Increased lithium clearance Increased plasma lithium level due to decreased lithium clearance Acute increased lithium clearance Usually no change in plasma lithium level; may be used to treat lithium-induced polyuria

Loop diuretics Amiloride

Nonsteroidal anti-inflammatory drugs

Increased plasma lithium level due to decreased renal lithium clearance (exceptions are aspirin and sulindac) Decreased plasma lithium level due to increased renal lithium clearance May increase plasma lithium level

Bronchodilators (aminophylline, theophylline) Angiotensin-converting enzyme inhibitors Cyclosporine

11.11

Decreased lithium clearance

Inhibitors of the Renin-Angiotensin System Pre-kallikrein Angiotensinogen Renin

Activated factor XII

Kininogen

+

+ Kallikrenin

Angiotensin I +

Angiotensin converting enzyme Kininase II

Angiotensin II

+ : stimulation

Bradykinin +

Arachidonic acid

Inactive peptide +

Increased aldosterone release Potentiation of sympathetic activity Increased Ca2+ current

A

Vasoconstriction

Prostaglandins

Vasodilation

Cough?

FIGURE 11-16 Soon after the release of this useful class of antihypertensive drugs, the syndrome of functional acute renal insufficiency was described as a class effect. This phenomenon was first observed in patients with renal artery stenosis, particularly when the entire renal mass was affected, as in bilateral renal artery stenosis or in renal transplants with stenosis to a solitary kidney [26]. Acute renal dysfunction appears to be related to loss of postglomerular

efferent arteriolar vascular tone and in general is reversible after withdrawing the angiotensin-converting enzyme (ACE) inhibitor [27]. Inhibition of the ACE kinase II results in at least two important effects: depletion of angiotensin II and accumulation of bradykinin [28]. The role of the latter effect on renal perfusion pressure is not clear, A. To understand the angiotensin I converting enzyme inhibitor–induced drop in glomerular filtration rate, it is important to understand the physiologic role of the renin-angiotensin system in the regulation of renal hemodynamics, B. When renal perfusion drops, renin is released into the plasma and lymph by the juxtaglomerular cells of the kidneys. Renin cleaves angiotensinogen to form angiotensin I, which is cleaved further by converting enzyme to form angiotensin II, the principal effector molecule in this system. Angiotensin II participates in glomerular filtration rate regulation in a least two ways. First, angiotensin II increases arterial pressure—directly and acutely by causing vasoconstriction and more “chronically” by increasing body fluid volumes through stimulation of renal sodium retention; directly through an effect on the tubules, as well as by stimulating thirst (Continued on next page)

11.12

Acute Renal Failure

+: vasoconstriction B1. Normal condition

–: vasodilation Autoregulation + – Afferent arteriole

Efferent arteriole

Glomerulus

Myogenic reflex (Laplace) Tubuloglomerular feedback B2. Perfusion pressure reduced but still within autoregulatory range (congestive heart failure, renal artery stenosis, diuretic therapy, nephrotic syndrome cirrhosis, sodium restriction depletion, advanced age [age >80])

+ –

Tubule

PGE2 –

+ Local angiotensin II

B3. Perfusion pressure seriously reduced (prerenal azotemia)

PGE2 –

Intraglomerular pressure

+ Sympathetic activity angiotensin II

B

+ Local angiotensin II

FIGURE 11-16 (Continued) and indirectly via aldosterone. Second, angiotensin II preferentially constricts the efferent arteriole, thus helping to preserve glomerular capillary hydrostatic pressure and, consequently, glomerular filtration rate. When arterial pressure or body fluid volumes are sensed as subnormal, the reninangiotensin system is activated and plasma renin activity and angiotensin II levels increase. This may occur in the context of clinical settings such as renal artery stenosis,

dietary sodium restriction or sodium depletion as during diuretic therapy, congestive heart failure, cirrhosis, and nephrotic syndrome. When activated, this reninangiotensin system plays an important role in the maintenance of glomerular pressure and filtration through preferential angiotensin II–mediated constriction of the efferent arteriole. Thus, under such conditions the kidney becomes sensitive to the effects of blockade of the reninangiotensin system by angiotensin I–converting enzyme inhibitor or angiotensin II receptor antagonist. The highest incidence of renal failure in patients treated with ACE inhibitors was associated with bilateral renovascular disease [27]. In patients with already compromised renal function and congestive heart failure, the incidence of serious changes in serum creatinine during ACE inhibition depends on the severity of the pretreatment heart failure and renal failure. Volume management, dose reduction, use of relatively short-acting ACE inhibitors, diuretic holiday for some days before initiating treatment, and avoidance of concurrent use of nonsteroidal antiinflammatory drug (hyperkalemia) are among the appropriate measures for patients at risk. Acute interstitial nephritis associated with angiotensin I–converting enzyme inhibition has been described [29]. (Adapted from Opie [30]; with permission.)

Nonsteroidal Anti-inflammatory Drugs Patients at risk for NSAID-induced acute renal failure ↑Renin-angiotensin axis ↑Angiotensin II

↑Adrenergic nervous system ↑Catecholamines

Renal vasoconstriction ↓Renal function

"Normalized" renal function –

Inhibition by NSAID

–

Compensatory vasodilation induced by renal prostaglandin synthesis

FIGURE 11-17 Mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) disrupt the compensatory vasodilatation response of renal prostaglandins to vasoconstrictor hormones in patients with prerenal conditions. Most of the renal abnormalities encountered clinically as a result of NSAIDs can be attributed to the action of these compounds on prostaglandin production in the kidney [31]. Sodium chloride and water retention are the most common side effects of NSAIDs. This should not be considered drug toxicity because it represents a modification of a physiologic control mechanism without the production of a true functional disorder in the kidney.

Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents

FIGURE 11-18 Conditions associated with risk for nonsteroidal anti-inflammatory drugs (NSAID)-induced acute renal failure. NSAIDs can induce acute renal decompensation in patients with various renal and extrarenal clinical conditions that cause a decrease in blood perfusion to the kidney [32]. Renal prostaglandins play an important role in the maintenance of homeostasis in these patients, so disruption of counter-regulatory mechanisms can produce clinically important, and even severe, deterioration in renal function.

PREDISPOSING FACTORS FOR NSAIDINDUCED ACUTE RENAL FAILURE Severe heart disease (congestive heart failure) Severe liver disease (cirrhosis) Nephrotic syndrome (low oncotic pressure) Chronic renal disease Age 80 years or older Protracted dehydration (several days)

Physiologic stimulus

Inflammatory stimuli

COX-1 constitutive Stomach Kidney Intestine Platelets Endothelium PGE2

TxA2

PGI2

Physiologic functions

Inhibition by NSAID

11.13

COX-2 inducible Inflammatory sites (macrophages, synoviocytes) Inflammatory PGs

Proteases

Inflammation

O2 -

FIGURE11-19 Inhibition by nonsteroidal anti-inflammatory drugs (NSAIDs) on pathways of cyclo-oxygenase (COX) and prostaglandin synthesis [33]. The recent demonstration of the existence of functionally distinct isoforms of the cox enzyme has major clinical significance, as it now appears that one form of cox is operative in the gastric mucosa and kidney for prostaglandin generation (COX-1) whereas an inducible and functionally distinct form of cox is operative in the production of prostaglandins in the sites of inflammation and pain (COX-2) [33]. The clinical therapeutic consequence is that an NSAID with inhibitory effects dominantly or exclusively upon the cox isoenzyme induced at a site of inflammation may produce the desired therapeutic effects without the hazards of deleterious effects on the kidneys or gastrointestinal tract. PG—prostaglandin; TxA2—thromboxane A2.

11.14

Acute Renal Failure

EFFECTS OF NSAIDS ON RENAL FUNCTION Renal Syndrome

Mechanism

Risk Factors

Prevention/Treatment [34]

Sodium retension and edema

↓ Prostaglandin

NSAID therapy (most common side effect)

Stop NSAID

Hyperkalemia

↓ Prostaglandin ↓ Potassium to distal tubule ↓ Aldosterone/reninangiotensin

Renal disease Heart failure Diabetes Multiple myeloma Potassium therapy Potassium-sparing diuretic

Stop NSAID Avoid use in high-risk patients

Acute deterioration of renal function

↓ Prostaglandin and disruption of hemodynamic balance

Liver disease Renal disease Heart failure Dehydration Old age

Nephrotic syndrome with: Interstitial nephritis Papillary necrosis

↑ Lymphocyte recruitment and activation Direct toxicity

Fenoprofen Combination aspirin and acetaminophen abuse

Stop NSAID Avoid use in high-risk patients

Stop NSAID Dialysis and steroids (?) Stop NSAID Avoid long-term analgesic use

FIGURE 11-20 Summary of effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on renal function [31]. All NSAIDs can cause another type of renal dysfunction that is associated with various levels of functional impairment and characterized by the nephrotic syndrome together with interstitial nephritis. Characteristically, the histology of this form of NSAID–induced nephrotic syndrome consists of minimal-change glomerulonephritis with tubulointerstitial nephritis. This is an

unusual combination of findings and in the setting of protracted NSAID use is virtually pathognomic of NSAID-related nephrotic syndrome. A focal diffuse inflammatory infiltrate can be found around the proximal and distal tubules. The infiltrate consists primarily of cytotoxic T lymphocytes but also contains other T cells, some B cells, and plasma cells. Changes in the glomeruli are minimal and resemble those of classic minimalchange glomerulonephritis with marked epithelial foot process fusion. Hyperkalemia, an unusual complication of NSAIDs, is more likely to occur in patients with pre-existing renal impairment, cardiac failure, diabetes, or multiple myeloma or in those taking potassium supplements, potassium-sparing diuretic therapy, or intercurrent use of an angiotensin-converting enzyme inhibitor. The mechanism of NSAID hyperkalemia—suppression of prostaglandin-mediated renin release—leads to a state of hyporeninemic hypoaldosteronism. In addition, NSAIDs, particularly indomethacin, may have a direct effect on cellular uptake of potassium. The renal saluretic response to loop diuretics is partially a consequence of intrarenal prostaglandin production. This component of the response to loop diuretics is mediated by an increase in renal medullary blood flow and an attendant reduction in renal concentrating capacity. Thus, concurrent use of an NSAID may blunt the diuresis induced by loop diuretics.

Contrast Medium–Associated Nephrotoxicity RISK FACTORS THAT PREDISPOSE TO CONTRAST ASSOCIATED NEPHROPATHY Confirmed

Suspected

Disproved

Chronic renal failure Diabetic nephropathy Severe congestive heart failure Amount and frequency of contrast media Volume depletion or hypotension

Hypertension Generalized atherosclerosis Abnormal liver function tests Hyperuricemia Proteinuria

Myeloma Diabetes without nephropathy

FIGURE 11-21 Risk factors that predispose to contrast-associated nephropathy. In random populations undergoing radiocontrast imaging the incidence of contrasts associated nephropathy defined by a change in serum creatinine of more than 0.5 mg/dL or a greater than 50% increase over baseline, is between 2% and 7%. For confirmed high-risk patients (baseline serum creatinine values greater than 1.5 mg/dL) it rises to 10% to 35%. In addition, there are suspected risk factors that should be taken into consideration when considering the value of contrast-enhanced imaging.

Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents

Hypersomolar radiocontrast medium

↑PGE2 ↑ANF

Systemic ↑Endothelin ↓ATPase hypoxemia ↑Vasopressin ↑Adenosine ↑Blood viscosity Osmotic load to distal tubule ↓PGI2

↑RBF ↓↓RBF Calcium antagonists Theophylline

– Net ↑O2 consumption

Net ↓O2 delivery

Cell injury ↑TH protein

↑Intrarenal number of macrophages, T cells Stimulation of mesangium

Tubular obstruction

↓RBF

↓GFR

–

Superoxidase – dismutase

Reactive O2 species lipid peroxidase

Contrast associated nephropathy

FIGURE 11-22 A proposed model of the mechanisms involved in radiocontrast medium–induced renal dysfunction. Based on experimental mod-

PREVENTION OF CONTRAST ASSOCIATED NEPHROPATHY Hydrate patient before the study (1.5 mL/kg/h) 12 h before and after. Hemodynamically stabilize hemodynamics. Minimize amount of contrast medium administered. Use nonionic, iso-osmolar contrast media for patients at high risk (see Figure 11-21).

FIGURE 11-23 Prevention of contrast-associated nephropathy. The goal of management is the prevention of contrast-associated nephropathy.

11.15

els, a consensus is developing to the effect that contrast-associated nephropathy involves combined toxic and hypoxic insults to the kidney [35]. The initial glomerular vasoconstriction that follows the injection of radiocontrast medium induces the liberation of both vasoconstrictor (endothelin, vasopressin) and vasodilator (prostaglandin E2 [PGE2], adenosine, atrionatiuretic factor {ANP}) substances. The net effect is reduced oxygen delivery to tubule cells, especially those in the thick ascending limb of Henle. Because of the systemic hypoxemia, raised blood viscosity, inhibition of sodium-potassium–activated ATPase and the increased osmotic load to the distal tubule at a time of reduced oxygen delivery, the demand for oxygen increases, resulting in cellular hypoxia and, eventually cell death. Additional factors that contribute to the acute renal dysfunction of contrast-associated nephropathy are the tubule obstruction that results from increased secretion of Tamm-Horsfall proteins and the liberation of reactive oxygen species and lipid peroxidation that accompany cell death. As noted in the figure, calcium antagonists and theophylline (adenosine receptor antagonist) are thought to act to diminish the degree of vasoconstriction induced by contrast medium. The clinical presentation of contrast-associated nephropathy involves an asymptomatic increase in serum creatinine within 24 hours of a radiographic imaging study using contrast medium, with or without oliguria [36]. We have recently reviewed the clinical outcome of 281 patients with contrast-associated nephropathy according to the presence or absence of oliguric acute renal failure at the time of diagnosis. Of oliguric acute renal failure patients, 32% have persistent elevations of serum creatinine at recovery and half require permanent dialysis. In the absence of oliguric acute renal failure the serum creatinine value does not return to baseline in 24% of patients, approximately a third of whom require permanent dialysis. Thus, this is not a benign condition but rather one whose defined risks are not only permanent dialysis but also death. GFR—glomerular filtration rate; RBF—renal blood flow; TH—Tamm Horsfall protein. Thus it is important to select the least invasive diagnostic procedure that provides the most information, so that the patient can make an informed choice from the available clinical alternatives. Since radiographic contrast imaging is frequently performed for diabetic nephropathy, congestive heart failure, or chronic renal failure, concurrent administration of renoprotective agents has become an important aspect of imaging. A list of maneuvers that minimize the risk of contrast-associated nephropathy is contained in this table. The correction of prestudy volume depletion and the use of active hydration before and during the procedure are crucial to minimizing the risk of contrast-associated nephropathy. Limiting the total volume of contrast medium and using nonionic, isoosmolar media have proven to be protective for high-risk patients. Pretreatment with calcium antagonists is an intriguing but unsubstantiated approach.

11.16

Acute Renal Failure

References 1. Bennett WM, Porter GA: Overview of clinical nephrotoxicity. In Toxicology of the Kidney, edn 2. Edited by Hook JB, Goldstein RS. Raven Press, 1993:61–97.

20. Verpooten GA, Cools FJ, Van der Planken MG, et al.: Elevated plasminogen activator inhibitor levels in cyclosporin-treated renal allograft recipients. Nephrol Dial Transplant 1996, 11:347–351.

2. Thadhani R, Pascual M, Bonventre JV: Acute renal failure. N Engl J Med 1996, 334:1448–1460.

21. Vestergaard P, Amdisen A, Hansen AE, Schou M: Lithium treatment and kidney function. Acta Psychiatry Scand 1979; 60:504–520.

3. De Broe ME: Prevention of aminoglycoside nephrotoxicity. In Proc EDTA-ERA. Edited by Davison AM, Guillou PJ. London:BailliËre Tindal, 1985:959–973.

22. Johnson GF, Hunt G, Duggin GG, et al.: Renal function and lithium treatment: initial and follow-up tests in manic-depressive patients. J Affective Disord 1984; 6:249–263.

4. Lietman PS: Aminoglycosides and spectinoycin: aminocylitols. In Principles and Practice of Infectious Diseases, edn 2, Part I. Edited by Mandel GL, Doublas RG Jr, Bennett JE. New York: John Wiley & Sons, 1985:192–206.

23. Coppen A, Bishop ME, Bailey JE, et al.: Renal function in lithium and non–lithium-treated patients with affective disorders. Acta Psychiatry Scand 1980; 62:343–355.

5. Kaloyanides GJ, Pastoriza-Munoz E: Aminoglycoside nephrotoxicity. Kidney Int 1980, 18:571–582. 6. Molitoris BA. Cell biology of aminoglycoside nephrotoxicity: newer aspects. Curr Opin Nephrol Hypertens 1997, 6:384–388. 7. De Broe ME, Paulus GJ, Verpooten GA, et al.: Early effects of gentamicin, tobramycin, and amikacin on the human kidney. Kidney Int 1984, 25:643–652. 8. Giuliano RA, Verpooten GA, Verbist L, et al.: In vivo uptake kinetics of aminoglycosides in the kidney cortex of rats. J Pharmacol Exp Ther 1986, 236:470–475. 9. Giuliano RA, Verpooten GA, De Broe ME: The effect of dosing strategy on kidney cortical accumulation of aminoglycosides in rats. Am J Kidney Dis 1986, 8:297–303. 10. Verpooten GA, Giuliano RA, Verbist L, et al.: A once-daily dosage schedule decreases the accumulation of gentamicin and netilmicin in the renal cortex of humans. Clin Pharmacol Ther 1989, 44:1–5. 11. De Broe ME, Verbist L, Verpooten GA: Influence of dosage schedule on renal cortical accumulation of amikacin and tobramycin in man. J Antimicrob Chemother 1991, 27 (suppl C):41–47. 12. Bennett WM, Plamp CE, Gilbert DN, et al.: The influence of dosage regimen on experimental gentamicin nephrotoxicity: dissociation of peak serum levels from renal failure. J Infect Dis 1979, 140:576–580. 13. Moore RD, Smith CR, Lipsky JJ, et al.: Risk factors for nephrotoxicity in patients treated with aminoglycosides. Ann Intern Med 1984, 100:352–357. 14. Zager RA: A focus of tissue necrosis increases renal susceptibility to gentamicin administration. Kidney Int 1988; 33:84–90. 15. Andreoli TE: On the anatomy of amphotericin B-cholesterol pores in lipid bilayer membranes. Kidney Int 1973, 4:337–45. 16. Bernardo J, Sabra R, Branch RA: Amphotericin B. In Clinical Nephrotoxins—Renal Injury From Drugs and Chemicals. Edited by De Broe ME, Porter GA, Bennett WM, Verpooten GA. Dordrecht: Kluwer Academic, 1998:135–151. 17. Bennett WM: Mechanisms of acute and chronic nephrotoxicity from immunosuppressive drugs. Renal Failure 1996, 18:453–460. 18. de Mattos AM, Olyaei AJ, Bennett WM: Pharmacology of immunosuppressive medications used in renal diseases and transplantation. Am J Kidney Dis 1996, 28:631–667. 19. Vanrenterghem Y, Lerut T, Roels L, et al.: Thromboembolic complications and haemostatic changes in cyclosporin-treated cadaveric kidney allograft recipients. Lancet 1985, 1:999–1002.

24. Battle DC, Dorhout-Mees EJ: Lithium and the kidney. In Clinical nephrotoxins—renal injury from drugs and chemicals. Edited by De Broe ME, Porter GA, Bennett WM, Verpooten GA. Dordrecht: Kluwer Academic, 1998:383–395. 25. Jorgensen F, Larsen S, Spanager E, et al.: Kidney function and quantitative histological changes in patients on long-term lithium therapy. Acta Psychiatry Scand 1984, 70:455–462. 26. Hricik DE, Browning PJ, Kopelman R, et al.: Captopril-induced functional renal insufficiency in patients with bilateral renal artery stenosis or renal artery stenosis in a solitary kidney. N Engl J Med 1983, 308:373–376. 27. Textor SC: ACE inhibitors in renovascular hypertension. Cardiovasc Drugs Ther 1990; 4:229–235. 28. de Jong PE, Woods LL: Renal injury from angiotensin I converting enzyme inhibitors. In Clinical nephrotoxins—renal injury from drugs and chemicals. Edited by De Broe ME, Porter GA, Bennett WM, Verpooten GA. Dordrecht: Kluwer Academic, 1998:239–250. 29. Smith WR, Neil J, Cusham WC, Butkus DE: Captopril associated acute interstitial nephritis. Am J Nephrol 1989, 9:230–235. 30. Opie LH: Angiotensin-converting enzyme inhibitors. New York: Willy-Liss, 1992; 3. 31. Whelton A, Watson J: Nonsteroidal anti-inflammatory drugs: effects on kidney function. In Clinical Nephrotoxins—Renal Injury From drugs and Chemicals. Edited by De Broe ME, Porter GA, Bennett WM, Verpooten GA. Dordrecht: Kluwer Academic, 1998:203–216. 32. De Broe ME, Elseviers MM: Analgesic nephropathy. N Engl J Med 1998, 338:446–452. 33. Mitchell JA, Akarasereenont P, Thiemermann C, et al.: Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci USA 1993, 90(24):11693–11697. 34. Bennett WM, Henrich WL, Stoff JS: The renal effects of nonsteroidal anti-inflammatory drugs: summary and recommendations. Am J Kidney Dis 1996, 28(1 Suppl 1):S56–S62. 35. Heyman SN, Rosen S, Brezis M: Radiocontrast nephropathy: a paradigm for the synergism between toxic and hypoxic insults in the kidney. Exp Nephrol 1994, 2:153. 36. Porter GA, Kremer D: Contrast associated nephropathy: presentation, pathophysiology and management. In Clinical nephrotoxins—Renal Injury From Drugs and Chemicals. Edited by De Broe ME, Porter GA, Bennett WM, Verpooten GA. Dordrecht: Kluwer Academic, 1998:317–331.

Diagnostic Evaluation of the Patient with Acute Renal Failure Brian G. Dwinnell Robert J. Anderson

A

cute renal failure (ARF) is abrupt deterioration of renal function sufficient to result in failure of urinary elimination of nitrogenous waste products (urea nitrogen and creatinine). This deterioration of renal function results in elevations of blood urea nitrogen and serum creatinine concentrations. While there is no disagreement about the general definition of ARF, there are substantial differences in diagnostic criteria various clinicians use to define ARF (eg, magnitude of rise of serum creatinine concentration). From a clinical perspective, for persons with normal renal function and serum creatinine concentration, glomerular filtration rate must be dramatically reduced to result in even modest increments (eg, 0.1 to 0.3 mg/dL) in serum creatinine concentration. Moreover, several studies demonstrate a direct relationship between the magnitude of serum creatinine increase and mortality from ARF. Thus, the clinician must carefully evaluate all cases of rising serum creatinine. The process of urine formation begins with delivery of blood to the glomerulus, filtration of the blood at the glomerulus, further processing of the filtrate by the renal tubules, and elimination of the formed urine by the renal collecting system. A derangement of any of these processes can result in the clinical picture of rapidly deteriorating renal function and ARF. As the causes of ARF are multiple and since subsequent treatment of ARF depends on a clear delineation of the cause, prompt diagnostic evaluation of each case of ARF is necessary.

CHAPTER

12

12.2

Acute Renal Failure

RATIONALE FOR ORGANIZED APPROACH TO ACUTE RENAL FAILURE

PRESENTING FEATURES OF ACUTE RENAL FAILURE

Common Rising BUN or creatinine Oligoanuria Less common Symptoms of uremia Characteristic laboratory abnormalities

Common Present in 1%–2% of hospital admissions Develops after admission in 1%–5% of noncritically ill patients Develops in 5%–20% after admission to an intensive care unit Multiple causes Prerenal Postrenal Renal Therapy dependent upon diagnosing cause Prerenal: improve renal perfusion Postrenal: relieve obstruction Renal: identify and treat specific cause Poor outcomes Twofold increased length of stay Two- to eightfold increased mortality Substantial morbidity

FIGURE 12-1 Rationale for an organized approach to acute renal failure (ARF). An organized approach to the patient with ARF is necessary, as this disorder is common and is caused by several insults that operate via numerous mechanisms. Successful amelioration of the renal failure state depends on early identification and treatment of the cause of the disorder [1–7]. If not diagnosed and treated and reversed quickly, it can lead to substantial morbidity and mortality.

FIGURE 12-2 Presenting features of acute renal failure (ARF). ARF usually comes to clinical attention by the finding of either elevated (or rising) blood urea nitrogen (BUN) or serum creatinine concentration. Less commonly, decreased urine output ( less than 20 mL per hour) heralds the presence of ARF. It is important to acknowledge, however, that at least half of all cases of ARF are nonoliguric [2–6]. Thus, healthy urine output does not ensure normal renal function. Rarely, ARF comes to the attention of the clinician because of symptoms of uremia (eg, anorexia, nausea, vomiting, confusion, pruritus) or laboratory findings compatible with renal failure (metabolic acidosis, hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, hypermagnesemia, anemia).

Blood Urea Nitrogen, Creatinine, and Renal Failure OVERVIEW OF BLOOD UREA NITROGEN AND SERUM CREATININE

Source Constancy of production Renal handling Value as marker for glomerular filtration rate Correlation with uremic symptoms

Blood Urea Nitrogen

Serum Creatinine

Protein that can be of exogenous or endogenous origin Variable Completely filtered; significant tubular reabsorption Modest

Nonenzymatic hydrolysis of creatine released from skeletal muscle More stable Completely filtered; some tubular secretion

Good

Poor

Good in steady state

FIGURE 12-3 Overview of blood urea nitrogen (BUN) and serum creatinine. Given the central role of BUN and serum creatinine in determining the presence of renal failure, an understanding of the metabolism of these substances is needed. Urea nitrogen derives from the breakdown of proteins that are delivered to the liver. Thus, the urea nitrogen production rate

can vary with exogenous protein intake and endogenous protein catabolism. Urea nitrogen is a small, uncharged molecule that is not protein bound, and as such, it is readily filtered at the renal glomerulus. Urea nitrogen undergoes renal tubular reabsorption by specific transporters. This tubular reabsorption limits the value of BUN as a marker for glomerular filtration. However, the BUN usually correlates with the symptoms of uremia. By contrast, the production of creatinine is usually more constant unless there has been a marked reduction of skeletal muscle mass (eg, loss of a limb, prolonged starvation) or diffuse muscle injury. Although creatinine undergoes secretion into renal tubular fluid, this is very modest in degree. Thus, a steady-stable serum creatinine concentration is usually a relatively good marker of glomerular filtration rate as noted in Figure 12-5.

Diagnostic Evaluation of the Patient with Acute Renal Failure

BLOOD UREA NITROGEN (BUN)-CREATININE RATIO > 10

< 10

Increased protein intake Catabolic state Fever Sepsis Trauma Corticosteroids Tissue necrosis Tetracyclines Diminished urine flow Prerenal state Postrenal state

Starvation Advanced liver disease Postdialysis state Drugs that impair tubular secretion Cimetidine Trimethoprim Rhabdomyolysis

FIGURE 12-4 The blood urea nitrogen (BUN)-creatinine ratio. Based on the information in Figure 12-3, the BUN-creatinine ratio often deviates from the usual value of about 10:1. These deviations may have modest diagnostic implications. As an example, for reasons as yet unclear, tubular reabsorption of urea nitrogen is enhanced in low-urine flow states. Thus, a high BUN-creatinine ratio often occurs in prerenal and postrenal (see Fig. 12-6) forms of renal failure. Similarly, enhanced delivery of amino acids to the liver (as with catabolism, corticosteroids, etc.) can enhance urea nitrogen formation and increase the BUN-creatinine ratio. A BUN-creatinine ratio lower than 10:1 can occur because of decreased urea nitrogen formation (eg, in protein malnutrition, advanced liver disease), enhanced creatinine formation (eg, with rhabdomyolysis), impaired tubular secretion of creatinine (eg, secondary to trimethoprim, cimetidine), or relatively enhanced removal of the small substance urea nitrogen by dialysis.

FIGURE 12-5 Correlation of steady-state serum creatinine concentration and glomerular filtration rate (GFR).

CORRELATION OF STEADY-STATE SERUM CREATININE CONCENTRATION AND GLOMERULAR FILTRATION RATE (GFR)

Creatinine (mg/dL)

12.3

GFR (mL/min)

1 2 4 8 16

100 50 25 12.5 6.25

Renal Failure

Favors acute

Favors chronic

Normal

Kidney size

Small

Normal

Carbamylated hemoglobin

High

Absent

Broad casts on urinalysis

Present

Absent

History of kidney disease, hypertension, abnormal urinalysis

Present

Often present

Anemia, metabolic acidosis, hyperkalemia, hyperphosphatemia

Usually present

Usually complete

Reversibility with time

Sometimes, partial

FIGURE 12-6 Categories of renal failure. Once the presence of renal failure is ascertained by elevated blood urea nitrogen (BUN) or serum creatinine value, the clinician must decide whether it is acute or chronic. When previous values are available for review, this judgment is made relatively easily. In the absence of such values, the factors depicted here may be helpful. Hemoglobin potentially undergoes nonenzymatic carbamylation of its terminal valine [8]. Thus, similar to the hemoglobin A1C value as an index of blood sugar control, the level of carbamylated hemoglobin is an indicator of the degree and duration of elevated BUN, but, this test is not yet widely available. The presence of small kidneys strongly suggests that renal failure is at least in part chronic. From a practical standpoint, because even chronic renal failure often is partially reversible, the clinician should assume and evaluate for the presence of acute reversible factors in all cases of acute renal failure.

12.4

Acute Renal Failure

Categorization of Causes of Acute Renal Failure Acute renal failure

Prerenal causes

Vascular disorders

Renal causes

Glomerulonephritis

Postrenal causes

Interstitial nephritis

Ischemia

Tubular necrosis

Toxins

Pigments

FIGURE 12-7 Acute renal failure (ARF). This figure depicts the most commonly used schema to classify and diagnostically approach the patient with ARF [1, 6, 9]. The most common general cause of ARF (60% to 70% of cases) is prerenal factors. Prerenal causes include those secondary to renal hypoperfusion, which occurs in the setting of extracellular fluid loss (eg, with vomiting, nasogastric suctioning, gastrointestinal hemorrhage, diarrhea, burns, heat stroke, diuretics, glucosuria), sequestration of extracellular fluid (eg, with pancreatitis,

VASOMOTOR MECHANISMS CONTRIBUTING TO ACUTE RENAL FAILURE Decreased Renal Perfusion Pressure Extracellular fluid volume loss or sequestration Impaired cardiac output Antihypertensive medications Sepsis

Afferent Arteriolar Constriction

Efferent Arteriolar Dilation

Sepsis Medications (NSAIDs, cyclosporine, contrast medium, amphotericin, alpha-adrenergic agonists) Hypercalcemia Postoperative state Hepatorenal syndrome

Converting enzyme inhibitors Angiotensin II receptor antagonists

abdominal surgery, muscle crush injury, early sepsis), or impaired cardiac output. In most prerenal forms of ARF, one or more of the vasomotor mechanisms noted in Figure 12-8 is operative. The diagnostic criteria for prerenal ARF are delineated in Figure 12-9. Once prerenal forms of ARF have been ruled out, postrenal forms (ie, obstruction to urine flow) should be considered. Obstruction to urine flow is a less common (5% to 15% of cases) cause of ARF but is nearly always amenable to therapy. The site of obstruction can be intrarenal (eg, crystals or proteins obstructing the terminal collecting tubules) or extrarenal (eg, blockade of the renal pelvis, ureters, bladder, or urethra). The diagnosis of postrenal forms of ARF is supported by data outlined in Figure 12-10. After preand postrenal forms of ARF have been considered, attention should focus on the kidney. When considering renal forms of ARF, it is helpful to think in terms of renal anatomic compartments (vasculature, glomeruli, interstitium, and tubules). Acute disorders involving any of these compartments can lead to ARF. FIGURE 12-8 Vasomotor mechanisms contributing to acute renal failure (ARF). Most prerenal forms of ARF have operational one or more of the vasomotor mechanisms depicted here [6]. Collectively, these factors lead to diminished glomerular filtration and ARF. NSAIDs— nonsteroidal anti-inflammatory drugs.

Diagnostic Evaluation of the Patient with Acute Renal Failure

DIAGNOSIS OF POSSIBLE PRERENAL CAUSES OF ACUTE RENAL FAILURE History

Examination

Laboratory/Other

Extracellular fluid loss or sequestration from skin, gastrointestinal and/or renal source (see Fig. 12-15) Orthostatic lightheadedness Thirst Oliguria Symptoms of heart failure Edema

Orthostatic hypotension and tachycardia Dry mucous membranes No axillary moisture Decreased skin turgor Evidence of congestive heart failure Presence of edema

Normal urinalysis Urinary indices compatible with normal tubular function (see Fig. 12-14) Elevated BUN-creatinine ratio Improved renal function with correction of the underlying cause Rarely, chest radiography, cardiac ultrasound, gated blood pool scan, central venous and/or Swan-Ganz wedge pressure recordings

DIAGNOSIS OF POSSIBLE POSTRENAL CAUSES OF ACUTE RENAL FAILURE History

Examination

Laboratory/Other

Very young or very old age Nocturia Decreased size or force of urine stream Anticholinergic or alpha-adrenergic agonist medications Bladder, prostate, pelvic, or intra-abdominal cancer Fluctuating urine volume Oligoanuria Suprapubic pain Urolithiasis Medication known to produce crystalluria (sulfonamides, acyclovir, methotrexate, protease inhibitors)

Distended bladder Enlarged prostate Abnormal pelvic examination

Abnormal urinalysis Elevated BUN-creatinine ratio Elevated postvoiding residual volume Abnormal renal ultrasound, CT or MRI findings Improvement after drainage

POSTOPERATIVE ACUTE RENAL FAILURE Frequency

Predisposing Factors

Preventive Strategies

Elective surgery 1%–5% Emergent or vascular surgery 5%–10%

Comorbidity results in decreased renal reserve The surgical experience decreases renal function (volume shifts, vasoconstriction) A second insult usually occurs (sepsis, reoperation, nephrotoxin, volume/cardiac issue)

Avoid nephrotoxins Minimize hospital-acquired infections (invasive equipment) Selective use of volume expansion, vasodilators, inotropes Preoperative hemodynamic optimization in selected cases Increase tissue oxygenation delivery to supranormal levels in selected cases

12.5

FIGURE 12-9 Diagnosis of possible prerenal causes of acute renal failure (ARF). Prerenal events are the most common factors that lead to contemporary ARF. The historical, physical examination, and laboratory and other investigations involved in identifying a prerenal form of ARF are outlined here [1]. BUN—blood urea nitrogen.

FIGURE 12-10 Diagnosis of possible postrenal causes of acute renal failure (ARF). Postrenal causes of ARF are less common (5% to 15% of ARF population) but are nearly always amenable to therapy. This figure depicts the historical, physical examination and tests that can lead to an intrarenal (crystal deposition) or extrarenal (blockade of the collecting system) form of obstructive uropathy [1, 6, 9, 10]. BUN—blood urea nitrogen; CT—computed tomography; MRI—magnetic resonance imaging.

FIGURE 12-11 Postoperative acute renal failure (ARF). The postoperative setting of ARF is very common. This figure depicts data on the frequency, predisposing factors, and potential strategies for preventing postoperative ARF [11, 12].

12.6

Acute Renal Failure

Diagnostic Steps in Evaluating Acute Renal Failure STEPWISE APPROACH TO DIAGNOSIS OF ACUTE RENAL FAILURE Step 1

Step 2

Step 3

History Record review Physical examination Urinary bladder catherization (if oligoanuric) Urinalysis (see Fig. 12-15)

Consider urinary diagnostic Consider selected indices (see Fig. 12-16) therapeutic trials Consider need for further evaluation to exclude urinary tract obstruction Consider need for more data to assess intravascular volume or cardiac output status Consider need for additional blood tests Consider need for evaluation of renal vascular status

Step 4 Consider renal biopsy Consider empiric therapy for suspected diagnosis

FIGURE 12-12 Stepwise approach to diagnosis of acute renal failure (ARF). The multiple causes, predisposing factors, and clinical settings demand a logical, sequential approach to each case of ARF. This figure presents a four-step approach to assessing ARF patients in an effort to delineate the cause in a timely and cost-effective manner. Step 1 involves a focused history, record review, and examination. The salient features of these analyses are noted in more detail in Figure 12-13. In many cases, a single bladder catheterization is needed to assess the degree of residual volume, which should be less than 30 to 50 mL. Urinalysis is a critical part of the initial evaluation of all patients with ARF. Generally, a relatively normal urinalysis suggests either a prerenal or postrenal cause, whereas a urinalysis containing cells and casts is most compatible with a renal cause. A detailed schema of urinalysis interpretation in the setting of ARF is depicted in Figure 12-15. Usually, after Step 1 the clinician has a reasonably good idea of the likely cause of the ARF. Sometimes, the information noted under Step 2 is needed to ascertain definitively the cause of the ARF. More details of Step 2 are depicted in Figure 12-14. Oftentimes, urinary diagnostic indices (see Fig. 12-16),

are helpful in differentiating between prerenal (intact tubular function) and acute tubular necrosis (impaired tubular function) as the cause of renal failure. Sometimes, further evaluation (usually ultrasonography, less commonly computed tomography or magnetic resonance imaging) is needed to exclude the possibility of bilateral ureteric obstruction (or single ureteric obstruction in patients with a single kidney). Occasionally, additional studies such as central venous pressure or left ventricular filling pressure determinations are needed to better assess whether prerenal factors are contributing to the ARF. When the cause of the ARF continues to be difficult to ascertain and renal vascular disorders (see Fig. 12-17 and 12-18), glomerulonephritis (see Fig. 12-19) or acute interstitial nephritis (see Fig. 12-20) remain possibilities, additional blood analyses and other tests described in Figures 12-18 through 12-20 may be indicated. Sometimes, selected therapeutic trials (eg, volume expansion, maneuvers to increase cardiac index, ureteric stent or nephrostomy tube relief of obstruction) are necessary to document the cause of ARF definitively. Empiric therapy (eg, corticosteroids for suspected acute allergic interstitial nephritis) is given as both a diagnostic and a therapeutic maneuver in selected cases. Rarely, despite all efforts, the cause of the ARF remains unknown and renal biopsy is necessary to establish a definitive diagnosis.

Diagnostic Evaluation of the Patient with Acute Renal Failure

FIRST STEP IN EVALUATION OF ACUTE RENAL FAILURE

History Disorders that suggest or predispose to renal failure: hypertension, diabetes mellitus, human immunodeficiency virus, vascular disease, abnormal urinalyses, family history of renal disease, medication use, toxin or environmental exposure, infection, heart failure, vasculitis, cancer Disorders that suggest or predispose to volume depletion: vomiting, diarrhea, pancreatitis, gastrointestinal bleeding, burns, heat stroke, fever, uncontrolled diabetes mellitus, diuretic use, orthostatic hypotension, nothing-by-mouth status, nasogastric suctioning Disorders that suggest or predispose to obstruction: stream abnormalities, nocturia, anticholingeric medications, stones, urinary tract infections, bladder or prostate disease, intra-abnominal malignancy, suprapubic or flank pain, anuria, fluctuating urine volumes Symptoms of renal failure: anorexia, vomiting, reversed sleep pattern, puritus Record review Recent events (procedures, surgery) Medications (see Fig. 12-22) Vital signs Intake and output Body weights Blood chemistries and hemogram

Physical examination Skin: rash suggestive of allergy, palpable purpura of vasculitis, livedo reticularis and digital infarctions suggesting atheroemboli Eyes: hypertension, diabetes mellitus, Hollenhorst plaques, vasculitis, candidemia Lungs: rales, rubs Heart: evidence of heart failure, pericardial disease, jugular venous pressure Vascular system: bruits, pulses, abdominal aortic aneurysm Abdomen: flank or suprapubic masses, ascites, costovertebral angle pain Extremities: edema, pulses, compartment syndromes Nervous system: focal findings, asterixis, mini-mental status examination Consider bladder catheterization Urinalysis (see Fig. 12-13)

FIGURE 12-13 First step in evaluation of acute renal failure.

SECOND STEP IN EVALUATION OF ACUTE RENAL FAILURE Urine diagnostic indices (see Fig. 12-16) Consider need for further evaluation for obstruction Ultrasonography, computed tomography, or magnetic resonance imaging Consider need for additional blood tests Vasculitis/glomerulopathy: human immunodeficiency virus infections, antineutrophilic cytoplasmic antibodies, antinuclear antibodies, serologic tests for hepatitis, systemic bacterial endocarditis and streptococcal infections, rheumatoid factor, complement, cryoglobins Plasma cell disorders: urine for light chains, serum analysis for abnormal proteins Drug screen/level, additional chemical tests Consider need for evaluation of renal vascular supply Isotope scans, Doppler sonography, angiography Consider need for more data to assess volume and cardiac status Swan-Ganz catheterization

FIGURE 12-14 Second step in evaluation of acute renal failure.

12.7

12.8

Acute Renal Failure

Urinalysis in acute renal failure

Normal

Prerenal, postrenal, high oncotic pressure (dextran, mannitol)

Abnormal

RBC RBC casts Proteinuria

WBC WBC casts

Eosinophils

RTE cells Pigmented casts

Crystalluria

Low grade proteinuria

Glomerulopathy, vasculitis, thrombotic microangiopathy

Pyelonephritis, interstitial nephritis

Allergic interstitial nephritis, atheroemboli, glomerulopathy

ATN, myoglobinuria, hemoglobinuria

Uric acid, drugs or toxins

Plasma cell dyscrasia

FIGURE 12-15 Urinalysis in acute renal failure (ARF). A normal urinalysis suggests a prerenal or postrenal form of ARF; however, many patients with ARF of postrenal causes have some cellular elements on urinalysis. Relatively uncommon causes of ARF that usually present with oligoanuria and a normal urinalysis are mannitol toxicity and large doses of dextran infusion. In these disorders, a “hyperoncotic state” occurs in which glomerular capillary oncotic pressure, combined with the intratubular hydrostatic pressure, exceeds the glomerular capillary hydrostatic pressure and stop glomerular filtration. Red blood cells (RBCs) can be seen with all renal forms of ARF. When RBC casts are present, glomerulonephritis or vasculitis is most likely.

Urinary diagnostic indices in acute renal failure

Prerenal Hyaline casts >1.020 >500 <20 <1 <7 <7

Renal Urinalysis Specific gravity Uosm (mOsm/kg H2O) Una (mEq/L) FE Na (%) FE uric acid (%) FE lithium (%)

Abnormal ~1.010 >300 >40 >2 >15 >20

White blood cells (WBCs) can also be present in small numbers in the urine of patients with ARF. Large numbers of WBCs and WBC casts strongly suggest the presence of either pyelonephritis or acute interstitial nephritis. Eosinolphiluria (Hansel’s stain) is often present in either allergic interstitial nephritis or atheroembolic disease [13, 14]. Renal tubular epithelial (RTE) cells and casts and pigmented granular casts typically are present in pigmenturia-associated ARF (see Fig. 12-21) and in established acute tubular necrosis (ATN). The presence of large numbers of crystals on urinalysis, in conjunction with the clinical history, may suggest uric acid, sulfonamides, or protease inhibitors as a cause of the renal failure. FIGURE 12-16 Urinary diagnostic indices in acute renal failure (ARF). These indices have traditionally been used in the setting of oliguria, to help differentiate between prerenal (intact tubular function) and acute tubular necrosis (ATN, impaired tubular function). Several caveats to interpretation of these indices are in order [1]. First, none of these is completely sensitive or specific in differentiating the prerenal from the ATN form of ARF. Second, often a continuum exists between early prerenal conditions and late prerenal conditions that lead to ischemic ATN. Most of the data depicted here are derived from patients relatively late in the progress of ARF when the serum creatinine concentrations were 3 to 5 mg/dL. Third, there is often a relatively large “gray area,” in which the various indices do not give definitive results. Finally, some of the indices (eg, fractional excretion of endogenous lithium [FE lithium]) are not readily available in the clinical setting. The fractional excretion (FE) of a substance is determined by the formula: U/P substance  U/P creatinine  100. U/P—urine-plasma ratio.

Diagnostic Evaluation of the Patient with Acute Renal Failure

12.9

Vascular Mechanisms Involved in Acute Renal Failure VASCULAR CAUSES OF ACUTE RENAL FAILURE Arterial

Venous

Large vessels Renal artery stenosis Thrombosis Cross-clamping Emboli Atheroemboli Endocarditis Atrial fibrillation Mural thrombus Tumor

Occlusion Clot Tumor

FIGURE 12-17 Vascular causes of acute renal failure (ARF). Once prerenal and postrenal causes of ARF have been excluded, attention should be focused on the kidney. One useful means of classifying renal causes of ARF is to consider the anatomic compartments of the kidney. Thus, disorders of the renal vasculature (see Fig. 12-18), glomerulus (see Fig. 12-19), interstitium (see Fig. 12-20) and tubules can all result in identical clinical pictures of ARF [1]. This figure depicts the disorders of the renal arterial and venous systems that can result in ARF [15].

Small vessels Cortical necrosis malignant hypertension Scleroderma Vasculitis Antiphospholipid syndrome Thrombotic microangiopathies Hemolytic-uremic syndrome Thrombotic thrombocytopenic purpura Postpartum Medications (mitomycin C, cyclosporine, tacrolimus)

DIAGNOSIS OF POSSIBLE VASCULAR CAUSE OF ACUTE RENAL FAILURE History

Examination

Laboratory/Other

Factors that predispose to vascular disease (smoking, hypertension, diabetes mellitus, hyperlipidemia) Claudication, stroke, myocardial infarction Surgical procedure on aorta Catheterization procedure involving aorta Selected clinical states (scleroderma, pregnancy) Selected medications, toxins (cyclosporine, mitomycin C, cocaine, tacrolimus) Constitutional symptoms

Marked hypertension Atrial fibrillation Scleroderma Palpable purpura Abdominal aortic aneurysm Diminished pulses Infarcted toes Hollendhorst plaques Vascular bruits Stigmata of bacterial endocarditis Illeus

Thrombocytopenia Microangiopathic hemolysis Coagulopathy Urinalysis with hematuria and low-grade proteinuria Abnormal renal isotope scan and/or Doppler ultrasonography Renal angiography Renal or extrarenal tissue analysis

FIGURE 12-18 Diagnosis of a possible vascular cause of acute renal failure (ARF). This figure depicts the historical, physical examination, and testing procedures that often lead to diagnosis of a “vascular cause” of ARF [1, 15, 16].

12.10

Acute Renal Failure

Acute Glomerulonephritis DIAGNOSIS OF A POSSIBLE ACUTE GLOMERULAR PROCESS AS THE CAUSE OF ACUTE RENAL FAILURE

History

Examination

Laboratory/Other

Recent infection Sudden onset of edema, dyspnea Systemic disorder (eg, lupus erythematosus, Wegener’s granulomatosis, Goodpasture’s syndrome) No evidence of other causes of renal failure

Hypertension Edema Rash Arthropathy Prominent pulmonary findings Stigmata of bacterial endocarditis or visceral abscess

Urinalysis with hematuria, red cell casts, and proteinuria Serologic or culture evidence of recent infection Laboratory evidence of immunemediated process (low complement, cryoglobulinemia, antinuclear antibody, anti-DNA, rheumatoid factor, anti–glomerular basement membrane antibody, antineutrophilic cytoplasmic antibody) Renal tissue examination

FIGURE 12-19 Diagnosis of a possible acute glomerular process as the cause of acute renal failure (ARF). Acute glomerulonephritis is a relatively rare cause of ARF in adults. In the pediatric age group, acute glomerulonephritis and a disorder of small renal arteries (hemolytic-uremic syndrome) are relatively common causes. This figure depicts the historical, examination, and laboratory findings that collectively may support a diagnosis of acute glomerulonephritis as the cause of ARF [16, 17].

Interstitial Nephritis DIAGNOSIS OF POSSIBLE ACUTE INTERSTITIAL NEPHRITIS AS THE CAUSE OF ACUTE RENAL FAILURE

History

Examination

Laboratory/Other

Medication exposure Severe pyelonephritis Systemic infection

Fever Rash Back or flank pain

Abnormal urinalysis (white blood cells or cell casts, eosinophils, eosinophilic casts, low-grade proteinuria, sometimes hematuria) Eosinophilia Urinary diagnositc indices compatible with a renal cause of renal failure (see Fig. 12-16) Uptake on gallium or indium scan Renal biopsy

FIGURE 12-20 Diagnosis of possible acute interstitial nephritis as the cause of acute renal failure (ARF). This figure outlines the historical, physical examination and other investigative methods that can lead to identification of acute interstitial nephritis as the cause of ARF [18].

Diagnostic Evaluation of the Patient with Acute Renal Failure

12.11

Acute Tubular Necrosis DIAGNOSIS OF POSSIBLE PIGMENT-ASSOCIATED FORMS OF ACUTE RENAL FAILURE Myoglobinuria

Hemoglobinuria

History

Examination

Laboratory

History

Examination

Laboratory

Trauma to muscles Condition known to predispose to nontraumatic rhabdomyolysis Muscle pain or stiffness Dark urine

Can be normal Muscle edema, weakness, pain Neurovascular entrapment or compartment syndromes in severe cases Flank pain

Serum creatinine disproportionately elevated related to BUN Elevated (10-fold) enzymes (CK, SGOT, LDH, adolase) Elevations of plasma potassium, uric acid, phosphorus, and hypocalcemia Urinalysis with pigmented granular casts, () stick reaction for blood in the absence of hematuria, and myoglobin test if available Clear plasma

Condition associated with intravascular hemolysis (red cell trauma, antibodymediated hemolysis, direct red cell toxicity, sickle cell disease)

Can be normal Pallor Flank pain

Normocytic anemia High red cell LDH fraction Reticulocytosis Low haptoglobin Urinalysis with pigmented granular casts, () stick reaction for blood in absence of hemataria and reddish brown or pink plasma

FIGURE 12-21 Diagnosis of possible pigment-associated forms of acute renal failure (ARF). Once prerenal and postrenal forms of ARF have been ruled out and renal vascular, glomerular, and interstitial processes seem unlikely, a diagnosis of acute tubular necrosis (ATN) is probable. A diagnosis of ATN is thus one of exclusion (of other causes of ARF). In the majority of cases when ATN is present, one or more of the three predisposing conditions have been identified to be operational. These conditions include renal ischemia due to a prolonged prerenal state, nephrotoxin exposure, and sometimes pigmenturia. A diagnosis

of ATN is supported by the absence of other causes of ARF, the presence of one or more predisposing factors, and the presence of urinary diagnostic indices and urinalysis suggested of ATN (see Figs. 12-15 and 12-16). A pigmenturic disorder (myloglobinuria or hemoglobinuria) can predispose to ARF. This figure depicts the historical, physical examination, and supporting diagnostic tests that often lead to a diagnosis of pigment-associated ARF [19]. BUN—blood urea nitrogen; CK—creatinine kinase; SGOT—serum glutamic-oxaloacetic transaminase; LDH—lactic dehydrogenase.

Nephrotoxin Acute Renal Failure NEPHROTOXIC ACUTE RENAL FAILURE Prerenal Diuretics Interleukin 2 CEIs Antihypertensive agents Tubular toxicity Aminoglyosides Cisplatin Vancomycin Foscarnet Pentamidine Radiocontrast Amphotercin Heavy metals

Vasoconstriction NSAIDs Radiocontrast agents Cyclosporine Tacrolimus Amphotericin Endothelial injury Cyclosporine Mitomycin C Tacrolimus Cocaine Conjugated estrogens Quinine

Crystalluria Sulfonamides Methotrexate Acyclovir Triamterene Ethylene glycol Protease inhibitors Glomerulopathy Gold Penicillamine NSAIDs Interstitial nephritis Multiple

FIGURE 12-22 Nephrotoxin acute renal failure (ARF). A variety of nephrotoxins have been implicated in causing 20% to 30% of all cases of ARF. These potential nephrotoxins can act through a variety of mechanisms to induce renal dysfunction [6, 20, 21]. CEI—converting enzyme inhibitor; NSAID—nonsteroidal anti-inflammatory drugs.

12.12

Acute Renal Failure

References 1. Anderson RJ, Schrier RW: Acute renal failure. In Diseases of the Kidney. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown; 1997:1069–1113. 2. Hou SH, Bushinsky D, Wish JB, Harrington JT: Hospital-acquired renal insufficiency: A prospective study. Am J Med 1983, 74:243–248. 3. Shusterman N, Strom BL, Murray TG, et al.: Risk factors and outcome of hospital-acquired acute renal failure. Am J Med 1987, 83:65–71. 4. Levy EM, Viscoli CM, Horwitz RI: The effect of acute renal failure on mortality. JAMA 1996, 275:1489–1494. ~ F, Pascual J: Epidemiology of acute renal failure: A prospective, 5. Liano

12. Kellerman PS: Perioperative care of the renal patient. Arch Intern Med 1994, 154:1674–1681. 13. Nolan CR, Anger MS, Kelleher SP: Eosinophiluria —a new method of detection and definition of the clinical spectrum. N Engl J Med 1986, 315:1516–1519. 14. Wilson DM, Salager TL, Farkouh ME: Eosinophiluria in atheroembolic renal disease. Am J Med 1991, 91:186–191. 15. Abuelo JG: Diagnosing vascular causes of acute renal failure. Ann Intern Med 1995, 123:601–614. 16. Falk RJ, Jennette JC: ANCA small-vessel vasculitis. J Am Soc Nephrol 1997, 8:314–322.

6. Thadhani R, Pascual M, Bonventre JV: Acute renal failure. New Engl J Med 1996, 334:1448–1460.

17. Kobrin S, Madacio MP: Acute poststreptococcal glomerulonephritis and other bacterial infection-related glomerulonephritis. In Diseases of the Kidney. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown; 1997:1579–1594.

7. Feest TG, Round A, Hamad S: Incidence of severe acute renal failure in adults: Results of a community-based study. Br Med J 1993, 306:481–483.

18. Eknoyan G: Acute tubulointerstitial nephritis. In Diseases of the Kidney. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown; 1997:1249–1272.

8. Davenport A: Differentiation of acute from chronic renal impairment by detection of carbamylated hemoglobin. Lancet 1993, 341:1614–1616. 9. Mendell JA, Chertow GM: A practical approach to acute renal failure. Med Clin North Am 1997, 81:731–748. 10. Kopp JB, Miller KD, Mican JM, et al.: Crystalluria and urinary tract abnormalities associated with indinovir. Ann Intern Med 1997, 127:119–125.

19. Don BR, Rodriguez RA, Humphreys MH: Acute renal failure associated with pigmenturia as crystal deposits. In Diseases of the Kidney. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown; 1997:1273–1302.

multicenter, community-based study. Kid Int 1996, 50:811–818.

11. Charlson ME, MacKenzie CR, Gold JP, Shires T: Postoperative changes in serum creatinine. Ann Surg 1989, 209:328–335.

20. Chaudbury O, Ahmed Z: Drug-induced nephrotoxicity. Med Clin North Am 1997, 81:705–717. 21. Palmer B, Henrich WL: Nephrotoxicity of nonsteroidal anti-inflammatory agents, analgesics, and angiotensin converting enzyme inhibitors. In Diseases of the Kidney. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown; 1997:1167–1188.

Pathophysiology of Ischemic Acute Renal Failure: Cytoskeletal Aspects Bruce A. Molitoris Robert Bacallao

I

schemia remains the major cause of acute renal failure (ARF) in the adult population [1]. Clinically a reduction in glomerular filtration rate (GFR) secondary to reduced renal blood flow can reflect prerenal azotemia or acute tubular necrosis (ATN). More appropriate terms for ATN are acute tubular dysfunction or acute tubular injury, as necrosis only rarely is seen in renal biopsies, and renal tubular cell injury is the hallmark of this process. Furthermore, the reduction in GFR during acute tubular dysfunction can now, in large part, be related to tubular cell injury. Ischemic ARF resulting in acute tubular dysfunction secondary to cell injury is divided into initiation, maintenance, and recovery phases. Recent studies now allow a direct connection to be drawn between these clinical phases and the cellular phases of ischemic ARF (Fig. 13-1). Thus, renal function can be directly related to the cycle of cell injury and recovery. Renal proximal tubule cells are the cells most injured during renal ischemia (Fig. 13-2) [2,3]. Proximal tubule cells normally reabsorb 70% to 80% of filtered sodium ions and water and also serve to selectively reabsorb other ions and macromolecules. This vectorial transport across the cell from lumen to blood is accomplished by having a surface membrane polarized into apical (brush border membrane) and basolateral membrane domains separated by junctional complexes (Fig. 13-3) [4]. Apical and basolateral membrane domains are biochemically and functionally different with respect to many parameters, including enzymes, ion channels, hormone receptors, electrical resistance, membrane transporters, membrane lipids, membrane fluidity, and cytoskeletal associations. This epithelial cell polarity is essential for normal cell function, as demonstrated by the vectorial transport of sodium from the lumen to the blood (see Fig. 13-3). The establishment

CHAPTER

13

13.2

Acute Renal Failure

and maintenance of this specialized organization is a dynamic and ATP dependent multistage process involving the formation and maintenance of cell-cell and cell-substratum attachments and the targeted delivery of plasma membrane components to the appropriate domains [5]. These processes are very dependent on the cytoskeleton, in general, and the cytoskeletal membrane interactions mediated through F-actin (see Fig. 13-2, 13-3), in particular. Ischemia in vivo and cellular ATP depletion in cell culture models (“chemical ischemia”) are known to produce characteristic surface membrane structural, biochemical, and functional abnormalities in proximal tubule cells. These alterations occur in a duration-dependent fashion and are illustrated in Figures 13-2 and 13-3 and listed in Figure 13-4. Ischemia-induced alterations in the actin cytoskeleton have been postulated to mediate many of the aforementioned surface membrane changes [2,6,7]. This possible link between ischemia-induced actin cytoskeletal alterations and surface membrane structural and functional abnormalities is suggested by several lines. First, the actin cytoskeleton is known to play fundamental roles in surface membrane formation and stability, junctional complex formation and regulation, Golgi structure and function, and cell–extracellular membrane attachment [2,4,5,8]. Second, proximal tubule cell actin cytoskeleton is extremely sensitive to ischemia and ATP depletion [9,10]. Third, there is a strong correlation between the time course of actin and surface membrane alterations during ischemia or ATP depletion [2,9,10]. Finally, many of the characteristic surface membrane changes

RELATIONSHIP BETWEEN THE CLINICAL AND CELLULAR PHASES OF ISCHEMIC ACUTE RENAL FAILURE Clinical Phases

Cellular Phases

Prerenal azotemia ↓ Initiation ↓ Maintenance ↓ Recovery

Vascular and cellular adaptation ↓ ATP depletion, cell injury ↓ Repair, migration, apoptosis, proliferation ↓ Cellular differentiation

induced by ischemia can be mimicked by F-actin disassembly mediated by cytochalasin D [11]. Although these correlations are highly suggestive of a central role for actin alterations in the pathophysiology of ischemia-induced surface membrane damage they fall short in providing mechanistic data that directly relate actin cytoskeletal changes to cell injury. Proximal tubule cell injury during ischemia is also known to be principally responsible for the reduction in GFR. Figure 13-5 illustrates the three known pathophysiologic mechanisms that relate proximal tubule cell injury to a reduction in GFR. Particularly important is the role of the cytoskeleton in mediating these three mechanisms of reduced GFR. First, loss of apical membrane into the lumen and detachment of PTC result in substrate for cast formation. Both events have been related to actin cytoskeletal and integrin polarity alterations [12–15]. Cell detachment and the loss of integrin polarity are felt to play a central role in tubular obstruction (Fig. 13-6). Actin cytoskeletalmediated tight junction opening during ischemia occurs and results in back-leak of glomerular filtrate into the blood. This results in ineffective glomerular filtration (Fig. 13-7). Finally, abnormal proximal sodium ion reabsorption results in large distal tubule sodium delivery and a reduction in GFR via tubuloglomerular feedback mechanisms [2,16,17]. In summary, ischemia-induced alterations in proximal tubule cell surface membrane structure and function are in large part responsible for cell and organ dysfunction. Actin cytoskeletal dysregulation during ischemia has been shown to be responsible for much of the surface membrane structural damage. FIGURE 13-1 Relationship between the clinical and cellular phases of ischemic acute renal failure. Prerenal azotemia results from reduced renal blood flow and is associated with reduced organ function (decreased glomerular filtration rate), but cellular integrity is maintained through vascular and cellular adaptive responses. The initiation phase occurs when renal blood flow decreases to a level that results in severe cellular ATP depletion that, in turn, leads to acute cell injury. Severe cellular ATP depletion causes a constellation of cellular alterations culminating in proximal tubule cell injury, cell death, and organ dysfunction [2]. During the clinical phase known as maintenance, cells undergo repair, migration, apoptosis, and proliferation in an attempt to re-establish and maintain cell and tubule integrity [3]. This cellular repair and reorganization phase results in slowly improving cell and organ function. During the recovery phase, cell differentiation continues, cells mature, and normal cell and organ function return [18].

Pathophysiology of Ischemic Acute Renal Failure: Cytoskeletal Aspects

A

B

C

D

E

F

MV

ZO

ZA MT

N

x HD ECM

G

x

13.3

FIGURE 13-2 Ischemic acute renal failure in the rat kidney. Light A, B, transmission electron, C, D, and immunofluorescence E, F, microscopy of control renal cortical sections, A, C, E, and after moderate ischemia induced by 25 minutes of renal artery occlusion, B, D, F. Note the extensive loss of apical membrane structure, B, D, in proximal (PT) but not distal tubule cells. This has been shown to correlate with extensive alterations in F-actin as shown by FITC-phalloidin labeling, E, F. G, Drawing of a proximal tubule cell under physiologic conditions. Note the orderly arrangement of the actin cytoskeleton and its extensive interaction with the surface membrane at the zonula occludens (ZO, tight junction) zonula adherens (ZA, occludens junction), interactions with ankyrin to mediate Na+, K+-ATPase [2] stabilization and cell adhesion molecule attachment [5,8]. The actin cytoskeleton also mediates attachment to the extracellular matrix (ECM) via integrins [12,15]. Microtubules (MT) are involved in the polarized delivery of endocytic and exocytic vesicles to the surface membrane. Finally, F-actin filaments bundle together via actin-bundling proteins [19] to mediate amplification of the apical surface membrane via microvilli (MV). The actin bundle attaches to the surface membrane by the actin-binding proteins myosin I and ezrin [19,20].

13.4

Acute Renal Failure

Proximal tubule cell

ADP +P 1

ATP + K

Ischemia

D

d ate nti e r iffe

+ Na + ADP K ATP

Recovery

Inj

ure

d

Na+ + K ATP

+P 1

Death

Apoptosis

ADP +P 1

ECM Na+

d Un

d ate nti e r iffe

ISCHEMIA INDUCED PROXIMAL TUBULE CELL ALTERATIONS Alterations Surface Membrane Alterations 1. Microvilli fusion, internalization, fragmentation and luminal shedding resulting in loss of surface membrane area and tubular obstruction 2. Loss of surface membrane polarity for lipids and proteins 3. Junctional complex dissociation with unregulated paracellular permeability (backleak) 4. Reduced PTC vectorial transport Actin Cytoskeletal Alterations 1. Polymerization of actin throughout the cell cytosol 2. Disruption and delocalization of F-actin structures including stress fibers, cortical actin and the junctional ring 3. Accumulation of intracellular F-actin aggregates containing surface membrane proteins—myosin I, the tight junction proteins ZO-1, ZO-2, cingulin 4. Disruption and dissociation of the spectrin cytoskeleton 5. Disruption of microtubules during early reflow in vivo 6. The cytoskeleton of proximal tubule cells, as compared to distal tubule cells, is more sensitive to ischemia in vivo and ATP depletion in vitro

Necrosis

References [21] [2,22,23] [6,24–27] [28] [6,16,29] [2,7,16] [20,30] [31,32] [33] [6,16,34]

FIGURE 13-3 Fate of an injured proximal tubule cell. The fate of a proximal tubule cell after an ischemic episode depends on the extent and duration of the ischemia. Cell death can occur immediately via necrosis or in a more programmed fashion (apoptosis) hours to days after the injury. Fortunately, most cells recover either in a direct fashion or via an intermediate undifferentiated cellular pathway. Again, the severity of the injury determines the route taken by a particular cell. Adjacent cells are often injured to varying degrees, especially during mild to moderate ischemia. It is believed that the rate of organ functional recovery relates directly to the severity of cell injury during the initiation phase. ECM—extracellular membrane; Na+—sodium ion; K+—potassium ion; P1—phosphate.

FIGURE 13-4 Ischemia induced proximal tubule cell alterations.

13.5

Pathophysiology of Ischemic Acute Renal Failure: Cytoskeletal Aspects

Efferent arteriole

Glomerular plasma flow

Glomerular hydrostatic pressure

Glomerular filtration

Intratubular pressure

B

Afferent arteriolar constriction

Glomerular pressure

C

D Obstruction

Obstructing cast

Backleak

Leakage of filtrate

D RG

RGD

RG D

Afferent arteriole

FIGURE 13-5 Mechanisms of proximal tubule cell—mediated reductions in glomerular filtration rate (GFR) following ischemic injury. A, GFR depends on four factors: 1) adequate blood flow to the glomerulus; 2) an adequate glomerular capillary pressure as determined by afferent and efferent arteriolar resistance; 3) glomerular permeability; and 4) low intratubular pressure. B, Afferent arteriolar constriction diminishes GFR by reducing blood flow—and, therefore, glomerular capillary pressure. This occurs in response to a high distal sodium delivery and is mediated by tubular glomerular feedback. C, Obstruction of the tubular lumen by cast formation increases tubular pressure and, when it exceeds glomerular capillary pressure, a marked decrease or no filtration occurs. D, Back-leak occurs when the paracellular space between cells is open for the flux of glomerular filtrate to leak back into the extracellular space and into the blood stream. This is believed to occur through open tight junctions.

D RG

D RG

Normal

D RG

A

RGD

B

A

FIGURE 13-6 Overview of potential therapeutic effects of cyclic integrin-binding peptides. A, During ischemic injury, tubular obstruction occurs as a result of loss of apical membrane, cell contents, and detached cells released into the lumen. B, Also, basolateral integrins diffuse to the apical region of the cell. Biotinylated cyclic peptides containing the sequence cRGDDFV bind to desquamated cells in the ascending limb of the loop of Henle and in proximal tubule cells in ischemic rat kidneys. The desquamated cells can adhere to injured cells or aggregate, causing tubule obstruction. (Continued on next page)

13.6

Acute Renal Failure

cRGDDFLG

1400

x

x

cRGDDFV

cRDADFV Control

1200

GFR, µl/min

1000

x

800

*** x

** x

Day 2

Day 3

* ** x

600

FIGURE 13-6 (Continued) C, When cyclic peptides that contain the RGD canonical binding site of integrins are perfused intra-arterially, the peptides ameliorate the extent of acute renal failure, as demonstrated by a higher glomerular filtration rate (GFR) in rats receiving peptide containing the RGD sequence. B, Proposed mechanism of renal protection by cyclic RGD peptides. By adhering to the RGD binding sites of the integrins located on the apical plasma membrane or distributed randomly on desquamated cells, the cyclic peptide blocks cellular aggregation and tubular obstruction [12–15]. (Courtesy of MS Goligorski, MD.)

400 200 0

C

0

Pre-Op

Day 1

TER vs. Time

80

ATP depleted ATP depleted

70

Control

Repletion buffer added

TER, Ω -cm2

60 50 40 30 20 10

A

0 0

C

10

20

30

40 Time,min

60

90

120

150

FIGURE 13-7 Functional and morphologic changes in tight junction integrity associated with ischemic injury or intracellular ATP depletion. A and B, Ruthenium red paracellular permeability in rat proximal tubules. A, In control kidneys, note the electron-dense staining of the brush border, which cuts off at the tight junctions (tj, arrows). B, Sections from a perfusion-fixed kidney after 20 minutes of renal artery crossclamp [35]. The electron-dense staining can be seen at cell contact sites beyond the tight junction (arrows). The paracellular pathway is no longer sealed by the tight junction, permitting backleak of the electron-dense ruthenium red. C, Changes in the transepithelial resistance (TER) versus time during ATP depletion and ATP repletion [36]. Paracellular resistance to electron movement (Continued on next page)

B

Pathophysiology of Ischemic Acute Renal Failure: Cytoskeletal Aspects

D

E

13.7

FIGURE 13-7 (Continued) (the TER falls to zero with ATP depletion). The cellular junctional complex that controls the TER is the tight junction. When the TER falls to zero, this suggests that tight junction structural integrity has been compromised. D and E, Staining of renal epithelial cells with antibodies that bind to a component of the tight junction, ZO-1 [37]. D, ZO-1 staining in untreated Mardin-Darby carnine kidney (MDCK) cells. ZO-1 is located at the periphery of cells at cell contact sites, forming a continuous linear contour. E, In ATP–depleted cells the staining pattern is discontinuous. F and G, Ultrastructural analysis of the tight junction in MDCK cells. In untreated MDCK cells, electron micrographs of the tight junction shows a continuous ridge like structure in freeze fracture preparations [38]. In ATP depleted cells the strands are disrupted, forming aggregates (arrows). Note that the continuous strands are no longer present and large gaps are observable.

F

G

Acknowledgment These studies were in part supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grants DK 41126 (BAM) and DK4683 (RB) and by an American Heart

Association Established Investigator Award (BAM), a VA Merrit Review Grant (BAM), and a NKF Clinical Scientist Award (RB).

13.8

Acute Renal Failure

References 1.

~o F, Pascual J, Madrid Acute Renal Failure Study Group: Lian Epidemiology of acute renal failure: A prospective, multicenter, community-based study. Kidney Int 1996, 50:811–818.

2.

Molitoris BA, Wagner MC: Surface membrane polarity of proximal tubular cells: Alterations as a basis for malfunction. Kidney Int 1996, 49:1592–1597.

3.

Thadhani R, Pascual M, Bonventre JV: Acute renal failure. N Engl J Med 1996, 334:1448–1457.

4.

Drubin DG, Nelson WJ: Origins of cell polarity. Cell 1996, 84:335–344.

5.

Mays RW, Nelson WJ, Marrs JA: Generation of epithelial cell polarity: Roles for protein trafficking, membrane-cytoskeleton, and E-cadherin–mediated cell adhesion. Cold Spring Harbor Symposia on Quantitative Biol 1995, 60:763–773.

6.

7.

8.

Bacallao R, Garfinkel A, Monke S, et al.: ATP depletion: A novel method to study junctional properties in epithelial tissues. I. Rearrangement of the actin cytoskeleton. J Cell Sci 1994, 107:3301–3313. Kroshian VM, Sheridan AM, Lieberthal W: Functional and cytoskeletal changes induced by sublethal injury in proximal tubular epithelial cells. Am J Physiol 1994, F21–F30. Fish EM, Molitoris BA: Alterations in epithelial polarity and the pathogenesis of disease states. N Engl J Med 1994, 330:1580–1588.

9.

Glaumann B, Glauman H, Berezesky IK, et al.: Studies on the cellular recovery from injury II. Ultrastructural studies on the recovery of the pars convoluta of the proximal tubule of the rat kidney from temporary ischemia. Virchows Arch B 1977, 24:1–18. 10. Kellerman PS, Norenberg SL, Jones GM: Early recovery of the actin cytoskeleton during renal ischemic injury in vivo. Am J Kidney Dis 1996, 16:33–42.

11. Kellerman PS, Clark RAF, Hoilien CA, et al.: Role of microfilaments in the maintenance of proximal tubule structural and functional integrity. Am J Physiol 1990, 259:F279–F285. 12. Noiri E, Gailit J, Gurrath M, et al.: Cyclic RGD peptides ameliorate ischemic acute renal failure in rats. Kidney Int 1994, 46:1050–1058. 13. Noiri E, Goligorsky MS, Som P: Radiolabeled RGD peptides as diagnostic tools in acute renal failure and tubular obstruction. J Am Soc Nephrol 1996, 7:2682–2688. 14. Romanov V, Noiri E, Czerwinski G, et al.: Two novel probes reveal tubular and vascular RGD binding sites in the ischemic rat kidney. Kidney Int 1997, 52:92–102. 15. Goligorsky MS, Noiri E, Romanov V, et al.: Therapeutic potential of RGD peptides in acute renal failure. Kidney Int 1997, 51:1487–1493. 16. Molitoris BA, Dahl R, Geerdes AE: Cytoskeleton disruption and apical redistribution of proximal tubule Na+,K+-ATPase during ischemia. Am J Physiol 1992, 263:F488–F495. 17. Alejandro V, Scandling JD, Sibley RK, et al.: Mechanisms of filtration failure during postischemic injury of the human kidney: A study of the reperfused renal allograft. J Clin Invest 1995, 95:820–831. 18. Bacallao R, Fine LG: Molecular events in the organization of renal tubular epithelium: From nephrogenesis to regeneration. Am J Physiol 1989, 257:F913–F924. 19. Molitoris BA: Putting the actin cytoskeleton into perspective: pathophysiology of ischemic alterations. Am J Physiol 1997, 272:F430–F433.

20. Wagner MC, Molitoris BA: ATP depletion alters myosin Ib cellular location in LLC-PK1 cells. Am J Physiol 1997, 272:C1680–C1690. 21. Venkatachalam MA, Jones DB, Rennke HG, et al.: Mechanism of proximal tubule brush border loss and regeneration following mild ischemia. Lab Invest 1981, 45:355–365. 22. Ritter D, Dean AD, Guan ZH, et al.: Polarized distribution of renal natriuretic peptide receptors in normal physiology and ischemia. Am J Physiol 1995, 269:F918–F925. 23. Alejandro VSJ, Nelson WJ, Huie P, et al.: Postischemic injury, delayed function and Na+/K+-ATPase distribution in the transplanted kidney. Kidney Int 1995, 48:1308–1315. 24. Donohoe JF, Venkatachalam MA, Benard DB, et al.: Tubular leakage and obstruction after renal ischemia: Structural-functional correlations. Kidney Int 1978, 13:208–222. 25. Molitoris BA, Falk SA, Dahl RH: Ischemic-induced loss of epithelial polarity. Role of the tight junction. J Clin Invest 1989, 84:1334–1339. 26. Mandel LJ, Bacallao R, Zampighi G: Uncoupling of the molecular fence and paracellular gate functions in epithelial tight junctions. Nature 1993, 361:552–555. 27. Kwon O, Nelson J, Sibley RK, et al.: Backleak, tight junctions and cell-cell adhesion in postischemic injury to the renal allograft (Abstract). J Am Soc Nephrol 1996, 7:A2907. 28. Molitoris BA. Na+-K+-ATPase that redistributes to apical membrane during ATP depletion remains functional. Am J Physiol 1993, 265:F693–F597. 29. Kellerman PS: Exogenous adenosine triphosphate (ATP) proximal tubule microfilament structure and function in vivo in a maleic acid model of ATP depletion. J Clin Invest 1993, 92:1940–1949. 30. Tsukamoto T, Nigam SK: ATP depletion causes tight junction proteins to form large, insoluble complexes with cytoskeletal proteins in renal epithelial cells. J Biol Chem 1997, 273:F463–F472. 31. Molitoris BA, Dahl R, Hosford M: Cellular ATP depletion induces disruption of the spectrin cytoskeletal network. Am J Physiol 1996, 271:F790–F798. 32. Edelstein CL, Ling H, Schrier RW: The nature of renal cell injury. Kidney Int 1997, 51:1341–1351. 33. Abbate M, Bonventre JV, Brown D: The microtubule network of renal epithelial cells is disrupted by ischemia and reperfusion. Am J Physiol 1994, 267:F971–F978. 34. Sheridan AM, Schwartz JH, Kroshian VM, et al.: Renal mouse proximal tubular cells are more susceptible than MDCK cells to chemical anoxia. Am J Physiol 1993, 265:F342–F350. 35. Molitoris BA, Falk SA, Dahl RH: Ischemia-induced loss of epithelial polarity. Role of the tight junction. J Clin Invest 1989, 84:1334–1339. 36. Doctor RB, Bacallao R, Mandel LJ: Method for recovering ATP content and mitochondrial function after chemical anoxia in renal cell cultures. Am J Physiol 1994, 266:C1803–C1811. 37. Stevenson BR, Siliciano JD, Mooseker MS, et al.: Identification of ZO-1: A high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia. J Cell Biol 1986, 103:755–766. 38. Mandel LJ, Bacallao R, Zampighi G: Uncoupling of the molecular ‘fence’ and paracellular ‘gate’ functions in epithelial tight junctions. Nature 1993, 361:552–555.

Pathophysiology of Ischemic Acute Renal Failure Michael S. Goligorsky Wilfred Lieberthal

A

cute renal failure (ARF) is a syndrome characterized by an abrupt and reversible kidney dysfunction. The spectrum of inciting factors is broad: from ischemic and nephrotoxic agents to a variety of endotoxemic states and syndrome of multiple organ failure. The pathophysiology of ARF includes vascular, glomerular and tubular dysfunction which, depending on the actual offending stimulus, vary in the severity and time of appearance. Hemodynamic compromise prevails in cases when noxious stimuli are related to hypotension and septicemia, leading to renal hypoperfusion with secondary tubular changes (described in Chapter 13). Nephrotoxic offenders usually result in primary tubular epithelial cell injury, though endothelial cell dysfunction can also occur, leading to the eventual cessation of glomerular filtration. This latter effect is a consequence of the combined action of tubular obstruction and activation of tubuloglomerular feedback mechanism. In the following pages we shall review the existing concepts on the phenomenology of ARF including the mechanisms of decreased renal perfusion and failure of glomerular filtration, vasoconstriction of renal arterioles, how formed elements gain access to the renal parenchyma, and what the sequelae are of such an invasion by primed leukocytes.

CHAPTER

14

14.2

Acute Renal Failure

Vasoactive Hormones Ischemic or toxic insult Tubular injury and dysfunction

Hemodynamic changes

Afferent arteriolar vasoconstriction

Mesangial contraction

Reduced GPF and P

Reduced glomerular filtration surface area available for filtration and a fall in Kf

Reduced tubular reabsorption of NaCl

Increased delivery of NaCl to distal nephron (macula densa) and activation of TG feedback

FIGURE 14-1 Pathophysiology of ischemic and toxic acute renal failure (ARF). The severe reduction in glomerular filtration rate (GFR) associated with established ischemic or toxic renal injury is due to the combined effects of alterations in intrarenal hemodynamics and tubular injury. The hemodynamic alterations associated with ARF include afferent arteriolar constriction and mesangial contraction, both of

Ischemic or toxic injury to the kidney Increase in vasoconstrictors

Deficiency of vasodilators

Angiotensin II Endothelin Thromboxane Adenosine Leukotrienes Platelet-activating factor

PGI2 EDNO

Imbalance in vasoactive hormones causing persistent intrarenal vasoconstriction Persistent medullary hypoxia

Backleak of glomerular filtrate

Backleak of urea, creatinine, and reduction in "effective GFR"

Tubular obstruction

Compromises patency of renal tubules and prevents the recovery of renal function

which directly reduce GFR. Tubular injury reduces GFR by causing tubular obstruction and by allowing backleak of glomerular filtrate. Abnormalities in tubular reabsorption of solute may contribute to intrarenal vasoconstriction by activating the tubuloglomerular (TG) feedback system. GPF—glomerular plasmaflow; P—glomerular pressure; Kf— glomerular ultrafiltration coefficient.

FIGURE 14-2 Vasoactive hormones that may be responsible for the hemodynamic abnormalities in acute tubule necrosis (ATN). A persistent reduction in renal blood flow has been demonstrated in both animal models of acute renal failure (ARF) and in humans with ATN. The mechanisms responsible for the hemodynamic alterations in ARF involve an increase in the intrarenal activity of vasoconstrictors and a deficiency of important vasodilators. A number of vasoconstrictors have been implicated in the reduction in renal blood flow in ARF. The importance of individual vasoconstrictor hormones in ARF probably varies to some extent with the cause of the renal injury. A deficiency of vasodilators such as endotheliumderived nitric oxide (EDNO) and/or prostaglandin I2 (PGI2) also contributes to the renal hypoperfusion associated with ARF. This imbalance in intrarenal vasoactive hormones favoring vasoconstriction causes persistent intrarenal hypoxia, thereby exacerbating tubular injury and protracting the course of ARF.

14.3

Pathophysiology of Ischemic Acute Renal Failure

Glomerular basement membrane Glomerular capillary endothelial cells

M Glomerular epithelial cells

M Mesangial cell contraction Angiotensin II Endothelin–1 Thromboxane Sympathetic nerves

FIGURE 14-3 The mesangium regulates single-nephron glomerular filtration rate (SNGFR) by altering the glomerular ultrafiltration coefficient (Kf). This schematic diagram demonstrates the anatomic relationship between glomerular capillary loops and the mesangium. The mesangium is surrounded by capillary loops. Mesangial cells (M) are specialized pericytes with contractile elements that can respond to vasoactive hormones. Contraction of mesangium can close and prevent perfusion of anatomically associated glomerular capillary loops. This decreases the surface area available for glomerular filtration and reduces the glomerular ultrafiltration coefficient.

Mesangial cell relaxation Prostacyclin EDNO

Afferent arteriole Periportal cell Extraglomerular mesangial cells Macula densa cells

FIGURE 14-4 A, The topography of juxtaglomerular apparatus (JGA), including macula densa cells (MD), extraglomerular mesangial cells (EMC), and afferent arteriolar smooth muscle cells (SMC). Insets schematically illustrate, B, the structure of JGA; C, the flow of information within the JGA; and D, the putative messengers of tubuloglomerular feedback responses. AA—afferent arteriole; PPC—peripolar cell; EA—efferent arteriole; GMC—glomerular mesangial cells. (Modified from Goligorsky et al. [1]; with permission.)

Glomerus

A

AA AA

AA

MD

MD

SMC+GC

G

GMC

GMC

EA

C

G

EMC G

EMC

GMC

EA

B

PPC

PPC

PPC EMC

MD

D

Chloride Adenosine PGE2 Angiotensin Nitric oxide Osmolarity Unknown?

EA

14.4

Acute Renal Failure

The normal tubuloglomerular (TG) feedback mechanism 4. Afferent arteriolar and mesangial contraction reduce SNGFR back toward control levels.

3. Renin is released from specialized cells of JGA and the intrarenal renin angiotensin system generates release of angiotensin II locally.

2. The composition of filtrate passing the macula densa is altered and stimulates the JGA.

1. SNGFR increases causing increase in delivery of solute to the distal nephron.

A

Role of TG feedback in ARF 4. Afferent arteriolar and mesangial contraction reduce SNGFR below normal levels.

1. Renal epithelial cell injury reduces reabsorption of NaCl by proximal tubules.

B

3. Local release of angiotensin II is stimulated.

2. The composition of filtrate passing the macula densa is altered and stimulates the JGA.

FIGURE 14-5 The tubuloglomerular (TG) feedback mechanism. A, Normal TG feedback. In the normal kidney, the TG feedback mechanism is a sensitive device for the regulation of the single nephron glomerular filtration rate (SNGFR). Step 1: An increase in SNGFR increases the amount of sodium chloride (NaCl) delivered to the juxtaglomerular apparatus (JGA) of the nephron. Step 2: The resultant change in the composition of the filtrate is sensed by the macula densa cells and initiates activation of the JGA. Step 3: The JGA releases renin, which results in the local and systemic generation of angiotensin II. Step 4: Angiotensin II induces vasocontriction of the glomerular arterioles and contraction of the mesangial cells. These events return SNGFR back toward basal levels. B, TG feedback in ARF. Step 1: Ischemic or toxic injury to renal tubules leads to impaired reabsorption of NaCl by injured tubular segments proximal to the JGA. Step 2: The composition of the filtrate passing the macula densa is altered and activates the JGA. Step 3: Angiotensin II is released locally. Step 4: SNGFR is reduced below normal levels. It is likely that vasoconstrictors other than angiotensin II, as well as vasodilator hormones (such as PGI2 and nitric oxide) are also involved in modulating TG feedback. Abnormalities in these vasoactive hormones in ARF may contribute to alterations in TG feedback in ARF.

Pathophysiology of Ischemic Acute Renal Failure

FIGURE 14-6 Metabolic basis for the adenosine hypothesis. A, Osswald’s hypothesis on the role of adenosine in tubuloglomerular feedback. B, Adenosine metabolism: production and disposal via the salvage and degradation pathways. (A, Modified from Osswald et al. [2]; with permission.)

Osswald's Hypothesis Increased ATP hydrolysis (increased distal Na+ load) Increased generation of adenosine Activation of JGA

Afferent arteriolar vasoconstriction Nerve endings

[Na+]

Na+

ATP Adenosine

Adenosine

↓ Renin secretion

Renincontaining cells

ANG II Vascular smooth muscle

–

[Cl ]

↓ GFR

ANG I Signal Transmission

Mediator(s)

Effects

A

Adenosine nucleotide metabolism ATP

ADP

AMP

Adenosine

A2

Receptors Transporter

5'nu cle

ot id a

se

se AD Pa

AT Pas

e

A1

Phosphorylation or degradation

ATP

ADP

AMP Salvage pathway

B

14.5

Adenosine

Inosine

Hypoxanthine

Degradation pathway Uric acid

Xanthine

14.6

Acute Renal Failure FIGURE 14-7 Elevated concentration of adenosine, inosine, and hypoxanthine in the dog kidney and urine after renal artery occlusion. (Modified from Miller et al. [3]; with permission.)

Adenosine, nmoles/mL

20 15 10 5

Hypoxanthine, nmoles/mL

Inosine, nmoles/mL

0 25 20 15 10 5 0 30 25 20 15 10 5 0 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

Volume collected, mL

Post Ischemia Glomerul I SNGFR: 17.4±1.7 nL/min PFR: 66.6±5.6 nL/min

B

A

Anti-endothelin

Glomeruli II SNGFR: 27.0±3.1 nL/min PFR: 128.7±14.4 nL/min

FIGURE 14-8 Endothelin (ET) is a potent renal vasoconstrictor. Endothelin (ET) is a 21 amino acid peptide of which three isoforms—ET-1, ET-2 and ET-3—have been described, all of which have been shown to be present in renal tissue. However, only the effects of ET-1 on the kidney have been clearly elucidated. ET-1 is the most potent vasoconstrictor known. Infusion of ET-1 into the kidney induces profound and long lasting vasoconstriction of the renal circulation. A, The appearance of the rat kidney during the infusion of ET-1 into the inferior branch of the main renal artery. The lower pole of the kidney perfused by this vessel is profoundly vasoconstricted and hypoperfused. B, Schematic illustration of function in separate populations of glomeruli within the same kidney. The entire kidney underwent 25 minutes of ischemia 48 hours before micropuncture. Glomeruli I are nephrons not exposed to endothelin antibody; Glomeruli II are nephrons that received infusion with antibody through the inferior branch of the main renal artery. SNGFR—single nephron glomerular filtration rate; PFR—glomerular renal plasma flow rate. (From Kon et al. [4]; with permission.)

Pathophysiology of Ischemic Acute Renal Failure

FIGURE 14-9 Biosynthesis of mature endothelin-1 (ET-1). The mature ET-1 peptide is produced by a series of biochemical steps. The precursor of active ET is pre-pro ET, which is cleaved by dibasic pairspecific endopeptidases and carboxypeptidases to yield a 39–amino acid intermediate termed big ET-1. Big ET-1, which has little vasoconstrictor activity, is then converted to the mature 21–amino acid ET by a specific endopeptidase, the endothelinconverting enzyme (ECE). ECE is localized to the plasma membrane of endothelial cells. The arrows indicate sites of cleavage of pre-pro ET and big ET.

Pre–proendothelin–1 NH2

COOH 53

74

92

Lys–Arg

14.7

203

Arg–Arg Dibasic pair–specific endopeptidase(s)

Big endothelin COOH

NH3

Trp–Val

Leu Ser Ser Cys Ser Cys Met

Endothelin converting enzyme (ECE)

NH3

Asp

Mature endothelin

Lys Glu

Cys Val Tyr Phe Cys His Leu Asp Ile

Ile Trp COOH

ET

Plasma Mature ET

ETB receptor

E EC Endothelium

NO

PGI2

Cyclic GMP

Cyclic AMP

ECE

Mature ET ETA receptor

ETB receptor

Vascular smooth muscle Vasoconstriction

Vasodilation

FIGURE 14-10 Regulation of endothelin (ET) action; the role of the ET receptors. Pre-pro ET is produced and converted to big ET. Big ET is converted to mature, active ET by endothelin-converting enzyme (ECE) present on the endothelial cell membrane. Mature ET secreted onto the basolateral aspect of the endothelial cell binds to two ET receptors (ETA and ETB); both are present on vascular smooth muscle (VSM) cells. Interaction of ET with predominantly expressed ETA receptors on VSM cells induces vasoconstriction. ETB receptors are predominantly located on the plasma membrane of endothelial cells. Interaction of ET-1 with these endothelial ETB receptors stimulates production of nitric oxide (NO) and prostacyclin by endothelial cells. The production of these two vasodilators serves to counterbalance the intense vasoconstrictor activity of ET-1. PGI2—prostaglandin I2.

14.8

Acute Renal Failure

Ischemia

Number of rats

10

Vehicle BQ123

BQ123(0.1mg/kg • min, for 3h)

8 6 4 2 0

A

Basal

GFR, mL/h

150

24h control

1

2

3

4

5

6

14

4

5

6

14

4

5

6

14

Ischemia

120

BQ123(0.1mg/kg • min, for 3h)

90 60 30 0

Plasma K+, mEq/L

B

Basal 10

24h control

Ischemia

8

1

2

3

FIGURE 14-11 Endothelin-1 (ET-1) receptor blockade ameliorates severe ischemic acute renal failure (ARF) in rats. The effect of an ETA receptor antagonist (BQ123) on the course of severe postischemic ARF was examined in rats. BQ123 (light bars) or its vehicle (dark bars) was administered 24 hours after the ischemic insult and the rats were followed for 14 days. A, Survival. All rats that received the vehicle were dead by the 3rd day after ischemic injury. In contrast, all rats that received BQ123 post-ischemia survived for 4 days and 75% recovered fully. B, Glomerular filtration rate (GFR). In both groups of rats GFR was extremely low (2% of basal levels) 24 hours after ischemia. In BQ123-treated rats there was a gradual increase in GFR that reached control levels by the 14th day after ischemia. C, Serum potassium. Serum potassium increased in both groups but reached significantly higher levels in vehicle-treated compared to the BQ123-treated rats by the second day. The severe hyperkalemia likely contributed to the subsequent death of the vehicle treated rats. In BQ123-treated animals the potassium fell progressively after the second day and reached normal levels by the fourth day after ischemia. (Adapted from Gellai et al. [5]; with permission.)

BQ123(0.1mg/kg • min, for 3h)

6 4 2 0 Basal

C

24h control

1

2

3

Posttreatment days

Lipid Membrane

Phospholipase A2 Arachidonic acid NSAID

Cycloxygenase PGG2 Prostaglandin intermediates Thromboxane TxA2

PGH2

PGF2

PGI2 Prostacyclin

PGE2

FIGURE 14-12 Production of prostaglandins. Arachidonic acid is released from the plasma membrane by phospholipase A2. The enzyme cycloxygenase catalyses the conversion of arachidonate to two prostanoid intermediates (PGH2 and PGG2). These are converted by specific enzymes into a number of different prostanoids as well as thromboxane (TXA2). The predominant prostaglandin produced varies with the cell type. In endothelial cells prostacyclin (PGI2) (in the circle) is the major metabolite of cycloxygenase activity. Prostacyclin, a potent vasodilator, is involved in the regulation of vascular tone. TXA2 is not produced in endothelial cells of normal kidneys but may be produced in increased amounts and contribute to the pathophysiology of some forms of acute renal failure (eg, cyclosporine A–induced nephrotoxicity). The production of all prostanoids and TXA2 is blocked by nonsteroidal anti-inflammatory agents (NSAIDs), which inhibit cycloxygenase activity.

Pathophysiology of Ischemic Acute Renal Failure

FIGURE 14-13 Endothelin (ET) receptor blockade ameliorates acute cyclosporineinduced nephrotoxicity. Cyclosporine A (CSA) was administered intravenously to rats. Then, an ET receptor anatgonist was infused directly into the right renal artery. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were reduced by the CSA in the left kidney. The ET receptor antagonist protected GFR and RPF from the effects of CSA on the right side. Thus, ET contributes to the intrarenal vasoconstriction and reduction in GFR associated with acute CSA nephrotoxicity. (From Fogo et al. [6]; with permission.)

Aorta

Intra–arterial infusion of ETA receptor antagonist

Cyclosporine A in circulation

CSA

Right renal artery

Left renal artery

GFR and RPF: near normal

GFR and RPF: Reduced 20-25% below normal

Right kidney

Left kidney

Normal basal state Circulating levels of vasoconstrictors: Low Afferent arteriolar tone normal Intrarenal levels of prostacyclin: Low

Intraglomerular  P normal

A

GFR normal Intravascular volume depletion Circulating levels of vasoconstrictors: High Afferent arteriolar tone normal or mildly reduced Intrarenal levels of prostacyclin: High Intraglomerular  P normal or mildly reduced

B

GFR normal or mildly reduced Intravascular volume depletion and NSAID administration Circulating levels of vasoconstrictors: High Afferent arteriolar tone severely increased Intrarenal levels of prostacyclin: Low

C

14.9

Intraglomerular  P severely reduced

GFR severely reduced

FIGURE 14-14 Prostacyclin is important in maintaining renal blood flow (RBF) and glomerular filtration rate (GFR) in “prerenal” states. A, When intravascular volume is normal, prostacyclin production in the endothelial cells of the kidney is low and prostacyclin plays little or no role in control of vascular tone. B, The reduction in absolute or “effective” arterial blood volume associated with all prerenal states leads to an increase in the circulating levels of a number of of vasoconstrictors, including angiotensin II, catecholamines, and vasopressin. The increase in vasoconstrictors stimulates phospholipase A2 and prostacyclin production in renal endothelial cells. This increase in prostacyclin production partially counteracts the effects of the circulating vasoconstrictors and plays a critical role in maintaining normal or nearly normal RBF and GFR in prerenal states. C, The effect of cycloxygenase inhibition with nonsteroidal anti-inflammatory drugs (NSAIDs) in prerenal states. Inhibition of prostacyclin production in the presence of intravascular volume depletion results in unopposed action of prevailing vasoconstrictors and results in severe intrarenal vascasoconstriction. NSAIDs can precipitate severe acute renal failure in these situations.

14.10

Acute Renal Failure

A. VASODILATORS USED IN EXPERIMENTAL ACUTE RENAL FAILURE (ARF)

Vasodilator

ARF Disorder

Time Given in Relation to Induction

Propranolol

Ischemic

Before, during, after

Phenoxybenzamine Clonidine Bradykinin Acetylcholine Prostaglandin E1 Prostaglandin E2 Prostaglandin I2 Saralasin Captopril Verapamil Nifedipine Nitrendipine Diliazem Chlorpromazine Atrial natriuretic peptide

Toxic Ischemic Ischemic Ischemic Ischemic Ischemic, toxic Ischemic Toxic, ischemic Toxic, ischemic Ischemic, toxic Ischemic Toxic Toxic Toxic Ischemic, toxic

Before, during, after After Before, during Before, after After Before, during Before, during, after Before Before Before, during, after Before Before, during Before, during, after Before After

Observed Effect ↓Scr, BUN if given before, during; no effect if given after Prevented fall in RBF ↓Scr, BUN ↑RBF, GFR ↑RBF; no change in GFR ↑RBF; no change in GFR ↑GFR ↑GFR ↑RBF; no change in Scr, BUN ↑RBF; no change in Scr, BUN ↑RBF, GFR in most studies ↑GFR ↑GFR ↑GFR; ↓recovery time ↑GFR; ↓recovery time ↑RBF, GFR

BUN—blood urea nitrogen; GFR—glomerular filtration rate; RBF—renal blood flow; Scr–serum creatinine.

B. VASODILATORS USED TO ALTER COURSE OF CLINICAL ACUTE RENAL FAILURE (ARF) Vasodilator

ARF Disorder

Observed Effect

Remarks

Dopamine Phenoxybenzamine Phentolamine Prostaglandin A1 Prostaglandin E1 Dihydralazine Verapamil Diltiazem Nifedipine Atrial natriuretic peptide

Ischemic, toxic Ischemic, toxic Ischemic, toxic Ischemic Ischemic Ischemic, toxic Ischemic Transplant, toxic Radiocontrast Ischemic

Improved V, Scr if used early No change in V, RBF No change in V, RBF No change in V, Scr ↑RBF, no change v, Ccr ↑RBF, no change V, Scr ↑Ccr or no effect ↑Ccr or no effect No effect ↑Ccr

Combined with furosemide

Used with dopamine Used with NE

Prophylactic use

Ccr—creatinine clearance; NE—norepinephrine; RBF—renal blood flow; Scr—serum creatinine; V—urine flow rate.

FIGURE 14-15 Vasodilators used in acute renal failure (ARF). A, Vasodilators used in experimental acute ARF. B, Vasodilators used to alter the course of clinical ARF. (From Conger [7]; with permission.)

14.11

Pathophysiology of Ischemic Acute Renal Failure NH2

+

NH2

NH

NADPH NADP+ O2 H 2O

+

NH2

NOH

NH2

+

Modular structure of nitric oxide synthases H BH4 ARG CaM FMN FAD

O

+ 1/ 1 2 NADPH /2 NADP

O2

NH

Target domain

H 2O

NH

Dimerization site(s) 13–14 + • NO

BH4

BH4

Oxygenase domain

NADPH

Reductase domain

18–20

nNOS

2–3

nitric oxide

4–5 6 7–9 10–12 1516–17 16–18 11–12

21–23

24–29

2–3 4 5–7

19–21

22–26

eNOS +

+

COO–

NH3

+

COO–

NH3

G

A L-arginine

N -hydroxy-L-arginine

1

COO–

NH3

L-citrulline

FIGURE 14-16 Chemical reactions leading to the generation of nitric oxide (NO), A, and enzymes that catalize them, B. (Modified from Gross [8]; with permission.)

M iNOS

19–21 2–3 4–5 6 7–9 10–11 13 14–18 2–3 4–8 9–12 Mammalian P450 Reductases Bacterial Flavodoxins Plant Ferredoxin NADPH Reductases B. mega P450 DHF Reductases Mammalian Syntrophins (GLGF Motif) B

L-arginine L-citrulline

Nitric oxide

GTP GC

Smooth muscle

Vasodilatation

cGMP Target cell death Neurotransmission Hemoglobin

CNS and PNS

NO3– + NO2– cGMP

A

Urine excretion

Leukocyte – migration

Endothelium-dependent vasodilators +

– NO•

+ L-Arginine

Platelet aggregation

+ NOS NO•

Nitroglycerin

+ GTP

C

sGC +

+

cGMP Relaxation

ANP pGC

B

DNA damage Activation of apoptotic signal Thiols

mM

Heme- & ironcontaining proteins

µM ROIs

nM

Inhibition of iron-containing enzymes

Immune cells

Shear stress

22–26 13–16

M NO concentration

NOS

8–10 1314–15 12–13

Guanylate cyclase

Time

Cell death Apoptosis Induction of stress proteins Inactivation of enzymes Antioxidant cGMP (cellular signal)

Consequences

FIGURE 14-17 Major organ, A, and cellular, B, targets of nitric oxide (NO). A, Synthesis and function of NO. B, Intracellular targets for NO and pathophysiological consequences of its action. C, Endotheliumdependent vasodilators, such as acetylcholine and the calcium ionophore A23187, act by stimulating eNOS activity thereby increasing endothelium-derived nitric oxide (EDNO) production. In contrast, other vasodilators act independently of the endothelium. Some endothelium-independent vasodilators such as nitroprusside and nitroglycerin induce vasodilation by directly releasing nitric oxide in vascular smooth muscle cells. NO released by these agents, like EDNO, induces vasodilation by stimulating the production of cyclic guanosine monophosphate (cGMP) in vascular smooth muscle (VSM) cells. Atrial natriuretic peptide (ANP) is also an endothelium-independent vasodilator but acts differently from NO. ANP directly stimulates an isoform of guanylyl cyclase (GC) distinct from soluble GC (called particulate GC) in VSM. CNS—central nervous system; GTP—guanosine triphosphate; NOS—nitric oxide synthase; PGC—particulate guanylyl cyclase; PNS—peripheral nervous system; ROI—reduced oxygen intermediates; SGC—soluble guanylyl cyclase. (A, From Reyes et al. [9], with permission; B, from Kim et al. [10], with permission.)

14.12

Acute Renal Failure FIGURE 14-18 Impaired production of endothelium-dependent nitric oxide (EDNO) contributes to the vasoconstriction associated with established acute renal failure (ARF). Ischemia-reperfusion injury in the isolated erythrocyte-perfused kidney induced persistant intarenal vasoconstriction. The endothelium-independent vasodilators (atrial natriuretic peptide [ANP] and nitroprusside) administered during the reflow period caused vasodilation and restored the elevated intrarenal vascular resistance (RVR) to normal. In marked contrast, two endothelium-dependent vasodilators (acetylcholine and A23187) had no effect on renal vascular resistance after ischemia-reflow. These data suggest that EDNO production is impaired following ischemic injury and that this loss of EDNO activity contributes to the vasoconstriction associated with ARF. (Adapted from Lieberthal [11]; with permission.)

Ischemia (I) alone I + ANP I+ nitroprusside I+ Acetylcholine I + A23187 0 20 40 80 60 Increase in RVR above control, %

60

150

O2

BUN Hypoxia

40 P<.001

30

2.5 1.5

Hypoxia + L-Arg P<.05

50 P<.01

Hypoxia

mg/dL

Percent LDH release

O2

P<.001

30

*

1.0

* *

0.5

Control

0

20

30 Time, min

40

50

B

P<.001

50 40 30 NS

20 10 0 Normoxia Hypoxia Wild type mice

Normoxia Hypoxia iNOS knockout mice

SCR

10

S

0

A

Ischemia AS

0

Vehicle

Control

10

LDH release, %

Cr

P<.001

20

C

*

0 3.0

0

40

*

*

50

Control

10

60

100

Hypoxia + L-NAME

P<.001

20

mg/dL

50

FIGURE 14-19 Deleterious effects of nitric oxide (NO) on the viability of renal tubular epithelia. A, Hypoxia and reoxygenation lead to injury of tubular cells (filled circles); inhibition of NO production improves the viability of tubular cells subjected to hypoxia and reoxygenation (triangles in upper graph), whereas addition of L-arginine enhances the injury (triangles in lower graph). B, Amelioration of ischemic injury in vivo with antisense oligonucleotides to the iNOS: blood urea nitrogen (BUN), and creatinine (CR) in rats subjected to 45 minutes of renal ischemia after pretreatment with antisense phosphorothioate oligonucleotides (AS) directed to iNOS or with sense (S) and scrambled (SCR) constructs. C, Resistance of proximal tubule cells isolated from iNOS knockout mice to hypoxia-induced injury. LDH—lactic dehydrogenase. (A, From Yu et al. [12], with permission; B, from Noiri et al. [13], with permission; C, from Ling et al. [14], with permission.)

Pathophysiology of Ischemic Acute Renal Failure

Radiocontrast

Medulla

Cortex Percent of baseline

Iothalamate

100

100

50

50

0

0

Normal kidneys

Iothalamate

200

Compensatory increase in PGI2 and EDNO release

Chronic renal insufficiency

Increased endothelin

Reduced or absent increase in PGI2 or EDNO

150 100

100

50

50 Iothalamate

0

Mild vasoconstriction

Severe vasoconstriction

No loss of GFR

Acute renal failure

0 0

A

14.13

20 40 Minutes No pretreatment (n = 6)

60

0

20 40 Minutes

60

Pretreatment with L-NAME (n = 6)

FIGURE 14-20 Proposed role of nitric oxide (NO) in radiocontrast-induced acute renal failure (ARF). A, Administration of iothalamate, a radiocontrast dye, to rats increases medullary blood flow. Inhibitors of either prostaglandin production (such as the NSAID, indomethacin) or inhibitors of NO synthesis (such as L-NAME) abolish the compensatory increase in medullary blood flow that occurs in response to radiocontrast administration. Thus, the stimulation of prostaglandin and NO production after radiocontrast administration is important in maintaining medullary perfusion and oxygenation after administration of contrast agents. B, Radiocontrast stimulates the production of vasodilators (such as prostaglandin [PGI2] and endothelium-dependent nitric oxide [EDNO]) as well as endothelin and other vasoconstrictors within

B

the normal kidney. The vasodilators counteract the effects of the vasoconstrictors so that intrarenal vasoconstriction in response to radiocontrast is usually modest and is associated with little or no loss of renal function. However, in situations when there is preexisting chronic renal insufficiency (CRF) the vasodilator response to radiocontrast is impaired, whereas production of endothelin and other vasoconstrictors is not affected or even increased. As a result, radiocontrast administration causes profound intrarenal vasoconstriction and can cause ARF in patients with CRF. This hypothesis would explain the predisposition of patients with chronic renal dysfunction, and especially diabetic nephropathy, to contrastinduced ARF. (A, Adapted from Agmon and Brezis [15], with permission; B, from Agmon et al. [16], with permission.)

FIGURE 14-21 Cellular calcium metabolism and potential targets of the elevated cytosolic calcium. A, Pathways of calcium mobilization. B, Pathophysiologic mechanisms ignited by the elevation of cytosolic calcium concentration. (A, Adapted from Goligorsky [17], with permission; B, from Edelstein and Schrier [18], with permission.)

14.14

Acute Renal Failure

*

60 100 *

*

* * *

40 200

* Significant vs. time 0

150

Hypoxia

0

A

60

*

*

300

80

20

10

NS

Post NE Verapamil before NE P<.001

40 P<.05

20 CIn, mL/min

*

Pl stained nuclei, %

Estimated [Ca2+]i , nM

400

Pre NE

0 60 NS

20

40

0

20

30

Time, min

FIGURE 14-22 Pathophysiologic sequelae of the elevated cytosolic calcium (C2+). A, The increase in cytosolic calcium concentration in hypoxic rat proximal tubules precedes the tubular damage as assessed by propidium iodide (PI) staining. B, Administration of calcium channel inhibitor

Verapamil after NE

P<.001

P<.02

0

B

Control

1h

24 h

verapamil before injection of norepinephrine (cross-hatched bars) significantly attenuated the drop in inulin clearance induced by norepinephrine alone (open bars). (A, Adapted from Kribben et al. [19], with permission; B, adapted from Burke et al. [20], with permission.) FIGURE 14-23 Dynamics of heat shock proteins (HSP) in stressed cells. Mechanisms of activation and feedback control of the inducible heat shock gene. In the normal unstressed cell, heat shock factor (HSF) is rendered inactive by association with the constitutively expressed HSP70. After hypoxia or ATP depletion, partially denatured proteins (DP) become preferentially associated with HSC73, releasing HSF and allowing trimerization and binding to the heat shock element (HSE) to initiate the transcription of the heat shock gene. After translation, excess inducible HSP (HSP72) interacts with the trimerized HSF to convert it back to its monomeric state and release it from the HSE, thus turning off the response. (Adapted from Kashgarian [21]; with permission.)

14.15

Pathophysiology of Ischemic Acute Renal Failure

Free Radical Pathways in the Mitochondrion Catalase/GPx complex? Hydrogen H2O 2 peroxide Outer membrane Inner membrane

H 2O 2

O2

Superoxide anion Mn-SOD (tetramer) Matrix

2O2

Hydrogen peroxide

Hydroperoxyl radical –

HO2 HO2

(From glycolysis/ TCA cycle) e–

–

Hepatocyte (and other cells) Golgi complex

O2

Tissue EC–SOD

+ 2H+

Endoplasmic reticulum

Mitochondrion

Secretory vesicle Heparin sulfate proteoglycans

Chromosome (chrom) 4

Manganese superoxide dismatase (Mn-SOD) mRNA

Extracellular superoxide dismutase (EC-SOD) mRNA

Catalase mRNA chrom 11

GPx (tetramer)

Se

chrom 21

H2O+O2 +GSSG

Glutathione peroxidase (GPx) mRNA Cu,Zn–SOD (dimer)

2O2–

Glutathione (dimer)

Glutathione (monomer)

+2GSH

Peroxisome Copper–zinc superoxide dismutase (Cu,Zn–SOD) mRNA

Plasma membrane damaged (enlarged below)

+O2

+2H+

Lipid peroxidation of plasma membrane

Perxisome reactions Oxidative enzyme (eg, urate oxidase)

Phospholipid hydroperoxide glutathione peroxidase (PHGPx)

LOH+ GSSG+

2GSH's + LOOH OH LO

Catalase (tetramer)

H LO

Heme

Inside cell LH

2H2O+O2 LH

Hydrogen peroxide

+ O2

GPx subunit

chrom 3

Catalase subunit

+

2H+ H 2O 2

chrom 6

RH2 + O2

Plasma EC–SOD Proteinase?

LH

LH

RH Lipid radical

L LOO

LOOH

L Vitamin E (a-Tocopherol–) inhibits lipid peroxidation chain reaction

R

Lipid peroxide O

Lipid

LOOH LH e–

Free radical

LH

O LOO

H

Outside cell

Lipid chain collpases (now hydrophilic)

FIGURE 14-24 Cellular sources of reactive oxygen species (ROS) defense systems from free radicals. Superoxide and hydrogen peroxide are produced during normal cellular metabolism. ROS are constantly being produced by the normal cell during a number of physiologic reactions. Mitochondrial respiration is an important source of superoxide production under normal conditions and can be increased during ischemia-reflow or gentamycininduced renal injury. A number of enzymes generate superoxide and hydrogen peroxide during their catalytic cycling. These include cycloxygenases and lipoxygenes that catalyze prostanoid and leukotriene synthesis. Some cells (such as leukocytes, endothelial cells, and vascular smooth muscle cells) have NADH/ or NADPH oxidase enzymes in the plasma membrane that are capable of generating superoxide. Xanthine oxidase, which converts hypoxathine to xanthine, has been implicated as an important source of ROS after ischemia-reperfusion injury. Cytochrome p450, which is bound to the membrane of the endoplasmic reticulum, can be increased by the presence of high concentrations of metabolites that are oxidized by this cytochrome or by injurious events that uncouple the activity of the p450. Finally, the oxidation of small molecules including free heme, thiols, hydroquinines, catecholamines, flavins, and tetrahydropterins, also contribute to intracellular superoxide production. (Adapted from [22]; with permission.)

14.16

Acute Renal Failure FIGURE 14-25 Evidence suggesting a role for reactive oxygen metabolites in acute renal failure. The increased ROS production results from two major sources: the conversion of hypoxanthine to xanthine by xanthine dehydrogenase and the oxidation of NADH by NADH oxidase(s). During the period of ischemia, oxygen deprivation results in the massive dephosphorylation of adenine nucleotides to hypoxanthine. Normally, hypoxanthine is metabolized by xanthine dehydrogenase which uses NAD+ rather than oxygen as the acceptor of electrons and does not generate free radicals. However, during ischemia, xanthine dehydrogenase is converted to xanthine oxidase. When oxygen becomes available during reperfusion, the metabolism of hypoxanthine by xanthine oxidase generates superoxide. Conversion of NAD+ to its reduced form, NADH, and the accumulation of NADH occurs during ischemia. During the reperfusion period, the conversion of NADH back to NAD+ by NADH oxidase also results in a burst of superoxide production. (From Ueda et al. [23]; with permission.)

EVIDENCE SUGGESTING A ROLE FOR REACTIVE OXYGEN METABOLITES IN ISCHEMIC ACUTE RENAL FAILURE

Enhanced generation of reactive oxygen metabolites and xanthine oxidase and increased conversion of xanthine dehydrogenase to oxidase occur in in vitro and in vivo models of injury. Lipid peroxidation occurs in in vitro and in vivo models of injury, and this can be prevented by scavengers of reactive oxygen metabolites, xanthine oxidase inhibitors, or iron chelators. Glutathione redox ratio, a parameter of “oxidant stress” decreases during ischemia and markedly increases on reperfusion. Scavengers of reative oxygen metabolites, antioxidants, xanthine oxidase inhibitors, and iron chelators protect against injury. A diet deficient in selenium and vitamin E increases susceptibility to injury. Inhibition of catalase exacerbates injury, and transgenic mice with increased superoxide dismutase activity are less susceptible to injury.

250

3.0

*P < 0.001

150 100 16*

*P < 0.001

2.0 1.5 1.0 8*

8*

50

6*

26

0.5

4*

13*

6*

5*

4*

8* 18

+Fe3+

Iron stores (Ferritin) Release of free iron

Hydrogen Peroxide (H2O2)

Fe2+ Fe3+ OH

Hydroxyl Radical (OH–)

HB

FO

FIGURE 14-26 Effect of different scavengers of reactive oxygen metabolites and iron chelators on, A, blood urea nitrogen (BUN) and, B, creatinine in gentamicin-induced acute renal failure. The numbers shown above the error bars indicate the number of animals in each group. Benz—sodium benzoate; Cont—control group; DFO—deferoxamine; DHB— 2,3 dihydroxybenzoic acid; DMSO— dimethyl sulfoxide; DMTU—dimethylthiourea; Gent—gentamicin group. (From Ueda et al. [23]; with permission.)

+D

+D

O

nz +Be

U

MS +D

t

MT +D

t Con

B

Gen

HB

FO

+D

+D

nz

O

Superoxide O2–

+Be

MS +D

t

+D

MT

Gen

Con

U

0.0 t

0

A

16

2.5

200 Creatinine, mg/dL

Plasma urea nitrogen, mg/dL

24

FIGURE 14-27 Production of the hydroxyl radical: the Haber-Weiss reaction. Superoxide is converted to hydrogen peroxide by superoxide dismutase. Superoxide and hydrogen peroxide per se are not highly reactive and cytotoxic. However, hydrogen peroxide can be converted to the highly reactive and injurious hydroxyl radical by an iron-catalyzed reaction that requires the presence of free reduced iron. The availability of free “catalytic iron” is a critical determinant of hydroxyl radical production. In addition to providing a source of hydroxyl radical, superoxide potentiates hydroxyl radical production in two ways: by releasing free iron from iron stores such as ferritin and by reducing ferric iron and recycling the available free iron back to the ferrous form. The heme moiety of hemoglobin, myoglobin, or cytochrome present in normal cells can be oxidized to metheme (Fe3+). The further oxidation of metheme results in the production of an oxyferryl moiety (Fe4+=O), which is a long-lived, strong oxidant which likely plays a role in the cellular injury associated with hemoglobinuria and myoglobinuria. Activated leukocytes produce superoxide and hydrogen peroxide via the activity of a membrane-bound enzyme NADPH oxidase. This superoxide and hydrogen peroxide can be converted to hydroxyl radical via the Haber-Weiss reaction. Also, the enzyme myeloperoxidase, which is specific to leukocytes, converts hydrogen peroxide to another highly reactive and injurious oxidant, hypochlorous acid.

14.17

Pathophysiology of Ischemic Acute Renal Failure

:O–O• + •N–O

:O2•–

:O–O–N–O 22 kcal/mol ...Large Gibbs energy

6.7 x 109 M–1•s–1 [NO]

Initiation

ONOO– ...Faster than SOD

LH + OH•

Propagation L• + O2

O 2 + H 2O 2 1 x 109 M–1•s–1 [SOD] H O O O O N O N O N O• OH ...Peroxynitrous OH• A acid in trans

LOO•

LOO• + LH

LOOH + L•

Termination L• + L•

B

L–L

LOO• + NO•

LOONO

ONOO–

Cortex

X: SOD, Cu2+, Fe3+

X

FIGURE 14-28 Cell injury: point of convergence between the reduced oxygen intermediates–generating and reduced nitrogen intermediates– generating pathways, A, and mechanisms of lipid peroxidation, B.

H2O + L•

Medulla

XO NO2• Tyr

116 KD

116 KD

66 KD

66 KD

NO2

A

OH

R

Nitrotyrosine

C

CI

LN

C

CI

LN

C

R Unsaturated fatty acid

Free R' radical

R

R'

•

O O

OO•

Free Control

Control Ischemia

R

L-Nil + Ischemia

R'

•

B FIGURE 14-29 Detection of peroxynitrite production and lipid peroxidation in ischemic acute renal failure. A, Formation of nitrotyrosine as an indicator of ONOO- production. Interactions between reactive oxygen species such as the hydroxyl radical results in injury to the ribose-phosphate backbone of DNA. This results in singleand double-strand breaks. ROS can also cause modification and deletion of individual bases within the DNA molecule. Interaction between reactive oxygen and nitrogen species results in injury to the ribose-phosphate backbone of DNA, nuclear DNA fragmentation (single- and double-strand breaks) and activation of poly(ADP)-ribose synthase. B, Immunohistochemical staining of kidneys with antibodies to nitrotyrosine. C, Western blot analysis of nitrotyrosine. D, Reactions describing lipid peroxidation and formation of hemiacetal products. The interaction of oxygen radicals with lipid bilayers leads to the removal of hydrogen atoms from the unsaturated fatty acids bound to phospholipid. This

radical

O2 OO•

O O

R

O2

Lipid based peroxyradical (LOO•)

R'

OH

R

O

R' HNE HNE

Ab

OH O

X Protein

D

(X: Cys, His, Lys)

O

OH

X Formation of stable hemiacetal adducts

process is called lipid peroxidation. In addition to impairing the structural and functional integrity of cell membranes, lipid peroxidation can lead to a self-perpetuating chain reaction in which additional ROS are generated. (Continued on next page)

14.18

Acute Renal Failure

Cortex

Control

Control Ischemia

Medulla

L-Nil + Ischemia

E FIGURE 14-29 (Continued) E, Immunohistochemical staining of kidneys with antibodies to HNE–modified proteins. F, Western blot analysis of HNE expression. C—control; CI—central ischemia; LN—ischemia with L-Nil pretreatment (Courtesy of E. Noiri, MD.)

C

CI

LN

C

CI

LN

F

Leukocytes in Acute Renal Failure Inactive leukocyte

Activated leukocyte

Leukocyte adhesion molecules β2 integrins (LFA1 or Mac1) Selections Endothelial adhesion molecules ICAM Ligand for leukocyte selections

FIGURE 14-30 Role of adhesion molecules in mediating leukocyte attachment to endothelium. A, The normal inflammatory response is mediated by the release of cytokines that induce leukocyte chemotaxis and activation. The initial interaction of leukocytes with endothelium is mediated by the selectins and their ligands both of which are present on leukocytes and endothelial cells, (Continued on next page)

Selection–mediated rolling of leukocytes

Firm adhesion of leukocytes (integrin–mediated) Diapedesis

Tissue injury

A

Release of oxidants proteases elastases

Pathophysiology of Ischemic Acute Renal Failure

FIGURE 14-29 (Continued) B. Selectin-mediated leukocyte-endothelial interaction results in the rolling of leukocytes along the endothelium and facilitates the firm adhesion and immobilization of leukocytes. Immobilization of leukocytes to endothelium is mediated by the 2-integrin adhesion molecules on leukocytes and their ICAM ligands on endothelial cells. Immobilization of leukocytes is necessary for diapedesis of leukocytes between endothelial cells into parenchymal tissue. Leukocytes release proteases, elastases, and reactive oxygen radicals that induce tissue injury. Activated leukocytes also elaborate cytokines such as interleukin 1 and tumor necrosis factor which attract additional leukocytes to the site, causing further injury.

B. LEUKOCYTE ADHESION MOLECULES AND THEIR LIGANDS POTENTIALLY IMPORTANT IN ACUTE RENAL FAILURE Major Families

Cell Distribution

Selectins L-selectin P-selectin E-selectin Carbohydrate ligands for selectins Sulphated polysacharides Oligosaccharides Integrins CD11a/CD18 CD11b/CD18 Immunoglobulin G–like ligands for integrins Intracellular adhesion molecules (ICAM)

125

Endothelium Leukocytes Leukocytes Leukocytes

Endothelial cells

75 50

Anti-ICAM antibody Vehicle

2 Plasma creatinine

Blood urea nitrogen

Leukocytes Endothelial cells Endothelial cells

Anti-ICAM antibody Vehicle

100

1.5 1 0.5

25 0

0 0 24 48 72 Time following ischemia-reperfusion, d

A

B

0 24 48 72 96 Time following ischemia-reperfusion, d

Myeloperoxidase activity

Vehicle Anti-ICAM antibody

750 500 250 0 0

FIGURE 14-31 Neutralizing anti–ICAM antibody ameliorates the course of ischemic renal failure with blood urea nitrogen, A, and plasma creatinine, B. Rats subjected to 30 minutes of bilateral renal ischemia or a sham-operation were divided into three groups that received either anti-ICAM antibody or its vehicle. Plasma creatinine levels are shown at 24, 48, and 72 hours. ICAM antibody ameliorates the severity of renal failure at all three time points. (Adapted from Kelly et al. [24]; with permission.)

FIGURE 14-32 Neutralizing anti-ICAM-1 antibody reduces myeloperoxidase activity in rat kidneys exposed to 30 minutes of ischemia. Myeloperoxidase is an enzyme specific to leukocytes. Anti-ICAM antibody reduced myeloperoxidase activity (and by inference the number of leukocytes) in renal tissue after 30 minutes of ischemia. (Adapted from Kelly et al. [24]; with permission.)

1250 1000

14.19

4 24 48 Time after reperfusion, hrs

72

14.20

Acute Renal Failure

Mechanisms of Cell Death: Necrosis and Apoptosis FIGURE 14-33 Apoptosis and necrosis: two distinct morphologic forms of cell death. A, Necrosis. Cells undergoing necrosis become swollen and enlarged. The mitochondria become markedly abnormal. The main morphoplogic features of mitochondrial injury include swelling and flattening of the folds of the inner mitochondrial membrane (the christae). The cell plasma membrane loses its integrity and allows the escape of cytosolic contents including lyzosomal proteases that cause injury and inflammation of the surrounding tissues. B, Apoptosis. In contrast to necrosis, apoptosis is associated with a progressive decrease in cell size and maintenance of a functionally and structurally intact plasma membrane. The decrease in cell size is due to both a loss of cytosolic volume and a decrease in the size of the nucleus. The most characteristic and specific morphologic feature of apoptosis is condensation of nuclear chromatin. Initially the chromatin condenses against the nuclear membrane. Then the nuclear membrane disappears, and the condensed chromatin fragments into many pieces. The plasma membrane undergoes a process of “budding,” which progresses to fragmentation of the cell itself. Multiple plasma membrane–bound fragments of condensed DNA called apoptotic bodies are formed as a result of cell fragmentation. The apoptotic cells and apoptotic bodies are rapidly phagocytosed by neighboring epithelial cells as well as professional phagocytes such as macrophages. The rapid phagocytosis of apoptotic bodies with intact plasma membranes ensures that apoptosis does not cause any surrounding inflammatory reaction.

[Ca2+]i ?

?

Signal transduction pathways

Mitochondrion Mitochondrial permeability transition

Induction phase

B

?

Regulation by Hcl-2 and its relatives ?

Positive feedback loop Consequences of permeability transition: Disruption of ∆ψm and mitochondrial biogenesis Breakdown of energy metabolism Uncoupling of respiratory chain Calcium release frommitochondrial matrix Hyperproduction of superoxide anion Depletion of glutathione

Activation of ICE/ced-3-like proteases ?

Effector phase

A

? NAD/NADH Increase in ATP [Ca2+]i depletion depletion

Cytoplasmic effects Disruption of anabolic reactions Dilatation of ER Activation of proteases Disruption of intracellular calcium compartimentalization Disorganization of cytoskeleton

Tyrosin kinases G-proteins ?

Nucleus Activation of endonucleases Activation of repair enzymes (ATP depletion) Activation of poly(ADP) ribosly transferase (NAD depletion) Chromatinolysis, nucleolysis

Degradation phase

ROS effects

FIGURE 14-34 Hypothetical schema of cellular events triggering apoptotic cell death. (From Kroemer et al. [25]; with permission.)

Pathophysiology of Ischemic Acute Renal Failure

14.21

FIGURE 14-35 Phagocytosis of an apoptotic body by a renal tubular epithelial cell. Epithelial cells dying by apoptosis are not only phagocytosed by macrophages and leukocytes but by neighbouring epithelial cells as well. This electron micrograph shows a normal-looking epithelial cell containing an apoptotic body within a lyzosome. The nucleus of an epithelial cell that has ingested the apoptotic body is normal (white arrow). The wall of the lyzosome containing the apoptotic body (black arrow) is clearly visible. The apoptotic body consists of condensed chromatin surrounded by plasma membrane (black arrowheads).

Nucleosome ~200 bp Internucleosome "Linker" regions

DNA fragmentation

Apoptosis

Necrosis

Loss of histones

800 bp 600 bp

400 bp 200 bp

DNA electrophoresis Apoptic "ladder" pattern

Necrotic "smear" pattern

FIGURE 14-36 DNA fragmentation in apoptosis vs necrosis. DNA is made up of nucleosomal units. Each nucleosome of DNA is about 200 base pairs in size and is surrounded by histones. Between nucleosomes are small stretches of DNA that are not surrounded by histones and are called linker regions. During apoptosis, early activation of endonuclease(s) causes double-strand breaks in DNA between nucleosomes. No fragmentation occurs in nucleosomes because the DNA is “protected” by the histones. Because of the size of nucleosomes, the DNA is fragmented during apoptosis into multiples of 200 base pair pieces (eg, 200, 400, 600, 800). When the DNA of apoptotic cells is electrophoresed, a characteristic ladder pattern is found. In contrast, necrosis is associated with the early release of lyzosomal proteases, which cause proteolysis of nuclear histones, leaving “naked” stretches of DNA not protected by histones. Activation of endonucleases during necrosis therefore cause DNA cleavage at multiple sites into double- and single-stranded DNA fragments of varying size. Electrophoresis of DNA from necrotic cells results in a smear pattern.

14.22

Acute Renal Failure FIGURE 14-37 Potential causes of apoptosis in acute renal failure (ARF). The same cytotoxic stimuli that induce necrosis cause apoptosis. The mechanism of cell death induced by a specific injury depends in large part on the severity of the injury. Because most cells require constant external signals, called survival signals, to remain viable, the loss of these survival signals can trigger apoptosis. In ARF, a deficiency of growth factors and loss of cell-substrate adhesion are potential causes of apoptosis. The death pathways induced by engagement of tumour necrosis factor (TNF) with the TNF receptor or Fas with its receptor (Fas ligand) are well known causes of apoptosis in immune cells. TNF and Fas can also induce apoptosis in epithelial cells and may contribute to cell death in ARF.

POTENTIAL CAUSES OF APOPTOSIS IN ACUTE RENAL FAILURE Loss of survival factors Deficiency of renal growth factors (eg, IGF-1, EGF, HGF) Loss of cell-cell and cell-matrix interactions Receptor-mediated activators of apoptosis Tumor necrosis factor Fas/Fas ligand Cytotoxic events Ischemia; hypoxia; anoxia Oxidant injury Nitric oxide Cisplati

Apoptotic Trigger

Commitment phase Anti-apoptic factors

Pro-apoptic factors

BclXL Bcl–2

BAD Bax Execution phase

Crma p35

Caspase activation ? Point of no return? Proteolysis of multiple intracellular substrates

Apoptosis

FIGURE 14-38 Apoptosis is mediated by a highly coordinated and genetically programmed pathway. The response to an apoptotic stimulus can be divided into a commitment and execution phases. During the commitment phase the balance between a number of proapoptotic and antiapoptotic mechanisms determine whether the cell survives or dies by apoptosis. The BCL-2 family of proteins consists of at least 12 isoforms, which play important roles in this commitment phase. Some of the BCL-2 family of proteins (eg, BCL-2 and BCL-XL) protect cells from apoptosis whereas other members of the same family (eg, BAD and Bax) serve proapoptotic functions. Apoptosis is executed by a final common pathway mediated by a class of cysteine proteases-caspases. Caspases are proteolytic enzymes present in cells in an inactive form. Once cells are commited to undergo apoptosis, these caspases are activated. Some caspases activate other caspases in a hierarchical fashion resulting in a cascade of caspase activation. Eventually, caspases that target specific substrates within the cell are activated. Some substrates for caspases that have been identified include nuclear membrane components (such as lamin), cytoskeletal elements (such as actin and fodrin) and DNA repair enzymes and transcription elements. The proteolysis of this diverse array of substrates in the cell occurs in a predestined fashion and is responsible for the characteristic morphologic features of apoptosis.

Pathophysiology of Ischemic Acute Renal Failure

Stress

• Restoration of fluid and electrolyte balance • ETR antagonists Kf • Ca channel inhibitors • ATP-Mg • ETR antagonists • Ca channel inhibitors

Loss of tubular integrity and function

Hemodynamic compromise

RBF

PMN infiltration

• Dopamine • ANP • IGF-1

• ICAM-1 antibody • RGD

Back leak

Obstruction • Mannitol • Lasix • ANP • RGD

• IGF-1l • T4 • HGF

• Avoidance and discontinuation of nephrotoxins • Survival factors (HGF, IGF-1) • ATP-Mg • T4 • NOS inhibitors

14.23

FIGURE 14-39 Therapeutic approaches, both experimental and in clinical use, to prevent and manage acute renal failure based on its pathogenetic mechanisms. ETR—ET receptor; GFR— glomerular filtration rate; HGF—hepatocyte growth factor 1; IGF-1—insulin-like growth factor 1; Kf—glomerular ultrafiltration coefficient; NOS—nitric oxide synthase; PMN— polymorphonuclear leukocytes; RBF—renal blood flow; T4—thyroxine.

GFR and maintenance phase Restoration of renal hemodynamics

Reparation of tubular integrity and function Recovery

References 1. Goligorsky M, Iijima K, Krivenko Y, et al.: Role of mesangial cells in macula densa-to-afferent arteriole information transfer. Clin Exp Pharm Physiol 1997, 24:527–531. 2. Osswald H, Hermes H, Nabakowski G: Role of adenosine in signal transmission of TGF. Kidney Int 1982, 22(Suppl. 12):S136–S142. 3. Miller W, Thomas R, Berne R, Rubio R: Adenosine production in the ischemic kidney. Circ Res 1978, 43(3):390–397. 4. Kon V, et al.: Glomerular actions of endothelin in vivo. J Clin Invest 1989, 83:1762–1767. 5. Gellai M, Jugus M, Fletcher T, et al.: Reversal of postischemic acute renal failure with a selective endothelin A receptor antagonist in the rat. J Clin Invest 1994, 93:900–906. 6. Fogo, et al.: Endothelin receptor antagonism is protective in vivo in acute cyclosporine toxicity. Kidney Int 1992, 42:770–774. 7. Conger J: NO in acute renal failure. In: Nitric Oxide and the Kidney. Edited by Goligorsky M, Gross S. New York:Chapman and Hall, 1997. 8. Gross S: Nitric oxide synthases and their cofactors. In: Nitric Oxide and the Kidney. Edited by Goligorsky M, Gross S. New York:Chapman and Hall, 1997. 9. Reyes A, Karl I, Klahr S: Role of arginine in health and in renal disease. Am J Physiol 1994, 267:F331–F346. 10. Kim Y-M, Tseng E, Billiar TR: Role of NO and nitrogen intermediates in regulation of cell functions. In: Nitric Oxide and the Kidney. Edited by Goligorsky M, Gross S. New York:Chapman and Hall, 1997. 11. Lieberthal W:Renal ischemia and reperfusion impair endotheliumdependent vascular relaxation. Am J Physiol 1989, 256:F894–F900. 12. Yu L, Gengaro P, Niederberger M, et al.: Nitric oxide: a mediator in rat tubular hypoxia/reoxygenation injury. Proc Natl Acad Sci USA 1994, 91:1691–1695. 13. Noiri E, Peresleni T, Miller F, Goligorsky MS: In vivo targeting of iNOS with oligodeoxynucleotides protects rat kidney against ischemia. J Clin Invest 1996, 97:2377–2383.

14. Ling H, Gengaro P, Edelstein C, et al.: Injurious isoform of NOS in mouse proximal tubular injury. Kidney Int, 1998, 53:1642 15. Agmon Y, et al.: Nitric oxide and prostanoids protect the renal outer medulla from radiocontrast toxicity in the rat. J Clin Invest 1994, 94:1069–1075. 16. Agmon Y, Brezis M: NO and the medullary circulation. In: Nitric Oxide and the Kidney. Edited by Goligorsky M, Gross S. New York:Chapman and Hall, 1997. 17. Goligorsky MS: Cell biology of signal transduction. In: Hormones, autacoids, and the kidney. Edited by Goldfarb S, Ziyadeh F. New York:Churchill Livingstone, 1991. 18. Edelstein C, Schrier RW: The role of calcium in cell injury. In: Acute Renal Failure: New Concepts and Therapeutic Strategies. Edited by Goligorsky MS, Stein JH. New York:Churchill Livingstone, 1995. 19. Kribben A, Wetzels J, Wieder E, et al.:Evidence for a role of cytosolic free calcium in hypoxia-induced proximal tubule injury. J Clin Invest 1994, 93:1922. 20. Burke T, Arnold P, Gordon J, Schrier RW: Protective effect of intrarenal calcium channel blockers before or after renal ischemia. J Clin Invest 1984, 74:1830. 21. Kashgarian M: Stress proteins induced by injury to epithelial cells. In: Acute Renal Failure: New Concepts and therapeutic strategies. Edited by Goligorsky MS, Stein JH. New York:Churchill Livingstone, 1995. 22. J NIH Research 23. Ueda N, Walker P, Shah SV: Oxidant stress in acute renal failure. In: Acute Renal Failure: New Concepts and Therapeutic Strategies. Edited by Goligorsky MS, Stein JH. New York:Churchill Livingstone, 1995. 24. Kelly KJ, et al.: Antibody to anyi-cellular adhesion molecule-1 protects the kidney against ischemic injury. Proc Natl Acad Sci USA 1994, 91:812–816. 25. Kroemer G, Petit P, Zamzami N, et al.: The biochemistry of programmed cell death. FASEB J 1995, 9:1277–1287.

Pathophysiology of Nephrotoxic Acute Renal Failure Rick G. Schnellmann Katrina J. Kelly

H

umans are exposed intentionally and unintentionally to a variety of diverse chemicals that harm the kidney. As the list of drugs, natural products, industrial chemicals and environmental pollutants that cause nephrotoxicity has increased, it has become clear that chemicals with very diverse chemical structures produce nephrotoxicity. For example, the heavy metal HgCl2, the mycotoxin fumonisin B1, the immunosuppresant cyclosporin A, and the aminoglycoside antibiotics all produce acute renal failure but are not structurally related. Thus, it is not surprising that the cellular targets within the kidney and the mechanisms of cellular injury vary with different toxicants. Nevertheless, there are similarities between chemicalinduced acute tubular injury and ischemia/reperfusion injury. The tubular cells of the kidney are particularly vulnerable to toxicant-mediated injury due to their disproportionate exposure to circulating chemicals and transport processes that result in high intracellular concentrations. It is generally thought that the parent chemical or a metabolite initiates toxicity through its covalent or noncovalent binding to cellular macromolecules or through their ability to produce reactive oxygen species. In either case the activity of the macromolecule(s) is altered resulting in cell injury. For example, proteins and lipids in the plasma membrane, nucleus, lysosome, mitochondrion and cytosol are all targets of toxicants. If the toxicant causes oxidative stress both lipid peroxidation and protein oxidation have been shown to contribute to cell injury. In many cases mitochondria are a critical target and the lack of adenosine triphosphate (ATP) leads to cell injury due to the dependence of renal function on aerobic metabolism. The loss of ATP leads

CHAPTER

15

15.2

Acute Renal Failure

to disruption of cellular ion homeostasis with decreased cellular K+ content, increased Na+ content and membrane depolarization. Increased cytosolic free Ca2+ concentrations can occur in the early or late phase of cell injury and plays a critical role leading to cell death. The increase in Ca2+ can activate calcium activated neutral proteases (calpains) that appear to contribute to the cell injury that occurs by a variety of toxicants. During the late phase of cell injury, there is an increase in Cl- influx, followed by the influx of increasing larger molecules that leads to cell lysis. Two additional enzymes appear to play an important role in cell injury, particularly oxidative injury. Phospholipase A2 consists of a family of enzymes in which the activity of the cytosolic form increases during oxidative injury and contributes to cell death. Caspases are a family of cysteine proteases that are activated following oxidative injury and contribute to cell death.

Following exposure to a chemical insult those cells sufficiently injured die by one of two mechanisms, apoptosis or oncosis. Clinically, a vast number of nephrotoxicants can produce a variety of clinical syndromes-acute renal failure, chronic renal failure, nephrotic syndrome, hypertension and renal tubular defects. The evolving understanding of the pathophysiology of toxicant-mediated renal injury has implications for potential therapies and preventive measures. This chapter outlines some of the mechanisms thought to be important in toxicant-mediated renal cell injury and death that leads to the loss of tubular epithelial cells, tubular obstruction, “backleak” of the glomerular filtrate and a decreased glomerular filtration rate. The recovery from the structural and functional damage following chemical exposures is dependent on the repair of sublethally-injured and regeneration of noninjured cells.

Clinical Significance of Toxicant-Mediated Acute Renal Failure CLINICAL SIGNIFICANCE OF TOXICANT–MEDIATED RENAL FAILURE Nephrotoxins may account for approximately 50% of all cases of acute and chronic renal failure. Nephrotoxic renal injury often occurs in conjunction with ischemic acute renal failure. Acute renal failure may occur in 2% to 5% of hospitalized patients and 10% to 15% of patients in intensive care units. The mortality of acute renal failure is approximatley 50% which has not changed significantly in the last 40 years. Radiocontrast media and aminoglycosides are the most common agents associated with nephrotoxic injury in hospitalized patients. Aminoglycoside nephrotoxicity occurs in 5% to 15% of patients treated with these drugs.

REASONS FOR THE KIDNEY’S SUSCEPTIBILITY TO TOXICANT INJURY Receives 25% of the cardiac output Sensitive to vasoactive compounds Concentrates toxicants through reabsorptive and secretive processes Many transporters result in high intracellular concentrations Large luminal membrane surface area Large biotransformation capacity Baseline medullary hypoxia

FIGURE 15-2 Reasons for the kidney’s susceptibility to toxicant injury.

FIGURE 15-1 Clinical significance of toxicant-mediated renal failure.

FACTORS THAT PREDISPOSE THE KIDNEY TO TOXICANT INJURY Preexisting renal dysfunction Dehydration Diabetes mellitus Exposure to multiple nephrotoxins

FIGURE 15-3 Factors that predispose the kidney to toxicant injury.

Pathophysiology of Nephrotoxic Acute Renal Failure

15.3

EXOGENOUS AND ENDOGENOUS CHEMICALS THAT CAUSE ACUTE RENAL FAILURE Antibiotics Aminoglycosides (gentamicin, tobramycin, amikacin, netilmicin) Amphotericin B Cephalosporins Ciprofloxacin Demeclocycline Penicillins Pentamidine Polymixins Rifampin Sulfonamides Tetracycline Vancomycin Chemotherapeutic agents Adriamycin Cisplatin Methotraxate Mitomycin C Nitrosoureas (eg, streptozotocin, Iomustine) Radiocontrast media Ionic (eg, diatrizoate, iothalamate) Nonionic (eg, metrizamide)

Immunosuppressive agents Cyclosporin A Tacrolimus (FK 506) Antiviral agents Acyclovir Cidovir Foscarnet Valacyclovir Heavy metals Cadmium Gold Mercury Lead Arsenic Bismuth Uranium Organic solvents Ethylene glycol Carbon tetrachloride Unleaded gasoline

Vasoactive agents Nonsteroidal anti-inflammatory drugs (NSAIDs) Ibuprofen Naproxen Indomethacin Meclofenemate Aspirin Piroxicam Angiotensin-converting enzyme inhibitors Captopril Enalopril Lisinopril Angiotensin receptor antagonists Losartan

Other drugs Acetaminophen Halothane Methoxyflurane Cimetidine Hydralazine Lithium Lovastatin Mannitol Penicillamine Procainamide Thiazides Lindane Endogenous compounds Myoglobin Hemoglobin Calcium Uric acid Oxalate Cystine

FIGURE 15-4 Exogenous and endogenous chemicals that cause acute renal failure.

Proximal convoluted tubule (S1/S2 segments) Aminoglycosides Cephaloridine Cadmium chloride Potassium dichromate

Renal vessels NSAIDs ACE inhibitors Cyclosporin A

Papillae Phenacetin

Glomeruli Interferon–α Gold Penicillamine Proximal straight tubule (S3 segment) Cisplatin Mercuric chloride Dichlorovinyl–L–cysteine

Interstitium Cephalosporins Cadmium NSAIDs

FIGURE 15-5 Nephrotoxicants may act at different sites in the kidney, resulting in altered renal function. The sites of injury by selected nephrotoxicants are shown. Nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme (ACE) inhibitors, cyclosporin A, and radiographic contrast media cause vasoconstriction. Gold, interferon-alpha, and penicillamine can alter glomerular function and result in proteinuria and decreased renal function. Many nephrotoxicants damage tubular epithelial cells directly. Aminoglycosides, cephaloridine, cadmium chloride, and potassium dichromate affect the S1 and S2 segments of the proximal tubule, whereas cisplatin, mercuric chloride, and dichlorovinyl-L-cysteine affect the S3 segment of the proximal tubule. Cephalosporins, cadmium chloride, and NSAIDs cause interstitial nephritis whereas phenacetin causes renal papillary necrosis.

15.4

Acute Renal Failure Prerenal azotemia

Renal vasoconstriction

Intravascular volume

Increased tubular pressure n e p h r o t o x i t c o a n t

E x p o s u r e

Tubular obstruction Intratubular casts

Sympathetic tone

"Back-leak" of glomerular filtrate Functional abnormalties

GFR

Capillary permeability

Endothelial injury

Tubular damage Persistent medullary hypoxia Physical constriction of medullary vessels Hemodynamic Glomerular hydrostatic alterations pressure Intrarenal vasoconstriction Perfusion pressure Efferent tone Afferent tone Glomerular factors

Hypertension Endothelin Nitric oxide Thromboxane Prostaglandins

Renal and systemic vasoconstriction

Intrarenal factors

Obstruction

Vascular smooth muscle sensitivity to vasoconstrictors

Cyclosporin A

Angiotensin II Tubular cell injury

Glomerular ultrafiltration Postrenal failure

FIGURE 15-6 Mechanisms that contribute to decreased glomerular filtration rate (GFR) in acute renal failure. After exposure to a nephrotoxicant, one or more mechanisms may contribute to a reduction in the GFR. These include renal vasoconstriction resulting in prerenal azotemia (eg, cyclosporin A) and obstruction due to precipitation of a drug or endogenous substances within the kidney or collecting ducts (eg, methotrexate). Intrarenal factors include direct tubular obstruction and dysfunction resulting in tubular backleak and increased tubular pressure. Alterations in the levels of a variety of vasoactive mediators (eg, prostaglandins following treatment with nonsteroidal anti-inflammatory drugs) may result in decreased renal perfusion pressure or efferent arteriolar tone and increased afferent arteriolar tone, resulting in decreased in glomerular hydrostatic pressure. Some nephrotoxicants may decrease glomerular function, leading to proteinuria and decreased renal function.

Striped interstitial fibrosis GFR

FIGURE 15-7 Renal injury from exposure to cyclosporin A. Cyclosporin A is one example of a toxicant that acts at several sites within the kidney. It can injure both endothelial and tubular cells. Endothelial injury results in increased vascular permeability and hypovolemia, which activates the sympathetic nervous system. Injury to the endothelium also results in increases in endothelin and thromboxane A2 and decreases in nitric oxide and vasodilatory prostaglandins. Finally, cyclosporin A may increase the sensitivity of the vasculature to vasoconstrictors, activate the renin-angiotensin system, and increase angiotensin II levels. All of these changes lead to vasoconstriction and hypertension. Vasoconstriction in the kidney contributes to the decrease in glomerular filtration rate (GFR), and the histologic changes in the kidney are the result of local ischemia and hypertension.

Renal Cellular Responses to Toxicant Exposures Nephrotoxic insult to the nephron

Uninjured cells

Compensatory hypertrophy

Cellular adaptation

Injured cells

Cellular proliferation Re-epithelialization

Cell death

Cellular repair

Cellular adaptation

Differentiation

Structural and functional recovery of the nephron

FIGURE 15-8 The nephron’s response to a nephrotoxic insult. After a population of cells are exposed to a nephrotoxicant, the cells respond and ultimately the nephron recovers function or, if cell death and loss is extensive, nephron function ceases. Terminally injured cells undergo cell death through oncosis or apoptosis. Cells injured sublethally undergo repair and adaptation (eg, stress response) in response to the nephrotoxicant. Cells not injured and adjacent to the injured area may undergo dedifferentiation, proliferation, migration or spreading, and differentiation. Cells that were not injured may also undergo compensatory hypertrophy in response to the cell loss and injury. Finally the uninjured cells may also undergo adaptation in response to nephrotoxicant exposure.

Pathophysiology of Nephrotoxic Acute Renal Failure Loss of polarity, tight junction integrity, cell–substrate adhesion, simplification of brush border

Intact tubular epithelium

Cell death

Toxic injury

Necrosis

α β

Cast formation and tubuler obstruction

Na+/K+=ATPase β1 Integrin RGD peptide

FIGURE 15-9 After injury, alterations can occur in the cytoskeleton and in the normal distribution of membrane proteins such as Na+, K+ATPase and 1 integrins in sublethally injured renal tubular cells. These changes result in loss of cell polarity, tight junction integrity, and cell-substrate adhesion. Lethally injured cells undergo oncosis or apoptosis, and both dead and viable cells

Migrating spreading cells

Cell proliferation

Basement membrane Toxicant inhibition of cell repair

Apoptosis

Sloughing of viable and nonviable cells with intraluminal cell-cell adhesion

Cytoskeleton Extracellular matrix

Sublethally injured cells

15.5

Toxicant inhibition of cell migration/spreading

Toxicant inhibition of cell proliferation

may be sloughed into the tubular lumen. Adhesion of sloughed cells to other sloughed cells and to cells remaining adherent to the basement membrane may result in cast formation, tubular obstruction, and further compromise the glomerular filtration rate. (Adapted from Fish and Molitoris [1], and Gailit et al. [2]; with permission.) FIGURE 15-10 Potential sites where nephrotoxicants can interfere with the structural and functional recovery of nephrons.

15.6

Acute Renal Failure 140

Percent of control

120 100

Oncosis

Apoptosis

80 60 Cell number/confluence Mitochondrial function Active Na+ transport + Na -coupled glucose transport GGT activity

40 20 0 0

1

2

3

4

5

Blebbing

Budding

6

Time after exposure, d

FIGURE 15-11 Inhibition and repair of renal proximal tubule cellular functions after exposure to the model oxidant t-butylhydroperoxide. Approximately 25% cell loss and marked inhibition of mitochondrial function active (Na+) transport and Na+-coupled glucose transport occurred 24 hours after oxidant exposure. The activity of the brush border membrane enzyme -glutamyl transferase (GGT) was not affected by oxidant exposure. Cell proliferation and migration or spreading was complete by day 4, whereas active Na+ transport and Na+-coupled glucose transport did not return to control levels until day 6. These data suggest that selective physiologic functions are diminished after oxidant injury and that a hierarchy exists in the repair process: migration or spreading followed by cell proliferation forms a monolayer and antedates the repair of physiologic functions. (Data from Nowak et al. [3].)

Necrosis

Phagocytosis inflammation

Phagocytosis by macrophages or nearby cells

FIGURE 15-12 Apoptosis and oncosis are the two generally recognized forms of cell death. Apoptosis, also known as programmed cell death and cell suicide, is characterized morphologically by cell shrinkage, cell budding forming apoptotic bodies, and phagocytosis by macrophages and nearby cells. In contrast, oncosis, also known as necrosis, necrotic cell death, and cell murder, is characterized morphologically by cell and organelle swelling, plasma membrane blebbing, cell lysis, and inflammation. It has been suggested that cell death characterized by cell swelling and lysis not be called necrosis or necrotic cell death because these terms describe events that occur well after the cell has died and include cell and tissue breakdown and cell debris. (From Majno and Joris [4]; with permission.)

Mechanisms of Toxicant-Mediated Cellular Injury Transport and biotransformation Toxicant whose primary mechanism of action is ATP depletion

Toxicants in general

Apoptosis

Oncosis

Cell death

Cell death

Oncosis

Apoptosis

Toxicant concentration

Toxicant concentration

FIGURE 15-13 The general relationship between oncosis and apoptosis after nephrotoxicant exposure. For many toxicants, low concentrations cause primarily apoptosis and oncosis occurs principally at higher concentrations. When the primary mechanism of action of the nephrotoxicant is ATP depletion, oncosis may be the predominant cause of cell death with limited apoptosis occurring.

Pathophysiology of Nephrotoxic Acute Renal Failure

GSH-Hg-GSH GSH-Hg-GSH CYS-Hg-CYS

GSH-Hg-GSH

γ-GT ?

GLY-CYS-Hg-CYS-GLY

Acivicin

CYS-Hg-CYS Lumen

Dipeptidase

+

CYS-Hg-CYS Na

Neutral amino acid transporter

– R-Hg-R– CYS-Hg-CYS GSH-Hg-GSH Na+ α-Ketoglutarate α-Ketoglutarate Dicarboxylate Organic anion transporter transporter

Proximal tubular cell

Blood

Urine

CYS-Hg-CYS Na

+

Organic anions (PAH or probenecid)

α-Ketoglutarate

Na+ Dicarboxylic acids

α-Ketoglutarate

Biotransformation

Altered activity of critical macromolecules

FIGURE 15-14 The importance of cellular transport in mediating toxicity. Proximal tubular uptake of inorganic mercury is thought to be the result of the transport of mercuric conjugates (eg, diglutathione mercury conjugate [GSH-Hg-GSH], dicysteine mercuric conjugate [CYS-Hg-CYS]). At the luminal membrane, GSH-Hg-GSH appears to be metabolized by (-glutamyl transferase ((-GT) and a dipeptidase to form CYS-Hg-CYS. The CYS-Hg-CYS may be taken up by an amino acid transporter. At the basolateral membrane, mercuric conjugates appear to be transported by the organic anion transporter. (-Ketoglutarate and the dicarboxylate transporter seem to play important roles in basolateral membrane uptake of mercuric conjugates. Uptake of mercuric-protein conjugates by endocytosis may play a minor role in the uptake of inorganic mercury transport. PAH—para-aminohippurate. (Courtesy of Dr. R. K. Zalups.)

– R-Hg-R– CYS-Hg-CYS GSH-Hg-GSH

Toxicant

High-affinity binding to macromolecules

15.7

Reactive intermediate

Redox cycling

Covalent binding to macromolecules

Increased reactive oxygen species

Damage to critical macromolecules

Oxidative damage to critical macromolecules

FIGURE 15-15 Covalent and noncovalent binding versus oxidative stress mechanisms of cell injury. Nephrotoxicants are generally thought to produce cell injury and death through one of two mechanisms, either alone or in combination. In some cases the toxicant may have a high affinity for a specific macromolecule or class of macromolecules that results in altered activity (increase or decrease) of these molecules, resulting in cell injury. Alternatively, the parent nephrotoxicant may not be toxic until it is biotransformed into a reactive intermediate that binds covalently to macromolecules and in turn alters their activity, resulting in cell injury. Finally, the toxicant may increase reactive oxygen species in the cells directly, after being biotransformed into a reactive intermediate or through redox cycling. The resulting increase in reactive oxygen species results in oxidative damage and cell injury.

Cell injury Cell repair

Cell death

Plasma RSG

Plasma RSG

R-SG

R + SG 1. R-SG

6.

Glomerular filtration 2. R-SG 3. 4. γ-Glu

Na+ Plasma R-Cys

7. R-Cys Na+

Plasma R-NAC

8. R-NAC Na+

5. R-Cys 12. NH3+H3CCOCO2H 10. 11. R-SH 13. Covalent binding Cell injury R-NAC

Basolateral membrane

9. Brush border membrane

R-Cys

R-NAC

Gly

FIGURE 15-16 This figure illustrates the renal proximal tubular uptake, biotransformation, and toxicity of glutathione and cysteine conjugates and mercapturic acids of haloalkanes and haloalkenes (R). 1) Formation of a glutathione conjugate within the renal cell (R-SG). 2) Secretion of the R-SG into the lumen. 3) Removal of the -glutamyl residue (-Glu) by -glutamyl transferase. 4) Removal of the glycinyl residue (Gly) by a dipeptidase. 5) Luminal uptake of the cysteine conjugate (R-Cys). Basolateral membrane uptake of R-SG (6), R-Cys (7), and a mercapturic acid (N-acetyl cysteine conjugate; R-NAC)(8). 9) Secretion of R-NAC into the lumen. 10) Acetylation of R-Cys to form R-NAC. 11) Deacetylation of R-NAC to form R-Cys. 12) Biotransformation of the penultimate nephrotoxic species (R-Cys) by cysteine conjugate -lyase to a reactive intermediate (R-SH), ammonia, and pyruvate. 13) Binding of the reactive thiol to cellular macromolecules (eg, lipids, proteins) and initiation of cell injury. (Adapted from Monks and Lau [5]; with permission.)

15.8

Acute Renal Failure

A

B Representative starting material

Submitochondrial fractions A. Untreated B. TFEC (30 mg/kg) Mr (kDa) 228 109

P99 P84 P66 P52 P42

70

Inter

Outer

Matrix

Inner

Inter

Outer

C

Matrix

Inner

44

FIGURE 15-17 Covalent binding of a nephrotoxicant metabolite in vivo to rat kidney tissue, localization of binding to the mitochondria, and identification of three proteins that bind to the nephrotoxicant. A, Binding of tetrafluoroethyl-L-cysteine (TFEC) metabolites in vivo to rat kidney tissue detected immunohistochemically. Staining was localized to the S3 segments of the proximal tubule, the segment that undergoes necrosis. B, Immunoreactivity in untreated rat kidneys. C, Isolation and fractionation of renal cortical mitochondria from untreated and TFEC treated rats and immunoblot analysis revealed numerous proteins that bind to the nephrotoxicant (innerinner membrane, matrix-soluble matrix, outer-outer membrane, inter-intermembrane space). The identity of three of the proteins that bound to the nephrotoxicant: P84, mortalin (HSP70-like); P66, HSP 60; and P42, aspartate aminotransferase. Mr—relative molecular weight. (From Hayden et al. [6], and Bruschi et al. [7]; with permission.)

Lipid peroxidation and mitochondrial dysfunction HH HO• •H

R Lipid

H 2O Hydrogen abstraction R Lipid radical

Diene conjugation R

• H O2 R •O–O H LH

O O

O

O

HOO H Fe(II) Fe(III)

Malondialdehyde

•O H

Lipid radical, conjugated diene

Oxygen addition R Lipid peroxyl radical

Hydrogen abstraction L• R Lipid hydroperoxide

Fenton reaction HO• R Lipid alkoxyl radical

Fragmentation H H

•

H LH • L

R

H O

Lipid aldehyde

H H

H

H

Ethane

FIGURE 15-18 A simplified scheme of lipid peroxidation. The first step, hydrogen abstraction from the lipid by a radical (eg, hydroxyl), results in the formation of a lipid radical. Rearrangement of the lipid radical results in conjugated diene formation. The addition of oxygen results in a lipid peroxyl radical. Additional hydrogen abstraction results in the formation of a lipid hydroperoxide. The Fenton reaction produces a lipid alkoxyl radical and lipid fragmentation, resulting in lipid aldehydes and ethane. Alternatively, the lipid peroxyl radical can undergo a series of reactions that result in the formation of malondialdehyde.

15.9

Pathophysiology of Nephrotoxic Acute Renal Failure 50

Control DCVC DCVC + DEF (1 mM) DCVC + DPPD (50µM)

80 LDH release, %

40 LDH release, %

100

Control TBHP (0.5 mmol) TBHP + DEF (1 mM) TBHP + DPPD (2 µM)

30 20 10

60 40 20

0

0 0

1

2

3

A

4

5

6

0

1

2

B

Time, h

1.2

3

4

5

6

Time, h

2.0 +1 mM DEF

Lipid peroxidation, nmol MDA•mg protein–1

Lipid peroxidation, nmol MDA•mg protein–1

1.0 0.8 0.6 0.4 0.2 0.0

C

Control

TBHP

+1 mM DEF

+2 µM DPPD

FIGURE 15-19 A–D, Similarities and differences between oxidant-induced and halocarbon-cysteine conjugate–induced renal proximal tubular lipid peroxidation and cell death. The model oxidant t-butylhydroperoxide (TBHP) and the halocarbon-cysteine conjugate dichlorovinyl-L-cysteine (DCVC) caused extensive lipid peroxidation after 1 hour of exposure and cell death (lactate dehydrogenase (LDH) release) over 6-hours’ exposure. The iron chelator deferoxamine (DEF) and the antioxidant N,N’-diphenyl-1, 4-phenylenediamine (DPPD) completely blocked both the lipid

ALTERATION OF RENAL TUBULAR CELL ENERGETICS AFTER EXPOSURE TO TOXICANTS Decreased oxygen delivery secondary to vasoconstriction Inhibition of mitochondrial respiration Increased tubular cell oxygen consumption

1.6

+50 µM DPPD

1.2 0.8 0.4 0.0

D

Control

DCVC

peroxidation and cell death caused by TBHP. In contrast, while DEF and DPPD completely blocked the lipid peroxidation caused by DCVC, cell death was only delayed. These results suggest that the iron-mediated oxidative stress caused by TBHP is responsible for the observed toxicity, whereas the iron-mediated oxidative stress caused by DCVC accelerates cell death. One reason that cells die in the absence of iron-mediated oxidative stress is that DCVC causes marked mitochondrial dysfunction. (Data from Groves et al. [8], and Schellmann [9].) FIGURE 15-20 Mechanisms by which nephrotoxicants can alter renal tubular cell energetics.

15.10

Acute Renal Failure FIGURE 15-21 Some of the mitochondrial targets of nephrotoxicants: 1) nicotinamide adenine dinucleotide (NADH) dehydrogenase; 2) succinate dehydrogenase; 3) coenzyme Q–cytochrome C reductase; 4) cytochrome C; 5) cytochrome C oxidase; 6) cytochrome Aa3; 7) H+-Pi contransporter; 8) F0F1ATPase; 9) adenine triphosphate/diphosphate (ATP/ADP) translocase; 10) protonophore (uncoupler); 11) substrate transporters.

Substrates 11

Cephaloridine

Atractyloside Ochratoxin A

TCA cycle

ADP

Bromohydroquinone

9 ATP

Dichlorovinyl–L–cysteine Tetrafluoroethyl–L–cysteine Pentachlorobutadienyl–L–cysteine Citrinin Ochratoxin A Hg2+ CN–

1

H+

ATP

H+

3

H+ Oligomycin

4 5

H+

Pi

6 O2

8

2

Pi H+

7

Matrix

H 2O

Ochratoxin A

10

Pentachlorobutadienyl–L–cysteine H+ Citrinin FCCP

Inner membrane Outer membrane

Disruption of ion homeostasis Na+

Na+

ATPase

– – –

ATP

Na+

Na+

ATPase

ATP

–

Cl–

Cl–

–

Cl

– – –

+

K

K+ –

K+

A

Cl–

B

Antimycin A

K+

Na+ Na+ ATPase Na+

ATPase

ATP

ATP Cl–

K+

Cl–

Cl–

Cl–

K+

A Antimycin A

100 90 80 70 60 50 40 30 20 10 0

Na+

K+

B Antimycin A

K+

H 2O

Membrane potential

QO2 K+

H 2O

ATP

0

FIGURE 15-22 Early ion movements after mitochondrial dysfunction. A, A control renal proximal tubular cell. Within minutes of mitochondrial inhibition (eg, by antimycin A), ATP levels drop, resulting in inhibition of the Na+, K+-ATPase. B, Consequently, Na+ influx, K+ efflux, membrane depolarization, and a limited degree of cell swelling occur.

Na+

Relative cellular changes

H 2O

Na+

5 Antimycin A

10

15

20

25

30

Time, min

FIGURE 15-23 A graphic of the phenomena diagrammed in Figure 15-22.

FIGURE 15-24 The late ion movements after mitochondrial dysfunction that leads to cell death/lysis. A, Cl- influx occurs as a distinct step subsequent to Na+ influx and K+ efflux. B, Following Cl- influx, additional Na+ and water influx occur resulting in terminal cell swelling. Ultimately cell lysis occurs.

Relative cellular changes

Pathophysiology of Nephrotoxic Acute Renal Failure

100 90 80 70 60 50 40 30 20 10 0

Na

15.11

FIGURE 15-25 A graph of the phenomena depicted in Figures 15-22 through 1524, illustrating the complete temporal sequence of events following mitochondrial dysfunction. QO2—oxygen consumption.

+

Cl– Membrane potential

QO2

H 2O

Ca++

K+

ATP

0

5

10

Antimycin A

15

20

25

30

Time, min

Disregulation of regulatory enzymes er Ca2+

BIOCHEMICAL CHARACTERISTICS OF CALPAIN ATP

2+

Ca (1 mM)

Ca2+ (100 nM)

Mitochondria

ATP

Ca2+

FIGURE 15-26 A simplified schematic drawing of the regulation of cytosolic free Ca2+.

Endopeptidase Heterodimer: 80-kD catalytic subunit, 30-kD regulatory subunit —Calpain and -calpain are ubiquitously distributed cytosolic isozymes —Calpain and -calpain have identical regulatory subunits but distinctive catalytic subunits —Calpain requires a higher concentration of Ca2+ for activation than -calpain Phospholipids reduce the Ca2+ requirement Substrates: cytoskeletal and membrane proteins and enzymes

FIGURE 15-27 Biochemical characteristics of calpain. FIGURE 15-28 Calpain translocation. Proposed pathways of calpain activation and translocation. Both calpain subunits may undergo calcium (Ca2+)-mediated autolysis within the cytosol and hydrolyze cytosolic substrates. Calpains may also undergo Ca2+-mediated translocation to the membrane, Ca2+-mediated, phospholipid-facilitated autolysis and hydrolyze membrane-associated substrates. The autolyzed calpains may be released from the membrane and hydrolyze cytosolic substrates. (From Suzuki and Ohno [10], and Suzuki et al. [11]; with permission.)

Acute Renal Failure

35

40

30

35 LDH release, %

LDH release, %

15.12

25 20 15

30 25 20 15

10

10

5

5

0

A

0 CON

TFEC

+C12

BHQ

+C12

TBHP

B

+C12

FIGURE 15-29 A, B, Dissimilar types of calpain inhibitors block renal proximal tubular toxicity of many agents. Renal proximal tubular suspensions were pretreated with the calpain inhibitor 2 (CI2) or PD150606 (PD). CI2 is an irreversible inhibitor of calpains that binds to the active site of the enzyme. PD150606 is a reversible inhibitor of calpains that binds to the calcium (Ca2+)-binding

CON

TFEC

+PD

BHQ

+PD

TBHP

+PD

domain on the enzyme. The toxicants used were the haloalkane cysteine conjugate tetrafluoroethyl-L-cysteine (TFEC), the alkylating quinone bromohydroquinone (BHQ), and the model oxidant tbutylhydroperoxide (TBHP). The release of lactate dehydrogenase (LDH) was used as a marker of cell death. CON—control. (From Waters et al. [12]; with permission.)

FIGURE 15-30 One potential pathway in which calcium (Ca2+) and calpains play a role in renal proximal tubule cell death. These events are subsequent to mitochondrial inhibition and ATP depletion. 1) -Calpain releases endoplasmic reticulum (er) Ca2+ stores. 2) Release of er Ca2+ stores increases cytosolic free Ca2+ concentrations. 3) The increase in cytosolic free Ca2+ concentration mediates extracellular Ca2+ entry. (This may also occur as a direct result of er Ca2+ depletion.) 4) The influx of extracellular Ca2+ further increases cytosolic free Ca2+ concentrations. 5) This initiates the translocation of nonactivated m-calpain to the plasma membrane (6). 7) At the plasma membrane nonactivated m-calpain is autolyzed and hydrolyzes a membrane-associated substrate. 8) Either directly or indirectly, hydrolysis of the membrane-associated substrate results in influx of extracellular chloride ions (Cl-). The influx of extracellular Cl- triggers terminal cell swelling. Steps a–d represent an alternate pathway that results in extracellular Ca2+ entry. (Data from Waters et al. [12,13,14].) FIGURE 15-31 Biochemical characteristics of several identified phospholipase A2s.

PROPERTIES OF PHOSPHOLIPASE A2 GROUP Characteristics

Secretory

Cytosolic

Localization Molecular mass Arachidonate preference Ca2+ required Ca2+ role

Secreted ~14 kDa  mM Catalysis

Cytosolic ~85 kDa  (M Memb. Assoc.

Ca2+-Independent Cytosolic ~40 kDa  None None

Membrane unknown  None None

15.13

Pathophysiology of Nephrotoxic Acute Renal Failure 50

80 LLC-cPLA2 LLC-vector

LDH release, % total

AA release, %

40

LLC-cPLA2 LLC-PK1 LLC-vector

70

30 20 10

60 50 40 30 20 10

0

0 30

60

A

90

120

0.0

LLC-cPLA2 LLC-sPLA2 LLC-vector

50 40 30 20 10 0 0.0

C

0.1

0.2

0.3 [H2O2], mmol

0.4

0.5

0.5

FIGURE 15-33 Potential role of caspases in cell death in LLC-PK1 cells exposed to antimycin A. A, Time-dependent effects of antimycin A treatment on caspase activity in LLC-PK1 cells. B, C, The effect of two capase inhibitors on antimycin A–induced DNA damage and cell death, respectively. Antimycin A is an inhibitor of mitochondrial electron transport.

r II bito

rI bito

Con trol

C

Inhi

B

Inhi

0 Ant imy cin A

Cell death, %

0 r II

30 10 20 Time of antimycin A treatment, min

bito

0

20 10

Con trol

0

30

25

Inhi

50

50

rI

100

40 75

bito

150

100

Ant imy cin A

Residual double-stranded DNA, %

∆ Increase in caspase activity, units/mg protein

0.4

50

200

A

0.3 [H2O2], mmol

Inhi

LDH release, % total

60

0.2

FIGURE 15-32 The importance of the cytosolic phospholipase A2 in oxidant injury. A, Time-dependent release of arachidonic acid (AA) from LLC-PK1 cells exposed to hydrogen peroxide (0.5 mM). B and C, The concentration-dependent effects of hydrogen peroxide on LLC-PK1 cell death (using lactate dehydrogenase [LDH] release as marker) after 3 hours’ exposure. Cells were transfected with 1) the cytosolic PLA2 (LLC-cPLA2), 2) the secretory PLA2 (LLC-sPLA2), 3) vector (LLC-vector), or 4) were not transfected (LLC-PK1). Cells transfected with cytosolic PLA2 exhibited greater AA release and cell death in response to oxidant exposure than cells transfected with the vector or secretory PLA2 or not transfected. These results suggest that activation of cytosolic PLA2 during oxidant injury contributes to cell injury and death. (From Sapirstein et al. [15]; with permission.)

80 70

0.1

B

Time, min

Inhibitor 1 is IL-1 converting enzyme inhibitor 1 (YVAD-CHO) and inhibitor II is CPP32/apopain inhibitor (DEVD-CHO). These results suggest that caspases are activated after mitochondrial inhibition and that caspases may contribute to antimycin A–induced DNA damage and cell death. (From Kaushal et al. [16]; with permission.)

15.14

Acute Renal Failure

References 1.

Fish EM, Molitoris BA: Alterations in epithelial polarity and the pathogenesis of disease states. N Engl J Med 1994, 330:1580.

2.

Gailit J, Colfesh D, Rabiner I, et al.: Redistribution and dysfunction of integrins in cultured renal epithelial cells exposed to oxidative stress. Am J Physiol 1993, 264:F149.

3.

Nowak G, Aleo MD, Morgan JA, Schnellmann RG: Recovery of cellular functions following oxidant injury. Am J Physiol 1998, 274:F509.

4.

Majno G, Joris I: Apoptosis, oncosis and necrosis. Am J Pathol 1995, 146:3.

5.

Monks TJ, Lau SS: Renal transport processes and glutathione conjugate–mediated nephrotoxicity. Drug Metab Dispos 1987, 15:437.

6.

Hayden PJ, Ichimura T, McCann DJ, et al.: Detection of cysteine conjugate metabolite adduct formation with specific mitochondrial proteins using antibodies raised against halothane metabolite adducts. J Biol Chem 1991, 266:18415. Bruschi SA, West KA, Crabb JW, et al.: Mitochondrial HSP60 (P1 protein) and a HSP70-like protein (mortalin) are major targets for modification during S-(1,1,2,2-tetrafluoroethyl)-L-cysteine–induced nephrotoxicity. J Biol Chem 1993, 268:23157. Groves CE, Lock EA, Schnellmann RG: Role of lipid peroxidation in renal proximal tubule cell death induced by haloalkene cysteine conjugates. Toxicol Appl Pharmacol 1991, 107:54. Schnellmann RG: Pathophysiology of nephrotoxic cell injury. In Diseases of the Kidney. Edited by Schrier RW, Gottschalk CW. Boston:Little Brown; 1997:1049.

7.

8.

9.

10. Suzuki K, Ohno S: Calcium activated neutral protease: Structure-function relationship and functional implications. Cell Structure Function 1990, 15:1. 11. Suzuki K, Sorimachi H, Yoshizawa T, et al.: Calpain: Novel family members, activation, and physiologic function. Biol Chem HoppeSeyler 1995, 376:523. 12. Waters SL, Sarang SS, Wang KKW, Schnellmann RG: Calpains mediate calcium and chloride influx during the late phase of cell injury. J Pharmacol Exp Ther 1997, 283:1177. 13. Waters SL, Wong JK, Schnellmann RG: Depletion of endoplasmic reticulum calcium stores protects against hypoxia- and mitochondrial inhibitor–induced cellular injury and death. Biochem Biophys Res Commun 1997, 240:57. 14. Waters SL, Miller GW, Aleo MD, Schnellmann RG: Neurosteroid inhibition of cell death. Am J Physiol 1997, 273:F869. 15. Sapirstein A, Spech RA, Witzgall R, Bonventre JV: Cytosolic phospholipase A2 (PLA2), but not secretory PLA2, potentiates hydrogen peroxide cytotoxicity in kidney epithelial cells. J Biol Chem 1996, 271:21505. 16. Kaushal GP, Ueda N, Shah SV: Role of caspases (ICE/CED3 proteases) in DNA damage and cell death in response to a mitochondrial inhibitor, antimycin A. Kidney Int 1997, 52:438.

Acute Renal Failure: Cellular Features of Injury and Repair Kevin T. Bush Hiroyuki Sakurai Tatsuo Tsukamoto Sanjay K. Nigam

A

lthough ischemic acute renal failure (ARF) is likely the result of many different factors, much tubule injury can be traced back to a number of specific lesions that occur at the cellular level in ischemic polarized epithelial cells. At the onset of an ischemic insult, rapid and dramatic biochemical changes in the cellular environment occur, most notably perturbation of the intracellular levels of ATP and free calcium and increases in the levels of free radicals, which lead to alterations in structural and functional cellular components characteristic of renal epithelial cells [1–7]. These alterations include a loss of tight junction integrity, disruption of actin-based microfilaments, and loss of the apical basolateral polarity of epithelial cells. The result is loss of normal renal cell function [7–12]. After acute renal ischemia, the recovery of renal tubule function is critically dependent on reestablishment of the permeability barrier, which is crucial to proper functioning of epithelial tissues such as renal tubules. After ischemic injury the formation of a functional permeability barrier, and thus of functional renal tubules, is critically dependent on the establishment of functional tight junctions. The tight junction is an apically oriented structure that functions as both the “fence” that separates apical and basolateral plasma membrane domains and the major paracellular permeability barrier (gate). It is not yet clear how the kidney restores tight junction structure and function after ischemic injury. In fact, tight junction assembly under normal physiological conditions remains ill-understood; however, utilization of the

CHAPTER

16

16.2

Acute Renal Failure

“calcium switch” model with cultured renal epithelial cells has helped to elucidate some of the critical features of tight junction bioassembly. In this model for tight junction reassembly, signaling events involving G proteins, protein kinase C, and calcium appear necessary for the reestablishment of tight junctions [13–19]. Tight junction injury and recovery, like that which occurs after ischemia and reperfusion, has similarly been modeled by subjecting cultured renal epithelial cells to ATP depletion (“chemical anoxia”) followed by repletion. While there are many similarities to the calcium switch, biochemical studies have recently revealed major differences, for example, in the way tight junction proteins interact with the cytoskeleton [12]. Thus, important insights into the basic and applied biology of tight junctions are likely to be forthcoming from further analysis of the ATP depletion-repletion model. Nevertheless, it is likely that, as in the calcium switch model, tight junction reassembly is regulated by classical signaling pathways that might potentially be pharmacologically modulated to enhance recovery after ischemic insults. More prolonged insults can lead to greater, but still sublethal, injury. Key cellular proteins begin to break down. Many of these (eg, the tight junction protein, occludin, and the adherens junction

protein, E-cadherin) are membrane proteins. Matrix proteins and their integrin receptors may need to be resynthesized, along with growth factors and cytokines, all of which pass through the endoplasmic reticulum (ER). The rate-limiting events in the biosynthesis and assembly of these proteins occur in the ER and are catalyzed by a set of ER-specific molecular chaperones, some of which are homologs of the cytosolic heat-shock proteins [20]. The levels of mRNAs for these proteins may increase 10-fold or more in the ischemic kidney, to keep up with the cellular need to synthesize and transport these new membrane proteins, as well as secreted ones. If the ischemic insult is sufficiently severe, cell death and/or detachment leads to loss of cells from the epithelium lining the kidney tubules. To recover from such a severe insult, cell regeneration, differentiation, and possibly morphogenesis, are necessary. To a limited extent, the recovery of kidney tubule function after such a severe ischemic insult can be viewed as a recapitulation of various steps in renal development. Cells must proliferate and differentiate, and, in fact, activation of growth factor–mediated signaling pathways (some of the same ones involved in kidney development) appears necessary to ameliorate renal recovery after acute ischemic injury [21–30].

The Ischemic Epithelial Cell Functional renal tubules Uninjured cells

Ischemic insult Injured cells

↓ATP; ↑[CA2+]i; ↑Free radicals; Other changes?

Tight junction disruption

Apical-basolateral polarity disruption

Microfilament disruption

Dysfunctional renal tubular epithelial cells Remove insult

Continued insult

Cellular repair

Cell loss (detachment or death)

Cell regenertation, differentiation, and morphogenesis Remove insult

FIGURE 16-1 Ischemic acute renal failure (ARF). Flow chart illustrates the cellular basis of ischemic ARF. As described above, renal tubule epithelial cells undergo a variety of biochemical and structural changes in response to ischemic insult. If the duration of the insult is sufficiently short, these alterations are readily reversible, but if the insult continues it ultimately leads to cell detachment and/or cell death. Interestingly, unlike other organs in which ischemic injury often leads to permanent cell loss, a kidney severely damaged by ischemia can regenerate and replace lost epithelial cells to restore renal tubular function virtually completely, although it remains unclear how this happens.

Acute Renal Failure: Cellular Features of Injury and Repair

FIGURE 16-2 Typical renal epithelial cell. Diagram of a typical renal epithelial cell. Sublethal injury to polarized epithelial cells leads to multiple lesions, including loss of the permeability barrier and apical-basolateral polarity [7–12]. To recover, cells must reestablish intercellular junctions and repolarize to form distinct apical and basolateral domains characteristic of functional renal epithelial cells. These junctions include those necessary for maintaining the permeability barrier (ie, tight junctions), maintaining cell-cell contact (ie, adherens junctions and desmosomes), and those involved in cell-cell communication (ie, gap junctions). In addition, the cell must establish and maintain contact with the basement membrane through its integrin receptors. Thus, to understand how kidney cells recover from sublethal ischemic injury it is necessary to understand how renal epithelial cells form these junctions. Furthermore, after lethal injury to tubule cells new cells may have to replace those lost during the ischemic insult, and these new cells must differentiate into epithelial cells to restore proper function to the tubules.

Brush border

Tight junction Adherens junction

Terminal web Actin cortical ring

Desmosome

16.3

Intermediate filaments

Gap junction

Na+, K+, ATPase

Integrins

Extracellular matrix

Occludin

Symplekin 7H6 Cingulin

p130 ZO–1 ZO–2

Actin filaments Fodrin

Paracellular space

FIGURE 16-3 The tight junction. The tight junction, the most apical component of the junctional complex of epithelial cells, serves two main functions in epithelial cells: 1) It separates the apical and basolateral plasma membrane domains of the cells, allowing for vectorial transport of ions and molecules; 2) it provides the major framework for the paracellular permeability barrier, allowing for generation of chemical and electrical gradients [31]. These functions are critically important to the proper functioning of renal tubules. The tight junction is comprised of a number of proteins (cytoplasmic and transmembrane) that interact with a similar group of proteins between adjacent cells to form the permeability barrier [16, 32–37]. These proteins include the transmembrane protein occludin [35, 38] and the cytosolic proteins zonula occludens 1 (ZO-1), ZO-2 [36], p130, [39], cingulin [33, 40], 7H6 antigen [34] and symplekin [41], although other as yet unidentified components likely exist. The tight junction also appears to interact with the actin-based cytoskeleton, probably in part through ZO-1–fodrin interactions.

16.4

Acute Renal Failure

Reassembly of the Permeability Barrier Reutilization of existing junctional components

Synthesis of new junctional components

Polarized renal epithelial cells

Nonpolarized renal epithelial cells

Nonpolarized renal epithelial cells

Intact intercellular junctions

Compromised intercellular junctions

Damaged disassembled intercellular junctions

Cell death Apoptosis Necrosis

Deplete ATP

Short-term ATP depletion 0–1 h

Replete ATP

Long-term ATP depletion 2.5-4 h

Replete ATP

Severe ATP depletion 6+ h

FIGURE 16-4 Cell culture models of tight junction disruption and reassembly. The disruption of the permeability barrier, mediated by the tight junction, is a key lesion in the pathogenesis of tubular dysfunction after ischemia and reperfusion. Cell culture models employing ATP depletion and repletion protocols are a commonly used approach for understanding the molecular

occludin

ZO-1

fodrin

control

ATP depletion (1 hr)

ATP repletion (3hrs)

FIGURE 16-5 Immunofluorescent localization of proteins of the tight junction after ATP depletion and repletion. The cytosolic protein zonula

Occludin

Occludin Fodrin ZO–1

ZO–1

Fodrin ZO–2

Actin filament

Ischemia ATP depletion

ZO–2

Actin filament

Membrane vesicle?

mechanisms underlying tight junction dysfunction in ischemia and how tight junction integrity recovers after the insult [6, 12, 42]. After short-term ATP depletion (1 hour or less) in Madin-Darby canine kidney cells, although some new synthesis probably occurs, by and large it appears that reassembly of the tight junction can proceed with existing (disassembled) components after ATP repletion. This model of short-term ATP depletion-repletion is probably most relevant to transient sublethal ischemic injury of renal tubule cells. However, in a model of longterm ATP depletion (2.5 to 4 hours), that probably is most relevant to prolonged ischemic (though still sublethal) insult to the renal tubule, it is likely that reestablishment of the permeability barrier (and thus of tubule function) depends on the production (message and protein) and bioassembly of new tight junction components. Many of these components (membrane proteins) are assembled in the endoplasmic reticulum.

occludens 1 (ZO-1), and the transmembrane protein occludin are integral components of the tight junction that are intimately associated at the apical border of epithelial cells. This is demonstrated here by indirect immunofluorescent localization of these two proteins in normal kidney epithelial cells. After 1 hour of ATP depletion this association appears to change, occludin can be found in the cell interior, whereas ZO-1 remains at the apical border of the plasma membrane. Interestingly, the intracellular distribution of the actin-cytoskeletal–associated protein fodrin also changes after ATP depletion. Fodrin moves from a random, intracellular distribution and appears to become co-localized with ZO-1 at the apical border of the plasma membrane. These changes are completely reversible after ATP repletion. These findings suggest that disruption of the permeability barrier could be due, at least in part, to altered association of ZO-1 with occludin. In addition, the apparent co-localization of ZO-1 and fodrin at the level of the tight junction suggests that ZO-1 is becoming intimately associated with the cytoskeleton. FIGURE 16-6 ATP depletion causes disruption of tight junctions. Diagram of the changes induced in tight junction structure by ATP depletion. ATP depletion causes the cytoplasmic tight junction proteins zonula occludens 1 (ZO-1) and ZO-2 to form large insoluble complexes, probably in association with the cytoskeletal protein fodrin [12], though aggregation may also be significant. Furthermore, occludin, the transmembrane protein of the tight junction, becomes localized to the cell interior, probably in membrane vesicles. These kinds of studies have begun to provide insight into the biochemical basis of tight junction disruption after ATP depletion, although how the tight junction reassembles during recovery of epithelial cells from ischemic injury remains unclear.

Acute Renal Failure: Cellular Features of Injury and Repair

Low calcium (LC)

16.5

FIGURE 16-7 Madin-Darby canine kidney (MDCK) cell calcium switch. Insight into the molecular mechanisms involved in the assembly of tight junctions (that may be at least partly applicable to the ischemia-reperfusion setting) has been gained from the MDCK cell calcium switch model [43]. MDCK cells plated on a permeable support form a monolayer with all the characteristics of a tight, polarized transporting epithelium. Exposing such cell monolayers to conditions of low extracellular calcium (less than 5M) causes the cells to lose cell-cell contact and to “round up.” Upon switching back to normal calcium media (1.8 mM), the cells reestablish cell-cell contact, intercellular junctions, and apical-basolateral polarity. These events are accompanied by profound changes in cell shape and reorganization of the actin cytoskeleton. (From Denker and Nigam [19]; with permission)

Calcium switch (NC)

A

B

C

D

FIGURE 16-8 Protein kinase C (PKC) is important for tight junction assembly. Immunofluorescent localization of the tight junction protein zonula occludens 1 (ZO-1) during the Madin-Darby canine kidney (MDCK) cell calcium switch. In low-calcium media MDCK cells are round and have little cellcell contact. Under these conditions, ZO-1 is found in the cell interior and has little, if any, membrane staining, A. After 2 hours incubation in normal calcium media, MDCK cells undergo significant changes in cell shape and make extensive cell-cell contact along the lateral portions of the plasma membrane. B, Here, ZO-1 has redistributed to areas of cell-cell contact with little apparent intracellular staining. This process is blocked by treatment with either 500 nM calphostin C, C, or 25M H7, D, inhibitors of PKC. These results suggest that PKC plays a role in regulating tight junction assembly. Similar studies have demonstrated roles for a number of other signaling molecules, including calcium and G proteins, in the assembly of tight junctions [12, 13, 16–19, 37, 44–46]. An analogous set of signaling events is likely responsible for tight junction reassembly after ischemia. (From Stuart and Nigam [16]; with permission.)

16.6

Acute Renal Failure FIGURE 16-9 Signalling molecules that may be involved in tight junction assembly. Model of the potential signaling events involved in tight junction assembly. Tight junction assembly probably depends on a complex interplay of several signaling molecules, including protein kinase C (PKC), calcium (Ca2+), heterotrimeric G proteins, small guanodine triphosphatases (Rab/Rho), and tyrosine kinases [13–16, 18, 37, 44–53]. Although it is not clear how this process is initiated, it depends on cell-cell contact and involves wide-scale changes in levels of intracellular free calcium. Receptor/CAM—cell adhesion molecule; DAG—diacylglycerol; ER—endoplasmic reticulum; G—alpha subunit of GTP-binding protein; IP3—inositol trisphosphate. (From Denker and Nigam [19]; with permission.)

PKC

P-Tyr P-Ser P Gα

Effector

Tyr-kinases ?TP

DAG 2+ Ca + IP3

Rab/Rho

?Receptor/CAM ER

The Endoplasmic Reticulum Stress Response in Ischemia mRNA Ribosome Free chaperones

Secretioncompetent

reutilization

protein Dissociation of chaperones ATP ADP

Protein folding Peptidyl-prolyl isomerization N-linked glycosylation Disulfide bond formation

n ein ot tio Pr iza r e m go oli

Misassembled protein

Degradation Misfolded protein Resident ER proteolytic pathway? To proteasome?

To Golgi

FIGURE 16-10 Protein processing in the endoplasmic reticulum (ER). To recover from serious injury, cells must synthesize and assemble new membrane (tight junction proteins) and secreted (growth factors) proteins. The ER is the initial site of synthesis of all membrane and secreted proteins. As a protein is translocated into the lumen of the ER it begins to interact with a group of resident ER proteins called molecular chaperones [20, 54–57]. Molecular chaperones bind transiently to and interact with these nascent polypeptides as they fold, assemble, and oligomerize [20, 54, 58]. Upon successful completion of folding or assembly, the molecular chaperones and the secretioncompetent protein part company via a reaction that requires ATP hydrolysis, and the chaperones are ready for another round of protein folding [20, 59–61]. If a protein is recognized as being misfolded or misassembled it is retained within the ER via stable association with the molecular chaperones and is ultimately targeted for degradation [62]. Interestingly, some of the more characteristic features of epithelial ischemia include loss of cellular functions mediated by proteins that are folded and assembled in the ER (ie, cell adhesion molecules, integrins, tight junctional proteins, transporters). This suggests that proper functioning of the proteinfolding machinery of the ER could be critically important to the ability of epithelial cells to withstand and recover from ischemic insult. ADP—adenosine diphosphate.

Acute Renal Failure: Cellular Features of Injury and Repair

45' Ischemia GAPDH

BiP

BiP

grp94

grp94

ERp72

ERp72

1

2

FIGURE 16-11 Ischemia upregulates endoplasmic reticulum (ER) molecular chaperones. Molecular chaperones of the ER are believed to function normally to prevent inappropriate intra- or intermolecular interactions during the folding and assembly of proteins [20, 54]. However, ER molecular chaperones are also part of the “quality control” apparatus involved in the recognition, retention, and degradation of proteins that fail to fold or assemble properly as they transit the ER [20, 54]. In fact, the messages encoding the ER molecular chaperones are known to increase in response to intraorganelle accumulation of such malfolded proteins [11, 20, 54, 55]. Here, Northern blot analysis of total RNA from either whole kidney or cultured epithelial cells demonstrates that ischemia or ATP depletion induces the mRNAs that encode the ER molecular chaperones, including immunoglobulin binding protein (BiP), 94 kDa glucose regulated protein (grp94), and 72 kDa endoplasmic reticulum protein (Erp72) [11]. This suggests not only that ischemia or ATP depletion causes the accumulation of malfolded proteins in the ER but that a major effect of ischemia and ATP depletion could be perturbation of the “folding environment” of the ER and disruption of protein processing. GAPDH—glyceraldehyde-3phosphate dehydrogenase; Hsp70—70 kDa heat-shock protein. (From Kuznetsov et al. [11]; with permission.)

15' Ischemia

GAPDH

3

1

A

2

3

A B Thyroid Cell Line

Kidney Cell Line 28 S rRNA

GAPDH

BiP BiP grp94 grp94 ERp72 ERp72 Hsp70

Hsp70

1

2

3

4

5

1

6

2

3

4

D C

C

MED

PBS

1M

5M

10M

Antimycin A

1

2

3

4

5

Tg

A

16.7

B

FIGURE 16-12 ATP depletion perturbs normal endoplasmic reticulum (ER) function. Because ATP and a proper redox environment are necessary for folding and assembly [20, 54, 63, 64] and ATP depletion alters ATP levels and the redox environment, the secretion of proteins is perturbed under these conditions. Here, Western blot analysis of the culture media from thyroid epithelial cells subjected to ATP depletion (ie, treatment with antimycin A, an inhibitor of oxidative phosphorylation) illustrates this point. A, Treatment with as little as 1M antimycin A for 1 hour completely blocks the secretion of thyroglobulin (Tg) from these cells. (Continued on next page)

16.8

Acute Renal Failure FIGURE 16-12 (Continued) B–D, Moreover, indirect immunofluorescence with antithyroglobulin antibody demonstrates that the nonsecreted protein is trapped almost entirely in the ER. Together with data from Northern blot analysis, this suggests that perturbation of ER function and disruption of the secretory pathway is likely to be a key cellular lesion in ischemia [11]. MED—control media; PBS—phosphate-buffered saline. (From Kuznetsov et al. [11]; with permission.)

D

C Antimycin A MED

PBS

1

5

10

Tg

grp94

BiP

ERp72 1

2

3

4

5

FIGURE 16-13 ATP depletion increases the stability of chaperone-folding polypeptide interactions in the endoplasmic reticulum (ER). Immunoglobulin binding protein (BiP), and perhaps other ER molecular chaperones, associate with nascent polypeptides as they are folded and assembled in ER [20, 54, 56, 57, 65–73]. The dissociation of these proteins requires hydrolysis of ATP [69]. Thus, when levels of ATP drop, BiP should not dissociate from the secretory proteins and the normally transient interaction should become more stable. Here, the associations of ER molecular chaperones with a model ER secretory protein is examined by Western blot analysis of thyroglobulin (Tg) immunoprecipitates from thyroid cells subjected to ATP depletion. After treatment with antimycin A, there is an increase in the amounts of ER molecular chaperones (BiP, grp94 and ERP72) which co-immunoprecipitate with antithyroglobulin antibody [11], suggesting that ATP depletion causes stabilization of the interactions between molecular chaperones and secretory proteins folded and assembled in the ER. Moreover, because a number of proteins critical to the proper functioning of polarized epithelial cells (ie, occludin, E-cadherin, Na-K-ATPase) are folded and assembled in the ER, this suggests that recovery from ischemic injury is likely to depend, at least in part, on the ability of the cell to rescue the protein-folding and assembly apparatus of the ER. Control media (MED) and phosphate buffered saline (PBS)—no ATP depletion; 1, 5, 10M antimycin A—ATP-depleting conditions. (From Kuznetsov et al. [11]; with permission.)

16.9

Acute Renal Failure: Cellular Features of Injury and Repair

Growth Factors and Morphogenesis Basement membrane degrading proteinases

Cytoskeletal rearrangement

Integrin receptors for interstitial matrix

Terminal nephron

Proteinases Cell-surface receptors for proteinases (uPA-R, ? for MMPs)

Arcade

A

B

Lack of integrin-mediated basement membrane initiated signaling

FIGURE 16-14 Kidney morphogenesis. Schematics demonstrate the development of the ureteric bud and metanephric mesenchyme during kidney organogenesis. During embryogenesis, mutual inductive events between the metanephric mesenchyme and the ureteric bud give rise to primordial structures that differentiate and fuse to form functional nephrons [74-76]. Although the process has been described morphologically, the nature and identity of molecules involved in the signaling and regulation of these events remain unclear. A, Diagram of branching tubulogenesis of the ureteric bud during kidney organogenesis. The ureteric bud is induced by the metanephric mesenchyme to branch and elongate to form the urinary collecting system [74-76]. B, Model of cellular events involved in ureteric bud branching. To branch and elongate, the ureteric bud must digest its way through its own basement membrane, a highly complicated complex of extracellular matrix proteins. It is believed that this is accomplished by cellular projections, “invadopodia,” which allow for localized sites of proteolytic activity at their tips [77-81]. C, Mesenchymal cell compaction. The metanephric mesenchyme not only induces ureteric bud branching but is also induced by the ureteric bud to epithelialize and differentiate into the proximal through distal tubule [74–76]. (From Stuart and Nigam [80] and Stuart et al. [81]; with permission.)

Uninduced mesenchyme

Condensing cells

S-shaped body

C

Tubulogenesis in vitro Basic research

Applied research

Renal development

Renal diseases Renal injury and repair Renal cystic diseases Urogenital abnormalities Hypertension Artificial kidneys

FIGURE 16-15 Potential of in vitro tubulogenesis research. Flow chart indicates relevance of in vitro models of kidney epithelial cell branching tubulogenesis to basic and applied areas of kidney research. While results from such studies provide critical insight into kidney development, this model system might also contribute to the elucidation of mechanisms involved in kidney injury and repair for a number of diseases, including tubular epithelial cell regeneration secondary to acute renal failure. Moreover, these models of branching tubulogenesis could lead to therapies that utilize tubular engineering as artificial renal replacement therapy [82].

16.10

Acute Renal Failure

Mitogenesis

Motogenesis

Growth factor

Cell proliferation

Cell movement

Cell organization Morphogenesis

Antiapoptosis

Cell survival

FIGURE 16-16 Cellular response to growth factors. Schematic representation of the pleiotrophic effects of growth factors, which share several properties and are believed to be important in the development and morphogenesis of organs and tissues, such as those of the kidney. Among these properties are the ability to regulate or activate numerous cellular signaling responses, including proliferation (mitogenesis), motility (motogenesis), and differentiation (morphogenesis). These characteristics allow growth factors to play critical roles in a number of complex biological functions, including embryogenesis, angiogenesis, tissue regeneration, and malignant transformation [83].

DD

Remodeling of cell substratum

A

B

C

D

FIGURE 16-17 Motogenic effect of growth factors—hepatocyte growth factor (HGF) induces cell “scattering.” During development or regeneration the recruitment of cells to areas of new growth is vital. Growth factors have the ability to induce cell movement. Here, subconfluent monolayers of either Madin-Darby canine kidney (MDCK) C, D, or murine inner medullary collecting duct (mIMCD) A, B, cells were grown for 24 hours in the absence, A, C, or presence B, D, of 20 ng/mL HGF. Treatment of either

type of cultured renal epithelial cell with HGF induced the dissociation of islands of cells into individual cells. This phenomenon is referred to as scattering. HGF was originally identified as scatter factor, based on its ability to induce the scattering of MDCK cells [83]. Now, it is known that HGF and its receptor, the transmembrane tyrosine kinase c-met, play important roles in development, regeneration, and carcinogenesis [83]. (From Cantley et al. [84]; with permission.)

Acute Renal Failure: Cellular Features of Injury and Repair

Growth factors

FIGURE 16-18 Three-dimensional extracellular matrix gel tubulogenesis model. Model of the three-dimensional gel culture system used to study

A

the branching and tubulogenesis of renal epithelial cells. Analyzing the role of single factors (ie, extracellular matrix, growth factors, cell-signaling processes) involved in ureteric bud branching tubulogenesis in the context of the developing embryonic kidney is an extremely daunting task, but a number of model systems have been devised that allow for such investigation [77, 79, 85]. The simplest model exploits the ability of isolated kidney epithelial cells suspended in gels composed of extracellular matrix proteins to form branching tubular structures in response to growth factors. For example, Madin-Darby canine kidney (MDCK) cells suspended in gels of type I collagen undergo branching tubulogenesis reminiscent of ureteric bud branching morphogenesis in vivo [77, 79]. Although the results obtained from such studies in vitro might not correlate directly with events in vivo, this simple, straightforward system allows one to easily manipulate individual components (eg, growth factors, extracellular matrix components) involved in the generation of branching epithelial tubules and has provided crucial insights into the potential roles that these various factors play in epithelial cell branching morphogenesis [77, 79, 84–87].

B

FIGURE 16-19 An example of the branching tubulogenesis of renal epithelial cells cultured in threedimensional extracellular matrix gels. Microdissected mouse embryonic kidneys (11.5 to 12.5 days) were cocultured with A, murine inner medullary collecting duct

Pregnant SV40–transgenic mouse

Isolate embryos

Dissect out embryonic kidney

Isolate metanephric mesenchyme

Isolate ureteric bud

Culture to obtain immortalized cells

16.11

(mIMCD) or, B, Madin-Darby canine kidney (MDCK) cells suspended in gels of rat-tail collagen (type I). Embryonic kidneys (EK) induced the formation of branching tubular structures in both mIMCD and MDCK cells after 48 hours of incubation at 37oC. EKs produce a number of growth factors, including hepatocyte growth factor, transforming growth factor-alpha, insulin-like growth factor, and transforming growth factor–, which have been shown to effect tubulogenic activity [86–93]. Interestingly, many of these same growth factors have been shown to be effective in the recovery of renal function after acute ischemic insult [21–30]. (From Barros et al. [87]; with permission.)

FIGURE 16-20 Development of cell lines derived from embryonic kidney. Flow chart of the establishment of ureteric bud and metanephric mesenchymal cell lines from day 11.5 mouse embryo. Although the results obtained from the analysis of kidney epithelial cells— Madin-Darby canine kidney (MDCK) or murine inner medullary collecting duct (mIMCD) seeded in three-dimensional extracellular matrix gels has been invaluable in furthering our understanding of the mechanisms of epithelial cell branching tubulogenesis, questions can be raised about the applicability to embryonic development of results using cells derived from terminally differentiated adult kidney epithelial cells [94]. Therefore, kidney epithelial cell lines have been established that appear to be derived from the ureteric bud and metanephric mesenchyme of the developing embryonic kidney of SV-40 transgenic mice [94, 95]. These mice have been used to establish a variety of “immortal” cell lines.

16.12

Acute Renal Failure

A

B

C

FIGURE 16-21 Ureteric bud cells undergo branching tubulogenesis in threedimensional extracellular matrix gels. Cell line derived from ureteric bud (UB) and metanephric mesenchyme from day 11.5 mouse embryonic kidney undergo branching tubulogenesis in three-dimensional extracellular matrix gels. Here, UB cells have been induced to form branching tubular structures in response to “conditioned” media collected from the culture of metanephric mesenchymal cells. During normal kidney morphogenesis, these two embryonic cell types undergo a mutually inductive process that ultimately leads to the formation of functional nephrons [74–76]. This model system illustrates this process, ureteric bud cells being induced by factors secreted from metanephric mesenchymal cells. Thus, this system could represent the simplest in

Free HGF and empty c-Met receptor

HGF binding to c-Met receptor

C–Met

C–Met

HGF

HGF

HGF

Plasma membrane Gab-1

Gab-1

Dimerization of c-Met receptor and activation of Gab 1 HGF

HGF HGF

C–Met

Gab-1

Growth factor binding

HGF

HGF HGF

Plasma membrane Gab-1

vitro model with the greatest relevance to early kidney development [94]. A, UB cells grown for 1 week in the presence of conditioned media collected from cells cultured from the metanephric mesenchyme. Note the formation of multicellular cords. B, After 2 weeks’ growth under the same conditions, UB cells have formed more substantial tubules, now with clear lumens. C, Interestingly, after 2 weeks of culture in a three-dimensional gel composed entirely of growth factor–reduced Matrigel, ureteric bud cells have not formed cords or tubules, only multicellular cysts. Thus, changing the matrix composition can alter the morphology from tubules to cysts, indicating that this model might also be relevant to renal cystic disease, much of which is of developmental origin. (From Sakurai et al. [94]; with permission.)

Plasma membrane Gab-1

Gab-1

Transduction of Gab-1 signal leading to branching tubulogenesis

FIGURE 16-22 Signalling pathway of hepatocyte growth factor action. Diagram of the proposed intracellular signaling pathway involved in hepatocyte growth factor (HGF)–mediated tubulogenesis. Although HGF is perhaps the best-characterized of the growth factors involved in epithelial cell-branching tubulogenesis, very little of its mechanism of action is understood. However, recent evidence has shown that the HGF receptor (c-Met) is associated with Gab-1, a docking protein believed to be involved in signal transduction [96]. Thus, on binding to c-Met, HGF activates Gab-1–mediated signal transduction, which, by an unknown mechanism, affects changes in cell shape and cell movement or cell-cell–cell-matrix interactions. Ultimately, these alterations lead to epithelial cell–branching tubulogenesis.

Branching morphogenesis

Up-regulation of proteases Mitogenic response Motogenic response Alteration of cytoskeleton Other responses

FIGURE 16-23 Mechanism of growth factor action. Proposed model for the generalized response of epithelial cells to growth factors, which the depends on their environment. Epithelial cells constantly monitor their surrounding environment via extracellular receptors (ie, integrin receptors) and respond accordingly to growth factor stimulation. If the cells are in the appropriate environment, growth factor binding induces cellular responses necessary for branching tubulogenesis. There are increases in the levels of extracellular proteinases and of structural and functional changes in the cytoarchitecture that enable the cells to form branching tubule structures.

Acute Renal Failure: Cellular Features of Injury and Repair

16.13

GROWTH FACTORS IN DEVELOPMENTAL AND RENAL RECOVERY Growth Factor

Expression Following Renal Ischemia

Effect of Exogenous Administration

Branching/Tubulogenic Activity

HGF EGF HB-EGF TGF- IGF KGF bFGF GDNF TGF- PDGF

Increased [97] Unclear [98,99] Increased [100] Unclear Increased [101] Increased [102] Undetermined Undetermined Increased† [98] Increased† [98]

Enhanced recovery [103] Enhanced recovery [104,105] Undetermined Enhanced recovery [106] Enhanced recovery [107,108] Undetermined Undetermined Undetermined Undetermined Undetermined

Facilatory [109,110] Facilatory [111] Facilatory [111] Facilatory [111] Facilatory [112,113] Undetermined Facilatory [112] Facilatory [114] Inhibitory for branching [115] No effect [112]

*Increase in endogenous biologically active EGF probably from preformed sources; increase in EGF-receptor mRNA †Chemoattractants for macrophages and monocytes (important source of growth promoting factors)

FIGURE 16-24 Growth factors in development and renal recovery. This table describes the roles of different growth factors in renal injury or in branching tubulogenesis. A large variety of growth factors have been tested for their ability either to mediate ureteric branching

tubulogenesis or to affect recovery of kidney tubules after ischemic or other injury. Interestingly, growth factors that facilitate branching tubulogenesis in vitro also enhance the recovery of injured renal tubules.

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Acute Renal Failure: Cellular Features of Injury and Repair 69. Rothman JE: Polypeptide chain binding proteins: catalysts of protein folding and related processes in cells. Cell 1989, 59:591–601. 70. Blount P, Merlie JP: BIP associates with newly synthesized subunits of the mouse muscle nicotinic receptor. J Cell Biol 1991, 113:1125–1132. 71. Melnick J, Aviel S, Argon Y: The endoplasmic reticulum stress protein GRP94, in addition to BiP, associates with unassembled immunoglobulin chains. J Biol Chem 1992, 267:21303–21306. 72. Pind S, Riordan J, Williams D: Participation of the endoplasmic reticulum chaperone calnexin (p88, IP90) in the biogenesis of the cystic fibrosis transmembrane conductance regulator. J Biol Chem 1994, 269:12784–12788. 73. Kuznetsov G, Chen L, Nigam S: Multiple molecular chaperones complex with misfolded large oligomeric glycoproteins in the endoplasmic reticulum. J Biol Chem 1997, 272:3057–3063. 74. Saxen L: Organogenesis of the Kidney. Cambridge: Cambridge University Press; 1987. 75. Brenner BM: Determinants of epithelial differentiation during early nephrogenesis. J Am Soc Nephrol 1990, 1:127–139. 76. Nigam SK, Aperia A, Brenner BM: Development and maturation of the kidney. In The Kidney. Edited by Brenner BM. Philadelphia: WB Saunders; 1996. 77. Montesano R, Schaller G, Orci L: Induction of epithelial tubular morphogenesis in vitro by fibroblast-derived soluble factors. Cell 1991, 66:697–711. 78. Montesano R, Matsumoto K, Nakamura T, Orci L: Identification of a fibroblast-derived epithelial morphogen as hepatocyte growth factor. Cell 1991, 67:901–908. 79. Santos OFP, Nigam SK: HGF-induced tubulogenesis and branching of epithelial cells is modulated by extracellular matrix and TGF-. Dev Biol 1993, 160:293–302. 80. Stuart RO, Barros EJG, Ribeiro E, Nigam SK: Epithelial tubulogenesis through branching morphogenesis: Relevance to collecting system development. J Am Soc Nephrol 1995, 6:1151–1159. 81. Stuart RO, Nigam SK: Development of the tubular nephron. Semin Nephrol 1995, 15:315–326. 82. Sakurai H, Nigam SK: In vitro branching tubulogenesis: Implications for developmental and cystic disorders, nephron number, renal repair and nephron engineering. Kidney Int 1998, 54:14–26. 83. Matsumoto K, Nakamura T: Emerging multipotent aspects of hepatocyte growth factor. J Biochem 1996, 119:591–600. 84. Cantley LG, Barros EJG, Gandhi M, et al.: Regulation of mitogenesis, motogenesis, and tubulogenesis by hepatocyte growth factor in renal collecting duct cells. Am J Phisiol 1994, 267:F271–F280. 85. Perantoni AO, Williams CL, Lewellyn AL: Growth and branching morphogenesis of rat collecting duct anlagen in the absence of metanephric mesenchyme. Differentiation 1991, 48:107–113. 86. Santos OF, Barros EJ, Yang X-M, et al.: Involvement of hepatocyte growth factor in kidney development. Dev Biol 1994, 163:525–529. 87. Barros EJG, Santos OF, Matsumoto K, et al.: Differential tubulogenic and branching morphogenetic activities of growth factors: Implications for epithelial tissue development. Proc Natl Acad Sci USA 1995, 92:4412–4416. 88. Rogers S, Ryan G, Hammerman MR: Insulin-like growth factors I and II are produced in metanephros and are required for growth and development in vitro. J Cell Biol 1991, 113:1447–1453. 89. Rogers SA, Ryan G, Hammerman MR: Metanephric transforming growth factor alpha is required for renal organogenesis in vitro. Am J Physiol 1992, 262:F533–F539. 90. Liu Z, Wada J, Alvares K, et al.: Distribution and relevance of insulinlike growth factor I receptor in metanephric development. Kidney Int 1993, 44:1242–1250. 91. Liu J, Baker J, Perkins A, et al.: Mice carrying null mutations of the genes encoding insulin-like growth factor I (IGF-1) and type I IGF receptor (IGF1R). Cell 1993, 75:59–72. 92. Sakurai H, Tsukamoto T, Kjelsberg C, et al.: EGF receptor ligands are a large fraction of in vitro branching morphogens secreted by embryonic kidney. Am J Physiol 1997, 273:F463–F472.

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Molecular Responses and Growth Factors Steven B. Miller Babu J. Padanilam

T

he kidney possesses a remarkable capacity for restoring its structure and functional ability following an ischemic or toxic insult. It is unique as a solid organ in its ability to suffer an injury of such magnitude that the organ can fail for weeks and yet recover full function. Studying the natural regenerative process after an acute renal insult has provided new insights into the pathogenesis of acute renal failure (ARF) and possible new therapies. These therapies may limit the extent of injury or even accelerate the regenerative process and improve outcomes for patients suffering with ARF. In this chapter we illustrate some of the molecular responses of the kidney to an acute insult and demonstrate the effects of therapy with growth factors in the setting of experimental models of ARF. We conclude by demonstrating strategies that will provide future insights into the molecular response of the kidney to injury. The regions of the nephron most susceptible to ischemic injury are the distal segment (S3) of the proximal tubule and the medullary thick ascending limb of the loop of Henle. Following injury, there is loss of the epithelial lining as epithelial cells lose their integrin-mediated attachment to basement membranes and are sloughed into the lumen. An intense regenerative process follows. Normally quiescent renal tubule cells increase their nucleic acid synthesis and undergo mitosis. It is theorized that surviving cells situated close to or within the denuded area dedifferentiate and enter mitotic cycles. These cells then redifferentiate until nephron segment integrity is restored. The molecular basis that regulates this process is poorly-understood. After an injury, there is a spectrum of cell damage that is dependent on the type and severity of the insult. If the intensity of the insult is limited, cells become dysfunctional but survive. More severe injury results in detachment of cells from the tubule basement membranes, resulting in necrosis. Still other cells have no apparent damage and may proliferate to reepithelialize the damaged nephron segments. Thus, several

CHAPTER

17

17.2

Acute Renal Failure

different processes are required to achieve structural and functional integrity of the kidney after a toxic or ischemic insult: 1) uninjured cells must proliferate and reepithelialize damaged nephron segments; 2) nonlethally damaged cells must recover;

Subcellular Organelles

Cytosol

Cellular Plasma membrane Noninjured cells

Insult

↓ATP ↑Ca2+

ER blebbing Mitochondrial switching

Brush border sloughing Loss of membrane protein orientation

Nonlethally injured cells

Nephron/Kidney

1 Growth factors

Dysfunction ± morphological changes 2

Cell death

FIGURE 17-1 Schematic representation of some of the events pursuant to a renal insult and epithelial cell repair. Subcellular; Initial events include a decrease in cellular ATP and an increase in intracellular free calcium. There is blebbing of the endoplasmic reticulum with mitochondrial swelling and dysfunction. The brush border of the proximal tubules is sloughed into the tubule lumen, and there is redistribution of membrane proteins with the loss of cellular polarity. Cellular; At a cellular level this results in three populations of tubule cells, depending on the severity of the insult. Some cells are intact and are poised to participate in the proliferative process (Pathway 1). Growth factors participate by

Basement membrane

and 3) some damaged cells may actually die—not as a result of the initial insult but through a process of programmed cell death known as apoptosis. Figure 17-1 provides a schematic representation of the renal response to an ischemic or toxic injury.

Cell proliferation

Reepithelialization of nephron

1

Cellular recovery

1

2

Recovery of nephron structure and function

stimulating cells to undergo mitosis. Nonlethally injured cells have the potential to follow one of two pathways. In the appropriate setting, perhaps stimulated by growth factors, these cells may recover with restoration of cellular integrity and function (Pathway 2); however, if the injury is significant the cell may still die, but through a process of programmed cell death or apoptosis. The third population of cells are those with severe injury that undergo necrotic cell death. Nephron/Kidney; With the reepithelialization of damaged nephron segments and cellular recovery of structural and functional integrity, renal function is restored. (Modified from Toback [1]; with permission.) FIGURE 17-2 Growth regulation after an acute insult in regenerating renal tubule epithelial cells. Under the influence of growth-stimulating factors the damaged renal tubule epithelium is capable of regenerating with restoration of tubule integrity and function. The growth factors may be 1) produced by the tubule epithelium itself and act locally in an autocrine, juxtacrine or paracrine manner; 2) produced by surrounding cells to work in a paracrine manner; or 3) presented to the regenerating area via the circulation mediated by an endocrine mechanism. Cells at the edge of an injured nephron segment are illustrated on the left. These cells proliferate in response to the growth-stimulating factors. The middle cell is in the process of dividing and the cell on the right is migrating into the area of injury. (Adapted from Toback [1]; with permission.)

Molecular Responses and Growth Factors

17.3

Growth Factors in Acute Renal Failure FIGURE 17-3 At least three growth factors have now been demonstrated to be useful as therapeutic agents in animal models of acute renal failure (ARF). These include epidermal growth factor (EGF), insulin-like growth factor I (IGF-I) and hepatocyte growth factor (HGF). All have efficacy in ischemia models and in a variety of toxic models of ARF. In addition, both IGF-I and HGF are beneficial when therapy is delayed and ARF is “established” after an ischemic insult. IGF-I has the additional advantage in that it also ameliorates the course of renal failure when given prophylactically before an acute ischemic insult.

GROWTH FACTORS IN ACUTE RENAL FAILURE

EGF Ischemic and toxic IGF-I Ischemic and toxic Pretreatment and established ARF

HGF Ischemic and toxic Established ARF

ARF—acute renal failure; EGF—epidermal growth factor; HGF—hepatocyte growth factor; IGF-I—insulin-like growth factor.

DCT

Prepro-EGF mRNA

PCT

CTAL

OMCD MTAL

IMCD

FIGURE 17-4 Expression of messenger RNA (mRNA) for prepro–epidermal growth factor (EGF) in kidney. This schematic depicts the localization of mRNA for prepro-EGF under basal states in kidney. Prepro-EGF mRNA is localized to the medullary thick ascending limbs (MTAL) and distal convoluted tubules (DCT). Immunohistochemical studies demonstrate that under basal conditions the peptide is located on the luminal membrane with the active peptide actually residing within the tubule lumen. It is speculated that, during pathologic states, preformed EGF is either transported or routed to the basolateral membrane or can enter the interstitium via backleak. After a toxic or ischemic insult, expression of EGF is rapidly suppressed and can remain low for a long time. Likewise, total renal content and renal excretion of EGF decreases. CTAL—cortical thick ascending limb; IMCD—inner medullary collecting duct; OMCD—outer medullary collecting duct; and PCT—proximal convoluted tubule.

17.4

Acute Renal Failure FIGURE 17-5 Production of epidermal growth factor (EGF), insulin-like growth factor (IGF-I), and hepatocyte growth factor (HGF) by various tissues. EGF, IGF-I, and HGF have all been demonstrated to improve outcomes in various animal models of acute renal failure (ARF). All three growth-promoting factors are produced in the kidneys and in a variety of other organs. The local production is probably most important for recovery from an acute renal insult. The influence of production in other organs in the setting of ARF has yet to be determined. This chapter deals primarily with local production and actions of EGF, IGF-I, and HGF.

GROWTH FACTOR PRODUCTION

EGF Submandibular salivary glands Kidney Others

IGF-I Liver Lung Kidney Heart Muscle Other organs

HGF Liver Spleen Kidney Lung Other organs

DCT

EGF-receptor binding

PCT

CTAL GLOM

OMCD MTAL

IMCD

FIGURE 17-6 Receptor binding for epidermal growth factor (EGF). EGF binding in kidney under basal conditions is extensive. The most significant specific binding occurs in the proximal convoluted (PCT) and proximal straight tubules. There is also significant EGF binding in the glomeruli (GLOM), distal convoluted tubules (DCT), and the entire collecting duct (OMCD, IMCD). After an ischemic renal insult, EGF receptor numbers increase. This change in the renal EGF system may be responsible for the beneficial effect of exogenously administered EGF is the setting of acute renal failure. CTAL—cortical thick ascending loop.

Molecular Responses and Growth Factors

EGF

P

P

P

P

GAP PKC

SHC

PI3K

Grb2

PLCγ DAG + IP3 Ca2+ CamK

PIP

SOS

PI-3,4 P2

PIP2 Signal transduction

RasGDP

RasGTP

RAF MAPKK ERK1/ ERK2 Gene transcription Growth differentiation

FIGURE 17-7 Epidermal growth factor (EGF)–mediated signal transduction pathways. The EGF receptor triggers the phospholipase C-gamma (PLC-gamma), phosphatidylinositol-3 kinase (PI3K), and mitogen-activated protein kinase (MAPK) signal transduction pathways described in the text that follows. Growth factors exert their downstream effects through their plasma membrane–bound protein tyrosine kinase (PTK) receptors. All known PTK receptors are found to have four major domains: 1) a glycosylated extracellular ligand-binding domain; 2) a transmembrane domain that anchors the receptor to the plasma membrane; 3) an intracellular tyrosine kinase domain; and 4) regulatory domains for the PTK activity. Upon ligand binding, the receptors dimerize and autophosphorylate, which leads to a cascade of intracellular events resulting in cellular proliferation, differentiation, and survival. The tyrosine phosphorylated residues in the cytoplasmic domain of PTK are of utmost importance for its interactions with cytoplasmic proteins involved in EGF–mediated signal transduction pathways. The interactions of cytoplasmic proteins are governed by specific domains termed Src homology type 2 (SH2) and type 3 (SH3) domains. The SH2 domain is a conserved 100–amino acid sequence initially characterized in the PTK-Src and binds to tyrosine phosphorylated motifs in proteins; the SH3 domain binds to their targets through proline-rich sequences. SH2 domains have been found in a multitude of signal transducers and docking proteins such as growth factor receptor–bound protein 2 (Grb2), phophatidylinositol-3 kinase (p85-PI3K), phospholipase C-gamma (PLC-gamma), guanosine triphosphatase (GTPase)–activating protein of ras (ras-GAP), and signal transducer and activator of transcription 3 (STAT-3). Upon ligand binding and phosphorylation of PTKs, SH2–domain containing proteins interact with the receptor kinase domain. PLC-gamma on interaction with the PTK, becomes phosphorylated and catalyzes the turnover of phosphatidylinositol (PIP2) to two other second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG).

17.5

DAG activates protein kinase C; IP3 raises the intracellular calcium (Ca2+) levels by inducing its release from intracellular stores. Ca2+ is involved in the activation of the calmodulin-dependent CAM-kinase, which is a serine/threonine kinase. A more important signal transduction pathway activated by PTKs concerns the ras pathway. The ras cycle is connected to activated receptors via the adapter protein Grb2 and the guanosine diphosphateguanosine triphosphate exchange factor Sos (son of sevenless). GDP-ras, upon phosphorylation, is converted to its activated form, GTP-ras. The activated ras activates another Ser/Thr kinase called raf-1, which in turn activates another kinase, the mitogen activated protein kinase kinase (MAPKK). MAPKK activates the serine/threonine kinases, and extracellular signal-regulated kinases Erk1 and 2. Activation of Erk1/2 leads to translocation into the nucleus, where it phosphorylates key transcription factors such as Elk-1, and c-myc. Phosphorylated Elk-1 associates with serum response factor (SRF) and activates transcription of c-fos. The protein products of c-fos and c-jun function cooperatively as components of the mammalian transcription factor AP-1. AP-1 binds to specific DNA sequences in putative promoter sequences of target genes and regulates gene transcription. Similarly, c-myc forms a heterodimer with another immediate early gene max and regulates transcription. The expression of c-fos, c-jun, and Egr-1 is found to be upregulated after ischemic renal injury. Immunohistochemical analysis showed the spatial expression of c-fos and Egr-1 to be in thick ascending limbs, where cells are undergoing minimal proliferation as compared with the S3 segments of the proximal tubules. This may suggest that the expression of immediate early genes after ischemic injury is not associated with cell proliferation. Several mechanisms control the specificity of RTK signaling: 1) the specific ligandreceptor interaction; 2) the repertoire of substrates and signaling molecules associated with the activated RTK; 3) the existence of tissue-specific signaling molecules; and 4) the apparent strength and persistence of the biochemical signal. Interplay of these factors can determine whether a given ligandreceptor interaction lead to events such as growth, differentiation, scatter or survival.

17.6

Acute Renal Failure DCT

IGF-1 mRNA

DCT

IGF-receptor binding

PCT

CTAL

PCT

CTAL GLOM

OMCD MTAL

IMCD

FIGURE 17-8 Expression of mRNA for insulin-like growth factor I (IGF-I). Under basal conditions, a variety of nephron segments can produce IGF-I. Glomeruli (GLOM), medullary and cortical thick ascending limbs (MTAL/CTAL), and collecting ducts (OMCD, IMCD) are all reported to produce IGF-I. Within hours of an acute ischemic renal insult, the expression of IGF-I decreases; however, 2 to 3 days after the insult, when there is intense regeneration, there is an increase in the expression of IGF-I in the regenerative cells. In addition, extratubule cells, predominantly macrophages, express IGF-I in the regenerative period. This suggests that IGF-I works by both autocrine and paracrine mechanisms during the regenerative process. DCT/PCT—distal/proximal convoluted tubule.

GLOM

OMCD MTAL

IMCD

FIGURE 17-9 Receptor binding for insulin-like growth factor I (IGF-I). IGF-I binding sites are conspicuous throughout the normal kidney. Binding is higher in the structures of the inner medulla than in the cortex. After an acute ischemic insult, there is a marked increase in IGF-I binding throughout the kidney. The increase appears to be greatest in the regenerative zones, which include structures of the cortex and outer medulla. These findings suggest an important trophic effect of IGF-I in the setting of acute renal injury. CTAL/MTAL—cortical/medullary thick ascending loop; DCT/PCT—distal/proximal convoluted tubule; GLOM—glomerulus; OMCD/IMCD—outer/inner medullary collecting duct.

Molecular Responses and Growth Factors

IGF-I IGF-IR

Other substrates SHC Grb2 P110 p85

SOS

PI3-kinase signaling

Crk II IRS-1/IRS-2 C3G

Akt SYP

nck

Grb2

BAD

SOS

Cell survival Phosphotyrosine dephosphorylation

Ras

Growth, differentiation Raf-1

MEKs

ERKs EGF-R MBP

S6-kinase

TF

Gene expression

17.7

FIGURE 17-10 Diagram of intracellular signaling pathways mediated by the insulin-like growth factor I (IGF-IR) receptor. IGF-IR when bound to IGF-I undergoes autophosphorylation on its tyrosine residues. This enhances its intrinsic tyrosine kinase activity and phosphorylates multiple substrates, including insulin receptor substrate 1 (IRS-1), IRS-2, and Src homology/collagen (SHC). IRS-1 upon phosphorylation associates with the p85 subunit of the PI3-kinase (PI3K) and phosphorylates PI3-kinase. PI3K upon phosphorylation converts phosphoinositide-3 phosphate (PI-3P) into PI-3,4-P2, which in turn activates a serine-thronine kinase Akt (protein kinase B). Activated Akt kinase phosphorylates the proapoptotic factor Bad on a serine residue, resulting in its dissociation from B-cell lymphoma-X (Bcl-XL) . The released Bcl-XL is then capable of suppressing cell death pathways that involve the activity of apoptosis protease activating factor (Apaf-1), cytochrome C, and caspases. A number of growth factors, including platelet-derived growth factor (PDGF) and IGF 1 promotes cell survival. Activation of the PI3K cascade is one of the mechanisms by which growth factors mediate cell survival. Phosphorylated IRS-1 also associates with growth factor receptor bound protein 2 (Grb2), which bind son of sevenless (Sos) and activates the ras-raf-mitogen activated protein (ras/raf-MAP) kinase cascade. SHC also binds Grb2/Sos and activates the ras/raf-MAP kinase cascade. Other substrates for IGF-I are phosphotyrosine phosphatases and SH2 domain containing tyrosine phosphatase (Syp). Figure 17-7 has details on the other signaling pathways in this figure. MBP—myelin basic protein; nck—an adaptor protein composed of SH2 and SH3 domains; TF—transcription factor.

17.8

Acute Renal Failure

DCT

HGF mRNA HGF receptor mRNA

PCT

CTAL

OMCD MTAL

IMCD

FIGURE 17-11 Expression of hepatocyte growth factor (HGF) mRNA and HGF receptor mRNA in kidney. While the liver is the major source of circulating HGF, the kidney also produces this growth-promoting peptide. Experiments utilizing in situ hybridization, immunohistochemistry, and reverse transcription–polymerase chain reaction (RT-PCR) have demonstrated HGF production by interstitial cells but not by any nephron segment. Presumably, these interstitial cells are macrophages and endothelial cells. Importantly, HGF expression in kidney actually increases within hours of an ischemic or toxic insult. This expression peaks within 6 to 12 hours and is followed a short time later by an increase in HGF bioactivity. HGF thus seems to act as a renotrophic factor, participating in regeneration via a paracrine mechanism; however, its expression is also rapidly induced in spleen and lung in animal models of acute renal injury. Reported levels of circulating HGF in patients with acute renal failure suggest that an endocrine mechanism may also be operational. The receptor for HGF is the c-met proto-oncogene product. Receptor binding has been demonstrated in kidney in a variety of sites, including the proximal convoluted (PCT) and straight tubules, medullary and cortical thick ascending limbs (MTAL, CTAL), and in the outer and inner medullary collecting ducts (OMCD, IMCD). As with HGF peptide production, expression of c-met mRNA is induced by acute renal injury.

Molecular Responses and Growth Factors Pro-HGF convertase Mature HGF

Membrane bound Pro-HGF

Matrix soluble pro-HGF uPa

GTP-γas Raf-1

HGFR

S

Urokinase receptor

Extracellular

S

Antiapoptosis

BAG-1 Y Y

SHC

Y Y

PIP2 PLC-γ DAG

mSos1

P Grb2

P

Y

Y

P

P

Y

Y

P

IP3

Gab 1 p85 MAP kinases kinases (MEK S)

PI3K

C-SγC

STAT3

Focal adhesion

MAP kinases (ERK5)

TF

Scatter

SRE TF

Nuclear membrane

Growth TF

DETERMINANT MECHANISMS FOR OUTCOMES OF ACUTE RENAL FAILURE

Mitogenic Morphogenic Cell migration Hemodynamic Cytoprotective

Cytosol

Anabolic Alter leukocyte function Alter inflammatory process Apoptosis Others

Transcription Gene

PKC λ, β, γ activation

17.9

FIGURE 17-12 Model of hepatocyte growth factor (HGF)/c-met signal transduction. In the extracellular space, single-chain precursors of HGF bound to the proteoglycans at the cell surface are converted to the active form by urokinase plasminogen activator (uPA), while the matrix soluble precursor is processed by a serum derived pro-HGF convertase. HGF, upon binding to its receptor c-met, induces its dimerization as well as autophosphorylation of tyrosine residues. The phosphorylated residue binds to various adaptors and signal transducers such as growth factor receptor bound protein-2 (Grb2), p85-PI3 kinase, phospholipase C-gamma (PLC-gamma), signal transducer and activator of transcription-3 (STAT-3) and Src homology/collagen (SHC) via Src homology 2 (SH2) domains and triggers various signal transduction pathways. A common theme among tyrosine kinase receptors is that phosphorylation of different specific tyrosine residues determines which intracellular transducer will bind the receptor and be activated. In the case of HGF receptor, phosphorylation of a single multifunctional site triggers a pleiotropic response involving multiple signal transducers. The synchronous activation of several signaling pathways is essential to conferring the distinct invasive growth ability of the HGF receptor. HGF functions as a scattering (dissociation/motility) factor for epithelial cells, and this ability seems to be mediated through the activation of STAT-3. Phosphorylation of adhesion complex regulatory proteins such as ZO-1, betacatenin, and focal adhesion kinase (FAK) may occur via activation of c-src. Another Bcl2 interacting protein termed BAG-1 mediates the antiapoptotic signal of HGF receptor by a mechanism of receptor association independent from tyrosine residues.

FIGURE 17-13 Mechanisms by which growth factors may possibly alter outcomes of acute renal failure (ARF). Epidermal growth factor, insulin-like growth factor, and hepatocyte growth factor (HGF) have all been demonstrated to improve outcomes when administered in the setting of experimental ARF. While the results are the same, the respective mechanisms of actions of each of these growth factors are probably quite different. Many investigators have examined individual growth factors for a variety of properties that may be beneficial in the setting of ARF. This table lists several of the properties examined to date. Suffice it to say that the mechanisms by which the individual growth factors alter the course of experimental ARF is still unknown.

17.10

Acute Renal Failure

ACTIONS OF GROWTH FACTORS IN ACUTE RENAL FAILURE

Actions

IGF-I

EGF

Protein mRNA Receptiors Vascular Anabolic Mitogenic Apoptosis

↓/↑ ↓/↑ ↑ ↑ ↑ ↑ ↓

↑/↓ ↓ ↑ ↓ ←→ ↑↑↑

↓↓

FIGURE 17-14 Selected actions of growth factors in the setting of acute renal failure (ARF). After an acute renal injury, a spectrum of molecular responses occur involving the local expression of growth factors and their receptors. In addition, there is considerable variation in the mechanisms by which the growth factors are beneficial for ARF. After an

acute renal insult there is an initial decrease in both insulin-like growth factor (IGF-I) peptide and mRNA, which recovers over several days but only after the regenerative process is under way. The pattern with epidermal growth factor (EGF) is different in that a transient increase in available mature peptide from cleavage of preformed EGF is followed by a pronounced and prolonged decrease in both peptide and message. Both peptide and message for hepatocyte growth factor (HGF) are transiently increased in kidney after a toxic or an ischemic insult. The receptors for all three growth factors are increased after injury, which may be crucial to the response to exogenous administration. The mechanism by which the different growth factors act in the setting of acute renal injury is quite variable. IGF-I is known to increase renal blood flow and glomerular filtration rate in both normal animals and those with acute renal injury. To the other extreme, EGF is a vasoconstrictor and HGF is vasoneutral. IGF-I has an additional advantage in that it has anabolic properties, and ARF is an extremely catabolic state. Neither EGF nor HGF seems to affect nutritional parameters. Finally, both EGF and HGF are potent mitogens for renal proximal tubule cells, the nephron segment is most often damaged by ischemic acute renal injury, whereas IGF-I is only a modest mitogen. Likewise, both EGF and HGF appear to be more effective than IGF-I at inhibiting apoptosis in the setting of acute renal injury, but it is not clear whether this is an advantage or a disadvantage.

Clinical Use of Growth Factors in Acute Renal Failure HGF

↑ ↑ ←→ ←→ ↑↑↑

Serum creatinine, mg/dL

↑

4

+Vehicle +IGF-I

* * * * *

2

*

*

0 0

FIGURE 17-15 Rationale for the use of insulin-like growth factor IGF-I in the setting of acute renal failure (ARF). Of the growth factors that have been demonstrated to improve outcomes after acute renal injury, the most progress has been made with IGF-I. From this table, it is evident that IGF-I has a broad spectrum of activities, which makes it a logical choice for treatment of ARF. An agent that increased renal plasma flow and glomerular filtration rate and was mitogenic for proximal tubule cells and anabolic would address several features of ARF.

2 4 Time after ischemia, d

6

FIGURE 17-16 Serial serum creatinine values in rats with ischemic acute renal failure (ARF) treated with insulin-like growth factor (IGF-I) or vehicle. This is the original animal experiment that demonstrated a benefit from IGF-I in the setting of ARF. In this study, IGF-I was administered beginning 30 minutes after the ischemic insult (arrow). Data are expressed as mean ± standard error. Significant differences between groups are indicated by asterisks. This experiment has been reproduced, with variations, by several groups, with similar findings. IGF-I has now been demonstrated to be beneficial when administered prophylactically before an ischemic injury and when started as late as 24 hours after reperfusion when injury is established. It has also been reported to improve outcomes for a variety of toxic injuries and is beneficial in a model of renal transplantation with delayed graft function and in cyclosporine-induced acute renal insufficiency. (From Miller et al. [2]; with permission.)

Molecular Responses and Growth Factors 280 + Vehicle + IGF-I

Body weight, g

* *

*

*

220

17.11

FIGURE 17-17 Body weights of rats with ischemic acute renal failure (ARF) treated with insulin-like growth factor (IGF-I) or vehicle. Unlike epidermal growth factor or hepatocyte growth factor (HGF), IGF-I is anabolic even in the setting of acute renal injury. These data are from the experiment described in Figure 17-16. As the data in this figure demonstrate, ARF is a highly catabolic state: vehicle-treated animals experience 15% weight reduction. Animals that received IGF-I experienced only a 5% reduction in body weight and were back to baseline by 7 days. Data are expressed as mean ± standard error. Significant differences between groups are indicated by asterisks. (From Miller et al. [2]; with permission.)

160 0

2 4 Time after ischemia, d

6

A FIGURE 17-18 Photomicrograph of kidneys from rats with acute renal failure (ARF) treated with insulin-like growth factor (IGF-I) or vehicle. These photomicrographs are of histologic sections stained with hematoxylin and eosin originating from kidneys of rats that received vehicle or IGF 1 after ischemic renal injury. Kidneys were obtained 7 days after the insult. There is evidence of considerable residual injury in the kidney from the vehicle-treated rat (A): dilation and simplification of tubules, interstitial calcifi-

B cations, and papillary proliferations the tubule lumen of proximal tubules. The kidney obtained from the IGF-I–treated rat (B) appears almost normal, showing evidence of regeneration and restoration of normal renal architecture. In this experiment the histologic appearance of kidneys from the IGF-I–treated animals was statistically better than that of the vehicle-treated controls, as determined by a pathologist blinded to therapy. (From Miller et al. [2]; with permission.)

17.12

Acute Renal Failure

↓↓

RATIONALE FOR INSULIN-LIKE GROWTH FACTOR I (IGF-I) IN ACUTE RENAL FAILURE

Renal dysfunction, %

FIGURE 17-19 Reported therapeutic trials of insulin-like growth factor (IGF-I) in humans. Based on the compelling animal data and the fact that there are clearly identified disease states involving both

35 30 25 20 15 10 5 0

*P<0.05 Chi square

over- and underexpression of IGF-I, this is the first growth factor that has been used in clinical trials for kidney disease. Listed above are a variety of studies of the effects of IGF-I in humans. This peptide has now been examined in several published studies of both acute and chronic renal failure. Additional studies are currently in progress. In the area of acute renal failure there are now two reported trials of IGF-I. In the initial study IGF-I or placebo was administered to patients undergoing surgery involving the suprarenal aorta or the renal arteries. This group was selected as it best simulated the work that had been reported in animal trials of ischemic acute renal injury. Fifty-four patients were randomized in a double-blind, placebo-controlled trial of IGF-I to prevent the acute decline in renal function frequently associated with this type of surgery. The primary end-point in this study was the incidence of renal dysfunction, defined as a reduction of the glomerular filtration rate as compared with a preoperative baseline, at each of three measurements obtained during the 3 postoperative days. Modern surgical techniques have decreased the incidence of acute renal failure to such a low level, even in this high-risk group, so as to make it impractical to perform a single center trial with enough power to obtain differences in clinically important end-points. Thus, this trial was intended only to offer “proof of concept” that IGF-I is useful for patients with acute renal injuries.

Receptors are present on proximal tubules Regulates proximal tubule metabolism and transport

* Increases renal plasma flow and glomerular filtration rates Mitogenic for proximal tubule cells Enhanced expression after acute renal injury Anabolic Placebo IGF-I Treatment groups

FIGURE 17-20 Incidence of postoperative renal dysfunction treated with insulin (IGF-I) or placebo. IGF-I significantly reduced the incidence of postoperative renal dysfunction in these high-risk patients. Renal dysfunction occurred in 33% of those who received placebo but in only 22% of patients treated with IGF-I. The groups were well-matched with respect to age, sex, type of operation, ischemia time, and baseline renal function as defined by serum creatinine or glomerular filtration rate. The IGF-I was tolerated well: no side effects were attributed to the drug. Secondary end-points such as discharge, serum creatinine, length of hospitalization, length of stay in the intensive care unit, or duration of intubation were not significantly different between the two groups. (Adapted from Franklin, et al. [3]; with permission.)

THERAPEUTIC TRIALS OF INSULIN-LIKE GROWTH FACTOR I IN HUMANS

FIGURE 17-21 Summary of an abstract describing the trial of insulin-like growth factor (IGF-I) in the treatment of patients with established acute renal failure (ARF). Based on the accumulated animal and human data, a multicenter, double-blind, randomized, placebo-controlled trial was performed to examine the effects of IGF-I in patients with established ARF. Enrolled patients had ARF of a wide variety of causes, including surgery, trauma, hypertension, sepsis, and nephrotoxic injury. Approximately 75 patients were enrolled, treatment being initiated within 6 days of the renal insult. Renal function was evaluated by iodothalimate clearance. Unfortunately, at an interim analysis (the study was originally designed to enroll 150 patients) there was no difference in renal function or survival between the groups. The investigators recognized several potential problems with the trial, including the severity of many patients’ illnesses, the variety of causes of the renal injury, and delay in initiating therapy [4].

Molecular Responses and Growth Factors

Growth hormone–resistant short stature

17.13

Corticosteroid therapy Postoperative state

Laron-type dwarfism Insulin-dependent and non–insulin-dependent diabetes mellitus Acute renal failure Chronic renal failure

Anabolic agent in catabolic states AIDS (Protein wasting malnutrition) Burns

FIGURE 17-22 Advantages of insulin-like growth factor (IGF-I) in the treatment of acute renal failure. The limited data obtained to date on the use of IGF-I for acute renal failure demonstrate that the peptide is welltolerated and may be useful in selected patient populations. Additional human trials are ongoing including use in the settings of renal transplantation and chronic renal failure.

LACK OF EFFECT OF RECOMBINANT FIGURE 17-23 Limitations in the use of growth factors to treat acute renal failure (ARF). The disappointing results of several recent clinical trials of ARF therapy reflect the fact that our understanding of its pathophysiology is still limited. Screening compounds using animal models may be irrelevant. Most laboratories use relatively young animals, even though ARF frequently affects older humans, whose organ regenerative capacity may be limited. In addition, our laboratory models are usually based on a single insult, whereas many of our patients suffer repeated or multiple insults. Until we gain a better understanding of the basic pathogenic mechanisms of ARF, studies in human patients are likely to be frustrating.

Future Directions HUMAN IGF-I IN PATIENTS WITH ARF* Multicenter, doubleblind, randomized, placebo-controlled ARF secondary to surgery, trauma, hypertensive nephropathy, sepsis, or drugs Treated within the first 6 days for 14 days Evaluated renal function and mortality

*No difference between the groups were observed in final values or changes in values for glomerular filtration

1 Hour

1 Day

↑ ↑ ↑ ←→

←→ ←→ ←→ ↓

↑ ↑

↑ ←→

2 Days

↓

↓

↑

↑

↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ (6 h) ↓ (6 h)

↑ ↑ ↑ ↑ ↑ ↑ ↓

5 Days

←→ ↑ ↓

↑ ↑ ↑ ↑

←→

References Bardella et al. [5] Ouellette et al. [6] Bonventre et al. [7] Witzgall et al. [8] Safirstein et al. [9] “ Goes et al. [10] “ “ “ Singh et al. [11] “ “ “ Soifer et al. [12] Firth and Ratcliffe [13] “ (Table continued on next page)

FIGURE 17-24 A list of genes whose expression is induced at various time points by ischemic renal injury. The molecular response of the kidney to an ischemic insult is complex and is the subject of investigations by several laboratories. (Continued on next page)

17.14

Acute Renal Failure

Well-tolerated

Safe in short-term studies Experience with diseases of overexpression and underexpression Did not worsen outcomes IGF-I—insulin-like growth factor.

GROWTH I FACTOR LIMITATIONS

FIGURE 17-24 (Continued) Several genes have already been identified to be induced or down-regulated after ischemia and reperfusion. This table lists genes whose expression is

N ACUTE RENAL FAILURE Lack of basic knowledge of the pathophysiology of ARF No screening system for compounds to treat ARF Animal models may not be relevant Animal studies have not predicted results in human trials Difficulty of identifying appropriate target populations

altered as a result of ischemic injury. It is not clear at present if the varied expression of these genes plays a role in cell injury, survival, or proliferation.

Molecular Responses and Growth Factors

FIGURE 17-25 Schematic representation of differential display. In a complex organ like the kidney, ischemic renal injury triggers altered expression of various cell factors and vascular components. Depending on the severity of the insult, expression of these genes can vary in individual cells, leading to their death, survival, or proliferation. A better understanding of the various factors and the signal transduction pathways transduced by them that contribute to cell death can lead to development of therapeutic strategies to interfere with the process of cell death. Similarly, identification of factors that are involved in initiating cell migration, dedifferentiation, and proliferation may lead to therapy aimed at accelerating the regeneration program. To identify the various factors involved in cell injury and regeneration, powerful methods for identification and cloning of differentially expressed genes are critical. One such method that has been used extensively by several laboratories is the differential display polymerase chain reaction (DD-PCR). In this schematic, mRNA is derived from kidneys of shamoperated (controls) and ischemia-injured rats, some pretreated with insulin-like growth factor (IGF-I). The mRNAs are reverse transcribed using an anchored deoxy thymidine-oligonucleotide (oligo-dT) primer (Example: dT[12]-MX, where M represent G, A, or C, and X represents one of the four nucleotides). An anchored primer limits the reverse transcription to a subset of mRNAs. The first strand cDNA is then PCR amplified using an arbitrary 10 nucleotide-oligomer primer and the anchored primer. The PCR reaction is performed in the presence of radioactive or fluorescence-labeled nucleotides, so that the amplified fragments can be displayed on a sequencing gel. Bands of interest can be excised from the gel and used for further characterization. ARF—acute renal failure.

ARF—acute renal failure.

MOLECULAR RESPONSE TO RENAL ISCHEMIC/REPERFUSION INJURY Genes Transcription factors c-jun c-fos Egr-1 Kid 1 Cytokines JE KC IL-2 IL-10 IFN- GM-CSF MIP-2 IL-6 IL-11 LIF PTHrP Endothelin 1 Endothelin 3

Sham

Sham +IGF-1

ARF

17.15

ARF + IGF-1

1 2 3

4

FIGURE 17-26 Schematic representation of a differential display gel in which mRNA from kidneys is reverse-transcribed and polymerase chain reaction (PCR) amplified (see Figure 17-25). The PCR amplification is conducted in the presence of radioactive nucleotides. The cDNA fragments corresponding to the 3’ end of the mRNA species are displayed by running them on a sequencing gel, followed by autoradiography. The arrows show bands corresponding to mRNA transcripts that are expressed differentially 1) in response to insulin-like growth factor (IGF-I) treatment and induction of ischemic injury; 2) in an IGF-I–dependent manner; 3) in response to induction of ischemic injury; and 4) to genes that are down-regulated after induction of ischemic injury. ARF—acute renal failure.

17.16

Acute Renal Failure

References 1. Toback GF: Regeneration after acute tubular necrosis. Kidney Int 1992, 41:226–246. 2. Miller SB, Martin DR, Kissane J, Hammerman, MR: Insulin-like growth factor I accelerates recovery from ischemic acute tubular necrosis in the rat. Proc Natl Acad Sci USA 1992, 89:11876–11880. 3. Franklin SC, Moulton M, Sicard GA, et al.: Insulin-like growth factor I preserves renal function postoperatively. Am J Physiol 1997, 272:F257–F259. 4. Kopple JD, Hirschberg R, Guler H-P, et al.: Lack of effect of recombinant human insulin-like growth factor I (IGF-I) in patients with acute renal failure (ARF). J Amer Soc Nephro 1996, 7:1375. 5. Bardella L, Comolli R: Differential expression of c-jun, c-fos and hsp 70 mRNAs after folic acid and ischemia reperfusion injury: effect of antioxidant treatment. Exp Nephrol 1994, 2:158–165. 6. Ouellette AJ, et al.: Expression of two “immediate early” genes, Egr-1 and c-fos, in response to renal ischemia and during compensatory renal hypertrophy in mice. J Clin Invest 1990, 85:766–771. 7. Bonventre JV, et al.: Localization of the protein product of the immediate early growth response gene, Egr-1, in the kidney after ischemia and reperfusion. Cell Regulation 1991, 2:251–60. 8. Witzgall R, et al.: Kid-1, a putative renal transcription factor: regulation during ontogeny and in response to ischemia and toxic injury. Mol Cell Biol 1993, 13:1933–1942. 9. Safirstein R, et al.: Expression of cytokine-like genes JE and KC is increased during renal ischemia. Amer J Physiol 1991, 261:F1095–F1101. 10. Goes N, et al.: Ischemic acute tubular necrosis induces an extensive local cytokine response. Evidence for induction of interferon-gamma, transforming growth factor-beta 1, granulocyte-macrophage colony–stimulating factor, interleukin-2, and interleukin-10. Transplantation 1995, 59:565–572. 11. Singh AK, et al.: Prominent and sustained upregulation of MIP-2 and gp130 signaling cytokines in murine renal ischemic-reperfusion injury. J Am Soc Nephrol 1997, 8:595A. 12. Soifer NE, et al.: Expression of parathyroid hormone–related protein in the rat glomerulus and tubule during recovery from renal ischemia. J Clin Invest 1993, 92:2850–2857. 13. Firth JD, Ratcliffe PJ: Organ distribution of the three rat endothelin messenger RNAs and the effects of ischemia on renal gene expression. J Clin Invest 1992, 90:1023–1031. 14. Witzgall R, et al.: Localization of proliferating cell nuclear antigen, vimentin, c-Fos, and clusterin in the postischemic kidney. Evidence for a heterogeneous genetic response among nephron segments, and a large pool of mitotically active and dedifferentiated cells. J Clin Invest 1994, 93:2175–2188. 15. Basile DP, Liapis H, Hammerman MR: Expression of bcl-2 and bax in regenerating rat renal tubules following ischemic injury. Am J Physiol 1997, 272:F640–F647. 16. Matejka GL, Jennische E: IGF-I binding and IGF-1 mRNA expression in the post-ischemic regenerating rat kidney. Kidney Int 1992, 42(5):1113–1123.

17. Ishibashi K, et al.: Expressions of receptor for hepatocyte growth factor in kidney after unilateral nephrectomy and renal injury. Biochem Biophys Res Commun 1993, 187:1454–1459. 18. Safirstein R, et al.: Changes in gene expression after temporary renal ischemia. Kidney Int 1990, 37:1515–1521. 19. Basile DP, et al.: Increased transforming growth factor-beta 1 expression in regenerating rat renal tubules following ischemic injury. Amer J Physiol 1996, 270:F500–F509. 20. Padanilam BJ, Hammerman MR: Ischemia-induced receptor for activated C kinase (RACK1) expression in rat kidneys. Amer J Physiol 1997, 272:F160–F166. 21. Pombo CM, et al.: The stress-activated protein kinases are major c-Jun amino-terminal kinases activated by ischemia and reperfusion. J Biol Chem 1994, 269:26546–26551. 22. Safirstein R: Gene expression in nephrotoxic and ischemic acute renal failure [editorial]. J Am Soc Nephrol 1994, 4:1387–1395. 23. Safirstein R, Zelent AZ, Price PM: Reduced renal prepro-epidermal growth factor mRNA and decreased EGF excretion in ARF. Kid Int 1989, 36:810–815. 24. Raju VS, Maines, MD: Renal ischemia/reperfusion up-regulates heme oxygenase-1 (HSP32) expression and increases cGMP in rat heart. J Pharmacol Exp Ther 1996, 277:1814–1822. 25. Van Why SK, et al.: Induction and intracellular localization of HSP-72 after renal ischemia. Am J Physiol 1992, 263:F769–F775. 26. Padanilam BJ, Martin DR, Hammerman MR: Insulin-like growth factor I–enhanced renal expression of osteopontin after acute ischemic injury in rats. Endocrinology 1996, 137:2133–2140. 27. Walker PD: Alterations in renal tubular extracellular matrix components after ischemia-reperfusion injury to the kidney. Lab Invest 1994, 70:339–345. 28. Van Why SK, et al.: Expression and molecular regulation of Na+-K+ATPase after renal ischemia. Am J Physiol 1994, 267:F75–F85. 29. Wang Z, et al.: Ischemic-reperfusion injury in the kidney: overexpression of colonic H+-K+-ATPase and suppression of NHE-3. Kidney Int 1997, 51:1106–1115. 30. McKanna JA, et al.: Localization of p35 (annexin I, lipocortin I) in normal adult rat kidney and during recovery from ischemia. J Cell Physiol 1992, 153:467–76. 31. Nakamura H, et al.: Subcellular characteristics of phospholipase A2 activity in the rat kidney. Enhanced cytosolic, mitochondrial, and microsomal phospholipase A2 enzymatic activity after renal ischemia and reperfusion. J Clin Invest 1991, 87:1810–1818. 32. Lewington AJP, Padanilam BJ, Hammerman MR: Induction of calcyclin after ischemic injury to rat kidney. Am J Physiol 1997, 273(42):F380–F385.

Nutrition and Metabolism in Acute Renal Failure Wilfred Druml

A

dequate nutritional support is necessary to maintain protein stores and to correct pre-existing or disease-related deficits in lean body mass. The objectives for nutritional support for patients with acute renal failure (ARF) are not much different from those with other catabolic conditions. The principles of nutritional support for ARF, however, differ from those for patients with chronic renal failure (CRF), because diets or infusions that satisfy minimal requirements in CRF are not necessarily sufficient for patients with ARF. In patients with ARF modern nutritional therapy must include a tailored regimen designed to provide substrate requirements with various degrees of stress and hypercatabolism. If nutrition is provided to a patient with ARF the composition of the dietary program must be specifically designed because there are complex metabolic abnormalities that affect not only water, electrolyte, and acid-base-balance but also carbohydrate, lipid, and protein and amino acid utilization. In patients with ARF the main determinants of nutrient requirements (and outcome) are not renal dysfunction per se but the degree of hypercatabolism caused by the disease associated with ARF, the nutritional state, and the type and frequency of dialysis therapy. Pre-existing or hospital-acquired malnutrition has been identified as an important contributor to the persisting high mortality in critically ill persons. Thus, with modern nutritional support requirements must be met for all nutrients necessary for preservation of lean body mass, immunocompetence, and wound healing for a patient who has acquired ARF—in may instances among other complications. At the same time the specific metabolic alterations and demands in ARF and the impaired excretory renal function must be respected to limit uremic toxicity. In this chapter the multiple metabolic alterations associated with ARF are reviewed, methods for estimating nutrient requirements are discussed and, current concepts for the type and composition of nutritional programs are summarized. This information is relevant for designing nutritional support in an individual patient with ARF.

CHAPTER

18

18.2

Acute Renal Failure

NUTRITION IN ACUTE RENAL FAILURE Goals Preservation of lean body mass Stimulation of wound healing and reparatory functions Stimulation of immunocompetence Acceleration of renal recovery (?) But not (in contrast to stable CRF) Minimization of uremic toxicity (perform hemodialysis and CRRT as required) Retardation of progression of renal failure Thus, provision of optimal but not minimal amounts of substrates

METABOLIC PERTURBATIONS IN ACUTE RENAL FAILURE Determined by

Plus

Renal dysfunction (acute uremic state) Underlying illness The acute disease state, such as systemic inflammatory response syndrome (SIRS) Associated complications (such as infections)

Specific effects of renal replacement therapy Nonspecific effects of extracorporeal circulation (bioincompatibility)

FIGURE 18-1 Nutritional goals in patients with acute renal failure (ARF). The goals of nutritional intervention in ARF differ from those in patients with chronic renal failure (CRF): One should not provide a minimal intake of nutrients (to minimize uremic toxicity or to retard progression of renal failure, as recommended for CRF) but rather an optimal amount of nutrients should be provided for correction and prevention of nutrient deficiencies and for stimulation of immunocompetence and wound healing in the mostly hypercatabolic patients with ARF [1].

FIGURE 18-2 Metabolic perturbations in acute renal failure (ARF). In most instances ARF is a complication of sepsis, trauma, or multiple organ failure, so it is difficult to ascribe specific metabolic alterations to ARF. Metabolic derangements will be determined by the acute uremic state plus the underlying disease process or by complications such as severe infections and organ dysfunctions and, last but not least by the type and frequency of renal replacement therapy [1, 2]. Nevertheless, ARF does not affect only water, electrolyte, and acid base metabolism: it induces a global change of the metabolic environment with specific alterations in protein and amino acid, carbohydrate, and lipid metabolism [2].

Metabolic Alterations in Acute Renal Failure Energy metabolism FIGURE 18-3 Energy metabolism in acute renal failure (ARF). In experimental animals ARF decreases oxygen consumption even when hypothermia and acidosis are corrected (uremic hypometabolism) [3]. In contrast, in the clinical setting oxygen consumption of patients with various form of renal failure is remarkably little changed [4]. In subjects with chronic renal failure (CRF), advanced uremia (UA), patients on regular hemodialysis therapy (HD) but also in patients with uncomplicated ARF (ARFNS) resting energy expenditure (REE) was comparable to that seen in controls (N). However, in patients with ARF and sepsis (ARFS) REE is increased by approximately 20%. Thus, energy expenditure of patients with ARF is more determined by the underlying disease than acute uremic state and taken together these data indicate that when uremia is well-controlled by hemodialysis or hemofiltration there is little if any change in energy metabolism in ARF. In contrast to many other acute disease processes ARF might rather decrease than increase REE because in multiple organ dysfunction syndrome oxygen consumption was significantly higher in patients without impairment of renal function than in those with ARF [5]. (From Schneeweiss [4]; with permission.)

Nutrition and Metabolism in Acute Renal Failure

ESTIMATION OF ENERGY REQUIREMENTS Calculation of resting energy expenditure (REE) (Harris Benedict equation): Males: 66.47  (13.75  BW)  (5  height)  (6.76  age) Females: 655.1  (9.56  BW)  (1.85  height)  (4.67  age) The average REE is approximately 25 kcal/kg BW/day Stress factors to correct calculated energy requirement for hypermetabolism: Postoperative (no complications) 1.0 Long bone fracture 1.15–1.30 Cancer 1.10–1.30 Peritonitis/sepsis 1.20–1.30 Severe infection/polytrauma 1.20–1.40 Burns ( approxim. REE  % burned body surface area) 1.20–2.00 Corrected energy requirements (kcal/d)  REE  stress factor

18.3

FIGURE 18-4 Estimation of energy requirements. Energy requirements of patients with acute renal failure (ARF) have been grossly overestimated in the past and energy intakes of more than 50 kcal/kg of body weight (BW) per day (ie, about 100% above resting energy expenditure (REE) haven been advocated [6]. Adverse effects of overfeeding have been extensively documented during the last decades, and it should be noted that energy intake must not exceed the actual energy consumption. Energy requirements can be calculated with sufficient accuracy by standard formulas such as the Harris Benedict equation. Calculated REE should be multiplied with a stress factor to correct for hypermetabolic disease; however, even in hypercatabolic conditions such as sepsis or multiple organ dysfunction syndrome, energy requirements rarely exceed 1.3 times calculated REE [1].

Protein metabolism FIGURE 18-5 Protein metabolism in acute renal failure (ARF): activation of protein catabolism. Protein synthesis and degradation rates in acutely uremic and sham-operated rats. The hallmark of metabolic alterations in ARF is activation of protein catabolism with excessive release of amino acids from skeletal muscle and sustained negative nitrogen balance [7, 8]. Not only is protein breakdown accelerated, but there also is defective muscle utilization of amino acids for protein synthesis. In muscle, the maximal rate of insulin-stimulated protein synthesis is depressed by ARF and protein degradation is increased, even in the presence of insulin [9]. (From [8]; with permission.)

18.4

Acute Renal Failure

FIGURE 18-6 Protein metabolism in acute renal failure (ARF): impairment of cellular amino acid transport. A, Amino acid transport into skeletal muscle is impaired in ARF [10]. Transmembranous uptake of the amino acid analogue methyl-amino-isobutyrate (MAIB) is reduced in uremic tissue in response to insulin (muscle tissue from uremic animals, black circles, and from sham-operated animals, open circles, respectively). Thus, insulin responsiveness is reduced in ARF tissue, but, as can be seen from the parallel shift

of the curves, insulin sensitivity is maintained (see also Fig. 18-14). This abnormality can be linked both to insulin resistance and to a generalized defect in ion transport in uremia; both the activity and receptor density of the sodium pump are abnormal in adipose cells and muscle tissue [11]. B, The impairment of rubidium uptake (Rb) as a measure of Na-K-ATPase activity is tightly correlated to the reduction in amino acid transport. (From [10,11]; with permission.)

FIGURE 18-7 Protein catabolism in acute renal failure (ARF). Amino acids are redistributed from muscle tissue to the liver. Hepatic extraction of amino acids from the circulation—hepatic gluconeogenesis, A, and ureagenesis, B, from amino acids all are increased in ARF [12]. The dominant mediator of protein catabolism in ARF is this accel-

erated hepatic gluconeogenesis, which cannot be suppressed by exogenous substrate infusions (see Fig. 18-15). In the liver, protein synthesis and secretion of acute phase proteins are also stimulated. Circles—livers from acutely uremic rats; squares—livers from sham operated rats. (From Fröhlich [12]; with permission.).

Nutrition and Metabolism in Acute Renal Failure

18.5

FIGURE 18-8 Protein catabolism in acute renal failure (ARF): contributing factors. The causes of hypercatabolism in ARF are complex and multifold and present a combination of nonspecific mechanisms induced by the acute disease process and underlying illness and associated complications, specific effects induced by the acute loss of renal function, and, finally, the type and intensity of renal replacement therapy.

A major stimulus of muscle protein catabolism in ARF is insulin resistance. In muscle, the maximal rate of insulin-stimulated protein synthesis is depressed by ARF and protein degradation is increased even in the presence of insulin [9]. Acidosis was identified as an important factor in muscle protein breakdown. Metabolic acidosis activates the catabolism of protein and oxidation of amino acids independently of azotemia, and nitrogen balance can be improved by correcting the metabolic acidosis [13]. These findings were not uniformly confirmed for ARF in animal experiments [14]. Several additional catabolic factors are operative in ARF. The secretion of catabolic hormones (catecholamines, glucagon, glucocorticoids), hyperparathyroidism which is also present in ARF (see Fig. 18-22), suppression of or decreased sensitivity to growth factors, the release of proteases from activated leukocytes—all can stimulate protein breakdown. Moreover, the release of inflammatory mediators such as tumor necrosis factor and interleukins have been shown to mediate hypercatabolism in acute disease [1, 2]. The type and frequency of renal replacement therapy can also affect protein balance. Aggravation of protein catabolism, certainly, is mediated in part by the loss of nutritional substrates, but some findings suggest that, in addition, both activation of protein breakdown and inhibition of muscular protein synthesis are induced by hemodialysis [15]. Last (but not least), of major relevance for the clinical situation is the fact that inadequate nutrition contributes to the loss of lean body mass in ARF. In experimental animals, starvation potentiates the catabolic response of ARF [7].

FIGURE 18-9 Amino acid pools and amino acid utilization in acute renal failure (ARF). As a consequence of these metabolic alterations, imbalances in amino acid pools in plasma and in the intracellular compartment occur in ARF. A typical plasma amino acid pattern is seen [16]. Plasma concentrations of cysteine (CYS), taurine (TAU), methionine (MET), and phenylalanine (PHE) are elevated, whereas plasma levels of valine (VAL) and leucine (LEU) are decreased. Moreover, elimination of amino acids from the intravascular space is altered. As expected from the stimulation of hepatic

extraction of amino acids observed in animal experiments, overall amino acid clearance and clearance of most glucoplastic amino acids is enhanced. In contrast, clearances of PHE, proline (PRO), and, remarkably, VAL are decreased [16, 17]. ALA— alanine; ARG—arginine; ASN—asparagine; ASP—aspartate; CIT—citrulline; GLN—glutamine; GLU—glutamate; GLY— glycine; HIS—histidine; ORN—ornithine; PRO—proline; SER— serine; THR—threonine; TRP—tryptophan; TYR—tyrosine. (From Druml et al. [16]; with permission.)

CONTRIBUTING FACTORS TO PROTEIN CATABOLISM IN ACUTE RENAL FAILURE Impairment of metabolic functions by uremia toxins Endocrine factors Insulin resistance Increased secretion of catabolic hormones (catecholamines, glucagon, glucocorticoids) Hyperparathyroidism Suppression of release or resistance to growth factors Acidosis Systemic inflammatory response syndrome (activation of cytokine network) Release of proteases Inadequate supply of nutritional substrates Loss of nutritional substrates (renal replacement therapy)

18.6

Acute Renal Failure

FIGURE 18-10 Metabolic functions of the kidney and protein and amino acid metabolism in acute renal failure (ARF). Protein and amino acid metabolism in ARF are also affected by impairment of the metabolic functions of the kidney itself. Various amino acids are synthe-

sized or converted by the kidneys and released into the circulation: cysteine, methionine (from homocysteine), tyrosine, arginine, and serine [18]. Thus, loss of renal function can contribute to the altered amino acid pools in ARF and to the fact that several amino acids, such as arginine or tyrosine, which conventionally are termed nonessential, might become conditionally indispensable in ARF (see Fig. 18-11) [19]. In addition, the kidney is an important organ of protein degradation. Multiple peptides are filtered and catabolized at the tubular brush border, with the constituent amino acids being reabsorbed and recycled into the metabolic pool. In renal failure, catabolism of peptides such as peptide hormones is retarded. This is also true for acute uremia: insulin requirements decrease in diabetic patients who develop of ARF [20]. With the increased use of dipeptides in artificial nutrition as a source of amino acids (such as tyrosine and glutamine) which are not soluble or stable in aqueous solutions, this metabolic function of the kidney may also gain importance for utilization of these novel nutritional substrates. In the case of glycyl-tyrosine, metabolic clearance progressively decreases with falling creatinine clearance (open circles, 7 healthy subjects and a patient with unilateral nephrectomy*) but extrarenal clearance in the absence of renal function (black circles) is sufficient for rapid utilization of the dipeptide and release of tyrosine [21]. (From Druml et al. [21]; with permission.)

FIGURE 18-11 Amino acids in nutrition of acute renal failure (ARF): Conditionally essential amino acids. Because of the altered metabolic environment of uremic patients certain amino acids designated as nonessential for healthy subjects may become conditionally indispensable to ARF

patients: histidine, arginine, tyrosine, serine, cysteine [19]. Infusion of arginine-free amino acid solutions can cause life-threatening complications such as hyperammonemia, coma, and acidosis. Healthy subjects readily form tyrosine from phenylalanine in the liver: During infusion of amino acid solutions containing phenylalanine, plasma tyrosine concentration rises (circles) [22]. In contrast, in patients with ARF (triangles) and chronic renal failure (CRF, squares) phenylalanine infusion does not increase plasma tyrosine, indicating inadequate interconversion. Recently, it was suggested that glutamine, an amino acid that traditionally was designated non-essential exerts important metabolic functions in regulating nitrogen metabolism, supporting immune functions, and preserving the gastrointestinal barrier. Thus, it can become conditionally indispensable in catabolic illness [23]. Because free glutamine is not stable in aqueous solutions, dipeptides containing glutamine are used as a glutamine source in parenteral nutrition. The utilization of dipeptides in part depends on intact renal function, and renal failure can impair hydrolysis (see Fig. 18-10) [24]. No systematic studies have been published on the use of glutamine in patients with ARF, and it must be noted that glutamine supplementation increases nitrogen intake considerably.

Nutrition and Metabolism in Acute Renal Failure

18.7

Protein requirements ESTIMATING THE EXTENT OF PROTEIN CATABOLISM Urea nitrogen appearance (UNA) (g/d)  Urinary urea nitrogen (UUN) excretion  Change in urea nitrogen pool  (UUN  V)  (BUN2  BUN1) 0.006  BW  (BW2  BW1)  BUN2/100 If there are substantial gastrointestinal losses, add urea nitrogen in secretions:  volume of secretions  BUN2 Net protein breakdown (g/d)  UNA  6.25 Muscle loss (g/d) UNA  6.25  5 V is urine volume; BUN1 and BUN2 are BUN in mg/dL on days 1 and 2 BW1 and BW2 are body weights in kg on days 1 and 2

FIGURE 18-13 Amino acid and protein requirements of patients with acute renal failure (ARF). The optimal intake of protein or amino acids is affected more by the nature of the underlying cause of ARF and the extent of protein catabolism and type and frequency of dialysis than by kidney dysfunction per se. Unfortunately, only a few studies have attempted to define the optimal requirements for protein or amino acids in ARF: In nonhypercatabolic patients, during the polyuric phase of ARF protein intake of 0.97 g/kg body weight per day was required to achieve a positive nitrogen balance [25]. A similar number (1.03g/kg

FIGURE 18-12 Estimation of protein catabolism and nitrogen balance. The extent of protein catabolism can be assessed by calculating the urea nitrogen appearance rate (UNA), because virtually all nitrogen arising from amino acids liberated during protein degradation is converted to urea. Besides urea in urine (UUN), nitrogen losses in other body fluids (eg, gastrointestinal, choledochal) must be added to any change in the urea pool. When the UNA rate is multiplied by 6.25, it can be converted to protein equivalents. With known nitrogen intake from the parenteral or enteral nutrition, nitrogen balance can be estimated from the UNA calculation.

body weight per day) was derived from a study in which, unfortunately, energy intake was not kept constant [6]. In the polyuric recovery phase in patients with sepsis-induced ARF, a nitrogen intake of 15 g/day (averaging an amino acid intake of 1.3 g/kg body weight per day) as compared to 4.4 g/kg per day (about 0.3 g/kg amino acids) was superior in ameliorating nitrogen balance [26]. Several recent studies have tried to evaluate protein and amino acid requirements of critically ill patients with ARF. Kierdorf and associates found that, in these hypercatabolic patients receiving continuous hemofiltration therapy, the provision of amino acids 1.5 g /kg body weight per day was more effective in reducing nitrogen loss than infusion of 0.7 g (3.4 versus 8.1 g nitrogen per day) [27]. An increase of amino acid intake to 1. 74 g/kg per day did not further ameliorate nitrogen balance. Chima and coworkers measured a mean PCR of 1.7 g kg body weight per day in 19 critically ill ARF patients and concluded that protein needs in these patients range between 1.4 and 1.7 g/kg per day [28]. Similarly, Marcias and coworkers have obtained a protein catabolic rate (PCR) of 1.4 g/kg per day and found an inverse relationship between protein and energy provision and PCR and again recommended protein intake of 1.5 to 1.8 g/kg per day [29]. Similar conclusions were drawn by Ikitzler in evaluating ARF patients on intermittent hemodialysis therapy [30]. (From Kierdorf et al. [27]; with permission.)

18.8

Acute Renal Failure

Glucose metabolism

FIGURE 18-14 Glucose metabolism in acute renal failure (ARF): Peripheral insulin resistance. ARF is commonly associated with hyperglycemia. The major cause of elevated blood glucose concentrations is insulin resistance [31]. Plasma insulin concentration is elevated. Maximal insulin-stimulated glucose uptake by skeletal muscle is decreased by 50 %, A, and muscular glycogen synthesis is impaired, B. However, insulin concentrations that cause half-maximal stimulation of glucose uptake are normal, pointing to a postreceptor defect rather

than impaired insulin sensitivity as the cause of defective glucose metabolism. The factors contributing to insulin resistance are more or less identical to those involved in the stimulation of protein breakdown (see Fig. 18-8). Results from experimental animals suggest a common defect in protein and glucose metabolism: tyrosine release from muscle (as a measure of protein catabolism) is closely correlated with the ratio of lactate release to glucose uptake [9]. (From May et al. [31]; with permission.) FIGURE 18-15 Glucose metabolism in acute renal failure (ARF): Stimulation of hepatic gluconeogenesis. A second feature of glucose metabolism (and at the same time the dominating mechanism of accelerated protein breakdown) in ARF is accelerated hepatic gluconeogenesis, mainly from conversion of amino acids released during protein catabolism. Hepatic extraction of amino acids, their conversion to glucose, and urea production are all increased in ARF (see Fig. 18-7) [12]. In healthy subjects, but also in patients with chronic renal failure, hepatic gluconeogenesis from amino acids is readily and completely suppressed by exogenous glucose infusion. In contrast, in ARF hepatic glucose formation can only be decreased, but not halted, by substrate supply. As can be seen from this experimental study, even during glucose infusion there is persistent gluconeogenesis from amino acids in acutely uremic dogs (•) as compared with controls dogs (o) whose livers switch from glucose release to glucose uptake [32]. These findings have important implications for nutrition support for patients with ARF: 1) It is impossible to achieve positive nitrogen balance; 2) Protein catabolism cannot be suppressed by providing conventional nutritional substrates alone. Thus, for future advances alternative means must be found to effectively suppress protein catabolism and preserve lean body mass. (From Cianciaruso et al. [32]; with permission.)

Nutrition and Metabolism in Acute Renal Failure

18.9

Lipid metabolism FIGURE 18-16 Lipid metabolism in acute renal failure (ARF). Profound alterations of lipid metabolism occur in patients with ARF. The triglyceride content of plasma lipoproteins, especially very low-density (VLDL) and low-density ones (LDL) is increased, while total cholesterol and in particular high-density lipoprotein (HDL) cholesterol are decreased [33,34]. The major cause of lipid abnormalities in ARF is impairment of lipolysis. The activities of both lipolytic systems, peripheral lipoprotein lipase and hepatic triglyceride lipase are decreased in patients with ARF to less than 50% of normal [35]. Maximal postheparin lipolytic activity (PHLA), hepatic triglyceride lipase (HTGL), and peripheral lipoprotein lipase (LPL) in 10 controls (open bars) and eight subjects with ARF (black bars). However, in contrast to this impairment of lipolysis, oxidation of fatty acids is not affected by ARF. During infusion of labeled long-chain fatty acids, carbon dioxide production from lipid was comparable between healthy subjects and patients with ARF [36]. FFA—free fatty acids. (Adapted from Druml et al. [35]; with permission.) FIGURE 18-17 Impairment of lipolysis and elimination of artificial lipid emulsions in acute renal failure (ARF). Fat particles of artificial fat emulsions for parenteral nutrition are degraded as endogenous very low-density lipoprotein is. Thus, the nutritional consequence of the impaired lipolysis in ARF is delayed elimination of intravenously infused lipid emulsions [33, 34]. The increase in plasma triglycerides during infusion of a lipid emulsion is doubled in patients with ARF (N=7) as compared with healthy subjects (N=6). The clearance of fat emulsions is reduced by more than 50% in ARF. The impairment of lipolysis in ARF cannot be bypassed by using medium-chain triglycerides (MCT); the elimination of fat emulsions containing long chain triglycerides (LCT) or MCT is equally retarded in ARF [34]. Nevertheless, the oxydation of free fatty acid released from triglycerides is not inpaired in patients with ARF [36]. (From Druml et al. [34]; with permission.)

18.10

Acute Renal Failure

Electrolytes and micronutrients CAUSES OF ELECTROLYTE DERANGEMENTS IN ACUTE RENAL FAILURE Hyperkalemia

Hyperphosphatemia

Decreased renal elimination Increased release during catabolism 2.38 mEq/g nitrogen 0.36 mEq/g glycogen Decreased cellular uptake/ increased release Metabolic acidosis: 0.6 mmol/L rise/0.1 decrease in pH

Decreased renal elimination Increased release from bone Increased release during catabolism: 2 mmol/g nitrogen Decreased cellular uptake/utilization and/or increased release from cells

FIGURE 18-19 Electrolytes in acute renal failure (ARF): hypophosphatemia and hypokalemia. It must be noted that a considerable number of patients with ARF do not present with hyperkalemia or hyperphosphatemia, but at least 5% have low serum potassium and more than 12% have decreased plasma phosphate on admission [38]. Nutritional support, especially parenteral nutrition with low electrolyte content, can cause hypophosphatemia and hypokalemia in as many as 50% and 19% of patients respectively [39,40]. In the case of phosphate, phosphate-free artificial nutrition causes hypophosphatemia within a few days, even if the patient was hyperphosphatemic on admission (black circles) [41]. Supplementation of 5 mmol per day was effective in maintaining normal plasma phosphate concentrations (open squares), whereas infusion of more than 10 mmol per day resulted in hyperphosphatemia, even if the patients had decreased phosphate levels on admission (open circles). Potassium or phosphate depletion increases the risk of developing ARF and retards recovery of renal function. With modern nutritional support, hyperkalemia is the leading indication for initiation of extracorporeal therapy in fewer than 5% of patients [38]. (Adapted from Kleinberger et al. [41]; with permission.)

FIGURE 18-18 Electrolytes in acute renal failure (ARF): causes of hyperkalemia and hyperphosphatemia. ARF frequently is associated with hyperkalemia and hyperphosphatemia. Causes are not only impaired renal excretion of electrolytes but release during catabolism, altered distribution in intracellular and extracellular spaces, impaired cellular uptake, and acidosis. Thus, the type of underlying disease and degree of hypercatabolism also determine the occurrence and severity of electrolyte abnormalities. Either hypophosphatemia or hyperphosphatemia can predispose to the development and maintenance of ARF [37].

FIGURE 18-20 Micronutrients in acute renal failure (ARF): water-soluble vitamins. Balance studies on micronutrients (vitamins, trace elements) are not available for ARF. Because of losses associated with renal replacement therapy, requirements for water-soluble vitamins are expected to be increased also in patients with ARF. Malnutrition with depletion of vitamin body stores and associated hypercatabolic underlying disease in ARF can further increase the need for vitamins. Depletion of thiamine (vitamin B1) during continuous hemofiltration and inadequate intake can result in lactic acidosis and heart failure [42]. This figure depicts the evolution of plasma lactate concentration before and after administration of 600 mg thiamine in two patients. Infusion of 600 mg of thiamine reversed the metabolic abnormality within a few hours. An exception to this approach to treatment is ascorbic acid (vitamin C); as a precursor of oxalic acid the intake should be kept below 200 mg per day because any excessive supply may precipitate secondary oxalosis [43]. (From Madl et al. [42]; with permission.)

Nutrition and Metabolism in Acute Renal Failure

FIGURE 18-21 Micronutrients in acute renal failure (ARF): fat-soluble vitamins (A, E, K). Despite the fact that fat-soluble vitamins are not lost during hemodialysis and hemofiltration, plasma concentrations of vitamins A and E are depressed in patients with ARF and requirements are increased [44]. Plasma concentrations of vitamin K (with broad variations of individual values) are normal in ARF. Most commercial multivitamin preparations for parenteral infusions contain the recommended daily allowances of vitamins and can safely be used in ARF patients. (From Druml et al. [44]; with permission.)

18.11

FIGURE 18-22 Hypocalcemia and the vitamin D–parathyroid hormone (PTH) axis in acute renal failure (ARF). ARF is also frequently associated with hypocalcemia secondary to hypoalbuminemia, elevated serum phosphate, plus skeletal resistance to calcemic effect of PTH and impairment of vitamin-D activation. Plasma concentration of PTH is increased. Plasma concentrations of vitamin D metabolites, 25-OH vitamin D3 and 1,25-(OH)2 vitamin D3, are decreased [44]. In ARF caused by rhabdomyolysis rebound hypercalcemia may develop during the diuretic phase. (Adapted from Druml et al. [44]; with permission.) FIGURE 18-23 Micronutrients in acute renal failure (ARF): antioxidative factors. Micronutrients are part of the organism’s defense mechanisms against oxygen free radical induced injury to cellular components. In experimental ARF, antioxidant deficiency of the organism (decreased vitamin E or selenium status) exacerbates ischemic renal injury, worsens the course, and increases mortality, whereas repletion of antioxidant status exerts the opposite effect [45]. These data argue for a crucial role of reactive oxygen species and peroxidation of lipid membrane components in initiating and mediating ischemia or reperfusion injury. In patients with multiple organ dysfunction syndrome and associated ARF (lightly shaded bars) various factors of the oxygen radical scavenger system are profoundly depressed as compared with healthy subjects (black bars): plasma concentrations of vitamin C, of -carotene, vitamin E, selenium, and glutathione all are profoundly depressed, whereas the end-product of lipid peroxidation, malondialdehyde, is increased (double asterisk, P < 0.01; triple asterisk, P < 0.001). This underlines the importance of supplementation of antioxidant micronutrients for patients with ARF. (Adapted from Druml et al. [46]; with permission.)

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Acute Renal Failure

Metabolic Impact of Renal Replacement Therapy METABOLIC EFFECTS OF CONTINUOUS RENAL REPLACEMENT THERAPY Amelioration of uremia intoxication (renal replacement) Plus Heat loss Excessive load of substrates (eg, lactate, glucose) Loss of nutrients (eg, amino acids, vitamins) Elimination of short-chain proteins (hormones, mediators?) Induction or activation of mediator cascades Stimulation of protein catabolism?

FIGURE 18-24 Metabolic impact of extracorporeal therapy. The impact of hemodialysis therapy on metabolism is multifactorial. Amino acid and protein metabolism are altered not only by substrate losses but also by activation of protein breakdown mediated by release of leukocyte-derived proteases, of inflammatory mediators (interleukins and tumor necrosis factor) induced by blood-membrane interactions or endotoxin. Dialysis can also induce inhibition of muscle protein synthesis [15]. In the management of patients with acute renal failure (ARF), continuous renal replacement therapies (CRRT), such as continuous

(arteriovenous) hemofiltration (CHF) and continuous hemodialysis have gained wide popularity. CRRTs are associated with multiple metabolic effects in addition to “renal replacement” [47]. By cooling of the extracorporeal circuit and infusion of cooled substitution fluids, CHF may induce considerable heat loss (350 to 700 kcal per day). On the other hand, hemofiltration fluids contain lactate as anions, oxidation of which in part compensates for the heat loss. This lactate load can result in hyperlactemia in the presence of liver dysfunction or increased endogenous lactate formation such as in circulatory shock. Several nutrients with low protein binding and small molecular weight (sieving coefficient 0.8 to 1.0), such as vitamins or amino acids are eliminated during therapy. Amino acid losses can be estimated from the volume of the filtrate and average plasma concentration, and usually this accounts for a loss of approximately 0.2 g/L of filtrate and, depending on the filtered volume, 5 to 10 g of amino acid per day, respectively, representing about 10 % of amino acid input, but it can be even higher during continuous hemodiafiltration [48]. With the large molecular size cut-off of membranes used in hemofiltration, small proteins such as peptide hormones are filtered. In view of their short plasma half-life hormone losses are minimal and probably not of pathophysiologic importance. Quantitatively relevant elimination of mediators by CRRT has not yet been proven. On the other hand, prolonged blood-membrane interactions can induce consequences of bioincompatibility and activation of various endogenous cascade systems.

Nutrition, Renal Function, and Recovery

FIGURE 18-25 A, B, Impact of nutritional interventions on renal function and course of acute renal failure (ARF). Starvation accelerates protein breakdown and impairs protein synthesis in the kidney, whereas refeeding exerts the opposite effects [49]. In experimental animals, provision of amino acids or total parenteral nutrition accelerates tissue repair and recovery of renal function [50]. In patients, however, this has been much more difficult to prove, and only one study has reported on a positive effect of TPN on the resolution of ARF [51].

Infusion of amino acids raised renal cortical protein synthesis as evaluated by 14C-leucine incorporation and depressed protein breakdown in rats with mercuric chloride–induced ARF [49]. On the other hand, in a similar model of ARF, infusions of varying quantities of essential amino acids (EAA) and nonessential amino acids (NEAA) did not provide any protection of renal function and in fact increased mortality [52]. However, in balance available evidence suggests that provision of substrates may enhance tissue regeneration and wound healing, and potentially, also renal tubular repair [49]. (From Toback et al. [50]; with permission.)

Nutrition and Metabolism in Acute Renal Failure

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FIGURE 18-26 Impact of nutritional interventions on renal function in acute renal failure (ARF). Amino acid infused before or during ischemia or nephrotoxicity may enhance tubule damage and accelerate loss of renal function in rat models of ARF. In part, this therapeutic paradox [53] from amino acid alimentation in ARF is related to the increase in metabolic work for transport processes when oxygen supply is limited, which may aggravate ischemic injury [54]. Similar observations have been made with excess glucose infusion during renal ischemia. Amino acids may as well exert a protective effect on renal function. Glycine, and to a lesser degree alanine, limit tubular injury in ischemic and nephrotoxic models of ARF [55]. Arginine (possibly by producing nitric oxide) reportedly acts to preserve renal perfusion and tubular function in both nephrotoxic and ischemic models of ARF, whereas inhibitors of nitric oxide synthase exert an opposite effect [56,57]. In myoglobininduced ARF the drop in renal blood flow (black circles, ARF controls) is prevented by L-arginine infusion (black triangles) [57]. (From Wakabayashi et al. [57]; with permission.)

FIGURE 18-27 Impact of endocrine-metabolic interventions on renal function and course of acute renal failure (ARF). Various other endocrine-metabolic interventions (eg, thyroxine, human growth hormone [HGH], epidermal growth factor, insulin-like growth factor 1 [IGF-1]) have been shown to accelerate regeneration after experimental ARF [51]. In a rat model of postischemic ARF, treatment with IGF-1 starting 5 hours after induction of ARF accelerates recovery from

ischemic ARF, A, but also reduces the increase in BUN and improves nitrogen balance, B, [58]. (open circles) ARF plus vehicle; (black circles, sham-operated rats plus vehicle; open squares, ARF plus rhIGF-I; black squares, sham operated rats plus rhIGFI.) Unfortunately, efficacy of these interventions was not uniformly confirmed in clinical studies [59, 60]. (From Ding et al. [58]; with permission.)

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Acute Renal Failure

Decision Making, Patient Classification, and Nutritional Requirements DECISIONS FOR NUTRITION IN PATIENTS WITH ACUTE RENAL FAILURE Decisions dependent on Patients ability to resume oral diet (within 5 days?) Nutritional status Underlying illness/degree of associated hypercatabolism 1. What patient with acute renal failure needs nutritional support? 2. When should nutritional support be initiated? 3. At what degree of impairment in renal function should the nutritional regimen be adapted for renal failure? 4. In a patient with multiple organ dysfunction, which organ determines the type of nutritional support? 5. Is enteral or parenteral nutrition the most appropriate method for providing nutritional support?

FIGURE 18-28 Nutrition in patients with acute renal failure (ARF): decision making. Not every patient with ARF requires nutritional support. It is important to identify those who will benefit and to define the optimal time to initiate therapy [1]. The decision to initiate nutritional support is influenced by the patient’s ability to cover nutritional requirements by eating, in addition to the nutritional status of the patient as well as the type of

underlying illness involved. In any patient with evidence of malnourishment, nutritional therapy should be instituted regardless of whether the patient will be likely to eat. If a well-nourished patient can resume a normal diet within 5 days, no specific nutritional support is necessary. The degree of accompanying catabolism is also a factor. For patients with underlying diseases associated with excess protein catabolism, nutritional support should be initiated early. If there is evidence of malnourishment or hypercatabolism, nutritional therapy should be initiated early, even if the patient is likely to eat before 5 days. Modern nutritional strategies should be aimed at avoiding the development of deficiency states and of “hospitalacquired malnutrition.” During the acute phase of ARF (the first 24 hours after trauma or surgery) nutritional support should be withheld because nutrients infused during this “ebb phase” are not utilized, could increase oxygen requirements, and aggravate tissue injury and renal dysfunction. The nutritional regimen should be adapted for renal failure when renal function is impaired. The multiple metabolic alterations characteristic of ARF occur when kidney function is below 30% of normal. Thus, when creatinine clearance falls below 50 to 30 mL per minute/1.73 m2 (or serum creatinine rises above 2.5 to 3.0 mg/dL) the nutritional regimen should be adapted to ARF. With the exception of severe hepatic failure and massively deranged amino acid metabolism (hyperammonemia) or protein synthesis (depletion of coagulation factors) renal failure is the major determinant of the nutritional regimen in patients with multiple organ dysfunction. Enteral feeding is preferred for all patients, including those with ARF. Nevertheless, for a large portion of patients, parenteral nutrition—total or partial—will be necessary to meet nutritional requirements.

Nutrition and Metabolism in Acute Renal Failure

PATIENT CLASSIFICATION AND SUBSTRATE REQUIREMENTS IN PATIENTS WITH ACUTE RENAL FAILURE

Extent of Catabolism Mild

Moderate

Severe

Excess urea appearance (above nitrogen intake) Clinical setting (examples)

>6 g

6–12 g

>12 g

Drug toxicity

Elective surgery ± infection

Severe injury or sepsis

Mortality Dialysis or hemofiltration frequency Route of nutrient administration Energy recommendations (kcal/kg BW/d) Energy substrates Glucose (g/kg BW/d) Fat (g/kg BW/d) Amino acids/protein (g/kg/d)

20 % Rare Oral

60% As needed Enteral or parenteral

>80% Frequent Enteral or parenteral

25

25–30

25–35

Glucose 3.0–5.0

Glucose + fat 3.0–5.0 0.5–1.0 0.8–1.2 EAA  NEAA Enteral formulas Glucose 50%–70%  fat emulsions 10% or 20%

Glucose  fat 3.0–5.0 (max. 7.0) 0.8–1.5 1.0–1.5 EAA  NEAA Enteral formulas Glucose 50%–70% + fat emulsions 10% or 20%

Nutrients used

0.6–1.0 EAA (NEAA) Foods

EAA + specific NEAA solutions (general or “nephro”) Multivitamin and multitrace element preparations BW—body weight; EAA—essential amino acids; NEAA—nonessential amino acids.

FIGURE 18-29 Patient classification: substrate requirements. Ideally, a nutritional program should be designed for each individual acute renal failure (ARF) patient. In clinical practice, it has proved useful to distinguish three groups of patients based on the extent of protein catabolism associated with the underlying disease and resulting levels of dietary requirements. Group I includes patients without excess catabolism and a UNA of less than 6 g of nitrogen above nitrogen intake per day. ARF is usually caused by nephrotoxins (aminoglycosides, contrast media, mismatched blood transfusion). In most cases, these patients are fed orally and the prognosis for recovery of renal function and survival is excellent. Group II consists of patients with moderate hypercatabolism and a UNA exceeding nitrogen intake 6 to 12 g of nitrogen per day. Affected patients frequently suffer from complicating infections, peritonitis, or moderate injury in association with ARF. Tube feeding or intravenous nutritional support is generally required, and dialysis or hemofiltration often becomes necessary to limit waste product accumulation. Group III are patients who develop ARF in association with severe trauma, burns, or overwhelming infection. UNA is markedly elevated (more than 12 g of nitrogen above nitrogen intake). Treatment strategies are usually complex and include parenteral nutrition, hemodialysis or continuous hemofiltration plus blood pressure and ventilatory support. To reduce catabolism and avoid protein depletion nutrient requirements are high and dialysis is used to maintain fluid balance and blood urea nitrogen below 100 mg/dL. Mortality in this group of patients exceeds 60% to 80%, but it is not the loss of renal function that accounts for the poor prognosis. It is superimposed hypercatabolism and the severity of the underlying illness. (Adapted from Druml [1]; with permission.)

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18.16

Acute Renal Failure

Enteral Nutrition FIGURE 18-30 Enteral nutrition (tube feeding). The gastrointestinal tract should be used whenever possible because enteral nutrients may help to maintain gastrointestinal function and the mucosal barrier and thus prevent translocation of bacteria and systemic infection [61]. Even small amounts of enteral diets exert a protective effect on the intestinal mucosa. Recent animal experiments suggest that enteral feeds may exert additional advantages in acute renal failure (ARF) patients [63]: in glycerol-induced ARF in rats enteral feeding improved renal perfusion, A, and preserved renal function, B. For patients with ARF who are unable to eat because of cerebral impairment, anorexia, or nausea, enteral nutrition should be provided through small, soft feeding tubes with the tip positioned in the stomach or jejunum [61]. Feeding solutions can be administered by pump intermittently or continuously. If given continuously, the stomach should be aspirated every 2 to 4 hours until adequate gastric emptying and intestinal peristalsis are established. To avoid diarrhea, the amount and concentration of the solution should be increased gradually over several days until nutritional requirements are met. Undesired, but potentially treatable side effects include nausea, vomiting, abdominal distension and cramping and diarrhea. (From Roberts et al. [62]; with permission.)

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Nutrition and Metabolism in Acute Renal Failure

SPECIFIC ENTERAL FORMULAS FOR NUTRITIONAL SUPPORT OF PATIENTS WITH RENAL FAILURE

Amin-Aid Volume (mL) Calories (kcal) (cal/mL) Energy distribution Protein:fat:carbohydrates (%) kcal/g N Proteins (g) EAA (%) NEAA (%) Hydrolysate (%) Full protein (%) Nitrogen (g) Carbohydrates (g) Monodisaccharides (%) Oligosaccharides (%) Polysaccharides (%) Fat (g) LCT (%) Essential GA (%) MCT (%) Nonprotein (cal/g N) Osmol (mOsm/kg) Sodium (mmol/L) Potassium (mmol/L) Phosphate (mmol) Vitamins Minerals

Travasorb renal*

Salvipeptide nephro†

Survimed renal‡

Suplena§

Nepro§

750 1467 1.96

1050 1400 1.35

500 1000 2.00

1000 1320 1.32

500 1000 2.00

500 1000 2.00

4:21:75 832:1 14.6 100 — — — 1.76 274 100 — — 34.6

7:12:81 389:1 24.0 60 30 — — 3.6 284 100 — — 18.6 30 18 70 363 590 — — 16.1 a b

8:22:70 313:1 20.0 23 20 23 34 3.2 175 3 28 69 24 50 31 50 288 507 7.2 1.5 6.13 a a

6:10:84 398:1 20.8

6:43:51 418:1 15.0

14:43:43 179:1 35

100 2.4 128 10

100 5.6 108 12

502 1095 11 — — b b

100 — 3.32 276

88 15.2 52 30 374 600 15.2 8 6.4 a a

48 100 22 0 393 635 32 27.0 11.0 a a

90 47.8 100 0 154 615 34.0 28.5 11.0 a a

* 3 bags  810 mL  1050 mL † component I  component II  350 mL = 500 mL ‡ 4 bags  800 mL  1000 mL § Liquid formula, cans 8 fl oz (237.5 mL), supplemented with carnitine, taurine with a low-protein (Suplena) or moderate-protein content (Nepro) a 2000 kcal/d meets RDA for most vitamins/trace elements b Must be added EAA—essential amino acids; FA—fatty acids; LCT—long-chain triglycerides; MCT—medium-chain triglycerides; N—nitrogen; NEAA—non-essential amino acids.

FIGURE 18-31 Enteral feeding formulas. There are standardized tube feeding formulas designed for subjects with normal renal function that can also be given to patients with acute renal failure (ARF). Unfortunately, the fixed composition of nutrients, including proteins and high content of electrolytes (especially potassium and phosphate) often limits their use for ARF. Alternatively, enteral feeding formulas designed for nutritional therapy of patients with chronic renal failure (CRF) can be used. The preparations listed here may have advantages also for patients

with ARF. The protein content is lower and is confined to highquality proteins (in part as oligopeptides and free amino acids), the electrolyte concentrations are restricted. Most formulations contain recommended allowances of vitamins and minerals. In part, these enteral formulas are made up of components that increase the flexibility in nutritional prescription and enable adaptation to individual needs. The diets can be supplemented with additional electrolytes, protein, and lipids as required. Recently, ready-touse liquid diets have also become available for renal failure patients.

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Acute Renal Failure

Parenteral Nutrition RENAL FAILURE FLUID—ALL-IN-ONE SOLUTION

Component

Quantity

Glucose 40%–70%

500 mL

Fat emulsion 10%–20%

500 mL

Amino acids 6.5%–10%

500 mL

Water-soluble vitamins Fat-soluble vitamins* Trace elements* Electrolytes

Daily Daily Twice weekly As required

Insulin

As required

Remarks In the presence of severe insulin resistance switch to D30W Start with 10%, switch to 20% if triglycerides are < 350 mg/dL General or special “nephro” amino acid solutions, including EAA and NEAA Limit vitamin C intake < 200 mg/d Caveats: toxic effects Caveats: hypophosphatemia or hypokalemia after initiation of TPN Added directly to the solution or given separately

* Combination products containing the recommended daily allowances.

FIGURE 18-32 Parenteral solutions. Standard solutions are available with amino acids, glucose, and lipids plus added vitamins, trace elements, and electrolytes contained in a single bag (“total admixture” solutions, “all-in-one” solutions). The stability of fat emulsions in such mixtures should be tested. If hyperglycemia is present, insulin can be added to the solution or administered separately. To ensure maximal nutrient utilization and avoid metabolic derangements as mineral imbalance, hyperglycemia or blood urea nitrogen rise, the infusion should be started at a slow rate (providing about 50% of requirements) and gradually increased over several days. Optimally, the solution should be infused continuously over 24 hours to avoid marked derangements in substrate concentrations in the presence of impaired utilization for several nutritional substrates in patients with acute renal failure. EAA, NEAA—essential and nonessential amino acids; TPN—total parenteral nutrition.

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Nutrition and Metabolism in Acute Renal Failure

AMINO ACID SOLUTIONS FOR THE TREATMENT OF ACUTE RENAL FAILURE (“NEPHRO” SOLUTIONS)

Rose-Requirements Amino acids (g/L) ( g/%) Volume (mL) (mOsm/L) Nitrogen (g/L) Essential amino acids (g/L) Isoleucine Leucine Lysine acetate/HCl Methionine Phenylalanine Threonine Tryptophan Valine

1.40 2.20 1.60 2.20 2.20 1.00 0.50 1.60

Nonessential amino acids (g/L) Alanine Arginine Glycine Histidine Proline Serine Tyrosine Cysteine

RenAmin (Clintec)

Aminess (Clintec)

Aminosyn RF (Abbott)

65 6.5 500 600 10

52 5.2 400 416 8.3

52 5.2 1000 475 8.3

5.00 6.00 4.50 5.00 4.90 3.80 1.60 8.20 5.60 6.30 3.00 4.20 3.50 3.00 0.40

5.25 8.25 6.00 8.25 8.25 3.75 1.88

4.62 7.26 5.35 7.26 7.26 3.30 1.60 5.20

6.00

6.00

4.12

4.29

NephrAmine (McGaw) 54 5.4 1000 435 6.5 5.60 8.80 6.40 8.80 8.80 4.00 2.00 6.40

2.50

0.20

Nephrotect (Fresenius) 100 10 500 908 16.3 5.80 12.80 12.00 2.00 3.50 8.20 3.00 8.70 6.20 8.20 6.30* 9.80 3.00 7.60 3.00† 0.40

* Glycine is a componenet of the dipeptide. † Tyrosine is included as dipeptide (glycyl-L-tyrosine).

FIGURE 18-33 Amino acid (AA) solutions for parenteral nutrition in acute renal failure (ARF). The most controversial choice regards the type of amino acid solution to be used: either essential amino acids (EAAs) exclusively, solutions of EAA plus nonessential amino acids (NEAAs), or specially designed “nephro” solutions of different proportions of EAA and specific NEAA that might become “conditionally essential” for ARF (see Fig. 18-11). Use of solutions of EAA alone is based on principles established for treating chronic renal failure (CRF) with a low-protein diet and an EAA supplement. This may be inappropriate as the metabolic adaptations to low-protein diets in response to CRF may not have occurred in patients with ARF. Plus, there are fundamental differences in the goals of nutritional therapy in the two groups of patients, and consequently, infusion solutions of EAA may be sub-optimal. Thus, a solution should be chosen that includes both essential and nonessential amino acids (EAA, NEAA) in standard propor-

tions or in special proportions designed to counteract the metabolic changes of renal failure (“nephro” solutions), including the amino acids that might become conditionally essential in ARF. Because of the relative insolubility of tyrosine in water, dipeptides containing tyrosine (such as glycyl-tyrosine) are contained in modern nephro solutions as the tyrosine source [22, 23]. One should be aware of the fact that the amino acid analogue N-acetyl tyrosine, which previously was used frequently as a tyrosine source, cannot be converted into tyrosine in humans and might even stimulate protein catabolism [21]. Despite considerable investigation, there is no persuasive evidence that amino acid solutions enriched in branched-chain amino acids exert a clinically significant anticatabolic effect. Systematic studies using glutamine supplementation for patients with ARF are lacking (see Fig. 18-11).

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Acute Renal Failure FIGURE 18-34 Energy substrates in total parenteral nutrition (TPN) in acute renal failure (ARF): glucose and lipids. Because of the well-documented effects of overfeeding, energy intake of patients with ARF must not exceed their actual energy expenditure (ie, in most cases 100% to 130% of resting energy expenditure [REE]; see Figs. 18-3 and 18-4) [2]. Glucose should be the principal energy substrate because it can be utilized by all organs, even under hypoxic conditions, and has the potential for nitrogen sparing. Since ARF impairs glucose tolerance, insulin is frequently necessary to maintain normoglycemia. Any hyperglycemia must be avoided because of the untoward associated side effects—such as aggravation of tissue injury, glycation of proteins, activation of protein catabolism, among others [2]. When intake is increased above 5 g/kg of body weight per day infused glucose will not be oxidized but will promote lipogenesis with fatty infiltration of the liver and excessive carbon dioxide production and hypercarbia. Often, energy requirements cannot be met by glucose infusion without adding large amounts of insulin, so a portion of the energy should be supplied by lipid emulsions [2]. The most suitable means of providing the energy substrates for parenteral nutrition for patients with ARF is not glucose or lipids, but glucose and lipids [2]. In experimental uremia in rats, TPN with 30% of nonprotein energy as fat promoted weight gain and ameliorated the uremic state and survival [63]. (From Wennberg et al. [63]; with permission.) FIGURE 18-35 Energy substrates in parenteral nutrition: lipid emulsions. Advantages of intravenous lipids include high specific energy content, low osmolality, provision of essential fatty acids and phospholipids to prevent deficiency syndromes, fewer hepatic side effects (such as steatosis, hyperbilirubinemia), and reduced carbon dioxide production, especially relevant for patients with respiratory failure. Changes in lipid metabolism associated with acute renal failure (ARF) should not prevent the use of lipid emulsions. Instead, the amount infused should be adjusted to meet the patient’s capacity to utilize lipids. Usually, 1 g/kg of body weight per day of fat will not increase plasma triglycerides substantially, so about 20% to 25% of energy requirements can be met [1]. Lipids should not be administered to patients with hyperlipidemia (ie, plasma triglycerides above 350 mg/dL) activated intravascular coagulation, acidosis (pH below 7.25), impaired circulation or hypoxemia. Parenteral lipid emulsions usually contain long-chain triglycerides (LCT), most derived from soybean oil. Recently, fat emulsions containing a mixture of LCT and medium-chain triglycerides (MCT) have been introduced for intravenous use. Proposed advantages include faster elimination from the plasma owing to higher affinity to the lipoprotein lipase enzyme, complete, rapid, and carnitine-independent metabolism, and a triglyceridelowering effect; however, use of MCT does not promote lipolysis, and elimination of triglycerides of both types of fat emulsions is equally retarded in ARF [34]. (Adapted from [34]; with permission.)

Nutrition and Metabolism in Acute Renal Failure

SUGGESTED SCHEDULE FOR MINIMAL MONITORING OF PARENTERAL NUTRITION

Metabolic Status Variables

Unstable

Stable

Blood glucose Osmolality Electrolytes (Na+, K+, Cl+) Calcium, phosphate, magnesium Daily BUN increment Urea nitrogen appearance rate Triglycerides Blood gas analysis, pH Ammonia Transaminases  bilirubin

1–6  daily Daily Daily Daily Daily Daily Daily Daily 2  weekly 2  weekly

Daily 2 weekly Daily 3 weekly Daily 2  weekly 2  weekly 1 weekly 1  weekly 1  weekly

18.21

FIGURE 18-36 Complications and monitoring of nutritional support in acute renal failure (ARF). Complications: Technical problems and infectious complications originating from the central venous catheter, chemical incompatibilities, and metabolic complications of parenteral nutrition are similar in ARF patients and in nonuremic subjects. However, tolerance to volume load is limited, electrolyte derangements can develop rapidly, exaggerated protein or amino acid intake stimulates excessive blood urea nitrogen (BUN) and waste product accumulation and glucose intolerance, and decreased fat clearance can cause hyperglycemia and hypertriglyceridemia. Thus, nutritional therapy for ARF patients requires more frequent monitoring than it does for other patient groups, to avoid metabolic complications. Monitoring: This table summarizes laboratory tests that monitor parenteral nutrition and avoid metabolic complications. The frequency of testing depends on the metabolic stability of the patient. In particular, plasma glucose, potassium, and phosphate should be monitored repeatedly after the start of parenteral nutrition.

References 1. Druml W: Nutritional support in acute renal failure. In Nutrition and the Kidney. Edited by Mitch WE, Klahr S. Philadelphia: LippincottRaven, 1998. 2. Druml W, Mitch WE: Metabolism in acute renal failure. Sem Dial 1996, 9:484–490. 3. Om P, Hohenegger M: Energy metabolism in acute uremic rats. Nephron 1980, 25:249–253. 4. Schneeweiss B, Graninger W, Stockenhuber F, et al.: Energy metabolism in acute and chronic renal failure. Am J Clin Nutr 1990, 52:596–601. 5. Soop M, Forsberg E, Thˆrne A, Alvestrand A: Energy expenditure in postoperative multiple organ failure with acute renal failure. Clin Nephrol 1989, 31:139–145. 6. Spreiter SC, Myers BD, Swenson RS: Protein-energy requirements in subjects with acute renal failure receiving intermittent hemodialysis. Am J Clin Nutr 1980, 33:1433–1437. 7. Mitch WE: Amino acid release from the hindquarter and urea appearance in acute uremia. Am J Physiol 1981, 241:E415–E419. 8. Salusky IB, Flügel-Link RM, Jones MR, Kopple JD: Effect of acute uremia on protein degradation and amino acid release in the rat hemicorpus. Kidney Int 1983, 24(Suppl. 16):S41–S42. 9. Clark AS, Mitch WE: Muscle protein turnover and glucose uptake in acutely uremic rats. J Clin Invest 1983, 72:836–845. 10. Maroni BJ, Karapanos G, Mitch WE: System A amino acid transport in incubated muscle: Effects of insulin and acute uremia. Am J Physiol 1986, 251:F74–F80. 11. Druml W, Kelly RA, Mitch WE, May RC: Abnormal cation transport in uremia. J Clin Invest 1988, 81:1197–1203. 12. Fröhlich J, Hoppe-Seyler G, Schollmeyer P, et al.: Possible sites of interaction of acute renal failure with amino acid utilization for gluconeogenesis in isolated perfused rat liver. Eur J Clin Invest 1977, 7:261–268. 13. May RC, Kelly RA, Mitch WE: Mechanisms for defects in muscle protein metabolism in rats with chronic uremia: The influence of metabolic acidosis. J Clin Invest 1987; 79:1099–1103.

14. Kuhlmann MK, Shahmir E, Maasarani E, et al.: New experimental model of acute renal failure and sepsis in rats. JPEN 1994, 18:477–485. 15. Bergström J: Factors causing catabolism in maintenance hemodialysis patients. Miner Electrolyte Metab 1992, 18:280–283. 16. Druml W, Bürger U, Kleinberger G, et al.: Elimination of amino acids in acute renal failure. Nephron 1986, 42:62–67. 17. Druml W, Fischer M, Liebisch B, et al.: Elimination of amino acids in renal failure. Am J Clin Nutr 1994, 60:418–423. 18. Mitch WE, Chesney RW: Amino acid metabolism by the kidney. Miner Electrolyte Metab 1983, 9:190–202. 19. Laidlaw SA, Kopple JD: Newer concepts of indispensable amino acids. Am J Clin Nutr 1987, 46:593–605. 20. Naschitz JE, Barak C, Yeshurun D: Reversible diminished insulin requirement in acute renal failure. Postgrad Med J 1983, 59:269–271. 21. Druml W, Lochs H, Roth E, et al.: Utilisation of tyrosine dipeptides and acetyl-tyrosine in normal and uremic humans. Am J Physiol 1991, 260:E280–E285. 22. Druml W, Roth E, Lenz K, et al.: Phenylalanine and tyrosine metabolism in renal failure. Kidney Int 1989, 36(Suppl 27):S282–S286. 23. Fürst P. Stehle P: The potential use of dipeptides in clinical nutrition. Nutr Clin Pract 1993, 8:106–114. 24. Hübl W, Druml W, Roth E, Lochs H: Importance of liver and kidney for the utilization of glutamine-containing dipeptides in man. Metabolism 1994, 43:1104–1107. 25. Hasik J, Hryniewiecki L, Baczyk K, Grala T: An attempt to evaluate minimum requirements for protein in patients with acute renal failure. Pol Arch Med Wewn 1979, 61:29–36. 26. Lopez-Martinez J, Caparros T, Perez-Picouto F: Nutrition parenteral en enfermos septicos con fracaso renal agudo en fase poliurica. Rev Clin Esp 1980, 157:171–178. 27. Kierdorf H: Continuous versus intermittent treatment: Clinical results in acute renal failure. Contrib Nephrol 1991, 93:1–12.

18.22

Acute Renal Failure

28. Chima CS, Meyer L, Hummell AC, et al.: Protein catabolic rate in patients with acute renal failure on continuous arteriovenous hemofiltration and total parenteral nutrition. J Am Soc Nephrol 1993, 3:1516–1521. 29. Macias WL, Alaka KJ, Murphy MH, et al.: Impact of nutritional regimen on protein catabolism and nitrogen balance in patients with acute renal failure. JPEN 1996, 20:56–62. 30. Ikizler TA, Greene JH, Wingard RL, Hakim RM: Nitrogen balance in acute renal failure patients. J Am Soc Nephrol 1995, 6:466A. 31. May RC, Clark AS, Goheer MA, Mitch WE: Specific defects in insulin-mediated muscle metabolism in acute uremia. Kidney Int 1985, 28:490–497. 32. Cianciaruso B, Bellizzi V, Napoli R, et al.: Hepatic uptake and release of glucose, lactate and amino acids in acutely uremic dogs. Metabolism 1991, 40:261–290. 33. Druml W, Laggner A, Widhalm K, et al.: Lipid metabolism in acute renal failure. Kidney Int 1983, 24(Suppl 16):S139–S142. 34. Druml W, Fischer M, Sertl S, et al.: Fat elimination in acute renal failure: Long-chain versus medium-chain triglycerides. Am J Clin Nutr 1992, 55:468–472. 35. Druml W, Zechner R, Magometschnigg D, et al.: Post-heparin lipolytic activity in acute renal failure. Clin Nephrol 1985, 23:289–293. 36. Adolph M, Eckart J, Metges C, et al.: Oxidative utilization of lipid emulsions in septic patients with and without acute renal failure. Clin Nutr 1995, 14(Suppl 2):35A. 37. Dobyan DC, Bulger RE, Eknoyan G: The role of phosphate in the potentiation and amelioration of acute renal failure. Miner Electrolyte Metab 1991, 17:112–115. 38. Druml W, Lax F, Grimm G, et al.: Acute renal failure in the elderly— 1975–1990. Clin Nephrol 1994, 41:342–349. 39. Kurtin P, Kouba J: Profound hypophosphatemia in the course of acute renal failure. Am J Kidney Dis 1987, 10:346–349. 40. Marik PE, Bedigian MK: Refeeding hypophosphatemia in critically ill patients in an intensive care unit. Arch Surg 1996, 131:1043–1047. 41. Kleinberger G, Gabl F, Gassner A, et al.: Hypophosphatemia during parenteral nutrition in patients with renal failure. Wien Klin Wochenschr 1978, 90:169–172. 42. Madl Ch, Kranz A, Liebisch B, et al.: Lactic acidosis in thiamine deficiency. Clin Nutr 1993, 12:108–111. 43. Friedman AL, Chesney RW, Gilbert EF, et al.: Secondary oxalosis as a complication of parenteral alimentation in acute renal failure. Am J Nephrol 1983, 3:248–252. 44. Druml W, Schwarzenhofer M, Apsner R, Hörl WH: Fat soluble vitamins in acute renal failure. Miner Electrolyte Metab 1998, 24:220–226. 45. Zurovsky Y, Gispaan I: Antioxidants attenuate endotoxin-induced acute renal failure in rats. Am J Kidney Dis 1995, 25:51–57. 46. Druml W, Bartens C, Stelzer H, et al.: Impact of acute renal failure on antioxidant status in multiple organ failure syndrome. JASN 1993, 4:314A.

47. Druml W: Impact of continuous renal replacement therapies on metabolism. Int J Artif Organs 1996, 19:118–120. 48. Frankenfeld DC, Badellino MM, Reynolds HN, et al.: Amino acid loss and plasma concentration during continuous hemodiafiltration. JPEN 1993, 17:551–561. 49. Toback FG: Regeneration after acute tubular necrosis. Kidney Int 1992, 41:226–246. 50. Toback FG, Dodd RC, Maier ER, Havener LJ: Amino acid administration enhances renal protein metabolism after acute tubular necrosis. Nephron 1983, 33:238–243. 51. Abel RM, Beck CH, Abbott WM, et al.: Improved survival from acute renal failure after treatment with intravenuous essential amino acids and glucose: Results of a prospective double-blind study. N Engl J Med 1973, 288:695–699. 52. Oken DE, Sprinkel M, Kirschbaum BB, Landwehr DM: Amino acid therapy in the treatment of experimental acute renal failure in the rat. Kidney Int 1980, 17:14–23. 53. Zager RA, Venkatachalam MA: Potentiation of ischemic renal injury by amino acid infusion. Kidney Int 1983, 24:620–625. 54. Brezis M, Rosen S, Spokes K, et al.: Transport-dependent anoxic cell injury in the isolated perfused rat kidney. Am J Pathol 1984, 116:327–341. 55. Heyman SN, Rosen S, Silva P, et al.: Protective action of glycine in cisplatin nephrotoxicity. Kidney Int 1991, 40:273–279. 56. Schramm L, Heidbreder E, Lopau K, et al.: Influence of nitric oxide on renal function in toxic renal failure in the rat. Miner Electrolyte Metab 1996, 22:168–177. 57. Wakabayashi Y, Kikawada R: Effect of L-arginine on myoglobininduced acute renal failure in the rabbit. Am J Physiol 1996, 270:F784–F789. 58. Ding H, Kopple JD, Cohen A, Hirschberg R: Recombinant human insulin-like growth factor-1 accelerates recovery and reduces catabolism in rats with ischemic acute renal failure. J Clin Invest 1993, 91:2281–2287. 59. Franklin SC, Moulton M, Sicard GA, et al.: Insulin-like growth factor 1 preserves renal function postoperatively. Am J Physiol 1997, 272:F257–F259. 60. Hirschberg R, Kopple JD, Guler HP, Pike M: Recombinant human insulin-like growth factor-1 does not alter the course of acute renal failure in patients. 8th Int. Congress Nutr Metabol Renal Disease, Naples 1996. 61. Druml W, Mitch WE: Enteral nutrition in renal disease. In Enteral and Tube Feeding. Edited by Rombeau JL, Rolandelli RH. Philadelphia: WB Saunders, 1997:439–461. 62. Roberts PR, Black KW, Zaloga GP: Enteral feeding improves outcome and protects against glycerol-induced acute renal failure in the rat. Am J Respir Crit Care Med 1997, 156:1265–1269. 63. Wennberg A, Norbeck HE, Sterner G, Lundholm K: Effects of intravenous nutrition on lipoprotein metabolism, body composition, weight gain and uremic state in experimental uremia in rats. J Nutr 1991, 121:1439–1446.

Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Therapies, and Peritoneal Dialysis Ravindra L. Mehta

O

ver the last decade, significant advances have been made in the availability of different dialysis methods for replacement of renal function. Although the majority of these have been developed for patients with end-stage renal disease, more and more they are being applied for the treatment of acute renal failure (ARF). The treatment of ARF, with renal replacement therapy (RRT), has the following goals: 1) to maintain fluid and electrolyte, acid-base, and solute homeostasis; 2) to prevent further insults to the kidney; 3) to promote healing and renal recovery; and 4) to permit other support measures such as nutrition to proceed without limitation. Ideally, therapeutic interventions should be designed to achieve these goals, taking into consideration the clinical course. Some of the issues that need consideration are the choice of dialysis modality, the indications for and timing of dialysis intervention, and the effect of dialysis on outcomes from ARF. This chapter outlines current concepts in the use of dialysis techniques for ARF.

CHAPTER

19

19.2

Acute Renal Failure

Dialysis Methods DIALYSIS MODALITIES FOR ACUTE RENAL FAILURE Intermittent therapies Hemodialysis (HD) Single-pass Sorbent-based Peritoneal (IPD) Hemofiltration (IHF) Ultrafiltration (UF)

Continuous therapies Peritoneal (CAPD, CCPD) Ultrafiltration (SCUF) Hemofiltration (CAVH, CVVH) Hemodialysis (CAVHD, CVVHD) Hemodiafiltration (CAVHDF, CVVHDF) CVVHDF

FIGURE 19-1 Several methods of dialysis are available for renal replacement therapy. While most of these have been adapted from dialysis procedures developed for end-stage renal disease several variations are available specifically for ARF patients [1] . Of the intermittent procedures, intermittent hemodialysis (IHD) is currently the standard form of therapy worldwide for treatment of ARF in both intensive care unit (ICU) and non-ICU settings. The vast majority of IHD is performed using single-pass systems with moderate blood flow rates (200 to 250 mL/min) and countercurrent dialysate flow rates of 500 mL/min. Although this method is very efficient, it is also associated with hemodynamic instability resulting from the large shifts of solutes and fluid over a short time. Sorbent system IHD that regenerates small volumes of dialysate with an in-line Sorbent cartridge have not been very popular; however, they are a useful adjunct if large amounts of water are not available or in disasters [2]. These systems depend on a sorbent cartridge with multiple layers of different chemicals to regenerate the dialysate. In addition to the advantage of needing a small amount of water (6 L for a typical

run) that does not need to be pretreated, the unique characteristics of the regeneration process allow greater flexibility in custom tailoring the dialysate. In contrast to IHD, intermittent hemodiafiltration (IHF), which uses convective clearance for solute removal, has not been used extensively in the United States, mainly because of the high cost of the sterile replacement fluid [3]. Several modifications have been made in this therapy, including the provision of on-line preparation of sterile replacement solutions. Proponents of this modality claim a greater degree of hemodynamic stability and improved middle molecule clearance, which may have an impact on outcomes. As a more continuous technique, peritoneal dialysis (PD) is an alternative for some patients. In ARF patients two forms of PD have been used. Most commonly, dialysate is infused and drained from the peritoneal cavity by gravity. More commonly a variation of the procedure for continuous ambulatory PD termed continuous equilibrated PD is utilized [4]. Dialysate is instilled and drained manually and continuously every 3 to six hours, and fluid removal is achieved by varying the concentration of dextrose in the solutions. Alternatively, the process can be automated with a cycling device programmed to deliver a predetermined volume of dialysate and drain the peritoneal cavity at fixed intervals. The cycler makes the process less labor intensive, but the utility of PD in treating ARF in the ICU is limited because of: 1) its impact on respiratory status owing to interference with diaphragmatic excursion; 2) technical difficulty of using it in patients with abdominal sepsis or after abdominal surgery; 3) relative inefficiency in removing waste products in “catabolic” patients; and 4) a high incidence of associated peritonitis. Several continuous renal replacement therapies (CRRT) have evolved that differ only in the access utilized (arteriovenous [nonpumped: SCUF, CAVH, CAVHD, CAVHDF] versus venovenous [pumped: CVVH, CVVHD, CVVHDF]), and, in the principal method of solute clearance (convection alone [UF and H], diffusion alone [hemodialyis (HD)], and combined convection and diffusion [hemodiafiltration (HDF)]).

CRRT techniques: SCUF A

A–V SCUF

V V

A

UFC Uf Qb = 50–200 mL/min Qf = 2–8 mL/min

No

Low

Low

A FIGURE 19-2 Schematics of different CRRT techniques. A, Schematic representation of SCUF therapy. B, Schematic representation of

V

P

Uf Qb = 50–200 mL/min Qf = 10–20 mL/min

TMP=50mmHg

High–flux

0

out

R

Mechanisms of function Pressure profile Membrane Reinfusion Diffusion Convection

CAVH–CVVH High–flux

in

Treatment

CVVH

V

Uf Qb = 50–100 mL/min Qf = 8–12 mL/min

TMP=30mmHg

0

R V

Mechanisms of function Pressure profile Membrane Reinfusion Diffusion Convection

SCUF

CAVH

V

P

Uf Qb = 50–100 mL/min Qf = 2–6 mL/min

Treatment

CRRT techniques: CAVH – CVVH V–V SCUF

in

Yes

Low

High

out

B

continuous arteriovenous or venovenous hemofiltration (CAVH/CVVH) therapy. (Continued on next page)

19.3

Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Therapies, and Peritoneal Dialysis

CRRT techniques: CAVHD – CVVHD A

CAVHD

P V

Dial. Out

Dial. in

V Dial. Out

Qb = 50–100 mL/min Qf=1–5 mL/min Qd=10–30 mL/min

TMP=50mmHg

0

No

High

C

P

V

Dial. Out Dial. In +Uf Qb = 100–200 Qd=20–40 mL/min Qf = 10–20 mL/min

Mechanisms of function Pressure profile Membrane Reinfusion Diffusion Convection

Treatment

Low

CVVHDF

V P

V

TMP=50mmHg

CAVHDF–CVVHDF Low–flux

R

Dial. Out Dial. In +Uf Qb = 50–100 Qd=10–20 mL/min Qf = 8–12 mL/min

Dial. in

Mechanisms of function Pressure profile Membrane Reinfusion Diffusion Convection

CAVHD–CVVHD

CAVHDF

A

V

Qb = 50–100 mL/min Qf=1–3 mL/min Qd= 10–20 mL/min

Treatment

CRRT techniques: CAVHDF – CVVHDF

CVVHD

0

High–flux

Yes

High

High

D

FIGURE 19-2 (Continued) C, Schematic representation of continuous arteriovenous/ venovenous hemodialysis (CAVHD-CVVHD) therapy. D, Schematic representation of continuous arteriovenous/ venovenous hemodiafiltration (CAVHDF/CVVHDF) therapy. A—artery; V—vein; Uf—ultrafiltrate; R—replacement fluid;

P—peristaltic pump; Qb—blood flow; Qf—ultrafiltration rate; TMP—transmembrane pressure; in—dilyzer inlet; out— dialyzer outlet; UFC—ultrafiltration control system; Dial— dialysate; Qd—dialysate flow rate. (From Bellomo et al. [5]; with permission.)

CONTINUOUS RENAL REPLACEMENT THERAPY: COMPARISON OF TECHNIQUES

Access Pump Filtrate (mL/h) Filtrate (L/d) Dialysate flow (L/h) Replacement fluid (L/d) Urea clearance (mL/min) Simplicity* Cost*

SCUF

CAVH

CVVH

AV No 100 2.4 0 0 1.7 1 1

AV No 600 14.4 0 12 10 2 2

VV Yes 1000 24 0 21.6 16.7 3 4

CAVHD AV No 300 7.2 1.0 4.8 21.7 2 3

CAVHDF AV No 600 14.4 1.0 12 26.7 2 3

CVVHD VV Yes 300 7.2 1.0 4.8 21.7 3 4

CVVHDF VV Yes 800 19.2 1.0 16.8 30 3 4

PD Perit. Cath. No† 100 2.4 0.4 0 8.5 2 3

* 1 = most simple and least expensive; 4 = most difficult and expensive † cycler can be used to automate exchanges, but they add to the cost and complexity

FIGURE 19-3 In contrast to intermittent techniques, until recently, the terminology for continuous renal replacement therapy (CRRT) techniques has been subject to individual interpretation. Recognizing this lack of standardization an international group of experts have proposed standardized terms for these therapies [5]. The basic premise in the development of these terms is to link the nomenclature to the operational characteristics of the different techniques. In general all these techniques use highly permeable synthetic membranes and differ in the driving force for solute removal. When arteriovenous (AV) circuits are used, the mean arterial pressure provides the pumping mechanism. Alternatively, external pumps generally utilize a venovenous (VV) circuit and permit better control of blood flow rates. The letters AV or VV in the terminology serve to identify the driving force in the technique. Solute removal in these techniques is achieved by convection, diffusion, or a combination of these two. Convective techniques include ultrafiltration (UF) and hemofiltration (H) and depend on solute removal by solvent drag [6].

Diffusion-based techniques similar to intermittent hemodialysis (HD) are based on the principle of a solute gradient between the blood and the dialysate. If both diffusion and convection are used in the same technique the process is termed hemodiafiltration (HDF). In this instance, both dialysate and a replacement solution are used, and small and middle molecules can both be removed easily. The letters UF, H, HD, and HDF identify the operational characteristics in the terminology. Based on these principles, the terminology for these techniques is easier to understand. As shown in Figure 19-1 the letter C in all the terms describes the continuous nature of the methods, the next two letters [AV or VV] depict the driving force and the remaining letters [UF, H, HD, HDF] represent the operational characteristics. The only exception to this is the acronym SCUF (slow continuous ultrafiltration), which remains as a reminder of the initiation of these therapies as simple techniques harnessing the power of AV circuits. (Modified from Mehta [7]; with permission.)

19.4

Acute Renal Failure

Operational Characteristics Anticoagulation Anticoagulation in Dialysis for ARF

Surface Platelet activation FIXa

Dialyzer Membrane Geometry Manufacture Dialysis technique

Patient Propagation

Initiation

Contact activation

Procoagulant surface

Uremia Drug therapy

Dialyzer preparation Anticoagulation Blood flow access

Thrombin Fibrin

FIGURE 19-4 Pathways of thrombogenesis in extracorporeal circuits. (Modified from Lindhout [8]; with permission.)

Heparin CRRT Anticoagulant heparin (~400µ/h)

Replacement Dialysate solutions 1.5% dianeal (A & B alternating) (1000mL/h)

Arterial

Venous Filter

catheter (a)

3–way stop cock

(b)

Anticoagulant 4%% trisodium citrate (~170 mL/h)

(c)

Ultrafiltrate (effluent dialysate plus net ultrafiltrate)

A

Citrate CRRT

(d)

catheter

Dialysate Calcium NA 117, K4, Mg 1., 1 mEq/10 mL Cl 122.5 mEq/L; (~40 mL/h) dextrose 0.1%–2.5% Replacement zero alkali Central solution zero calcium line 0.9%% saline (1000 mL/h)

Arterial

Venous Filter

catheter (a)

3–way stop cock

B

(b)

(d)

Ultrafiltrate (effluent dialysate plus net ultrafiltrate)

catheter (c)

FIGURE 19-5 Factors influencing dialysis-related thrombogenicity. One of the major determinants of the efficacy of any dialysis procedure in acute renal failure (ARF) is the ability to maintain a functioning extracorporeal circuit. Anticoagulation becomes a key component in this regard and requires a balance between an appropriate level of anticoagulation to maintain patency of the circuit and prevention of complications. Figures 19-4 and 19-5 show the mechanisms of thrombus formation in an extracorporeal circuit and the interaction of various factors in this process. (From Ward [9]; with permission.) FIGURE 19-6 Modalities for anticoagulation for continuous renal replacement therapy. While systemic heparin is the anticoagulant most commonly used for dialysis, other modalities are available. The utilization of these modalities is largely influenced by prevailing local experience. Schematic diagrams for heparin, A, and citrate, B, anticoagulation techniques for continuous renal replacement therapy (CRRT). A schematic of heparin and regional citrate anticoagulation for CRRT techniques. Regional citrate anticoagulation minimizes the major complication of bleeding associated with heparin, but it requires monitoring of ionized calcium. It is now well-recognized that the longevity of pumped or nonpumped CRRT circuits is influenced by maintaining the filtration fraction at less than 20%. Nonpumped circuits (CAVH/HD/HDF) have a decrease in efficacy over time related to a decrease in blood flow (BFR), whereas in pumped circuits (CVVH/HD/HDF) blood flow is maintained; however, the constant pressure across the membrane results in a layer of protein forming over the membrance reducing its efficacy. This process is termed concentration repolarization [10]. CAVH/CVVH—continuous arteriovenous/venovenous hemofiltration. (From Mehta RL, et al. [11]; with permission.)

19.5

Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Therapies, and Peritoneal Dialysis

Solute Removal Membrane

Blood

Dialysate

Blood

Membrane

Dialysate

Middle molecules

Small molecules

Diffusion

A

Convection

Concentration gradient based transfer. Small molecular weight substances (<500 Daltons) are transferred more rapidly.

Blood

Membrane

Dialysate

Adsorption

C

Several solutes are removed from circulation by adsorption to the membrane. This process is influenced by the membrane structure and charge.

B

Movement of water across the membrane carries solute across the membrane. Middle molecules are removed more efficiently.

FIGURE 19-7 Mechanisms of solute removal in dialysis. The success of any dialysis procedure depends on an understanding of the operational characteristics that are unique to these techniques and on appropriate use of specific components to deliver the therapy. Solute removal is achieved by diffusion (hemodialysis), A, convection (hemofiltration), B, or a combination of diffusion and convection (hemodiafiltration), C.

19.6

Acute Renal Failure

DETERMINANTS OF SOLUTE REMOVAL IN DIALYSIS TECHNIQUES FOR ACUTE RENAL FAILURE

Small solutes (MW <300)

Middle molecules (MW 500–5000)

LMW proteins (MW 5000–50,000)

Large proteins (MW >50,000)

IHD

CRRT

PD

Diffusion: Qb Membrane width Qd Diffusion Convection: Qf SC Convection Diffusion Adsorption Convection

Diffusion: Qd Convection: Qf

Diffusion: Qd Convection: Qf

Convection: Qf SC Convection Adsorption

Convection: Qf SC Convection

Convection

Convection

FIGURE 19-8 Determinants of solute removal in dialysis techniques for acute renal failure. Solute removal in these techniques is achieved by convection, diffusion, or a combination of these two. Convective techniques include ultrafiltration (UF) and hemofiltration (H) and they depend on solute removal by solvent drag [6]. As solute removal is solely dependent on convective clearance it can be enhanced only by increasing the volume of ultrafiltrate produced. While ultrafiltration requires fluid removal only, to prevent significant volume loss and resulting hemodynamic compromise, hemofiltration necessitates partial or total replacement of the fluid removed. Larger molecules are removed more efficiently by this process and, thus, middle molecular clearances are superior. In intermittent hemodialysis (IHD) ultrafiltration is achieved by modifying the transmembrane pressure and generally does not contribute significantly to solute removal. In peritoneal dialysis (PD) the UF depends on the osmotic gradient achieved by the concentration of dextrose solution (1.55% to 4.25%) utilized the

Dialyste flow, L/h 1.5 1

Dialysis time 4 h/d 4 h qod

352

268

Ultrafiltrate volume, Cycling Manual treatment time, hrs L/d 40 48 20 15 Dialysate inflow, L/wk 160 96

302

140 84

CAVHDF/CVVHDF

IHD

CAVH

72

PD

number of exchanges and the dwell time of each exchange. In continuous arteriovenous and venovenous hemodialysis in most situations ulrafiltration rates of 1 to 3 L/hour are utilized; however recently high-volume hemofiltration with 6 L of ultrafiltrate produced every hour has been utilized to remove middle– and large–molecular weight cytokines in sepsis [12]. Fluid balance is achieved by replacing the ultrafiltrate removed by a replacement solution. The composition of the replacement fluid can be varied and the solution can be infused before or after the filter. Diffusion-based techniques (hemodialysis) are based on the principle of a solute gradient between the blood and the dialysate. In IHD, typically dialysate flow rates far exceed blood flow rates (200 to 400 mL/min, dialysate flow rates 500 to 800 mL/min) and dialysate flow is single pass. However, unlike IHD, the dialysate flow rates are significantly slower than the blood flow rates (typically, rates are 100 to 200 mL/min, dialysate flow rates are 1 to 2 L/hr [17 to 34mL/min]), resulting in complete saturation of the dialysate. As a consequence, dialysate flow rates become the limiting factor for solute removal and provide an opportunity for clearance enhancement. Small molecules are preferentially removed by these methods. If both diffusion and convection are used in the same technique (hemodiafiltration, HDF) both dialysate and a replacement solution are used and small and middle molecules can both be easily removed.

FIGURE 19-9 Comparison of weekly urea clearances with different dialysis techniques. Although continuous therapies are less efficient than intermittent techniques, overall clearances are higher as they are utilized continuously. It is also possible to increase clearances in continuous techniques by adjustment of the ultrafiltration rate and dialysate flow rate. In contrast, as intermittent dialysis techniques are operational at maximum capability, it is difficult to enhance clearances except by increasing the size of the membrane or the duration of therapy. CAV/CVVHDF—continuous arteriovenous/venovenous hemodiafiltration; IHD—intermittent hemodialysis; CAVH—continuous arteriovenous hemodialysis; PD—peritoneal dialysis.

19.7

Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Therapies, and Peritoneal Dialysis

COMPARISON OF DIALYSIS PRESCRIPTION AND DOSE DELIVERED IN CRRT AND IHD

DRUG DOSING IN CRRT* Drug

Dialysis Prescription IHD Membrane characteristics Anticoagulation Blood flow rate Dialysate flow Duration Clearance

Variable permeability Short duration ≥200 mL/min ≥500 mL/min 3–4 hrs High

CRRT High permeability Prolonged <200 mL/min 17–34 mL/min Days Low

Dialysis Dose Delivered Patient factors Hemodynamic stability Recirculation Infusions Technique factors Blood flow Concentration repolarization Membrane clotting Duration Other factors Nursing errors Interference

IHD

CRRT

+++ +++ ++

+ + +

+++ + + +++

++ +++ +++ +

+ +

+++ ++++

FIGURE 19-10 Comparison of dialysis prescription and dose delivered in continuous renal replacement (CRRT) and intermittent hemodialysis (IHD). The ability of each modality to achieve a particular clearance is influenced by the dialysis prescription and the operational characteristics; however, it must be recognized that there may be a significant difference between the dialysis dose prescribed and that delivered. In general, IHD techniques are limited by available time, and in catabolic patients it may not be possible to achieve a desired level of solute control even by maximizing the operational characteristics.

Amikacin Netilmycin Tobramycin Vancomycin Ceftazidime Cefotaxime Ceftriaxone Ciprofloxacin Imipenem Metronidazole Piperacillin Digoxin Phenobarbital Phenytoin Theophylline

Normal Dose (mg/d)

Dose in CRRT (mg)

1050 420 350 2000 6000 12,000 4000 400 4000 2100 24,000 0.29 233 524 720

250 qd–bid 100–150 qd 100 qd 500 qd–bid 1000 bid 2000 bid 2000 qd 200 qd 500 tid–qid 500 tid–qid 4000 tid 0.10 qd 100 bid–qid 250 qd–bid 600–900 qd

* Reflects doses for continuous venovenous hemofiltration with ultrafiltration rate of 20 to 30 mL/min.

FIGURE 19-11 Drug dosing in continuous renal replacement (CRRT) techniques. Drug removal in CRRT techniques is dependent upon the molecular weight of the drug and the degree of protein binding. Drugs with significant protein binding are removed minimally. Aditionally, some drugs may be removed by adsorption to the membrane. Most of the commonly used drugs require adjustments in dose to reflect the continuous removal in CRRT. (Modified from Kroh et al. [13]; with permission.)

19.8

Acute Renal Failure

NUTRITIONAL ASSESSMENT AND SUPPORT WITH RENAL REPLACEMENT TECHNIQUES Parameters: Initial Assessment

IHD

CAVH/CVVH

CAVHD/CVVHDF

Energy assessment Dialysate dextrose absorption

HBE x AF x SF, or indirect calorimetry Negligible

Same Not applicable

Same 43% uptake 1.5% dextrose dialysate (525 calories/D) 45% uptake 2.5% dextrose dialysate (920 calories/D) Negligible absorption with dextrose free or dialysate 0.1–0.15% dextrose

Serum prealbumin Nitrogen in: protein in TPN +/enteral solutions/6.25 Nitrogen out: urea nitrogen appearance

Same Nitrogen in: same

Same Nitrogen in: same

UUN† Insensible losses Dialysis amino acid losses (1.0–1.5 N2/dialysis therapy)

Nitrogen out: ultrafiltrate urea nitrogen losses UUN† Insensible losses Ultrafiltrate amino acid losses (1.5–2.0 N2/D)

Nitrogen out: ultrafiltrate/dialysate urea nitrogen losses UUN† Insensible losses Ultrafiltrate/dialysate amino acid losses (1.5–2.0 N2/D)

Renal formulas with limited fluid, potassium, phosphorus, and magnesium

Standard TPN/enteral formulations. No fluid or electrolyte restrictions.

Standard TPN/enteral formulations when 0.1–0.15% dextrose dialysate used Modified formulations when 1.5–2.5% dextrose dialysate used TPN: Low-dextrose solutions to prevent carbohydrate overfeeding; amino acid concentration may be increased to meet protein requirements. Enteral: Standard formulas. May require modular protein to meet protein requirements without carbohydrate overfeeding.

Weekly HBE x AF x SF*, or indirect calorimetry Weekly Weekly

Same

Same

Same Same

Same Same

Protein assessment Visceral proteins Nitrogen balance: N2 in–N2 out

Nutrition support prescription: TPN/enteral nutrition

Reassessment of requirements and efficacy of nutrition support Energy assessment Serum prealbumin Nitrogen balance

* Harris Benedict equation multiplied by acimity and stress factors † Collect 24-hour urine for UUN if UOP ≥ 400 ml/d

FIGURE 19-12 Nutritional assessment and support with renal replacement techniques. A key feature of dialysis support in acute renal failure is to permit an adequate amount of nutrition to be delivered to the patient. The modality of dialysis and operational characteristics affect the nutritional support that can be provided. Dextrose

absorption occurs form the dialysate in hemodialysis and hemodiafiltration modalities and can result in hyperglycemia. Intermittent dialysis techniques are limited by time in their ability to allow unlimited nutritional support. (From Monson and Mehta [14]; with permission.)

Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Therapies, and Peritoneal Dialysis

19.9

Fluid Control OPERATING CHARACTERISTICS OF CRRT: FLUID REMOVAL VERSUS FLUID REGULATION

Ultrafiltration rate (UFR) Fluid management Fluid balance Volume removed Application

Fluid Removal

Fluid Regulation

To meet anticipated needs Adjust UFR Zero or negative balance Based on physician estimate Easy, similar to intermittent hemodialysis

Greater than anticipated needs Adjust amount of replacement fluid Positive, negative, or zero balance Driven by patient characteristics Requires specific tools and training

FIGURE 19-13 Operating characteristics of continuous renal replacement (CRRT): fluid removal versus fluid regulation. Fluid management is an integral component in the management of

APPROACHES FOR FLUID MANAGEMENT IN CRRT Approaches

Level 1

Level 2

Level 3

UF volume Replacement

Limited Minimal

Fluid balance

8h

Increase intake Adjusted to achieve fluid balance Hourly

UF pump Examples

Yes SCUF/CAVHD CVVHD

Yes/No CAVH/CVVH CAVHDF/CVVHDF

Increase intake Adjusted to achieve fluid balance Hourly Targeted Yes/No CAVHDF/CVVHDF CVVH

+++ + + +

++ +++ ++ ++

+ +++ +++ +++

+ +++ ++ +++

++ ++ ++ +

+++ + + +

Advantages Simplicity Achieve fluid balance Regulate volume changes CRRT as support Disadvantages Nursing effort Errors in fluid balance Hemodynamic instability Fluid overload

FIGURE 19-14 Approaches for fluid management in continuous renal replacement therapy (CRRT). CRRT techniques are uniquely situated in providing fluid regulation, as fluid management can be achieved with three levels of intervention [16]. In Level 1, the ultrafiltrate (UF) volume obtained is limited to match the anticipated needs for fluid balance. This calls for an estimate of the amount of fluid to be removed over 8 to 24 hours and subsequent calculation of the ultrafiltration rate. This strategy is similar to that commonly used for intermittent hemodialysis and differs only in that the time to remove fluid is 24

patients with acute renal failure in the intensive care setting. In the presence of a failing kidney, fluid removal is often a challenge that requires large doses of diuretics with a variable response. It is often necessary in this setting to institute dialysis for volume control rather than metabolic control. CRRT techniques offer a significant advantage over intermittent dialysis for fluid control [14,15]; however, if not carried out appropriately they can result in major complications. To utilize these therapies for their maximum potential it is necessary to recognize the factors that influence fluid balance and have an understanding of the principles of fluid management with these techniques. In general it is helpful to consider dialysis as a method for fluid removal and fluid regulation. hours instead of 3 to 4 hours. In Level 2 the ultrafiltrate volume every hour is deliberately set to be greater than the hourly intake, and net fluid balance is achieved by hourly replacement fluid administration. In this method a greater degree of control is possible and fluid balance can be set to achieve any desired outcome. The success of this method depends on the ability to achieve ultrafiltration rates that always exceed the anticipated intake. This allows flexibility in manipulation of the fluid balance, so that for any given hour the fluid status could be net negative, positive, or balanced. A key advantage of this technique is that the net fluid balance achieved at the end of every hour is truly a reflection of the desired outcome. Level 3 extends the concept of the Level 2 intervention to target the desired net balance every hour to achieve a specific hemodynamic parameter (eg, central venous pressure, pulmonary artery wedge pressure, or mean arterial pressure). Once a desired value for the hemodynamic parameter is determined, fluid balance can be linked to that value. Each level has advantages and disadvantages; in general greater control calls for more effort and consequently results in improved outcomes. SCUF— ultrafiltration; CAVHD/CVVHD—continuous arteriovenous/venovenous hemodialysis; CAVH/CVVH—continuous arteriovenous/venovenous hemofiltration; CAVHDF/CVVHDF—continuous arteriovenous/venovenous hemodiafiltration.

19.10

Acute Renal Failure

COMPOSITION OF REPLACEMENT FLUID AND DIALYSATE FOR CRRT Replacement Fluid Investigator Na+ ClHCO3K+ Ca2+ Mg2+ Glucose Acetate

Golper [19] 147 115 36 0 1.2 0.7 6.7 —

Kierdorf [20] 140 110 34 0 1.75 0.5 5.6 —

Lauer [21] 140 — — 2 3.5 1.5 — 41

Paganini [22] 140 120 6 2 4 2 10 40

Mehta [11] 140.5 115.5 25 0 4 — — —

Mehta [11] 154 154 — — — — — —

FIGURE 19-15 Composition of dialysate and replacement fluids used for continuous renal replacement therapy (CRRT). One of the key features of any dialysis method is the manipulation of metabolic balance. In general, this is achieved by altering composition of dialysate or replacement fluid . Most commercially available dialysate and replacement solutions have lactate as the base; however, bicarbonate-based solutions are being utilized more and more [17,18].

Dialysate Component (mEq/L) Sodium Potassium Chloride Lactate Acetate Calcium Magnesium Dextrose (g/dL)

1.5% Dianeal 132 — 96 35 — 3.5 1.5 1.5

Hemosol AG 4D 140 4 119 — 30 3.5 1.5 0.8

Hemosol LG 4D 140 4 109.5 40 — 4 1.5 .11

Replacement 17 mL/min Prefilter Prefilter Prepump Prepump BFR 83 mL/min BFR 117 mL/min

Postfilter BFR 100 mL/min

Filter Blood pump BFR 100 mL/min

Baxter 140 2 117 30 — 3.5 1.5 0.1

Citrate 117 4 121 — — — 1.5 0.1–2.5

FIGURE 19-16 Effect of site of delivery of replacement fluid: pre- versus postfilter continuous venovenous hemofiltration with ultrafiltration rate of 1 L/hour. Replacement fluids may be administered pre- or postfilter, depending on the circuit involved . It is important to recognize that the site of delivery can influence the overall efficacy of the procedure. There is a significant effect of fluid delivered prepump or postpump, as the amount of blood delivered to the filter is reduced in prepump dilution. BFR—blood flow rate.

Ultrafiltrate

50

%

40

Prefilter prepump Prefilter postpump Postfilter

30 20

22.6

19.5

23.9

47.6 41.6 35.7

32.2

32.2

26.3

10 0

CVVH 1L/h

CVVH 3L/h

CVVH 6L/h

FIGURE 19-17 Pre- versus postfilter replacement fluid: effect on filtration fraction. Prefilter replacement tends to dilute the blood entering the circuit and enhances filter longevity by reducing the filtration fraction; however, in continuous venovenous hemofiltration (CVVH) circuits the overall clearance may be reduced as the amount of solute delivered to the filter is reduced.

Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Therapies, and Peritoneal Dialysis

19.11

Applications and Indications for Dialytic Intervention INDICATIONS AND TIMING OF DIALYSIS FOR ACUTE RENAL FAILURE: RENAL REPLACEMENT VERSUS RENAL SUPPORT Renal Replacement

Renal Support

Purpose

Replace renal function

Support other organs

Timing of intervention Indications for dialysis

Based on level of biochemical markers Narrow

Based on individualized need Broad

Dialysis dose

Extrapolated from ESRD

Targeted for overall support

FIGURE 19-18 Dialysis intervention in acute renal failure (ARF): renal replacement versus renal support. An important consideration in the management of ARF is defining the goals of therapy. Several issues must be considered, including the timing of the intervention, the amount and frequency of dialysis, and the duration of therapy. In practice, these issues are based on individual preferences and experience, and no immutable criteria are followed [7,23]. Dialysis intervention in ARF is usually considered when there is clinical evidence of uremia symptoms or biochemical evidence of solute and fluid imbalance. An

POTENTIAL APPLICATIONS FOR CONTINUOUS RENAL REPLACEMENT THERAPY Renal Replacement

Renal Support

Extrarenal Applications

Acute renal failure Chronic renal failure

Fluid management Solute control Acid-base adjustments Nutrition Burn management

Cytokine removal ? sepsis Heart failure Cancer chemotherapy Liver support Inherited metabolic disorders

important consideration in this regard is to recognize that the patient with ARF is somewhat different than the one with endstage renal disease (ESRD). The rapid decline of renal function associated with multiorgan failure does not permit much of an adaptive response which characterizes the course of the patient with ESRD. As a consequence, the traditional indications for renal replacement may need to be redefined. For instance, excessive volume resuscitation, a common strategy for multiorgan failure, may be an indication for dialysis, even in the absence of significant elevations in blood urea nitrogen. In this respect, it may be more appropriate to consider dialysis intervention in the intensive care patient as a form of renal support rather than renal replacement. This terminology serves to distinguish between the strategy for replacing individual organ function and one to provide support for all organs. FIGURE 19-19 Potential applications for continuous renal replacement therapy (CRRT). CRRT techniques are increasingly being utilized as support modalities in the intensive care setting and are particularly suited for this function. The freedom to provide continuous fluid management permits the application of unlimited nutrition, adjustments in hemodynamic parameters, and achievement of steady-state solute control, which is difficult with intermittent therapies. It is thus possible to widen the indications for renal intervention and provide a customized approach for the management of each patient.

19.12

Acute Renal Failure

RELATIVE ADVANTAGES () AND DISADVANTAGES () OF CRRT, IHD, AND PD Variable Continuous renal replacement Hemodynamic stability Fluid balance achievement Unlimited nutrition Superior metabolic control Continuous removal of toxins Simple to perform Stable intracranial pressure Rapid removal of poisons Limited anticoagulation Need for intensive care nursing support Need for hemodialysis nursing support Patient mobility

CRRT

IHD

PD

            

            

            

DETERMINANTS OF THE CHOICE OF TREATMENT MODALITY FOR ACUTE RENAL FAILURE Patient Indication for dialysis Presence of multiorgan failure Access Mobility and location of patient Anticipated duration of therapy Dialysis process Components (eg, membrane, anticoagulation) Type (intermittent or continuous) Efficacy for solute and fluid balance Complications Outcome Nursing and other support Availability of machines Nursing support

FIGURE 19-20 Advantages () and disadvantages () of dialysis techniques. CRRT—continuous renal replacement therapy; IHD—intermittent hemodialysis; PD—peritoneal dialysis.

FIGURE 19-21 Determinants of the choice of treatment modality for acute renal failure. The primary indication for dialysis intervention can be a major determinant of the therapy chosen because different therapies vary in their efficacy for solute and fluid removal. Each technique has its advantages and limitations, and the choice depends on several factors. Patient selection for each technique ideally should be based on a careful consideration of multiple factors [1]. The general principle is to provide adequate renal support without adversely affecting the patient. The presence of multiple organ failure may limit the choice of therapies; for example, patients who have had abdominal surgery may not be suitable for peritoneal dialysis because it increases the risk of wound dehiscence and infection. Patients who are hemodynamically unstable may not tolerate intermittent hemodialysis (IHD). Additionally, the impact of the chosen therapy on compromised organ systems is an important consideration. Rapid removal of solutes and fluid, as in IHD, can result in a disequilibrium syndrome and worsen neurologic status. Peritoneal dialysis may be attractive in acute renal failure that complicates acute pancreatitis, but it would contribute to additional protein losses in the hypoalbuminemic patient with liver failure.

Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Therapies, and Peritoneal Dialysis

RECOMMENDATION FOR INITIAL DIALYSIS MODALITY FOR ACUTE RENAL FAILURE (ARF) Indication

Clinical Condition

Preferred Therapy

Uncomplicated ARF Fluid removal Uremia Increased intracranial pressure

Antibiotic nephrotoxicity Cardiogenic shock, CP bypass Complicated ARF in ICU Subarachnoid hemorrhage, hepatorenal syndrome Sepsis, ARDS Burns Theophylline, barbiturates Marked hyperkalemia Uremia in 2nd, 3rd trimester

IHD, PD SCUF, CAVH CVVHDF, CAVHDF, IHD CVVHD, CAVHD

Shock Nutrition Poisons Electrolyte abnormalities ARF in pregnancy

CVVH, CVVHDF, CAVHDF CVVHDF, CAVHDF, CVVH Hemoperfusion, IHD, CVVHDF IHD, CVVHDF PD

19.13

FIGURE 19-22 Recommendation for initial dialysis modality for acute renal failure (ARF). Patients with multiple organ failure (MOF) and ARF can be treated with various continuous therapies or IHD. Continuous therapies provide better hemodynamic stability; however, if not monitored carefully they can lead to significant volume depletion. In general, hemodynamically unstable, catabolic, and fluid-overloaded patients are best treated with continuous therapies, whereas IHD is better suited for patients who require early mobilization and are more stable. It is likely that the mix of modalities used will change as evidence linking the choice of modality to outcome becomes available. For now, it is probably appropriate to consider all these techniques as viable options that can be used collectively. Ideally, each patient should have an individualized approach for management of ARF.

CRRT IHD

100

S Creat, mg/dL

BUN, mg/dL

Outcomes

80 60 40 0 1 2

Urea, mmol/L

A

3 4 5 Days

6 7

8

B

50 40 30 20 0

1

2

3 Days

0 1 2

9

Survivors Non-survivors

4

5

6

6 5 4 3 2 1

FIGURE 19-23 Efficacy of continuous renal replacement therapy (CRRT) versus intermittent hemodialysis (IHD): effect on blood urea nitrogen, A, and creatinine levels, B, in acute renal failure.

CRRT IHD

3 4 5 6 Days

7 8

9

FIGURE 19-24 Blood urea nitrogen (BUN) levels in survivors and non-survivors in acute renal failure treated with continuous renal replacement therapy (CRRT). It is apparent that CRRT techniques offer improved solute control and fluid management with hemodynamic stability, however a relationship to outcome has not been demonstrated. In a recent retrospective analysis van Bommel [24] found no difference in BUN levels among survivors and nonsurvivors with ARF While it is clear that lower solute concentrations can be achieved with CRRT whether this is an important criteria impacting on various outcomes from ARF still needs to be determined. A recent study form the Cleveland Clinic suggests that the dose of dialysis may be an important determinant of outcome allowing for underlying severity of illness [25]. In this study the authors found that in patients with ARF, 65.4% of all IHD treatments resulted in lower Kt/V than prescribed. There appeared to be an influence of dose of dialysis on outcome in patients with intermediate levels of severity of illness as judged by the Cleveland Clinic Foundation acuity score for ARF (see Fig. 19-25). Patients receiving a higher Kt/V had a lower mortality than predicted. These data illustrate the importance of the underlying severity of illness, which is likely to be a major determinant of outcome and should be considered in the analysis of any studies.

Acute Renal Failure

1

Low Kt/V High Kt/V CCF score

Survival, %

19.14

0.8 0.6

BIOCOMPATIBLE MEMBRANES IN INTERMITTENT HEMODIALYSIS (IHD) AND ACUTE RENAL FAILURE (ARF): EFFECT ON OUTCOMES

0.4 0.2 0 0

5 10 15 Cleveland clinic ICU ARF score

Patients, n All patients recover of renal function Survival Patients nonoliguric before hemodialysis Development of oliguria with dialysis Recovery of renal function Survival Patients oliguric before hemodialysis Recovery of renal function Survival

20

FIGURE 19-25 Effect of dose of dialysis in acute renal failure (ARF) on outcome from ARF.

BCM Group

BICM Group

72 46 (64%) 41 (57%) 39 17 (44%) 31 (79%) 28 (74%) 33 15 (45%) 12 (36%)

81 35 (43%) 37 (46%) 46 32 (70%) 21 (46%) 22 (48%) 35 14 (40%) 15 (43%)

Probability 0.001 0.03 0.03 0.0004 0.003 ns ns

FIGURE 19-26 Biocompatible membranes in intermittent hemodialysis (IHD) and acute renal failure (ARF): effect on outcomes. The choice of dialysis membrane and its influence on survival from ARF has been of major interest to investigators over the last few years. While the evidence tends to support a survival advantage for biocompatible membranes, most of the studies were not well controlled. The most recent multicenter study showed an improvement in mortality and recovery of renal function with biocompatible membranes; however, this effect was not significant in oliguric patients. Further investigations are required in this area. NS—not significant.

MORTALITY IN ACUTE RENAL FAILURE: COMPARISON OF CRRT VERSUS IHD IHD

CRRT

Investigator

Type of Study

No

Mortality, %

No

Mortality, %

Change, %

P Value

Mauritz [32] Alarabi [33] Mehta [34] Kierdorf [20] Bellomo [35] Bellomo [36] Kruczynski [37] Simpson [38] Kierdorf [39] Mehta [40]

Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Prospective Prospective Prospective

31 40 24 73 167 84 23 58 47 82

90 55 85 93 70 70 82 82 65 41.5

27 40 18 73 84 76 12 65 48 84

70 45 72 77 59 45 33 70 60 59.5

20 10 13 16 11 25 49 12 4.5 18

ns ns ns < 0.05 ns < 0.01 < 0.01 ns ns ns

FIGURE 19-27 Continuous renal replacement therapy (CRRT) versus intermittent hemodialysis (IHD): effect on mortality. Despite significant advances in the management of acute renal failure (ARF) over the last four decades, the perception is that the associated mortality has not changed significantly [26]. Recent publications suggest that there may have been some improvement during the last decade [27]. Both IHD and peritoneal dialysis (PD) were the major therapies until a decade ago, and they improved the outcome from the 100% mortality of ARF to its current level. The effect of continuous renal replacement therapy on overall patient outcome is still unclear [28] . The

major studies done in this area do not show a survival advantage for CRRT [29,30]. Although several investigators have not been able to demonstrate an advantage of these therapies in influencing mortality, we believe this may represent the difficulty in changing a global outcome which is impacted by several other factors [31]. It is probably more relevant to focus on other outcomes such as renal functional recovery rather than mortality. We believe that continued research is required in this area; however, there appears to be enough evidence to support the use of CRRT techniques as an alternative that may be preferable to IHD in treating ARF in an intensive care setting.

Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Therapies, and Peritoneal Dialysis

19.15

Future Directions 1 Blood delivered to lumen of fibers in filter device (only one fiber shown)

4 Postfiltered blood delivered to extracapillary space of RAD

Filter unit Reabsorber unit

2 Filtrate conveyed to tubule lumens

3 Filtrate delivered to interiors of fibers in RAD

6 Transported and synthesized elements added to postfiltered blood, returned to general circulation

7 Concentrated metabolic wastes (urine) voided 5 Renal tubule cells lining fibers provide transport and metabolic function

FIGURE 19-28 Schematic for the bioartificial kidney. As experience with these techniques grows, innovations in technology will likely keep pace. Over the last 3 years, most of the major manufacturers of dialysis equipment have developed new pumps dedicated for continuous renal replacement therapy (CRRT). Membrane technology is also evolving, and antithrombogenic membranes are on the horizon [41]. Finally the application of these therapies is likely to expand to other arenas, including the treatment of sepsis, congestive heart failure [42], and multiorgan failure [43]. An exciting area of innovative research is the development of a bioartificial tubule utilizing porcine tubular epithelial cells grown in a hollow fiber to add tubular function to the filtrative function provided by dialysis [44]. These devices are likely to be utilized in combination with CRRT to truly provide complete RRT in the near future. (From Humes HD [44]; with permission.)

References 1.

2. 3.

4. 5. 6. 7. 8.

9.

Mehta RL: Therapeutic alternatives to renal replacement therapy for critically ill patients in acute renal failure. Semin Nephro 1994, 14:64–82. Shapiro WB: The current status of Sorbent hemodialysis. Semin Dial 1990, 3:40–45. Botella J, Ghezzi P, Sanz-Moreno C, et al.: Multicentric study on paired filtration dialysis as a short, highly efficient dialysis technique. Nephrol Dial Transplant 1991, 6:715–721. Steiner RW: Continuous equilibration peritoneal dialysis in acute renal failure. Perit Dial Intensive 1989, 9:5–7. Bellomo R, Ronco C, Mehta RL: Nomenclature for continuous renal replacement therapies. Am J Kidney Dis 1996, 28(5)S3:2–7. Henderson LW: Hemofiltration: From the origin to the new wave. Am J Kidney Dis 1996, 28(5)S3:100–104. Mehta RL: Renal replacement therapy for acute renal failure: Matching the method to the patient. Semin Dial 1993, 6:253–259. Lindhout T: Biocompatability of extracorporeal blood treatment. Selection of hemostatic parameters. Nephrol Dial Transplant 1994, 9(Suppl. 2):83–89. Ward RA: Effects of hemodialysis on corpulation and platelets: Are we measureing membrane biocompatability? Nephrol Dial Transplant 1995, 10(Suppl. 10):12–17.

10. Ronco C, Brendolan A, Crepaldi C, et al.: Importance of hollow fiber geometry in CAVH. Contrib Nephrol 1991, 15:175–178. 11. Mehta RL, McDonald BR, Aguilar MM, Ward DM: Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients. Kidney Int 1990, 38:976–981. 12. Grootendorst AF, Bouman C, Hoeben K, et al.: The role of continuous renal replacement therapy in sepsis multiorgan failure. Am J Kidney Dis 1996, 28(5) S3:S50–S57. 13. Kroh UF, Holl TJ, Steinhausser W: Management of drug dosing in continuous renal replacement therapy. Semin Dial 1996, 9:161–165. 14. Monson P, Mehta RL: Nutritional considerations in continuous renal replacement therapies. Semin Dial 1996, 9:152–160. 15. Golper TA: Indications, technical considerations, and strategies for renal replacement therapy in the intensive care unit. J Intensiv Care Med 1992, 7:310–317. 16. Mehta RL: Fluid management in continuous renal replacement therapy. Semin Dial 1996, 9:140–144. 17. Palevsky PM: Continuous renal replacement therapy component selection: replacement fluid and dialysate. Semin Dial 1996, 9:107–111. 18. Thomas AN, Guy JM, Kishen R, et al.: Comparison of lactate and bicarbonate buffered haemofiltration fluids: Use in critically ill patients. Nephrol Dial Transplant 1997, 12(6):1212–1217.

19.16

Acute Renal Failure

19. Golper TA: Continuous arteriovenous hemofiltration in acute renal failure. Am J Kidney Dis 1985, 6:373–386. 20. Kierdorf H: Continuous versus intermittent treatment: clinical results in acute renal failure. Contrib Nephrol 1991, 93:1–12. 21. Lauer 22. Paganini EP: Slow continuous hemofiltration and slow continuous ultrafiltration. Trans Am Soc Artif Intern Organs 1988, 34:63–66. 23. Schrier RW, Abraham HJ: Strategies in management of acute renal failure in the intensive therapy unit. In Current Concepts in Critical Care: Acute Renal Failure in the Intensive Therapy Unit. Edited by Bihari D, Neild G. Berlin:Springer-Verlag, 1990:193–214. 24. Van Bommel EFH, Bouvy ND, So KL, et al.: High risk surgical acute renal failure treated by continuous arterio venous hemodiafiltration: Metabolic control and outcomes in sixty patients. Nephron 1995, 70:185–196. 25. Paganini EP, Tapolyai M, Goormastic M, et al.: Establishing a dialysis therapy/patient outcome link in intensive care unit acute dialysis for patients with acute renal failure. Am J Kidney Dis 1996, 28(5)S3:81–90. 26. Wilkins RG, Faragher EB: Acute renal failure in an intensive care unit: Incidence, prediction and outcome. Anesthesiology 1983, 38:638. 27. Firth JD: Renal replacement therapy on the intensive care unit. Q J Med 1993, 86:75–77. 28. Bosworth C, Paganini EP, Cosentino F, et al.: Long term experience with continuous renal replacement therapy in intensive care unit acute renal failure. Contrib Nephrol 1991, 93:13–16. 29. Kierdorf H: Continuous versus intermittent treatment: Clinical results in acute renal failure. Contrib Nephrol 1991, 93:1–12. 30. Jakob SM, Frey FJ, Uhlinger DE: Does continuous renal replacement therapy favorably influence the outcome of patients? Nephrol Dial Transplant 1996, 11:1250–1235. 31. Mehta RL: Acute renal failure in the intensive care unit: Which outcomes should we measure? Am J Kidney Dis 1996, 28(5)S3:74–79. 32. Mauritz W, Sporn P, Schindler I, et al.: Acute renal failure in abdominal infection: comparison of hemodialysis and continuous arteriovenous hemofiltration. Anasth Intensivther Notfallmed 1986, 21:212–217.

33. Alarabi AA, Danielson BG, Wikstrom B, Wahlberg J: Outcome of continuous arteriovenous hemofiltration (CAVH) in one centre. Ups J Med Sci 1989, 94:299–303. 34. McDonald BR, Mehta RL: Decreased mortality in patients with acute renal failure undergoing continuous arteriovenous hemodialysis. Contrib Nephrol 1991, 93:51–56. 35. Bellomo R, Mansfield D, Rumble S, et al.: Acute renal failure in critical illness. Conventional dialysis versus acute continuous hemodiafiltration. Am Soc Artif Intern Organs J 1992, 38:654–657. 36. Bellomo R, Boyce N: Continuous venovenous hemodiafiltration compared with conventional dialysis in critically ill patients with acute renal failure. Am Soc Artif Intern Organs J 1993, 39:794–797. 37. Kruczynski K, Irvine-Bird K, Toffelmire EB, Morton AR: A comparison of continuous arteriovenous hemofiltration and intermittent hemodialysis in acute renal failure patients in the intensive care unit. Am Soc Artif Intern Organs J 1993, 39:778–781. 38. Simpson K, Allison MEM: Dialysis and acute renal failure: can mortality be improved? Nephrol Dial Transplant 1993, 8:946. 39. Kierdorf H: Einfuss der kontinuierlichen Hamofiltration auf Proteinkatabolismus, Mediatorsubstanzen und Prognose des akuten Nierenversagens [Habilitation-Thesis], Medical Faculty Technical University of Aachen, 1994. 40. Mehta RL, McDonald B, Pahl M, et al.: Continuous vs. intermittent dialysis for acute renal failure (ARF) in the ICU: Results from a randomized multicenter trial. Abstract A1044. JASN 1996, 7(9):1456. 41. Yang VC, Fu Y, Kim JS: A potential thrombogenic hemodialysis membranes with impaired blood compatibility. ASAIO Trans 1991, 37:M229–M232. 42. Canaud B, Leray-Moragues H, Garred LJ, et al.: Slow isolated ultrafiltration for the treatment of congestive heart failure. Am J Kidney Dis 1996, 28(5)S3:67–73. 43. Druml W: Prophylactic use of continuous renal replacement therapies in patients with normal renal function. Am J Kidney Dis 1996, 28(5)S3:114–120. 44. Humes HD, Mackay SM, Funke AJ, Buffington DA: The bioartificial renal tuble assist device to enhance CRRT in acute renal failure. Am J Kidney Dis 1997, 30(Suppl. 4):S28–S30.

Normal Vascular and Glomerular Anatomy Arthur H. Cohen Richard J. Glassock

T

he topic of normal vascular and glomerular anatomy is introduced here to serve as a reference point for later illustrations of disease-specific alterations in morphology.

CHAPTER

1

1.2

Glomerulonephritis and Vasculitis

Interlobar artery Arcuate artery

Renal artery Pelvis

Pyramid Interlobular artery

FIGURE 1-1 A, The major renal circulation. The renal artery divides into the interlobar arteries (usually 4 or 5 divisions) that then branch into arcuate arteries encompassing the corticomedullary junction of each renal pyramid. The interlobular arteries (multiple) originate from the arcuate arteries. B, The renal microcirculation. The afferent arterioles branch from the interlobular arteries and form the glomerular capillaries (hemi-arterioles). Efferent arterioles then reform and collect to form the post-glomerular circulation (peritubular capillaries, venules and renal veins [not shown]). The efferent arterioles at the corticomedullary junction dip deep into the medulla to form the vasa recta, which embrace the collecting tubules and form hairpin loops. (Courtesy of Arthur Cohen, MD.)

Ureter

A

Afferent arteriole

Interlobular artery

Glomerulus

Arcuate artery

Efferent arteriole Collecting tubule

B

Interlobar artery

Normal Vascular and Glomerular Anatomy

aa

ILA

1.3

FIGURE 1-2 (see Color Plate) Microscopic view of the normal vascular and glomerular anatomy. The largest intrarenal arteries (interlobar) enter the kidneys between adjacent lobes and extend toward the cortex on the side of a pyramid. These arteries branch dichotomously at the corticomedullary junction, forming arcuate arteries that course between the cortex and medulla. The arcuate arteries branch into a series of interlobular arteries that course at roughly right angles through the cortex toward the capsule. Blood reaches glomeruli through afferent arterioles, most of which are branches of interlobular arteries, although some arise from arcuate arteries. ILA—interlobular artery; aa—afferent arteriole.

FIGURE 1-3 Microscopic view of the juxtaglomerular apparatus. The juxtaglomerular apparatus (arrow) located immediately adjacent to the glomerular hilus, is a complex structure with vascular and tubular components. The vascular component includes the afferent and efferent arterioles, and the region between them is known as the lacis. The tubular component consists of the macula densa (arrowhead). The juxtaglomerular apparatus is an integral component of the renin-angiotensin system.

FIGURE 1-4 Electron micrograph of the arterioles. Modified smooth muscle cells of the arterioles of the juxtaglomerular apparatus produce and secrete renin. Renin is packaged in characteristic amorphous mature granules (arrow) derived from smaller rhomboid-shaped immature protogranules (arrowhead).

1.4

Glomerulonephritis and Vasculitis

FP

A FIGURE 1-5 (see Color Plate) Microscopic view of the glomeruli. Glomeruli are spherical “bags” of capillaries emanating from afferent arterioles and confined within the urinary space, which is continuous with the proximal tubule. The capillaries are partially attached to the mesangium, a continuation of the arteriolar wall consisting of

B mesangial cells (A, arrow) and the matrix (B, arrow). The free wall of glomerular capillaries, across which filtration takes place, consists of a basement membrane (arrowheads) covered by visceral epithelial cells with individual foot processes (FP) and lined by endothelial cells. FIGURE 1-6 Schematic illustration of a glomerulus and adjacent hilar structure. Note the relationship of mesangial cells to the juxtaglomerular apparatus and distal tubule (macula densa). Red—mesangial cells; blue—mesangial matrix; black—basement membrane; green—visceral and parietal epithelial cells; yellow—endothelial cells. (From Churg and coworkers [1]; with permission.)

FIGURE 1-7 Electron photomicrograph illustrating a portion of the ultrastructure of the glomerular capillary wall. The normal width of the lamina rara externa (LRE) plus the lamina densa (LD) plus the lamina rara interna (LRI) equals about 250 to 300 nm. The spaces between the foot processes (FP), having diameters of 20 to 60 nm, are called filtration slit pores. It is believed they are the path by which filtered fluid reaches the urinary space (U). The endothelial cells on the luminal aspect of the basement membrane (BM) are fenestrated, having diameters from 70 to 100 nm (see Fig. 1-9). The BM (LRE plus LD plus LRI) is composed of Type IV collagen and negativity charged proteoglycans (heparan sulfate). L—lumen. (From Churg and coworkers [1]; with permission.)

Normal Vascular and Glomerular Anatomy

1.5

FIGURE 1-8 Scanning electron microscopy of the glomerulus. The surface anatomy of the interdigitating foot processes of normal visceral epithelial cells (podocytes) is demonstrated. These cells and their processes cover the capillary, and ultrafiltration occurs between the fine branches of the cells. (From Churg and coworkers [1]; with permission.)

FIGURE 1-9 Scanning electron microscopy of the glomerulus. The surface anatomy of endothelial cells of a normal glomerulus is demonstrated. Note the fenestrated appearance. (From Churg and coworkers [1]; with permission.)

Reference 1.

Churg J, Bernstein J, Glassock RJ: Renal Disease. Classification and Atlas of Glomerular Diseases, edn 2. New York: Igaku-Shoin; 1995.

The Primary Glomerulopathies Arthur H. Cohen Richard J. Glassock

T

he primary glomerulopathies are those disorders that affect glomerular structure, function, or both in the absence of a multisystem disorder. The clinical manifestations are predominately the consequence of the glomerular lesion (such as proteinuria, hematuria, and reduced glomerular filtration rate). The combination of clinical manifestations leads to a variety of clinical syndromes. These syndromes include acute glomerulomphritis; rapidly progressive glomerulonephritis; chronic renal failure; the nephrotic syndrome or “asymptomatic” hematuria, proteinuria, or both.

CHAPTER

2

2.2

Glomerulonephritis and Vasculitis FIGURE 2-1 Each of these syndromes arises as a consequence of disturbances of glomerular structure and function. Acute glomerulonephritis consists of the abrupt onset of hematuria, proteinuria, edema, and hypertension. Rapidly progressive glomerulonephritis is characterized by features of nephritis and progressive renal insufficiency. Chronic glomerulonephritis features proteinuria and hematuria with indolent progressive renal failure. Nephrotic syndrome consists of massive proteinuria (>3.5 g/d in adults), hypoalbuminemia with edema, lipiduria, and hyperlipidemia. “Asymptomatic” hematuria, proteinuria, or both is not associated initially with renal failure or edema. Each of these syndromes may be complicated by hypertension.

CLINICAL SYNDROMES OF GLOMERULAR DISEASE Acute glomerulonephritis Rapidly progressive glomerulonephritis Chronic glomerulonephritis Nephrotic syndrome “Asymptomatic” hematuria, proteinuria, or both

%

% 100

5 4 2 5 1 7

% Others Lupus

90

10.8

Amyloid

5.9 1.6

Diabetes

80

Other proliferative

70

16.0 25.8

60

MCGN

9.8

Membranous

19.7

50 76

40 30

11.8

FSGS

20 Minimal changes

10

22

0 All children

5 10 15 20

30 40 50 Age at onset of NS

PRIMARY GLOMERULAR LESIONS Minimal change disease Focal segmental glomerulosclerosis with hyalinosis Membranous glomerulonephritis Membranoproliferative glomerulonephritis Mesangial proliferative glomerulonephritis Crescentic glomerulonephritis Immunoglobulin A nephropathy Fibrillary and immunotactoid glomerulonephritis Collagenofibrotic glomerulopathy Lipoprotein glomerulopathy

60

70

80

All adults

FIGURE 2-2 Age-associated prevalence of various glomerular lesions in nephrotic syndrome. This schematic illustrates the age-associated prevalence of various diseases and glomerular lesions among children and adults undergoing renal biopsy for evaluation of nephrotic syndrome (Guy’s Hospital and the International Study of Kidney Disease in Children) [1]. Both the systemic and primary causes of nephrotic syndrome are included. (Diabetes mellitus with nephropathy is underrepresented because renal biopsy is seldom needed for diagnosis.) The bar on the left summarizes the prevalence of various lesions in children aged 0 to 16 years; the bar on the right summarizes the prevalence of various lesions in adults aged 16 to 80 years. Note the high prevalence of minimal change disease in children and the increasing prevalence of membranous glomerulonephritis in the age group of 16 to 60 years. FSGS—focal segmental glomeruosclerosis; MCGN—mesangiocapillary glomerulonephritis. (From Cameron [1]; with permission.)

FIGURE 2-3 The primary glomerular lesions.

The Primary Glomerulopathies

2.3

Minimal Change Disease

A

B

FIGURE 2-4 Light and electron microscopy in minimal change disease (lipoid nephrosis). A, This glomerulopathy, one of many associated with nephrotic syndrome, has a normal appearance on light microscopy. No evidence of antibody (immune) deposits is seen on immunofluorescence. B, Effacement (loss) of foot processes of visceral epithelial cells is observed on electron microscopy. This last feature is the major morphologic lesion indicative of massive proteinuria.

Minimal change disease is considered to be the result of glomerular capillary wall damage by lymphokines produced by abnormal T cells. This glomerulopathy is the most common cause of nephrotic syndrome in children (>70%) and also accounts for approximately 20% of adult patients with nephrotic syndrome. This glomerulopathy typically is a corticosteroid-responsive lesion, and usually has a benign outcome with respect to renal failure.

100

80

60

40 ISKDC children Prednisone + Cyclophosphamide (11) Prednisone (75) Cyclophosphamide (25)

20 0

Cumulative percentage sustained remission

Complete remission, cumulative %

100

12 weeks 8 weeks

80

60

40

20 0

2

4

8

16 Weeks from starting treatment

28

FIGURE 2-5 Therapeutic response in minimal change disease. This graph illustrates the cumulative complete response rate (absence of abnormal proteinuria) in patients of varying ages in relation to type and duration of therapy [1]. Note that most children with minimal change disease respond to treatment within 8 weeks. Adults require prolonged therapy to reach equivalent response rates. Number of patients are indicated in parentheses. (From Cameron [2]; with permission.)

0

200

400

600

Days

FIGURE 2-6 Cyclophosphamide in minimal change disease. One of several controlled trials of cyclophosphamide therapy in pediatric patients that pursued a relapsing steroid-dependent course is illustrated. Note the relative freedom from relapse when children were given a 12-week course of oral cyclophosphamide. An 8-week course of chlorambucil (0.15–0.2 mg/kg/d) may be equally effective. (From Arbeitsgemeinschaft für pediatrische nephrologie [3]; with permission.)

2.4

Glomerulonephritis and Vasculitis 100

Cyclosporine Cyclophosphamide

Overall probability

80

60

FIGURE 2-7 Cyclosporine in minimal change disease. One of several controlled trials of cyclosporine therapy in this disease is illustrated. Note the relapses that occur after discontinuing cyclosporine therapy (arrow). Cyclophosphamide was given for 2 months, and cyclosporine for 9 months. Probability—actuarial probability of remaining relapse-free. (From Ponticelli and coworkers [4]; with permission.)

40

20

0 0

90

Number of patients Cyclosporine 36 Cyclophosphamide 30

180

270

36 29

360 450 Time, d 36 28

540

630

720

31 26

Focal Segmental Glomerulosclerosis

A FIGURE 2-8 Light and immunofluorescent microscopy in focal segmental glomerulosclerosis (FSGS). Patients with FSGS exhibit massive proteinuria (usually nonselective), hypertension, hematuria, and renal functional impairment. Patients with nephrotic syndrome often are not responsive to corticosteroid therapy. Progression to chronic renal failure occurs over many years, although in some patients renal failure may occur in only a few years. A, This glomerulopathy is defined primarily by its appearance on light microscopy. Only a portion of the glomerular population, initially

B in the deep cortex, is affected. The abnormal glomeruli exhibit segmental obliteration of capillaries by increased extracellular matrix–basement membrane material, collapsed capillary walls, or large insudative lesions. These lesions are called hyalinosis (arrow) and are composed of immunoglobulin M and complement C3 (B, IgM immunofluorescence). The other glomeruli usually are enlarged but may be of normal size. In some patients, mesangial hypercellularity may be a feature. Focal tubular atrophy with interstitial fibrosis invariably is present.

The Primary Glomerulopathies

2.5

FIGURE 2-9 Electron microscopy of focal segmental glomerulosclerosis. The electron microscopic findings in the involved glomeruli mirror the light microscopic features, with capillary obliteration by dense hyaline “deposits” (arrow) and lipids. The other glomeruli exhibit primarily foot process effacement, occasionally in a patchy distribution.

CLASSIFICATION OF FOCAL SEGMENTAL GLOMERULOSCLEROSIS WITH HYALINOSIS Primary (Idiopathic) Classic Tip lesion Collapsing

Secondary Human immunodeficiency virus–associated Heroin abuse Vesicoureteric reflux nephropathy Oligonephronia (congenital absence or hypoplasia of one kidney) Obesity Analgesic nephropathy Hypertensive nephrosclerosis Sickle cell disease Transplantation rejection (chronic) Vasculitis (scarring) Immunoglobulin A nephropathy (scarring)

FIGURE 2-10 Note that a variety of disease processes can lead to the lesion of focal segmental glomerulosclerosis. Some of these are the result of infections, whereas others are due to loss of nephron population. Focal sclerosis may also complicate other primary glomerular diseases (eg, Immunoglobulin A nephropathy).

CLASSIFICATION OF MEMBRANOUS GLOMERULONEPHRITIS Primary (Idiopathic) Secondary Neoplasia (carcinoma, lymphoma) Autoimmune disease (systemic lupus erythematosus thyroiditis) Infectious diseases (hepatitis B, hepatitis C, schistosomiasis) Drugs (gold, mercury, nonsteroidal anti-inflammatory drugs, probenecid, captopril) Other causes (kidney transplantation, sickle cell disease, sarcoidosis)

FIGURE 2-11 Most adult patients (75%) have primary or idiopathic disease. Most children have some underlying disease, especially viral infection. It is not uncommon for adults over the age of 60 years to have an underlying carcinoma (especially lung, colon, stomach, or breast).

2.6

Glomerulonephritis and Vasculitis

A

B

FIGURE 2-12 Histologic variations of focal segmental glomerulosclerosis (FSGS). Two important variants of FSGS exist. In contrast to the histologic appearance of the involved glomeruli, with the sclerotic segment in any location in the glomerulus, the glomerular tip lesion (A) is characterized by segmental sclerosis at an early stage of evolution, at the tubular pole (tip) of all affected glomeruli (arrow). Capillaries contain monocytes with abundant cytoplasmic lipids (foam cells), and the overlying visceral epithelial cells are enlarged and adherent to cells of the most proximal portion of the proximal

100

tubule. Some investigators have described a more favorable response to steroids and a more benign clinical course. The other variant, known as collapsing glomerulopathy, most likely represents a virulent form of FSGS. In this form of FSGS, most visceral epithelial cells are enlarged and coarsely vacuolated and most capillary walls are wrinkled or collapsed (B). These features indicate a severe lesion, with a corresponding rapidly progressing clinical course of the disease. Integral and concomitant acute abnormalities of tubular epithelia and interstitial edema occur.

<15 y (138) 15–59 y (68)

60 <15 y (62)

40 20

Minimal change disease FSGS

0 0

5

>60 y (20)

>15 y (60)

10 15 Years from onset

20

Survival, %

Survival, %

80

100 90 80 70 60 50 40 30 20 10 0

Without nephrotic syndrome

With nephrotic syndrome

0

FIGURE 2-13 Evolution of focal segmental glomerulosclerosis (FSGS). This graph compares the renal functional survival rate of patients with FSGS to that seen in patients with minimal change disease (in adults and children). Note the poor prognosis, with about a 50% rate of renal survival at 10 years. (From Cameron [2]; with permission.)

5

10 15 Years from onset

20

FIGURE 2-14 The outcome of focal segmental glomerulosclerosis according to the degree of proteinuria at presentation is shown. Note the favorable prognosis in the absence of nephrotic syndrome. Spontaneous or therapeutically induced remissions have a similar beneficial effect on long-term outcome. (From Ponticelli, et al. [5]; with permission.)

The Primary Glomerulopathies

2.7

Membranous Glomerulonephritis

A

B

C

D

E FIGURE 2-15 (see Color Plate) Light, immunofluorescent, and electron microscopy in membranous glomerulonephritis. Membranous glomerulonephritis is an immune complex–mediated glomerulonephritis, with the immune deposits localized to subepithelial aspects of almost all glomerular capillary walls. Membranous glomerulonephritis is the most common cause of nephrotic syndrome in adults in developed countries. In most instances (75%), the disease is idiopathic and the

antigen(s) of the immune complexes are unknown. In the remainder, membranous glomerulonephritis is associated with welldefined diseases that often have an immunologic basis (eg, systemic lupus erythematosus and hepatitis B or C virus infection); some solid malignancies (especially carcinomas); or drug therapy, such as gold, penicillamine, captopril, and some nonsteroidal anti-inflammatory reagents. Treatment is controversial. The changes by light and electron microscopy mirror one another quite well and represent morphologic progression that is likely dependent on duration of the disease. A, At all stages immunofluorescence discloses the presence of uniform granular capillary wall deposits of immunoglobulin G and complement C3. B, In the early stage the deposits are small and without other capillary wall changes; hence, on light microscopy, glomeruli often are normal in appearance. C, On electron microscopy, small electron-dense deposits (arrows) are observed in the subepithelial aspects of capillary walls. D, In the intermediate stage the deposits are partially encircled by basement membrane material. E, When viewed with periodic acid-methenamine stained sections, this abnormality appears as spikes of basement membrane perpendicular to the basement membrane, with adjacent nonstaining deposits. Similar features are evident on electron microscopy, with dense deposits and intervening basement membrane (D). Late in the disease the deposits are completely surrounded by basement membranes and are undergoing resorption.

2.8

Glomerulonephritis and Vasculitis FIGURE 2-16 Evolution of deposits in membranous glomerulonephritis. This schematic illustrates the sequence of immune deposits in red; basement membrane (BM) alterations in blue; and visceral epithelial cell changes in yellow. Small subepithelial deposits in membranous glomerulonephritis (predominately immunoglobulin G) initially form (A) then coalesce. BM expansion results first in spikes (B) and later in domes (C) that are associated with foot process effacement, as shown in gray. In later stages the deposits begin to resorb (dotted and crosshatched areas) and are accompanied by thickening of the capillary wall (D). (From Churg, et al. [6]; with permission.)

A

B

C

D

FIGURE 2-17 Natural history of membranous glomerulonephritis. This schematic illustrates the clinical evolution of idiopathic membranous glomerulonephritis over time. Almost half of all patients undergo spontaneous or therapy-related remissions of proteinuria. Another group of patients (25–40%), however, eventually develop chronic renal failure, usually in association with persistent proteinuria in the nephrotic range. (From Cameron [2]; with permission.)

100 Dead/ESRD

80

Nephrotic syndrome

%

60 Proteinuria

40 20

Remission

0 0

5 10 Years of known disease

15

The Primary Glomerulopathies

2.9

Membranoproliferative Glomerulonephritis

A

B

1 2 3 4 5

6

C FIGURE 2-18 (see Color Plate) Light, immunofluorescence, and electron microscopy in membranoproliferative glomerulonephritis type I. In these types of immune complex–mediated glomerulonephritis, patients often exhibit nephrotic syndrome accompanied by hematuria and depressed levels of serum complement C3. The morphology is varied, with at least three pathologic subtypes, only two of which are

at all common. The first, known as membranoproliferative (mesangiocapillary) glomerulonephritis type I, is a primary glomerulopathy most common in children and adolescents. The same pattern of injury may be observed during the course of many diseases with chronic antigenemic states; these include systemic lupus erythematosus and hepatitis C virus and other infections. In membranoproliferative glomerulonephritis type I, the glomeruli are enlarged and have increased mesangial cellularity and variably increased matrix, resulting in lobular architecture. The capillary walls often are thickened with double contours, an abnormality resulting from peripheral migration and interposition of mesangium (A). Immunofluorescence discloses granular to confluent granular deposits of C3 (B), immunoglobulin G, and immunoglobulin M in the peripheral capillary walls and mesangial regions. The characteristic finding on electron microscopy is in the capillary walls. C, Between the basement membrane and endothelial cells are, in order inwardly: (1) epithelial cell, (2) basement membrane, (3) electron-dense deposits, (4) mesangial cell cytoplasm, (5) mesangial matrix, and (6) endothelial cell. Electrondense deposits also are in the central mesangial regions. Subepithelial deposits may be present, albeit typically in small numbers. The electron-dense deposits may contain an organized (fibrillar) substructure, especially in association with hepatitis C virus infection and cryoglobulemia.

2.10

Glomerulonephritis and Vasculitis

A

C FIGURE 2-19 (see Color Plate) Light, immunofluorescence, and electron microscopy in membranoproliferative glomerulonephritis type II. In this disease, also

A B known as dense deposit disease, the glomeruli may be lobular or may manifest only mild widening of mesangium. A, The capillary walls are thickened, and the basement membranes are stained intensely positive periodic acid–Schiff reaction, with a refractile appearance. B, On immunofluorescence, complement C3 is seen in all glomerular capillary basement membranes in a coarse linear pattern. With the use of thin sections, it can be appreciated that the linear deposits actually consist of two thin parallel lines. Round granular deposits are in the mesangium. Coarse linear deposits also are in Bowman’s capsule and the tubular basement membranes. C, Ultrastructurally, the glomerular capillary basement membranes are thickened and darkly stained; there may be segmental or extensive involvement of the basement membrane. Similar findings are seen in Bowman’s capsule and tubular basement membranes; however, in the latter, the dense staining is usually on the interstitial aspect of that structure. Patients with dense deposit disease frequently show isolated C3 depression and may have concomitant lipodystrophy. These patients also have autoantibodies to the C3 convertase enzyme C3Nef.

The Primary Glomerulopathies

2.11

SERUM COMPLEMENT CONCENTRATIONS IN GLOMERULAR LESIONS Serum Concentration Lesion

C3

C4

C’H50

Other

Minimal change disease Focal sclerosis Membranous glomerulonephritis (idiopathic) Immunoglobulin A nephropathy Membranoproliferative glomerulonephritis: Type I Type II Acute poststreptococcal glomerulonephritis Lupus nephritis: (World Health Organization Class IV)

Normal Normal Normal Normal

Normal Normal Normal Normal

Normal Normal Normal Normal

– – – –

Moderate decrease Severe decrease Moderate decrease

Mild decrease Normal Normal

Mild decrease Mild decrease Mild decrease

– C3 nephritic factor+ Antistreptolysin 0 titer increased

Moderate to severe decrease Normal or mild decrease Normal or mild decrease Normal Normal or increased

Moderate to severe decrease Normal or mild decrease Severe decrease Normal Normal or increased

Mild decrease

anti–double-stranded DNA antibody+

Normal or mild decrease Moderate decrease Normal Normal

anti–double-stranded DNA antibody+ Cryoglobulins; hepatitis C ab – Antineutrophil cytoplasmic antibody+

(World Health Organization Class V) Cryoglobulinemia (hepatitis C) Amyloid Vasculitis C’H50—serum hemolytic complement activity.

FIGURE 2-20 The serum complement component concentration (C3 and C4) and serum hemolytic complement activity (C’H50) in various primary

CLASSIFICATION OF MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS TYPE I Primary (Idiopathic) Secondary Hepatitis C (with or without cryoglobulinemia) Hepatitis B Systemic lupus erythematosus Light or heavy chain nephropathy Sickle cell disease Sjögren’s syndrome Sarcoidosis Shunt nephritis Antitrypsin deficiency Quartan malaria Chronic thrombotic microangiopathy Buckley’s syndrome

and secondary glomerular lesions are depicted. Note the limited number of disorders associated with a low C3 or C4 level. FIGURE 2-21 Note that although there is the wide variety of underlying causes for the lesion of membranoproliferative glomerulonephritis hepatitis C, with or without cryoglobulinemia, accounts for most cases.

2.12

Glomerulonephritis and Vasculitis

Mesangial Proliferative Glomerulonephritis

A

C FIGURE 2-22 (see Color Plate) Light, immunofluorescence, and electron microscopy in mesangial proliferative glomerulonephritis. This heterogeneous group of disorders is characterized by increased mesangial cellularity in most of the glomeruli associated with granular immune deposits in the

B mesangial regions. Little if any increased cellularity is seen, despite the presence of deposits. In this latter instance, the term mesangial injury glomerulonephritis is more properly applied. The disorders are defined on the basis of the immunofluorescence findings, rather than on the presence or absence of mesangial hypercellularity. There are numerous disorders with this appearance; some have specific immunopathologic or clinical features (such as immunoglobulin A nephropathy, Henoch-Schonlein purpura, and systemic lupus erythematosus). Patients with primary mesangial proliferative glomerulonephritis typically exhibit the disorder in one of four ways: asymptomatic proteinuria, massive proteinuria often in the nephrotic range, microscopic hematuria, or proteinuria with hematuria. A, On light microscopy, widening of the mesangial regions is observed, often with diffuse increase in mesangial cellularity commonly of a mild degree. No other alterations are present. B, Depending on the specific entity or lesion, the immunofluorescence is of granular mesangial deposits. In the most common of these disorders, immunoglobulin M is the dominant or sole deposit. Other disorders are characterized primarily or exclusively by complement C3, immunoglobulin G, or C1q deposits. C, On electron microscopy the major finding is of small electron-dense deposits in the mesangial regions (arrow). Foot process effacement is variable, depending on the clinical syndrome (eg, whether massive proteinuria is present).

The Primary Glomerulopathies

2.13

Crescentic Glomerulonephritis

A

B

C

D

FIGURE 2-23 (see Color Plate) Crescentic glomerulonephritis. A crescent is the accumulation of cells and extracellular material in the urinary space of a glomerulus. The cells are parietal and visceral epithelia as well as monocytes and other blood cells. The extracellular material is fibrin, collagen, and basement membrane material. In the early stages of the disease, the crescents consist of cells and fibrin. In the later stages the crescents undergo organization, with disappearance of fibrin and replacement by collagen. Crescents represent morphologic consequences of severe capillary wall damage. A, In most instances, small or large areas of destruction of capillary walls (cells and basement membranes) are observed (arrow), thereby allowing fibrin, other high molecular weight substances, and blood cells to pass readily from capillary lumina into the urinary space. B, Immunofluorescence frequently discloses fibrin in the urinary space. C, The proliferating cells in Bowman’s space ultimately give rise to the typical crescent shape. Whereas crescents may complicate many forms of glomerulonephritis, they are most commonly associated with either antiglomerular basement membrane (AGBM) antibodies or antineu-

trophil cytoplasmic antibodies (ANCAs). The clinical manifestations are typically of rapidly progressive glomerulonephritis with moderate proteinuria, hematuria, oliguria, and uremia. The immunomorphologic features depend on the basic disease process. On light microscopy in both AGBM antibody–induced disease and ANCA–associated crescentic glomerulonephritis, the glomeruli without crescents often have a normal appearance. It is the remaining glomeruli that are involved with crescents. D, Anti-GBM disease is characterized by linear deposits of immunoglobulin G and often complement C3 in all capillary basement membranes, and in approximately two thirds of affected patients in tubular basement membranes. The ANCA-associated lesion typically has little or no immune deposits on immunofluorescence; hence the term pauciimmune crescentic glomerulonephritis is used. By electron microscopy, as on light microscopy, defects in capillary wall continuity are easily identified. Both AGBM- and ANCA-associated crescentic glomerulonephritis can be complicated by pulmonary hemorrhage (see Fig. 2-25).

2.14

Glomerulonephritis and Vasculitis

CLASSIFICATION OF CRESCENTIC GLOMERULONEPHRITIS Type

Serologic Pattern

Primary

Secondary

I II

Anti-GBM+ ANCAAnti-GBM- ANCA-

III IV

Anti-GBM- ANCA+ Anti-GBM+ANCA+

Anti-GBM antibody–mediated crescentic glomerular nephritis Idiopathic crescentic glomerular nephritis (with or without immune complex deposits) Pauci-immune crescentic glomerular nephritis (microscopic polyangiitis) Anti-GBM antibody–mediated crescentic glomerular nephritis with ANCA

Goodpasture’s disease Systemic lupus erythematosus, immunoglobulin A, MPGN cryoimmunoglobulin (with immune complex deposits Drug-induced crescentic glomerulonephritis Goodpasture’s syndrome with ANCA

ANCA—antineutrophil cytoplasmic antibody; anti-GBM—glomerular basement membrane antibody; MPGN— membranoproliferative glomerulonephritis.

FIGURE 2-24 Note that the serologic findings allow for a differentiation of the various forms of primary and secondary (eg, multisystem disease) forms of crescentic glomerulonephritis. FIGURE 2-25 Chest radiograph of alveolar hemorrhage. This patient has antiglomerular basement membrane–mediated glomerulonephritis complicated by pulmonary hemorrhage (Goodpasture’s disease). Note the butterfly appearance of the alveolar infiltrates characteristic of intrapulmonary (alveolar) hemorrhage. Such lesions can also occur in patients with antineutrophil cytoplasmic autoantibody–associated vasculitis and glomerulonephritis, lupus nephritis (SLE), cryoglobulinemia, and rarely in Henoch-Schonlein purpura (HSP).

The Primary Glomerulopathies

FIGURE 2-26 Evaluation of rapidly progressive glomerulonephritis. This algorithm schematically illustrates a diagnostic approach to the various causes of rapidly progressive glomerulonephritis (Figure 2-24), Serologic studies, especially measurement of circulating antiglomerular basement membrane antibodies, antineutrophil cytoplasmic antibodies, antinuclear antibodies, and serum complement component concentrations, are used for diagnosis. Serologic patterns (A through D)permit categorization of probable disease entities.

↑ Serum creatinine Proteinuria "Nephritic" sediment

Renal ultrasonography

Small kidneys

Normal or enlarged kidneys; no obstruction

Obstruction

Serology* Pattern type (A) aGBMA* + ANCA† –

(B)

(C)

(D)

– –

– +

+ +

Goodpasture's disease Type II IC-mediated Type I primary CrGN CGN SLE, HSP, and MPGN CryoIg, type V primary CrGN (idiopathic)

2.15

Microscopic Combined polyangiitis; type III form; type IV primary crescentic primary CrGN CrGN; Wegener's GN; drug-induced CrGN

*Antiglomerular basement membrane autoantibody by radioimmunoassay or enzyme-linked immunosorbent assay †Antineutrophil cytoplasmic autoantibody by indirect immunofluorescence, confirmed by antigen-specific assay (anti-MPO, anti-PR3, or both).

C-ANCA

A

P-ANCA

B

FIGURE 2-27 (see Color Plate) Antineutrophil cytoplasmic autoantibodies (ANCA). Frequently, ANCA are found in crescentic glomerulonephritis, particularly type III (Figure 2-24). Two varieties are seen (on alcohol-fixed slides). A, C-ANCA are due to antibodies reacting with cytoplasmic granule antigens (mainly proteinase-3). B, P-ANCA are due to antibodies reacting with other antigens (mainly myeloperoxidase).

2.16

Glomerulonephritis and Vasculitis

Immunoglobulin A Nephropathy

A

B

C

D

FIGURE 2-28 (see Color Plate) Light, immunofluorescence, and electron microscopy in immunoglobulin A (IgA) nephropathy. IgA nephropathy is a chronic glomerular disease in which IgA is the dominant or sole component of deposits that localize in the mesangial regions of all glomeruli. In severe or acute cases, these deposits also are observed in the capillary walls. This disorder may have a variety of clinical presentations. Typically, the presenting features are recurrent macroscopic hematuria, often coincident with or immediately after an upper respiratory infection, along with persistent microscopic hematuria and low-grade proteinuria between episodes of gross hematuria. Approximately 20% to 25% of patients develop end-stage renal disease over the 20 years after onset. A, On light microscopy, widening and often an increase in cellularity in the mesangial regions are observed, a process that affects the lobules of some glomeruli to a greater degree than others. This feature gives rise

to the term focal proliferative glomerulonephritis. In advanced cases, segmental sclerosis often is present and associated with massive proteinuria. During acute episodes, crescents may be present. B, Large round paramesangial fuchsinophilic deposits often are identified with Masson’s trichrome or other similar stains (arrows). C, Immunofluorescence defines the disease; granular mesangial deposits of IgA are seen with associated complement C3, and IgG or IgM, or both. IgG and IgM often are seen in lesser degrees of intensity than is IgA. D, On electron microscopy the abnormalities typically are those of large rounded electron-dense deposits (arrows) in paramesangial zones of most if not all lobules. Capillary wall deposits (subepithelial, subendothelial, or both) may be present, especially in association with acute episodes. In addition, capillary basement membranes may show segmental thinning and rarefaction.

The Primary Glomerulopathies

2.17

FIGURE 2-29 Natural history of immunoglobulin A (IgA) nephropathy. The evolution of IgA nephropathy over time with respect to the occurrence of end-stage renal failure (ESRF) is illustrated. The percentage of renal survival (freedom from ESRF) is plotted versus the time in years from the apparent onset of the disease. Note that on average about 1.5% of patients enter ESRF each year over the first 20 years of this nephropathy. Factors indicating an unfavorable outcome include elevated serum creatinine, tubulointerstitial lesions or glomerulosclerosis, and moderate proteinuria (>1.0 g/d). (Modified from Cameron [2].)

Fibrillary and Immunotactoid Glomerulonephritis

A

C FIGURE 2-30 (see Color Plate) Light, immunofluorescent, and electron microscopy in nonamyloid fibrillary glomerulonephritis. Fibrillary glomerulonephritis is an

B entity in which abnormal extracellular fibrils, typically ranging from 10- to 20-nm thick, permeate the glomerular mesangial matrix and capillary basement membranes. The fibrils are defined only on electron microscopy and have an appearance, at first glance, similar to amyloid. Congo red stain, however, is negative. Patients with fibrillary glomerulonephritis usually exhibit proteinuria often in the nephrotic range, with variable hematuria, hypertension, and renal insufficiency. A, On light microscopy the glomeruli display widened mesangial regions, with variable increase in cellularity and thickened capillary walls and often with irregularly thickened basement membranes, double contours, or both. B, On immunofluorescence, there is coarse linear or confluent granular staining of capillary walls for immunoglobulin G and complement C3 and similar staining in the mesangial regions. Occasionally, monoclonal immunoglobulin G k deposits are identified; in most instances, however, both light chains are equally represented. The nature of the deposits is unknown. C, On electron microscopy the fibrils are roughly 20-nm thick, of indefinite length, and haphazardly arranged. The fibrils permeate the mesangial matrix and basement membranes (arrow). The fibrils have been infrequently described in organs other than the kidneys.

2.18

A

C

Glomerulonephritis and Vasculitis

B FIGURE 2-31 (see Color Plate) Light, immunofluorescent, and electron microscopy in immunotactoid glomerulopathy. Immunotactoid glomerulopathy appears to be an immune-mediated glomerulonephritis. On electron microscopy the deposits are composed of multiple microtubular structures in subepithelial or subendothelial locations, or both, with lesser involvement of the mesangium. Patients with this disorder typically exhibit massive proteinuria or nephrotic syndrome. This glomerulopathy frequently is associated with lymphoplasmacytic disorders. A, On light microscopy the glomerular capillary walls often are thickened and the mesangial regions widened, with increased cellularity. B, On immunofluorescence, granular capillary wall and mesangial immunoglobulin G and complement C3 deposits are present. The ultrastructural findings are of aggregates of microtubular structures in capillary wall locations corresponding to granular deposits by immunofluorescence. C, The microtubular structures are large, ranging from 30- to 50-nm thick, or more (arrows).

The Primary Glomerulopathies

2.19

Collagenofibrotic Glomerulopathy

A

B

FIGURE 2-32 (see Color Plate) Collagenofibrotic glomerulopathy (collagen III glomerulopathy). The collagens normally found in glomerular basement membranes and the mesangial matrix are of types IV (which is dominant) and V. In collagenofibrotic glomerulopathy, accumulation of type III collagen occurs largely in capillary walls in a subendothelial location. It is likely that this disease is hereditary; however, because it is very rare, precise information regarding transmission is not known. Collagenofibrotic glomerulopathy originally was thought to be a variant of nail-patella syndrome. Current evidence suggests little relationship exists between the two disorders. Patients with collagen III glomerulopathy often

exhibit proteinuria and mild progressive renal insufficiency. For reasons that are not clear, hemolytic-uremic syndrome has evolved in a small number of pediatric patients. A, On light microscopy the capillary walls are thickened and mesangial regions widened by pale staining material. These features are in sharp contrast to the normal staining of the capillary basement membranes, as evidenced by the positive period acid–Schiff reaction. With this stain, collagen type III is not stained and therefore is much paler. Amyloid stains (Congo red) are negative. B, On electron microscopy, banded collagen fibrils are evident in the subendothelial aspect of the capillary wall.

References 1.

2.

3.

Cameron JS, Glassock RJ: The natural history and outcome of the nephrotic syndrome. In The Nephrotic Syndrome. Edited by Cameron JS and Glassock RJ. New York: Marcel Dekker, 1987. Cameron JS: The long-term outcome of glomerular diseases. In Diseases of the Kidney Vol II, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little Brown; 1996.

4.

Arbeitsgemeinschaft für pediatrische nephrologie. Cyclophosphamide treatment of steroid-dependent nephrotic syndrome: comparison of an eight-week with a 12-week course. Arch Dis Child 1987, 62:1102–1106.

6.

5.

Ponticelli C: Cyclosporine versus cyclophosphamide for patients with steroid-dependent and frequently relapsing idiopathic nephrotic syndrome. A multi-center randomized trial. Nephrol Dial Transplant 1993, 8:1326–1332. Ponticelli C, Glassock RJ: Treatment of Segmental Glomerulonephritis. Oxford: Oxford Medical Publishers, 1996:110. Churg J, Bernstein J, Glassock RJ: Renal Disease. Classification and Atlas of Glomerular Disease, edn 2. New York: Igaku-Shoin; 1995.

Heredofamilial and Congenital Glomerular Disorders Arthur H. Cohen Richard J. Glassock

T

he principal characteristics of some of the more common heredofamilial and congenital glomerular disorders are described and illustrated. Diabetes mellitus, the most common heredofamilial glomerular disease, is illustrated in Volume IV, Chapter 1. These disorders are inherited in a variety of patterns (X-linked, autosomal dominant, or autosomal recessive). Many of these disorders appear to be caused by defective synthesis or assembly of critical glycoprotein (collagen) components of the glomerular basement membrane.

CHAPTER

3

3.2

Glomerulonephritis and Vasculitis

FIGURE 3-1 Alport’s syndrome. Alport’s syndrome (hereditary nephritis) is a hereditary disorder in which glomerular and other basement membrane collagen is abnormal. This disorder is characterized clinically by hematuria with progressive renal insufficiency and proteinuria. Many patients have neurosensory hearing loss and abnormalities of

NC1 7S

A

100nm

the eyes. The disease is inherited as an X-linked trait; in some families, however, autosomal recessive and perhaps autosomal dominant forms exist. Clinically, the disease is more severe in males than in females. End-stage renal disease develops in persons 20 to 40 years of age. In some families, ocular manifestations, thrombocytopenia with giant platelets, esophageal leiomyomata, or all of these also occur. In the X-linked form of Alport’s syndrome, mutations occur in genes encoding the -5 chain of type IV collagen (COL4A5). In the autosomal recessive form of this syndrome, mutations of either -3 or -4 chain genes have been described. On light microscopy, in the early stages of the disease the glomeruli appear normal. With progression of the disease, however, an increase in the mesangial matrix and segmental sclerosis develop. Interstitial foam cells are common but are not used to make a diagnosis. Results of immunofluorescence typically are negative, except in glomeruli with segmental sclerosis in which segmental immunoglobulin M and complement (C3) are in the sclerotic lesions. Ultrastructural findings are diagnostic and consist of profound abnormalities of glomerular basement membranes. These abnormalities range from extremely thin and attenuated to considerably thickened membranes. The thickened glomerular basement membranes have multiple layers of alternating medium and pale staining strata of basement membrane material, often with incorporated dense granules. The subepithelial contour of the basement membrane typically is scalloped. FIGURE 3-2 Schematic of basement membrane collagen type IV. The postulated arrangement of type IV collagen chains in a normal glomerular basement membrane is illustrated. The joining of noncollagen (NC-1) and 75 domains creates a lattice (chicken wire) arrangement (A). In the glomerular basement membrane, 1 and 2 chains predominate in the triple helix (B), but 3, 4, 5, and 6 chains are also found (not shown). Disruption of synthesis of any of these chains may lead to anatomic and pathologic alternations, such as those seen in Alport’s syndrome. Arrows indicate fibrils. (From Abrahamson and coworkers [1]; with permission.)

-S--Sα1 -S--S- α1 α2 -S--S- α2 -S--Sα1 -S--S- α1 -S--S-

Hearing loss, dB

B

FIGURE 3-3 Neurosensory hearing defect in Alport’s syndrome. In patients with adult onset Alport’s syndrome, classic X-linked sensorineural hearing defects occur. These defects often begin with an auditory loss of high-frequency tone, as shown in this audiogram. The shaded area represents normal ranges. (Modified from Gregory and Atkin [2]; with permission.)

20 40 60 80 100 500 2K 4K 8K 10K 12K 14K 16K 18K Frequency

Heredofamilial and Congenital Glomerular Disorders

3.3

FIGURE 3-4 Thin basement membrane nephropathy. Glomeruli with abnormally thin basement membranes may be a manifestation of benign familial hematuria. Glomeruli with thin basement membranes many also occur in persons who do not have a family history of renal disease but who have hematuria, low-grade proteinuria, or both. Although the ultrastructural abnormalities have some similarities in common with the capillary basement membranes of Alport’s syndrome, these two glomerulopathies are not directly related. Clinically, persistent microscopic hematuria or occasional episodic gross hematuria are important features. Nonrenal abnormalities are absent. On light microscopy, the glomeruli are normal; no deposits are seen on immunofluorescence. Here, the electron microscopic abnormalities are diagnostic; all or virtually all glomerular basement membranes are markedly thin (<200 nm in adults) without other features such as splitting, layering, or abnormal subepithelial contours.

A

C FIGURE 3-5 (see Color Plate) Fabry’s disease. Fabry’s disease, also known as angiokeratoma corporis diffusum or Anderson-Fabry’s disease, is the result of deficiency

B of the enzyme -galactosidase with accumulation of sphingolipids in many cells. In the kidney, accumulation of sphingolipids especially affects glomerular visceral epithelial cells. Deposition of sphingolipids in the vascular tree may lead to premature coronary artery occlusion (angina or myocardial infarction) or cerebrovascular insufficiency (stroke). Involvement of nerves leads to painful acroparesthesias and decreased perspiration (anhidrosis). The most common renal manifestation is that of proteinuria with progressive renal insufficiency. On light microscopy, the morphologic abnormalities of the glomeruli primarily consist of enlargement of visceral epithelial cells and accumulation of multiple uniform small vacuoles in the cytoplasm (arrow in Panel A). Ultrastructurally, the inclusions are those of whorled concentric layers appearing as “zebra bodies” or myeloid bodies representing sphingolipids (B). These structures also may be observed in mesangial and endothelial cells and in arterial and arteriolar smooth muscle cells and tubular epithelia. At considerably higher magnification, the inclusions are observed to consist of multiple concentric alternating clear and dark layers, with a periodicity ranging from 3.9 to 9.8 nm. This fine structural appearance (best appreciated at the arrow) is characteristic of stored glycolipids (C).

3.4

Glomerulonephritis and Vasculitis FIGURE 3-6 Electron microscopy of nail-patella syndrome. This disorder having skeletal and renal manifestations affects the glomeruli, with accumulation of banded collagen fibrils within the substance of the capillary basement membrane. This accumulation appears as empty lacunae when the usual stains with electron microscopy (lead citrate and uranyl acetate) are used. However, as here, the fibrils easily can be identified with the use of phosphotungstic acid stain in conjunction with or instead of typical stains. Note that this disorder differs structurally from collagen type III glomerulopathy in which the collagen fibrils are subendothelial and not intramembranous in location. Patients with nail-patella syndrome may develop proteinuria, sometimes in the nephrotic range, with variable progression to end-stage renal failure. No distinguishing abnormalities are seen on light microscopy.

FIGURE 3-7 Radiography of nail-patella syndrome. The skeletal manifestations of nail-patella syndrome are characteristic and consist of absent patella and absent and dystrophic nails. These photographs illustrate absent patella (A) and the characteristic nail changes (B) that occur in patients with the disorder. (From Gregory and Atkin [2]; with permission.)

B

A

Heredofamilial and Congenital Glomerular Disorders

A FIGURE 3-8 (see Color Plate) Lecithin-cholesterol acyl transferase deficiency. Lipid accumulation occurs in this hereditary metabolic disorder, especially in extracellular sites throughout glomerular basement membranes and the mesangial matrix. A, On electron microscopy the lipid appears as multiple small lacunae, often with small round dense granular or membranous structures (arrows). Lipid-containing monocytes may be in the capillary lumina. B, The mesangial regions are widened on light microscopy, usually with expansion of the matrix that stains less intensely than normal. Basement

A FIGURE 3-9 (see Color Plate) Lipoprotein glomerulopathy. Patients with this rare disease, which often is sporadic (although some cases occur in the same family), exhibit massive proteinuria. Lipid profiles are characterized by increased plasma levels of cholesterol, triglycerides, and very low density lipoproteins. Most patients have heterozygosity for apolipoprotein E2/3 or E2/4. A, The glomeruli are the sites of massive intracapillary accumulation of lipoproteins, which appear as slightly tan masses (thrombi) dilating capillaries (arrows). Segmental

3.5

B membranes are irregularly thickened. Some capillary lumina may contain foam cells. Although quite rare, this autosomal recessive disease has been described in most parts of the world; however, it occurs most commonly in Norway. Patients exhibit proteinuria, often with microscopic hematuria usually noted in childhood. Renal insufficiency may develop in the fourth or fifth decade of life and may progress rapidly. Nonrenal manifestations include corneal opacification, hemolytic anemia, early atherosclerosis, and sea-blue histocytes in the bone marrow and spleen.

B mesangial hypercellularity or mesangiolysis may be present. With immunostaining for -lipoprotein, apolipoproteins E and B are identified in the luminal masses. B, Electron microscopic findings indicate the thrombi consist of finely granular material with numerous vacuoles (lipoprotein). Lipoprotein glomerulopathy may progress to renal insufficiency over a long period of time. Recurrence of the lesions in a transplanted organ has been reported infrequently. Lipid-lowering agents are mostly ineffective.

3.6

Glomerulonephritis and Vasculitis

A FIGURE 3-10 (see Color Plate) Nephropathic cystinosis. In older children and young adults, compared with young children, patients with cystinosis commonly exhibit glomerular involvement rather than tubulointerstitial disease. Proteinuria and renal insufficiency are the typical initial manifestations. A, As the most constant abnormality on light microscopy, glomeruli

A FIGURE 3-11 (see Color Plate) Finnish type of congenital nephrotic syndrome. Several disorders are responsible for nephrotic syndrome within the first few months to first year of life. The most common and important of these is known as congenital nephrotic syndrome of Finnish type because the initial descriptions emphasized the more common occurrence in Finnish families. This nephrotic syndrome is an inherited disorder in which infants exhibit massive proteinuria shortly after birth; typically, the placenta is enlarged. This disorder can be diagnosed in utero; increased -fetoprotein levels in amniotic fluid is a common feature. A, The microscopic appearance of

B have occasionally enlarged and multinucleated visceral epithelial cells (arrow). As the disease progresses, segmental sclerosis becomes evident as in the photomicrograph. B, Crystalline inclusions are identified on electron microscopy. The crystals of cysteine are usually dissolved in processing, leaving an empty space as shown here by the arrows.

B the kidneys is varied. Some glomeruli are small and infantile without other alterations, whereas others are enlarged, more mature, and have diffuse mesangial hypercellularity. Because of the massive proteinuria, some tubules are microcystically dilated, a finding responsible for the older term for this disorder, microcystic disease. Because this syndrome is primarily a glomerulopathy, the tubular abnormalities are a secondary process and should not be used to designate the name of the disease. B, On electron microscopy, complete effacement of the foot processes of visceral epithelial cells is observed.

Heredofamilial and Congenital Glomerular Disorders

FIGURE 3-12 Diffuse mesangial sclerosis. This disorder is exhibited within the first few months of life with massive proteinuria, often with

3.7

hematuria and progressive renal insufficiency. Currently, no evidence exists that this disorder is an inherited process with genetic linkage. The glomeruli characteristically are small compact masses of extracellular matrix with numerous or all capillary lumina being obliterated. As here, the visceral epithelial cells typically are arranged as a corona or crown overlying the contracted capillary tufts. Earlier stages of glomerular involvement are characterized by variable increase in mesangial cellularity. Immunofluorescence is typically negative for immunoglobulin deposits because this disorder is not immune mediated. In some patients, diffuse mesangial sclerosis may be part of the triad of the Drash syndrome characterized by ambiguous genitalia, Wilms’ tumor, and diffuse mesangial sclerosis. In some patients, only two of the three components may be present; however, some investigators consider all patients with diffuse mesangial sclerosis to be at risk for the development of Wilms’ tumor even in the absence of genital abnormalities. Thus, close observation or bilateral nephrectomy as prophylaxis against the development of Wilms’ tumor is employed occasionally.

References 1.

Abrahamson D, Van der Heurel GB, Clapp WL, et al.: Nephritogenic antigens in the glomerular basement membrane. In Immunologic Renal Diseases. Edited by Nielson EG, Couser, WG. Philadelphia: Lippincott-Raven, 1997.

2.

Gregory M, Atkin C: Alport’s syndrome, Fabry disease and nail-patella syndrome. In Diseases of the Kidney, Vol. I. edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little Brown, 1995.

Infection-Associated Glomerulopathies Arthur H. Cohen Richard J. Glassock

M

any glomerular diseases may be associated with acute and chronic infectious diseases of bacterial, viral, fungal, or parasitic origin. In many instances, the glomerular activators are transient and of little clinical consequence. In other instances, distinct clinical syndromes such as acute nephritis or nephrotic syndrome may be provoked. Some of the more important infection-related glomerular diseases are illustrated here. Others diseases, including human immunodeficiency virus and hepatitis, are also discussed in Volume IV.

CHAPTER

4

4.2

Glomerulonephritis and Vasculitis

A

C FIGURE 4-1 (see Color Plate) Light, immunofluorescent, and electron microscopy of poststreptococcal (postinfectious) glomerulonephritis. Glomerulonephritis may follow in the wake of cutaneous or pharyngeal infection with a limited number of “nephritogenic” serotypes of group A -hemolytic

B streptococcus. Typically, patients with glomerulonephritis exhibit hematuria, edema, proteinuria, and hypertension. Renal function frequently is depressed, sometimes severely. Most patients recover spontaneously, and a few go on to rapidly progressive or chronic indolent disease. A, On light microscopy the glomeruli are enlarged and hypercellular, with numerous leukocytes in the capillary lumina and a variable increase in mesangial cellularity. The leukocytes are neutrophils and monocytes. The capillary walls are single-contoured, and crescents may be present. B, On immunofluorescence, granular capillary wall and mesangial deposits of immunoglobulin G and complement C3 are observed (starry-sky pattern). Three predominant patterns occur depending on the location of the deposits; these include garlandlike, mesangial, and starry-sky patterns. C, The ultrastructural findings are those of electron-dense deposits, characteristically but not solely in the subepithelial aspects of the capillary walls, in the form of large gumdrop or hump-shaped deposits (arrow). However, electron-dense deposits also are found in the mesangial regions and occasionally subendothelial locations. Endothelial cells often are swollen, and leukocytes are not only found in the capillary lumina but occasionally in direct contact with basement membranes in capillary walls with deposits. Similar findings may be observed in glomerulonephritis after infectious diseases other than certain strains of Streptococci.

Infection-Associated Glomerulopathies

4.3

FIGURE 4-2 Infective endocarditis and shunt nephritis. The glomerulonephritis accompanying infective endocarditis or infected ventriculoatrial shunts or other indwelling devices is that of a postinfectious glomerulonephritis or membranoproliferative glomerulonephritis type I pattern, or both (see Fig. 2-18). In reality, the changes often are a combination of both. As shown here, this glomerulopathy is characterized by increased mesangial cellularity, with slight lobular architecture; occasionally thickened capillary walls, with double contours (arrow); and leukocytes in some capillary lumina. This glomerulus also has a small crescent.

A

C FIGURE 4-3 (see Color Plate) Human immunodeficiency virus (HIV) infection. Many forms of renal disease have been described in patients infected with HIV. Various immune complex–mediated glomerulonephritides associated with complicating infections are known; however, several disorders appear to be directly or indirectly related to HIV itself. Perhaps the more common of these is known as HIV-associated nephropathy (HIVAN). This disease is a form of the collapsing

B (focal segmental) glomerulosclerosis with significant tubular and interstitial abnormalities. A, In HIVAN, many visceral epithelial cells are enlarged, coarsely vacuolated, contain protein reabsorption droplets, and overlay capillaries with varying degrees of wrinkling and collapse of the walls (arrows). B, In HIVAN, the tubules are dilated and filled with a precipitate of plasma protein, and the tubular epithelial cells display various degenerative features (arrow). Ultrastructural findings are a combination of those expected for the glomerulopathy as well as those common to HIV infection. Thus, the foot processes of visceral epithelial cells are effaced and often detached from the capillary basement membranes. C, Common in HIV infection are tubuloreticular structures, modifications of the cytoplasm of endothelial cells in which clusters of microtubular arrays are in many cells (arrow). Some evidence suggests that HIV or viral proteins localize in renal epithelial cells and perhaps are directly or indirectly responsible for the cellular and functional damage. HIVAN often has a rapidly progressive downhill course, culminating in end-stage renal disease in as few as 4 months. HIVAN has a striking racial predilection; over 90% of patients are black. The other glomerulopathy that may be an integral feature of HIV infection is immunoglobulin A nephropathy. In this setting, HIV antigen may be part of the glomerular immune complexes and circulating immune complexes. The morphology and clinical course generally are the same as in immunoglobulin A nephropathy occurring in the non-HIV setting.

4.4

Glomerulonephritis and Vasculitis

A

B

HT

C FIGURE 4-4 (see Color Plate) Hepatitis C virus infection. The most common glomerulonephritis in patients infected with the hepatitis C virus is membranoproliferative glomerulonephritis with, in some instances, cryoglobulinemia and cryoglobulin precipitates in glomerular capillaries. Thus, the morphology is basically the same as in membranoproliferative glomerulonephritis type I (Fig. 2-18A–C). A, With cryoglobulins, precipitates of protein representing cryoglobulin in the capillary lumina and appearing as hyaline thrombi (HT)are observed (arrows), often with numerous monocytes in most capillaries. B, Immunofluorescence microscopy discloses

D peripheral granular to confluent granular capillary wall deposits of immunoglobulin M (IgM) and complement C3; the same immune proteins are in the luminal masses corresponding to hyaline thrombi (arrow). C, Electron microscopy indicates the luminal masses (HT). D, On electron microscopy the deposits also appear to be composed of curvilinear or annular structures (arrows). Hepatitis C viral antigen has been documented in the circulating cryoglobulins. Membranous glomerulonephritis with a mesangial component also has been infrequently described in patients infected with the hepatitis C virus.

Infection-Associated Glomerulopathies

A

C FIGURE 4-5 (see Color Plate) Hepatitis B virus infection. Several glomerulopathies have been described in association with hepatitis B viral infection. Until

4.5

B the isolation of the hepatitis C virus and its separation from the hepatitis B virus, membranoproliferative glomerulonephritis was considered a common immune complex–mediated manifestation of hepatitis B virus infection. However, more recent data indicate that this form of glomerulonephritis is a feature of hepatitis C virus infection rather than hepatitis B virus infection. In contrast, membranous glomerulonephritis, often with mesangial deposits and variable mesangial hypercellularity, is the glomerulopathy that is a common accompaniment of hepatitis B virus infection. Hepatitis B virus surface, core, or e antigens have been identified in the glomerular deposits. The morphology of the glomerular capillary walls is similar to the idiopathic form of membranous glomerulonephritis. A, Some degree of mesangial widening with increased cellularity occurs in most affected patients. B, Similarly, on immunofluorescence, uniform granular capillary wall deposits of immunoglobulin G (IgG), complement C3, and both light chains are disclosed (IgG). It sometimes is very difficult to identify mesangial deposits in this setting. C, In addition to the expected capillary wall changes, electron microscopy discloses deposits in mesangial regions of many lobules (the arrow indicates mesangial deposits; the arrowheads indicate subepithelial deposits).

Vascular Disorders Arthur H. Cohen Richard J. Glassock

V

ascular disorders of the kidney comprise a very heterogeneous array of lesions and abnormalities, depending on the site of the lesion and underlying pathogenesis. Here, three common disorders are the focus: thrombotic microangiopathies, benign and malignant nephrosclerosis, and vascular occlusive disease (atheroembolism). Vasculitis and renovascular hypertension are discussed in other chapters.

CHAPTER

5

5.2

Glomerulonephritis and Vasculitis

A

B

E

C

E FIGURE 5-1 Light microscopy of thrombotic microangiopathies. This group of disorders includes hemolytic-uremic syndrome and thrombotic

D thrombocytopenic purpura, malignant hypertension, and renal disease in progressive systemic sclerosis (scleroderma renal crises). A, These lesions are characterized primarily by fibrin deposition in the walls of the glomeruli (fibrin). B, This fibrin deposition is associated with endothelial cell swelling (arrow) and thickened capillary walls, sometimes with a double contour. Variable capillary wall wrinkling and luminal narrowing occur. Mesangiolysis (dissolution of the mesangial matrix and cells) is not uncommon and may be associated with microaneurysm formation. With further endothelial cell damage, capillary thrombi ensue. C, Arteriolar thrombi also may be present. In arterioles, fibrin deposits in the walls and lumina are known as thrombonecrotic lesions, with extension of this process into the glomeruli on occasion (arrow). The arterial walls are thickened, with loose concentric intimal proliferation. D, On electron microscopy, the subendothelial zones of the glomerular capillary wall are widened (arrows). Flocculent material accumulates, corresponding to mural fibrin, with associated endothelial cell swelling. E, With widespread arterial thrombosis, cortical necrosis is a common complicating feature. The necrotic cortex consists of pale confluent multifocal zones throughout the cortex.

Vascular Disorders

FIGURE 5-2 (see Color Plate) Microangiopathic hemolytic anemia. Bizarrely shaped and fragmented erythrocytes are commonly seen in Wright’s stained peripheral blood smears from patients with active lesions of thrombotic microangiopathy. These abnormally shaped erythrocytes presumably arise when the fibrin strands within small blood vessels shear the cell membrane, with imperfect resolution of the biconcave disk shape. The resultant intravascular hemolysis causes anemia, reticulocytosis, and reduced plasma haptoglobin level.

A FIGURE 5-4 Benign and malignant nephrosclerosis. In benign nephrosclerosis the artery walls are thickened with intimal fibrosis and luminal narrowing. Arteriolar walls are thickened with insudative lesions, a process affecting afferent arterioles almost exclusively. Both of these processes, which can be quite patchy, result in chronic ischemia. A, In glomeruli, chronic ischemia is manifested by gradual capillary wall wrinkling, luminal narrowing, and shrinkage and solidification of the tufts. B, As these processes progress, collagen forms internal to Bowman’s capsule, beginning at the vascu-

5.3

FIGURE 5-3 (see Color Plate) Disseminated intravascular coagulation. In disseminated intravascular coagulation, fibrin thrombi are typically found in many glomerular capillary lumina. In contrast to the thrombotic microangiopathies, in disseminated intravascular coagulation, fibrin is not primarily in vessel walls but in the lumina. Consequently, the capillary wall thickening, endothelial cell swelling, and fibrin accumulation in subendothelial locations are not features of this lesion. In the glomerulus illustrated, the fibrin is in many capillary lumina and appears as bright fuchsin positive (red) masses.

B lar pole and growing as a collar around the wrinkled ischemic tufts. This collagen formation ultimately is associated with tubular atrophy and interstitial fibrosis. In malignant nephrosclerosis the changes are virtually identical to those of thrombotic microangiopathies (Fig. 5-1 C). Malignant nephrosclerosis may be seen in essential hypertension, scleroderma, unilateral renovascular hypertension (with a contralateral or “unprotected” kidney), and as a complicating event in many chronic renal parenchymal diseases.

5.4

Glomerulonephritis and Vasculitis

A

C FIGURE 5-5 Vascular occlusive disease and thrombosis. Atheroemboli (cholesterol emboli) are most commonly associated with intravascular

B instrumentation of patients with severe arteriosclerosis. Most commonly, aortic plaques are complicated with ulceration and often adherent fibrin, A. Portions of plaques are dislodged and travel distally in the aorta. Because the kidneys receive a disproportionately large share of the cardiac output, they are a favored site of emboli. Typically, the emboli are in small arteries and arterioles, although glomerular involvement with a few cholesterol crystals in capillaries is not uncommon. Because of the size of the crystals, it is sometimes difficult if not impossible to identify them in glomerular capillaries in paraffin-embedded sections. In plastic-embedded sections prepared for electron microscopy, however, the crystals are quite easy to detect. On light microscopy, cholesterol is represented by empty crystalline spaces. In the early stages of the disease the crystals lie free in the vascular lumina. In time, the crystals are engulfed by multinucleated foreign body giant cells. B, In this light microscopic photograph, a few crystals are evident in the glomerular capillary lumina and in an arteriole (arrows). C, In the electron micrograph the elongated empty space represents dissolved cholesterol. Note that no cellular reaction is evident.

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis Garabed Eknoyan Luan D. Truong

A

s a rule, diseases of the kidney primarily affect the glomeruli, vasculature, or remainder of the renal parenchyma that consists of the tubules and interstitium. Although the interstitium and the tubules represent separate functional and structural compartments, they are intimately related. Injury initially involving either one of them inevitably results in damage to the other. Hence the term tubulointerstitial diseases is used. Because inflammatory cellular infiltrates of variable severity are a constant feature of this entity, the terms tubulointerstitial diseases and tubulointerstitial nephritis have come to be used interchangeably. The clinicopathologic syndrome that results from these lesions, commonly termed tubulointerstitial nephropathy, may pursue an acute or chronic course. The chronic course is discussed here. The abbreviation TIN is used to refer synonymously to chronic tubulointerstitial nephritis and tubulointerstitial nephropathy. TIN may be classified as primary or secondary in origin. Primary TIN is defined as primary tubulointerstitial injury without significant involvement of the glomeruli or vasculature, at least in the early stages of the disease. Secondary TIN is defined as secondary tubulointerstitial injury, which is consequent to lesions initially involving either the glomeruli or renal vasculature. The presence of secondary TIN is especially important because the magnitude of impairment in renal function and the rate of its progression to renal failure correlate better with the extent of TIN than with that of glomerular or vascular damage. Renal insufficiency is a common feature of chronic TIN, and its diagnosis must be considered in any patient who exhibits renal insufficiency. In most cases, however, chronic TIN is insidious in onset, renal insufficiency is slow to develop, and earliest manifestations of the disease are those of tubular dysfunction. As such, it is important to maintain a high

CHAPTER

6

6.2

Tubulointerstitial Disease

index of suspicion of this entity whenever any evidence of tubular dysfunction is detected clinically. At this early stage, removal of a toxic cause of injury or correction of the underlying systemic or renal disease can result in preservation of residual renal function. Of special relevance in patients who exhibit renal insufficiency caused by primary TIN is the absence or modest degree of

the two principal hallmarks of glomerular and vascular diseases of the kidney: salt retention, manifested by edema and hypertension; and proteinuria, which usually is modest and less than 1 to 2 g/d in TIN. These clinical considerations notwithstanding, a definite diagnosis of TIN can be established only by morphologic examination of kidney tissue.

Structure of the Interstitium FIGURE 6-1 Diagram of the approximate relative volume composition of tissue compartments at different segments of the kidney in rats. The interstitium of the kidney consists of peritubular and periarterial spaces. The relative contribution of each of these two spaces to interstitial volume varies, reflecting in part the arbitrary boundaries used in assessing them, but increases in size from the cortex to the papilla. In the cortex there is little interstitium because the peritubular capillaries occupy most of the space between the tubules. The cortical interstitial cells are scattered and relatively inconspicuous. In fact, a loss of the normally very close approximation of the cortical tubules is the first evidence of TIN. In the medulla there is a noticeable increase in interstitial space. The interstitial cells, which are in greater evidence, have characteristic structural features and an organized arrangement. The ground substance of the renal interstitium contains different types of fibrils and basementlike material embedded in a glycosaminoglycan-rich substance. (From Bohman [1]; with permission.)

C—Cortex IS—Inner stripe of outer medulla OS—Outer stripe of outer medulla IZ—Inner zone of medulla C OS IS IZ

10

50

100%

Extracellular space

Interstitial cells

Vessels

Tubules

Cortex

A

B

FIGURE 6-2 A, Electron micrograph of a rat kidney cortex, where C is the cortex. B, Schematic rendering, where the narrow interstitium is shown in black and the wide interstitium is shown by dots. The relative volume of the interstitium of the cortex is approximately 7%, consisting of about 3% interstitial cells and 4% extracellular space. The vasculature occupies another 6%; the remainder (ie, some 85% or more) is occupied by the tubules. The cortical interstitial space is unevenly distributed and has been divided into narrow and wide structural components. The tubules and peritubular capillaries either are closely apposed at several points, sometimes to the point of sharing a common basement membrane, or are separated by a very narrow space. This space, the so-called narrow interstitium, has been estimated to occupy 0.6% of cortical volume in rats. The narrow interstitium occupies about one-half to two-thirds of the cortical peritubular capillary surface area. The remainder of the cortical interstitium consists of irregularly shaped clearly discernible larger areas, the so-called wide interstitium. The wide interstitium has been estimated to occupy 3.4% of cortical volume in rats. The capillary wall facing the narrow interstitium is significantly more fenestrated than is that facing the wide interstitium. Functional heterogeneity of these interstitial spaces has been proposed but remains to be clearly defined. (From Bohman [1]; with permission.)

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis

6.3

Medulla FIGURE 6-3 Scanning electron micrograph of the inner medulla, showing a prominent collecting duct, thin wall vessels, and abundant interstitium. A gradual increase in interstitial volume from the outer medullary stripe to the tip of the papilla occurs. In the outer stripe of the outer medulla, the relative volume of the interstitium is slightly less than is that of the cortex. This volume has been estimated to be approximately 5% in rats. It is in the inner stripe of the outer medulla that the interstitium begins to increase significantly in volume, in increments that gradually become larger toward the papillary tip. The inner stripe of the outer medulla consists of the vascular bundles and the interbundle regions, which are occupied principally by tubules. Within the vascular bundles the interstitial spaces are meager, whereas in the interbundle region the interstitial spaces occupy some 10% to 20% of the volume. In the inner medulla the differentiation into vascular bundles and interbundle regions becomes gradually less obvious until the two regions merge. A gradual increase in the relative volume of the interstitial space from the base of the inner medulla to the tip of the papilla also occurs. In rats, the increment in interstitial space is from 10% to 15% at the base to about 30% at the tip. In rabbits, the increment is from 20% to 25% at the base to more than 40% at the tip.

Cell types B. RENAL INTERSTITIAL CELLS

A FIGURE 6-4 A, High-power view of the medulla showing the wide interstitium and interstitial cells, which are abundant, varied in shape, and arranged as are the rungs of a ladder. B, Renal interstitial cells. The interstitium contains two main cell types, whose numbers increase from the cortex to the papilla. Type I interstitial cells are fibroblastic cells that are active in the deposition and degradation of the interstitial matrix. Type I cells contribute to fibrosis in response to chronic irritation. Type II cells are macrophage-derived mononuclear cells with phagocytic and immunologic properties. Type II

Cortex

Outer medulla

Inner medulla

Fibroblastic cells Mononuclear cells

Fibroblastic cells Mononuclear cells

Pericytes Lipid-laden cells Mononuclear cells

cells are important in antigen presentation. Their cytokines contribute to recruitment of infiltrating cells, progression of injury, and sustenance of fibrogenesis. In the cortex and outer zone of the outer medulla, type I cells are more common than are type II cells. In the inner zone of the medulla, some type I cells form pericytes whereas others evolve into specialized lipid-laden interstitial cells. These specialized cells increase in number toward the papillary tip and are a possible source of medullary prostaglandins and of production of matriceal glycosaminoglycans. A characteristic feature of these medullary cells is their connection to each other in a characteristic arrangement, similar to the rungs of a ladder. These cells have a distinct close and regular transverse apposition to their surrounding structures, specifically the limbs of the loop of Henle and capillaries, but not to the collecting duct cells.

6.4

Tubulointerstitial Disease

Matrix FIGURE 6-5 Peritubular interstitium in the cortex at the interface of a tubule (T) on the left and a capillary (C) on the right. The inset shows the same space in cross section, including the basement membrane (BM) of the two compartments. The extracellular loose matrix is a hydrated gelatinous substance consisting of glycoproteins and glycosaminoglycans (hyaluronic acid, heparan sulfate, dermatan sulfate, and chondroitin sulfate) that are embedded within a fibrillar reticulum. This reticulum consists of collagen fibers (types I, III, and VI) and unbanded microfilaments. Collagen types IV and V are the principal components of the basement membrane lining the tubules. Glycoprotein components (fibronectin and laminin) of the basement membrane connect it to the interstitial cell membranes and to the fibrillar structures of the interstitial matrix. The relative increase in the interstitial matrix of the medulla may be important for providing support to the delicate tubular and vascular structures in this region. (From Lemley and Kriz [2]; with permission.)

Pathologic Features of Chronic TIN FIGURE 6-6 Primary chronic TIN. The arrow indicates a normal glomerulus. Apart from providing structural support, the interstitium serves as a conduit for solute transport and is the site of production of several cytokines and hormones (erythropoietin and prostaglandins). For the exchange processes to occur between the tubules and vascular compartment, the absorbed or secreted substances must traverse the interstitial space. The structure, composition, and permeability characteristics of the interstitial space must, of necessity, exert an effect on any such exchange. Although the normal structural and functional correlates of the interstitial space are poorly defined, changes in its composition and structure in chronic TIN are closely linked to changes in tubular function. In addition, replacement of the normal delicate interstitial structures by fibrosclerotic changes of chronic TIN would affect the vascular perfusion of the adjacent tubule, thereby contributing to tubular dysfunction and progressive ischemic injury.

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis

FIGURE 6-7 Secondary chronic TIN. The arrow indicates a glomerulus with a cellular crescent. The diagnosis of TIN can be established only by morphologic examination of kidney tissue. The extent of the lesions of TIN, whether focal or diffuse, correlates with the degree of impairment in renal function.

6.5

Tubular atrophy and dilation comprise a principal feature of TIN. The changes are patchy in distribution, with areas of atrophic chronically damaged tubules adjacent to dilated tubules displaying compensatory hypertrophy. In atrophic tubules the epithelial cells show simplification, decreased cell height, loss of brush border, and varying degrees of thickened basement membrane. In dilated tubules the epithelial cells are hypertrophic and the lumen may contain hyalinized casts, giving them the appearance of thyroid follicles. Hence the term thyroidization is used. The interstitium is expanded by fibrous tissue, in which are interspersed proliferating fibroblasts and inflammatory cells comprised mostly of activated T lymphocytes and macrophages. Rarely, B lymphocytes, plasma cells, neutrophils, and even eosinophils may be present. The glomeruli, which may appear crowded in some areas owing to tubulointerstitial loss, usually are normal in the early stages of the disease. Ultimately, the glomeruli become sclerosed and develop periglomerular fibrosis. The large blood vessels are unremarkable in the early phases of the disease. Ultimately, these vessels develop intimal fibrosis, medial hypertrophy, and arteriolosclerosis. These vascular changes, which also are associated with hypertension, can be present even in the absence of elevated blood pressure in cases of chronic TIN.

CONDITIONS ASSOCIATED WITH PRIMARY CHRONIC TIN

Immunologic diseases

Urinary tract obstructions

Hematologic diseases

Miscellaneous

Hereditary diseases

Endemic diseases

Systemic lupus erythematosus Sjögren syndrome Transplanted kidney Cryoglobulinemia Goodpasture’s syndrome Immunoglobulin A nephropathy Amyloidosis Pyelonephritis

Vesicoureteral reflux Mechanical

Sickle hemoglobinopathies Multiple myeloma Lymphoproliferative disorders Aplastic anemia

Vascular diseases Nephrosclerosis Atheroembolic disease Radiation nephritis Diabetes mellitus Sickle hemoglobinopathies Vasculitis

Medullary cystic disease Hereditary nephritis Medullary sponge kidney Polycystic kidney disease

Balkan nephropathy Nephropathia epidemica

Infections

Drugs

Heavy metals

Metabolic disorders

Granulomatous disease

Idiopathic TIN

Systemic Renal Bacterial Viral Fungal Mycobacterial

Analgesics Cyclosporine Nitrosourea Cisplatin Lithium Miscellaneous

Lead Cadmium

Hyperuricemiahyperuricosuria Hypercalcemiahypercalciuria Hyperoxaluria Potassium depletion Cystinosis

Sarcoidosis Tuberculosis Wegener’s granulomatosis

FIGURE 6-8 Tubulointerstitial nephropathy occurs in a motley group of diseases of varied and diverse causes. These diseases are arbitrarily grouped

together because of the unifying structural changes associated with TIN noted on morphologic examination of the kidneys.

6.6

Tubulointerstitial Disease

Pathogenesis of Chronic TIN Glomerular disease

Vascular damage

Altered filtration

Tubular ischemia

Reabsorption of noxious macromolecules

↑NH3→↑C3b→↑C5

b-9

Chronic tubular cell injury

Release of cytokines, proteinases adhesion molecules, growth factors

∆Cell balance

↑ Recruitment of antigenically activated cells

Fibroblast proliferation ↑Matrix deposition

Tubular atrophy

Interstitial fibrosis

Interstitial infiltrates

Tubular dysfunction ↓ Capillary perfusion

FIGURE 6-9 Schematic presentation of the potential pathways incriminated in the pathogenesis of chronic TIN caused by primary tubular injury (dark boxes) or secondary to glomerular disease (light boxes). The mechanism by which TIN is mediated remains to be elucidated. Chronic tubular epithelial cell injury appears to be pivotal in the process. The injury may be direct through cytotoxicity or indirect by the induction of an inflammatory or immunologic reaction. Studies in experimental models and humans provide compelling evidence for a role of immune mechanisms. The infiltrating lymphocytes have been shown to be activated immunologically. It is the inappropriate release of cytokines by the infiltrating cells and loss of regulatory balance of normal cellular regeneration that results in increased fibrous tissue deposition and tubular atrophy. Another potential mechanism of injury is that of increased tubular ammoniagenesis by the residual functioning but hypertrophic tubules. Increased tubular ammoniagenesis contributes to the immunologic injury by activating the alternate complement pathway. Altered glomerular permeability with consequent proteinuria appears to be important in the development of TIN in primary glomerular diseases. By the same token, the proteinuria that develops late in the course of primary TIN may contribute to the tubular cell injury and aggravate the course of the disease. In primary vascular diseases TIN has been attributed to ischemic injury. In fact, hypertension is probably the most common cause of TIN. The vascular lesions that develop late in the course of primary TIN, in turn, can contribute to the progression of TIN. (From Eknoyan [3]; with permission.)

Progressive loss of renal function

ROLE OF TUBULAR EPITHELIAL CELLS Chemoattractant cytokines

Pro-inflammatory cytokines

Monocyte chemoattractant peptide-1

Interleukin-6 (IL-6), IL-8

Osteopontin

Platelet-derived growth factor-

Chemoattractant lipids

Granulocyte -macrophage colony-stimulating factor

Endothelin-1

Transforming growth factor-1

RANTES

Tumor necrosis factor- From Palmer [4]; with permission.

Cell surface markers

Matrix proteins

Human leukocyte antigen class II

Collagen I, III, IV

Intercellular adhesion molecule-1 Vascular cell adhesion molecule-1

Laminin, fibronectin

FIGURE 6-10 The infiltrating interstitial cells contribute to the course TIN. However, increasing evidence exists for a primary role of the tubular epithelial cells in the recruitment of interstitial infiltrating cells and in perpetuation of the process. Injured epithelial cells secrete a variety of cytokines that have both chemoattractant and pro-inflammatory properties. These cells express a number of cell surface markers that enable them to interact with infiltrating cells. Injured epithelial cells also participate in the deposition of increased interstitial matrix and fibrous tissue. Listed are cytokines, cell surface markers, and matrix components secreted by the renal tubular cell that may play a role in the development of tubulointerstitial disease.

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis

6.7

Role of Infiltrating Cells

A

B

C

FIGURE 6-11 TIN showing early phase with focal (A) and more severe and diffuse (B) interstitial inflammatory cell infiltrates. Late phase showing thickened tubular basement membrane, distorted tubular shape, and cellular infiltration of the tubules, called tubulitis (C). The extent and severity of interstitial cellular infiltrates show a direct correlation with the severity of tubular atrophy and interstitial fibrosis. Experimental studies show the sequential accumulation of T cells and monocytes after the initial insult. Accumulation of these cells implicates their important role both in the early inflammatory stage of the disease and in the progression of subsequent injury. Immunohistologic examination utilizing monoclonal antibodies, coupled with conventional and electron microscopy, indicates that most of the mononuclear inflammatory cells comprising renal interstitial infiltrates are T cells. These T cells are immunologically activated in the absence of any evidence of tubulointerstitial immune deposits, even in classic examples of immune complex–mediated diseases such as systemic lupus erythematosus. The profile of immunocompetent cells suggests a major role for cell-mediated immunity in the tubulointerstitial lesions. The infiltrating cells may be of the helper-inducer subset or the cyotoxic-suppressor subset, although generally there seems to be a selective prevalence for the former variety. Lymphocytes that are peritubular and are seen invading the tubular epithelial cells, so-called tubulitis, are generally of the cytotoxic (CD8+) variety. The interstitial accumulation of monocytes and macrophages involves osteopontin (uropontin). Osteopontin is a secreted cell attachment glycoprotein whose messenger RNA expression becomes upregulated, and its levels are increased at the sites of tubular injury in proportion to the severity of tubular damage. The expression of other cell adhesion molecules (intercellular adhesion molecule-1, vascular cellular adhesion molecule-1, and E-selectin) also is increased at the sites of tubular injury. This increased expression may contribute to the recruitment of mononuclear cells and increase the susceptibility of renal cells to cell-mediated injury. Fibroblastic (type I) interstitial cells, which normally produce and maintain the extracellular matrix, begin to proliferate in response to injury. They increase their well-developed rough endoplasmic reticulum and acquire smooth muscle phenotype (myofibroblast). Growth kinetic studies of these cells reveal a significant increase in their proliferating capacity and generation time, indicating hyperproliferative growth.

6.8

Tubulointerstitial Disease Mechanisms Involved in Renal Interstitial Fibrosis Macrophage

Virus

TNF4 IL 1 TGF–3 PDGF GM–CSF

Protein

Sig na l

Lymphocyte

IL 2

IFN

l na Sig

DO HLA– DR DP

IL 4

Proliferating TH-Cell

Proliferating B-cell Epithelial cell IL 1

ICAM–1

Proximal tubulus

PDGF IL1 IL6 IL7 IL8 IIFNβ GM-CSF G-CSF M-CSF Factor x P (30/7.3)

Proliferation ↑↑

Fibroblast

Differentiation ↓ MF I – MF III PMF IV – PMF VI

Interstitial fibrosis

Synthesis ↑↑ and Secretion ↑ of collagen Fibrosin P 53/6.1

FIGURE 6-12 Expression of human leukocyte antigen class II and adhesion molecules released by injured tubular epithelial cells, as well as by infiltrating cells, modulate and magnify the process to repair the injury (Figure 6-10). When the process becomes unresponsive to controlling feedback mechanisms, fibroblasts proliferate and increase fibrotic matrix deposition. The precise mechanism of TIN remains to be identified. A number of pathogenetic

pathways have been proposed to operate at different stages of the disease process. Each of these individual pathways usually is part of a recuperative process that works in concert in response to injury. However, it is the loss of their controlling feedback in chronic TIN that seems to account for the altered balance and results in persistent cellular infiltrates, progressive fibrosis, and tubular degeneration.

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis

6.9

Patterns of Tubular Dysfunction PATTERNS OF TUBULAR DYSFUNCTION IN CHRONIC TIN Site of injury

Cause

Tubular dysfunction

Proximal tubule

Heavy metals Multiple myeloma Immunologic diseases Cystinosis

Decreased reabsorption of sodium, bicarbonate, glucose, uric acid, phosphate, amino acids

Distal tubule

Immunologic diseases Granulomatous diseases Hereditary diseases Hypercalcemia Urinary tract obstruction Sickle hemoglobinopathy Amyloidosis

Decreased secretion of hydrogen, potassium Decreased reabsorption of sodium

Medulla

Analgesic nephropathy Sickle hemoglobinopathy Uric acid disorders Hypercalcemia Infection Hereditary disorders Granulomatous diseases

Decreased ability to concentrate urine Decreased reabsorption of sodium

Papilla

Analgesic nephropathy Diabetes mellitus Infection Urinary tract obstruction Sickle hemoglobinopathy Transplanted kidney

Decreased ability to concentrate urine Decreased reabsorption of sodium

Cortex

FIGURE 6-13 The principal manifestations of TIN are those of tubular dysfunction. Because of the focal nature of the lesions that occur and the segmental nature of normal tubular function, the pattern of tubular dysfunction that results varies, depending on the major site of injury. The extent of damage determines the severity of tubular dysfunction. The hallmarks of glomerular disease (such as salt retention, edema, hypertension, proteinuria, and hematuria) are characteristically absent in the early phases of chronic TIN. The type of insult determines the segmental location of injury. For example, agents secreted by the organic pathway in the pars recta (heavy metals) or reabsorbed in the proximal tubule (light chain proteins) cause predominantly proximal tubular lesions. Depositional disorders (amyloidosis and hyperglobulinemic states) cause predominantly distal tubular lesions. Insulting agents that are affected by the urine concentrating mechanism (analgesics and uric acid) or medullary tonicity (sickle hemoglobinopathy) cause medullary injury.

The tubulointerstitial lesions are localized either to the cortex or medulla. Cortical lesions mainly affect either the proximal or distal tubule. Medullary lesions affect the loop of Henle and the collecting duct. The change in the normal function of each of these affected segments then determines the manifestations of tubular dysfunction. Essentially, the proximal nephron segment reabsorbs the bulk of bicarbonate, glucose, amino acids, phosphate, and uric acid. Changes in proximal tubular function, therefore, result in bicarbonaturia (proximal renal acidosis), 2-microglobinuria, glucosuria (renal glucosuria), aminoaciduria, phosphaturia, and uricosuria. The distal nephron segment secretes hydrogen and potassium and regulates the final amount of sodium chloride excreted. Lesions primarily affecting this segment, therefore, result in the distal form of renal tubular acidosis, hyperkalemia, and salt wasting. Lesions that primarily involve the medulla and papilla disproportionately affect the loops of Henle, collecting ducts, and the other medullary structures essential to attaining and maintaining medullary hypertonicity. Disruption of these structures, therefore, results in different degrees of nephrogenic diabetes insipidus and clinically manifests as polyuria and nocturia. Although this general framework is useful in localizing the site of injury, considerable overlap may be encountered clinically, with different degrees of proximal, distal, and medullary dysfunction present in the same individual. Additionally, the ultimate development of renal failure complicates the issue further because of the added effect of urea-induced osmotic diuresis on tubular function in the remaining nephrons. In this later stage of TIN, the absence of glomerular proteinuria and the more common occurrence of hypertension in glomerular diseases can be helpful in the differential diagnosis.

6.10

Tubulointerstitial Disease

Correlates of Tubular Dysfunction with Severity of Chronic TIN 1200

160 Chronic GN Acute GN PTIN Nephrosclerosis

140

1000 900 Maximal osmolality, mOs/kg

120

Inulin clearance, mL/min

Chronic GN Acute GN PTIN Nephrosclerosis

1100

100

80

60

800 700 600 500 400 300

40

200 20

100 0

0 0

1

2

3

A

4 5 6 7 8 9 Interstitial disease (total score)

10

11

B

Chronic GN Acute GN PTIN Nephrosclerosis

100

Ammonium excretion, µEq/min

90 80 70 60 50 40 30 20 10 0 0

C

1

2

3

4 5 6 7 8 9 Interstitial disease (total score)

10

11

1

2

3

4

5

6

7

8

9

10

11

12

Interstitial disease (total score)

FIGURE 6-14 Relationship of inulin clearance (A), maximum urine concentration (B), and ammonium excretion in response to an acute acid load (C) to the severity of tubulointerstitial nephritis. A close correlation exists between the severity of chronic TIN and impaired renal tubular and glomerular function. Repeated evaluations of kidney biopsy for the extent of tubulointerstitial lesions have shown a close correlation with renal function test results in tests performed before biopsy. These tests include those for inulin clearance, maximal ability to concentrate the urine, and ability to acidify the urine. This correlation has been validated in a variety of renal diseases, including primary and secondary forms of chronic TIN. (From Shainuck and coworkers [5]; with permission.)

1200 110

0

12

12

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis

6.11

Probability of maintaining renal function, %

Correlates of Chronic TIN with Progressive Renal Failure FIGURE 6-15 Effect on long-term prognosis of the presence of cortical chronic tubulointerstitial nephritis in patients with mesangioproliferative glomerulonephritis (n = 455), membranous nephropathy (n = 334), and membranoproliferative glomerulonephritis (n = 220). The extent of tubulointerstitial nephritis correlates not only with altered glomerular and tubular dysfunction at the time of kidney biopsy but also provides a prognostic index of the progression rate to endstage renal disease. As shown, the presence of interstitial fibrosis on the initial biopsy exerts a significant detrimental effect on the progression rate of renal failure in a variety of glomerular diseases. (From Eknoyan [3]; with permission.)

100 80

Normal interstitium

60 40 Interstitial fibrosis

20 0 0

2

4

6

8

10

12

14

16

Follow-up, y

Drugs Analgesic Nephropathy Acetaminophen Metabolism n–OH–p–acetophenetidine

p–phenetidine

Meth–hemoglobin Sulfhemoglobin

Cytochrome P–450

Reactive toxic metabolites

Phenactin p–acetophenetidine

Glucoronide sulfate

Paracetamol n–acetyl–p–aminophenol

Glutathione Covalent binding to cellular sulfhydryl

Glutathione conjugate

Cell death

Mercapturic acid

FIGURE 6-16 Metabolism of acetaminophen and its excretion by the kidney. Prolonged exposure to drugs can cause chronic TIN. Although a number of drugs (eg, lithium, cyclosporine, cisplatin, and nitrosoureas) have been implicated, the more commonly responsible agents are analgesics. As a rule, the lesions of analgesic nephropathy develop in persons who abuse analgesic combinations (phenacetin, or its main metabolite acetaminophen, plus aspirin, with or without caffeine). Experimental evidence indicates that phenacetin, or acetaminophen, plus aspirin taken alone are only moderately nephrotoxic and only at massive doses, but that the lesions can be more readily induced when these drugs are taken together. In all experimental studies the extent of renal injury has been dose-dependent and, when examined, water

diuresis has provided protection from analgesic-induced renal injury. Relative to plasma levels, both acetaminophen (paracetamol) and its excretory conjugate attain significant (fourfold to fivefold) concentrations in the medulla and papilla, depending on the state of hydration of the animal studied. The toxic effect of these drugs apparently is related to their intrarenal oxidation to reactive intermediates that, in the absence of reducing substances such as glutathione, become cytotoxic by virtue of their capacity to induce oxidative injury. Salicylates also are significantly (sixfold to thirteenfold above plasma levels) concentrated in the medulla and papilla, where they attain a level sufficient to uncouple oxidative phosphorylation and compromise the ability of cells to generate reducing substances. Thus, both agents attain sufficient renal medullary concentration to individually exert a detrimental and injurious effect on cell function, which is magnified when they are present together. By reducing the medullary tonicity, and therefore the medullary concentration of drug attained, water diuresis protects from analgesic-induced cell injury. A direct role of analgesic-induced injury can be adduced from the improvement of renal function that can occur after cessation of analgesic abuse.

6.12

Tubulointerstitial Disease

Pathogenesis of renal lesion associated with analgesic abuse

Cortex– normal Outer medula– patchy tubular damage a. tubular dilatation b. increased interstitial tissue c. casts: pigment Stage I

Papilla– possible microscopic changes

Cortex– normal Outer medula– increase in changes Papilla– necrosis and atrophy attached or separated

Stage II

Cortex– a. atrophy area overlying necrotic papilla b. hypertrophy Papilla– atrophic, necrotic Stage III

FIGURE 6-17 Course of the renal lesions in analgesic nephropathy. The intrarenal distribution of analgesics provides an explanation for the medullary location of the pathologic lesions of analgesic nephropathy. The initial lesions are patchy and consist of necrosis of the interstitial cells, thin limbs of the loops of Henle, and vasa recta of the papilla. The collecting ducts are spared. The quantities of tubular and vascular basement membrane and ground substance are increased. At this stage the kidneys are normal in size and no abnormalities have occurred in the renal cortex. With persistent drug exposure the changes extend to the outer medulla. Again, the lesions are initially patchy, involving the interstitial cells, loops of Henle, and vascular bundles. With continued analgesic abuse, the severity of the inner medullary lesions increases with sclerosis and obliteration of the capillaries, atrophy and degeneration of the loops of Henle and collecting ducts, and the beginning of calcification of the necrotic foci. Ultimately, the papillae become entirely necrotic, with sequestration and demarcation of the necrotic tissue. The necrotic papillae may then slough and are excreted into the urine or remain in situ, where they atrophy further and become calcified. Cortical scarring, characterized by interstitial fibrosis, tubular atrophy, and periglomerular fibrosis, develops over the necrotic medullary segments. The medullary rays traversing the cortex are usually spared and become hypertrophic, thereby imparting a characteristic cortical nodularity to the now shrunken kidneys. Visual observation of these configurational changes by computed tomography scan can be extremely useful in the diagnosis of analgesic nephropathy.

Size Right kidney

RV RA Left kidney

RA Spine

a

a

b

A

b

C

Appearance Bumpy contours Papillary calcifications

0 B

1–2

3–5

Number of indentations

>5 D

FIGURE 6-18 Computed tomography (CT) imaging criteria for diagnosing analgesic nephropathy. Renal size (A) is considered decreased if the sum of a and b (panels A and B) is less than 103 mm

in men and 96 mm in women. Bumpy contours are considered to be present if at least three indentations are evident (panels B and C). The scan can reveal papillary calcifications (panels B and D). Visual observation of the configurational changes illustrated in Figure 6-18 can be extremely useful in diagnosing the scarred kidney in analgesic nephropathy. A series of careful studies using CT scans without contrast material have provided imaging criteria for the diagnosis of analgesic nephropathy. Validation of these criteria currently is underway by a study at the National Institutes of Health. From studies comparing analgesic abusers to persons in control groups, it has been shown that a decrease in kidney size and bumpy contours of both kidneys provide a diagnostic sensitivity of 90% and a specificity of 95%. The additional finding of evidence of renal papillary necrosis provides a diagnostic sensitivity of 72% and specificity of 97%, giving a positive predictive value of 92%. RA— renal artery; RV— renal vein. (From DeBroe and Elseviers [6]; with permission.)

6.13

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis

CLINICAL FEATURES

1

2

a

a b

3 a b

c

b c

c

Female predominance, 60–85% Age, >30 y Personality disorders: introvert, dependent, anxiety, neurosis, family instability a—cortical nephron

Addictive habits: smoking, alcohol, laxatives, psychotropics, sedatives Causes of analgesic dependency: headache, 40–60%; mood, 6–30%; musculoskeletal pain, 20–30%

FIGURE 6-19 Certain personality features and clinical findings characterize patients prone to analgesic abuse. These patients tend to deny analgesic use on direct questioning; however, their history can be revealing. In all cases, a relationship exists between renal function and the duration, intensity, and quantity of analgesic consumed. The magnitude of injury is related to the quantity of analgesic ingested chronically over years. In persons with significant renal impairment, the average dose ingested has been estimated at about 10 kg over a mean period of 13 years. The minimum amount of drug consumption that results in significant renal damage is unknown. It has been estimated that a cumulative dose of 3 kg of the index compound, or a daily ingestion of 1 g/d over 3 years or more, is a minimum that can result in detectable renal impairment.

b—juxta medullary nephron

c—midcortical nephron

FIGURE 6-20 Diagram of cortical and juxtamedullary nephrons in the normal kidney (1). Papillary necrosis (2) and sloughing (3) result in loss of juxtamedullary nephrons. Cortical nephrons are spared, thereby preserving normal renal function in the early stages of the disease. The course of analgesic nephropathy is slowly progressive, and deterioration of renal function is insidious. One reason for these characteristics of the disease is that lesions beginning in the papillary tip affect only the juxtamedullary nephrons, sparing the cortical nephrons. It is only when the lesions are advanced enough to affect the whole medulla that the number of nephrons lost is sufficient to result in a reduction in filtration rate. However, renal injury can be detected by testing for sterile pyuria, reduced concentrating ability, and a distal acidifying defect. These features may be evident at levels of mild renal insufficiency and become more pronounced and prevalent as renal function deteriorates. Proximal tubular function is preserved in patients with mild renal insufficiency but can be abnormal in those with more advanced renal failure.

Cyclosporine

A FIGURE 6-21 A, Chronic TIN caused by cyclosporine. The arrow indicates the characteristic hyaline-type arteriolopathy of cyclosporine nephrotoxicity. B, Patchy nature of chronic TIN caused by cyclosporine. Note the severe TIN on the right adjacent to an otherwise intact area on the left. Tubulointerstitial nephritis has emerged as the most serious side effect of cyclosporine. Cyclosporine-mediated vasoconstriction of the cortical microvasculature has been implicated in the development of an occlusive arteriolopathy and tubular

B epithelial cell injury. Whereas these early lesions tend to be reversible with cessation of therapy, an irreversible interstitial fibrosis and mononuclear cellular infiltrates develop with prolonged use of cyclosporine, especially at high doses. The irreversible nature of TIN associated with the use of cyclosporine and its attendant reduction in renal function have raised concerns regarding the long-term use of this otherwise efficient immunosuppressive agent.

6.14

Tubulointerstitial Disease

Heavy Metals Lead Nephropathy

FIGURE 6-22 Lead nephropathy. Arrows indicate the characteristic intranuclear inclusions. Exposure to a variety of heavy metals results in development of chronic TIN. Of these metals, the more common and clinically important implicated agent is lead. Major sources of

exposure to lead are lead-based paints; lead leaked into food during storage or processing, particularly in illegal alcoholic beverages (moonshine); and increasingly, through environmental exposure (gasoline and industrial fumes). This insidious accumulation of lead in the body has been implicated in the causation of hyperuricemia, hypertension, and progressive renal failure. Gout occurs in over half of cases. Blood levels of lead usually are normal. The diagnosis is established by demonstrating increased levels of urinary lead after infusion of 1 g of the chelating agent erthylenediamine tetraacetic acid (EDTA). The renal lesions of lead nephropathy are those of chronic TIN. Cases examined early, before the onset of end-stage renal disease, show primarily focal lesions of TIN with relatively little interstitial cellular infiltrates. In more advanced cases the kidneys are fibrotic and shrunken. On microscopy, the kidneys show diffuse lesions of TIN. As expected from the clinical features, hypertensive vascular changes are prominent. Other heavy metals associated with TIN are cadmium, silicon, copper, bismuth, and barium. Sufficient experimental evidence and some weak epidemiologic evidence suggest a possible role of organic solvents in the development of chronic TIN.

Ischemic Vascular Disease Hypertensive Nephrosclerosis FIGURE 6-23 Chronic TIN associated with hypertension. The arrows indicate arterioles and small arteries with thickened walls. Tubular degeneration, interstitial fibrosis, and mononuclear inflammatory cell infiltration are part of the degenerative process that affects the kidneys in all vascular diseases involving the intrarenal vasculature with any degree of severity as to cause ischemic injury. Rarely, if the insult is sudden and massive (such as in fulminant vasculitis), the lesions are those of infarction and acute deterioration of renal function. More commonly, the vascular lesions develop gradually and go undetected until renal insufficiency supervenes. This chronic form of TIN accounts for the tubulointerstitial lesions of arteriolar nephrosclerosis in persons with hypertension. Ischemic vascular changes also contribute to the lesions of TIN in patients with diabetes, sickle cell hemoglobinopathy, cyclosporine nephrotoxicity, and radiation nephritis.

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis

6.15

FIGURE 6-24 Gross appearance of the kidney as a result of arteriolonephrosclerosis, showing the granular and scarified cortex.

Obstruction FIGURE 6-25 (see Color Plate) Chronic TIN secondary to vesicoureteral reflux (VUR). Clearly demonstrated is an area that is fairly intact (lower left corner) adjacent to one that shows marked damage. Urinary tract obstruction, whether congenital or acquired, is a common cause of chronic TIN. Clinically, superimposed infection plays a secondary, adjunctive, and definitely aggravating role in the progressive changes of TIN. However, the entire process can occur in the absence of infection. As clearly demonstrated in experimental models of obstruction, mononuclear inflammatory cell infiltration is one of the earliest responses of the kidney to ureteral obstruction. The infiltrating cells consist of macrophages and suppressor-cytotoxic lymphocytes. The release of various cytokines by the infiltrating cells of the hydronephrotic kidney appears to exert a significant modulating role in the transport processes and hemodynamic changes seen early in the course of obstruction. With persistent obstruction, changes of chronic TIN set in within weeks. Fibrosis gradually becomes prominent. FIGURE 6-26 Gross appearance of a hydronephrotic kidney caused by vesicoureteral reflux.

6.16

Tubulointerstitial Disease

Obstructive Nephropathy FIGURE 6-27 Glomerular lesion of advanced chronic TIN secondary to vesicoureteral reflux in a patient with massive proteinuria. Note the segmental sclerosis of the glomerulus and the reactive proliferation of the visceral epithelial cells. In persons with obstructive nephropathy, the onset of significant proteinuria (>2g/d) is an ominous sign of progressive renal failure. As a rule, most of these patients will have coexistent hypertension, and the renal vasculature will show changes of hypertensive arteriolosclerosis. The glomerular changes are ischemic in nature. In those with significant proteinuria, the lesions are those of focal and segmental glomerulosclerosis and hyalinosis. The affected glomeruli commonly contain immunoglobulin M and C3 complement on immunofluorescent microscopy. The role of an immune mechanism remains unclear. Autologous (Tamm-Horsfall protein and brush-border antigen) or bacterial antigen derivatives have been incriminated. Adaptive hemodynamic changes (hyperfiltration) in response to a reduction in renal mass, by the glomeruli of remaining intact nephrons of the hydronephrotic kidney, also have been implicated.

Hematopoietic Diseases Sickle Hemoglobinopathy

FIGURE 6-28 The kidney in sickle cell disease. Note the tubular deposition of hemosiderin. The principal renal lesion of hemoglobinopathy S is

that of chronic TIN. By far more prevalent and severe in patients with sickle cell disease, variable degrees of TIN also are common in those with the sickle cell trait, sickle cell–hemoglobin C disease, or sickle cell–thalassemia disease. The predisposing factors that lead to a propensity of renal involvement are the physicochemical properties of hemoglobin S that predispose its polymerization in an environment of low oxygen tension, hypertonicity, and low pH. These conditions are characteristic of the renal medulla and therefore are conducive to the intraerythrocyte polymerization of hemoglobin S. The consequent erythrocyte sickling accounts for development of the typical vascular occlusive lesions. Although some of these changes occur in the cortex, the lesions begin and are predominantly located in the inner medulla, where they are at the core of the focal scarring and interstitial fibrosis. These lesions account for the common occurrence of papillary necrosis. Examples of tubular functional abnormalities common and detectable early in the course of the disease are the following: impaired concentrating ability, depressed distal potassium and hydrogen secretion, tubular proteinuria, and decreased proximal reabsorption of phosphate, and increased secretion of uric acid and creatinine.

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis

6.17

Hematologic Diseases Plasma Cell Dyscrasias

A

B

C

FIGURE 6-29 (see Color Plate) A, Myeloma cast nephropathy. The arrow indicates a multinucleated giant cell. B, Light chain deposition disease. Note the changes indicative of chronic TIN and light chain deposition along the tubular basement membrane (dark purple). C, Immunofluorescent stain for  light chain deposition along the tubular basement membrane. The renal complications of multiple myeloma are a major risk factor in the morbidity and mortality of this neoplastic disorder. Whereas the pathogenesis of renal involvement is multifactorial (hypercalcemia and hyperuricemia), it is the lesions that result from the excessive production of light chains that cause chronic TIN. These lesions are initiated by the precipitation of the light chain dimers in the distal tubules and result in what has been termed myeloma cast nephropathy. The affected tubules are surrounded by multinucleated giant cells. Adjoining tubules show varying degrees of atrophy. The propensity of light chains to lead to myeloma cast nephropathy appears to be related to their concentration in the tubular fluid, the tubular fluid pH, and their structural configuration. This propensity accounts for the observation that increasing the flow rate of urine or its alkalinization will prevent or reverse the casts in their early stages of formation. Direct tubular toxicity of light chains also may contribute to tubular injury.  Light chains appear to be more injurious than are  light chains. Binding of human  and  light chains to human and rat proximal tubule epithelial cell brush-border membrane has been demonstrated. Epithelial cell injury associated with the absorption of these light chains in the proximal tubules has been implicated in the pathogenesis of cortical TIN. Another mechanism relates to the perivascular deposition of paraproteins, either as amyloid fibrils that are derived from  chains or as fragments of light chains that are derived from kappa chains, and produce the so-called light chain deposition disease. Of the various lesions, myeloma cast nephropathy appears to be the most common, being observed at autopsy in one third of cases, followed by amyloid deposition, which is present in 10% of cases. Light chain deposition is relatively rare, being present in less than 5% of cases.

6.18

Tubulointerstitial Disease

Metabolic Disorders Hyperuricemia

A FIGURE 6-30 A, Intratubular deposits of uric acid. B, Gouty tophus in the renal medulla. The kidney is the major organ of urate excretion and a primary target organ affected in disorders of its metabolism. Renal lesions result from crystallization of urate in the urinary outflow tract or the renal parenchyma. Depending on the load of urate, one of three lesions result: acute urate nephropathy, uric acid nephrothiasis, or chronic urate nephropathy. Whereas any of these lesions produce tubulointerstitial lesions, it is those of chronic urate nephropathy that account for most cases of chronic TIN. The principal lesion of chronic urate nephropathy is due to deposition of microtophi of amorphous urate crystals in the interstitium, with a surrounding giant-cell reaction. An earlier change, however, probably is due to the precipitation of birefringent uric acid crystals in the collecting tubules, with consequent tubular obstruction, dilatation, atrophy, and interstitial fibrosis. The renal injury in persons who develop lesions has been attributed to

B hyperacidity of their urine caused by an inherent abnormality in the ability to produce ammonia. The acidity of urine is important because uric acid is 17 times less soluble than is urate. Therefore, uric acid facilitates precipitation in the distal nephron of persons who do not overproduce uric acid but who have a persistently acidic urine. The previous notion that chronic renal disease was common in patients with hyperuricemia is now considered doubtful in light of prolonged follow-up studies of renal function in persons with hyperuricemia. Renal dysfunction could be documented only when the serum urate concentration was more than 10 mg/dL in women and more than 13 mg/dL in men for prolonged periods. The deterioration of renal function in persons with hyperuricemia of a lower magnitude has been attributed to the higher than expected occurrence of concurrent hypertension, diabetes mellitus, abnormal lipid metabolism, and nephrosclerosis.

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis

6.19

Hyperoxaluria

A

B

FIGURE 6-31 (see Color Plate) A, Calcium oxalate crystals (arrow) seen on light microscopy. B, Dark field microscopy. When hyperoxaluria is sudden and massive (such as after ethylene glycol ingestion) acute renal failure develops. Otherwise, in most cases of hyperoxaluria the overload is insidious and

chronic. As a result, interstitial fibrosis, tubular atrophy, and dilation result in chronic TIN with progressive renal failure. The propensity for recurrent calcium oxalate nephrolithiasis and consequent obstructive uropathy contribute to the tubulointerstitial lesions.

Granulomatous Diseases Malacoplakia 3

1

5

2

7

4

6

FIGURE 6-32 Schematic representation of the forms and course of renal involvement by malacoplakia: 1, normal kidney; 2, enlarged kidney resulting from interstitial nephritis without nodularity; 3, unifocal nodular involvement; 4, multifocal nodular involvement; 5, abscess formation with perinephric spread of malacoplakia; 6, cystic lesions; and 7, atrophic multinodular kidney after treatment. Interstitial granulomatous reactions are a rare but characteristic

hallmark of certain forms of tubulointerstitial disease. The best-known form is that of sarcoidosis. Interstitial granulomatous reactions also have been noted in renal tuberculosis, xanthogranulomatous pyelonephritis, renal malacoplakia, Wegener’s granulomatosis, renal candidiasis, heroin abuse, hyperoxaluria after jejunoileal bypass surgery, and an idiopathic form in association with anterior uveitis. The inflammatory lesions of malacoplakia principally affect the urinary bladder but may involve other organs, most notably the kidneys. The kidney lesions may be limited to one focus or may be multifocal. In three fourths of cases the renal involvement is multifocal, and in one third of cases both kidneys are involved. The lesions are nodular, well-demarcated, and variable in size. They may coalesce, developing foci of suppuration that may become cystic or calcified. The lesions usually are located in the cortex but may be medullary and result in papillary necrosis. (From Dobyan and coworkers [7]; with permission.)

6.20

Tubulointerstitial Disease

Endemic Diseases

FIGURE 6-33 Hemorrhagic TIN associated with Hantavirus infection. Two endemic diseases in which tubulointerstitial lesions are a predominant component are Balkan nephropathy and nephropathia epidemica. Endemic Balkan nephropathy is a progressive chronic tubulointerstitial nephritis whose occurrence is mostly clustered

in a geographic area bordering the Danube River as it traverses Romania, Bulgaria, and the former Yugoslavia. The cause of Balkan nephropathy is unknown; however, it has been attributed to genetic factors, heavy metals, trace elements, and infectious agents. The disease evolves in emigrants from endemic regions, suggesting a role for inheritance or the perpetuation of injury sustained before emigration. Initially thought to be restricted to Scandinavian countries, and thus termed Scandinavian acute hemorrhagic interstitial nephritis, Nephropathia epidemica has been shown to have a more universal occurrence. It therefore has been more appropriately renamed hemorrhagic fever with renal syndrome. As a rule the disease presents as a reversible acute tubulointerstitial nephritis but can progress to a chronic form. It is caused by a rodent-transmitted virus of the Hantavirus genus of the Bunyaviridae family, the so-called Hantaan virus. Humans appear to be infected by respiratory aerosols contaminated by rodent excreta. Antibodies to the virus are detected in the serum, and viruslike structures have been demonstrated in the kidneys of persons infected with the virus. Tubulointerstitial nephropathy caused by viral infection also has been reported in polyomavirus, cytomegalovirus, herpes simplex virus, human immunodeficiency virus, infectious mononucleosis, and Epstein-Barr virus.

Hereditary Diseases Hereditary Nephritis

A FIGURE 6-34 A, Interstitial foam cells in Alport’s syndrome. B, Late phase Alport’s syndrome showing chronic TIN and glomerular changes in a patient with massive proteinuria. Tubulointerstitial lesions are a prominent component of the renal pathology of a variety of hereditary diseases of the kidney, such as medullary cystic disease, familial juvenile nephronophthisis, medullary sponge kidney, and polycystic kidney disease. The primary disorder of these conditions is a tubular defect that results in the cystic dilation of the affected segment in some patients. Altered tubular basement membrane composition and

B associated epithelial cell proliferation account for cyst formation. It is the continuous growth of cysts and their progressive dilation that cause pressure-induced ischemic injury, with consequent TIN of the adjacent renal parenchyma. Tubulointerstitial lesions also are a salient feature of inherited diseases of the glomerular basement membrane. Notable among them are those of hereditary nephritis or Alport’s syndrome, in which a mutation in the encoding gene localized to the X chromosome results in a defect in the -5 chain of type IV collagen.

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis

Papillary Necrosis

A FIGURE 6-35 A, Renal papillary necrosis. The arrow points to the region of a sloughed necrotic papilla. B, Whole mount of a necrotic papilla. Arrows delineate focal necrosis principally affecting the medullary inner stripe. Renal papillary necrosis (RPN) develops in a variety of diseases that cause chronic tubulointerstitial nephropathy in which the lesion is more severe in the inner medulla. The basic lesion affects the vasculature with consequent focal or diffuse ischemic necrosis of the distal segments of one or more renal pyramids. In the affected papilla, the sharp demarcation of the lesion and coagulative necrosis seen in the early stages of the disease closely resemble those of infarction. The fact that the necrosis is anatomically limited to the papillary tips can be attributed to a variety of features unique to this site, especially those affecting the vasculature. The renal papilla receives its blood supply from the vasa recta. Measurements of medullary blood flow notwithstanding, it should be noted that much of the blood flow in the vasa recta serves the countercurrent exchange mechanism. Nutrient blood supply is provided by small capillary vessels that originate in each given region. The net effect is that the blood supply to the papillary tip is less than that to the rest of the medulla, hence its predisposition to ischemic necrosis. The necrotic lesions may be limited to only a few of the papillae or may involve several of the papillae in

B either one or both kidneys. The lesions are bilateral in most patients. In patients with involvement of one kidney at the time of initial presentation, RPN will develop in the other kidney within 4 years, which is not unexpected because of the systemic nature of the diseases associated with RPN. RPN may be unilateral in patients in whom predisposing factors (such as infection and obstruction) are limited to one kidney. Azotemia may be absent even in bilateral papillary necrosis, because it is the total number of papillae involved that ultimately determines the level of renal insufficiency that develops. Each human kidney has an average of eight pyramids, such that even with bilateral RPN affecting one papilla or two papillae in each kidney, sufficient unaffected renal lobules remain to maintain an adequate level of renal function. As a rule, RPN is a disease of an older age group, the average age of patients being 53 years. Nearly half of cases occur in persons over 60 years of age. More than 90% of cases occur in persons over 40 years of age, except for those caused by sickle cell hemoglobinopathy. RPN is much less common in children, in whom the chronic conditions associated with papillary necrosis are rare. However, RPN does occur in children in association with hypoxia, dehydration, and septicemia.

6.21

6.22

Tubulointerstitial Disease

Total Papillary Necrosis Renal Papillary Necrosis– Papillary Form

Normal

Lesion

Pyelogram

Early necrosis, mucosa normal, papilla swollen.

Normal calyx

Progressive necrosis, swelling, mucosal loss.

Irregular or fuzzy calyx

Sequestrian of necrotic area.

Sinus or "Arc Shadow"

Sinus formation begins. Sinus surrounds sequestrum.

"Ring Shadow"

Sequestrum extruded or resorbed.

"Clubbing" "Clubbed calyx" "Caliectasis"

Sequestrum calcifies.

"Ring Shadow" Obstruction

Extruded sequestrum

FIGURE 6-36 Schematic of the progressive stages of the papillary form of renal papillary necrosis and their associated radiologic changes seen on intravenous pyelography. Papillary necrosis occurs in one of two forms. In the medullary form, also termed partial papillary necrosis, the inner medulla is affected; however, the papillary tip and fornices remain intact. In the papillary form, also termed total papillary necrosis, the calyceal fornices and entire papillary tip are necrotic. In total papillary necrosis shown here, the lesion is characterized from the outset by necrosis, demarcation, and sequestration of the papillae, which ultimately slough

Renal Papillary Necrosis – Medullary Form Normal

Lesion

Pyelogram

Early focal, necrosis of medullary inner stripe.

Normal calyx

Progressive necrosis, coalescence of necrotic areas. Swelling. Mucosa normal.

Normal calyx

Mucosal break. Sequestration and sinus formation.

Sinus

Progressive sequestration, extrusion, or resorption of necrotic tissue.

Irregular sinus

Healing. Irregular medullary cavity with communicating sinus tract.

Irregular medullary cavity

into the pelvis and may be recovered in the urine. In most of these cases, however, the necrotic papillae are not sloughed but are either resorbed or remain in situ, where they becomes calcified or form the nidus of a calculus. In these patients, excretory radiologic examination and computed tomography scanning are diagnostic. Unfortunately, these changes may not be evident until the late stages of RPN, when the papillae already are shrunken and sequestered. In fact, even when the papillae are sloughed out, excretory radiography can be negative. The passage of sloughed papillae is associated with lumbar pain, which is indistinguishable from ureteral colic of any cause and is present in about half of patients. Oliguria occurs in less than 10% of patients. A definitive diagnosis of RPN can be made by finding portions of necrotic papillae in the urine. A deliberate search should be made for papillary fragments in urine collected during or after attacks of colicky pain of all suspected cases, by straining the urine through filter paper or a piece of gauze. The separation and passage of papillary tissue may be associated with hematuria, which is microscopic in some 40% to 45% of patients and gross in 20%. The hematuria can be massive, and occasionally, instances of exsanguinating hemorrhage requiring nephrectomy have been reported. (From Eknoyan and coworkers [8]; with permission.) FIGURE 6-37 Schematic of the progressive stages of the medullary form of renal papillary necrosis and their associated radiologic appearance seen on intravenous pyelography. In partial papillary necrosis the lesion begins as focal necrosis within the substance of the medullary inner stripe. The lesion progresses by coagulative necrosis to form a sinus to the papillary tip, with subsequent extrusion or resorption of the sequestered necrotic tissue. The medullary form of papillary necrosis is commonly encountered in persons with sickle cell hemoglobinopathy. The incidence of radiographically demonstrative papillary necrosis is as high as 33% to 65% in such persons.

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis

CONDITIONS ASSOCIATED WITH RENAL PAPILLARY NECROSIS Diabetes mellitus Urinary tract obstruction Pyelonephritis Analgesic nephropathy Sickle hemoglobinopathy Rejection of transplanted kidney Vasculitis Miscellaneous

FIGURE 6-38 Diabetes mellitus is the most common condition associated with papillary necrosis. The occurrence of capillary necrosis is likely more common than is generally appreciated, because pyelography (the best diagnostic tool for detection of papillary necrosis) is

Spectrum of Renal Papillary Necrosis

Obstruction

Diabetes

Infection

Analgesic abuse

Sickle Hgb

6.23

avoided in these patients because of dye-induced nephrotoxicity. When sought, papillary necrosis has been reported in as many as 25% of cases. Analgesic nephropathy accounts for 15% to 25% of papillary necrosis in the United States but accounts for as much as 70% of cases in countries in which analgesic abuse is common. Papillary necrosis also has been reported in patients receiving nonsteroidal anti-inflammatory drugs. Sickle hemoglobinopathy is another common cause of papillary necrosis, which, when sought by intravenous pyelography, is detected in well over half of cases. Infection is usually but not invariably a concomitant finding in most cases of RPN. In fact, with few exceptions, most patients with RPN ultimately develop a urinary tract infection, which represents a complication of papillary necrosis: that is, the infection develops after the primary underlying disease has initiated local injury to the renal medulla, with foci of impaired blood flow and poor tubular drainage. Infection contributes significantly to the symptomatology of RPN, because fever and chills are the presenting symptoms in two thirds of patients and a positive urine culture is obtained in 70%. However, RPN is not an extension of severe pyelonephritis. In most patients with florid acute pyelonephritis, RPN does not occur.

FIGURE 6-39 Spectrum and overlap of diseases principally associated with renal papillary necrosis (RPN). Although each disease can cause RPN, it is their coexistence (darkly shaded areas) that increases the risk, which is even greater after the onset of infection (lightly shaded areas). In most cases of RPN, more than one of the conditions associated with RPN is present. Thus, in most cases, the lesion seems to be multifactorial in origin. The pathogenesis of the lesion may be considered the result of an overlapping phenomenon, in which a combination of detrimental factors appear to operate in concert to cause RPN. As such, whereas each of the conditions alone can cause RPN, the coexistence of more than one predisposing factor in any one person significantly increases the risk for RPN. The contribution of any one of these factors to RPN would be expected to differ among individuals and at various periods during the course of the disease. To the extent that the natural course of RPN itself predisposes patients to development of infection of necrotic foci and obstruction by sloughed papillae, it may be difficult to assign a primary role for any of these processes in an individual patient. Furthermore, the occurrence of any of these factors (necrosis, obstruction, or infection) may itself initiate a vicious cycle that can lead to another of these factors and culminate in RPN.

References 1. 2. 3.

4.

Bohman S: The ultrastructure of the renal interstitium. Contemp Issues Nephrol 10:1–34, 1983. Lemley KV, Kriz W: Anatomy of the renal interstitium. Kidney Int 1991, 39:370–381. Eknoyan G: Chronic tubulointerstitial nephropathies. In Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little Brown; 1997:1983–2015. Palmer BF: The renal tubule in the progression of chronic renal failure. J Invest Med 1997, 45:346–361.

5.

6. 7. 8.

Schainuck LI, Striker GE, Cutler RE, Benditt EP: Structural-functional correlations in renal disease II. The correlations. Hum Pathol 1970, 1:631–641. DeBroe ME, Elseviers MM: Analgesic nephropathy. N Engl J Med 1998, 338:446–451. Dobyan DC, Truong LD, Eknoyan G: Renal malacoplakia reappraised. Am J Kidney Dis 1993, 22:243–252. Eknoyan G, Qunibi WY, Grissom RT, et al.: Renal papillary necrosis: an update. Medicine 1982, 61:55–73.

6.24

Tubulointerstitial Disease

Selected Bibliography Renal Interstitium

Drugs

Neilson EG: Symposium on the cell biology of tubulointerstitium. Kidney Int 1991, 39:369–556. Strutz F, Mueller GA: Symposium on Renal Fibrosis: prevention and progression. Kidney Int 1996, 49(suppl 54):1–90.

Boton R, Gaviria M, Battle DC: Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy. Am J Kidney Dis 1990, 10:329–345. Myer BD, Newton L: Cyclosporine induced chronic nephropathy: an obliterative microvascular renal injury. J Am Soc Nephrol 1991, 2(suppl 1):4551.

Chronic Tubulointerstitial Nephritis Eknoyan G, McDonald MA, Appel D, Truong LD: Chronic tubulointerstitial nephritis: correlation between structural and functional findings. Kidney Int 1990, 38:736–743. Jones CL, Eddy AA: Tubulointerstitial nephritis. Ped Nephrol 1992, 6:572–586. Nath KA: Tubulointerstitial changes as a major determinant in progression of renal damage. Am J Kidney Dis 1992, 20:1–17.

Pathogenesis Bohle A, Muller GA, Wehrmann M et al.: Pathogenesis of chronic renal failure in the primary glomerulopathies, renal vasculopathies and chronic interstitial nephritides. Kidney Int 1996, 49(suppl 54):2–9. Dodd S: The pathogenesis of tubulointerstitial disease and mechanisms of fibrosis. Curr Top Pathol 1995, 88:117–143. Haggerty DT, Allen DM: Processing and presentation of self and foreign antigens by the renal proximal tubule. J Immunol 1992, 148:2324–2331. Nath KA: Reshaping the interstitium by platelet-derived growth factor. Implications for progressive renal disease. Am J Path 1996, 148:1031–1036. Sedor JR: Cytokines and growth factors in renal injury. Semin Nephrol 1992, 12:428–440. Wilson CB: Nephritogenic tubulointers-titial antigens. Kidney Int 1991, 39:501–517. Yamato T, Noble NA, Miller DE, Border WA: Sustained expression of TGF-B1 underlies development of progressive kidney fibrosis. Kidney Int 1994, 45:916–927.

Correlation with Renal Failure D’Amico G, Ferrario F, Rastaldi MP: Tubulointerstitial damage in glomerular diseases: its role in the progression of renal damage. Am J Kidney Dis 1995, 26:124–132. Eddy AA: Experimental insights into tubulointerstitial disease accompanying primary glomerular lesions. J Am Soc Nephrol 1994, 5:1273–1287. Magil AB: Tubulointerstitial lesions in human membranous glomerulonephritis: relationship to proteinuria. Amer J Kidney Dis 1995, 25:375–379.

Analgesic Nephropathy Henrich WL, Agodoa LE, Barrett B, Bennett WM et al.: Analgesics and the Kidney. Summary and Recommendations to the Scientific Advisory Board of the National Kidney Foundation. Am J Kidney Dis 1996, 27:162–165 Nanra RS: Pattern of renal dysfunction in analgesic nephropathy. Comparison with glomerulonephritis. Nephrol Dialysis Transpl 1992, 7:384–390. Noels LM, Elseviers NM, DeBroe ME: Impact of legislative measures of the sales of analgesics and the subsequent prevalence of analgesic nephropathy: a comparative study in France, Sweden and Belgium. Nephrol Dial Transplant 1995, 10:167–174. Perneger TV, Whelton PK, Klag MJ: Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs. N Engl J Med 1994, 331:1675–1679. Sandler DP, Burr FR, Weinberg CR: Nonsteroidal anti-inflammatory drugs and risk of chronic renal failure. Ann Intern Med 1991, 115:165–172. Sandler DP, Smith JC, Weinberg CR et al.: Analgesic use and chronic renal disease. N Engl J Med 1989, 320:1238–1243.

Heavy Metals Batuman V: Lead nephropathy, gout, hypertension. Am J Med Sci 1993, 305:241–247. Batuman V, Maesaka JK, Haddad B et al.: Role of lead in gouty nephropathy. N Engl J Med 1981, 304:520–523. Fowler BA: Mechanisms of kidney cell injury from metals. Environ Health Perspec 1993, 100:57–63. Hu H: A 50-year follow-up of childhood plumbism. Hypertension, renal function and hemoglobin levels among survivors. Am J Dis Child 1991, 145:681–687. Staessen JA, Lauwerys RR, Buchet JP et al.: Impairment of renal function with increasing lead concentrations in the general population. N Engl J Med 1992, 327:151–156. Vedeen RP: Environmental renal disease: lead. cadmium, and Balkan endemic nephropathy. Kidney Int 34(suppl):4–8.

Ischemic Vascular Disease Freedman BI, Ishander SS, Buckalew VM et al.: Renal biopsy findings in presumed hypertensive nephrosclerosis. Am J Nephrol 1994, 14:90–94. Meyrier A, Simon P: Nephroangiosclerosis and hypertension: things are not as simple as you might think. Nephrol Dial Transplant 1996, 11:2116–1220. Schlesinger SD, Tankersley MR, Curtis JJ: Clinical documentation of end stage renal disease due to hypertension. Am J Kidney Dis 1994, 23:655–660.

Obstructive Nephropathy Arant BS Jr: Vesicoureteric reflux and renal injury. Am J Kidney Dis 1991, 17:491–511. Diamond JR: Macrophages and progressive renal disease in experimental hydronephrosis. Am J Kidney Dis 1995, 26:133–140. Klahr S: New insight into consequences and mechanisms of renal impairment in obstructive nephropathy. Am J Kidney Dis 1991, 18:689–699.

Hematologic Diseases Allon M: Renal abnormalities in sickle cell disease. Arch Intern Med 1990, 150:501–504. Falk RJ, Scheinmann JI, Phillips G et al.: Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin converting enzyme. N Engl J Med 1992, 326:910–915. Ivanyi B: Frequency of light chain deposition nephropathy relative to renal amyloidosis and Bence Jones cast nephropathy in a necropsy study of patients with myeloma. Arch Pathol Lab Med 1990, 114:986–987. Rota S, Mougenot B, Baudouin M: Multiple myeloma and severe renal failure: a clinicopathologic study of outcome and prognosis in 34 patients. Medicine 1987, 66:126–137. Sanders PW, Herrera GA, Kirk KA: Spectrum of glomerular and tubulointerstitial renal lesions associated with monotypical immunoglobulin light chain deposition. Lab Invest 1991, 64:527–537.

Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis

6.25

Metabolic Disorders

Viral Infections

Chaplin AJ: Histopathological occurrence and characterization of calcium oxalate. A review. J Clin Pathol 1977, 30:800–811.

Ito M, Hirabayashi N, Uno Y: Necrotizing tubulointerstitial nephritis associated with adenovirus infection. Human Pathol 1991, 22:1225–1231. Papadimitriou M.: Hantavirus nephropathy. Kidney Int 1995, 48:887–902.

Foley RJ, Weinman EJ: Urate nephropathy. Am J Med Sci 1984, 288:208–211. Hanif M, Mobarak MR, Ronan A: Fatal renal failure caused by diethylene glycol in paracetamol elixir: the Bangladesh epidemic. Br Med J 1995, 311:88–91.

Hereditary Diseases

Zawada ET, Johnson VH, Bergstein J: Chronic interstitial nephritis. Its occurrence with oxalosis and antitubular basement membrane antibodies after jejunal bypass. Arch Pathol Ub Med 1981, 105:379–383.

Fick GM, Gabow PA: Hereditary and acquired cystic disease of the kidney. Kidney Int 1994, 46:951–964. Gabow PA, Johnson AM, Kaehny VM: Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease. Kidney Int 1992, 41:1311–1319. Gregory MC, Atkin CL: Alports syndrome, Fabry’s disease and nail patella syndrome. In Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little Brown; 1997:561–590.

Granulomatous Diseases

Papillary Necrosis

Schneider JA, Lovell H, Calhoun F: Update on nephropathic cystinosis. Ped Nephrol 1990, 4:645–653.

Mignon F, Mery JP, Mougenot B, et al.: Granulomatous interstitial nephritis. Adv Nephrol 1984, 13:219–245. Viero RM, Cavallo T: Granulomatous interstitial nephritis. Hum Pathol 1995, 26:1345–1353.

Griffin MD, Bergstralk EJ, Larson TS: Renal papillary necrosis. A sixteen year clinical experience. J Am Soc Nephrol 1995, 6:248–256. Sabatini S, Eknoyan G, editors: Renal papillary necrosis. Semin Nephrol 1984, 4:1–106.

Urinary Tract Infection Alain Meyrier

T

he concern of renal specialists for urinary tract infections (UTIs) had declined with the passage of time. This trend is now being reversed, owing to new imaging techniques and to substantial progress in the understanding of host-parasite relationships, of mechanisms of bacterial uropathogenicity, and of the inflammatory reaction that contributes to renal lesions and scarring. UTIs account for more than 7 million visits to physicians’ offices and well over 1 million hospital admissions in the United States annually [1]. French epidemiologic studies evaluated its annual incidence at 53,000 diagnoses per million persons per year, which represents 1.05% to 2.10% of the activity of general practitioners. In the United States, the annual number of diagnoses of pyelonephritis in females was estimated to be 250,000 [2]. The incidence of UTI is higher among females, in whom it commonly occurs in an anatomically normal urinary tract. Conversely, in males and children, UTI generally reveals a urinary tract lesion that must be identified by imaging and must be treated to suppress the cause of infection and prevent recurrence. UTI can be restricted to the bladder (essentially in females) with only superficial mucosal involvement, or it can involve a solid organ (the kidneys in both genders, the prostate in males). Clinical signs and symptoms, hazards, imaging, and treatment of various types of UTIs differ. In addition, the patient’s background helps to further categorize UTIs according to age, type of urinary tract lesion(s), and occurrence in immunocompromised patients, especially with diabetes or pregnancy. Such various forms of UTI explain the wide spectrum of treatment modalities, which range from ambulatory, single-dose antibiotic treatment of simple cystitis in young females, to rescue nephrectomy for pyonephrosis in a diabetic with septic shock. This chapter categorizes the various forms of UTI, describes progress in diagnostic imaging and treatment, and discusses recent data on bacteriology and immunology.

CHAPTER

7

7.2

Tubulointerstitial Disease

Diagnosis

A

B

C

FIGURE 7-1 Urine test strips. Normal urine is sterile, but suprapubic aspiration of the bladder, which is by no means a routine procedure,

Schematic set up of a dip-slide container

would be the only way of proving it. Urinary tract infection (UTI) cannot be identified simply by the presence of bacteria in a voided specimen, as micturition flushes saprophytic urethral organisms along with the urine. Thus a certain number of colonyforming units of uropathogens are to be expected in the urine sample. Midstream collection is the most common method of urine sampling used in adults. When urine cannot be studied without delay, it must be stored at 4ºC until it is sent to the bacteriology laboratory. The urine test strip is the easiest means of diagnosing UTI qualitatively. This test detects leukocytes and nitrites. Simultaneous detection of the two is highly suggestive of UTI. This test is 95% sensitive and 75% specific, and its negative predictive value is close to 96% [3]. The test does not, however, detect such bacteria as Staphyloccocus saprophyticus, a strain responsible for some 3% to 7% of UTIs. Thus, treating UTI solely on the basis of test strip risks failure in about 15% of simple community-acquired infections and a much larger proportion of UTIs acquired in a hospital.

Interpretation after 24-hour incubation at 37°C

Paddle-holding Nonsignificant stopper

Significant

Agar

Moist sponge

103

104

105

106

107

FIGURE 7-2 Culture interpretation. Urinalysis must examine bacterial and leukocyte counts (per milliliter). An approximate way of estimating bacterial counts in the urine uses a dip-slide method: a plastic paddle covered on both sides with culture medium is

immersed in the urine, shaken, and incubated overnight. The most specific results, however, are provided by laboratory analysis, which allows precise counting of bacteria and leukocytes. Normal values for a midstream specimen are less than or equal to 105 Escherichia coli organisms and 104 leukocytes per milliliter. These classical “Kass criteria,” however, are not always reliable. In some cases of incipient cystitis the number of E. coli per milliliter can be lower, on the order of 102 to 104 [4]. When fecal contamination has been ruled out, growth of bacteria that are not normally urethral saprophytes indicates infection. This is the case for Pseudomonas, Klebsiella, Enterobacter, Serratia, and Moraxella, among others, especially in a hospital setting or after urologic procedures.

Urinary Tract Infection

CAUSES OF ASEPTIC LEUKOCYTURIA Self-medication before urine culture Sample contamination by cleansing solution Vaginal discharge Urinary stone Urinary tract tumor Chronic interstitial nephritis (especially due to analgesics) Fastidious microorganisms requiring special culture medium (Ureaplasma urealyticum, Chlamydia, Candida)

7.3

FIGURE 7-3 Leukocyturia. A significant number of leukocytes (more than 10,000 per milliliter) is also required for the diagnosis of urinary tract infection, as it indicates urothelial inflammation. Abundant leukocyturia can originate from the vagina and thus does not necessarily indicate aseptic urinary leukocyturia [1]. Bacterial growth without leukocyturia indicates contamination at sampling. Significant leukocyturia without bacterial growth (aseptic leukocyturia) can develop from various causes, among which self-medication before urinalysis is the most common.

Bacteriology A. MAIN MICROBIAL STRAINS RESPONSIBLE FOR URINARY TRACT INFECTION

Microbial Strain Escherichia coli Proteus mirabilis Klebsiella Enterobacter Enterococcus Staphylococcus saprophyticus Other species

Percent

100

First Episode or Delayed Relapse

Relapse Due to Early Reinfection

71%–79% 1.1%–9.7% — 1.0%–9.2% 1.0%–3.2% 3%–7% 2%–6%

60% 15% 20% — — — 5%

FIGURE 7-4 Principal pathogens of urinary tract infection (UTI). A and B, Most pathogens responsible for UTI are enterobacteriaceae with a high predominance of Escherichia coli. This is especially true of spontaneous UTI in females (cystitis and pyelonephritis). Other strains are less common, including Proteus mirabilis and more rarely gram-positive microbes. Among the latter, Staphylococcus saprophyticus deserves special mention, as this gram-positive pathogen is responsible for 5% to 15% of such primary infections, is not detected by the leukocyte esterase dipstick, and is resistant to antimicrobial agents that are active on gram-negative rods. C, Acute simple pyelonephritis is a common form of upper UTI in females and results from the encounter of a parasite and a host. In the absence of urologic abnormality, this renal infection is mostly due to uropathogenic strains of bacteria [5,6], a majority of cases to community-acquired E. coli. The clinical picture consists of fever, chills, renal pain, and a general discomfort. Tissue invasion is associated with a high erythrocyte sedimentation rate and C-reactive protein level well above 2 mg/dL.

Minimum Maximum

E. coli 60%

Other 5% 50 P. mirabilis 15% Klebsiella 20% 0

B

E. coli P. mirabilis Klebsiella Enterococcus S. saprophyticus Other Enterobacter

C

7.4

Tubulointerstitial Disease

Virulence Factors of Uropathogenic Strains Escherichia coli P

Fimbriae

S Type 1

Flagella Hemolysin

Aerobactin

+ Na+ Na

Fe3+

Erythrocyte

FIGURE 7-5 Bacterial uropathogenicity plays a major role in host-pathogen interactions that lead to urinary tract infection (UTI). For Escherichia coli, these factors include flagella necessary for motility, aerobactin necessary for iron acquisition in the iron-poor environment of the urinary tract, a pore-forming hemolysin, and, above all, presence of adhesins on the bacterial fimbriae, as well as on the bacterial cell surface. (From Mobley et al. [7]; with permission.)

Proteus mirabilis Fimbriae MR/P PMF ATF NAF

Deaminase

Urease

Flagella

Ni Urea

2+

[Keto acid]3Fe3+ Amino acid

NH3+CO2 IgA protease Hemolysin

Na+

Renal epithelial cell

FIGURE 7-7 Proteus mirabilis is endowed with other nonfimbrial virulence factors, including the property of secreting urease, which splits urea into NH3 and CO2.

FIGURE 7-6 An electron microscopic view of an Escherichia coli organism showing the fimbriae (or pili) bristling from the bacterial cell.

FIGURE 7-8 Staghorn calculi. Ammonium generation alkalinizes the urine, creating conditions favorable for build-up of voluminous struvite stones, which can progressively invade the entire pyelocalyceal system, forming staghorn calculi. These stones are an endless source of microbes, and the urinary tract obstruction perpetuates infection.

Urinary Tract Infection Fimbrial adhesive structures Type 1 Fimbriae Type P Fimbriae Adhesin

Fibrillum

7.5

Nonfimbrial adhesive structure

PapG

FimH

PapF

FimH, FimG

PapE

FimF, FimG

PapK

FimA ~100 FimA

Rigid fiber PapA Adhesins PapH

Pilin Minor subunits Adhesin

FIGURE 7-9 Schematic representation of morphology and composition of type P and type 1 adhesive structures. Bacterial adhesins are paramount in fostering attachment of the bacteria to the mucous membranes of the perineum and of the urothelium. There are several molecular forms of adhesins. The most studied is the pap G adhesin, which is located at the tip of the bacterial fimbriae (or pili). This lectin recognizes binding site conformations provided by oligosaccharide sequences present on the mucosal surface [8].

FIGURE 7-10 Uropathogenic strains of Escherichia coli readily adhere to epithelial cells. This figure shows two epithelial cells incubated in urine infected with E. coli–carrying pap adhesins. Numerous bacteria are scattered on the epithelial cell membranes. About half of all cases of cystitis are due to uropathogenic strains of E. coli–carrying adhesins. Females with primary pyelonephritis and no urologic abnormality harbor a uropathogenic strain in almost 100% of cases [5].

APPROPRIATE ANTIBIOTICS FOR URINARY TRACT INFECTIONS

Antibiotics Aminoglycosides Aminopenicillins Carboxypenicillins Ureidopenicillins Quinolones Fluoroquinolones Cephalosporins First generation Second generation Third generation Monobactams Carbapenem Cotrimoxazole Fosfomycin trometamole Nitroturantoin

General Indications

Pregnancy

Prophylaxis

+ +† + + +‡ +§

+* + + + -

+ +

+¶ + + + + + +** +††

+ + + + + -

+‡ +‡ +

* Aminoglycosides should not be prescribed during pregnancy except for very severe infection and for the shortest

possible duration. With the exception of amoxicillin plus clavulanic acid, aminopenicillins should not be prescribed as first-line treatment, owing to the frequency of primary resistance to this class of antibiotics. ‡ According to antibiotic sensitivity tests. § Fluoroquinolones carry a risk of tendon rupture (especially Achilles tendon). ¶ Oral administration only. ** Single-dose treatment of cystitis. †† Simple cystitis; not pyelonephritis or prostatitis.

FIGURE 7-11 Appropriate antibiotics for urinary tract infections (UTI). An appropriate antibiotic for treating UTI must be bactericidal and conform to the following general specifications: 1) its pharmacology must include, in case of oral administration, rapid absorption and attainment of peak serum concentrations; 2) its excretion must be predominantly renal; 3) it must achieve high concentrations in the renal or prostate tissue; 4) it must cover the usual spectrum of enterobacteria with reasonable chance of being effective on an empirical basis. Excluding special considerations for childhood and pregnancy, several classes of antibiotics fulfill these specifications and can be used alone or in combination. The choice also depends on market availability, cost, patient tolerance, and potential for inducing emergence of resistant strains.

7.6

Tubulointerstitial Disease

Classification of Urinary Tract Infection Upper versus lower urinary tract infection FIGURE 7-12 Cystitis in a female patient. In case of urinary tract infection (UTI), distinguishing between lower and upper tract infection is classical, but the distinction is also beside the point. The real point is to determine whether infection is confined to the bladder mucosa, which is the case in simple cystitis in females, or whether it involves solid organs (ie, prostatitis or pyelonephritis). The dots in this figure symbolize the presence of bacteria and leukocytes (ie, infection) in the relevant organ. Here, infection is confined to the bladder mucosa, which can be severely inflamed and edematous. This could be reflected radiographically by mucosal wrinkling on the cystogram. In some cases inflammation is severe enough to be accompanied by bladder purpura, which induces macroscopic hematuria but is not a particular grave sign.

FIGURE 7-13 Prostatitis. Anatomically, prostatitis involves the lower urinary tract, but invasion of prostate tissue affords easy passage of pathogens to the prostatic venous system— and, usually, poor penetration by antibiotics. Presence of bacteria in the bladder is also symbolized in this picture, but owing to free communication between bladder urine and prostate tissue, it can be accepted that pure cystitis does not exist in males.

FIGURE 7-14 Acute prostatitis can be complicated by ascending infection, that is, pyelonephritis.

FIGURE 7-15 Pyelonephritis in females. Essentially, this is an ascending infection caused by uropathogens. From the perineum the bacteria gain access to the bladder, ascending to the renal pelvocalyceal system and thence to the renal medulla, from which they spread toward the cortex. It has been shown that “pyelitis” cannot be considered a pathologic entity, as renal pelvis infection is invariably associated with nearby contamination of the renal medulla.

Urinary Tract Infection

7.7

CRITERIA FOR TISSUE INVASION Clinical Kidney or prostate infection is marked by fever over 38°C, chills, and pain. The patient appears acutely ill. Laboratory Tissue invasion is invariably accompanied by an erythrocyte sedimentation rate over 20 mm/h and serum C-reactive protein levels over 2.0 mg/dL. Blood cultures grow in 30%–50% of cases, which in an immunocompetent host indicates simply bacteremia, not septicemia. This reflects easy permeability between the urinary and the venous compartments of the kidney. Imaging When indicated, ultrasound imaging, tomodensitometry, and scintigraphy provide objective evidence of pyelonephritis. In case of vesicoureteral reflux, urinary tract infection necessarily involves the upper urinary tract.

FIGURE 7-17 Criteria for tissue invasion. FIGURE 7-16 Renal abscess formation. As specified elsewhere, renal abscess due to enterobacteriaceae (as opposed to hematogenous renal abscess, often of staphylococcal origin) can be considered a severe form of pyelonephritis with renal tissue liquefaction, ending in a walled-off cavity.

Primary versus secondary urinary tract infection FIGURE 7-19 Cystogram of a 65-year-old woman. A voluminous bladder tumor (arrows) infiltrates the bladder floor and the initial segment of the urethra.

FIGURE 7-18 An episode of urinary tract infection (UTI) should prompt consideration of whether it involves a normal urinary tract or, alternatively, if it is a complication of an anatomic malformation. This is especially true of relapsing UTI in both genders, and this hypothesis should be systematically raised in males and in children. Recurrent cystitis in females can be explained by hymeneal scars that pull open the urethral outlet during intercourse. Although rarely, other malformations that promote recurrent female cystitis are occasionally discovered, such as urethral diverticula (arrows). Finally, it should be recalled that recurrent or chronic cystitis in an older woman can also reveal an unsuspected bladder tumor.

7.8

Tubulointerstitial Disease FIGURE 7-20 Urethrocystogram of a man following acute prostatitis. In males, acute prostatitis may reveal urethral stenosis. Urethral stenosis is a good explanation for acute prostatitis. The beaded appearance of the stenosis (arrow) suggests an earlier episode of gonorrheal urethritis.

I

II

III

IV

V

FIGURE 7-21 The severity of vesicoureteral reflux (VUR) as graded in 1981 by the International Reflux Study Committee. When children have

A FIGURE 7-22 Cystogram demonstrating left ureteral reflux (A). The consequences on the left kidney (B) consist of calyceal distension and a clubbed appearance due to the destruction of the papillae and of

pyelonephritis, the possibility of VUR should always be considered. Childhood vesicoureteral reflux is five times more common in girls than in boys. It has a genetic background: several cases occasionally occur in the same family. Unless detected and corrected early, especially the most severe forms of this class and when urine is infected (one episode of pyelonephritis suffices), childhood VUR is a major cause of cortical scarring, renal atrophy, and in bilateral cases chronic renal insufficiency. The International Reflux Study classifies reflux grades as follows: I) ureter only; II) ureter, pelvis, and calyces, no dilation, and normal calyceal fornices; III) mild or moderate dilation or tortuosity of ureter and mild or moderate dilation of renal pelvis but no or slight blunting of fornices; IV) moderate dilation or tortuosity of ureter and moderate dilation of renal pelvis and calyces, complete obliteration of sharp angle of fornices but maintenance of papillary impressions in majority of calyces; V) gross dilation and tortuosity of ureter, gross dilation of renal pelvis and calyces. Papillary impressions are no longer visible in the majority of calyces. (From International Reflux Study Committee [9]; with permission.)

B the adjacent renal tissue. The calyceal cavities are very close to the renal capsule, indicating complete cortical atrophy. This picture is typical of chronic pyelonephritis secondary to vesicoureteral reflux.

Urinary Tract Infection

FIGURE 7-23 In case of bilateral, neglected vesicoureteral reflux, chronic pyelonephritis is bilateral and asymmetric. Here, the right kidney is globally atrophic. A typical cortical scar is seen on the outer aspect of the left kidney. The lower pole, however, is fairly well-preserved with nearly normal parenchymal thickness.

FIGURE 7-25 (see Color Plate) In children, isotopic cystography allows a diagnosis of vesicoureteral reflux with much less radiation than if cystography were carried out with iodinated contrast medium.

7.9

FIGURE 7-24 When intravenous pyelography discloses two ureters, the one draining the lower pyelocalyceal system crosses the upper ureter and opens into the bladder less obliquely than normally, allowing reflux of urine and explaining repeated attacks of pyelonephritis followed by atrophy of the lower pole of the kidney. Retrograde cystography is indicated for repeated episodes of pyelonephritis and when intravenous pyelography or computed tomography renal examination discovers cortical scars. In adults, retrograde cystography is obtained by direct catheterization of the bladder. FIGURE 7-26 In the paraplegic, and more generally in patients with spinal disease, neurogenic bladder is responsible for stasis, bladder distension, and diverticula. These functional and anatomic factors explain the frequency of chronic urinary tract infection complicated with bladder and upper urinary tract infectious stones.

7.10

Tubulointerstitial Disease

Imaging

FIGURE 7-27 When acute pyelonephritis occurs in a sound, immunocompetent female with no history of urologic disease, imaging can be limited to a plain abdominal film (to rule out renal and ureteral stones) and renal ultrasonography. Ultrasonography typically discloses a swollen kidney with loss of corticomedullary differentiation, denoting renal inflammatory edema. Images corresponding to the infected zones are more dense than normal renal tissue (arrows).

A FIGURE 7-29 Computed tomodensitometry. Simple pyelonephritis does not require much imaging; however, it should be remembered that there is no correlation between the severity of the clinical picture and the renal lesions. Therefore, a diagnosis of “simple” pyelonephritis at first contact can be questioned when response to treatment is not clear after 3 or 4 days. This is an indication for uroradiologic imaging, such as renal tomodensitometry followed by radiography of the urinary tract while it is still opacified by the contrast medium. The typical picture of acute pyelonephritis observed after contrast medium injection [10] consists of hypodensities of the infected

FIGURE 7-28 The ultrasound procedure occasionally discloses the cavity of a small renal abscess, a common complication of acute pyelonephritis, even in simple forms.

B areas in an edematous, swollen kidney. The pathophysiology of hypodense images has been elucidated by animal experiments in the primates [11] which have shown that renal infection with uropathogenic Escherichia coli induces intense vasoconstriction. Computed tomodensitometric images of acute pyelonephritis can take various appearances. The most common findings consist of one or several wedge-shaped or streaky zones of low attenuation extending from papilla to cortex, A. Hypodense images can be round, B. On this figure, the infected zone reaches the renal cortex and is accompanied with adjacent perirenal edema. Several such (Continued on next page)

Urinary Tract Infection

C

7.11

D FIGURE 7-29 (Continued) images can coexist in the same kidney, C. Marked juxtacortical, circumscribed hypodense zones, bulging under the renal capsule, D, usually correspond to lesions close to liquefaction and should be closely followed, as they can lead to abscess formation and opening into the perinephric space, E and F. (E and F from Talner et al. [10]; with permission.)

F

E

FIGURE 7-30 Comparative sensitivity of four diagnostic imaging techniques for acute pyelonephritis. Renal cortical scintigraphy using 99mTc-dimethyl succinic acid (DMSA) or 99mTc-gluconoheptonate (GH) is very sensitive for diagnosing acute pyelonephritis. It entails very little irradiation as compared with conventional radiography using contrast medium. Some nephrologists consider 99mTc-DMSA cortical scintigraphy as the first-line diagnostic imaging method for renal infection in children. It is interesting to compare its sensitivity with that of more conventional imaging methods. (From Meyrier and Guibert [5]; with permission.)

100 86

Percent

75

50

42

24

0 Renal scintigraphy

CT scan Ultrasonography

IVP (intravenous pyelography)

7.12

Tubulointerstitial Disease FIGURE 7-31 (see Color Plate) cortical imaging of simple pyelonephritis in a female. The clinical signs implicated the right kidney. (Contrary to conventional radiology, the right kidney appears on the right of the image.) The false colors indicate cortical renal blood supply from red (normal) to blue (ischemia). The right kidney is obviously involved with pyelonephritis, especially its poles. However, contrary to the results of computed tomography, which indicated right-sided pyelonephritis only, a focus of infection also occupies the lower pole of the right kidney. This picture illustrates the greater sensitivity of renal scintigraphy for diagnosing renal infection. It also indicates that clinically unilateral acute pyelonephritis can, in fact, be bilateral.

99mTc-DMSA

A FIGURE 7-32 Renal pathology in acute pyelonephritis. Renal pathology of human acute pyelonephritis is quite comparable to what is observed in experimental pyelonephritis in primates [11]. However, our knowledge of renal pathology in this condition in humans is based mainly on the most catastrophic cases, which required nephrectomy, like

A FIGURE 7-33 Histologic appearance of pyelonephritic kidney. A, The renal tissue is severely edematous and interspersed with inflammatory cells and hemorrhagic streaks. B, On another section, severe inflammation,

B the diabetes patient whose kidney is shown here. A, The surgically removed kidney is swollen, and its surface shows whitish zones. B, A section of the same organ shows white suppurative areas (scattered with small abscesses) extending eccentrically from the medulla to the cortex. There also were sloughed papillae (see Fig. 7-37).

B comprising a majority of polymorphonuclear leukocytes, induces tubular destruction and is accompanied by a typical infectious cast in a tubular lumen (arrow).

Urinary Tract Infection

Clinical picture compatible with acute pyelonephritis (APN) Urine culture and cytology ESR CRP Renal scintigraphy and/or CT scan

Negative. Reconsider diagnosis of APN

No renal lesion. Seek other infection

Renal lesions. Maintain diagnosis of APN

Abnormal. Call urologist

Positive Initial work-up Previous history of upper UTI

Yes

IVP

Secondary APN Treat Treat cause infection

Possible urinary tract obstruction or stone? No

No previous history of upper UTI

Plain abdominal radiograph Ultrasonography Primary APN Drug therapy only

Normal

Day 1

Start treatment with first-line antibiotics Good clinical response and lab. Confirmation of appropriate initial antibiotic choice

Atypical clinical response or Wrong initial antibiotic choice

Continue same treatment

Adapt antibiotic treatment

Further imaging (IVP, CT)

Normal. Consider drug intolerance

Days 2 to 4 or 5

Abnormal. Call urologist

Days 5 to 15

Day 15

End treatment Recurrence of bacteriuria Radiourological work-up. New treatment

Verify urine sterility

Sterile

Between days 30 and 45

No further investigations or treatment

7.13

FIGURE 7-34 A general algorithm for the investigation and treatment of acute pyelonephritis. Treatment of acute pyelonephritis is based on antibiotics selected from the list in Figure 7-11. Preferably, initial treatment is based on parenteral administration. It is debatable whether common forms of simple pyelonephritis initially require both an aminoglycoside and another antibiotic. Initial parenteral treatment for an average of 4 days should be followed by about 10 days of oral therapy based on bacterial sensitivity tests. It is strongly recommended that urine culture be carried out some 30 to 45 days after the end of treatment, to verify that bacteriuria has not recurred. APN—acute pyelonephritis; ESR—erythrocyte sedimentation rate; CRP—C-reactive protein; UTI—urinary tract infection; IVP—intravenous pyelography. (From Meyrier and Guibert [5]; with permission.)

7.14

Tubulointerstitial Disease FIGURE 7-35 (see Color Plate) Renal abscess. Like acute pyelonephritis, one third of cases of renal abscess occur in a normal urinary tract; in the others it is a complication of a urologic abnormality. The clinical picture is that of severe pyelonephritis. In fact, it can be conceptualized as an unfavorably developing form of acute pyelonephritis that progresses from presuppurative to suppurative renal lesions, leading to liquefaction and formation of a walled-off cavity. The diagnosis of renal abscess is suspected when, despite adequate treatment of pyelonephritis (described in Fig. 7-34), the patient remains febrile after day 4. Here, necrotic renal tissue is visible close to the abscess wall. The tubules are destroyed, and the rest of the preparation shows innumerable polymorphonuclear leukocytes within purulent material.

A FIGURE 7-36 Renal computed tomography (CT). In addition to ultrasound examination, CT is the best way of detecting and localizing a renal abscess. The abscess cavity can be contained entirely within

B the renal parenchyma, A, or bulge outward under the renal capsule, risking rupture into Gerota’s space, B.

Urinary Tract Infection

7.15

B

A

FIGURE 7-37 Urinary tract infection (UTI) in the immunocompromised host. UTI results from the encounter of a pathogen and a host. Natural defenses against UTI rest on both cellular and humoral defense mechanisms. These defense mechanisms are compromised by diabetes, pregnancy, and advanced age. Diabetic patients often harbor asymptomatic bacteriuria and are prone to severe forms of pyelonephritis requiring immediate hospitalization and aggressive treatment in an intensive care unit. A particular complication of upper renal infection in diabetes is papillary necrosis (see Fig. 7-32). The pathologic appearance of a sloughing renal papilla, A. The sloughed papilla is eliminated and can be recovered by sieving the urine, B. In other cases, the necrotic papilla obstructs the ureter, causing retention of infected urine and severely aggravating the pyelonephritis. C, It can lead to pyonephrosis (ie, complete destruction of the kidney), as shown on CT.

C

Nonpregnant

Pregnant

500 IgG

Antibody activity, % of control

0 1000

IgA

500

0 1000

IgM

500

0

A

0

0 2 Time of sampling, wks

2

FIGURE 7-38 Urinary tract infection (UTI) in an immunocompromised host. Pregnancy is associated with suppression of the host’s immune response, in the form of reduced cytotoxic T-cell activity and reduced circulating immunoglobulin G (IgG) levels. Asymptomatic bacteriuria is common during pregnancy and represents a major risk of ascending infection complicated by acute pyelonephritis. (Continued on next page)

7.16

Tubulointerstitial Disease

Nonpregnant

Pregnant

>250 IgG

1000

250

200

0 1000

IgA

Levels of IL-6, units/mL

Antibody activity, Abs 405 nm

500 150

100

50 20

500

20 0 0 0 0

B

2 0 Time of sampling, wks

2

FIGURE 7-38 (Continued) Petersson and coworkers [12] recently demonstrated that the susceptibility of the pregnant woman to acute UTI is accompanied by reduced serum antibody activity (IgG, IgA, IgM), reduced urine antibody activity (IgG, IgA), and low interleukin 6 (IL-6) response, A–C, respectively.

Nonpregnant

C

Pregnant

Serum

Nonpregnant

Pregnant

Urine

The last may indicate that pregnant women have a generally reduced level of mucosal inflammation. These factors may be crucial for explaining the frequency and the severity of acute pyelonephritis during pregnancy. (From Petersson et al. [12]; with permission.) FIGURE 7-39 Acute prostatitis as visualized sonographically. Acute prostatitis is common after urethral or bladder infection (usually by Escherichia coli or Proteus organisms). Another cause is prostate hematogenous contamination, especially by Staphylococcus. Signs and symptoms of acute prostatitis, in addition to fever, chills, and more generally the signs and symptoms of tissue invasion by infection described above, are accompanied by dysuria, pelvic pain, and septic urine. Acute prostatitis is an indication for direct ultrasound (US) examination of the prostate by endorectal probe. In this case of acute prostatitis in a young male, US examination disclosed a prostatic abscess (1) complicating acute prostatitis in the right lobe (2). Acute prostatitis is an indication for thorough radiologic imaging of the whole urinary tract, giving special attention to the urethra. Urethral stricture may favor prostate infection (see Fig. 7-20).

Urinary Tract Infection

7.17

Special Forms of Renal Infection

A

B

FIGURE 7-40 (see Color Plate) Xanthogranulomatous pyelonephritis (XPN). XPN is a special form of chronic renal inflammation caused by an abnormal immune response to infected obstruction [13]. This case in a middle-aged woman with a long history of renal stones is typical. For several months she complained of flank pain, fever, fatigue, anorexia and weight loss. Laboratory workup found inflammatory anemia and increased erythrocyte sedimentation rate and C-reactive protein levels. Urinalysis showed pyuria and culture grew Escherichia coli. CT scan of the right kidney showed replacement of the renal tissue by several rounded, low-density areas and detected an

obstructive renal stone. Nephrectomy was performed. A, The obstructive renal stone is shown by an arrowhead. The renal cavities are dilated. The xanthogranulomatous tissue (arrows) consists of several round, pseudotumoral masses with a typical yellowish color due to presence of lipids. In some instances such xanthogranulomatous tissue extends across the capsule into the perirenal fat and fistulizes into nearby viscera such as the colon or duodenum. B, Microscopic view of the xanthogranulomatous tissue. This part of the lesion is made of lipid structures composed of innumerable clear droplets.

Spectrum of renal malakoplakia Inflammation

Mononuclear cells (nonspecific)

Interstitial nephritis

Persistent inflammation

von Hansemann cells (prediagnostic)

Megalocytic interstitial nephritis

Ca2+ Defective cell function

Michaelis-Gutmann (MG) bodies (diagnostic)

Malakoplakia

B

A

Destuctive granulomas xanthogranulomatous pyelonephritis

Fibrosis "pseudosarcoma"

FIGURE 7-41 Malakoplakia. Malakoplakia (or malacoplakia), like xanthogranulomatous pyelonephritis, is also a consequence of abnormal macrophage response to gram-negative bacteria, A. Malakoplakia occurs in association with chronic UTI [14]. In more than 20% of cases, affected persons have some evidence of immunosuppression, especially corticos-

teroid therapy for autoimmune disease. In 13% of the published cases, malakoplakia involved a transplanted kidney. The female-male ratio is 3:1. Lesions can involve the kidney, the bladder, or the ureter and form pseudotumors. B, Histologically, malakoplakia is distinguished by large, pale, periodic acid–Schiff–positive macrophages (von Hansemann cells) containing calcific inclusions (Michaelis-Gutmann bodies). The larger ones are often free in the interstitium. Malakoplakia, an unusual form of chronic tubulointerstitial nephritis, must be recognized by early renal biopsy and can resolve, provided treatment consisting of antibiotics with intracellular penetration is applied for several weeks. (B, Courtesy of Gary S. Hill, MD.)

7.18

Tubulointerstitial Disease

References 1. Stamm WE, Hooton TM: Management of urinary tract infections in adults. N Engl J Med 1993, 329:1328–1334. 2. Pinson AG, Philbrick JT, Lindbeck GH, Schorling JB: ED management of acute pyelonephritis in women: A cohort study. Am J Emerg Med 1994, 12:271–278. 3. Pappas PG: Laboratory in the diagnosis and management of urinary tract infections. Med Clin North Am 1991, 75:313–325. 4. Kunin CM, VanArsdale White L, Tong HH: A reassessment of the importance of “low-count” bacteriuria in young women with acute urinary symptoms. Ann Intern Med 1993, 119:454–460. 5. Meyrier A, Guibert J: Diagnosis and drug treatment of acute pyelonephritis. Drugs 1992, 44:356–367. 6. Meyrier A: Diagnosis and management of renal infections. Curr Opin Nephrol Hypertens 1996, 5:151–157. 7. Mobley HLT, Island MD, Massad G: Virulence determinants of uropathogenic Escherichia coli and Proteus mirabilis. Kidney Int 1994, 46(Suppl. 47):S129–S136.

8. Roberts JA, Marklund BI, Ilver D, et al.: The Gal( 1-4)Gal– specific tip adhesin of Escherichia coli P-fimbriae is needed for pyelonephritis to occur in the normal urinary tract. Proc Natl Acad Sci USA 1994, 91:11889–11893. 9. International Reflux Study Committee: Medical versus surgical treatment of primary vesicoureteral reflux. J Urol 1981, 125:277. 10. Talner LB, Davidson AJ, Lebowitz RL, et al.: Acute pyelonephritis: Can we agree on terminology? Radiology 1994, 192:297–306. 11. Roberts JA: Etiology and pathophysiology of pyelonephritis. Am J Kidney Dis 1991, 17:1–9. 12. Petersson C, Hedges S, Stenqvist K, et al.: Suppressed antibody and interleukin-6 responses to acute pyelonephritis in pregnancy. Kidney Int 1994, 45:571–577. 13. Case records of the Massachusetts General Hospital. N Engl J Med 1995, 332:174–179. 14. Dobyan DC, Truong LD, Eknoyan G: Renal malacoplakia reappraised. Am J Kidney Dis 1993, 22:243–252.

Reflux and Obstructive Nephropathy James M. Gloor Vicente E. Torres

R

eflux nephropathy, or renal parenchymal scarring associated with vesicoureteral reflux (VUR), is an important cause of renal failure. Some studies have shown that in up to 10% of adults and 30% of children requiring renal replacement therapy for end-stage renal disease, reflux nephropathy is the cause of the renal failure. Reflux nephropathy is thought to result from the combination of VUR of infected urine into the kidney by way of an incompetent ureterovesical junction valve mechanism and intrarenal reflux. Acute inflammatory responses to the infection result in renal parenchymal damage and subsequent renal scarring. Loss of functioning renal mass prompt compensatory changes in renal hemodynamics that, over time, are maladaptive and result in glomerular injury and sclerosis. Clinically, reflux nephropathy may cause hypertension, proteinuria, and decreased renal function when the scarring is extensive. The identification of VUR raises the theoretic possibility of preventing reflux nephropathy. The inheritance pattern of VUR clearly is suggestive of a strong genetic influence. Familial studies of VUR are consistent with autosomal dominant transmission, and linkage to the major histocompatibility genes has been reported. Identification of infants with reflux detected on the basis of abnormalities seen on prenatal ultrasound examinations before urinary tract infection occurs may provide an opportunity for prevention of reflux nephropathy. In persons with VUR detected at the time of diagnosis of a urinary tract infection, avoidance of further infections may prevent renal injury. Nevertheless, the situation is far from clear. Most children with reflux nephropathy already have renal scars demonstrable at the time of the urinary tract infection that prompts the diagnosis of VUR. Most children found to have VUR do not develop further renal scarring after diagnosis, even after subsequent urinary tract infections. Other children may develop renal scars in the absence of further urinary tract infections. The best treatment of

CHAPTER

8

8.2

Tubulointerstitial Disease

VUR has not yet been firmly established. No clear advantage has been demonstrated for surgical correction of VUR versus medical therapy with prophylactic antibiotics after 5 years of follow-up examinations. New surgical techniques such as the submucosal injection of bioinert substances may have a role in select cases. The term obstructive nephropathy is used to describe the functional and pathologic changes in the kidney that result from obstruction to the flow of urine. Obstruction to the flow of urine

usually is accompanied by hydronephrosis, an abnormal dilation of the renal pelvis, and calices. However, because hydronephrosis can occur without functional obstruction, the terms obstructive nephropathy and hydronephrosis are not synonymous. Hydronephrosis is found at autopsy in 2% to 4% of cases. Obstructive nephropathy is responsible for approximately 4% of end-stage renal failure. Obstruction to the flow of urine can occur anywhere in the urinary tract and has many different causes.

CAUSES OF OBSTRUCTIVE NEPHROPATHY Intraluminal Calculus, clot, renal papilla, fungus ball Intrinsic Congenital: Calyceal infundibular obstruction Ureteropelvic junction obstruction Ureteral stricture or valves Posterior urethral valves Anterior urethral valves Urethral stricture Meatal stenosis Prune-belly syndrome Neoplastic: Carcinoma of the renal pelvis, ureter, or bladder Polyps

Extrinsic Congenital (aberrant vessels): Congenital hydrocalycosis Ureteropelvic junction obstruction Retrocaval ureter Neoplastic tumors: Benign tumors: Benign prostatic hypertrophy Pelvic lipomatosis Cysts Primary retroperitoneal tumors: Mesodermal origin (eg, sarcoma) neurogenic origin (eg, neurofibroma) Embryonic remnant (eg, teratoma) Retroperitoneal extension of pelvic or abdominal tumors: Uterus, cervix Bladder, prostate Rectum, sigmoid colon Metastatic tumor: Lymphoma Inflammatory: Retroperitoneal fibrosis Inflammatory bowel disease Diverticulitis Infection or abscess Gynecologic: Pregnancy Uterine prolapse Surgical disruption or ligation Functional Neurogenic bladder Drugs(anticholinergics, antidepressants, calcium channel blockers)

FIGURE 8-1 Obstructive nephropathy is responsible for end-stage renal failure in approximately 4% of persons. Obstruction to the flow of urine can occur anywhere in the urinary tract. Obstruction can be caused by luminal bodies; mural defects; extrinsic compression by vascular, neoplastic, inflammatory, or other processes; or dysfunction of the autonomic nervous system or smooth muscle of the urinary tract. The functional and clinical consequences of urinary tract obstruction depend on the developmental stage of the kidney at the time the obstruction occurs, severity of the obstruction, and whether the obstruction affects one or both kidneys.

Reflux and Obstructive Nephropathy

8.3

Anatomy of Vesicoureteric Reflux

Intramural ureter

FIGURE 8-2 Anatomy of the ureterovesical junction. The ureterovesical junction permits free antegrade urine flow from the upper urinary tract into the bladder and prevents retrograde urinary reflux from the bladder into the ureter and kidney. Passive compression of the distal submucosal portion of the ureter against the detrusor muscle as a result of bladder filling impedes vesicoureteral reflux (VUR). An active mechanism preventing reflux also has been proposed in which contraction of longitudinally arranged distal ureteral muscle fibers occludes the ureteral lumen, impeding retrograde urine flow [1–3]. (From Politano [4]; with permission.)

Submucosal ureter

Bladder wall

Ureter

A

B 12 mm

A'

C 8 mm

B'

D 5 mm

C'

E 2 mm

D'

0 mm

FIGURE 8-3 Tissue sagittal sections (upper panels) and cystoscopic appearances (lower panels) of the ureterovesical junction illustrating varying submucosal tunnel lengths. The length of the submucosal segment of the distal ureter is an important factor in determining the effectiveness of the ureteral valvular mechanism in preventing vesicoureteral reflux (VUR). In children without VUR, the ratio of tunnel length to ureteral diameter is significantly greater than in children with VUR [5,6]. (From Kramer [7]; with permission.)

E'

Cytoscopic view

FIGURE 8-4 Simple and compound papillae are illustrated [8,9]. Two types of renal papillae have been identified. Simple papillae are the most common type. They have slitlike papillary duct openings on their convex surface. These papillae are compressed by increases in pelvic pressure, preventing urine from entering the papillary ducts (intrarenal reflux). Compound papillae are formed by the fusion of two or more simple papillae. In compound papillae, some ducts open onto a flat or concave surface at less oblique angles. Increased intrapelvic pressure may permit intrarenal reflux. Compound papillae usually are found in the renal poles.

8.4

Tubulointerstitial Disease

Pathogenesis of Vesicoureteric Reflux and Reflux Nephropathy

FIGURE 8-5 Experimental vesicoureteric reflux in pigs. This pathology specimen demonstrates surgically induced vesicoureteric reflux in a 2-weekold male piglet. Note that the submucosal canal of one of the ureters has been unroofed.

A

B

FIGURE 8-7 Experimental vesicoureteric reflux in pigs. The polar location of acute suppurative pyelonephritis and evolution of parenchymal

FIGURE 8-6 Experimental vesicoureteric reflux in pigs: cystourethrogram showing intrarenal reflux. Reflux of radiocontrast medium into the renal parenchyma is seen. The pressure required to produce intrarenal reflux is lower in young children than it is in older children or adults, which is consistent with the observation that reflux scars occur more commonly in younger children [10].

C scars. In urinary tract infections, reflux of urine from the renal pelvis into the papillary ducts of compound papillae predominantly (Continued on next page)

Reflux and Obstructive Nephropathy

D

E

FIGURE 8-7 (Continued) located in the poles (intrarenal reflux) provides bacteria access to the renal parenchyma, resulting in suppurative pyelonephritis and subsequent polar scarring [11,12]. Intact (A, C, E) and coronally sectioned (B, D, F) kidneys illustrating the three stages of

8.5

F reflux nephropathy: Hemorrhagic with polymorphonuclear cell infiltrate (A, B); white, not retracted, with prominent mononuclear cell infiltrate (C, D), and retracted scan with prominent fibrosis (E, F). FIGURE 8-8 (see Color Plate) Experimental vesicoureteric reflux (VUR) in pigs: mesangiopathic lesions. Reflux of infected urine can result in glomerular lesions characterized by activation of mesangial cells, mesangial expansion, mesangial hypercellularity, and the presence of large granules. The granules test positive on periodic acid–Schiff reaction and are located inside cells with the appearance of macrophages. These glomerulopathic lesions occur by a process that does not require contiguity with the infected interstitium nor intrarenal reflux. These lesions are not related to reduction of renal mass. Similar glomerular lesions have been identified in piglets after intravenous administration of endotoxin. Whether similar glomerular lesions occur in infants or young children with VUR and reflux nephropathy is not known [13].

FIGURE 8-9 (see Color Plate) Experimental vesicoureteric reflux (VUR) in pigs: 99mTechnetium-dimercaptosuccinic acid (DMSA) scan demonstrating reflux nephropathy. Radionuclide imaging using DMSA has been found to be safe and effective in investigating reflux nephropathy [14]. DMSA is localized to the proximal renal tubules of the renal cortex. Parenchymal scars appear as a defect in the kidney outline, with reduced uptake of DMSA or by contraction of the whole kidney. Currently, DMSA radionuclide renal scanning is the most sensitive modality used to detect renal scars relating to reflux. New areas of renal scarring can be seen earlier with DMSA than with intravenous pyelography [15].

8.6

Tubulointerstitial Disease

Integrative View of Pathogenetic Mechanisms in Reflux Nephropathy Defective mesonephric mesoderm (ureteral bud) Abnormal induction of metanephric mesoderm VUR

High-voiding pressures

+

(In utero)

IRR + Virulent bacterial strain + Immune complexes Bacterial fragments Endotoxin

Susceptible host

Focal exudative reaction Glomerulopathy

Dysplasia

Inhibition of ureteral peristalsis Toxic urine component Delayed hypersensitivity

Pyelonephritic scar

Reduced nephron population

Hyperfiltration

Glomerulosclerosis

Sterile scar Back-pressure atrophy Diffuse interstitial fibrosis High-protein diet Hypertension Pregnancy

FIGURE 8-10 Integrative view of pathogenetic mechanisms in reflux nephropathy. Abnormalities of ureteral embryogenesis may result in a defective antireflux mechanism, permitting vesicoureteral reflux (VUR), incomplete bladder emptying, urinary stasis, and infection. Bacterial virulence factors modify the pathogenicity of different bacterial strains. Bacterial surface appendages such as fimbriae may interact with epithelial cell receptors of the urinary tract, enhancing bacterial adhesion to urothelium. Endotoxin is capable of inhibiting ureteral peristalsis, contributing to the extension of the infection into the upper urinary tract even in the absence of VUR. Inoculation of the renal parenchyma with bacteria produces an acute inflammatory response, resulting in the release of inflammatory mediators into the surrounding tissue. The acute inflammatory response elicited by the presence of infecting bacteria is responsible for the subsequent renal parenchymal injury. In addition, it is possible that immune complexes, bacterial fragments, and endotoxin resulting from infection may produce a glomerulopathy. Even in the absence of urinary tract infection, VUR associated with elevated intravesical pressure is capable of producing renal parenchymal scars. The developing kidney appears to be particularly susceptible. Renal tubular distention resulting from high intrapelvic pressure may exert an injurious effect on renal tubular epithelium. Compression of the surrounding peritubular capillary network by distended renal tubules may produce ischemia. During micturition, elevated intravesical pressure is transmitted to the renal pelvis and renal tubule. This transient pressure elevation may produce tubular disruption. Extravasation of urine into the surrounding parenchyma results in an immune-mediated interstitial nephritis and further renal injury. The reduction in functional renal mass produced by the interaction of the pathogenetic factors listed here induces compensatory hemodynamic changes in renal blood flow and the glomerular filtration rate. Over time, these compensatory changes may be maladaptive, may produce hyperfiltration and glomerulosclerosis, and may eventuate in renal insufficiency. (From Kramer [16]; with permission.)

Progressive renal insufficiency

FIGURE 8-11 Vesicoureteral reflux and renal dysplasia. An abnormal ureteral bud resulting from defective ureteral embryogenesis may penetrate the metanephric blastema at a site other than that required for optimum renal development, potentially resulting in renal dysplasia or hypoplasia [17].

Reflux and Obstructive Nephropathy

8.7

Diagnosis of Vesicoureteric Reflux and Reflux Nephropathy

I

II

III

IV

FIGURE 8-12 International system of radiographic grading of vesicoureteral reflux (VUR). The severity of VUR is most frequently classified according to the International Grading System of Vesicoureteral Reflux, using a standardized technique for performance of voiding cystourethrography. The definitions of this system are illustrated in Figure 8-4 and are as follows. In grade I, reflux only into the ureter occurs. In grade II, reflux into the ureter, pelvis, and calyces occurs. No dilation occurs, and the calyceal fornices are normal. In grade III, mild or moderate dilation, tortuosity, or both of the ureter are observed, with mild or moderate dilation of the renal pelvis. No or only slight blunting of the fornices is seen. In grade IV, moderate dilation, tortuosity, or both of the ureter occur, with moderate dilation of the renal pelvis and calyces. Complete obliteration of the sharp angle of the fornices is observed; however, the papillary impressions are maintained in most calyces. In grade V, gross dilation and tortuosity of the ureter occur; gross dilation of the renal pelvis and calyces is seen. The papillary impressions are no longer visible in most calyces [18].

V

Types of renal scarring

A

Mild

B

Severe

C "Back-pressure"

D End-stage

FIGURE 8-13 Grading of renal scarring associated with vesicoureteral reflux. Reflux renal parenchymal scarring detected on intravenous pyelography can be classified according to the system adopted by the

International Reflux Study Committee consisting of four grades of severity. In grade 1, mild scarring in no more than two locations is seen. More severe and generalized scarring is seen in grade 2 but with normal areas of renal parenchyma between scars. In grade 3, or so-called backpressure type, contraction of the whole kidney occurs and irregular thinning of the renal cortex is superimposed on widespread distortion of the calyceal anatomy, similar to changes seen in obstructive uropathy. Grade 4 is characterized by end-stage renal disease and a shrunken kidney having very little renal function [19]. Parenchymal scarring detected by radionuclide renal scintigraphy is classified similarly. A, In grade 1, no more than two scarred areas are detected. B, In grade 2, more than two affected areas are seen, with some areas of normal parenchyma between them. C, Grade 3 renal scarring is characterized by general damage to the entire kidney, similar to obstructive nephropathy. D, In grade 4, a contracted kidney in end-stage renal failure is seen, with less than 10% of total overall function [14].

FIGURE 8-14 Voiding cystourethrogram demonstrating bilateral grade 5 vesicoureteral reflux. Voiding cystourethrography is performed by filling the bladder with radiocontrast material and observing for reflux under fluoroscopy, either during the phase of bladder filling or during micturition. Contrast material is infused through a small urethral catheter under gravity flow.

8.8

Tubulointerstitial Disease FIGURE 8-15 Radionuclide cystogram demonstrating bilateral vesicoureteral reflux (VUR). This method using 99mtechnetium pertechnetate is useful in detecting VUR. Advantages of radionuclide cystography include lower radiation exposure, less interference with overlying bowel contents and bones, and higher sensitivity in detection of VUR. Radionuclide cystography is useful in follow-up examinations of patients known to have VUR, as a screening test in asymptomatic siblings of children with reflux and girls with urinary tract infections, and in serial examinations of children with neuropathic bladders at risk for developing VUR. Disadvantages of this method include less anatomic detail and inadequacy in evaluating the male urethra, making it unsuitable for screening boys for urinary tract infections [7].

A

B

FIGURE 8-16 A, Intravenous pyelogram and, B, nephrotomogram demonstrating grade 2 reflux nephropathy. Historically, this testing modality has been the one most commonly used to evaluate reflux nephropathy [7]. Irregular renal contour, parenchymal thinning, small renal size, and calyceal blunting all are radiographic signs of reflux nephropathy on intravenous pyelography [17]. Radiographic changes may

not be visible immediately after renal infection, because scars may not be fully developed for several years [20]. The advantages of intravenous pyelography in evaluating reflux nephropathy include precision in delineating renal anatomic detail and providing baseline measurements for future follow-up evaluations, renal growth, and scar formation. FIGURE 8-17 A, Posterior and, B, anterior views of 99mtechnetium-dimercaptosuccinic acid (DMSA) renal scan showing bilateral grade 2 reflux nephropathy. This nephropathy is characterized by focal areas of decreased radionuclide uptake predominantly affecting the lower renal poles.

A

B

8.9

Reflux and Obstructive Nephropathy 13 12

Predicted mean 95% predicted limits

11

Renal length, cm

10 9 8 7 6 5 4 3 2 0 2 4 6 8 10 12

A

C

Months

5

10

15

Years

FIGURE 8-18 Prenatal detection of vesicoureteral reflux (VUR). A, Ultrasonography showing mild fetal hydronephrosis. B, Postnatal voiding cystourethrogram (VCUG) showing grade 4 VUR. C, Graph showing small renal size in the same infant. Vesicoureteral reflux has been identified in neonates in whom prenatal ultrasonography examination reveals hydronephrosis [21–28]. Normal infants do not have VUR, even when born prematurely [29,30]. The severity of reflux often is not predictable on the basis of appearance on ultrasonography [22,31]. Hydronephrosis greater than 4 mm and less than 10 mm in the anteroposterior dimension on ultrasound examination after 20 weeks’ gestational age has been termed mild fetal hydronephrosis. Mild fetal hydronephrosis is associated with VUR in a significant percentage of infants [26,31]. Despite the absence of a previous urinary tract infection, many kidneys affected prenatally exhibit decreased function [22,24,32,33]. Unlike the focal parenchymal scars seen in infectionassociated reflux nephropathy, the parenchymal abnormalities seen in prenatal VUR are most commonly manifested by a generalized decrease in renal size (reflux nephropathy grade 3 or 4) [34,35].

B

%

8.10

Tubulointerstitial Disease

90 80 70 60 50 40 30 20 10 0

83

Male Female

FIGURE 8-19 Prenatal detection of vesicoureteral reflux (VUR): gender distribution versus VUR detected after urinary tract infection (UTI). VUR detected as part of the evaluation of prenatal hydronephrosis is most commonly identified in boys. In an analysis of six published studies of VUR diagnosed in a total of 124 infants with antenatally detected hydronephrosis, 83% of those affected were boys [33]. Conversely, VUR detected after a UTI most commonly affects girls. In the International Reflux Study in Children (IRSC) and Southwest Pediatric Nephrology Study Group (SWPNSG) investigations of VUR detected in a total of 380 children after UTI, 77% of those affected were girls [20,36].

77

23

17

Prenatally detected

Detected after UTI

Clinical Course of Vesicoureteric Reflux 50

50

%

40 30

30 20

20

21

4

5

10 0 1

2

3

Patients studied, %

FIGURE 8-20 Resolution of vesicoureteral reflux (VUR) detected prenatally at follow-up examinations over 2 years. Spontaneous resolution of VUR can occur in infants with reflux detected during the postnatal evaluation of prenatal urinary tract abnormalities. In an analysis of six investigations of VUR detected neonatally with a follow-up period of 2 years, resolution was seen in 50% of infants with grades I and II. High-grade reflux (grades IV to V) resolved in only 20% [33].

Grade 1 Grade 2 Grade 3 Grade 4–5

82 80

53 43

40 31 18 20

17 16

Resolution

Improvement

90 80 70 60 50 40 30 20 10 0

Grade 1 Grade 2 Grade 3

0

Vesicoureteral reflux grade

90 80 70 60 50 40 30 20 10 0

Resolved VUR, %

50

Unchanged

1

2

3 Years follow-up

4

5

FIGURE 8-21 Resolution of vesicoureteral reflux (VUR) detected postnatally after urinary tract infection: mild to moderate VUR. The Southwest Pediatric Nephrology Study Group (SWPNSG) prospectively observed 113 patients aged 4 months to 5 years with grades I to III VUR detected after urinary tract infection. The SWPNSG reported on 59 children followed up with serial excretory urograms and voiding cystourethrography for 5 years. Mild (grade I and II) VUR resolved after 5 years in the ureters of 80% of these children, and in most cases within 2 to 3 years. Grade III VUR resolved in only 46% of ureters in children with VUR [20]. FIGURE 8-22 Resolution of vesicoureteral reflux (VUR) detected postnatally after urinary tract infection at follow-up examinations over 5 years. Mild to moderate VUR spontaneously resolves in a significant percentage of children, whereas high-grade reflux resolves only rarely. The Southwest Pediatric Nephrology Study Group (SWPNSG) found that grades I and II VUR resolved in 80% of children with refluxing ureters at follow-up examinations over 5 years. In the Birmingham Reflux Study Group (BRSG), International Reflux Study in Children (IRSC), and SWPNSG investigations of high-grade VUR (grades III to V) in children, improvement in reflux severity was seen in 30% to 40% of affected ureters. Spontaneous resolution was rare and occurred in only 16% to 17% of children with refluxing ureters at follow-up examinations over 5 years [20,37,38].

8.11

Reflux and Obstructive Nephropathy

FIGURE 8-23 Resolution of grades III to V vesicoureteral reflux (VUR) detected postnatally after urinary tract infection: bilateral versus unilateral VUR. Spontaneous resolution of high-grade VUR is much more likely to occur in unilateral reflux. The International Reflux Study in Children (IRSC) showed that grades III to V VUR resolved in children in whom both kidneys were affected nearly five times as often (39%) as in those in whom VUR was bilateral (8%). In bilateral VUR, spontaneous resolution did not occur after 2 years of observation [38].

40 Unilateral Bilateral

Resolved VUR, %

35 30 25 20 15 10 5 0

Scarred or thinned, %

60

3

9

21 33 Months follow-up

45

57

IRSC BRSG

New scar formation, %

0

50 40 30 20 10 0 0

I–II

III

IV

Dilated

Vesicoureteral reflux grade

FIGURE 8-24 Frequency of parenchymal scarring at the time of diagnosis of vesicoureteral reflux (VUR). Many children in whom VUR is detected after a urinary tract infection already have evidence of renal parenchymal scarring. In two large prospective studies the frequency of scars seen in persons with VUR increased with VUR severity. The International Reflux Study in Children (IRSC) studied 306 children under 11 years of age with grades III to V VUR [36]. The frequency of parenchymal scarring or thinning increased from 10% in children with nonrefluxing renal units (in children with contralateral VUR) to 60% in those with severely refluxing grade V kidneys. In another large prospective study, the Birmingham Reflux Study Group (BRSG) reported renal scarring in 54% of 161 children under 14 years of age with severe VUR resulting in ureteral dilation (greater than grade 3 using the classification system adopted by the International Reflux Study in Children group) at the time reflux was detected [39]. Participants in these studies were children previously diagnosed as having had urinary tract infection.

18 16 14 12 10 8 6 4 2 0

IRSC SWPNSG

0

1

2

3 Years follow-up

4

5

FIGURE 8-25 Development of parenchymal scarring after diagnosis of vesicoureteral reflux (VUR). Parenchymal scarring occurs after diagnosis and initiation of therapy as well. The Southwest Pediatric Nephrology Study Group (SWPNSG) followed up 59 children with mild to moderate VUR (grades I to III) diagnosed after urinary tract infection [20]. None of the children studied had parenchymal scarring on intravenous pyelography at the time of diagnosis. Parenchymal scars were seen to develop in 10% of children over the course of 5 years of follow-up examinations, including some children without documented urinary tract infections during the period of observation. In this group, renal scarring occurred nearly three times more commonly in grade 3 VUR than it did in grades 1 and 2 VUR. In the International Reflux Study in Children (IRSC) (European group), a prospective study of high-grade VUR (grades III and IV), new scars developed in 16% of 236 children after 5 years’ observation [40].

FIGURE 8-26 Development of new renal scars versus age at diagnosis of vesicoureteral reflux (VUR). The frequency of new scar formation appears to be inversely related to age. The International Reflux Study in Children (IRSC) examined children with high-grade VUR and found that new scars developed in 24% under 2 years of age, 10% from 2 to 4 years of age, and 5% over 4 years of age [40].

8.12

Tubulointerstitial Disease

Renal scarring, %

Treatment of Vesicoureteric Reflux 18 16 14 12 10 8 6 4 2 0

Surgical Medical

0

5

10

15

20

25 30 35 40 Months follow-up

45

50

55

60

UTI versus pyelonephritis, %

Urinary tract infections, %

FIGURE 8-27 Effectiveness of medical versus surgical treatment: new scar formation at follow-up examinations over 5 years in children with highgrade vesicoureteral reflux (VUR). The International Reflux Study in Children (IRSC) (European group) was designed to compare the effectiveness of medical versus surgical therapy of VUR in children diagnosed after urinary tract infection. Surgery was successful in

40 35 30 25 20 15

38

39 34

28 21

10 5 0

40 35 30 25 20 15 10 5 0

Nonpyelonephritic UTI Pyelonephritis 17 29

21 10

Medical Surgical therapy therapy

BRSG-Surgical BRSG- Medical IRSC-Medical IRSC-Surgical SWPNSG

correcting VUR in 97.5% of 231 reimplanted ureters in 151 children randomized to surgical therapy. Medical therapy consisted of long-term antibiotic uroprophylaxis using nitrofurantoin, trimethoprim, or trimethoprim-sulfa. No statistically significant advantage was demonstrable for either treatment modality with respect to new scar formation after 5 years of observation in either study. New scars were identified in 20 of the 116 children treated surgically (17%) and 19 of the 155 children treated medically (16%) at follow-up examinations over 5 years. Those children treated surgically who developed parenchymal scars generally did so within the first 2 years after ureteral repeat implantation, whereas scarring occurred throughout the observation period in the group that did not have surgery. VUR persisted in 80% of children randomized to medical treatment after follow-up examinations over 5 years. The results of the IRSC paralleled the findings of the Birmingham Reflux Study Group (BRSG) investigation of medical versus surgical therapy for VUR in 161 children. After 2 years of observation, progressive or new scar formation was seen in 16% of children with refluxing ureters in the group treated surgically and 19% in the group treated medically. In contrast to the IRSC, however, new scar formation was rare after 2 years of observation in both groups [37,40]. FIGURE 8-28 Effectiveness of medical versus surgical treatment: incidence of urinary tract infections. Vesicoureteral reflux (VUR) predisposes affected persons to urinary tract infection owing to incomplete bladder emptying and urinary stasis. Medical therapy with uroprophylactic antibiotics and surgical correction of VUR have as a goal the prevention of urinary tract infection. In three prospective studies of 400 children with VUR (Southwest Pediatric Nephrology Study Group [SWPNSG], International Reflux Study in Children [IRSC], Birmingham Reflux Study Group [BRSG]) treated either medically or surgically and who were observed over 5 years the rate of infection was similar, ranging from 21% to 39%. The rate of infection was no different between the group treated medically and that treated surgically [20,37,39].

FIGURE 8-29 Effectiveness of medical versus surgical treatment: incidence of urinary tract infection versus pyelonephritis in severe vesicoureteral reflux (VUR). Although the incidence of urinary tract infections (UTIs) is the same in surgically and medically treated children with VUR, the severity of infection is greater in those treated medically. The International Reflux Study in Children (IRSC) (European group) studied 306 children with VUR and observed them over 5 years; 155 were randomized to medical therapy, and 151 had surgical correction of their reflux. Although the incidence of UTI statistically was no different between the groups (38% in the medical group, 39% in the surgical group), children treated medically had an incidence of pyelonephritis twice as high (21%) as those treated surgically (10%) [41].

Reflux and Obstructive Nephropathy

VUR detected Associated GU anomalies expected to affect VUR?

Yes

No

Treat appropriately

Severity of VUR

Mild (I-III)

Severe (IV-V)

Uroprophylaxis Hygiene education Surveillance urine cultures Annual VCUG

Functional study (Radionuclide or ExU)

Nonfunctioning kidney

Urinary tract infections?

Consider nephrectomy

Yes

No

Consider surgery

Resolution of VUR after 2 years

Yes

Female

Consider surgery

Surgical correction

Resolution of VUR after 2 years

Male

Consider surgery

Uroprophylaxis Annual VCUG

No

Long term followup to detect UTI

Functioning kidney

Consider observation off antibiotics

Yes

No

Long term followup

Surgery

FIGURE 8-30 Proposed treatment of vesicoureteral reflux (VUR) in children. This algorithm provides an approach to evaluate and treat VUR in children. In VUR associated with other genitourinary anomalies, therapy for reflux should be part of a comprehensive treatment plan directed toward correcting the underlying urologic malformation. Children with mild VUR should be treated with prophylactic antibiotics, attention to perineal hygiene and regular bowel habits, surveillance urine cultures, and annual voiding cystourethrogram (VCUG). Children with recurrent urinary tract infection on this regimen should be considered for

8.13

surgical correction. In children in whom VUR resolves spontaneously, a high index of suspicion for urinary tract infection should be maintained, and urine cultures should be obtained at times of febrile illness without ready clinical explanation. In persons in whom mild VUR fails to resolve after 2 to 3 years of observation, consideration should be given to voiding pattern. A careful voiding history and an evaluation of urinary flow rate may reveal abnormalities in bladder function that impede resolution of reflux. Correction of dysfunctional voiding patterns may result in resolution of VUR. In the absence of dysfunctional voiding, it is controversial whether older women with persistent VUR are best served by surgical correction or close observation with uroprophylactic antibiotic therapy and surveillance urine cultures, especially during pregnancy. Males with persistent low-grade VUR may be candidates for close observation with surveillance urine cultures while not receiving antibiotic therapy, especially if they are over 4 years of age and circumcised. Circumcision lowers the incidence of urinary tract infection. In severe VUR the function of the affected kidney should be evaluated with a functional study (radionuclide renal scan). High-grade VUR in nonfunctioning kidneys is unlikely to resolve spontaneously, and nephrectomy may be indicated to decrease the risk of urinary tract infection and avoid the need for uroprophylactic antibiotic therapy. In patients with functioning kidneys who have high-grade VUR, the likelihood for resolution should be considered. Severe VUR, especially if bilateral, is unlikely to resolve spontaneously. Proceeding directly to repeat implantation may be indicated in some cases. Medical therapy with uroprophylactic antibiotics and serial VCUG may also be used, reserving surgical therapy for those in whom resolution fails to occur.

Complications of Reflux Nephropathy FIGURE 8-31 Development of hypertension in 55 normotensive subjects with reflux nephropathy at follow-up examinations over 15 years. The incidence of hypertension in persons with reflux nephropathy increases with age and appears to develop most commonly in young adults within 10 to 15 years of diagnosis. In a cohort of 55 normotensive persons with reflux nephropathy observed for 15 years, 5% became hypertensive after 5 years. This percentage increased to 16% at 10 years, and 21% at 15 years. The grading system for severity of scarring was different from the system adopted by the International Reflux Study Committee. Nevertheless, using this system, 78% of persons in the group could be classified as having reflux nephropathy severity scores between 1 and 4 [42].

Hypertensive, %

25 20 15 10 5 0 0

5

10 Years

15

8.14

Tubulointerstitial Disease FIGURE 8-32 Frequency of hypertension versus severity of parenchymal scarring. The frequency of hypertension in persons with vesicoureteral reflux–related renal scars is higher than in the normal population. In adults with reflux nephropathy the incidence of hypertension can be correlated with the severity of renal scarring. Adding the individual grade of reflux (0–4) for the two kidneys results in a scale ranging from 0 (no scars) to 8 (severe bilateral scarring). Persons with cumulative scores of parenchymal scarring from 1 to 4 have a 30% incidence of hypertension, whereas 60% of those with scarring scores ranging from 5 to 8 have hypertension [42,43].

Hypertensive, %

100 80 60 40 20 0 1–4

5–8

Cumulative reflux scarring severity score

A

B

C

D

FIGURE 8-33 Glomerular hypertrophy and focal segmental glomerulosclerosis (FSGS) in severe reflux nephropathy. Reflux nephropathy resulting in reduced renal functional mass

induces compensatory changes in glomerular and vascular hemodynamics. These changes initially maintain the glomerular filtration rate but are maladaptive over time. A–D, Compensatory hyperfiltration results in renal injury manifested histologically by glomerular hypertrophy and FSGS and clinically as persistent proteinuria [44]. In reflux nephropathy, proteinuria is a poor prognostic sign, indicating that renal injury has occurred. The severity of proteinuria is inversely proportional to functioning renal mass and the glomerular filtration rate and directly proportional to the degree of global glomerulosclerosis. Surgical correction of vesicoureteral reflux has not been found to prevent further deterioration of renal function after proteinuria has developed. Hyperfiltration resulting from decreased renal mass continues and produces progressive glomerulosclerosis and loss of renal function. Evidence exists that inhibition of the renin-angiotensin system through the use of angiotensin-converting enzyme inhibitors decreases the compensatory hemodynamic changes that produce hyperfiltration injury. Thus, these inhibitors may be effective in slowing the progress of renal failure in reflux nephropathy.

Reflux and Obstructive Nephropathy

8.15

Pathogenesis of Obstructive Nephropathy FIGURE 8-34 Consequences of urinary tract obstruction for the developing kidney in animals. The effects of urinary tract obstruction on the developing kidney depend on the time of onset, location, and degree of obstruction. Ureteral obstruction during early pregnancy results in disorganization of the renal parenchyma (dysplasia) and a reduction in the number of nephrons. Partial or complete ureteral obstruction in neonates causes vasoconstriction, glomerular hypoperfusion, impaired ipsilateral renal growth, and interstitial fibrosis. The degree of impairment of the ipsilateral kidney, in the case of partial unilateral ureteral obstruction, and of compensatory hypertrophy of the contralateral kidney, in the case of partial or complete unilateral ureteral obstruction, is inversely related to the age of the animal at the time of obstruction. The older the animal, the less the impairment of the ipsilateral kidney and the less the compensatory growth of the contralateral kidney. In addition, the recovery of renal function after relief of urinary tract obstruction also decreases with the age of the animal [45].

Birth Neonate

Fetus

Adult

Dysplasia Number of nephrons Renal growth Compensatory hypertrophy* Recovery of function after relief of obstruction *When unilateral

FIGURE 8-35 Renal hemodynamic response to mild partial ureteral obstruction. Renal blood flow and the glomerular filtration rate may not change in mild partial ureteral obstruction, despite a significant reduction in glomerular capillary ultrafiltration coefficient (Kf). This is due to the increase in glomerular capillary hydraulic pressure (PGC) caused by a prostaglandin E2–induced reduction of afferent arteriolar resistance (RA) and an angiotensin II–induced elevation of efferent arteriolar resistance (RE). It is likely that other vasoactive factors, such as thromboxane A2, also play a role, particularly in more severe ureteral obstruction accompanied by reductions in renal blood flow and glomerular filtration rate [46]. PGE2—prostaglandin E2; PGI2—prostaglandin I2; Pt—tubule hydrostatic pressure.

PGE2, PGI2 Angiotensin II RA

PGC

RE

Kf

Pt

2 h post-obstruction

24 h post-obstruction

PGE2, PGI2 N0 RA

PGC

Endothelin TBX A 2 RE RBF (120%) GFR (80%)

PGC

RA

PGC

RE

RE RBF (50%) GFR (20%)

(Activation of renin-angiotensin) Unilateral

Pt RA

(Macrophage infiltration)

Angiotensin II

Pt RA

PGC

RE

+ ANP RBF (120%) GFR (80%) Pt

RBF (50%) GFR (20%) Bilateral

Pt

FIGURE 8-36 Acute renal hemodynamic response to unilateral or bilateral complete ureteral obstruction. In the first 2 hours after unilateral complete ureteral obstruction, there is a reduction in preglomerular

vascular resistance and an increase in renal blood flow mediated by increased production of prostaglandin E2 (PGE2), prostacyclin, and nitric oxide (NO). The increase in renal blood flow (RBF) and glomerular capillary pressure maintain the glomerular filtration rate (GFR) at approximately 80% of normal, despite an increase in intratubular pressure. As the ureteral obstruction persists, activation of the renin-angiotensin system and increased production of thromboxane A2 (TBXA2) and endothelin result in progressive vasoconstriction, with reductions in renal blood flow and glomerular capillary pressure. The glomerular filtration rate decreases to approximately 20% of baseline, despite normalization of the intratubular pressures. The hemodynamic changes in the early phase (0–2 h) of bilateral ureteral obstruction are similar to those observed after unilateral obstruction. As bilateral obstruction persists, however, there is an accumulation of atrial natriuretic peptide (ANP) that does not occur after unilateral obstruction. The increased ANP levels attenuate the afferent and enhance the efferent vasoconstrictions, with maintenance of normal glomerular capillary and elevated tubular pressures. Despite these differences in hemodynamic changes between unilateral and bilateral ureteral obstruction, the reductions in renal blood flow and glomerular filtration rate 24 hours after obstruction are similar [47–49]. PGC—glomerular capillary hydraulic pressure; PGI2—prostaglandin I2; Pt—tubule hydrostatic pressure; RA—afferent arteriolar resistance; RE—efferent arteriolar resistance.

8.16

Tubulointerstitial Disease

Change from baseline, %

300 Intrapelvic pressure Renal blood flow Glomerular filtration rate

200 100

FIGURE 8-37 Chronic renal hemodynamic response to complete unilateral ureteral obstruction. During complete ureteral obstruction, renal blood flow progressively decreases. Renal blood flow is 40% to 50% of normal after 24 hours, 30% at 6 days, 20% at 2 weeks, and 12% at 8 weeks [48].

Baseline –50 0

1

2

3

4

5

6

7

8

Weeks after obstruction

Cortex

Cortex

Medulla 40 Leukocytes, 105/g

Leukocytes, 105/g

40 30 20

Medulla

Release of obstruction

Release of obstruction

30 20 10

10 0 0

0

A

Control 4 h

12 h

24 h

Cortex

Medulla

B

Control 4 h

12 h

24 h

C

1

2

3 4 Days

5

6

7

0

1

2

3 4 Days

5

6

7

FIGURE 8-38 Development of interstitial cellular infiltrates in the renal cortex and medulla after ureteral obstruction. After ureteral obstruction there is a rapid influx of macrophages and suppressor T lymphocytes in the cortex and medulla (A) that is accompanied by an increase in urinary thromboxane B2 and a decrease in the glomerular filtration rate. The production of thromboxane A2 by the infiltrating macrophages (B) contributes to the renal vasoconstriction of chronic urinary tract obstruction. After release of the obstruction the cellular infiltration is slowly reversible, requiring several days to revert to near normal levels (C) [50,51].

Reflux and Obstructive Nephropathy

Tubular obstruction

Pt

PDGF

Osteopontin MCP

Renin, angiotensinogen, ACE, AT1 receptor

Bradykinin

Macrophages

TGF-ß

Nitric oxide

O–2 H 2O 2

EGF bcl2

CuZnSOD Catalase TIMP Collagen

Fibroblasts, myofibroblasts

Apoptosis, tubular drop-out

Tubulointerstitial fibrosis

FIGURE 8-39 Pathogenesis of tubulointerstitial fibrosis in obstructive nephropathy. This pathogenesis has been extensively studied. Increased expression of renin, angiotensinogen, angiotensinconverting enzyme (ACE), and the angiotensin II type 1 (AT1) receptor occurs in the

Obstruction

100 80 60 40 20 0 0

2

4

6

8

12

14

16

18

Weeks after obstruction

20

22

24

8.17

obstructed kidney. Angiotensin II can induce the synthesis of transforming growth factor  (TGF-), a cytokine that stimulates extracellular matrix synthesis and inhibits its degradation. Obstructive nephropathy is accompanied by downregulation of the kallikrein-kinin system and nitric oxide production that can be reversed by administration of a converting enzyme inhibitor or of L-arginine. The rapid upregulation of chemotactic factors such as monocyte chemoattractant peptide 1 (MCP-1) and osteopontin in the tubular epithelial cells, in response to increased intratubular pressure, contributes to the recruitment of macrophages. Macrophages produce fibroblast growth factor and induce fibroblast proliferation and myofibroblast transformation. The downregulation of epidermal growth factor (EGF), Bcl 2, and antioxidant enzymes and the increased production of superoxide and hydrogen peroxide (H2O2) contribute to an increased rate of apoptosis and tubular dropout [51– 57]. PDGF–platelet-derived growth factor; SOD—superoxide dismutase; TIMP—tissue inhibitor of metalloproteinases.

FIGURE 8-40 Recovery of renal function after relief of complete unilateral ureteral obstruction of variable duration. The recovery of the ipsilateral glomerular filtration rate after relief of a unilateral complete ureteral obstruction has been best studied in dogs and depends on the duration of the obstruction. Complete recovery occurs after 1 week of obstruction. The degree of recovery after 2 and 4 weeks of obstruction is only of 58% and 36%, respectively. No recovery occurs after 6 weeks of obstruction [58]. Rare reports of recovery of renal function in patients with longer periods of unilateral ureteral obstruction may represent high-grade partial obstruction rather than complete obstruction or may reflect differences in lymphatic drainage and renal anatomy between the human and canine kidneys [59].

8.18

Tubulointerstitial Disease

Clinical Manifestations of Obstructive Nephropathy Functional abnormalities in obstructed kidneys (unilteral or bilateral)

Damage to inner medulla

Na+reabsorption Loop of Henle

Medullary blood flow

( Na+/K+ ATPase) Collecting duct

Corticomedullary concentration gradient Resistance to ADH

Intraluminal negative potential Na+ wasting

Concentration defect

Consequences of bilateral obstruction

H+ secretion K+ secretion

H+-ATPase Na+/K+ ATPase

ECFV excess ANP Osmotic load (urea)

Clinical correlates

Excessive replacement Postobstructive diuresis after relief of bilateral obstruction (volume contraction, hypomagnesemia, other electrolyte abnormalities)

Hypernatremia when free water intake is inadequate

FIGURE 8-42 Clinical manifestations of obstructive nephropathy. These manifestations depend on the cause of the obstruction, its anatomic location, its severity, and its rate of development [61,68,69].

Urinary tract obstruction

Unilateral

Partial or complete • Pain (dull aching • Renin-dependent renal colic) hypertension • Susceptibility to • Erythrocytosis urinary tract (rare) infection and nephrolithiasis

Bilateral or solitary kidney

Partial

Hyperkalemic metabolic acidosis in partial bilateral ureteral obstruction

FIGURE 8-41 Clinical correlates of abnormalities of tubular function in obstructive nephropathy. Acute ureteral obstruction stimulates tubular reabsorption, resulting in increased urine osmolality and reduced urine sodium concentration [60]. In contrast, obstructive nephropathy is characterized by a reduced ability to concentrate the urine, reabsorb sodium, and secrete hydrogen ions (H+) and potassium. In unilateral obstructive nephropathy, these functional abnormalities do not have a clinical correlate because of the reduced glomerular filtration rate and immaterial contribution of the obstructed kidney to total renal function. Hyperkalemic metabolic acidosis and, when the intake of free water is not adequate, hypernatremia can occur in patients with partial bilateral ureteral obstruction or partial ureteral obstruction in a solitary kidney. Similarly, postobstructive diuresis can occur only after relief of bilateral ureteral obstruction or ureteral obstruction in a solitary kidney but not after relief of unilateral obstruction [61–67]. ADH>\#209>antidiuretic hormone; ANP—atrial natriuretic peptide; ECFV— extracellular fluid volume; Na-K ATPase— sodium-potassium adenosine triphosphatase.

Complete

• Polyuria, polydipsia • Anuria • Bladder • Uremia symptoms • Hypernatremia • Fluctuating • Volume contraction urine • Hyperkalemic output metabolic acidosis • Uremia • Volume-dependent hypertension

Reflux and Obstructive Nephropathy

8.19

Diagnosis of Obstructive Nephropathy 1.0 Furosemide Obstruction

Tracer activity

Baseline Saline Saline + furosemide

0.8

RI

0.6 0.4

Hydronephrosis without obstruction

0.2 Normal

A

C

0.0

B

Time

Partial obstruction

D

FIGURE 8-43 Diagnosis of obstructive nephropathy. A, Diuresis renography. B, Doppler ultrasonography. C, D, Magnetic resonance urogram utilizing a single shot fast spin echo technique with anterior-posterior projection (C) and left posterior oblique projection (D). Images demonstrate a widely patent right ureteropelvic junction in a patient with abdominal pain and suspected ureteropelvic junction obstruction. Administration of gadolinium is not required for this technique. Note also the urine in the bladder, cerebrospinal fluid in the spinal canal, and fluid in the small bowel. Ultrasonography is the procedure of choice to determine the presence or absence of a dilated renal pelvis or calices and to assess the degree of associated parenchymal atrophy.

Contralateral kidney

Nevertheless, obstruction rarely can occur without hydronephrosis, when the ureter and renal pelvis are encased in a fibrotic process and unable to expand. In contrast, mild dilation of the collecting system of no functional significance is not unusual. Even obvious hydronephrosis in some cases may not be associated with functional obstruction [70]. Diuresis renography is helpful when the functional significance of the dilation of the collecting system is in question [71,72]. Renal Doppler ultrasonography before and after administration of normal saline and furosemide also has been used to differentiate obstructive from nonobstructive pyelocaliectasis [73]. Other techniques such as excretory urography, computed tomography, and retrograde or antegrade ureteropyelography are helpful to determine the cause of the urinary tract obstruction. The utility of excretory urography is limited in patients with advanced renal insufficiency. In these cases magnetic resonance urography can provide coronal imaging of the renal collecting systems and ureters similar to that of conventional urography without the use of iodinated contrast. RI— resistive index. (C, D, Courtesy of B. F. King, MD.)

FIGURE 8-44 Diagnosis of obstructive nephropathy by postnatal renal ultrasonography, showing hydronephrosis in ureteropelvic junction obstruction. Renal ultrasonography is a sensitive test to detect hydronephrosis. The absence of ureteral dilation is consistent with obstruction at the level of the ureteropelvic junction.

8.20

Tubulointerstitial Disease

Before Furosemide

After Furosemide

1 min.

5 min.

10 min.

15 min.

Lt

Rt

Lt

Rt

FIGURE 8-45 Mercaptoacetyltriglycine-3 renal scan with furosemide in a newborn with left ureteropelvic junction obstruction. A diuretic renal scan using 99mtechnetium-mercaptoacetyltriglycine (99mTc-MAG-3) showing differential renal function (47% right kidney; 53% left kidney) at 1 to 2 minutes after radionuclide administration is seen. A significant amount of radionuclide remains in each kidney 15 minutes after administration. After administration of furosemide, however, the isotope is seen to disappear rapidly from the right kidney (t1/2 of radioisotope washout in 4.9 minutes) but persists in the hydronephrotic left kidney (t1/2 in 50.1 minutes). A t1/2 of the radioisotope in less than 10 minutes is thought to reflect a lack of significant obstruction. A t1/2 of over 20 minutes is suggestive of obstruction. Intermediate values of washout are indeterminate. The most appropriate therapy for infants with delayed renal pelvic radioisotope washout and diagnosis of ureteropelvic junction obstruction is controversial. Some authors advocate pyeloplasty to alleviate the obstruction based on renal scan results, whereas others advocate withholding surgery unless renal function deteriorates or hydronephrosis progresses.

Reflux and Obstructive Nephropathy

8.21

Posterior Urethral Valves

Type I

FIGURE 8-46 Posterior urethral valves. A, Illustrative diagram. B, Pathology specimen. Valvular obstruction at the posterior urethra is the most common cause of lower urinary tract obstruction in boys. Anatomically, the lesion most commonly is comprised of an oblique diaphragm with a slitlike perforation arising from the posterior urethra distal to the verumontanum and inserting at the midline anterior urethra. (From Kaplan and Scherz [74]; with permission.)

A

FIGURE 8-47 Excretory urogram of a patient with posterior urethral valves. Bladder outlet obstruction results in bladder wall thickening, trabeculation, and formation of diverticula. Increased intravesical pressure may result in vesicoureteral reflux, as is seen on the left. Obstruction resulting in increased intrarenal pressure may result in rupture at the level of a renal fornix, producing a urinoma, or perirenal collection of urine, as seen on the right.

B FIGURE 8-48 Voiding cystourethrogram (VCUG) demonstrating posterior urethral valves and dilation of the posterior urethra. Urethral valves are best detected by VCUG. The obstructing valves are seen as oblique or perpendicular folds with proximal urethral dilation and elongation. Distal to the valves the urinary stream is diminished. Alleviating the bladder outlet obstruction is indicated, either by lysis of the valves themselves or by way of vesicostomy, in small infants until sufficient growth occurs to make valve resection technically feasible.

8.22

Tubulointerstitial Disease

Ureterovesical Junction Obstruction FIGURE 8-49 Excretory urogram showing ureterovesical junction obstruction in a 2-year-old girl.

Retroperitoneal Fibrosis

A FIGURE 8-50 A–H, Idiopathic retroperitoneal fibrosis: computed tomography scans of the abdomen before (left panels, note right ureteral stent and mild left ureteropyelocaliectasis) and 7 years after ureterolysis (right panels, note omental interposition). Retroperitoneal fibrosis is characterized by the accumulation of inflammatory and fibrotic tissue around the aorta, between the renal hila and the pelvic brim. Most cases are idiopathic; the remainder are associated with immune-mediated connective tissue diseases, ingestion of drugs such as methysergide, abdominal aortic aneurysms, or malignancy. Idiopathic retroperitoneal fibrosis can be associated with mediasti-

B nal fibrosis, sclerosing cholangitis, Riedel’s thyroiditis, and fibrous pseudotumor of the orbit. In the clinical setting, patients with idiopathic retroperitoneal fibrosis exhibit systemic symptoms such as malaise, anorexia and weight loss, and abdominal or flank pain. Renal insufficiency is often seen and is caused by bilateral ureteral obstruction. Laboratory test results usually demonstrate anemia and an elevated sedimentation rate. The treatment is directed to the release of the ureteral obstruction, which initially can be achieved by placement of ureteral stents. Administration of corticosteroids is helpful to control the systemic manifestations of the disease and (Continued on next page)

Reflux and Obstructive Nephropathy

C

D

E

F

G

H

FIGURE 8-50 (Continued) often to reduce the bulk of the tumor and relieve the ureteral obstruction. Administration of corticosteroids, however, should be considered only when malignancy and retroperitoneal infection can be ruled out. As in other chronic renal diseases, administration of corticosteroids should be kept at the minimal level capable of controlling symptoms. Surgical ureterolysis, which consists of freeing

8.23

the ureters from the fibrotic mass, lateralizing them, and wrapping them in omentum to prevent repeat obstruction, is often necessary. Other immunosuppressive agents have been used rarely when the systemic manifestations of the disease cannot be controlled with safe doses of corticosteroids. In most cases the long-term outcome of idiopathic retroperitoneal fibrosis is satisfactory [75–77].

8.24

Tubulointerstitial Disease

References 1. Roshani H, Dabhoiwala NF, Verbeek FJ, Lamers WH: Functional anatomy of the human ureterovesical junction. Anat Rec 1996, 245:645–651.

24. Anderson PAM, Rickwood AMK: Features of primary vesicoureteric reflux detected by prenatal sonography. Br J Urol 1991, 67:267–271.

2. Noordzij JW, Dabhoiwala NF: A view on the anatomy of the ureterovesical junction. Scand J Urol Nephrol 1993, 27:371–380.

25. Stocks A, Richards D, Frentzen B, Richard G: Correlation of prenatal renal pelvic anteroposterior diameter with outcome in pregnancy. J Urol 1996, 155:1050–1052.

3. Thomson AS, Dabhoiwala NF, Verbeek FJ, Lamers WH: The functional anatomy of the ureterovesical junction. Br J Urol 1994, 73:284–291.

26. Adra AM, Mejides AA, Dennaoui MS, et al.: Fetal pyelectasis: Is it always “physiological”? [abstract]. Am J Obstet Gynecol 1995, 172:359.

4. Politano VA: Vesico-ureteral reflux. In Urologic Surgery, edn 2. Edited by Glenn JF. New York: Harper and Row Publishers, 1975:272–293.

27. Morin L, Cendron M, Garmel SH, et al.: Minimal fetal hydronephrosis: natural history and implications for treatment. Am J Obstet Gynecol 1995, 172:354. 28. Zerin JM, Ritchey MJ, Chang ACH: Incidental vesicoureteral reflux in neonates with antenatally detected hydronephrosis and other abnormalities. Radiology 1993, 187:157–160. 29. Peters PC, Johnson DE, Jackson JHJ: The incidence of vesicoureteral reflux in the premature child. J Urol 1967, 97:259–260. 30. Lich R Jr, Howerton LW Jr, Goode LS, Davis LA: The ureterovesical junction of the newborn. J Urol 1964, 92:436–438.

5. Paquin AJ: Ureterovesical junction: the description and evaluation of a technique. J Urol 1959, 82:573. 6. Stephens FD, Lenaghan D: The anatomical basis and dynamics of vesicoureteral reflux. J Urol 1962, 87:669. 7. Kramer, SA: Vesicoureteral reflux. In Clinical Pediatric Urology, edn 3. Edited by Kelalis PP, King LR, Belman AB. Philadelphia: WB Saunders Company, 1992:441–499. 8. Ransley PG, Risdon RA: Renal papillary morphology in infants and young children. Urol Res 1975, 3:111–113. 9. Ransley PG, Risdon RA: Renal papillary morphology and intrarenal reflux in the young pig. Urol Res 1975, 3:105–109. 10. Funston MR, Cremin BJ: Intrarenal reflux-papillary morphology and pressure relationships in children’s necropsy kidneys. Br J Radiol 1978, 51:665–670. 11. Ransley PG, Risdon RA: Reflux nephropathy: effects of antimicrobial therapy on the evolution of the early pyelonephritic scar. Kidney Int 1981, 20:733–742. 12. Torres VE, Kramer SA, Holley KE, et al.: Effect of bacterial immunization on experimental reflux nephropathy. J Urol 1984, 131:772. 13. Torres VE, Kramer SA, Holley KE, et al.: Interaction of multiple risk factors in the pathogenesis of experimental reflux nephropathy in the pig. J Urol 1985, 133:131–135. 14. Goldraich NP, Goldraich IH, Anselmi OE, Ramos OL: Reflux nephropathy: the clinical picture in South Brazilian children. Control Nephrol 1984, 39:52–67. 15. Scherz HC, Downs TM, Caeser R: The selective use of dimercaptosuccinic acid renal scans in children with vesicoureteral reflux. J Urol 1994, 152:628–631. 16. Kramer SA: Experimental vesicoureteral reflux. Dialogues Pediatr Urol 1984, 7:1. 17. Hinchliffe SA, Chan Y, Jones H, et al.: Renal hypoplasia and postnatally acquired cortical loss in children with vesicoureteral reflux. Pediatr Nephrol1992, 6:439–444. 18. Lebowitz RL, Olbing H, Parkkulainen K, et al.: International system of radiographic grading of vesicoureteral reflux. Pediatr Radiol 1985, 15:105. 19. Smellie JM, Edwards D, Hunter N, et al.: Vesico-ureteric reflux and renal scarring. Kidney Int 1975, 8:s65–s72. 20. Arant BS: Medical management of mild and moderate vesicoureteral reflux: followup studies of infants and young children. A preliminary report of the Southwest Pediatric Nephrology Study Group. J Urol 1992, 148:1683–1687. 21. Steele BT, Robitaille P, DeMaria J, Grignon A: Follow-up evaluation of prenatally recognized vesicoureteric reflux. J Pediatr 1989, 115:95–96. 22. Najmaldin A, Burge DM, Atwell JD: Reflux nephropathy secondary to intrauterine vesicoureteric reflux. J Pediatr Surg 1990, 25:387–390. 23. Marra G, Barbieri G, Dell’Agnola CA, et al.: Congenital renal damage associated with primary vesicoureteral reflux detected prenatally in male infants. J Pediatr 1994, 124:726–730.

31. Marra G, Barbieri G, Moioli C, et al.: Mild fetal hydronephrosis indicating vesicoureteric reflux. Arch Dis Child 1994, 70:F147–150. 32. Wallin L, Bajc M: The significance of vesicoureteric reflux on kidney development assessed by dimercaptosuccinate renal scintigraphy. Br J Urol 1994, 73:607–611. 33. Elder JS: Commentary: importance of antenatal diagnosis of vesicoureteral reflux. J Urol 1992, 148:1750–1754. 34. Crabbe DCG, Thomas DFM, Gordon AC, et al.: Use of 99mtechnetium-dimercaptosuccinic acid to study patterns of renal damage associated with prenatally detected vesicoureteral reflux. J Urol 1992, 148:1229–1231. 35. Sheridan M, Jewkes F, Gough DCS: Reflux nephropathy in the first year of life: role of infection. Pediatr Surg Int 1991, 6:214–216. 36. Weiss R, Tamminen-Mobius T, Koskimies O, et al.: Characteristics at entry of children with severe primary vesicoureteral reflux recruited for a multicenter international therapeutic trial comparing medical and surgical management. J Urol 1992, 148:1644–1649. 37. Taylor CM, White RHR: Prospective trial of operative vs. non-operative treatment of severe vesicoureteric reflux in children: five years’ observation. Br Med J 1987, 295:237–241. 38. Tamminen-Mobius T, Brunier E, Ebel K-D, et al.: Cessation of vesicoureteral reflux for 5 years in infants and children allocated to medical treatment. J Urol 1992, 148:1662–1666. 39. Astley R, Clark RC, Corkery JJ, et al.: Prospective trial of operative vs. non-operative treatment of severe vesicoureteric reflux: two years’ observation in 96 children. Br Med J 1983, 287:171–174. 40. Olbing H, Claesson I, Ebel K-D, et al.: Renal scars and parenchymal thinning in children with vesicoureteral reflux: a 5-year report of the International Reflux Study in Children (European branch). J Urol 1992, 148:1653–1656. 41. Jodal U, Koskimies O, Hanson E, et al.: Infection pattern in children with vesicoureteral reflux randomly allocated to operation or longterm antibacterial prophylaxis. J Urol 1992, 148:1650–1652. 42. Goonasekera CDA, Shah V, Wade A, et al.: 15-year follow-up of renin and blood pressure in reflux nephropathy. Lancet 1996, 347:640–643. 43. Torres V, Malek RS, Svensson JP: Vesicoureteral reflux in the adult: nephropathy, hypertension, and stones. J Urol 1983, 130:41–44. 44. Torres V, Velosa J, Holley KE, et al.: The progression of vesicoureteral reflux nephropathy. Ann Intern Med 1980, 92:776–784. 45. Chevalier RL: Effects of ureteral obstruction on renal growth. Semin Nephrol 1995, 15:353–360.

Reflux and Obstructive Nephropathy 46. Ichikawa I, Brenner BM: Local intrarenal vasoconstrictor-vasodilator interactions in mild partial ureteral obstruction. Am J Physiol 1979, 236:F131–140. 47. Dal Canton A: Effects of 24-hour unilateral ureteral obstruction on glomerular hemodynamics in rat kidney. Kidney Int 1979, 15:457. 48. Klahr S: Pathophysiology of obstructive nephropathy: a 1991 update. Semin Nephrol 1991, 11:156. 49. Marin-Grez M, Fleming JT: Atrial natriuretic peptide causes preglomerular vasodilatation and post-glomerular vasoconstriction in rat kidney. Nature 1986, 324:473. 50. Schreiner GF, Harris KPG, Purkerson ML, Klahr S: Immunological aspects of acute ureteral obstruction: immune cell infiltrate in the kidney. Kidney Int 1988, 34:487–493. 51. Diamond JR: Macrophages and progressive renal disease in experimental hydronephrosis. Am J Kidney Dis 1995, 26:133–140. 52. Chevalier RL: Growth factors and apoptosis in neonatal ureteral obstruction. J Am Soc Nephrol 1996, 7:1098–1105. 53. Ishidoya S, Morrisey J, McCracken R, Klahr S: Delayed treatment with enalapril halts tubulointerstitial fibrosis in rats with obstructive uropathy. Kidney Int 1996, 49:1110–1119. 54. Morrisey J, Ishidoya S, McCracken R, Klahr S: Nitric oxide generation ameliorates the tubulointerstitial fibrosis of obstructive nephropathy. J Am Soc Nephrol 1996, 7:2202–2212. 55. Ricardo SD, Ding G, Eufemio M, Diamond JR: Antioxidant expression in experimental hydronephrosis: role of mechanical stretch and growth factors. Am J Physiol 1997, 272:F789–F798. 56. Wright EJ, McCaffrey TA, Robertson AP, et al.: Chronic unilateral ureteral obstruction is associated with interstitial fibrosis and tubular expression of transforming growth factor-beta.Lab Invest 1996, 74:528–537. 57. Yanagisawa H: Dietary protein restriction normalized eicosanoid production in isolated glomeruli from rats with bilateral ureteral obstruction.Kidney Int 1994, 46:245. 58. Vaughn EDJ, Gillenwater JY: Recovery following complete chronic unilateral ureteral occlusion: functional, radiographic and pathologic alterations. J Urol 1971, 106:27–35. 59. Shapiro SR: Recovery of renal function after prolonged unilateral ureteral obstruction. J Urol 1976, 115:136–40. 60. Miller TR: Urinary diagnostic studies in acute renal failure: a prospective study. Ann Intern Med 1978, 89:47. 61. Batlle DC, Arruda JAL, Kurtzman NA: Hyperkalemic distal renal tubular acidosis associated with obstructive uropathy. N Engl J Med 1981, 304:373.

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62. Campbell HT, Bello-Reuss E, Klahr S: Hydraulic water permeability and transepithelial voltage in the isolated perfused rabbit cortical collecting tubule following acute unilateral ureteral obstruction. J Clin Invest 1985, 75:219. 63. Hanley MJ, Davidson K: Isolated nephron segments from rabbit models of obstructive uropathy. J Clin Invest 1982, 69:165. 64. Hwang S: Transport defects of rabbit inner medullary collecting duct cells in obstructive uropathy. Am J Physiol 1993, 264:F808. 65. Hwang S: Transport defects of rabbit medullary thick ascending limb cells in obstructive uropathy. J Clin Invest 1993, 91:21. 66. Kimura H, Mujais SK: Cortical collecting duct Na-K pump in obstructive uropathy. Am J Physiol 1990, 258:F1320. 67. Muto S, Asano Y: Electrical properties of the rabbit cortical collecting duct from obstructed kidneys after unilateral ureteral obstruction. J Clin Invest 1994, 94:1846. 68. Davis BB, Preuss HG, Murdaugh HVJ: Hypomagnesemia following the diuresis of post-renal obstruction and renal transplant. Nephron 1975, 14:275. 69. Landsberg L: Hypernatremia complicating partial urinary tract obstruction. N Engl J Med 1970, 283:746. 70. Whitherow RO, Whitaker RH: The predictive accuracy of antegrade pressure flow studies in equivocal upper tract obstruction. Br J Urol 1981, 53:496. 71. Koff SA, Thrall JN, Keyes JW: Diuretic radionuclide urography. A noninvasive method for evaluating nephroureteral dilatation. J Urol 1979, 122:451. 72. Whitfield HN: Furosemide intravenous urography in the diagnosis of pelviureteric junction obstruction. Br J Urol 1979, 51:445. 73. Shokeir AA, Nijman RJM, El-Azab M, Provoost AP: Partial ureteral obstruction: effect of intravenous normal saline and furosemide on the resistive index. J Urol 1997, 157:1074–1077. 74. Kaplan GW, Scherz HC: Infravesicle obstruction. In Clinical Pediatric Urology, edn 3. Edited by Kelalis PP, King LR, Belman AB. Philadelphia: WB Saunders Company; 1992:821–864. 75. Gilkeson GS, Allen NB: Retroperitoneal fibrosis: a true connective tissue disease. Rheum Dis North Am 1996, 22:23–38. 76. Kottra JJ, Dunnick NR: Retroperitoneal fibrosis. Radiol Clin North Am 1996, 34:1259–1275. 77. Massachusetts General Hospital: Case records–case 27–1996: N Engl J Med 1996, 335:650–655.

Cystic Diseases of the Kidney Yves Pirson Dominique Chauveau

A

kidney cyst is a fluid-filled sac arising from a dilatation in any part of the nephron or collecting duct. A sizable fraction of all kidney diseases—perhaps 10% to 15%—are characterized by cysts that are detectable by various imaging techniques. In some, cysts are the prominent abnormality; thus, the descriptor cystic (or polycystic). In others, kidney cysts are an accessory finding, or are only sometimes present, so that some question whether they are properly classified as cystic diseases of the kidney. In fact, the commonly accepted complement of cystic kidney diseases encompasses a large variety of disorders of different types, presentations, and courses. Dividing cystic disorders into genetic and “nongenetic” conditions makes sense, not only conceptually but clinically: in the former cystic involvement of the kidney often leads to renal failure and is most often associated with extrarenal manifestations of the inherited defect, whereas in the latter cysts rarely jeopardize renal function and generally are not part of a systemic disease. In the first section of this chapter we deal with nongenetic (ie, acquired and developmental) cystic disorders, emphasizing the imaging characteristics that enable correct identification of each entity. Some common pitfalls are described. A large part of the section on genetic disorders is devoted to the most common ones (eg, autosomal-dominant polycystic kidney disease), focusing on genetics, clinical manifestations, and diagnostic tools. Even in the era of molecular genetics, the diagnosis of the less common inherited cystic nephropathies relies on proper recognition of their specific renal and extrarenal manifestations. Most of these features are illustrated in this chapter.

CHAPTER

9

9.2

Tubulointerstitial Disease

General Features FIGURE 9-1 Principal cystic diseases of the kidney. Classification of the renal cystic disorders, with the most common ones printed in bold type. (Adapted from Fick and Gabow [1]; Welling and Grantham [2]; Pirson, et al. [3].)

PRINCIPAL CYSTIC DISEASES OF THE KIDNEY Nongenetic

Genetic

Acquired disorders Simple renal cysts (solitary or multiple) Cysts of the renal sinus (or peripelvic lymphangiectasis) Acquired cystic kidney disease (in patients with chronic renal impairment) Multilocular cyst (or multilocular cystic nephroma) Hypokalemia-related cysts Developmental disorders Medullary sponge kidney Multicystic dysplastic kidney Pyelocalyceal cysts

Autosomal-dominant Autosomal-dominant polycystic kidney disease Tuberous sclerosis complex von Hippel-Lindau disease Medullary cystic disease Glomerulocystic kidney disease Autosomal-recessive Autosomal-recessive polycystic kidney disease Nephronophthisis X-linked Orofaciodigital syndrome, type I

IMAGING CHARACTERISTICS OF THE MOST COMMON RENAL CYSTIC DISEASES Disease

Kidney Size

Cyst Size

Cyst Location

Liver

Simple renal cysts Acquired renal cystic disease Medullary sponge kidney ADPKD ARPKD NPH

Normal Most often small, sometimes large Normal or slightly enlarged Enlarged Enlarged Small

Variable (mm–10 cm) 0.5–2 cm mm Variable (mm–10 cm) mm increase with age mm–2 cm (when present)

All All Precalyceal All All Medullary

Normal Normal Normal (most often) Cysts (most often) CHF Normal

FIGURE 9-2 Characteristics of the most common renal cystic diseases detectable by imaging techniques (ultrasonography, computed tomography, magnetic resonance). In the context of family history and clinical findings, these allow the clinician to establish a definitive diagnosis

in the vast majority of patients. ADPKD—autosomal-dominant polycystic kidney disease; ARPKD—autosomal-recessive polycystic kidney disease; CHF—congenital hepatic fibrosis; NPH— nephronophthisis.

9.3

Cystic Diseases of the Kidney

Nongenetic Disorders FIGURE 9-3 Solitary simple cyst. Large solitary cyst found incidentally at ultrasonography (longitudinal scan) in the lower pole of the right kidney. Criteria for the diagnosis of simple cyst include absence of internal echoes, rounded outline, sharply demarcated, smooth walls, bright posterior wall echo (arrows). The latter occur because less sound is absorbed during passage through cyst than through the adjacent parenchyma. If these criteria are not satisfied, computed tomography can rule out complications and other diagnoses.

PREVALENCE OF SIMPLE RENAL CYSTS DETECTED BY ULTRASONOGRAPHY Prevalence, % ≥1 Cyst

≥2 Cysts*

≥3 Cysts*

≥1 Cyst in Each Kidney

Age group, y

M

F

M

F

M

F

M

F

15–29 30–49 50–69 ≥70

0 2 15 32

0 1 7 15

0 0 2 17

0 1 1 8

0 0 1 6

0 1 1 3

0 0 2 9

0 1 1 3

*Unilateral or bilateral. M—male; F—Female.

FIGURE 9-4 Prevalence of simple renal cysts detected by ultrasonography according to age in an Australian population of 729 persons prospectively screened by ultrasonography. The prevalence

increases with age and is higher in males. Cyst size also increases with age. Most simple cysts are located in the cortex. (From Ravine et al. [4]; with permission.)

9.4

Tubulointerstitial Disease

A FIGURE 9-5 A and B, Multiple simple cysts (one 7 cm in diameter in the lower pole of the left kidney and three 4 to 5 cm in diameter in the right kidney) detected by contrast-enhanced computed tomography (CT). Additional millimetric cysts might be suspected in both kidneys.

A FIGURE 9-6 A, Contrast-enhanced computed tomography (CT) shows a simple, 3-cm wide cyst of the renal sinus (arrows) found during investigation of renal calculi. Note subcapsular hematoma (arrowheads) detected after lithotripsy. B, Contrast-enhanced CT shows bilateral multiple cysts of the renal sinus, leading to chronic compression of the pelvis and subsequent renal atrophy.

B Each cyst exhibits the typical features of an uncomplicated simple cyst on CT: 1) homogeneous low density, unchanged by contrast medium; 2) rounded outline; 3) very thin (most often indetectable) wall; 4) distinct delineation from adjacent parenchyma.

B Ultrasonographic appearance mimicked hydronephrosis. Also known as hilar lymphangiectasis or peripelvic (or parapelvic) cysts, this acquired disorder consists of dilated hilar lymph channels. Its frequency is about 1% in autopsy series. Although usually asymptomatic, cysts of the renal sinus can cause severe urinary obstruction, B.

Cystic Diseases of the Kidney

A

9.5

B

FIGURE 9-7 A, Acquired cystic kidney disease (ACKD) detected by contrastenhanced computed tomography (CT) in a 71-year-old man on hemodialysis for 4 years. A, Note the several intrarenal calcifications, which are not unusual in dialysis patients. ACKD is characterized by the development of many cysts in the setting of chronic uremia. It can occur at any age, including childhood, whatever the original nephropathy. The diagnosis is based on detection of at least three to five cysts in each kidney in a patient who has chronic renal failure but not hereditary cystic disease. The prevalence of ACKD averages 10% at onset of dialysis treatment and subsequently increases, to reach 60% and 90% at 5 and 10 years into

Age <55 and > 3 years No on RRT and good clinical condition?

No screening

Yes Echography: ACKD?

No

Yes Suspicion of renal neoplasm?

No

Yes No Enhanced CT: confirmed neoplasm? Yes Nephrectomy and annual follow-up of contralateral kidney

Biennial echo

hemodialysis and peritoneal dialysis, respectively [5]. In the early stage, kidneys are small or even shrunken and cysts are usually smaller than 0.5 cm. Cyst numbers and kidney volume increase with time, as seen on this patient’s scan (B) repeated 8 years into dialysis. Advanced ACKD can mimic autosomal-dominant polycystic disease. ACKD sometimes regresses after successful transplantation; it can involve chronically rejected kidney grafts. Although ACKD is usually asymptomatic it may be complicated by bleeding—confined to the cysts or extending to either the collecting system (causing hematuria) or the perinephric spaces—and associated with renal cell carcinoma. (Courtesy of M. Jadoul.)

FIGURE 9-8 Screening for acquired cystic kidney disease (ACKD) and renal neoplasms in patients receiving renal replacement therapy (RRT). The major clinical concern with ACKD is the risk of renal cell carcinoma, often the tubulopapillary type, associated with this disorder: the incidence is 50-times greater than in the general population. Moreover, ACKD-associated renal carcinoma is more often bilateral and multicentric; however, only a minority of them evolve into invasive carcinomas or cause metastases [5]. There is no doubt that imaging should be performed when a dialysis patient has symptoms such as flank pain and hematuria, the question of periodic screening for ACKD and neoplasms in asymptomatic dialysis patients is still being debated. Using decision analysis incorporating morbidity and mortality associated with nephrectomy in dialysis patients, Sarasin and coworkers [6] showed that only the youngest patients at risk for ACKD benefit from periodic screening. On the basis of this analysis, it has been proposed that screening be restricted to patients younger than 55 years, who have been on dialysis at least 3 years and are in good general condition. Recognized risk factors for renal cell carcinoma in ACKD are male gender, uremia of long standing, large kidneys, and analgesic nephropathy.

9.6

Tubulointerstitial Disease FIGURE 9-9 Multilocular cyst (or multilocular cystic nephroma) of the right kidney, detected by ultrasonography (A) and contrast-enhanced CT-scan (B). Both techniques show the characteristic septa (arrow) dividing the mass into multiple sonolucent locules. This rare disorder is usually a benign tumor, though some lesions have been found to contain foci of nephroblastoma or renal clear cell carcinoma. The imaging appearance is actually indistinguishable from those of the cystic forms of Wilms’ tumor and renal clear cell carcinoma. (Courtesy of A. Dardenne.)

A

A

C

B

B FIGURE 9-10 A, contrast-enhanced computed tomography (CT) for evaluation of a left renal stone in a 67-year-old man. A cystic mass was found at the lower pole of the right kidney. Only careful examination revealed that the walls of the mass (arrows) were too thick for a simple cyst (see Fig. 9-5 for comparison). B, The echo pattern of the mass was very heterogeneous (arrows), clearly different from the echo-free appearance of a simple cyst (see Fig. 9-3 for comparison). C, Magnetic resonance imaging showed thick, irregular walls and a hyperintense central area (arrows). At surgery, the mass proved to be a largely necrotic renal cell carcinoma. Thus, although renal carcinoma is not a true cystic disease, it occasionally has a cystic appearance on CT and can mimic a simple cyst. (Courtesy of A. Dardenne.)

Cystic Diseases of the Kidney

9.7

FIGURE 9-11 Medullary sponge kidney (MSK) diagnosed by intravenous urography in 53-year-old woman with a history of recurrent kidney stones. Pseudocystic collections of contrast medium in the papillary areas (arrows) are the typical feature of MSK. They result from congenital dilatation of collecting ducts (involving part or all of one or both kidneys), ranging from mild ectasia (appearing on urography as linear striations in the papillae, or papillary “blush”) to frank cystic pools, as in this case (giving a spongelike appearance on section of the kidney). MSK has an estimated prevalence of 1 in 5000 [2]. It predisposes to stone formation in the dilated ducts: on plain films, clustering of calcifications in the papillary areas is very suggestive of the condition. MSK may be associated with a variety of other congenital and inherited disorders, including corporeal hemihypertrophy, Beckwith-Wiedemann syndrome (macroglossia, omphalocele, visceromegaly, microcephaly, and mental retardation), polycystic kidney disease (about 3% of patients with autosomal-dominant polycystic kidney disease have evidence of MSK), congenital hepatic fibrosis, and Caroli’s disease [7].

FIGURE 9-12 Multicystic dysplastic kidney (MCDK) found incidentally by enhanced CT in a 34-year-old patient. The dysplastic kidney is composed of cysts with mural calcifications (arrows). Note the compensatory hypertrophy of the right kidney and the incidental simple cysts in it. MCDK consists of a collection of cysts frequently described as resembling a bunch of grapes and an atretic ureter. No function can be demonstrated. Only unilateral involvement is compatible with life. Usually, the contralateral kidney is normal and exhibits compensatory hypertrophy. In some 30% of cases, however, it is also affected by some congenital abnormalities such as dysplasia or pelviureterical junction obstruction. In fact, among the many forms of renal dysplasia, MCDK is thought to represent a cystic variety.

FIGURE 9-13 Intravenous urography demonstrates multiple calyceal diverticula (arrows) in a 38-year-old woman who complained of intermittent flank pain. Previously, the ultrasonographic appearance had suggested the existence of polycystic kidney disease. Although usually smaller than 1 cm in diameter, pyelocalyceal diverticula occasionally are much larger, as in this case. They predispose to stone formation. Since ultrasonography is the preferred screening tool for cystic renal diseases, clinicians must be aware of both its pitfalls (exemplified in this case and in the case of parapelvic cysts; see Fig. 9-6) and its limited power to detect very small cysts.

9.8

Tubulointerstitial Disease

Genetic disorders GENETICS OF ADPKD Gene

Chromosome

PKD1 PKD2 PKD3

16 4 ?

Product

Patients with ADPKD, %

Polycystin 1 Polycystin 2 ?

80–90 10–20 Very few

NH2 Cysteine-rich domain Leucine-rich domain PKD1 domain C L B

C L B

C-type lectin domain Lipoprotein A domain

R E J

REJ domain

Transmembrane segment

Alpha helix coiled-coil R E J

Out Membrane In NH2 HOOC Polycystin 1

COOH Polycystin 2

FIGURE 9-14 Genetics of autosomal-dominant polycystic kidney disease (ADPKD). ADPKD is by far the most frequent inherited kidney disease. In white populations, its prevalence ranges from 1 in 400 to 1 in 1000. ADPKD is characterized by the development of multiple renal cysts that are variably associated with extrarenal (mainly hepatic and cardiovascular) abnormalities [1,2,3]. It is caused by mutations in at least three different genes. PKD1, the gene responsible in approximately 85% of the patients, located on chromosome 16, was cloned in 1994 [8]. It encodes a predicted protein of 460 kD, called polycystin 1. The vast majority of the remaining cases are accounted for by a mutation in PKD2, located on chromosome 4 and cloned in 1996 [9]. The PKD2 gene encodes a predicted protein of 110 kD called polycystin 2. Phenotypic differences between the two main genetic forms are detailed in Figure 9-19. The existence of (at least) a third gene is suggested by recent reports. FIGURE 9-15 Autosomal-dominant polycystic kidney disease: predicted structure of polycystin 1 and polycystin 2 and their interaction. Polycystin 1 is a 4302-amino acid protein, which anchors itself to cell membranes by seven transmembrane domains [10]. The large extracellular portion includes two leucine-rich repeats usually involved in protein-protein interactions and a C-type lectin domain capable of binding carbohydrates. A part of the intracellular tail has the capacity to form a coiled-coil motif, enabling either self-assembling or interaction with other proteins. Polycystin 2 is a 968-amino acid protein with six transmembrane domains, resembling a subunit of voltage-activated calcium channel. Like polycystin 1, the C-terminal end of polycystin 2 comprises a coiled-coil domain and is able to interact in vitro with PKD2 [11]. This C-terminal part of polycystin 2 also includes a calcium-binding domain. On these grounds, it has been hypothesized that polycystin 1 acts like a receptor and signal transducer, communicating information from outside to inside the cell through its interaction with polycystin 2. This coordinated function could be crucial during late renal embryogenesis. It is currently speculated that both polycystins play a role in the maturation of tubule epithelial cells. Mutation of polycystins could thus impair the maturation process, maintaining some tubular cells in a state of underdevelopment. This could result in both sustained cell proliferation and predominance of fluid secretion over absorption, leading to cyst formation (see Fig. 9-16 and references 12 and 13 for review). (From Hughes et al. [10] and Germino [12].)

Cystic Diseases of the Kidney

Thickened tubular basement membrane

Fluid Accumulation

Isolated cyst disconnected from its tubule of origin

Monoclonal proliferation leading to cyst formation

Occurrence of somatic mutation of the normal PKD1 allele in one tubular cell (the "second hit")

Normal tubule with germinal PKD1 mutation in each cell

FIGURE 9-16 Hypothetical model for cyst formation in autosomal-dominant polycystic kidney disease (ADPKD), relying on the “two-hit” mechanism as the primary event. The observation that only a minority of nephrons develop cysts, despite the fact that every tubular cell harbors germinal PKD1 mutation, is best accounted for by the two-hit model. This model implies that, in addition to the germinal mutation, a somatic (acquired) mutation involving the normal PKD1

Basolateral

Aden

ylate

Na+ cAMP K+ 2Cl–

Apical

cycla

ATP

se

(CFTR)

Cl–

PKA Bumetanide

DPC

+

2K ATP

+ + (Na -K -ATPase) 3Na+

ADP + Pi

Ouabain

H 2O

(

AQP)

Lumen H 2O Q (A P)

Na+

9.9

allele is required to trigger cyst formation (ie, a mechanism similar to that demonstrated for tumor suppressor genes in tuberous sclerosis complex and von Hippel-Lindau disease). The hypothesis is supported by both the clonality of most cysts and the finding of loss of heterozygosity in some of them [12]. Cell immaturity resulting from mutated polycystin would lead to uncontrolled growth, elaboration of abnormal extracellular matrix, and accumulation of fluid. Aberrant cell proliferation is demonstrated by the existence of micropolyps, identification of mitotic phases, and abnormal expression of proto-oncogenes. Abnormality of extracellular matrix is evidenced by thickening and lamination of the tubular basement membrane; involvement of extracellular matrix would explain the association of cerebral artery aneurysms with ADPKD. As most cysts are disconnected from their tubule of origin, they can expand only through net transepithelial fluid secretion, just the reverse of the physiologic tubular cell function [13]. Figure 9-17 summarizes our current knowledge of the mechanisms that may be involved in intracystic fluid accumulation.

FIGURE 9-17 Autosomal-dominant polycystic kidney disease (ADPKD): mechanisms of intracystic fluid accumulation [13,14]. The primary mechanism of intracystic fluid accumulation seems to be a net transfer of chloride into the lumen. This secretion is mediated by a bumetanide-sensitive Na+-K+-2Cl- cotransporter on the basolateral side and cystic fibrosis transmembrane regulator (CFTR) chloride channel on the apical side. The activity of the two transporters is regulated by protein kinase A (PKA) under the control of cyclic adenosine monophosphate (AMP). The chloride secretion drives movement of sodium and water into the cyst lumen through electrical and osmotic coupling, respectively. The pathway for transepithelial Na+ movement has been debated. In some experimental conditions, part of the Na+ could be secreted into the lumen via a mispolarized apical Na+-K+-ATPase (“sodium pump”); however, it is currently admitted that most of the Na+ movement is paracellular and that the Na+-K+-ATPase is located at the basolateral side. The movement of water is probably transcellular in the cells that express aquaporins on both sides and paracellular in others [13, 14]. AQP—aquaporine; DPC—diphenylamine carboxylic acid.

ADPKD: CLINICAL MANIFESTATIONS Manifestation Renal Hypertension Pain (acute and chronic) Gross hematuria Urinary tract infection Calculi Renal failure Hepatobiliary (see Fig. 9–23) Cardiovascular Cardiac valvular abnormality Intracranial arteries Aneurysm Dolichoectasia ? Ascending aorta dissection ? Coronary arteries aneurysm Other Pancreatic cysts Arachnoid cysts Hernia Inguinal Umbilical Spinal Meningeal Diverticula

Prevalence, %

Reference

Increased with age (80 at ESRD) 60 50 Men 20; women 60 20 50 at 60 y

[15] [3,16] [3,16] [3] [17] [18]

Odds ratio (95% Cl) PKD2 vs. PKD1

Tubulointerstitial Disease

0.46 (0.22-0.98)

1.0 0.47 (0.28-0.81)

0.8 0.6

0.28 (0.16-0.48)

0.18 (0.07-0.47)

0.4 0.2 0.0

20

[16]

8 2 Rare Rare

[3] [19]

9 8

[20] [21]

13 7 0.2

[22] [22] [23]

Hypertension Renal infection Subarachnoid history hemorrhage 80 70 60

75

74

PKD2 PKD1

Abdominal hernia

70

61

60

50 Age, y

9.10

40

35

30 20

FIGURE 9-18 Main clinical manifestations of autosomal-dominant polycystic kidney disease (ADPKD). Renal involvement may be totally asymptomatic at early stages. Arterial hypertension is the presenting clinical finding in about 20% of patients. Its frequency increases with age. Flank or abdominal pain is the presenting symptom in another 20%. The differential diagnosis of acute abdominal is detailed in Figure 9-22. Gross hematuria is most often due to bleeding into a cyst, and more rarely to stone. Renal infection, a frequent reason for hospital admission, can involve the upper collecting system, renal parenchyma or renal cyst. Diagnostic data are obtained by ultrasonography, excretory urography and CT: use of CT in cyst infection is described in Figure 9-21. Frequently, stones are radiolucent or faintly opaque, because of their uric acid content. The main determinants of progression of renal failure are the genetic form of the disease (see Fig. 9-19) and gender (more rapid progression in males). Hepatobiliary and intracranial manifestations are detailed in Figures 9-23 to 9-26. Pancreatic and arachnoid cysts are most usually asymptomatic. Spinal meningeal diverticula can cause postural headache. ESRD—end-stage renal disease.

10 0 Clinical presentation

End-stage renal failure Median age

Death

FIGURE 9-19 Autosomal-dominant polycystic kidney disease (ADPKD): phenotype PKD2 versus PKD1. Families with a PKD2 mutation have a milder phenotype than those with a PKD1 mutation. In this study comparing 306 PKD2 patients (from 32 families) with 288 PKD1 patients (17 families), PKD2 patients were, for example, less likely to be hypertensive, to have a history of renal infection, to suffer a subarachnoid hemorrhage, and to develop an abdominal hernia. As a consequence of the slower development of clinical manifestations, PKD2 patients were, on average, 26 years older at clinical presentation, 14 years older when they started dialysis, and 5 years older when they died. Early-onset ADPKD leading to renal failure in childhood has been reported only in the PKD1 variety. (Data from Hateboer [24].)

Cystic Diseases of the Kidney

A

B

C

D

FIGURE 9-20 Autosomal-dominant polycystic kidney disease (ADPKD): kidney involvement. Examples of various cystic involvements of kidneys in ADPKD. Degree of involvement depends on age at presentation and disease severity. A, With advanced disease as in this 54-year-old woman, renal parenchyma is almost completely replaced by innumerable cysts. Note also the cystic involvement of the liver. B, Marked asymmetry in the number and size of cysts between the two

9.11

kidneys may be observed, as in this 36-year-old woman. In the early stage of the disease, making the diagnosis may be more difficult (see Fig. 9-28 for the minimal sonographic criteria to make a diagnosis of ADPKD in PKD1 families). C, D, Contrast-enhanced CT is more sensitive than ultrasonography in the detection of small cysts. The presence of liver cysts helps to establish the diagnosis, as in this 38year-old man with PKD2 disease and mild kidney involvement.

9.12

Tubulointerstitial Disease

A

B

FIGURE 9-21 Autosomal-dominant polycystic kidney disease (ADPKD): kidney cyst infection. Course of severe cyst infection in the right kidney of a patient with ADPKD who was admitted for fever and acute right flank pain. Blood culture was positive for Escherichia coli. A, CT performed on admission showed several heterogeneous cysts in the right kidney (arrows). Infection did not respond to appropriate

ADPKD: SPECIFIC CAUSES OF ACUTE ABDOMINAL PAIN Cause Renal Cyst Bleeding Stone Infection Liver Cyst Infection Bleeding

Frequency

Fever

++++ ++ +

Mild (<38°C, maximum 2 days) or none With pyonephrosis High; prolonged with cyst involved

Rare Very Rare

High, prolonged Mild (<38°C, maximum 2 days) or none

antibiotherapy (fluoroquinolone). B, CT repeated 17 days later showed considerable enlargement of the infected cysts (arrows). Percutaneous drainage failed to control infection, and nephrectomy was necessary. This case illustrates the potential severity of cyst infection and the contribution of sequential CT in the diagnosis and management of complicated cysts. FIGURE 9-22 Autosomal-dominant polycystic kidney disease (ADPKD): specific causes of acute abdominal pain. The most frequent cause of acute abdominal pain related to ADPKD is intracyst bleeding. Depending on the amount of bleeding, it may cause mild, transient fever. It may or may not cause gross hematuria. Cyst hemorrhage is responsible for most high-density cysts and cyst calcifications demonstrated by CT. Spontaneous resolution is the rule. Excretory urography or enhanced CT is needed mostly to locate obstructive, faintly opaque stones. Stones may be treated by percutaneous or extracorporal lithotripsy. Renal infection may involve the upper collecting system, renal parenchyma, or cyst. Parenchymal infection is evidenced by positive urine culture and prompt response to antibiotherapy; cyst infection by the development of a new area of renal tenderness, quite often a negative urine culture (but a positive blood culture), and a slower response to antibiotherapy. CT demonstrates the heterogeneous contents and irregularly thickened walls of infected cysts. Cyst infection warrants prolonged anti-biotherapy [3]. An example of severe, intractable cyst infection is shown in Figure 9-21.

Cystic Diseases of the Kidney

9.13

ADPKD: HEPATOBILIARY MANIFESTATIONS Finding

Frequency

Asymptomatic liver cysts

Very common; increased prevalence with age (up to 80% at age 60) Uncommon (male/female ratio: 1/10)

Symptomatic polycystic liver disease Complicated cysts (hemorrhage, infection) Massive hepatomegaly Chronic pain/discomfort Early satiety Supine dyspnea Abdominal hernia Obstructive jaundice Hepatic venous outflow obstruction Congenital hepatic fibrosis Idiopathic dilatation of intrahepatic or extrahepatic biliary tract Cholangiocarcinoma

Rare (not dominantly transmitted) Very rare Very rare

FIGURE 9-23 Autosomal-dominant polycystic kidney disease (ADPKD): hepatobiliary manifestations. Liver cysts are the most frequent extrarenal manifestation of ADPKD. Their prevalence increases dramatically from the third to the sixth decade of life, reaching a plateau of 80% thereafter [25, 26]. They are observed earlier and are more numerous and extensive in women than in men. Though usually mild and asymptomatic, cystic liver involvement occasionally is massive and symptomatic (see Figure 9-24). Rare cases have been reported of congenital hepatic fibrosis or idiopathic dilatation of the intrahepatic or extrahepatic tract associated with ADPKD [25, 26].

A FIGURE 9-25 Autosomal-dominant polycystic kidney disease (ADPKD): intracranial aneurysm detection. Magnetic resonance angiography (MRA), A, and spiral computed tomography (CT) angiography, B, in two different patients, both with ADPKD, show an asymptomatic intracranial aneurysm (ICA) on the posterior communicating artery (arrow), A, and the anterior communicating artery (arrow), B, respectively. The prevalence of asymptomatic ICA in ADPKD is 8%, as compared with 1.2% in the general population. It reaches 16% in ADPKD patients with a family history of ICA [27]. The risk of

FIGURE 9-24 Autosomal-dominant polycystic kidney disease (ADPKD): polycystic liver disease. Contrast-enhanced CT in a 32-year-old woman with ADPKD, showing massive polycystic liver disease contrasting with mild kidney involvement. Massive polycystic liver disease can cause chronic pain, early satiety, supine dyspnea, abdominal hernia, and, rarely, obstructive jaundice, or hepatic venous outflow obstruction. Therapeutic options include cyst sclerosis and fenestration, hepatic resection, and, ultimately, liver transplantation [25, 26].

B ICA rupture in ADPKD is ill-defined. ICA rupture entails 30% to 50% mortality. It is generally manifested by subarachnoid hemorrhage, which usually presents as an excruciating headache. In this setting, the first-line diagnostic procedure is CT. Management should proceed under neurosurgical guidance [27]. Given the severe prognosis of ICA rupture and the possibility of prophylactic treatment, screening ADPKD patients for ICA has been considered. Screening can be achieved by either MRA or spiral CT angiography. Current indications for screening are presented in Figure 9-26. (Courtesy of T. Duprez and F. Hammer.)

9.14

Tubulointerstitial Disease

Age 18–40 years and family history of ICA?

No

No screening

Yes Brain MR angiography No or spiral CT scan: ICA? Yes

Repeat every 5 years

FIGURE 9-26 Autosomal-dominant polycystic kidney disease (ADPKD): intracranial aneurysm (ICA) screening. On the basis of decision analyses (taking into account ICA prevalence, annual risk of rupture, life expectancy, and risk of prophylactic treatment), it is currently proposed to screen for ICA 18 to 40-year-old ADPKD patients with a family history of ICA [25, 27]. Screening could also be offered to patients in high-risk occupations and those who want reassurance. Guidelines for prophylactic treatment are the same ones used in the general population: the neurosurgeon and the interventional radiologist opt for either surgical clipping or endovascular occlusion, depending on the site and size of ICA.

Conventional angiography Discuss management with neurosurgeon

ADPKD: PRESYMPTOMATIC DIAGNOSIS Presymptomatic diagnosis Is advisable in families when early management of affected patients would be altered (eg, because of history of intracranial aneurysm) Should be made available to persons at risk who are 18 years or older who request the test Should be preceded by information about the possibility of inconclusive results and the consequences of the diagnosis: If negative, reassurance If positive, regular medical follow-up, possible psychological burden, risk of disqualification from employment and insurances

FIGURE 9-27 Autosomal-dominant polycystic kidney disease (ADPKD): presymptomatic diagnosis. Presymptomatic diagnosis is aimed at both detecting affected persons (to provide follow-up and genetic counseling) and reassuring unaffected ones. Until a specific treatment for ADPKD is available, presymptomatic diagnosis in children is not advised except in rare families where early-onset disease is typical. Presymptomatic diagnosis is recommended when a family is planned and when early management of affected patients would be altered. The mainstay of screening is ultrasonography; diagnostic echographic criteria according to age in PKD1 families are depicted in Figure 9-28, and diagnosis by gene linkage in Figure 9-29.

ADPKD: ULTRASONOGRAPHIC DIAGNOSTIC CRITERIA Age

Cysts

15–29 30–59 ≥60

2, uni- or bilateral 2 in each kidney 4 in each kidney

Minimal number of cysts to establish a diagnosis of ADPKD in PKD1 families at risk.

FIGURE 9-28 Autosomal-dominant polycystic kidney disease (ADPKD): ultrasonographic diagnostic criteria. Ultrasound diagnostic criteria for the PKD1 form of ADPKD, as established by Ravine’s group on the basis of both a sensitivity and specificity study [4, 28]. Note that the absence of cyst before age 30 years does not rule out the diagnosis, the false-negative rate being inversely related to age. When ultrasound diagnosis remains equivocal, the next step should be either contrast-enhanced CT (more sensitive than ultrasonography in the detection of small cysts) or gene linkage (see Figure 9-29). A similar assessment is not yet available for the PKD2 form. (From Ravine et al. [28]; with permission.)

Cystic Diseases of the Kidney

I

?

?

1

Deceased Unaffected Affected ? Unknown status

2

II 1

3

2

4

5 1 b

III 1 2 a

IV 2 b

3

2 3 b

2 b

4 a

5 a

2 a

?

?

?

?

1

2

3

4

3 b

3 b

2 b

1 b

3 b

5 a

2 a

Life expectancy <5 yrs or contraindication to surgery or to immunosuppressants?

History of cyst infection? Yes

Yes

Pretransplant workup: Eligibility for transplantation? No No Very large kidneys or abdominal hernia?

Yes

No Remove kidney(s)?

Transplantation

or

Peritoneal dialysis

FIGURE 9-29 Example of the use of gene linkage to identify ADPKD gene carriers among generation IV of a PKD1 family. Two markers flanking the PKD1 gene were used. The first one (3’ HVR) has six possible alleles (1 through 6) and the other (p 26.6) is biallelic (a, b). In this family, the haplotype 2a is transmitted with the disease (see affected persons II5, III1, and III3). Thus, IV4 has a 99% chance of being a carrier of the mutated PKD1 gene, whereas her sisters (IV1, IV2, IV3) have a 99% chance of being disease free. Until direct gene testing for PKD1 and PKD2 is readily available, genetic diagnosis will rest on gene linkage. Such analysis requires that other affected and unaffected family members (preferably from two generations) be available for study. Use of markers on both sides of the tested gene is required to limit potential errors due to recombination events. Linkage to PKD1 is to be tested first, as it accounts for about 85% of cases.

5 a

No

Yes

9.15

Hemodialysis

FIGURE 9-30 Autosomal-dominant polycystic kidney disease (ADPKD): renal replacement therapy. Transplantation nowadays is considered in any ADPKD patient with a life expectancy of more than 5 years and with no contraindications to surgery or immunosuppression. Pretransplant workup should include abdominal CT, echocardiography, myocardial stress scintigraphy, and, if needed (see Figure 9-26), screening for intracranial aneurysm. Pretransplant nephrectomy is advised for patients with a history of renal cyst infection, particularly if the infections were recent, recurrent, or severe. Patients not eligible for transplantation may opt for hemodialysis or peritoneal dialysis. Although kidney size is rarely an impediment to peritoneal dialysis, this option is less desirable for patients with very large kidneys, because their volume may reduce the exchangeable surface area and the tolerance for abdominal distension. Outcome for ADPKD patients following renal replacement therapy is similar to that of matched patients with another primary renal disease [29, 30].

9.16

Tubulointerstitial Disease

CLINICAL FEATURES Finding Skin Hypomelanotic macules Facial angiofibromas Forehead fibrous plaques “Shagreen patches” (lower back) Periungual fibromas Central nervous system Cortical tubers Subependymal tumors (may be calcified) focal or generalized seizures Mental retardation/ behavioral disorder Kidney Angiomyolipomas Cysts Renal cell carcinoma Eye Retinal hamartoma Retinal pigmentary abnormality Liver (angiomyolipomas, cysts) Heart (rhabdomyoma) Lung (lymphangiomyomatosis; affects females)

Frequency, %

Age at onset, y

90 80 30 30 30

Childhood 5–15 ≥5 ≥10 ≥15

90 90

Birth Birth

80 50

0–1 0–5

60 30 2

Childhood Childhood Adulthood

50 10 40 2 1

Childhood Childhood Childhood Childhood ≥20

FIGURE 9-31 Tuberous sclerosis complex (TSC): clinical features. TSC is an autosomal-dominant multisystem disorder with a minimal prevalence of 1 in 10,000 [30, 31]. It is characterized by the development of multiple hamartomas (benign tumors composed of abnormally arranged and differentiated tissues) in various organs. The most common manifestations are dermatologic (see Fig. 9-32) and neurologic (see Fig. 9-33). Renal involvement occurs in 60% of cases and includes cysts (see Fig. 9-34). Retinal involvement, occurring in 50% of cases, is almost always asymptomatic. Liver involvement, occurring in 40% of cases, includes angiomyolipomas and cysts. Involvement of other organs is much rarer [31, 32].

B

A

FIGURE 9-32 (see Color Plate) Tuberous sclerosis complex (TSC): skin involvement. Facial angiofibromas, forehead plaque, A, and ungual fibroma, B, characteristic of TSC. Previously (and inappropriately) called adenoma sebaceum, facial angiofibromas are pink to red papules or nodules, often concentrated in the nasolabial folds. Forehead fibrous plaques appear as raised, soft patches of red or yellow skin. Ungual fibromas appear as peri- or subungual pink tumors; they are found more often on the toes than on the fingers and are more common in females. Other skin lesions include hypomelanotic macules and “shagreen patches” (slightly elevated patches of brown or pink skin). (Courtesy of A. Bourloud and C. van Ypersele.)

Cystic Diseases of the Kidney

9.17

FIGURE 9-33 Tuberous sclerosis complex (TSC): central nervous system involvement. Brain CT shows several subependymal, periventricular, calcified nodules characteristic of TSC. Subependymal tumors and cortical tubers are the two characteristic neurologic features of TSC. Calcified nodules are best seen on CT, whereas noncalcified tumors are best detected by magnetic resonance imaging. Clinical manifestations are seizures (including infantile spasms) occurring in 80% of infants, and varying degrees of intellectual disability or behavioral disorder, reported in 50% of children [32].

A FIGURE 9-34 Tuberous sclerosis complex (TSC): kidney involvement. Contrastenhanced CT, A, and gadolinium-enhanced T1 weighted magnetic resonance images, B, of a 15-year-old woman with TSC, show both a large, hypodense, heterogeneous tumor in the right kidney (arrows) characteristic of angiomyolipoma (AML) and multiple bilateral kidney cysts. Kidney cysts had been detected at birth. AML is a benign tumor composed of atypical blood vessels, smooth muscle cells, and fat tissue. While single AML is the most frequent kidney tumor in the general population, multiple and bilateral AMLs are characteristic of TSC. In TSC, AMLs develop at a younger age in females; frequency and size of the tumors increase with age. Diagnosis of AML by imaging techniques (ultrasonography [US], CT, magnetic resonance imagine [MRI]) relies on identification

B of fat into the tumor, but it is not always possible to distinguish between AML and renal cell carcinoma. The main complication of AML is bleeding with subsequent gross hematuria or potentially lifethreatening retroperitoneal hemorrhage. Cysts seem to be restricted to the TSC2 variety (see Fig. 9-35) [33]. Their extent varies widely from case to case. Occasionally, polycystic kidneys are the presenting manifestation of TSC2 in early childhood: in the absence of renal AML, the imaging appearance is indistinguishable from ADPKD. Polycystic kidney involvement leads to hypertension and renal failure that reaches end stage before age 20 years. Though the frequency of renal cell carcinoma in TSC is small, the incidence is increased as compared with that of the general population. (Courtesy of J. F. De Plaen and B. Van Beers.)

9.18

Tubulointerstitial Disease

VHL: ORGAN INVOLVEMENT

HG loci

PKD1

TSC2

Death

16 pter

Chromosome 16

FIGURE 9-35 Tuberous sclerosis complex (TSC): genetics. Representative examples of various contiguous deletions of the PKD1 and TSC2 genes in five patients with TSC and prominent renal cystic involvement (the size of the deletion in each patient is indicated). TSC is genetically heterogeneous. Two genes have been identified. The TSC1 gene is on chromosome 9, and TSC2 lies on chromosome 16 immediately adjacent and distal to the PKD1 gene. Half of affected families show linkage to TSC1 and half to TSC2. Nonetheless, 60% of TSC cases are apparently sporadic, likely representing new mutations (most are found in the TSC2 gene) [34]. The proteins encoded by the TSC1 and TSC2 genes are called hamartin and tuberin, respectively. They likely act as tumor suppressors; their precise cellular role remains largely unknown. The diseases caused by type 1 and type 2 TSC are indistinguishable except for renal cysts, which, so far, have been observed only in TSC2 patients [33], and for intellectual disability, which is more common in TSC2 patients [34]. (Adapted from Sampson, et al. [33].)

Findings Central nervous system Hemangioblastoma Cerebellar Spinal cord Endolymphatic sac tumor Eye/Retinal hemangioblastoma Kidney Clear cell carcinoma Cysts Adrenal glands/ Pheochromocytoma Pancreas Cysts Microcystic adenoma Islet cell tumor Carcinoma Liver (cysts)

Frequency, %

Mean age (range) at diagnosis, y 30 (9–71)

60 20 Rare 60

25 (8–70)

40 30 15

40 (18–70) 35 (15–60) 20 (5–60) 30 (13–70)

40 4 2 1 Rare

?

FIGURE 9-36 Von Hippel-Lindau disease (VHL): organ involvement. VHL is an autosomal-dominant multisystem disorder with a prevalence rate of roughly 1 in 40,000 [32, 35]. It is characterized by the development of tumors, benign and malignant, in various organs. VHL-associated tumors tend to arise at an earlier age and more often are multicentric than the sporadic varieties. Morbidity and mortality are mostly related to central nervous system hemangioblastoma and renal cell carcinoma. Involvement of cerebellum, retinas, kidneys, adrenal glands, and pancreas is illustrated (see Figures 9-37 to 9-41). The VHL gene is located on the short arm of chromosome 3 and exhibits characteristics of a tumor suppressor gene. Mutations are now identified in 70% of VHL families [36]. FIGURE 9-37 Von Hippel-Lindau disease (VHL): central nervous system involvement. Gadolinium-enhanced brain magnetic resonance image of a patient with VHL, shows a typical cerebellar hemangioblastoma, appearing as a highly vascular nodule (arrow) in the wall of a cyst (arrowheads) located in the posterior fossa. Hemangioblastomas are benign tumors whose morbidity is due to mass effect. Cerebellar hemangioblastomas may present with symptoms of increased intracranial pressure. Spinal cord involvement may be manifested as syringomyelia. (Courtesy of S. Richard.)

Cystic Diseases of the Kidney

9.19

FIGURE 9-38 (see Color Plate) Von Hippel-Lindau disease (VHL): retinal involvement. Ocular fundus, A, and corresponding fluorescein angiography, B, in a patient with VHL, shows two typical retinal hemangioblastomas. The smaller tumor (arrow) appears at the fundus as an intense red spot, whereas the larger (arrow heads) appears as a pink-orange lake with dilated, tortuous afferent and efferent vessels. Small peripheral lesions are usually asymptomatic, whereas large central tumors can impair vision. (Courtesy of B. Snyers.)

B A

FIGURE 9-39 Von Hippel-Lindau disease (VHL): kidney involvement. Contrastenhanced CT of a patient with VHL, showing the polycystic aspect of the kidneys. Renal involvement of VHL includes cysts (simple, atypical, and cystic carcinoma) and renal cell carcinoma [36, 37]. The latter is the leading cause of death from VHL. Occasionally, polycystic kidney involvement may mimic autosomal-dominant polycystic kidney disease. Both cystic involvement and sequelae of surgery can lead to renal failure. Nephron-sparing surgery is recommended [37].

FIGURE 9-40 Von Hippel-Lindau disease (VHL): adrenal gland involvement. Gadolinium-enhanced abdominal magnetic resonance image of a patient with VHL shows bilateral pheochromocytoma (arrows). Renal lesions include cysts and solid carcinomas (arrow heads). Pheochromocytoma may be the first manifestation of VHL. It tends to cluster within certain VHL families [36]. (Courtesy of H. Neumann.)

9.20

Tubulointerstitial Disease FIGURE 9-41 Von Hippel-Lindau disease (VHL): pancreas involvement. Contrastenhanced abdominal CT in a patient with VHL shows multiple cysts in both pancreas (especially the tail, arrows) and kidneys. The majority of pancreatic cysts are asymptomatic. When they are numerous and large, they can induce diabetes mellitus or steatorrhea. Other, rare pancreatic lesions include microcystic adenoma, islet cell tumor, and carcinoma.

VHL: SCREENING PROTOCOL Study

Affected persons

Relatives at risk

Physical examination 24-h Urine collection for metadrenaline and normetadrenaline Funduscopy Gadolinium MRI brain scan Abdomen

Annual Annual

Annual Annual

Annual Every 3 y (from age 10) Annual gadolinium MRI

Annual (age 5 to 60) Every 3 y (age 15 to 60) Annual echography or gadolinium MRI (age 15 to 60)

FIGURE 9-42 Von Hippel-Lindau disease. As most manifestations of VHL are potentially treatable, periodic examination of affected patients is strongly recommended. Though genetic testing is now very useful for presymptomatic identification of affected persons, it must be remembered that a mutation in the VHL gene currently is detected in only 70% of families. For persons at risk in the remaining families, a screening program is also proposed.

FIGURE 9-43 Medullary cystic disease (MCD). Contrast-enhanced CT in a 35year-old man with MCD. Multiple cysts are seen in the medullary area. Two daughters were also found to be affected. MCD is a very rare autosomal-dominant disorder characterized by medullary cysts detectable by certain imaging techniques (preferably computed tomography) and progressive renal impairment leading to endstage disease between 20 and 40 years of age. Dominant inheritance and early detection of kidney cysts distinguish MCD from autosomal-recessive nephronophthisis (see Fig. 9-48), even though the two may be indistinguishable on histologic examination.

Cystic Diseases of the Kidney

9.21

THERE IS A WHITE BOX PLACED OVER HANDWRITTEN TYPE.

A

B

C FIGURE 9-44 Glomerulocystic kidney disease (GCKD). Contrast-enhanced CT, A, in a 23-year-old woman with the sporadic form of GCKD shows

ARPKD: CLINICAL MANIFESTATIONS Renal Antenatal (ultrasonographic changes) Oligohydramnios with empty bladder Increased renal volume and echogenicity Neonatal period Dystocia and oligohydramnios Enlarged kidneys Renal failure Respiratory distress with pulmonary hypoplasia (possibly fatal) Infancy of childhood Nephromegaly (may regress with time) Hypertension (often severe in the first year of life) Chronic renal failure (slowly progressive, with a 60% probability of renal survival at 15 years of age and 30% at 25 years of age) Hepatic Portal fibrosis Intrahepatic biliary tract ectasia

multiple cysts, typically small cortical ones. This cystic pattern was verified in the nephrectomy specimen, B, obtained 8 months later at the time of kidney transplantation, and GCKD was confirmed by histopathologic examination with Masson’s trichrome stain. C, Cysts consisted of a dilatation of Bowman’s space surrounding a primitive-looking glomerulus. GCKD may be sporadic or genetically dominant. Among the familial cases, some patients are infants who have early-onset autosomal-dominant polycystic disease. In others (children or adults) the disease is unrelated to PKD1 and PKD2 and may or not progress to end-stage renal failure [38]. (Courtesy of D. Droz.) FIGURE 9-45 Autosomal-recessive polycystic kidney disease (ARPKD): clinical manifestations. ARPKD is characterized by the development of cysts originating from collecting tubules and ducts, invariably associated with congenital hepatic fibrosis. Its prevalence is about 1 in 40,000 [39]. In the most severe cases, with marked oligohydramnios and an empty bladder, the diagnosis may be suspected as early as the 12th week of gestation. Some neonates die from either respiratory distress or renal failure. In most survivors, the disease is recognized during the first year of life. The ultrasonographic (US) kidney appearance is depicted in Figure 9-46. Excretory urography shows medullary striations owing to tubular ectasia. Kidney enlargement may regress with time. End-stage renal failure develops before age 25 in 70% of patients. Liver involvement consists of portal fibrosis (see Fig. 9-47) and intrahepatic bilary ectasia, frequently resulting in portal hypertension (leading to hypersplenism and esophageal varices) and less often in cholangitis, respectively. US may show dilatation of the biliary ducts, and even cysts. The respective severity of kidney and liver involvement vary widely between families and even in a single kindred. A comparison of the diagnostic features of autosomal-dominant polycystic kidney disease (ADPKD) and ARPKD is summarized in Figure 9-2. Renal US of the parents of a child with ARPKD is, of course, normal. It should be noted that congenital hepatic fibrosis is found in rare cases of ADPKD with early-onset renal disease. The gene responsible for ARPKD has been mapped to chromosome 6. There is no evidence of genetic heterogeneity [40].

9.22

Tubulointerstitial Disease FIGURE 9-46 A and B, Autosomal-recessive polycystic kidney disease (ARPKD): renal imaging. On ultrasonography of a child with ARPKD the kidneys appear typically enlarged and uniformly hyperechogenic (owing to the presence of multiple small cysts), and demarcations of cortex, medulla, and sinus are lost. The ultrasonographic appearance is different in older children, because cysts can grow and become round; then they resemble the appearance of ADPKD. Figure 9-2 describes how to differentiate the two conditions. (Courtesy of P. Niaudet.)

A

B

FIGURE 9-47 Autosomal-recessive polycystic kidney disease (ARPKD): liver histology. Liver biopsy specimen from a child with ARPKD shows typical congenital hepatic fibrosis (hematoxylin eosin safran [HES] stain). This portal space is enlarged by fibrosis, and the number of biliary channels is increased, many of them being enlarged and all being irregular in outline. (Courtesy of S. Gosseye.)

FIGURE 9-48 Nephronophthisis (NPH): renal involvement. Kidney biopsy specimen visualized by light microscopy with periodic acid–Schiff stain, in a patient with juvenile NPH of an early stage. Note the typical thickening and disruption of the tubular basement membrane (appearing in red); the histiolymphocytic infiltration present at this stage is progressively replaced by interstitial fibrosis. NPH is an autosomal recessive disorder, accounting for 10% to 15% of all children admitted for end-stage renal failure. Although classified as a renal cystic disorder, NPH is characterized by chronic diffuse tubulointerstitial nephritis; the presence of cysts at the corticomedullary boundary (thus, the alternative term “medullary cystic disease,” now preferably reserved for the autosomal-dominant form; see Fig. 9-43) is a late manifestation of the disease. Clinical features include early polyuria-polydypsia, unremarkable urinalysis, frequent absence of hypertension, and eventually, end-stage renal failure at a median age of 13 (range 3 to 23) years. Ultrasonographic features are summarized in Figure 9-2; medullary cysts are sometimes detected. Associated disorders are detailed in Figure 9-49. A gene called NPH1 that has been identified on chromosome 2 accounts for about 80% of cases [41, 42]. In two thirds of them, a large homozygous deletion is detected in this gene [43]. (Courtesy of P. Niaudet.)

Cystic Diseases of the Kidney

NPH: EXTRARENAL INVOLVEMENT Retinitis pigmentosa (Senior-Loken syndrome) Multiple organ involvement, including Liver fibrosis Other rare features Skeletal changes (cone-shaped epiphyses) Cerebellar ataxia Mental retardation

A

9.23

FIGURE 9-49 Nephronophthisis (NPH): extrarenal involvement. Extrarenal involvement occurs in 20% of NPH cases. The most frequent finding is tapetoretinal degeneration (known as Senior-Loken syndrome), which often results in early blindness or progressive visual impairment. Other rare manifestations include liver (hepatomegaly, hepatic fibrosis), bone (cone-shaped epiphysis), and central nervous system (mental retardation, cerebellar ataxia) abnormalities, quite often in association.

B

FIGURE 9-50 Orofaciodigital syndrome (OFD). Contrast-enhanced CT, A, and the hands, B, of a 26-year-old woman with OFD type 1 (OFD1) [43]. Multiple cysts involve both kidneys. Note that they are smaller and more uniform than in ADPKD and that renal contours are preserved. Some cysts were also detected in liver and pancreas (arrow). Syndactyly was surgically corrected, and the digits of the hands are shortened (brachydactyly). OFD1 is a rare X-linked, dominant disorder, diagnosed almost exclusively in females, as affected males die in utero.

Characteristic dysmorphic features include oral (hyperplastic frenulum, cleft tongue, cleft palate or lip, malposed teeth), facial (asymmetry, broad nasal root), and digit (syn-brachy-polydactyly) abnormalities. Mental retardation is present in about half the cases. Kidneys may be involved by multiple (usually small) cysts, mostly of glomerular origin; renal failure occurs between the second and the seventh decade of life. Recognition of the dysmorphic features is the key to the diagnosis [44, 45]. (Courtesy of F. Scolari.)

References 1. 2.

3.

4.

5.

Fick GM, Gabow PA: Hereditary and acquired cystic disease of the kidney. Kidney Int 1994, 46:951–964. Welling LW, Grantham JJ: Cystic and developmental diseases of the kidney. In The Kidney. Edited by Brenner M. Philadelphia:WB Saunders Company; 1996:1828–1863. Pirson Y, Chauveau D, Grünfeld JP: Autosomal dominant polycystic kidney disease. In Oxford Textbook of Clinical Nephrology. Edited by Davison AM, Cameron JS, Grünfeld JP, et al. Oxford:Oxford University Press; 1998:2393–2415. Ravine D, Gibson RN, Donlan J, Sheffield LJ: An ultrasound renal cyst prevalence survey: Specificity data for inherited renal cystic diseases. Am J Kidney Dis 1993, 22:803–807. Levine E: Acquired cystic kidney disease. Radiol Clin North Am 1996, 34:947–964.

6. Sarasin FP, Wong JB, Levey AS, Meyer KB: Screening for acquired cystic kidney disease: A decision analytic perspective. Kidney Int 1995, 48:207–219. 7. Hildebrandt F, Jungers P, Grünfeld JP: Medullary cystic and medullary sponge renal disorders. In Diseases of the Kidney. Edited by Schrier RW, Gottschalk CW. Boston: Little Brown; 1997:499–520. 8. The European Polycystic Kidney Disease Consortium: The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell 1994, 77:881–894. 9. Mochizuki T, Wu G, Hayashi T, et al.: PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 1996, 272:1339–1342. 10. Hughes J, Ward CJ, Peral B, et al.: The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nature Genet 1995, 10:151–160.

9.24

Tubulointerstitial Disease

11. Qian F, Germino FJ, Cai Y, et al.: PKD1 interacts with PKD2 through a probable coiled-coil domain. Nature Genet 1997, 16:179–183. 12. Germino GG: Autosomal dominant polycystic kidney disease: a twohit model. Hospital Pract 1997, 81–102.

30. Culleton B, Parfrey PS: Management of end-stage renal failure and problems of transplantation in autosomal dominant polycystic kidney disease. In Polycystic Kidney Disease. Edited by Watson ML, Torres VE. Oxford:Oxford University Press; 1996:450–461.

13. Grantham JJ: The etiology, pathogenesis, and treatment of autosomal dominant polycystic kidney disease: Recent advances. Am J Kidney Dis 1996, 28:788–803.

31. Torres VE: Tuberous sclerosis complex. In Polycystic Kidney Disease. Edited by Watson ML, Torres VE. Oxford:Oxford University Press; 1996:283–308.

14. Devuyst O, Beauwens R: Ion transport and cystogenesis: The paradigm of autosomal dominant polycystic kidney disease. Adv Nephrol 1998, (in press).

32. Huson SM, Rosser EM: The Phakomatoses. In Principles and Practice of Medical Genetics. Edited by Rimoin DL, Connor JM, Pyeritz RE. New York:Churchill Livingstone; 1997: 2269–2302.

15. Parfrey PS, Barrett BJ: Hypertension in autosomal dominant polycystic kidney disease. Curr Opin Nephrol Hypertens 1995, 4:460–464.

33. Sampson JR, Maheshwar MM, Aspinwall R, et al.: Renal cystic disease in tuberous sclerosis: Role of the polycystic kidney disease 1 gene. Am J Human Genet 1997, 61:843–851.

16. Gabow PA: Autosomal dominant polycystic kidney disease. N Engl J Med 1993, 329:332–342. 17. Torres WE, Wilson DM, Hattery RR, Segura JW: Renal stone disease in autosomal dominant polycystic kidney disease. Am J Kidney Dis 1993, 22:513–519. 18. Choukroun G, Itakura Y, Albouze G, et al.: Factors influencing progression of renal failure in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1995, 6:1634–1642. 19. Schievink WI, Torres VE, Wiebers DO, Huston J III: Intracranial arterial dolichoectasia in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1997, 8:1298–1303. 20. Torra R, Nicolau C, Badenas C, et al.: Ultrasonographic study of pancreatic cysts in autosomal dominant polycystic kidney disease. Clin Nephrol 1997, 47:19–22. 21. Schievink WI, Huston J III, Torres VA, Marsh WR: Intracranial cysts in autosomal dominant polycystic kidney disease. J Neurosurg 1995, 83:1004–1007. 22. Gabow PA: Autosomal dominant polycystic kidney disease—more than a renal disease. Am J Kidney Dis 1990, 16:403–413. 23. Schievink WI, Torres VE: Spinal meningeal diverticula in autosomal dominant polycystic kidney disease. Lancet 1997, 349:1223–1224. 24. Hateboer N, Dijk M, Torra R, et al.: Phenotype PKD2 vs. PKD1; results from the European concerted action. J Am Soc Nephrol 1997, 8:373A. 25. Chauveau D, Pirson Y, Le Moine A, et al.: Extrarenal manifestations in autosomal dominant polycystic kidney disease. Adv Nephrol 1997, 26:265–289. 26. Torres VE: Polycystic liver disease. In Polycystic Kidney Disease. Edited by Watson ML, Torres VE. Oxford: Oxford University Press; 1996:500–529. 27. Pirson Y, Chauveau D: Intracranial aneurysms in autosomal dominant polycystic kidney disease. In Polycystic Kidney Disease. Edited by Watson ML, Torres VE. Oxford:Oxford University Press; 1996:530–547. 28. Ravine D, Gibson RN, Walker RG, et al.: Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1. Lancet 1994, 343:824–827. 29. Pirson Y, Christophe JL, Goffin E: Outcome of renal replacement therapy in autosomal dominant polycystic kidney diseases. Nephrol Dial Transplant 1996, 11 (suppl. 6):24–28.

34. Jones AC, Daniells CE, Snell RG, et al.: Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis. Hum Molec Genet 1997, 6:2155–2161. 35. Michels V: Von Hippel-Lindau disease. In Polycystic Kidney Disease. Edited by Watson ML, Torres VE. Oxford:Oxford University Press; 1996:309–330. 36. Neumann HPH, Zbar B: Renal cysts, renal cancer and von HippelLindau disease. Kidney Int 1997, 51:16–26. 37. Chauveau D, Duvic C, Chretien Y, et al.: Renal involvement in von Hippel-Lindau disease. Kidney Int 1996, 50:944–951. 38. Sharp CK, Bergman SM, Stockwin JM, et al.: Dominantly transmitted glomerulocystic kidney disease: A distinct genetic entity. J Am Soc Nephrol 1997, 8:77–84. 39. Gagnadoux MF, Broyer M: Polycystic kidney disease in children. In Oxford Textbook of Clinical Nephrology. Edited by Davison AM, Cameron JS, Grünfeld JP, et al. Oxford:Oxford University Press; 1998:2385–2393. 40. Zerres K, Mücher G, Bachner L, et al.: Mapping of the gene for autosomal recessive polycystic kidney disease (ARPKD) to chromosome 6p21-cen. Nature Genet 1994, 7:429–432. 41. Antignac C, Arduy CH, Beckmann JS, et al.: A gene for familial juvenile nephronophthisis (recessive medullary cystic kidney disease) maps to chromosome 2p. Nature Genet 1993, 3:342–345. 42. Hildebrandt F, Otto E, Rensing C, et al.: A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nature Genet 1997, 17:149–153. 43. Konrad M, Saunier S, Heidet L, et al.: Large homozygous deletions of the 2q13 region are a major cause of juvenile nephronophthisis. Hum Molec Genet 1996, 5: 367–371. 44. Scolari F, Valzorio B, Carli O, et al.: Oral-facial-digital syndrome type I: An unusual cause of hereditary cystic kidney disease. Nephrol Dial Transplant 1997, 12:1247–1250. 45. Feather SA, Winyard PJD, Dodd S, Woolf AS: Oral-facial-digital syndrome type 1 is another dominant polycystic kidney disease: Clinical, radiological and histopathological features of a new kindred. Nephrol Dial Transplant 1997, 12:1354–1361.

Toxic Nephropathies Jean-Louis Vanherweghem

T

ubular interstitial structures of the kidney are particularly vulnerable in face of toxic compounds. High concentration of the toxics in de medulla as well as medullary hypoxia and renal hypoperfusion could explain this particularity. Clinical nephrotoxicity involves toxins of diverse origin. The culprits are often registered and non registered drugs either prescribed or purchased over the counter. Other major causes result from occupational and industrial exposures. Sometimes, the identification of the nephrotoxin requires astuteness and long investigations especially in cases of environmental toxins or prolonged intake of unregulated drugs or natural products. A correct diagnosis of the causes is, however, the key for future prevention of renal diseases. The diagnosis of “chronic interstitial nephritis of unknown origin” should, therefore, no longer be used.

CHAPTER

10

10.2

Tubulointerstitial Disease

Exposure to Nephrotoxins FIGURE 10-1 Chronic exposure to drugs, occupational hazards, or environmental toxins can lead to chronic interstitial renal diseases. The following are the major causes of chronic interstitial renal diseases: occupational exposure to heavy metals; abuse of over-the-counter analgesics; misuse of germanium; chronic intake of mesalazine for intestinal disorders, lithium for depression, and cyclosporine in renal and nonrenal diseases; and environmental or iatrogenic exposure to fungus or plant nephrotoxins (ochratoxins, aristolochic acids).

TOXIC CAUSES OF CHRONIC TUBULOINTERSTITIAL RENAL DISEASES Metals (Environmental or Occupational Exposure) Lead Cadmium Drugs or Additives (Use, Misuse, or Abuse) Lithium Germanium Analgesics Cyclosporine Mesalazine Fungus and Plant Toxins (Environmental or Iatrogenic Exposure) Ochratoxins Aristolochic acids

Exposure to Metals FIGURE 10-2 Occupational exposure to metals and risks for chronic renal failure. Comparison of the occupational histories of 272 patients with chronic renal failure with those of a matched control group having normal renal function has shown an increased risk of chronic renal failure after exposure to mercury, tin, chromium, copper, and lead. In this study the increased risk with exposure to cadmium was not statistically significant. Squares indicate odds ratios; circles indicate CIs. (Adapted from Nuyts and coworkers [1]; with permission.)

Odds ratio (95% confidence intervals)

30 25 20 15 10 5 0 Mercury

Tin

Chromium Copper

Lead

Cadmium

Odds ratio

C1 >

C1 <

Mercury

5130

1020

25,700

Tin

3720

1220

11,300

Chromium

2770

1210

6330

Copper

2540

1160

5530

Lead

2110

1230

4360

Cadmium

2200

900

8250

Toxic Nephropathies

10.3

Lead nephropathy CAUSES OF LEAD NEPHROPATHY

CLINICAL MANIFESTATIONS OF LEAD NEPHROPATHY Gout Arterial hypertension Renal failure (interstitial type)

Environmental Eating paint from lead-painted furniture, woodwork, and toys in children Lead-contaminated flour Home lead-contaminated drinking water from lead pipes Drinking of moonshine whiskey Occupational Lead-producing plants: lead smelters, battery plants

FIGURE 10-3 Lead nephropathy associated with environmental and occupational exposure. Epidemiologic observations have established the relationship between lead exposure and renal failure in association with children eating lead paint in their homes, chronic ingestion of leadcontaminated flour, lead-loaded drinking water in homes, and drinking of illegal moonshine whiskey [2,3]. Occupational exposure in lead-producing industries also has been associated with a higher incidence of renal dysfunction.

Days

1

2

8 AM

8 PM

EDTA 1 g

1g

IM

IM

FIGURE 10-5 Ethylenediamine tetraacetic acid (EDTA)–lead mobilization test in lead nephropathy. EDTA (calcium disodium acetate) for detecting lead nephropathy. This test consists of a 24-hour urinary lead excretion over 3 consecutive days after administration of 2 g of EDTA by intramuscular route on the first day in divided doses 12 hours apart. Persons without excessive lead exposure excrete less than 0.6 mg of lead during the day after receiving 2 g of EDTA parenterally. In the presence of renal failure, the excretion is delayed; however, the cumulative total remains less than 0.6 mg over 3 days (From Batuman and coworkers [3]; with permission.)

3

Urinary collection

FIGURE 10-4 Gout and hypertension are the major clinical manifestations of lead nephropathy. The prominent feature of early hyperuricemia in lead nephropathy may explain the confusion between lead nephropathy and gout nephropathy. Lead urinary excretion after ethylenediamine tetraacetic acid (EDTA)–lead mobilization testing may help with the correct diagnosis [3].

Lead, mg

Excessive lead exposure:

120

I

1500

II

IV

100 80 60 40

III

IV

V

Lead, mg/72 h

Creatinine clearance, mL/min

No < 0.6 Yes >0.6

20

0 Blood pressure N Gout A

1000 III II

500 I

+

B

0

V

FIGURE 10-6 Ethylenediamine tetraacetic acid (EDTA)– lead mobilization test in chronic renal failure of uncertain origin (A–C). In a study of 296 patients without history of lead exposure, the results of this test were abnormal in 15.4% (II) of patients with hypertension and normal renal function and in 56.1% of patients with renal failure of uncertain origin (in 44.1% of the patients without associated gout (III) and in 68.7% of the patients with associated gout (IV), respectively). (Continued on next page)

10.4

Patients with abnormal test results, %

Tubulointerstitial Disease FIGURE 10-6 (Continued) The EDTA–lead mobilization test was normal in normotensive subjects with normal renal function and in patients with chronic renal failure (I) of well-known origin (V). (Adapted from Sanchez-Fructuoso and coworkers [4].)

IV

50

C

III

II

0

Glomerular filtration rate, mL/min/1.73 m2

Cadmium nephropathy FIGURE 10-7 Decrease in renal function after 25-year exposure to cadmium (Cd). In workers exposed to cadmium for an average time of 25 years, a progressive decrease in renal function occurs during a 5-year follow-up period, despite removal from cadmium exposure 10 years earlier. On average, the glomerular filtration rate was shown to be decreased to 31 mL/min/1.73 m2 after 5 years instead of the expected age-related value of 5 mL/min/1.73 m2. (Adapted from Roels and coworkers [5].)

110 105 100 95 90 85 80 75 70

Expected values Cd exposure

5

6 8 9 7 10 11 Removal from Cd exposure, y

Graph values I

II

III

IV

NEP

43

53

50

76

CC16

16

17

25

124

RBP

80

122

132

594

ß2-m

73

112

102

834

Creatinine, µg/g

800 600

* 834

NEP CC16 RBP ß2–m *P < 0.05

* 594

200 * *

0 I

II

III

IV

I

II

III

IV

Creatinine clearance, mL/min

103

103

90*

79*

Urinary Cd, µg/g/creatinine

0.55

1.34

3.28*

8.45*

FIGURE 10-8 Tubular markers in cadmium workers. Impairment of renal proximal tubular epithelium induced by cadmium can be documented by an increase in urinary excretion of urinary neutral endopeptidase 24.11 (NEP), an enzyme of the proximal tubule brush borders, as well as by an increase in microproteinuria: Clara cell protein (CC16), retinol-binding protein (RBP) and 2-microglobulin (2-m). The data were obtained from 106 healthy persons working in cadmium smelting plants. These markers could be used for the screening of cadmium workers. (Adapted from Nortier and coworkers [6].)

Toxic Nephropathies

10.5

Lithium nephropathy LITHIUM NEPHROTOXICITY Reversible polyuria and polydipsia Persistent nephrogenic diabetes insipidus Incomplete distal tubular acidosis Chronic renal failure (chronic interstitial fibrosis)

FIGURE 10-9 Lithium acts both distally and proximally to antidiuretic hormone–induced generation of cyclic adenosine monophosphatase. Polyuria and polydipsia can occur in up to 40% of patients on lithium therapy and are considered harmless and reversible. However, nephrogenic diabetes insipidus may persist months after lithium has been discontinued [7]. Lithium also induces an impairment of distal urinary acidification. Chronic renal failure secondary to chronic interstitial fibrosis may appear in up to 21% of patients on maintenance lithium therapy for more than 15 years [8]. However, these observations are still a matter of debate [7].

FIGURE 10-10 (see Color Plate) Lithium nephropathy. A 22-year-old female patient was on maintenance lithium therapy (lithium carbonate 750 mg/d) for 5 years. She presented with polyuria (6500 mL/d) and moderate renal failure (creatinine clearance, 60 mL/min). Proteinuria was not present, and the urinary sediment was unremarkable. A renal biopsy showed focal interstitial fibrosis with scarce inflammatory cell infiltrate, tubular atrophy, and characteristic dilated tubule (microcyst formation). Half of the glomeruli (not shown) were sclerotic. (Magnification  125, periodic acid–Schiff reaction.)

Germanium nephropathy CIRCUMSTANCES OF CHRONIC RENAL FAILURE SECONDARY TO GERMANIUM SUPPLEMENTS

Ge-dioxyde elixir, food additives, or capsules (used to improve health in normal persons [Japan]) Ge-lactate-citrate (used to rebuild the immune system) in patients with HIV infection (Switzerland) Ge-lactate-citrate (used to improve health) in patients with cancer (the Netherlands) Ge-dioxyde elixir (used to restore health) in patients with chronic hepatitis (Japan)

FIGURE 10-11 Germanium (atomic number, 32; atomic weight, 72.59) is contained in soil, plants, and animals as a trace metal. It is widely used in the industrial fields because of its semiconductive capacity. The increased use of natural remedies and trace elements to protect, improve, or restore the health has lead regular supplementation with germanium salts either through food addition or by the means of elixirs and capsules. The chronic supplementation by germanium salts was at the origin of the development of chronic renal failure secondary to a tubulointerstitial nephritis [9–12].

10.6

Tubulointerstitial Disease

A

B

FIGURE 10-12 Light microscopy of renal tissue in a patient with chronic renal failure secondary to the chronic intake of germanium, showing focal tubular atrophy and focal interstitial lymphocyte infiltration. A, Hematoxylin and eosin stain. (Magnification  162.)

Renal tubular epithelial cells show numerous dark small inclusions. B, Periodic acid–Schiff reaction. (Magnification,  350). (From Hess and coworkers [12]; with permission).

Exposure to Analgesics

Normal papilla Swollen Forniceal erosion

Detachment Calcification

FIGURE 10-13 Analgesic nephropathy and papillary necrosis. The characteristic feature of analgesic nephropathy is the papillary necrosis process that begins with swollen papillae and continues with forniceal erosion, detachment, and calcification of necrotic papillae. FIGURE 10-14 Pathology of analgesic nephropathy. Nephrectomy showing a kidney reduced in size with necrosed and calcified papillae.

10.7

Toxic Nephropathies

CLINICAL FEATURES OF ANALGESIC NEPHROPATHY Daily consumption of analgesic mixtures Women Headache Gastrointestinal disturbances Urinary tract infection Papillary necrosis (clinical) Papillary calcifications (computed tomography scan)

FIGURE 10-15 Radiologic appearance of papillary necrosis in analgesic nephropathy. The pyelogram was obtained by pyelostomy. It shows a swollen papilla (upper calyx), forniceal erosions (middle calyx), and detachment of papilla, or filling defect (lower calyx).

25

FIGURE 10-16 Classic analgesic nephropathy is a slowly progressive disease resulting from the daily consumption over several years of mixtures containing analgesics usually combined with caffeine, codeine, or both. Caffeine and codeine create psychological dependence. Most cases of analgesic nephropathy occur in women. In 80% of the cases, analgesics were taken for persistent headache. Gastrointestinal complaints are also frequent, as are urinary tract infections. Evidence of clinical papillary necrosis (fever and pain) is present in 20% of cases. Calcifications of papillae (detected by computed tomography scan) are present in 65% of persons who abuse analgesics [13]. FIGURE 10-17 Worldwide epidemiology of analgesic nephropathy. The frequency of analgesic nephropathy in patients with end-stage renal diseases (ESRD) varies greatly within and among countries [14–16]. The highest prevalence rates of end-stage renal disease from analgesic nephropathy occur in South Africa (22%), Switzerland and Australia (20%), Belgium (18%), and Germany (15%). In Belgium, the prevalence is 36% in the north and 10% in the south. In Great Britain, the rate is 1% nationwide; in Scotland it is 26%. In United States, the rate is 5% nationwide, 13% in North Carolina, and 3% in Washington, DC. In Canada, the rate is 6% nationwide.

EPIDEMIOLOGY OF ANALGESIC NEPHROPATHY AMONG ESRD PATIENTS Australia Belgium Canada Germany South Africa Switzerland United Kingdom United States

20% 18% 6% 15% 22% 20% 1% 5%

Prevalence (EDTA, 1989) Analgesic nephropathy Unknown cause

20

%

15 10 5

in Spa

y Ital

nce Fra

al Por tug

rlan ds the Ne

any rm Ge F.R .

stri a Au

Bel giu m

itze rlan d

0

Sw

100% 80% 80% 35–40% 30–48% 20% 65%

FIGURE 10-18 Prevalence of analgesic nephropathy versus nephropathy with unknown cause. Crossnational comparisons in Europe indicate that the proportion of cases of end-stage renal disease attributed to analgesics varies considerably; however, it is inversely proportional to unknown causes. These findings suggest an underestimation of the prevalence of analgesic nephropathy in several countries, probably owing to the lack of well-defined criteria for diagnosis [13,15]. EDTA—European Dialysis and Transplant Association. (From Elseviers and coworkers [13]; with permission).

10.8

1983 sales of mixtures containing two analgesic components

Tubulointerstitial Disease

Pills taken in lifetime < 5000 ≥ 5000

Odds ratio, 95% confidence intervals

10.0

5.0

1.0 0

A

3000

Belgium Rs = 0.86 P< 0.001

2000

1000

0 0

Acetaminiophen

Aspirin

B

40 30 10 20 1991 prevalence of analgesic nephropathy, %

50

FIGURE 10-19 Risk of analgesic nephropathy associated with specific types of analgesics. The initial reports of analgesic nephropathy chiefly concerned phenacetin mixtures. Phenacetin

Renal volume Right kidney

Indentations RA

A

A

RV

RA

A

SP B B Decreased: A + B < 103 mm (males) < 96 mm (females)

Criteria Decrease in renal size Bumpy contours Papillary calcifications

Papillary calcifications

Left kidney

0

B

Sensitivity, % 95 50 87

1–2

3–5 Bumpy contours

D. PERCENTAGES OF SENSITIVITY AND SPECIFICITY

E

has been replaced with acetaminophen in analgesia mixtures without significant changes in the cause of analgesic nephropathy in some countries [15]. A, The risk factor for end-stage renal disease of unknown cause is increased in relationship to the cumulative intake of acetaminophen as well as nonsteroidal anti-inflammatory drugs but not to aspirin. Moreover, mixtures containing several analgesic compounds were shown to be more nephrotoxic than are simple drugs. B, In Belgium, the prevalence of analgesic nephropathy in 1991 was strongly correlated with sales of analgesic mixtures in 1983. Rs—coefficient of correlation. (A, Adapted from Perneger and coworkers [17]; B, adapted from Elseviers and De Broe [18]; with permission).

Specificity, % 10 90 97

>5

C

FIGURE 10-20 High performance of computed tomography (CT) scan for diagnosing analgesic nephropathy. Three criteria may be used to diagnose analgesic nephropathy by CT scan: decrease in renal size, measured by the sum of both sides of the rectangle enclosing the kidney at the level of the renal vessels (A); indentations counted at the level at which most indentations are present (more than three are qualified of bumpy contours) (B); and papillary calcifications (C). Percentages of sensitivity and specificity are given for the three criteria (D). Example of papillary calcifications on CT scan (E). RA— renal artery; RV—renal vein; SP—spine. (Adapted from Elseviers and De Broe [19]; with permission).

Toxic Nephropathies

HONCOCH3

OC2H5

NCOCH3

O

OH

O

O

OH

FIGURE 10-21 Malignancies of the urinary tract and their association with analgesic nephropathy. Malignancies of the renal pelvis and ureters were reported in up to 9% of patients with analgesic nephropathy. This high prevalence can be explained by the appearance of carcinogenic substances in the major pathways of the metabolism of phenacetin. Probable carcinogenic substances are indicated by a plus sign.

N-hydroxyp-ocetophenetidine HNCOCH3

HNCOCH3

NH2

HNOH

10.9

NO

OH [OH] OC2H5

OC2H5

OC2H5

Phenacetin (p-ocetophenetidine) HNCOCH3

NH2

OC2H5

OC2H5

N-hydroxyp-phenetidine

p-nitrosophenetidine

H 2N

O

OH

OC2H5 OH N-acetyl-p-amino- 2-hydroxyphenol (NAPA) phenetidine

OH NH2

H

OC2H5 Arene oxide

OC2H5 NIH shift

FIGURE 10-22 Malignant uroepithelial tumors of the upper urinary tract in patients with analgesic nephropathy. A, Pyelogram showing a filling defect, indicating a tumor of the renal pelvis. B, Retrograde pyelography showing a long malignant stricture of the ureter, causing ureteral dilation and hydronephrosis. (Courtesy of W Lornoy, MD, OL Vrouwziekenhuis, MD.)

A

B

10.10

Tubulointerstitial Disease

Exposure to Cyclosporine Cyclosporine toxicity

Cyclosporine induced hypertension

Cyclosporine Cyclosporine Intestinal absorption 25–30%

Acute effects

Liver cytochrome P450

Inactive metabolites

Sympathetic nervous system

Chronic effects Endothelium Thromboxane Endothelin

Renal vasoconstruction

Inhibition Ketoconazole Verapamil Diltiazem Erythromycin

Cytosol calcium

Chronic renal failure

Sodium chloride retention Hypertension

FIGURE 10-23 Toxicity of cyclosporine. Cyclosporine is a neutral fungal hydrophobic 11-amino acid cyclic polypeptide. Cyclosporine is metabolized by hepatic cytochrome P450 to multiple less active and less toxic metabolites. Drugs that inhibit cytochrome P450 enzymes such as ketoconazole, verapamil, diltiazem, and erythromycin increase the concentration of cyclosporine and may thus precipitate renal side effects [20,21].

Mechanisms of cyclosporine renal injury Cyclosporine Renin

Sustained vasoconstriction

Angiotensin II

Renal ischemia

TGF-ß Interstitial fibrosis

FIGURE 10-24 Cyclosporine and hypertension. Hypertension can develop in 10% to 80% of patients treated with cyclosporine, depending on dosage and length of the exposure. Cyclosporine increases cytosol calcium and, thus, enhances arteriolar smooth muscle responsiveness to vasoconstrictive stimuli. Vasoconstrictive effects of cyclosporine also are mediated by enhanced thromboxane action, sympathetic nerve stimulation, and release of endothelin. Renal vasoconstriction results in salt retention and hypertension. In chronic exposure to cyclosporine, hypertension also is a part of cyclosporine-induced chronic renal failure [22].

FIGURE 10-25 Pathogenesis of cyclosporine nephropathy. Chronic administration of cyclosporine may induce sustained renal vasoconstriction. Impairment of renal blood flow leads to tubulointerstitial fibrosis. Cyclosporine increases the recruitment of renin-containing cells along the afferent arteriole. Hyperplasia of the juxtaglomerular apparatus increases angiotensin II levels that, in turn, stimulate tumor growth factor- (TGF-) secretion, resulting in interstitial fibrosis [20].

Toxic Nephropathies

CyA, 7.5 mg/kg

60 40 20

60 40 20 0

0

A

8 Weeks

CyA, 5 mg/kg

80 60 40 20 0 0

24 Months Uveitis

80 60 40 20 0

0

B

Psoriasis

100 Glomerular filtration rate, % of normal values

80

CyA, 10 to 6 mg/kg

100 Glomerular filtration rate, % of normal values

80

0

D

CyA, 9.3 mg/kg

100 Glomerular filtration rate, % of normal values

Glomerular filtration rate, % of normal values

100

10.11

13 Months Autoimmune diseases

0

C

36 Months Cardiac transplantations

FIGURE 10-26 Cyclosporine (CyA) nephrotoxicity in nonrenal diseases. A, Patients treated with cyclosporine (7.5 mg/kg) for psoriasis experienced a median decrease to 84% of the initial values in the glomerular filtration rate after 8 weeks of therapy. B, Of patients treated with cyclosporine (9.3 mg/kg) for autoimmune diseases, 21% showed cyclosporine nephropathy on biopsy, with a decrease to 60% of the initial values in renal function. C, Patients with cardiac transplantation treated with high doses of cyclosporine (10 to 6 mg/kg) developed a reduction to 57% of the initial values in renal function 36 months after transplantation. Patients treated with azathioprine did not show any reduction in renal function. D, Patients receiving cyclosporine (5 mg/kg) for uveitis for 2 years showed a decrease in glomerular filtration rate to 65% of the initial values. (Panel A adapted from Ellis and coworkers [23]; panel B adapted from Feutren and Mihatsch [24]; panel C adapted from Myers and Newton [25]; and panel D adapted from Deray and coworkers [26].)

A FIGURE 10-27 Morphology of cyclosporine nephropathy on renal biopsy of a patient with cardiac transplantation. Two different types of lesions are seen in cyclosporine nephropathy. A, Arteriolopathy: Hyalin, paucicellular thickening of the intima with focal wall necrosis results in narrowing of the vascular lumen (magnification  300

B periodic acid–Schiff reaction). B, A striped form of interstitial fibrosis characterized by irregularly distributed areas of stripes of interstitial fibrosis and tubular atrophy in the renal cortex. Tubules in other areas were normal (magnification x 100 periodic acid–Schiff reaction).

10.12

Tubulointerstitial Disease

Exposure to Aminosalicylic Acid 10.6 C.P. man born January 19, 1971

8 6

4.0

B FIGURE 10-28 Aminosalicylic acid and chronic tubulointerstitial nephritis. A, A 36-year-old man suffering from Crohn’s disease exhibited severe renal failure after 23 months of treatment with 5-aminosalicylic acid (5-ASA, or Pentasa, Hoechst Marion Roussel, Kansas City, MO). B, The first renal biopsy showing widening and massive cellular infiltration of the interstitium, tubular atrophy, and relative spacing of glomeruli. C, The second renal biopsy 8 months, after discontinuation of the drug and moderate improvement of the renal function, again showing important cellular infiltration

y1 , 19 96 De c1 , 19 96

Methyl- 16 mg/d prednisolone

Ma

Hemodialysis

rch

199 1 199 2 rch

t 3,

Ma

Oc

Renal biopsy

23, 199 4 2, 1 994

Oral Pentasa® 500 mg/d, 3 x per day

3.9

32 mg/d

Renal biopsy

v2 2 De , 1994 c2 De , 1994 c2 De 2, 199 c3 1, 4 Jan 1994 6, 1 995

1.1

No

2 0

A

4.2

IBD diagnosis

Ma

4

4.9

Feb

Seerum creatinine, mg/dL

10

C of the interstitium tubular atrophy, and fibrosis. Several atrophic tubules are surrounded by one or more layers of -smooth muscle actin positive cells. The patient had normal renal function on beginning treatment with 5-ASA. After 5 years of 5-ASA therapy, the patient demonstrated severe impaired renal function. The association between the use of 5-ASA and development of chronic tubulointerstitial nephritis in patients with inflammatory bowel disease (IBD) has gained recognition in recent years [27,28]. (Courtesy of ME De Broe, MD.)

Toxic Nephropathies

10.13

Exposure to Ochratoxins FIGURE 10-29 Ochratoxin nephropathy. Ochratoxin A is a mycotoxin produced by various species of Aspergillus and Penicillium. Ochratoxins contaminate foods (mainly cereals) for humans as well as for cattle. Ochratoxins are mutagenic, oncogenic, and nephrotoxic. Ochratoxins are responsible for chronic nephropathy in pigs and also may be the cause of endemic Balkan nephropathy and some chronic interstitial nephropathies seen in North Africa and France [29].

Ochratoxin A OH

COOH

O

– CH2- CH-NH-CO-

CH3 CI

R. Danube

Contamination of cereals Chronic nephropathy in pigs Endemic Balkan nephropathy Chronic interstitial nephritis in Tunisia Chronic interstitial nephritis in France (?)

Austria Slovenia R. Sava

CLINICAL FEATURES OF BALKAN NEPHROPATHY

Hungary

Croatia R. S

ava

Romania

Slavonski Brod

Bneljina

Bosnia and Herezgovina

Oravita Turn Severin Belgrade Lazarevac Paracin

Sarajevo

Nis

be

anu

R. D Mikhaylovgrad

Yugoslavia

Vratsa

Italy

Sofia

Residence in an endemic area Occupational history of farming Progressive renal failure Microproteinuria of tubular type Unremarkable urinary sediment Small and shrunken kidneys Associated urothelial tumors

Bulgaria

Macedonia Albania Greece

FIGURE 10-30 Endemic Balkan nephropathy. Endemic nephropathy is encountered in some well-defined areas of the Balkans. Distribution (dark areas) is along the affluents of the Danube, in a few areas on the plains and low hills owing to high humidity and rainfall. (From Stefanovic and Polenakovic [30]; with permission.)

FIGURE 10-31 Clinical features in Balkan nephropathy. Balkan nephropathy is characterized by progressive renal failure in residents (generally farmers) living in endemic areas for over 10 years. The urinary sediment is unremarkable and no proteinuria is seen, except for a microproteinuria of tubular type. The kidneys are small and shrunken. Urothelial cancers are frequently associated with Balkan nephropathy [29,30].

10.14

Tubulointerstitial Disease

A

B

FIGURE 10-32 Pathology of Balkan nephropathy. Balkan nephropathy is characterized by pure interstitial fibrosis with marked tubular atrophy (A) and by

hyperplasia of the myocythial cells with narrowing of the lumen of the vessel (B) (From Stefanovic and M. Polenakovic [30]; with permission).

80

12.8

10

1.6

0 Endemic Nonendemic Areas of Balkan nephropathy

FIGURE 10-34 Balkan nephropathy and ochratoxin A in food. A survey of homeproduced foodstuffs in the Balkans has revealed that contamination with ochratoxin A is more frequent in areas in which endemic nephropathy is prevalent (endemic areas) than in areas in which nephropathy is absent. (Adapted from Krogh and coworkers [31].)

Number of urothelial cancers per million inhabitants

Cereal samples contaminated by ochratoxin, %

FIGURE 10-33 Pathology of ochratoxin nephropathy. In addition to interstitial fibrosis, large hyperchromatic nuclei in tubular epithelial cells are shown by the arrow (interstitial caryomegalic nephropathy). (Masson trichrome stain, magnification x 160.) The renal biopsy was obtained from a woman from France who had renal failure (creatinine clearance 40 mL/min) without significant proteinuria and urinary sediment abnormalities. Ochratoxin levels were 367 and 1810 ng/mL, respectively, in the patient’s blood and urine. (From Godin and coworkers [29].)

74.2

70 60 50 40 30 20 10 0

3.2

Endemic Nonendemic Areas of Balkan nephropathy

FIGURE 10-35 Balkan nephropathy and urothelial cancers. Urothelial cancers appear as a frequent complication of Balkan nephropathy. An increased prevalence of upper tract urothelial tumors is described in inhabitants of areas in which Balkan nephropathy is endemic. (Adapted from Godin and coworkers [29].)

Toxic Nephropathies

10.15

Exposure to Chinese Herbs FIGURE 10-36 Epidemiology of Chinese herbs nephropathy. Chinese herbs nephropathy was described for the first time in Belgium in 1993 [32]. A peak incidence of new cases of women with rapidly progressive interstitial nephritis in Brussels during 1992 lead to suspicion of a new cause of renal disease. The relationship between this new renal disease and the recent introduction of Chinese herbs (namely, Stephania tetrandra) in a slimming regimen was established [32]. The withdrawal from the market of this herb has decreased the incidence of interstitial nephritis in Brussels, Belgium.

Chinese herb nephropathy (number of new cases)

Release of Chinese herb (so-called Stephania tetrandra) on Belgian market

40 90

92

32

31

30 24

20

15

10

7 1

1

1989

1990

5

0 1991

1992 1993 Year

1994

1995

1996

A. CHINESE HERBAL MEDICINE Chinese Name

Western name

Chemical Marker

Han fang-ji Guang fang-ji

Stephania tetrandra Aristolochia fang chi

Tetrandrine Aristolochic acid

30

Chinese herbs (Number of batches)

30

20

10

7 5

0

B

4

+A, +T +A, –T –A, +T –A, –T +A, aristolochic acid present –A, aristolochic acid absent +T, tetrandrine present –T, tetrandine absent

FIGURE 10-37 Role of Aristolochia in Chinese herbs nephropathy. Stephania tetrandra was the Chinese herb chronologically associated with the development of Chinese herbs nephropathy. However, tetrandrine, the alkaloid characterizing Stephania tetrandra was not found in the capsules taken by the patients. In fact, confusion between Stephania tetrandra and Aristolochia fang chi was done in the delivery of Chinese herbs in Belgium [33]. Chinese characters and the pingin name of Stephania tetrandra (Han fang-ji) are identical to that of Aristolochia fang chi (Guang fang-ji). Investigations conducted on batches of Stephania tetrandra powders distributed in Belgium have shown that most of them contained aristolochic acids (characteristic of Aristolochia) and not tetrandrine (From Vanhaelen and coworkers [33] and P Daenens, Katholiek Universiteit Leuven, Belgium, report of expertise 1996.)

10.16

Tubulointerstitial Disease

DNA ADDUCTS FORMED BY ARISTOLOCHIC ACID IN RENAL TISSUE Chinese Herb Nephropathy (n = 5)

Controls (n = 6)

0.7–5.3 per 107 nucleotides

0

FIGURE 10-38 DNA aristolochic acid adducts in kidney tissues of patients with Chinese herbs nephropathy. The role of Aristolochia in the pathogenesis of Chinese herbs nephropathy was confirmed by the demonstration of DNA aristolochic acid adducts (a biomarker of aristolochic acids exposure) in renal tissue of patients with Chinese herbs nephropathy, whereas these adducts were absent in the renal tissue of control cases. (Adapted from Schmeiser and coworkers [34].)

CLINICAL FEATURES OF CHINESE HERB NEPHROPATHY Rapidly progressive renal failure Microproteinuria of tubular type Unremarkable urinary sediment Small and shrunken kidneys Valvular hear diseases (dexfenfluramine-associated therapy), 30% Associated urothelial cancers

FIGURE 10-39 The clinical features of Chinese herbs nephropathy are characterized by rapidly progressive renal failure without both urinary sediment abnormalities and proteinuria except for a microproteinuria of tubular type. The kidneys are small and shrunken. Vascular heart diseases are associated in 30% of cases (probably owing to dexfenfluramine administered with the Chinese herbs for slimming purposes) [35]. Some cases of associated urothelial cancers also are described [36,37].

FIGURE 10-40 Photographic image of the pathology of Chinese herbs nephropathy. Chinese herbs nephropathy is characterized by a large reduction in kidney volume. Moreover, an associated tumor of the lower ureter is shown.

A

B

FIGURE 10-41 (see Color Plate) Pathology of Chinese herb nephropathy. The major pathologic lesion consists of extensive interstitial fibrosis with atrophy and loss of the tubules, predominantly located in superficial cortex [38,39]. A, A low-power view of transition between superficial cortex (left) and deep cortex (right) shows an

extensive interstitial fibrosis with relative sparing of glomeruli. (Masson trichrome stain, magnification  50.) B, A normal glomerulus surrounded by a paucicellular interstitial fibrosis and atrophic tubules. (Masson’s trichrome stain, magnification  300.)

10.17

Toxic Nephropathies

NEP

log ug/24 h

ug/24 h

40 30 20

0

0

A

5 log ug/24 h

20

10 Normal Renal End-stage renal function failure renal disease After exposure to Chinese herbs

RBP

4 3 2

4 3 2 1 0

Controls

B

B2–m

5

30

10

Controls

CC16

40

log ug/24 h

50

Normal Renal End-stage renal function failure renal disease After exposure to Chinese herbs

Controls

C

Normal Renal End-stage renal function failure renal disease After exposure to Chinese herbs

FIGURE 10-42 A–D, Microproteinuria and neutral endopeptidase enzymuria in Chinese herbs nephropathy. Proximal tubular injury in Chinese herbs nephropathy is demonstrated by a significant increase in urinary excretion of microproteins (Clara cell protein, CC16; 2-microglobulin [2-m] and retinol binding protein [RBP]) as well as a decrease in urinary excretion of neutral endopeptidase (NEP) a marker of the brush border tubular mass. (Adapted from Nortier and coworkers [40].)

1 0

D

Controls Normal Renal End-stage renal function failure renal disease After exposure to Chinese herbs

FIGURE 10-43 Chinese herbs nephropathy and renal pelvic carcinoma. Urothelial cancers are associated with Chinese herbs nephropathy [36,37]. Shown is a filling defect (arrow) in the renal pelvis in an antegrade pyelogram obtained from a patient with Chinese herbs nephropathy and hematuria. (From Vanherweghem and coworkers [37]; with permission).

10.18

Tubulointerstitial Disease

A

B

FIGURE 10-44 Pathology of urothelial tumors associated with Chinese herbs nephropathy. Microscopic pattern is shown of a lower urothelial tumor obtained by ureteronephrectomy of a native kidney in a patients with transplantation who has Chinese herbs nephropathy (the macroscopic appearance of the nephrectomy

1/P creatinine ratio

0.7 Controls, n = 23 Steroids, n = 12

0.6

is shown in Fig. 10-40). A, Part of the urothelial proliferation. Plurifocal thickening of the urothelium is present. (Hematoxylin and eosin stain x 50.) B, In situ transitional cell carcinoma with high mitotic rate. (Magnification x 400 periodic acid– Schiff reaction.)

TOXIC CHRONIC INTERSTITIAL NEPHROPATHIES WITH UROTHELIAL CANCERS

0.5 0.4

Analgesic nephropathy (phenetidin compounds) Balkan nephropathy (ochratoxins) Chinese herbs nephropathy (aristolochic acids)

0.3 0.2 0.1 –6

–3

0

3 6 Months

9

12

FIGURE 10-45 Effects of steroids on the evolution of renal failure in Chinese herbs nephropathy. Steroid therapy was shown to decrease the evolution of renal failure in a subgroup of patients with Chinese herbs nephropathy [41]. The evolution is shown of the 1/P creatinine ratio of patients with Chinese herbs nephropathy, 12 of whom were treated with steroids as compared with 23 not treated with steroids (control group). In the control group the 1/P creatinine curve was limited to 6 months of follow-up because at 12 months, 17 of the 23 patients were on renal replacement therapy. (From Vanherweghem and coworkers [41]; with permission.)

FIGURE 10-46 Of interest is the association between chronic renal interstitial fibrosis and urothelial cancers. This association appears, at least, in three chronic toxic nephropathies: analgesic nephropathy, Balkan nephropathy, and Chinese herbs nephropathy. This association indicates that nephrotoxins promoting interstitial fibrosis (analgesics, ochratoxins, and aristolochic acids) also may be oncogenic substances.

Toxic Nephropathies

10.19

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22. Luke RG: Mechanism of cyclosporine-induced hypertension. Am J Hypertens 1991, 4:468-471.

2.

Nuyts GD, Daelemans RA, Jorens PG, et al.: Does lead play a role in the development of chronic renal disease? Nephrol Dial Transplant 1991, 6:307–315.

23. Ellis CN, Fradin MS, Messana JM, et al.: Cyclosporine for plaquetype psoriasis. N Engl J Med 1991, 324:277–284.

3.

Batuman V, Maesaka JK, Haddad B, et al.: The role of lead in gout nephropathy. N Engl J Med 1981, 304:520–523.

4.

Sanchez-Fructuoso AI, Torralbo A, Arroyo M, et al.: Occult lead intoxication as a cause of hypertension and renal failure. Nephrol Dial Transplant 1996, 11:1775–1780.

5.

Roels HA, Lauwerys RR, Buchet JP, et al.: Health significance of cadmium induced renal dysfunction: a five year follow up. Br J Ind Med 1989, 46:755–764.

6.

Nortier J, Bernard A, Roels H, et al.: Urinary neutral endopeptidase in workers exposed to cadmium: interaction with cigarette smoking. Occup Environ Med 1997, 54:432–436.

7.

Walker RG: Lithium nephrotoxicity. Kidney Int 1993, 44(suppl 42):S93–S98.

8.

24. Feutren G, Mihatsch MJ: Risk factors for cyclosporine-induced nephropathy in patients with autoimmune diseases. N Engl J Med 1992, 326: 1654–1660. 25. Myers BD, Newton L: Cyclosporin induced chronic nephropathy: an obliterative renal injury. J Am Soc Nephrol 1991, 2:S45–S52. 26. Deray G, Benhmida M, Le Hoang P, et al. Renal function and blood pressure in patients receiving long-term, low-dose cyclosporine therapy for idiopathic autoimmune uveitis. Ann Intern Med 1992, 117:578–583. 27. World MJ, Stevens PE, Ashton MA, Rainford DJ: Mesalazine-associated interstitial nephritis. Nephrol Dial Transplant 1996, 11:614–621. 28. De Broe ME, Stolear JC, Nouwen EJ, Elseviers MM: 5-Aminosalicylic acid (5-ASA) and chronic tubulointerstitial nephritis in patients with chronic inflammatory bowel disease: Is there a link? Nephrol Dial Transplant 1997; 12:1839–1841.

Bendz H, Aurell M, Balldin J, et al.: Kidney damage in long-term lithium patients: a cross-sectional study of patients with 15 years or more on lithium. Nephrol Dial Transplant 1994, 9:1250–1254. 9. Sanai T, Okuda S, Onoyama K, et al.: Germanium dioxide-induced nephropathy: a new type of renal disease. Nephron 1990, 54:53–60. 10. Van Der Spoel JI, Stricker BH, Esseveld MR, Schipper MEI: Dangers of dietary germanium supplements. Lancet 1990, 336:117. 11. Takeuchi A, Yoshizawa N, Oshima S, et al.: Nephrotoxicity of germanium compounds: report of a case and review of the literature. Nephron 1992, 60:436–442. 12. Hess B, Raisin J, Zimmermann A, et al.: Tubulointerstitial nephropathy persisting 20 months after discontinuation of chronic intake of germanium lactate citrate. Am J Kidney Dis 1993, 21:548–552.

29. Godin M, Fillastre JP, Simon P, et al.: L’ochratoxine est-elle néphrotoxique chez l’homme ? In Actualités Néphrologiques. Edited by Brentano JL, Bach JF, Kreis H, Grunfeld JP. Paris: Flammarion–Medecine Sciences; 1996:225–250.

13. Elseviers MM, Bosteels V, Cambier P, et al.: Diagnostic criteria of analgesic nephropathy in patients with end-stage renal failure: results of the Belgian study. Nephrol Dial Transplant 1992, 7:479–486. 14. Drukker W, Schwarz A, Vanherweghem JL: Analgesic nephropathy: an underestimated cause of end-stage renal disease. Int J Artif Organs 1986, 9:216–243. 15. Klag MJ, Whelton PK, Perneger TV: Analgesics and chronic renal disease. Curr Opinion Nephrol Hypertens 1996, 5:236–241. 16. Vanherweghem JL, Even-Adin D: Epidemiology of analgesic nephropathy in Belgium. Clin Nephrol 1982, 17:129–133. 17. Perneger TV, Whelton PK, Klag MJ: Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs. N Engl J Med 1994, 331:1675–1679. 18. Elseviers MM, De Broe ME: Analgesic nephropathy in Belgium is related to the sales of particular analgesic mixtures. Nephrol Dial Transplant 1994, 9:41–46. 19. Elseviers MM, De Schepper A, Corthouts R, et al.: High diagnostic performance of CT scan for analgesic nephropathy in patients with incipient to severe renal failure. Kidney Int 1995, 48:1316–1323. 20. Shihab FS: Cyclosporine nephropathy: pathophysiology and clinical impact. Sem Nephrol 1996, 16:536–547. 21. Bennett WM, De Mattos A, Meyer MM, et al.: Chronic cyclosporine nephropathy: The Achilles’ heel of immunosuppressive therapy. Kidney Int 1996, 50:1089–1100.

33. Vanhaelen M, Vanhaelen-Fastre R, But P, Vanherweghem JL: Identification of aristolochic acid in Chinese herbs. Lancet 1994, 343:174.

30. Stefanovic V, Polenakovic MH: Balkan nephropathy: kidney disease beyond the Balkans? Am J Nephrol 1991, 11:1–11. 31. Krogh P, Hald B, Plestina R, Ceovic S: Balkan (endemic) nephropathy and foodborn ochratoxin A: preliminary results of a survey of foodstuffs. Acta Path Microbiol Scand Sect B 1977, 85:238–240. 32. Vanherweghem JL, Depierreux M, Tielemans C, et al.: Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 1993, 341:387–391.

34. Schmeiser HH, Bieler CA, Wiessler M, et al.: Detection of DNAadducts formed by aristolochic acid in renal tissue from patients with Chinese herbs nephropathy. Cancer Res 1996, 56:2025–2028. 35. Vanherweghem JL: Association of valvular heart disease with Chinese herbs nephropathy. Lancet 1997, 350:1858. 36. Cosijns JP, Jadoul M, Squifflet JP: Urothelial malignancy in nephropathy due to Chinese herbs. Lancet 1994, 344:118. 37. Vanherweghem JL, Tielemans C, Simon J, Depierreux M: Chinese herbs nephropathy and renal pelvic carcinoma. Nephrol Dial Transplant 1995, 10:270–273. 38. Depierreux M, Van Damme B, Vanden Houte K, Vanherweghem JL: Pathologic aspects of a newly described nephropathy related to the prolonged use of Chinese herbs. Am J Kidney Dis 1994, 24:172–180. 39. Cosijns JP, Jadoul M, Squifflet JP et al.: Chinese herbs nephropathy: a clue to Balkan endemic nephropathy? Kidney Int 1994, 45:1680–1688. 40. Nortier JL, Deschodt-Lankman MM, Simon S, et al. Proximal tubular injury in Chinese herbs nephropathy: monitoring by neutral endopeptidase enzymuria. Kidney Int 1997, 51:288–293. 41. Vanherweghem JL, Abramowicz D, Tielemans C, Depierreux M: Effects of steroids on the progression of renal failure in chronic interstitial renal fibrosis: a pilot study in Chinese herbs nephropathy. Am J Kidney Dis 1996, 27:209–215.

Metabolic Causes of Tubulointerstitial Disease Steven J. Scheinman

A

variety of metabolic conditions produce disease of the renal interstitium and tubular epithelium. In many cases, disease reflects the unique functional features of the nephron, in which the ionic composition, pH, and concentration of both the tubular and interstitial fluid range widely beyond the narrow confines seen in other tissues. Recent genetic discoveries have offered new insights into the molecular basis of some of these conditions, and have raised new questions. This chapter discusses nephrocalcinosis, the relatively nonspecific result of a variety of hypercalcemic and hypercalciuric states, as well as the renal consequences of hyperoxaluria, hypokalemia, and hyperuricemia.

CHAPTER

11

11.2

Tubulointerstitial Disease

Hypercalcemia inhibits reabsorption of NaCl, Ca, and Mg

Hypercalcemia inhibits reabsorption of water

RENAL EFFECTS OF CALCIUM Hypercalcemia Collecting duct Resistance to vasopressin, leading to isotonic polyuria Thick ascending limb of the loop of Henle Impaired sodium chloride reabsorption, leading to modest salt wasting Inhibition of calcium transport, leading to hypercalciuria Inhibition of magnesium transport, leading to hypomagnesemia Renal vasculature Arteriolar vasoconstriction Reduction in ultrafiltration coefficient Hypercalciuria Microscopic hematuria Nephrocalcinosis Impaired urinary acidification

FIGURE 11-1 The recent discovery of the calcium-sensing receptor and increased understanding of its expression along the nephron have provided explanations for many of the known effects of hypercalcemia to cause clinical disturbances in renal tubular function [1]. In the parathyroid gland the calcium-sensing receptor allows the cell to sense extracellular levels of calcium and transduce that signal to regulate parathyroid hormone production and release. In the nephron, expression of the calcium receptor can be detected on the apical surface of cells of the papillary collecting duct, where calcium inhibits antidiuretic hormone action. Thus, hypercalcemia impairs urinary concentration and leads to isotonic polyuria. The most intense expression of the calcium receptor is in the thick ascending limb of the loop of Henle, particularly the cortical portion, where the calcium receptor protein is located on the basolateral side of the cells; this explains the known effects of hypercalcemia in inhibiting reabsorption of calcium, magnesium, and sodium chloride in the thick ascending limb [2]. In addition, hypercalcemia causes hypercalciuria through an increased filtered calcium load and suppression of parathyroid hormone release with a consequent reduction in calcium reabsorption. Ca—calcium; Mg—magnesium; NaCl—sodium chloride.

FIGURE 11-2 Hypercalcemia leads to renal vasoconstriction and a reduction in the glomerular filtration rate. However, no expression of the calcium-sensing receptor has been reported so far in renal vascular or glomerular tissue. Calcium receptor expression is present in the proximal convoluted tubule, on the basolateral side of cells of the distal convoluted tubule, and on the basolateral side of macula densa cells. Functional correlates of calcium receptor expression at these sites are not yet clear [3]. Hypercalciuria leads to microscopic hematuria and, in fact, is the most common cause of microscopic hematuria in children. The mechanism is presumed to involve microcrystallization of calcium salts in the tubular lumen. Conflicting effects of calcium on urinary acidification have been reported in clinical settings in which other factors, such as parathyroid hormone levels, may explain the observations. whether or not it is the result of renal tubular acidosis, Nephrocalcinosis often is associated with impaired urinary acidification, whether or not it is the result of renal tubular acidosis.

Metabolic Causes of Tubulointerstitial Disease

CAUSES OF NEPHROCALCINOSIS Medullary (total) Primary hyperparathyroidism Distal renal tubular acidosis Medullary sponge kidney Idiopathic hypercalciuria Dent’s disease Milk-alkali syndrome Oxalosis Hypomagnesemia-hypercalciuria Sarcoidosis Renal papillary necrosis Hypervitaminosis D Other* Undiscovered causes Cortical (total)

97.6 32.4 19.5 11.3 5.9 4.3 3.2 3.2 1.6 1.6 1.6 1.6 4.0 6.7 2.4

Adapted from Wrong [3]; with permission.

11.3

FIGURE 11-3 Nephrocalcinosis represents calcification of the renal parenchyma. It is primarily medullary in most cases except in dystrophic calcification associated with inflammatory, toxic, or ischemic disease. Nephrocalcinosis can be seen in association with chronic or severe hypercalcemia or in a variety of hypercalciuric states. The spectrum of causes of nephrocalcinosis is described by Wrong [3]. The numbers represent the percentage of the total of 375 patients. It is likely that the case mix is affected to some extent by Wrong’s interests in, eg, renal tubular acidosis (RTA) and Dent’s disease, but this is by far the largest published series. As in other studies, the most important causes of nephrocalcinosis are primary hyperparathyroidism, distal RTA, and medullary sponge kidney. The primary factor predisposing patients to renal calcification in many of these conditions is hypercalciuria, as occurs in idiopathic hypercalciuria, Dent’s disease, milk-alkali syndrome, sarcoidosis, hypervitaminosis D, and often in distal RTA. In distal RTA and milk-alkali syndrome, relative or absolute urinary alkalinity promote precipitation of calcium phosphate crystals in the tubular lumena, and hypocitraturia is an important contributing factor in distal RTA. Causes of cortical nephrocalcinosis in this study included acute cortical necrosis, chronic glomerulonephritis, and chronic pyelonephritis.

* Other causes include Bartter syndrome, idiopathic Fanconi syndrome, hypothy-

roidism, and severe acute tubular necrosis.

Impaired urinary acidification

Alkaline urine

Systemic acidosis Hypercalciuria

Hypokalemia

Decreased urinary citrate excretion

Resorption of bone mineral Reduced renal tubular calcium reabsorption

Hypercalciuria

CaPO4 precipitation

FIGURE 11-4 Nephrocalcinosis in type I (distal) renal tubular acidosis. Nephrocalcinosis and nephrolithiasis are common complications in distal renal tubular acidosis (RTA-1). Several factors contribute to the pathogenesis. The most important of these factors are a reduction in urinary excretion of citrate and a persistently alkaline urine. Citrate inhibits the growth of calcium stones; its excretion is reduced in RTA-1 as a result of

both systemic acidosis and hypokalemia. The high urine pH favors precipitation of calcium phosphate (CaPO4). Thus, RTA-1 should be suspected in any patient with pure calcium phosphate stones [4]. Systemic acidosis also promotes hypercalciuria, although not all patients with RTA-1 have excessive urinary calcium excretion [5]. Hypercalciuria results from resorption of bone mineral and the consequent increased filtered load of calcium as acidosis leads to consumption of bone buffers. Acidosis also has a direct effect of inhibiting renal tubular calcium reabsorption. Conversely, nephrocalcinosis from other causes can impair urinary acidification and lead to RTA in some patients. The mainstay of therapy for RTA-1 is potassium citrate, which corrects acidosis, replaces potassium, restores urinary citrate excretion, and reduces urinary loss of calcium [5]. (From Buckalew [5]; with permission.)

11.4

Tubulointerstitial Disease

Lumen

NKCC2

Epithelial cell of the thick ascending limb of the loop of Henle

Na+ 2Cl– K+ ROMK

Blood

ClC-Kb

K+

Na+ ATP K+

FIGURE 11-5 Bartter syndrome. Bartter syndrome is a hereditary renal functional disorder characterized by hypokalemic metabolic alkalosis, renal salt wasting with normal or low blood pressure, polyuria, and hypercalciuria. Other features include juxtaglomerular hyperplasia, secondary hyperreninemia and hyperaldosteronism, and excessive urinary excretion of prostaglandin E. It often has been noted that patients with Bartter syndrome appear as if they were chronically exposed to loop diuretics; in fact, the major differential diagnosis is with diuretic abuse. Bartter syndrome often presents with growth retardation in children, and nephrocalcinosis is common. Bartter syndrome is inherited as an autosomal recessive trait. The speculation that this syndrome could be explained by impaired reabsorption in the loop of Henle has now been confirmed by molecular studies. R.P. Lifton’s group [6–8] identified loss-offunction mutations in three genes encoding different proteins, each

involved in the coordinated transport of salt in the thick ascending limb of the loop of Henle. In this nephron segment, sodium chloride is transported into the cell together with potassium by the bumetamide-inhibitible sodium-potassium-2 chloride cotransporter (NKCC2). Recycling of potassium back to the lumen through an apical potassium channel (ROMK) allows an adequate supply of potassium for optimal activity of the NKCC2. Chloride exits the basolateral side of the cell through a voltage-gated chloride channel (ClC-Kb), and sodium is expelled separately by the sodium-potassium adenosine triphosphatase cotransporter. Inactivating mutations in NKCC2, ROMK, and ClC-Kb have been identified in patients with Bartter syndrome [6–8]. Approximately 20% of filtered calcium is reabsorbed in the thick ascending limb, and inactivation of any of these three transport proteins can lead to hypercalciuria. Nephrocalcinosis occurs in almost all patients with mutations in NKCC2 or ROMK, but it is less common in patients with a mutation in the basolateral chloride channel ClC-Kb, even though patients with chloride-channel mutations currently make up the largest reported group [8]. This interesting observation is unexplained at present. In addition, a significant number of patients with Bartter syndrome have been found to have normal coding sequences for all three of these genes, indicating that mutations in other gene(s) may explain Bartter syndrome in some patients. In contrast, the Gitelman variant of Bartter syndrome is associated with hypocalciuria. In this respect these patients resemble people treated with thiazide diuretics. In fact, mutations have been found in the thiazide-sensitive sodium chloride cotransporter of the distal tubule [9]. Hypomagnesemia is common and often severe, and patients with Gitelman syndrome do not develop nephrocalcinosis. ATP—adenosine triphosphate. (From Simon and coworkers [8]; with permission.) FIGURE 11-7 Noncontrast abdominal radiograph in a 24-year-old man with X-linked nephrolithiasis (Dent’s disease). The patient had recurrent calcium nephrolithiasis beginning in childhood and developed end-stage renal disease requiring dialysis at 40 years of age. Extensive medullary calcinosis is evident.

FIGURE 11-6 Nephrocalcinosis. Ultrasound image of right kidney in a patient with primary hyperparathyroidism. Echogenicity of the renal cortex is comparable to that of the adjacent liver. The dense nephrocalcinosis is entirely medullary. (Courtesy of Robert Botash, MD.)

Metabolic Causes of Tubulointerstitial Disease

X-LINKED NEPHROLITHIASIS (DENT’S DISEASE)

Low molecular weight proteinuria Other defects in proximal tubular function Hypercalciuria Nephrocalcinosis Calcium stones Renal failure Rickets

Males who are affected

Females who are carriers

Extreme Variable Occurs early in most Nearly all have it Common but not universal Common but not universal Present in some

Absent, mild, or moderate Uncommon Present in half Rare Uncommon Rare Not reported

FIGURE 11-8 Syndromes of X-linked nephrolithiasis have been reported under various names, including Dent’s disease in the United Kingdom, X-linked recessive hypophosphatemic rickets in Italy and France, and a syndrome of low molecular weight (LMW) proteinuria with hypercalciuria and nephrocalcinosis in Japanese schoolchildren. Mutations in a gene encoding a voltage-gated chloride channel (ClC-5) are present in all of these syndromes, establishing that they represent variants of one disease [10]. The disease occurs most often in boys, with microscopic hematuria, proteinuria, and hypercalciuria. Many but not all have recurrent nephrolithiasis from an early age. Affected males excrete extremely large quantities of LMW proteins, particularly 2microglobulin and retinol-binding protein. Other defects of proximal tubular function, including hypophosphatemia, aminoaciduria, glycosuria, or hypokalemia, occur variably and often intermittently. Many affected males have mild to moderate polyuria and nocturia, and they often exhibit this symptom on presentation. Urinary acidification is usually normal, and patients do not have acidosis in the absence of advanced renal insufficiency. Nephrocalcinosis is common by the teenage years, and often earlier. Renal failure is common and often progresses to end-stage renal disease by the fourth or fifth decade, although some patients escape it. Renal biopsy documents a nonspecific pattern of interstitial fibrosis and tubular atrophy, with glomerular sclerosis that is probably secondary [11].

Rickets occurs early in childhood in some patients but is absent in most patients with X-linked nephrolithiasis (Dent’s disease). In a few families, all affected males have had rickets. In other families, rickets is present in only one of several males sharing the same mutation. At present, the variability of this feature and other features of the disease is unexplained and may reflect dietary or environmental factors or the participation of other genes in the expression of the phenotype. Females who are carriers often have mild to moderate LMW proteinuria. This abnormality can be used clinically as a screening test, but LMW protein excretion will not be abnormal in all heterozygous females. Approximately half of women who are carriers have hypercalciuria, but other biochemical abnormalities are rare. Although symptomatic nephrolithiasis and even renal insufficiency have been reported in female carriers, they are very uncommon. The gene for ClC-5 that is mutated in X-linked nephrolithiasis (Dent’s disease) is expressed in the endosomal vacuoles of the proximal tubule; it appears to be important in acidification of the endosome. Thus, defective endosomal function would explain the LMW proteinuria. The mechanism of hypercalcinuria remains unexplained at present. This gene belongs to the family of voltagegated chloride channels that includes ClC-Kb, one of the gene mutations in some patients with Bartter syndrome. To date, 32 mutations have been reported in 40 families, and nearly all are unique [11].

11.5

11.6

Tubulointerstitial Disease

HYPEROXALURIA Type

Mechanism

Clinical consequences

Primary (genetic): PH1

Functional deficiency of AGT

Nephrolithiasis Nephrocalcinosis and progressive renal failure Systemic oxalosis (kidneys, bones, cartilage, teeth, eyes, peripheral nerves, central nervous system, heart, vessels, bone marrow) Nephrolithiasis

PH2 Secondary: Dietary Enteric

Metabolism from excess of precursors Pyridoxine deficiency

Functional deficiency of DGDH Sources include for example spinach, rhubarb, beets, peanuts, chocolate, and tea Enhanced oxalate absorption because of increased oxalate solubility, bile salt malabsorption, and altered gut flora (eg, inflammatory bowel disease and bowel resection) Ascorbate Ethylene glycol, glycine, glycerol, xylitol, methoxyflurane Cofactor for AGT

FIGURE 11-9 Oxalate is a metabolic end-product of limited solubility in physiologic solution. Thus, the organism is highly dependent on urinary excretion, which involves net secretion. Normal urine is supersaturated with respect to calcium oxalate. Crystallization is prevented by a number of endogenous inhibitors, including citrate. A mild excess of oxalate load, as occurs with excessive dietary intake, contributes to nephrolithiasis. A more severe oxalate overload, as in type 1 primary hyperoxaluria, can lead to organ damage through tissue deposition of calcium oxalate and possibly through the toxic effects of glyoxalate [12]. Two types of primary hyperoxaluria (PH) have been identified (Fig. 11-10), of which type 1 (PH1) is much more common. PH1 results from absolute or functional deficiency of the liver-specific enzyme alanine:glyoxalate aminotransferase (AGT). This deficiency leads to calcium oxalate nephrolithiasis in childhood, with nephrocalcinosis and progressive renal failure. Because the kidney is the main excretory route for oxalate, in the face of excessive oxalate production even mild degrees of renal insufficiency can lead to systemic deposition of oxalate in a wide variety of tissues. It is interesting that the liver itself is spared from calcium oxalate deposition. Clinical consequences include heart block and cardiomyopathy, severe peripheral vascular insufficiency and calcinosis cutis, and bone pain and fractures. Many of these conditions are exacerbated by the effects of end-stage renal disease. In contrast, PH2 is much more rare than is PH1. Patients with PH2 have recurrent nephrolithiasis. Nephrocalcinosis, renal failure, and systemic oxalosis have not been reported in PH2. The metabolic defect in PH2 appears to be a functional deficiency of D-glycerate dehydrogenase (DGDH) [12]. Secondary causes of hyperoxaluria include dietary excess, enteric hyperabsorption, and enhanced endogenous production resulting

Increased risk of nephrolithiasis Nephrolithiasis Nephrocalcinosis Systemic oxalosis (rarely) Nephrolithiasis Tubular obstruction by crystals leading to acute renal failure Nephrolithiasis

from either exposure to metabolic precursors of oxalate or pyridoxine deficiency. Normally, dietary sources of oxalate account for only approximately 10% of urinary oxalate. Restriction of dietary oxalate can be effective in some patients with kidney stones who are hyperoxaluric, but even conscientious adherence to dietary restriction is disappointing in many patients who may have mild metabolic hyperoxaluria, an entity that probably exists but is poorly understood. Intestinal absorption of oxalate can be enhanced markedly in patients with bowel disease, particularly inflammatory bowel disease or after extensive bowel resection or jejunoileal bypass. In this setting, several mechanisms have been described including a) enhanced oxalate solubility as a consequence of binding of calcium to fatty acids in patients with fat malabsorption; b) a direct effect of malabsorbed bile salts to enhance absorption of oxalate by intestinal mucosa, and c) altered gut flora with reduction in the population of oxalate-metabolizing bacteria [4,12]. Because of the important role of the colon in absorbing oxalate, ileostomy abolishes enteric hyperoxaluria [4]. Excessive endogenous production of oxalate occurs in patients ingesting large quantities of ascorbic acid, which may increase the risk of nephrolithiasis. In the setting of acute exposure to large quantities of metabolic precursors, such as ingestion of ethylene glycol or administration of glycine or methoxyflurane, tubular obstruction by calcium oxalate crystals can lead to acute renal failure. Pyridoxine deficiency is associated with increased oxalate excretion clinically in humans and experimentally in animals; it can contribute to mild hyperoxaluria. In all patients with primary hyperoxaluria, a trial of pyridoxine therapy should be given, because some patients will have a beneficial response.

Metabolic Causes of Tubulointerstitial Disease

Primary hyproxaluria metabolism Peroxisome

Cytosol

Glycolate

Glycolate DGDH

Glycine

Block in PH2

Glyoxylate

Glycine

AGT Block in PH1 Oxalate

Oxalate

FIGURE 11-10 Metabolic events in the primary hyperoxalurias. Primary hyperoxaluria type 1 (PH1) results from functional deficiency of the peroxisomal enzyme alanine:glyoxalate aminotransferase (AGT). PH2 results from a deficiency of the cytosolic enzyme d-glycerate dehydrogenase (DGDH), which also functions as glyoxalate reductase. This figure presents a simplified illustration of the metabolic

A FIGURE 11-11 Sequential biopsies of a transplanted kidney documenting progressive recurrence of renal oxalosis. This patient with primary hyperoxaluria type I received renal transplantation, without liver transplantation, at 24 years of age. Panels A–D show tissue stained with hematoxylin

11.7

consequences of these defects. Both diseases are inherited as autosomal recessive traits. In PH1, much clinical, biochemical, and molecular heterogeneity exists. Liver AGT catalytic activity is absent in approximately two thirds of patients with PH1. It is detectable in the remaining third, however, in whom the enzyme is targeted to the mitochondria rather than peroxisomes. Absence of peroxisomal AGT activity leads to impaired transamination of glyoxalate to glycine, with excessive production of oxalate and, usually, glycolate. In PH2, deficiency of cytosolic DGDH results in overproduction of oxalate and glycine. Mild cases of PH1, without nephrocalcinosis or systemic oxalosis, resemble PH2 clinically, but the two usually can be distinguished by measurement of urinary glycolate and glycine. Assay of AGT activity in liver biopsy specimens can be diagnostic in PH1 even when renal failure prevents analysis of urinary excretion. The gene encoding AGT has been localized to chromosome 2q37.3 and has been cloned and sequenced. Mutations in this gene have been identified in patients with absent enzymatic activity, abnormal enzyme targeting to mitochondria, aggregation of AGT within peroxisomes, and absence of both enzymatic activity and immunoreactivity. However, mutations have not been identified in all patients with PH1 who have been studied, and molecular diagnosis is not yet routinely available [12]. (Adapted from Danpure and Purdue [12].)

B and eosin. Panels A–C show specimens viewed by polarization microscopy, all at the same low-power magnification, from biopsies taken after transplantation within the first year (A), third year (B), (Continued on next page)

11.8

Tubulointerstitial Disease

C

D

Multinucleated giant cells Ox

Oxalate crystals Ox Ox

Ox

Ox

Ox

Ox

E

FIGURE 11-11 (Continued) and fifth year (C), following renal transplantation. Deposition of oxalate crystals became progressively more severe with time, and the kidney failed after 5 years. Panel D illustrates a higher-power magnification, without polarization, of the biopsy at 5 years, showing a

radial array of oxalate crystals and phagocytosis of small crystals by multinucleated giant cells (E). Conservative treatment of PH1 is of limited efficacy. Dietary restriction has little effect on the course of the disease. High-dose pyridoxine should be tried in all patients, but many patients do not respond. Strategies to prevent calcium oxalate stone formation include a high fluid intake (recommended in all patients), magnesium oxide (because magnesium increases the solubility of calcium oxalate salts), and inorganic phosphate. Lithotripsy or surgery may be necessary but do not alter the progression of nephrocalcinosis [12,13]. Hemodialysis is superior to peritoneal dialysis in its ability to remove oxalate, but neither one is able to maintain a rate of oxalate removal sufficient to keep up with the production rate in patients with PH1. Once end-stage renal disease develops, hemodialysis does not prevent the progression of systemic oxalosis. In some patients, renal transplantation accompanied by an aggressive program of management has been followed by a good outcome for years [14]. However, oxalosis often recurs in the transplanted kidney, particularly if any degree of renal insufficiency develops for any reason. In recent years, liver transplantation has been used with success, with or without renal transplantation, and offers the prospect of definitive cure. Results of liver transplantation are best in patients who have not yet developed significant renal insufficiency [12]. (Courtesy of Paul Shanley, MD.)

Metabolic Causes of Tubulointerstitial Disease

11.9

URIC ACID AND RENAL DISEASE Disease

Clinical setting

Features

Therapeutic issues

Uric acid nephrolithiasis

Hyperuricosuria

Acute uric acid nephropathy

Cytotoxic chemotherapy for leukemia or lymphoma; occasionally spontaneous

Uric acid nephrolithiasis Calcium nephrolithiasis Intratubular obstruction by uric acid crystals in acidic urine

Chronic gouty nephropathy

Gout or hyperuricemia in the setting of hypertension, preexisting renal disease, advanced age, vascular disease, inflammatory reaction, and chronic exposure to lead Autosomal dominant inheritance

Allopurinol; alkalinize urine Allopurinol Prevention with allopurinol, fluids, and alkalinization Acute dialysis as indicated Hemodialysis for renal failure

Familial hyperuricemic nephropathy

FIGURE 11-12 Uric acid contributes to the risk of kidney stones in several ways. Pure uric acid stones occur in patients with hyperuricosuria, particularly when the urine is acidic. Thus, therapy involves both allopurinol and alkalinization with potassium alkali salts. Hyperuricosuria also promotes calcium oxalate stone formation. In these patients, calcium nephrolithiasis can be prevented by therapy with allopurinol. The mechanism may involve heterogenous nucleation of calcium oxalate by uric acid microcrystals, binding of endogenous inhibitors of calcium crystallization, or “salting out” of calcium oxalate by urate [4]. Acute uric acid nephropathy occurs most often in the setting of brisk cell lysis from cytotoxic therapy or radiation for myeloproliferative or lymphoproliferative disorders or other tumors highly responsive to therapy. Uric acid nephropathy can uncommonly occur spontaneously in malignancies or other states of high uric acid production. Examples are infants with the Lesch-Nyhan syndrome who have excessive uric acid production resulting from deficiency of hypoxanthine-guanine phosphoribosyltransferase deficiency and, rarely, adults with gout who become volume-contracted and whose urine is concentrated and acidic. The mechanism involves intratubular obstruction by crystals of uric acid in the setting of an acute overwhelming load of uric acid, particularly in acidic urine. In recent years, the widespread use of an effective prophylactic regimen for chemotherapy has made acute uric acid nephropathy much less common [15]. This regimen includes preparation of the patient with high-dose allopurinol, volume-expanding the patient to maintain a dilute urine, and alkaline diuresis. In patients whose tumor lysis leads to hyperphosphatemia, however, it is important to discontinue urinary alkalinization or else calcium phosphate precipitation may occur. Occasionally, patients will develop renal failure despite these measures. In such patients, hemodialysis is preferable to peritoneal

Intrarenal tophi; sodium urate crystals in interstitium with accompanying destructive inflammatory reaction

Interstitial fibrosis, chronic inflammation; crystals are rare

No consensus regarding allopurinol

dialysis because of the higher clearance rates for uric acid. Frequent hemodialysis, even multiple times per day, may be necessary to prevent extreme hyperuricemia and facilitate recovery of renal function. A modification of continuous arteriovenous hemodialysis has recently been reported to be effective in management of these patients [16]. Chronic gouty nephropathy is a term referring to deposition of sodium urate crystals in the renal interstitium, with an accompanying destructive inflammatory reaction. As a specific entity with intrarenal tophi, gouty nephropathy appears to have become uncommon. It appears clear that long-standing hyperuricemia alone is not sufficient to cause this condition in most patients, and that renal failure in patients with hyperuricemia or gout is almost always accompanied by other predisposing conditions, particularly hypertension or exposure to lead [17]. Familial hyperuricemic nephropathy is an entity that now has been reported in over 40 kindreds. It is characterized by recurrent gout, often occurring in youth and even childhood; hyperuricemia; and renal failure. Histopathology reveals interstitial inflammation and fibrosis, almost always without evidence of urate crystal deposition, although this has been found in two patients. In contrast to gouty nephropathy, hypertension usually is absent until renal failure is advanced. The hyperuricemia appears to reflect decreased renal excretion of urate rather than overproduction of urate. Although hyperuricemia precedes and is disproportionate to any degree of renal failure, the role, if any, that uric acid plays in the pathogenesis of the renal failure remains unclear. These is no consensus among authors regarding the potential value of allopurinol in this disease. The inheritance follows an autosomal dominant pattern, but, beyond this, the genetics of the disease are not understood [18,19].

11.10

Tubulointerstitial Disease

References 1. Hebert SC: Extracellular calcium-sensing receptor: implications for calcium and magnesium handling in the kidney. Kidney Int 1996, 50:2129–2139. 2. Riccardi D, Hall A, Xu J, et al.: Localization of the extracellular Ca2+ (polyvalent) cation-sensing receptor in kidney. Am J Physiol (Renal Fluid Electrolyte Physiol), 1998, in press. 3. Wrong OM: Nephrocalcinosis. In The Oxford Textbook of Clinical Nephrology. Edited by Davison AM, et al. London: Oxford University Press; 1997:1378–1396. 4. Coe FL, Parks JH, Asplin JR: The pathogenesis and treatment of kidney stones. N Engl J Med 1992, 327:1141–1152. 5. Buckalew VM: Nephrolithiasis in renal tubular acidosis. J Urol 1989, 141:731–737. 6. Simon DB, Karet FE, Hamdan JM, et al.: Bartter’s syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nature Genet 1996, 13:183–188. 7. Simon DB, Karet FE, Rodriguez-Soriano J, et al.: Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the K+ channel, ROMK. Nature Genet 1996, 14:152–156. 8. Simon DB, Bindra RS, Mansfield TA, et al.: Mutations in the chloride channel gene, CLCNKB, cause Bartter’s syndrome type III. Nature Genet 1997, 17:171–178. 9. Simon DB, Nelson-Williams C, Bia MJ, et al.: Gitelman’s variant of Bartter’s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nature Genet 1996, 12:24–30. 10. Lloyd SE, Pearce SHS, Fisher SE, et al.: A common molecular basis for three inherited kidney stone diseases. Nature 1996, 379:445–449.

11. Scheinman SJ: X-linked hypercalciuric nephrolithiasis: clinical syndromes and chloride channel mutations. Kidney Int 1998, 53:3–17. 12. Danpure CJ, Purdue PE: Primay hyperoxaluria. In The Metabolic and Molecular Bases of Inherited Disease, edn 6. Edited by Scriver CR, et al. New York: McGraw-Hill; 1995:2385–2424. 13. Scheinman JI: Primary hyperoxaluria. Miner Electrolyte Metab 1994, 20:340–351. 14. Katz A, Freese D, Danpure CJ, et al.: Success of kidney transplantation in oxalosis is unrelated to residual hepatic enzyme activity. Kidney Int 1992, 42:1408–1411. 15. Razis E, Arlin ZA, Ahmed T, et al.: Incidence and treatment of tumor lysis syndrome in patients with acute leukemia. Acta Haematol 1994, 91:171–174. 16. Pichette V, Leblanc M, Bonnardeaux A, et al.: High dialysate flow rate continuous arteriovenous hemodialysis: a new approach for the treatment of acute renal failure and tumor lysis syndrome. Am J Kidney Dis 1994, 23:591–596. 17. Beck LH: Requiem for gouty nephropathy. Kidney Int 1986, 30:280–287. 18. Puig JG, Miranda ME, Mateos FA, et al. Hereditary nephropathy associated with hyperuricemia and gout. Arch Intern Med 1993, 153:357–365. 19. Reiter L, Brown MA, Edmonds J: Familial hyperuricemic nephropathy. Am J Kidney Dis 1995, 25:235–241.

Renal Tubular Disorders Lisa M. Guay-Woodford

I

nherited renal tubular disorders involve a variety of defects in renal tubular transport processes and their regulation. These disorders generally are transmitted as single gene defects (Mendelian traits), and they provide a unique resource to dissect the complex molecular mechanisms involved in tubular solute transport. An integrated approach using the tools of molecular genetics, molecular biology, and physiology has been applied in the 1990s to identify defects in transporters, channels, receptors, and enzymes involved in epithelial transport. These investigations have added substantial insight into the molecular mechanisms involved in renal solute transport and the molecular pathogenesis of inherited renal tubular disorders. This chapter focuses on the inherited renal tubular disorders, highlights their molecular defects, and discusses models to explain their underlying pathogenesis.

CHAPTER

12

12.2

Tubulointerstitial Disease

Overview of Renal Tubular Disorders OVERVIEW OF RENAL TUBULAR DISORDERS INHERITED AS MENDELIAN TRAITS Inherited disorder Renal glucosuria Glucose-galactose malabsorption syndrome Acidic aminoaciduria

Transmission mode

Defective protein

Cystinuria

AR

Lysinuric protein intolerance

AR

Hartnup disease Blue diaper syndrome Neutral aminoacidurias: Methioninuria Iminoglycinuria Glycinuria Hereditary hypophosphatemic rickets with hypercalciuria X-linked hypophosphatemic rickets

? AR AR

Sodium-glucose transporter 2 Sodium-glucose transporter 1 Sodium-potassium–dependent glutamate transporter Apical cystine-dibasic amino acid transporter Basolateral dibasic amino acid transporter ? Kidney-specific tryptophan transporter ?

AR

? Sodium-phosphate cotransporter

Inherited Fanconi’s syndrome isolated disorder Inherited Fanconi’s syndrome associated with inborn errors of metabolism Carbonic anhydrase II deficiency Distal renal tubular acidosis Bartter-like syndromes: Antenatal Bartter variant Classic Bartter variant Gitelman’s syndrome Pseudohypoparathyroidism: Type Ia Type Ib Low-renin hypertension: Glucocorticoid-remedial aldosteronism Liddle’s syndrome Apparent mineralocorticoid excess Pseudohypoaldosteronism: Type 1 Type 2 (Gordon’s syndrome) Nephrogenic diabetes insipidus: X-linked Autosomal Urolithiases: Cystinuria Dent’s disease X-linked recessive nephrolithiasis X-linked recessive hypophosphatemic rickets Hereditary renal hypouricemia

?AR, AD AR AR

X-linked dominant AR and AD AR AR AR AD AR AR AR

Phosphate-regulating with endopeptidase features on the X chromosome ? – Carbonic anhydrase type II ? Basolateral anion exchanger (AE1) NKCC2, ROMK, ClC-K2 ClC-K2b NCCT

AD ?

Guanine nucleotide–binding protein

AD AD AR

Chimeric gene (11-hydroxylase and aldosterone synthase)  and  subunits of the sodium channel 11--hydroxysteroid dehydrogenase

AR and AD AD

 and  subunits of the sodium channel ?

X-linked recessive AR and AD

Arginine vasopressin 2 receptor Aquaporin 2 water channel

AR

Apical cystine–dibasic amino acid transporter Renal chloride channel (ClC-5) Renal chloride channel (ClC-5) Renal chloride channel (ClC-5) ? Urate transporter

X-linked X-linked X-linked AR

AD—autosomal dominant; AR—autosomal recessive; ClC-K2—renal chloride channel; NCCT—thiazide-sensitive cotransporter; NKCC2—bumetanide-sensitive cotransporter; ROMK—inwardly rectified.

FIGURE 12-1 Inherited renal tubular disorders generally are transmitted as autosomal dominant, autosomal recessive, X-linked dominant, or X-linked recessive traits. For many of these disorders, the identification of the disease-susceptibility gene and its associated defective protein product has begun to provide insight into the molecular pathogenesis of the disorder.

Renal Tubular Disorders

12.3

Renal Glucosuria 400

Tmax Observed curve Threshold

Glucose reabsorption, mg/min 1.73m2

200

0 0

200

400

600

400 Normal Type B renal glucosuria

200 Type A renal glucosuria

0 0

200

400

Filtered glucose load, mg/min 1.73m2

600

FIGURE 12-2 Physiology and pathophysiology of glucose titration curves. Under normal physiologic conditions, filtered glucose is almost entirely reabsorbed in the proximal tubule by way of two distinct sodiumcoupled glucose transport systems. In the S1 and S2 segments, bulk reabsorption of glucose load occurs by way of a kidney-specific high-capacity transporter, the sodium-glucose transporter-2 (SGLT2) [1]. The residual glucose is removed from the filtrate in the S3 segment by way of the high-affinity sodium-glucose transporter-1 (SGLT1) [2]. This transporter also is present in the small intestine. As are all membrane transport systems, glucose transporters are saturable. The top panel shows that increasing the glucose concentration in the tubular fluid accelerates the transport rate of the glucose transporters until a maximal rate is achieved. The term threshold applies to the point that glucose first appears in the urine. The maximal overall rate of glucose transport by the proximal tubule SGLT1 and SGLT2 is termed the Tmax. Glucose is detected in urine either when the filtered load is increased (as in diabetes mellitus) or, as shown in the bottom panel, when a defect occurs in tubular reabsorption (as in renal glucosuria). Kinetic studies have demonstrated two types of glucosuria caused by either reduced maximal transport velocity (type A) or reduced affinity of the transporter for glucose (type B) [3]. Mutations in the gene encoding SGLT1 cause glucose-galactose malabsorption syndrome, a severe autosomal recessive intestinal disorder associated with mild renal glucosuria (type B). Defects in SGLT2 result in a comparatively more severe renal glucosuria (type A). However, this disorder is clinically benign. Among members of the basolateral glucose transporter (GLUT) family, only GLUT1 and GLUT2 are relevant to renal physiology [4]. Clinical disorders associated with mutations in the genes encoding these transporters have yet to be described. (From Morris and Ives [5]; with permission.)

12.4

Tubulointerstitial Disease

Aminoacidurias CLASSIFICATION OF INHERITED AMINOACIDURIAS Major categories

Forms

OMIM number*

Amino acids involved

Acidic amino acids Basic amino acids and cystine

Acidic aminoaciduria Cystinuria Lysinuric protein intolerance Isolated cystinuria Lysinuria Hartnup disease

222730 220100, 600918, 104614 222690, 222700, 601872 238200 – 234500, 260650

Blue diaper syndrome Iminoglycinuria Glycinuria Methioninuria

211000 242600 138500 –

Glutamate, aspartate Cystine, lysine, arginine, ornithine Lysine, arginine, ornithine Cystine Lysine Alanine, asparagine, glutamine, histidine, isoleucine, leucine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine Tryptophan Glycine, proline, hydroxyproline Glycine Methionine

Neutral amino acids

*OMIM—Online Mendelian Inheritance in Man (accessible at http://www3.ncbi.nlm.nih.gov/omin/).

FIGURE 12-3 Over 95% of the filtered amino acid load is normally reabsorbed in the proximal tubule. The term aminoaciduria is applied when more than 5% of the filtered load is detected in the urine. Aminoaciduria can occur in the context of metabolic defects, which elevate plasma amino acid concentrations and thus increase the glomerular filtered load. Aminoaciduria can be a feature of generalized proximal tubular dysfunction caused by toxic nephropathies or Fanconi’s syndrome. In addition, aminoaciduria can arise from genetic defects in one of the several amino acid transport systems in the proximal tubule. Three distinct groups of inherited aminoacidurias are distinguished based on the net charge of the target amino acids at neutral pH: acidic (negative charge), basic (positive charge), and neutral (no charge) [5]. Acidic aminoaciduria involves the transport of glutamate and aspartate and results from a defect in the high-affinity sodiumpotassium–dependent glutamate transporter [6]. It is a clinically benign disorder. Four syndromes caused by defects in the transport of basic amino acids or cystine have been described: cystinuria, lysinuric protein intolerance, isolated cystinuria, and isolated lysinuria.

Cystine actually is a neutral amino acid that shares a common carrier with the dibasic amino acids lysine, arginine, and ornithine. The transport of all four amino acids is disrupted in cystinuria. The rarer disorder, lysinuric protein intolerance, results from defects in the basolateral transport of dibasic amino acids but not cystine. Increased intracelluar concentrations of lysine, arginine, and ornithine are associated with disturbances in the urea cycle and consequent hyperammonemia [7]. Disorders involving the transport of neutral amino acids include Hartnup disease, blue diaper syndrome, methioninuria, iminoglycinuria, and glycinuria. Several neutral amino acid transporters have been cloned and characterized. Clinical data suggest that Hartnup disease involves a neutral amino acid transport system in both the kidney and intestine, whereas blue diaper syndrome involves a kidney-specific tryptophan transporter [5]. Methioninuria appears to involve a separate methionine transport system in the proximal tubule. Case reports describe seizures, mental retardation, and episodic hyperventilation in affected patients [8]. The pathophysiologic basis for this phenotype is unclear. Iminoglycinuria and glycinuria are clinically benign disorders.

Renal Tubular Disorders

ROSENBERG CLASSIFICATION OF CYSTINURIAS Category

Phenotype

Intestinal transport defect

Heterozygote Homozygote

No abnormality Cystinuria, basic aminoaciduria, cystine stones

Cystinine, basic amino acids

Heterozygote Homozygote

Excess excretion of cystine and basic amino acids Cystinuria, basic aminoaciduria, cystine stones

Basic amino acids only

Heterozygote Homozygote

Excess excretion of cystine and basic amino acids Cystinuria, basic aminoaciduria, cystine stones

None

I

II

III

From Morris and Ives [5]; with permission.

12.5

FIGURE 12-4 In this autosomal recessive disorder the apical transport of cystine and the dibasic amino acids is defective. Differences in the urinary excretion of cystine in obligate heterozygotes and intestinal amino acid transport studies in homozygotes have provided the basis for defining three distinct phenotypes of cystinuria [9]. Genetic studies have identified mutations in the gene (SCL3A1) encoding a high-affinity transporter for cystine and the dibasic amino acids in patients with type I cystinuria [10,11]. In patients with type III cystinuria, SCL3A1 was excluded as the disease-causing gene [12]. A second cystinuria-susceptibility gene recently has been mapped to chromosome 19 [13].

FIGURE 12-5 Urinary cystine crystals. Excessive urinary excretion of cystine (250 to 1000 mg/d of cystine/g of creatinine) coupled with its poor solubility in urine causes cystine precipitation with the formation of characteristic urinary crystals and urinary tract calculi. Stone formation often causes urinary tract obstruction and the associated problems of renal colic, infection, and even renal failure. The treatment objective is to reduce urinary cystine concentration or to increase its solubility. High fluid intake (to keep the urinary cystine concentration below the solubility threshold of 250 mg/L) and urinary alkalization are the mainstays of therapy. For those patients refractory to conservative management, treatment with sulfhydryl-containing drugs, such as D-penicillamine, mercaptopropionylglycine, and even captopril can be efficacious [14,15].

12.6

Tubulointerstitial Disease

Renal Hypophosphatemic Rickets INHERITED FORMS OF HYPOPHOSPHATEMIC RICKETS Disorder

Vitamin D

Parathyroid hormone

Serum calcium

Urinary calcium

Treatment

X-linked hypophosphatemic rickets Hereditary hypophosphatemic rickets with hypercalciuria

Low, low normal Elevated

Normal, high normal Low, low normal

Low, normal Normal

Elevated Elevated

Calciferol, phosphate supplementation Phosphate supplementation

Vitamin D—1,25-dihydroxy-vitamin D3

FIGURE 12-6 Several inherited disorders have been described that result in isolated renal phosphate wasting. These disorders include X-linked hypophosphatemic rickets (HYP), hereditary hypophosphatemic rickets with hypercalciuria (HHRH), hypophosphatemic bone disease (HBD), autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), and X-linked recessive hypophosphatemic rickets (XLRH). These inherited disorders share two common features: persistent hypophosphatemia caused by decreased renal tubular phosphate (Pi) reabsorption (expressed as decreased ratio of plasma concentration at which maximal phosphate reabsorption occurs [TmP] to glomerular filtration rate [GFR], [TmP/GFR], a normogram derivative of the fractional excretion of

PEX (endopeptidase) Phosphatonin

Na

Degradation

ATP 3Na+

+

2K+

Pi 1α-hydroxylase

25-Vitamin D Lumen

ADP

1,25-Vitamin D

Interstitium

FIGURE 12-7 Proposed pathogenesis of X-linked hypophosphatemic rickets (HYP). HYP, the most common defect in renal phosphate (Pi) transport, is transmitted as an X-linked dominant trait. The disorder is character-

Pi); and associated metabolic bone disease, eg, rickets in children or osteomalacia in adults [5]. These disorders can be distinguished on the basis of the renal hormonal response to hypophosphatemia, the biochemical profile, and responsiveness to therapy. In addition, the rare disorder XLRH is associated with nephrolithiasis. The clinical features of the two most common disorders HYP and HHRH are contrasted here. Whereas both disorders have defects in renal Pi reabsorption, the renal hormonal response to hypophosphatemia is impaired in HYP but not in HHRH. Indeed, in children with HHRH, phosphate supplementation alone can improve growth rates, resolve the radiologic evidence of rickets, and correct all biochemical abnormalities except the reduced TmP GFR [5]. ized by growth impairment in children, metabolic bone disease, phosphaturia, and abnormal bioactivation of vitamin D [16]. Cell culture, parabiosis, and transplantation experiments have demonstrated that the defect in HYP is not intrinsic to the kidney but involves a circulating humoral factor other than parathyroid hormone [16,17]. Phosphate is transported across the luminal membrane of the proximal tubule by a sodium-phosphate cotransporter (NaPi). This transporter is regulated by multiple hormones. Among these is a putative phosphaturic factor that has been designated phosphatonin [18]. It is postulated that phosphatonin inhibits Pi reabsorption by way of the sodium-coupled phosphate cotransporter, and it depresses serum 1,25-dihydroxy-vitamin D3 production by inhibiting 1--hydroxlase activity and stimulating 24-hydroxylase activity. Positional cloning studies in families with HYP have identified a gene, designated PEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome), that is mutated in patients with X-linked hypophosphatemia [19]. PEX, a neutral endopeptidase, presumably inactivates phosphatonin. Defective PEX activity would lead to decreased phosphatonin degradation, with excessive phosphaturia and deranged vitamin D metabolism. A similar scenario associated with increased phosphatonin production has been proposed as the basis for oncogenic hypophosphatemic osteomalacia, an acquired disorder manifested in patients with tumors of mesenchymal origin [17]. Na+—sodium ion; K+—potassium ion.

Renal Tubular Disorders

12.7

Fanconi’s Syndrome FIGURE 12-8 Fanconi’s syndrome is characterized by two components: generalized dysfunction of the proximal tubule, leading to impaired net reabsorption of bicarbonate, phosphate, urate, glucose, and amino acids; and vitamin D–resistant metabolic bone disease [20]. The clinical manifestations in patients with either the hereditary or acquired form of Fanconi’s syndrome include polyuria, dehydration, hypokalemia, acidosis, and osteomalacia (in adults) or impaired growth and rickets (in children). Inherited Fanconi’s syndrome occurs either as an idiopathic disorder or in association with various inborn errors of metabolism.

INHERITED FANCONI’S SYNDROME Disorder

OMIM number*

Idiopathic Cystinosis Hepatorenal tyrosinemia (tyrosinemia type I) Hereditary fructose intolerance Galactosemia Glycogen storage disease type I Wilson’s disease Oculocerebrorenal (Lowe’s) syndrome Vitamin-D–dependent rickets

227700, 227800 219800, 219900, 219750 276700 229600 230400 232200 277900 309000 264700

*OMIM—Online Mendelian Inheritance in Man (accessible at http://www3.ncbi.nlm.nih.gov/omin/). From Morris and Ives [5]; with permission.

Na+

Na (1) Na+

(4)

ATP 3Na+

(2)

2K+

S ADP (3)

ADP H+

ATP

ATP

Lumen

Interstitium

FIGURE 12-9 Proposed pathogenic model for Fanconi’s syndrome. The underlying pathogenesis of Fanconi’s syndrome has yet to be determined. It is likely, however, that the various Mendelian diseases associated

with Fanconi’s syndrome cause a global disruption in sodiumcoupled transport systems rather than a disturbance in specific transporters. Bergeron and coworkers [20] have proposed a pathophysiologic model that involves the intracellular gradients of sodium, adenosine triphosphate (ATP), and adenosine diphosphate (ADP). A transepithelial sodium gradient is established in the proximal tubule cell by sodium (Na) entry through Na-solute cotransport systems (Na-S) (1) and Na exit through the sodium-potassium adenosine triphosphatase (Na-K ATPase) (2). This Na gradient drives the net uptake of cotransported solutes. A small decrease in the activity of the Na-K ATPase cotransporter may translate into a proportionally larger increment in the Na concentration close to the luminal membrane, thus decreasing the driving force that energizes all Na-solute cotransport systems. Concomitantly, reciprocal ATP and ADP gradients are established in the cell by the activity of membrane bound ATPases (Na-K ATPase (2) and hydrogen-ATPase (3)) and mitochondrial (4) ATP synthesis. A small reduction in mitochondrial rephosphorylation of ADP may result in a juxtamembranous accumulation of ADP and a reciprocal decrease in ATP, altering the ADP-ATP ratio and downregulating pump activities. Therefore, a relatively small mitochondrial defect may be amplified by the effects on the intracellular sodium gradients and ADP-ATP gradients and may lead to a global inhibition of Na-coupled transport. H+—hydrogen ion.

12.8

Tubulointerstitial Disease

Renal Tubular Acidoses FIGURE 12-10 Renal tubular acidosis (RTA) is characterized by hyperchloremic metabolic acidosis caused by abnormalities in renal acidification, eg, decreased tubular reabsorption of bicarbonate or reduced urinary excretion of ammonium (NH4+). RTA can result from a number of disease processes involving either inherited or acquired defects. In addition, RTA may develop from an isolated defect in tubular transport; may involve multiple tubular transport abnormalities, eg, Fanconi’s syndrome; or may be associated with a systemic disease process. Isolated proximal RTA (type II) is rare, and most cases of proximal RTA occur in the context of Fanconi’s syndrome. Inherited forms of classic distal RTA (type I) are transmitted as both autosomal dominant and autosomal recessive traits. Inherited disorders in which RTA is the major clinical manifestation are summarized.

INHERITED RENAL TUBULAR ACIDOSES Disorder

Transmission mode

Isolated proximal RTA

Autosomal recessive

Carbonic anhydrase II deficiency

Autosomal recessive

Isolated distal RTA

Autosomal dominant

Distal RTA with sensorineural deafness

Autosomal recessive

RTA—renal tubular acidosis.

Distal tubule: α intercalated cell Cl–

Proximal tubule

Interstitium

K+ CO2 + H2O

–

H2CO3

CA2

H+

HCO3

–

Na+ HCO3–

Na+ H –

HCO3

OH–

CO2

K+

–

+

–

HCO3 CA2

H+

Na+

Cl–

H2CO3

CA4 CO2

H+

K+

H+

Lumen

–

HCO3

FIGURE 12-11 Carbonic anhydrase II deficiency. Carbonic anhydrase II deficiency is an autosomal recessive disorder characterized by renal tubular acidosis (RTA), with both proximal and distal components, osteopetrosis, and cerebral calcification. Carbonic anhydrase catalyzes the reversible hydration of carbon dioxide (CO2), and thereby accelerates the conversion of carbon dioxide

and water to hydrogen ions (H+) and bicarbonate (HCO-3) [21]. A least two isoenzymes of carbonic anhydrase are expressed in the kidney and play critical roles in urinary acidification. In the proximal tubule, bicarbonate reabsorption is accomplished by the combined action of both luminal carbonic anhydrase type IV (CA4) and cytosolic carbonic anhydrase type II (CA2), the luminal sodium-hydrogen exchanger, and the basolateral sodium-bicarbonate exchanger. Impaired bicarbonate reabsorption in the proximal tubule is the underlying defect in type II or proximal RTA. In the distal nephron, carbonic anhydrase type II is expressed in the intercalated cells of the cortical collecting duct. There carbonic anhydrase type II plays a critical role in catalyzing the condensation of hydroxy ions, generated by the proton-translocating H+adenosine triphosphatase (H+ ATPase), with carbon dioxide to form bicarbonate. In carbonic anhydrase type II deficiency, the increase in intracellular pH impairs the activity of the proton-translocating H-ATPase. Carbonic anhydrase inhibitors (eg, acetazolamide) act as weak diuretics by blocking bicarbonate reabsorption. Cl-—chloride ion; H2CO3—carbonic acid; K+—potassium ion; Na+—sodium ion.

Renal Tubular Disorders Cl–

Cortical collecting duct

K+

Principal cell

Cl–

–

α intercalated cell

–

α intercalated cell

HCO3

CA2 OH–

CO2 K+

Lumen –

Na+

K+

H+

K+

H+ Cl–

Outer medullary collecting duct

K+

Principal cell

Cl–

HCO3

K+

Lumen +

H 2O

H+

K+

H+

FIGURE 12-12 Distal renal tubular acidosis (RTA). The collecting duct is the principal site of distal tubule acidification, where the final 5% to 10% of the filtered bicarbonate load is reabsorbed

12.9

and the hydrogen ions (H+) generated from dietary protein catabolism are secreted. The distal nephron is composed of several distinct segments, eg, the connecting tubule, cortical collecting duct, and medullary collecting duct. The tubular epithelia within these segments are composed of two cell types: principal cells that transport sodium, potassium, and water; and intercalated cells that secrete hydrogen ions and bicarbonate (HCO-3) [22]. Urinary acidification in the distal nephron depends on several factors: an impermeant luminal membrane capable of sustaining large pH gradients; a lumen-negative potential difference in the cortical collecting duct that supports both hydrogen and potassium ion (K+) secretion; and secretion of hydrogen ions by the intercalated cells of the cortical and medullary collecting ducts at a rate sufficient to regenerate the bicarbonate consumed by metabolic protons [22]. Abnormalities in any of these processes could result in a distal acidification defect. Recent studies in families with isolated autosomal dominant distal RTA have identified defects in the basolateral chloridebicarbonate exchanger, AE1 [23,24]. Defects in various components of the H+-adenosine triphosphatase (H+ ATPase) and subunits of the H+-K+ ATPase (H+\K+ ATPase) also have been proposed as the basis for other hereditary forms of distal RTA. CA2—cytosolic carbonic anhydrase type II; Cl-—chloride ion; CO2—carbon dioxide; Na+—sodium ion; OH-—hydroxy ions.

Bartter-like Syndromes CLINICAL FEATURES DISTINGUISHING BARTTER-LIKE SYNDROMES

Feature Age at presentation Prematurity, polyhydramnios Delayed growth Delayed cognitive development Polyuria, polydipsia Tetany Serum magnesium Urinary calcium excretion Nephrocalcinosis Urine prostaglandin excretion Clinical response to indomethacin

Classic Bartter’s syndrome

Gitelman’s syndrome

Antenatal Bartter’s syndrome

Infancy, early childhood +/++ +/++ Rare Low in 20% Normal to high +/High +/-

Childhood, adolescence + ++ Low in about 100% Low Normal -

In utero, infancy ++ +++ + +++ Low-normal to normal Very high ++ Very high Often life-saving

From Guay-Woodford [25]; with permission.

FIGURE 12-13 Familial hypokalemic, hypochloremic metabolic alkalosis, or Bartter’s syndrome, is not a single disorder but rather a set of closely related disorders. These Bartter-like syndromes share many of the same physiologic derangements but differ with regard to the age of onset, presenting symptoms, magnitude of urinary potassium and prostaglandin excretion, and extent of urinary calcium excretion. At least three clinical phenotypes have been distinguished: classic Bartter’s syndrome, the antenatal hypercalciuric variant (also called hyperprostaglandin E syndrome), and hypocalciuric-hypomagnesemic Gitelman’s syndrome [25].

12.10

Tubulointerstitial Disease

Lumen

FIGURE 12-14 Transport systems involved in transepithelial sodium-chloride transport in the thick ascending limb (TAL). Clinical data suggest that the primary defect in the antenatal and classic Bartter syndrome variants involves impaired sodium chloride transport in the TAL. Under normal physiologic conditions, sodium chloride is transported across the apical membrane by way of the bumetanide-sensitive sodium-potassium-2chloride (Na-K-2Cl) cotransporter (NKCC2). This electroneutral transporter is driven by the low intracellular sodium and chloride concentrations generated by the sodium-potassium pump and the basolateral chloride channels and potassium-chloride cotransporter. In addition, apical potassium recycling by way of the low-conductance potassium channel (ROMK) ensures the efficient functioning of the Na-K-2Cl cotransporter. The activity of the ROMK channel, in turn, is regulated by a number of cell messengers, eg, calcium (Ca2+) and adenosine triphosphate (ATP), as well as by the calcium-sensing receptor (CaR), prostaglandin EP3 receptor, and vasopressin receptor (V2R) by way of cAMP-dependent pathways and arachidonic acid (AA) metabolites, eg, 20-hydroxy-eicosatetraenoic acid (20-HETE). The positive transluminal voltage (Vte) drives the paracellular reabsorption of calcium ions and magnesium ions (Mg2+) [25]. cAMP—cyclic adenosine monophosphate; PGE2— prostaglandin E2; PKA—protein kinase A.

Interstitium Ca2+ sensing receptor

AA Na+ K+ 2Cl–

3Na+ 2K+ K+ Cl–

20 HETE K+

Ca2+ Cl–

ATP ATP

V2R

cAMP

Stimulatory Inhibitory

EP3 PGE2

Vte + Ca2+ Mg2+

Defective NKCC2

Gene defect Pathophysiology

Defective ROMK

Defective CIC-Kb

Defective NaCl transport in TAL Volume contraction

↑ NaCl delivery to the distal nephron

↓ Voltage-driven paracellular reabsorption of Ca2+ and Mg2+

↑ Renin ↑ Angiotensin II (AII)

↑ Kallikrein

↑ Aldosterone

Normotension Blunted vascular response to AII and norepinephrine

↑ H+ and K+ secretion

Metabolic alkalosis Hypokalemia ↑ PGE2

↑ Urinary prostaglandins

↑ Bone reabsorption

Fever

Hypercalciuria Hypermagnesuria

Impaired vasopressinstimulated urinary concentration Hyposthenuria

FIGURE 12-15 Proposed pathogenic model for the antenatal and classic variants of Bartter’s syndrome. Genetic studies have identified mutations in the genes encoding the bumetanide-sensitive sodium-potassium-2chloride cotransporter (NKCC2), luminal ATP–regulated potassium channel (ROMK), and kidney-specific chloride channel (ClC-K2). These findings support the theory of a primary defect in thick ascending limb (TAL) sodium-chloride (Na-Cl) reabsorption in, at least, subsets of patients with the antenatal or classic variants of Bartter’s syndrome. In the proposed model the potential interrelationships of the complex set of pathophysiologic phenomena are illustrated. The resulting clinical manifestations are highlighted in boxes [25]. Ca2+— calcium ion; H+—hydrogen ion; K+—potassium ion; Mg2+—magnesium ion; PGE2— prostaglandin E2.

12.11

Renal Tubular Disorders

Gene defect Pathophysiologic model

DefectiveHypercalciuria NaCl transport in DCT

Volume contraction

FIGURE 12-16 Proposed pathogenic model for Gitelman’s syndrome. The electrolyte disturbances evident in Gitelman’s syndrome also are observed with administration of thiazide diuretics, which inhibit the sodium-chloride (Na-Cl) cotransporter in the distal convoluted tubule (DCT). In families with Gitelman’s syndrome, genetic studies have identified defects in the gene encoding the thiazidesensitive cotransporter (NCCT) protein. The proposed pathogenic model is predicated on loss of function of the NCCT protein and, thus, most closely applies to those patients who inherit Gitelman’s syndrome as an autosomal recessive trait. Given that the physiologic features of this syndrome are virtually indistinguishable in familial and sporadic cases, it may be reasonable to propose the same pathogenesis for all patients with Gitelman’s syndrome. However, it is important to caution that evidence for NCCT mutations in sporadic cases has not yet been established [25]. Ca2+—calcium ion; Cl-—chloride ion; H+—hydrogen ion; K+—potassium ion; Mg2+—magnesium ion; Na+—sodium ion.

Defective NCCT

↑ NaCl delivery to the distal nephron

Cl– efflux mediates cell hyperpolarization

↑ H+ and K+ secretion

↑ Ca2+ reabsorption

Metabolic alkalosis hypokalemia

Hypocalciuria

? ↓ Na+-dependent Mg2+ reabsorption in DCT

↑ Renin ↑ Angiotensin II (AII) ↑ Aldosterone

Hypermagnesuria

Pseudohypoparathyroidism CLINICAL SUBTYPES OF PSEUDOHYPOPARATHYROIDISM Disorder

Pathophysiology

Pseudohypoparathyroidism type Ia Pseudohypoparathyroidism type Ib

Defect in guanine nucleotide—binding protein Resistance to parathyroid hormone, normal guanine nucleotide—binding protein activity ? Defect in parathyroid hormone receptor

FIGURE 12-17 Pseudohypoparathyroidism applies to a heterogeneous group of hereditary disorders whose common feature is resistance to parathyroid hormone (PTH). Affected patients are hypocalcemic and hyperphosphatemic, despite elevated plasma PTH levels. Hypocalcemia and hyperphophatemia result from the combined effects of defective PTHmediated calcium reabsorption in the distal convoluted tubule and reduced formation of 1,25-dihydroxy-vitamin D3. The latter leads to defects in renal phosphate excretion, calcium mobilization from bone, and gastrointestinal calcium reabsorption. Differences in clinical features and urinary cyclic adenosine monophosphate response to infused PTH provide the basis for distinguishing three distinct subtypes of pseudohypoparathyroidism (type Ia, type Ib, and type II) [26].

Skeletal anomalies

Associated endocrinopathies

Yes No

Yes No

Pseudohypoparathyroidism type Ia (Albright’s hereditary osteodystrophy) is associated with a myriad of physical abnormalities and resistance to multiple adenylate cyclase–coupled hormones, most notably thyrotropin and gonadotropin [27]. The molecular defect in a guanine nucleotide–binding protein (Gs) blocks the coupling of PTH and other hormone receptors to adenylate cyclase. The molecular defect has not been identified in type Ib, although specific resistance to PTH suggests a defect in the PTH receptor. Oral supplementation with 1,25 dihydroxy-vitamin D3 and, if necessary, oral calcium, is used to correct the hypocalcemia and minimize PTH-induced bone disease [26]. Pseudohypoparathroidism type II may be an acquired disease.

12.12

Tubulointerstitial Disease

Disorders of Aldosterone-Regulated Transport (A) GRA chimeric gene Aldosterone synthetase

11-OHase Unequal crossover

Aldosterone synthetase

Chimeric gene

11-OHase

(B) Amiloride-sensitive Na+ channel Na+

Na+

K+ Aldosterone (A)

K+ channel (A) GRA (B) Liddle's (C) AME

MR

Degradation

Cortisol (C)

FIGURE 12-18 Aldosterone-regulated transport in the cortical collecting duct and defects causing low-renin hypertension. The mineralocorticoid aldosterone regulates electrolyte excretion and intravascular volume by way of its action in the principal cells of the cortical collecting duct. The binding of aldosterone to its nuclear receptor (MR) leads directly or indirectly to increased activity of the apical sodium (Na) channel

and the basolateral sodium-potassium adenosine triphosphatase (Na-K ATPase). Sodium moves from the lumen into the cell and down its electrochemical gradient, thus generating a lumen-negative transepithelial voltage that drives potassium secretion from the principal cells and hydrogen secretion from the intercalated cells. The type I mineralocorticoid receptor (MR) is nonspecific and can bind both aldosterone and cortisol, but not cortisone. The selective receptor specificity for aldosterone is mediated by the kidney isoform of the enzyme, 11--hydroxysteroid dehydrogenase, which oxidizes intracellular cortisol to its metabolite cortisone. Three hypertensive syndromes, glucocorticoid-remedial aldosteronism (GRA), Liddle’s syndrome, and apparent mineralocorticoid excess (AME), share a common clinical phenotype that is characterized by normal physical examinations, hypokalemia, and very low plasma renin activity. The molecular defect in GRA derives from an unequal crossover event between two adjacent genes encoding 11--hydroxylase and aldosterone synthase (A). The resulting chimeric gene duplication fuses the regulatory elements of 11--hydroxylase and the coding sequence of aldosterone synthase. Consequently, aldosterone is ectopically synthesized in the adrenal zona fasciculata and its synthesis regulated by adrenocorticotropic hormone rather than its physiologically normal secretagogue, angiotensin II [28]. Activating mutations in the  and  regulatory subunits of the epithelial sodium channel (B) are responsible for Liddle’s syndrome [29]. Deficiency of the kidney type 2 isozyme of 11--hydroxysteroid dehydrogenase (C) can render type I MR responsive to cortisol and produce the syndrome of apparent mineralocorticoid excess [30]. Inhibitors of this enzyme (eg, licorice) also can produce an acquired form of apparent mineralocorticoid excess. Medical management of these disorders focuses on dietary sodium restriction, blocking the sodium channel with the potassium-sparing diuretics triamterene and amiloride, downregulating the ectopic aldosterone synthesis with glucocorticoids (GRA), or blocking the MR using the competitive antagonist spironolactone (GRA and AME).

Renal Tubular Disorders

Low-renin hypertension

– Family history

+ Family history

Abnormal PE Serum

Virilization

Low serum K+ 11β-hydroxylase deficiency

Gordon's syndrome

Diagnosis:

Hypogonadism

Low-normal

High-normal

Urinary steroid profile:

Normal PE

K+

TH180x0F THAD

Negligible urinary aldosterone

GRA

Liddle's syndrome

17α-hydroxylase deficiency

Pseudohypoaldosteronism type I Autosomal recessive

Autosomal dominant Pseudohypoaldosteronism type II (Gordon’s syndrome)

FIGURE 12-19 Algorithm for evaluating patients with lowrenin hypertension. Glucocorticoid-remedial aldosteronism (GRA), Liddle’s syndrome, and apparent mineralocorticoid excess (AME) can be distinguished from one another by characteristic urinary steroid profiles [31]. K+—potassium ion; PE—physical examination; TH18oxoF/THAD—ratio of urinary 18-oxotetrahydrocortisol (TH18oxoF) to urinary tetrahydroaldosterone (normal: 0–0.4; GRA patients: >1); THF + alloTHF/THE—ratio of the combined urinary tetrahydrocortisol and allotetrahydrocortisol to urinary tetrahydrocortisone (normal: <1.3; AME patients: 5–10-fold higher).

THF + alloTHF THE AME

CLINICAL SUBTYPES OF PSEUDOHYPOALDOSTERONISM Disorder

12.13

Clinical features

Treatment

Dehydration, severe neonatal salt wasting, hyperkalemia, metabolic acidosis Elevated plasma renin activity Severity of electrolyte abnormalities may diminish after infancy Mild salt wasting Hypertension, hyperkalemia, mild hyperchloremic metabolic acidosis Undetectable plasma renin activity

Sodium chloride supplementation Ion-binding resin; dialysis

Thiazide diuretics

FIGURE 12-20 Mineralocorticoid resistance with hyperkalemia (pseudohypoaldosteronism) includes at least three clinical subtypes, two of which are hereditary disorders. Pseudohypoaldosteronism type I (PHA1) is characterized by severe neonatal salt wasting, hyperkalemia,

and metabolic acidosis. The diagnosis is supported by elevated plasma renin and plasma aldosterone concentrations. Life-saving interventions include aggressive sodium chloride supplementation and treatment with ion-binding resins or dialysis to reduce the hyperkalemia. This autosomal recessive form of PHA1 results from inactivating mutations in the  or  subunits of the epithelial sodium channel [32]. A milder form of PHA1 with autosomal dominant inheritance also has been described; however, the molecular defect remains unexplained [33]. Adolescents or adults with hyperkalemic, hyperchloremic metabolic acidosis, low-normal renin and aldosterone levels, and hypertension have been recently described and classified as having pseudohypoaldosteronism type II (PHA2) or Gordon’s syndrome [34]. Phenotypically, this disorder is the mirror image of Gitelman’s syndrome; however, the thiazidesensitive cotransporter (NCCT) has been excluded as a candidate gene [35].

12.14

Tubulointerstitial Disease

Nephrogenic Diabetes Insipidus FIGURE 12-21 The relationship between urine osmolality and plasma arginine vasopressin (AVP). Nephrogenic diabetes insipidus (NDI) is characterized by renal tubular unresponsiveness to the antidiuretic hormone AVP or its antidiuretic analogue 1-desamino-8-D-arginine vasopressin (DDAVP). In both the congenital and acquired forms of this disorder the clinical picture is dominated by polyuria, polydipsia, and hyposthenuria despite often elevated AVP levels [17]. (From Robertson et al. [36]; with permission.)

Primary polydipsia Pituitary diabetes insipidus

1200

Urine osmolality, mOsm/kg

1000 800 600 400 NDI

200 0 0

1

2

3 4 5 Plasma AVP, pg/mL

10

15

Physiologic

AQP3

–ADH

Pathophysiologic

AQP2 H 2O

X-linked NDI

V2R

AQP3

H 2O V2R

AQP4

AQP4

Autosomal recessive NDI

AQP2 AQP3

+ADH

AQP2 AQP3

ATP

ATP H 2O

V2R

H 2O

V2R

cAMP

cAMP

AQP4 Interstitium

AQP2

AQP4 Lumen

Interstitium

Lumen

FIGURE 12-22 Pathogenic model for nephrogenic diabetes insipidus (NDI). The principle cell of the inner medullary collecting duct is the site where fine tuning of the final urinary composition and

volume occurs. As shown, the binding of arginine vasopressin (AVP) to the vasopressin V2 receptor (V2R) stimulates a series of cyclic adenosine monophosphate– (cAMP) mediated events that results in the fusion of cytoplasmic vesicles carrying water channel proteins (aquaporin-2 [AQP2]), with the apical membrane, thereby increasing the water permeability of this membrane. Water exits the cell through the basolateral water channels AQP3 and AQP4. In the absence of AVP, water channels are retrieved into cytoplasmic vesicles and the water permeability of the apical membrane returns to its baseline low rate [37]. Genetic studies have identified mutations in two proteins involved in this water transport process, the V2 receptor and AQP2 water channels. Most patients (>90%) inherit NDI as an X-linked recessive trait. In these patients, defects in the V2 receptor have been identified. In the remaining patients, the disease is transmitted as either an autosomal recessive or autosomal dominant trait involving mutations in the AQP2 gene [38,39]. ADH— antidiuretic hormone; ATP—adenosine triphosphate.

Renal Tubular Disorders

12.15

Urolithiases INHERITED CAUSES OF UROLITHIASES Disorder

Stone characteristics

Treatment

Cystinuria

Cystine

Dent’s disease X-linked recessive nephrolithiasis X-linked recessive hypophosphatemic rickets Hereditary renal hypouricemia

Calcium-containing Calcium-containing Calcium-containing

High fluid intake, urinary alkalization Sulfhydryl-containing drugs High fluid intake, urinary alkalization High fluid intake, urinary alkalization High fluid intake, urinary alkalization

Hypoxanthine-guanine phosphoribosyltransferase deficiency Xanthinuria Primary hyperoxaluria

Uric acid

Uric acid, calcium oxalate

Xanthine Calcium oxalate

High fluid intake, urinary alkalization Allopurinol High fluid intake, urinary alkalization Allopurinol High fluid intake, dietary purine restriction High fluid intake, dietary oxalate restriction Magnesium oxide, inorganic phosphates

FIGURE 12-23 Urolithiases are a common urinary tract abnormality, afflicting 12% of men and 5% of women in North America and Europe [40]. Renal stone formation is most commonly associated with hypercalciuria. Perhaps in as many as 45% of these patients, there seems to be a familial predisposition. In comparison, a group of relatively rare disorders exists, each of which is transmitted as a Mendelian trait and causes a variety of different crystal nephropathies. The most common of these disorders is cystinuria, which involves defective cystine and dibasic

amino acid transport in the proximal tubule. Cystinuria is the leading single gene cause of inheritable urolithiasis in both children and adults [41,42]. Three Mendelian disorders, Dent’s disease, X-linked recessive nephrolithiasis, and X-linked recessive hypophosphatemic rickets cause hypercalciuric urolithiasis. These disorders involve a functional loss of the renal chloride channel ClC-5 [43]. The common molecular basis for these three inherited kidney stone diseases has led to speculation that ClC-5 also may be involved in other renal tubular disorders associated with kidney stones. Hereditary renal hypouricemia is an inborn error of renal tubular transport that appears to involve urate reabsorption in the proximal tubule [16]. In addition to renal transport deficiencies, defects in metabolic enzymes also can cause urolithiases. Inherited defects in the purine salvage enzymes hypoxanthine-guanine phosphoribosyltransferase (HPRT) and adenine phosphoribosyltransferase (APRT) or in the catabolic enzyme xanthine dehydrogenase (XDH) all can lead to stone formation [44]. Finally, defective enzymes in the oxalate metabolic pathway result in hyperoxaluria, oxalate stone formation, and consequent loss of renal function [45].

Acknowledgment The author thanks Dr. David G. Warnock for critically reviewing this manuscript.

References 1. Wells R, Kanai Y, Pajor A, et al.: The cloning of a human cDNA with similarity to the sodium/glucose cotransporter. Am J Physiol 1992, 263:F459–F465. 2. Hediger M, Coady M, Ikeda T, Wright E: Expression cloning and cDNA sequencing of the Na/glucose co-transporter. Nature 1987, 330:379–381. 3. Woolf L, Goodwin B, Phelps C: Tm-limited renal tubular reabsorption and the genetics of renal glycosuria. J Theor Biol 1966, 11:10–21. 4. Meuckler M: Facilitative glucose transporters. Euro J Biochem 1994, 219:713–725. 5. Morris JR, Ives HE: Inherited disorders of the renal tubule. In The Kidney. Edited by Brenner B, Rector F. Philadelphia: WB Saunders, 1996:1764–1827. 6. Kanai Y, Hediger M: Primary structure and functional characterization of a high affinity glutamate transporter. Nature 1992, 360:467–471.

7. Oynagi K, Sogawa H, Minawi R,et al.: The mechanism of hyperammonemia in congenital lysinuria. J Pediatr 1979, 94:255. 8. Smith A, Strang L: An inborn error of metabolism with the urinary excretion of -hydroxybutric acid and phenyl-pyruvic acid. Arch Dis Child 1958, 33:109. 9. Rosenberg LE, Downing S, Durant JL, Segal S: Cystinuria: biochemical evidence for three genetically distinct diseases. J Clin Invest 1966, 45:365–371. 10. Pras E, Arber N, Aksentijevich I, et al.: Localization of a gene causing cystinuria to chromosome 2p. Nature Genet 1994, 6:415–419. 11. Calonge MJ, Gasparini P, Chillaron J, et al.: Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine. Nature Genet 1994, 6:420–425. 12. Calonge M, Volpini V, Bisceglia L, et al.: Genetic heterogeneity in cystinuria: the SLC3A1 gene is linked to type I but not to type III cystinuria. Proc Am Acad Sci USA 1995, 92:9667–9671.

12.16

Tubulointerstitial Disease

13. Wartenfeld R, Golomb E, Katz G, Bale S, et al.: Molecular analysis of cystinuria in Libyan Jews: exclusion of the SLC3A1 gene and mapping a new locus on 19q. Am J Med Genet 1997, 60:617–624.

30. White P, Mune T, Rogerson F, et al.: 11--hydroxysteroid dehydrogenase and its role in the syndrome of apparent mineralocorticoid excess. Pediatr Res 1997, 41:25–29.

14. Stephens AD: Cystinuria and its treatment: 25 years’ experience at St. Bartholomew’s Hospital. J Inherited Metab Dis 1989, 12:197–209.

31. Yiu V, Dluhy R, Lifton R, Guay-Woodford L: Low peripheral plasma renin activity as a critical marker in pediatric hypertension. Pediatr Nephrol 1997, 11:343–346.

15. Perazella M, Buller G: Successful treatment of cystinuria with captopril. Am J Kidney Dis 1993, 21:504–507. 16. Grieff M: New insights into X-linked hypophosphatemia. Curr Opin Nephrol Hypertens 1997, 6:15–19. 17. Robertson GL: Vasopressin in osmotic regulation in man. Annu Rev Med 1974, 25:315. 18. Econs M, Drezner M: Tumor-induced osteomalacia: unveiling a new hormone. N Engl J Med 1994, 330:1679–1681. 19. The HYP Consortium: A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nature Genet 1995, 11:130–136. 20. Bergeron M, Gougoux A, Vinay P: The renal Fanconi syndrome. In The Metabolic and Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill, 1995:3691–3704. 21. Sly W, Hu P: The carbonic anhydrase II deficiency syndrome: osteopetrosis with renal tubular acidosis and cerebral calcification. In The Metabolic and Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 1965:3581–3602. 22. Bastani B, Gluck S: New insights into the pathogenesis of distal renal tubular acidosis. Miner Electrolyte Metab 1996, 22:396–409.

32. Chang S, Grunder S, Hanukoglu A, et al.: Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalemic acidosis, pseudohypoaldosteronism type 1. Nature Genet 1996, 12:248–253. 33. Kuhle U: Pseudohypoaldosteronism: mutation found, problem solved? Mol Cell Endocrinol 1997, 133:77–80. 34. Gordon R: Syndrome of hypertension and hyperkalemia with normal glomerular filtration rate. Hypertension 1986, 8:93–102. 35. Mansfield T, Simon D, Farfel Z, et al.: Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q2. Nature Genet 1997, 16:202–205. 36. Robertson GL, et al: Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma. J Clin Invest 1973, 52:2340–2352. 37. Bichet D, Osche A, Rosenthal W: Congenital nephrogenic diabetes insipidus. JASN 1997, 12:1951–1958. 38. van Lieburg A, Verdijk M, Knoers N, et al.: Patients with autosomal recessive nephrogenic diabetes insipidus homozygous for mutations in the aquaporin 2 water channel gene. Am J Hum Genet 1994, 55:648–652.

23. Bruce L, Cope D, Jones G, et al.: Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (band 3, AE1) gene. J Clin Invest 1997, 100:1693–1707. 24. Jarolim P, Shayakul C, Prabakaran D, et al.: Autosomal dominant distal renal tubular acidosis is associated in three families with heterozygosity for the R589H mutation in the AE1 (band 3) Cl-/HCO-3 exchanger. J Biol Chem, 1998, 273:6380–6388. 25. Guay-Woodford L: Bartter syndrome: unraveling the pathophysiologic enigma. Am J Med, 1998, 105:151–161. 26. Spiegel A, Weinstein L: Pseudohypoparathyroidism. In The Metabolic and Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 1995:3073–3085.

39. Bichet D, Arthus M-F, Lonergan M, et al.: Autosomal dominant and autosomal recessive nephrogenic diabetes insipidus: novel mutations in the AQP2 gene. J Am Soc Nephrol 1995, 6:717A.

27. Van Dop C: Pseudohypoparathyroidism: clinical and molecular aspects. Semin Nephrol 1989, 9:168–178.

44. Cameron J, Moro F, Simmonds H: Gout, uric acid and purine metabolism in paediatric nephrology. Pediatr Nephrol 1993, 7:105–118.

28. Lifton RP, Dluhy RG, Powers M., et al.: A chimaeric 11--hydroxylase aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992, 355:262–265.

45. Danpure C, Purdue P: Primary Hyperoxaluria. In The Metabolic and Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 1995:2385–2424.

29. Shimkets RA, Warnock DG, Bositis CM, et al.: Liddle’s syndrome: heritable human hypertension caused by mutations in the  subunit of the epithelial sodium channel. Cell 1994, 79:407–414.

40. Coe F, Parks J, Asplin J: The pathogenesis and treatment of kidney stones. N Engl J Med 1992, 327:1141–1152. 41. Segal S, Thier S: Cystinuria. In The Metabolic and Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle D. York: McGraw-Hill; 1995:3581–3602. 42. Polinsky MS, Kaiser BA, Baluarte HJ: Urolithiasis in childhood. Pediatr Clin North Am 1987, 34:683–710. 43. Lloyd S, Pearce S, Fisher S, et al.: A common molecular basis for three inherited kidney stone diseases. Nature 1996, 379:445–449.

The Kidney in Blood Pressure Regulation L. Gabriel Navar L. Lee Hamm

D

espite extensive animal and clinical experimentation, the mechanisms responsible for the normal regulation of arterial pressure and development of essential or primary hypertension remain unclear. One basic concept was championed by Guyton and other authors [1–4]: the long-term regulation of arterial pressure is intimately linked to the ability of the kidneys to excrete sufficient sodium chloride to maintain normal sodium balance, extracellular fluid volume, and blood volume at normotensive arterial pressures. Therefore, it is not surprising that renal disease is the most common cause of secondary hypertension. Furthermore, derangements in renal function from subtle to overt are probably involved in the pathogenesis of most if not all cases of essential hypertension [5]. Evidence of generalized microvascular disease may be causative of both hypertension and progressive renal insufficiency [5,6]. The interactions are complex because the kidneys are a major target for the detrimental consequences of uncontrolled hypertension. When hypertension is left untreated, positive feedback interactions may occur that lead progressively to greater hypertension and additional renal injury. These interactions culminate in malignant hypertension, stroke, other sequelae, and death [7]. In normal persons, an increased intake of sodium chloride leads to appropriate adjustments in the activity of various humoral, neural, and paracrine mechanisms. These mechanisms alter systemic and renal hemodynamics and increase sodium excretion without increasing arterial pressure [3,8]. Regardless of the initiating factor, decreases in sodium excretory capability in the face of normal or increased sodium intake lead to chronic increases in extracellular fluid volume and blood volume. These increases can result in hypertension. When the derangements also include increased levels of humoral or neural factors that directly cause vascular smooth muscle constriction, these effects increase peripheral vascular resistance or decrease vascular capacitance. Under these conditions the effects of subtle increases in blood volume are compounded because of increases in the blood volume relative to

CHAPTER

1

1.2

Hypertension and the Kidney

Aortic pressure, mm Hg

160

Isolated systolic hypertension (61 y)

120

Aortic blood flow, mL/s

80

A

400 0

Normotensive (56 y)

Arterial pressure, mm Hg

the capacitance, often referred to as the effective blood volume. Through the mechanism of pressure natriuresis, however, the increases in arterial pressure increase renal sodium excretion, allowing restoration of sodium balance but at the expense of persistent elevations in arterial pressure [9]. In support of this overall concept, various studies have demonstrated strong relationships between kidney disease and the incidence of hypertension. In addition, transplantation studies have shown that normotensive recipients from genetically hypertensive donors have a higher likelihood of developing hypertension after transplantation [10]. This unifying concept has helped delineate the cardinal role of the kidneys in the normal regulation of arterial pressure as well as in the pathophysiology of hypertension. Many different

B

200 180 160 140 120 100 80 60 40 20

extrinsic influences and intrarenal derangements can lead to reduced sodium excretory capability. Many factors also exist that alter cardiac output, total peripheral resistance, and cardiovascular capacitance. Accordingly, hypertension is a multifactorial dysfunctional process that can be caused by a myriad of different conditions. These conditions range from stimulatory influences that inappropriately enhance tubular sodium reabsorption to overt renal pathology, involving severe reductions in filtering capacity by the renal glomeruli and associated marked reductions in sodium excretory capability. An understanding of the normal mechanisms regulating sodium balance and how derangements lead to altered sodium homeostasis and hypertension provides the basis for a rational approach to the treatment of hypertension.

C

A

B

PP = 72 mm Hg PP = 40 mm Hg PP = 30 mm Hg

500

600 700 800 900 Arterial volume, mL

FIGURE 1-1 Aortic distensibility. The cyclical pumping nature of the heart places a heavy demand on the distensible characteristics of the aortic tree. A, During systole, the aortic tree is rapidly filled in a fraction of a second, distending it and increasing the hydraulic pressure. B, The distensibility characteristics of the arterial tree determine the pulse pressure (PP) in response to a specific stroke volume. The normal relationship is shown in curve A, and arrows designate the PP. A highly distensible arterial tree, as depicted in curve B, can accommodate the stroke volume with a smaller PP. Pathophysiologic processes and aging lead to decreases in aortic distensibility. These decreases lead to marked increases in PP and overall mean arterial pressure for any given arterial volume, as shown in curve C. Decreased distensibility is partly responsible for the isolated systolic hypertension often found in elderly persons. Recordings of actual aortic pressure and flow profiles in persons with normotension and systolic hypertension are shown in panel A [11,12]. (Panel B Adapted from Vari and Navar [4] and Panel A from Nichols et al. [12].)

HEMODYNAMIC DETERMINANTS For any vascular bed: Arterial pressure gradient Blood flow = Vascular resistance For total circulation averaged over time: Blood flow = cardiac output Therefore, Arterial pressure - right atrial pressure Cardiac output = Total peripheral resistance and: Mean arterial pressure = Cardiac output  total peripheral resistance

FIGURE 1-2 Hemodynamic determinants of arterial pressure. During the diastolic phase of the cardiac cycle, the elastic recoil characteristics of the arterial tree provide the kinetic energy that allows a continuous delivery of blood flow to the tissues. Blood flow is dependent on the arterial pressure gradient and total peripheral resistance. Under normal conditions the right atrial pressure is near zero, and thus the arterial pressure is the pressure gradient. These relationships apply for any instant in time and to timeintegrated averages when the mean pressure is used. The time-integrated average blood flow is the cardiac output that is normally 5 to 6 L/min for an adult of average weight (70 to 75 kg).

1.3

The Kidney in Blood Pressure Regulation

Dietary Insensible losses Urinary intake (skin, respiration, fecal) excretion

+

–

–

Arterial baroreflexes Atrial reflexes Renin-angiotensin-aldosterone Adrenal catecholamines Vasopressin Natriuretic peptides Endothelial factors: nitric oxide, endothelin kallikrein-kinin system Prostaglandins and other eicosanoids

Net sodium and fluid balance

ECF volume Arterial pressure Blood volume

Mean circulatory pressure

(Autoregulation)

Neurohumoral systems

Total peripheral resistance

Interstitial fluid volume

Venous return

Heart rate and contractility

Cardiac output

FIGURE 1-3 Volume determinants of arterial pressure. The two major determinants of arterial pressure, cardiac output and total peripheral resistance, are regulated by a combination of short- and long-term mechanisms. Rapidly adjusting mechanisms regulate peripheral vascular resistance, cardiovascular capacitance, and cardiac performance. These mechanisms include the neural and humoral mechanisms listed. On a long-term basis, cardiac output is determined by venous return, which is regulated primarily by the mean circulatory pressure. The mean circulatory pressure depends on blood volume and overall cardiovascular capacitance. Blood volume is closely linked to extracellular fluid (ECF) volume and sodium balance, which are dependent on the integration of net intake and net losses [13]. (Adapted from Navar [3].)

Cardiovascular capacitance

If increased

Concentrated urine: Increased free water reabsorption

6

Thirst: Increased water intake

5

+

Na+ and Cl– Quantity of Extracellular concentrations ÷ = NaCl in ECF fluid volume in ECF volume

–

If decreased NaCl losses (urine insensible)

A

Blood volume, L

Antidiuretic hormone release

NaCl intake

Decreased water intake Increased salt intake

FIGURE 1-4 A, Relationship between net sodium balance and extracellular fluid (ECF) volume. Sodium balance is intimately linked to volume balance because of powerful mechanisms that tightly regulate plasma and ECF osmolality. Sodium and its accompanying anions constitute the major contributors to ECF osmolality. The integration of sodium intake and losses establishes the net amount of sodium in the body, which is compartmentalized primarily in the ECF volume. The quotient of these two parameters (sodium and volume) determines the sodium concentration and, thus, the osmolality. Osmolality is subject to very tight regulation by vasopressin and other mechanisms. In particular, vasopressin is a very powerful regulator of plasma osmolality; however, it achieves this regulation primarily by regulating the relative solute-free water retention or excretion by the kidney [13–15]. The important point is that the osmolality is rapidly regulated by adjusting the ECF volume to the total solute present. Corrections of excesses in extracellular fluid volume involve more complex interactions that regulate the sodium excretion rate.

4 3 2

Antidiuretic hormone inhibition Dilute urine: Increased solute-free water excretion

Edema

0 10

B

15 Extracellular fluid volume, L

20

B, Relationship between the ECF volume and blood volume. Under normal conditions a consistent relationship exists between the total ECF volume and blood volume. This relationship is consistent as long as the plasma protein concentration and, thus, the colloid osmotic pressure are regulated appropriately and the microvasculature maintains its integrity in limiting protein leak into the interstitial compartment. The shaded area represents the normal operating range [13]. A chronic increase in the total quantity of sodium chloride in the body leads to a chronic increase in ECF volume, part of which is proportionately distributed to the blood volume compartment. When accumulation is excessive, disproportionate distribution to the interstitium may lead to edema. Chronic increases in blood volume increase mean circulatory pressure (see Fig. 1-3) and lead to an increase in arterial pressure. Therefore, the mechanisms regulating sodium balance are primarily responsible for the chronic regulation of arterial pressure. (Panel B adapted from Guyton and Hall [13].)

1.4

Hypertension and the Kidney

Intrarenal Mechanisms Regulating Sodium Balance Sodium excretion, normal

6 High sodium intake Normal sodium intake Low sodium intake

5

B

A

4 3

2

Elevated sodium intake

4

2 1

C

5 1

Normal sodium intake Reduced

3

0 60

80

100 120 140 160 Renal arterial pressure, mm Hg

180

200

Filtered sodium load, µmol/min/g

FIGURE 1-5 Arterial pressure and sodium excretion. In principle, sodium balance can be regulated by altering sodium intake or excretion by the kidney. However, intake is dependent on dietary preferences and usually is excessive because of the abundant salt content of most foods. Therefore, regulation of sodium balance is achieved primarily by altering urinary sodium excretion. It is therefore of major significance that, for any given set of conditions and neurohumoral environment, acute elevations in arterial pressure produce natriuresis, whereas

150 100 50

Low Normal High

0

Fractional sodium reabsorption, %

100 98 96 94 92

Fractional sodium excretion, %

8 6 4 2 0 75 100 125 150 175 Renal arterial pressure, mm Hg

reductions in arterial pressure cause antinatriuresis [9]. This phenomenon of pressure natriuresis serves a critical role linking arterial pressure to sodium balance. Representative relationships between arterial pressure and sodium excretion under conditions of normal, high, and low sodium intake are shown. When renal function is normal and responsive to sodium regulatory mechanisms, steady state sodium excretion rates are adjusted to match the intakes. These adjustments occur with minimal alterations in arterial pressure, as exemplified by going from point 1 on curve A to point 2 on curve B. Similarly, reductions in sodium intake stimulate sodiumretaining mechanisms that prevent serious losses, as exemplified by point 3 on curve C. When the regulatory mechanisms are operating appropriately, the kidneys have a large capability to rapidly adjust the slope of the pressure natriuresis relationship. In doing so, the kidneys readily handle sodium challenges with minimal long-term changes in extracellular fluid (ECF) volume or arterial pressure. In contrast, when the kidney cannot readjust its pressure natriuresis curve or when it inadequately resets the relationship, the results are sodium retention, expansion of ECF volume, and increased arterial pressure. Failure to appropriately reset the pressure natriuresis is illustrated by point 4 on curve A and point 5 on curve C. When this occurs the increased arterial pressure directly influences sodium excretion, allowing balance between intake and excretion to be reestablished but at higher arterial pressures. (Adapted from Navar [3].)

FIGURE 1-6 Intrarenal responses to changes in arterial pressure at different levels of sodium intake. The renal autoregulation mechanism maintains the glomerular filtration rate (GFR) during changes in arterial pressure, GFR, and filtered sodium load. These values do not change significantly during changes in arterial pressure or sodium intake [3,16]. Therefore, the changes in sodium excretion in response to arterial pressure alterations are due primarily to changes in tubular fractional reabsorption. Normal fractional sodium reabsorption is very high, ranging from 98% to 99%; however, it is reduced by increased sodium chloride intake to effect the large increases in the sodium excretion rate. These responses demonstrate the importance of tubular reabsorptive mechanisms in modulating the slope of the pressure natriuresis relationship. (Adapted from Navar and Majid [9].)

The Kidney in Blood Pressure Regulation

RA

πB<1

πga=25

PB=20 Pg=60

EFP=9

GFR=Kf• EFP

πge=37

πi=8

Tubular reabsorption

Pi=6

RE

Pc=20

15

πc=37

25

RV

PCU=Kr• ERP

Vascular resistance, mm Hg•min•g/mL

Glomerular filtration rate, mL/min•g

FIGURE 1-7 Hemodynamic mechanisms regulating sodium excretion. Many different neurohumoral mechanisms, paracrine factors, and drugs exist that can influence sodium excretion and the pressure natriuresis relationship. These modulators may influence sodium excretion by altering changes in filtered load or changes in tubular reabsorption. Filtered load depends primarily on hemodynamic mechanisms that regulate the forces operating at the glomerulus. As shown, the glomerular filtration rate (GFR) is determined by the filtration coefficient (Kf) and the effective filtration pressure (EFP). The EFP is a distributed force determined by the glomerular pressure (Pg), the pressure in Bowman’s space (PB), and the plasma colloid osmotic pressure within the glomerular capillaries (πg). The πg increases progressively along the length

0.6 0.4 0.2 0 RA

20 15

RE

10 5 0

Renal blood flow, mL/min•g

5 4 3 2 1 0 0

50

100

150

Renal arterial pressure, mm Hg

200

1.5

of the glomerular capillaries as protein-free fluid is filtered such that filtration is greatest in the early segments of the glomerular capillaries, as designated by the large arrow. The glomerular forces, EFP, and blood flow are regulated by mechanisms that control the vascular smooth muscle tone of the afferent and efferent arterioles and of the intraglomerular mesangial cells. The filtration coefficient also is subject to regulation by neural, humoral, and paracrine influences [17]. Changes in tubular reabsorption can result from alterations of various processes governing both active and passive transport along the nephron segments. Peritubular capillary uptake (PCU) of the tubular reabsorbate is mediated by the net colloid osmotic pressure gradient (πc - πi). As a result of the filtration of protein-free filtrate, the plasma colloid osmotic pressure entering the peritubular capillaries is markedly increased. Thus, the colloid osmotic gradient exceeds the outwardly directed hydrostatic pressure gradient (Pc - Pi). Appropriate responses of one or more of these modulating mechanisms allow the kidneys to respond rapidly and efficiently to changes in sodium chloride intake [3,17]. πB—colloid osmotic pressure in Bowman’s space; πga—colloid osmotic pressure in initial parts of glomerular cappillaries; πge—colloid osmotic pressure in terminal segments of glomerular capillaries; RA—resistance of preglomerular arterioles; RE—efferent resistance; RV—venous resistance. (Adapted from Navar [3].)

FIGURE 1-8 Renal autoregulatory mechanism. Because the glomerular filtration rate (GFR) is so responsive to changes in the glomerular forces, highly efficient mechanisms have been developed to maintain a stable intrarenal hemodynamic environment [16]. These powerful mechanisms adjust vascular smooth muscle tone in response to various extrinsic disturbances. During changes in arterial pressure, renal blood flow and the GFR are autoregulated with high efficiency as a consequence of adjustments in the vascular resistance of the preglomerular arterioles. Although efferent resistance also can be regulated by other mechanisms, it does not participate significantly over most of the autoregulatory range. The GFR, filtered sodium load, and the intrarenal pressures are maintained stable in the face of various extrarenal disturbances by the autoregulatory mechanism. (Adapted from Navar [3].)

1.6

Hypertension and the Kidney

Arterial pressure

Plasma colloid Proximal tubular osmotic pressure and loop of Henle reabsorption

Collection pipette

Macula densa

Wax blocking pipette

Perfusion pipette

Glomerulotubular balance Glomerular pressure and plasma flow

Glomerular filtration rate

Preglomerular resistance

Proximal to distal tubule flow

Vascular effector (afferent arteriole)

Early distal tubule: flow-related changes in fluid composition

B

40

30 Single nephron GFR, nL/min

Proximal tubule

Macula densa: Sensor mechanism Transmitter

A

High sodium intake, ECF volume expansion

20 Normal

10 Low sodium intake Decreased ECF volume

0 0

C

Distal tubule

10

20 30 Late proximal perfusion rate, nL/min

40

FIGURE 1-9 Tubuloglomerular feedback (TGF) and myogenic mechanisms. Two mechanisms are responsible for efficient renal autoregulation: the TGF and myogenic mechanisms. The TGF mechanism is explained here. A, Increases in distal tubular flow past the macula densa generate signals from the macula densa cells to the afferent arterioles to elicit

vasoconstriction, whereas decreases in flow cause afferent vasodilation [16,18,19]. Blocking flow to the distal tubule or interrupting the feedback loop attenuates the autoregulatory efficiency of the glomerular filtration rate (GFR), glomerular pressure, and renal blood flow. B, Individual tubules can be blocked and perfused downstream, while collections are made or pressure measured in an early tubular segment. C, When the tubule is perfused at increased flows, the glomerular pressure and GFR of that nephron decrease. The shaded area in the normal relationship represents the normal operating level of the TGF mechanism. This mechanism helps stabilize the filtered load and the solute and sodium load to the distal nephron segment. The responsiveness of the TGF mechanism is modulated by changes in sodium intake and in extracellular fluid (ECF) volume status. At high sodium intake and ECF volume expansion the sensitivity of the TGF mechanism is low, thus allowing greater spillover of salt to the distal nephron. During low sodium intake and other conditions associated with ECF volume contraction, the sensitivity of the TGF mechanism is markedly increased to minimize spillover into the distal nephron and maximize sodium retention. The hormonal and paracrine mechanisms responsible for regulating TGF sensitivity are discussed subsequently. The myogenic mechanism is intrinsic to the vessel wall and responds to changes in wall tension to regulate vascular smooth muscle tone. Preglomerular arteries and afferent arterioles but not efferent arterioles exhibit myogenic responses to changes in wall tension [16,20]. The residual autoregulatory capacity that exists during blockade of the tubuloglomerular feedback mechanism indicates that the myogenic mechanism contributes about half to the autoregulatory efficiency of the renal vasculature. (Figure adapted from Navar [3].)

The Kidney in Blood Pressure Regulation Agents that increase cytosolic calcium: Angiotensin II, vasopressin, epinephrine (α), TXA2, leukotrienes, adenosine (A1), ATP, norepinephrine, endothelin VoltageReceptoroperated operated channel 2+ Ca channel 2+ Ca

Agents that increase cAMP (or cGMP): Epinephrine (β), PTH, PGI2, PGE2, ANP, dopamine, nitric oxide, adenosine (A2)

Calcium-activated potassium channel K+

Chloride channel_ Cl +

Ca2+ Ca2+

– R R

cAMP

Gq

Na+

PLC Phosphoinositides

Gi

Ad Cy Ca2+

Phosphorylated MLCK (inactive)

DAG + IP3

SR

Active MLCK

Ca2+-Cal Calmodulin

cAMP

PKA

Ca2+

PKC

Gs

MLC

MLCK

Phosphorylated MLC

Tension development

Actin

Smooth muscle cell

FIGURE 1-10 Cellular mechanisms of vascular smooth muscle contraction. The vascular resistances of different arteriolar segments are ultimately regulated by the contractile tone of the corresponding vascular smooth muscle cells. Shown are the various membrane activation mechanisms and signal transduction events leading to a change in cytosolic calcium ions (Ca2+), cyclic AMP (cAMP), and phosphorylation of myosin light chain kinase. Many of the circulating hormones and paracrine factors that increase or decrease vascular smooth muscle

tone are identified. Ad Cy—adenylate cyclase; ANP—atrial natriuretic protein; Cal—calmodulin; cGMP—cyclic GMP; DAG—1,2-diacylglycerol; Gq, Gi, Gs—G proteins; IP3—inositol 1,4,5-triphosphate; MLC—myosin light chain; MLCK—myosin light chain kinase; PGE2—prostaglandin E2; PGI2—prostaglandin I2; PKA—protein kinase A; PKC—protein kinase C; PLC—phospholipase C; PTH—parathyroid hormone; R—receptor; SR—sarcoplasmic reticulum; TXA2 — thromboxane A2. (Adapted from Navar et al. [16].)

FIGURE 1-11 Differential activating mechanisms in afferent and efferent arterioles. The relative contributions of the activation pathways are different in afferent and efferent arterioles. Increases in cytosolic Ca2+ in afferent arterioles appear to be primarily by calcium ion (Ca2+) entry by way of receptor- and voltage-dependent Ca2+ channels. The efferent arterioles are less dependent on voltage-dependent Ca2+ channels. These differential mechanisms in the renal vasculature are exemplified by comparing the afferent and efferent arteriolar responses to angiotensin II before and after treatment with Ca2+ channel blockers. A, These experiments were done using the juxtamedullary nephron preparation that allows direct visualization of the renal microcirculation [21]. AA—afferent arteriole; ArA—arcuate artery; PC—peritubular capillaries; V—vein; VR—vasa recta. (Continued on next page)

A

1.7

1.8

Hypertension and the Kidney

Afferent arteriole

30

FIGURE 1-11 (Continued) B, Both afferent and efferent arterioles constrict in response to angiotensin II [22]. Ca2+ channel blockers, dilate only the afferent arterioles and prevents the afferent vasoconstriction responses to angiotensin II. In contrast, Ca2+ channel blockers do not significantly vasodilate efferent arterioles and do not block the vasoconstrictor effects of angiotensin II. Thus, afferent and efferent arterioles can be differentially regulated by various hormones and paracrine agents. (Panel A from Casellas and Navar [21]; panel B from Navar et al. [23].)

Efferent arteriole

Diameter, µ

25

20 Control Ca2+ channel blockers

15

B

0.1 nM 10 nM

0.1 nM 10 nM

10 Control

Angiotensin II

Control

Angiotensin II

Smooth muscle cell Vasoconstriction

Vasodilation

EDHF

NO PGI 2 Relaxing factors

EDCF PGF2α Endothelin Constricting factors

TXA2

Angiotensin II

ACE

Endothelial cell Angiotensin I Shear stress

Thrombin Insulin

Bradykinin Platelet activating ATP-ADP Serotonin Leukotrienes factor Acetylcholine

Histamine

FIGURE 1-12 Endothelial-derived factors. In addition to serving as a diffusion barrier, the endothelial cells lining the vasculature participate actively in the regulation of vascular function. They do so by responding to various circulating hormones and physical stimuli and releasing

Sodium excretion, normal

Renal arterial pressure

Shear stress

Endothelial nitric oxide release

Vascular dilation but counteracted by autoregulation

Diffusion to tubules

3 2 1

Control NOS inhibition

50 75 100 125 150 Renal arterial pressure, mm Hg

Epithelial cGMP Decreased sodium reabsorption

Sodium excretion

paracrine agents that alter vascular smooth muscle tone and influence tubular transport function. (Examples are shown.) Angiotensinconverting enzyme (ACE) is present on endothelial cells and converts angiotensin I to angiotensin II. Nitric oxide is formed by nitric oxide synthase, which cleaves nitric oxide from L-arginine. Nitric oxide diffuses from the endothelial cells to activate soluble guanylate cyclase and increases cyclic GMP (cGMP) levels in vascular smooth muscle cells, thus causing vasodilation. Agents that can stimulate nitric oxide are shown. The relative amounts of the various factors released by endothelial cells depend on the physiologic circumstances and pathophysiologic status. Thus, endothelial cells can exert vasodilator or vasoconstrictor effects. At least one major influence participating in the normal regulation of vascular tone is nitric oxide. EDCF—endothelial derived constrictor factor; EDHF—endothelial derived hyperpolarizing factor; PGF2—prostaglandin F2; PGI2—prostaglandin I2; TXA2— thromboxane A2. (Adapted from Navar et al. [16].)

FIGURE 1-13 Nitric oxide in mediation of pressure natriuresis. Several recent studies have demonstrated that nitric oxide also directly affects tubular sodium transport and may be an important mediator of the changes induced by arterial pressure in sodium excretion, as described in Figure 1-5 [9,24]. Increases in arteriolar shear stress caused by increases in arterial pressure stimulate production of nitric oxide. Nitric oxide may exert direct effects to inhibit tubule sodium reabsorptive mechanisms and may elicit vasodilatory actions. Nitric oxide increases intracellular cyclic GMP (cGMP) in tubular cells, which leads to a reduced reabsorption rate through cGMP-sensitive sodium entry pathways [24,25]. When formation of nitric oxide is blocked by agents that prevent nitric oxide synthase activity, sodium excretion is reduced and the pressure natriuresis relationship is markedly suppressed. Thus, nitric oxide may exert a critical role in the regulation of arterial pressure by influencing vascular tone throughout the cardiovascular system and by serving as a mediator of the changes induced by the arterial pressure in tubular sodium reabsorption. (Adapted from Navar [3].)

The Kidney in Blood Pressure Regulation

DCT

PCT 60%

7% CCD PST

TALH 30%

DLH

2% –3%

OMCD

IMCD ALH

< 1% Filtered NA+ load = Plasma Na × Glomerular filtration rate = 140 mEq/L × 0.120 L/min = 16.8 mEq/min × 1440 min/d = 24,192 mEq/min Urinary Na+ excretion = 200 mEq/d Fractional Na excretion = 0.83% Fractional Na reabsorption = 99.17%

Peritubular capillary Lateral intercellular ∆P space

Na K

∆π (–)

Na Active transcellular

[K ] +

Na

K K

Na+ (–)

Cells

Tubule lumen

Paracellular (passive)

[Na+]

1.9

FIGURE 1-14 Tubular transport processes. Sodium excretion is the difference between the very high filtered load and net tubular reabsorption rate such that, under normal conditions less than 1% of the filtered sodium load is excreted. The percentage of reabsorption of the filtered load occurring in each nephron segment is shown. The end result is that normally less than 1% of the filtered load is excreted; however, the exact excretion rate can be changed by many mechanisms. Despite the lesser absolute sodium reabsorption in the distal nephron segments, the latter segments are critical for final regulation of sodium excretion. Therefore, any factor that changes the delicate balance existing between the hemodynamically determined filtered load and the tubular reabsorption rate can lead to marked alterations in sodium excretion. ALH—thin ascending limb of the loop of Henle; CCD—cortical collecting duct; DCT—distal convoluted tubule; DLH—thin descending limb of the loop of Henle; IMCD—inner medullary collecting duct; OMCD—outer medullary collecting duct; PCT—proximal convoluted tubule; PST—proximal straight tubule; TALH—thick ascending limb of the loop of Henle.

FIGURE 1-15 Proximal tubule reabsorptive mechanisms. The proximal tubule is responsible for reabsorption of 60% to 70% of the filtered load of sodium. Reabsorption is accomplished by a combination of both active and passive transport mechanisms that reabsorb sodium and other solutes from the lumen into the lateral spaces and interstitial compartment. The major driving force for this reabsorption is the basolateral sodium-potassium ATPase (Na+-K+ ATPase) that transports Na+ out of the proximal tubule cells in exchange for K+. As in most cells, this maintains a low intracellular Na+ concentration and a high intracellular K+ concentration. The low intracellular Na+ concentration, along with the negative intracellular electrical potential, creates the electrochemical gradient that drives most of the apical transport mechanisms. In the late proximal tubule, a lumen to interstitial chloride concentration gradient drives additional net solute transport. The net solute transport establishes a small osmotic imbalance that drives transtubular water flow through both transcellular and paracellular pathways. In the tubule, water and solutes are reabsorbed isotonically (water and solute in equivalent proportions). The reabsorbed solutes and water are then further reabsorbed from the lateral and interstitial spaces into the peritubular capillaries by the colloid osmotic pressure, which establishes a predominant reabsorptive force as discussed in Figure 1-7. P—transcapillary hydrostatic pressure gradient; π—transcapillary colloid osmotic pressure gradient.

1.10

Hypertension and the Kidney

Proximal tubule cells

Lumen

Regulation of reabsorption _

ATP

Na+ Glucose

ADP Na+ H+ Anion

_

Na+ _ HCO3 CO3 Ca2+

_

3Na+

_

Cl

3Na+ 2 K+

Stimulation Angiotensin II Adrenergic agents or increased renal nerve activity Increased luminal flow or solute delivery Increased filtration fraction Inhibition Volume expansion (via increased backleak) Atrial natriuretic peptide Dopamine Increased interstitial pressure

FIGURE 1-16 Major transport pathways across proximal tubule cells. At the apical membrane, sodium is transported in conjunction with organic solutes (such as glucose, amino acids, and citrate) and inorganic anions (such as phosphate and sulfate). The major mechanism for sodium entry into the cells is sodium-hydrogen exchange (the isoform NHE3). Chloride transport

Lumen Furosemide Cell _ 2Cl-

Thick ascending limb cells ATP

Na

K+ or NH4+ +10mv

ADP

K+ Na+ H+

CI

_

Regulation of reabsorbtion Stimulation Antidiuretic hormone 3Na+ β-adrenergic agents 2 K+ Mineralocorticoids Inhibition Hypertonicity Prostaglandin E2 Acidosis Calcium

pathways across the apical membrane may include a coupled sodium chloride entry step or chloride anion exchange that is coupled with sodium-hydrogen exchange. Major transport pathways at the basolateral membrane include the ubiquitous and preeminent sodium-potassium ATPase (Na+-K+ ATPase) that creates the major driving force. The other major pathway is a sodium-bicarbonate transport system that transports the equivalent of one sodium ion coupled with the equivalent of three bicarbonate ions (HCO-3). Because this transporter transports two net charges out the electrically negative cell, membrane voltage partially drives this transport pathway. A basolateral sodium-calcium exchanger is important in regulating cell calcium. Not shown are several other pathways that predominantly transport protons or other ions and organic substrates. Several major regulatory factors are listed.

FIGURE 1-17 Sodium transport mechanisms in the thick ascending limb of the loop of Henle. The major sodium chloride reabsorptive mechanism in the thick ascending limb at the apical membrane is the sodiumpotassium-chloride cotransporter. This electroneutral transporter is inhibited by furosemide and other loop diuretics and is stimulated by a variety of factors. Potassium is recycled across the apical membrane into the lumen, creating a positive voltage in the lumen. An apical sodium-hydrogen exchanger also exists that may function to reabsorb some sodium bicarbonate. The sodium-potassium ATPase (Na+-K+ ATPase) at the basolateral membrane again is the driving force. The basolateral chloride channel and possibly other chloride cotransporters are important in mediating chloride efflux across the basolateral membrane. Sodium and chloride are reabsorbed without water in this segment because water is impermeable across the apical membrane of the thick ascending limb. Thus, the tubular fluid osmolality in this nephron segment is hypotonic.

The Kidney in Blood Pressure Regulation

Thiazides

Distal tubule and connecting tubule cells

_ Na _ Cl

ATP 3Na+ 2 K+

Amiloride

Na+

1.11

FIGURE 1-18 Mechanisms of sodium chloride reabsorption in the distal tubule. The distal convoluted tubule and subsequent connecting tubule have a variety of sodium transport mechanisms. The distal tubule has predominantly a sodium chloride cotransporter, which is inhibited by thiazide diuretics. In the connecting tubule, sodium channels and a sodium-hydrogen exchange mechanism also are present. Amiloride inhibits sodium channel activity. Again the sodium-potassium ATPase (Na+-K+ ATPase) on the basolateral membrane provides most of the driving force for sodium reabsorption.

ADP

_

Na+ H+

Collecting duct principal cell Lumen

Cell ATP

Na+

ADP

_ Amiloride K+

Regulation of reabsorbtion Stimulation Aldosterone 3Na+ Antidiuretic hormone 2 K+ Inhibition Prostaglandins Nitric oxide Atrial natriuretic peptide Bradykinin Na+_ 2CI K+ (IMCD)

FIGURE 1-19 Mechanism of sodium chloride reabsorption in collecting duct cells. Sodium transport in the collecting duct is mainly via amiloridesensitive sodium channels in the apical membrane. Some evidence for other mechanisms such as an electroneutral sodium-chloride cotransport mechanism and a different sodium channel also has been reported. Again, the basolateral sodium-potassium ATPase (Na+-K+ ATPase) creates the driving force for overall sodium transport. There are some differences between the cortical collecting duct and the deeper inner medullary collecting duct (IMCD). In the cortical collecting duct, sodium transport occurs in the predominant principal cell type interspersed between acid-base transporting intercalated cells. The principal cell also is an important site of potassium secretion by way of apical potassium channels and water transport via antidiuretic sensitive water channels. Regulation of sodium channels may involve either insertion (from subapical compartments) or activation of preexisting sodium channels.

1.12

Hypertension and the Kidney

Systemic Factors Regulating Arterial Pressure and Sodium Excretion Medulla

Baroreceptor firing rate, impulses/s

NTS Normal

Glossopharyngeal nerve

∆I

Afferents

Resetting

Carotid sinus

∆P

NA DN

Efferents 100 Arterial pressure, mm Hg

Atrial receptors

Bulbospinal pathway epinephrine

Vagus nerve

Arterial pressure

–

Aortic arch Preganglionic sympathetics (acetylcholine)

Heart rate

Postganglionic Sympathetics Vascular smooth muscle TPR

FIGURE 1-20 Neural and sympathetic influences. The neural reflexes serve as the principal mechanisms for the rapid regulation of arterial pressure. The neural reflexes also exert a long-term role by influencing sodium excretion. The pathways and effectors of the arterial baroreflex and atrial pressure-volume reflex are depicted. The arrows indicate increased or decreased activity in response to an acute reduction in arterial pressure which is sensed by the baroreceptors in the aortic arch and carotid sinus. The insert depicts the relationship between the arterial blood pressure and baroreflex primary afferent firing rate. At the normal level of mean arterial pressure of approximately 100 mm Hg, the sensitivity (I/P) is set at the maximum level. After chronic resetting of the baroreceptors, the peak sensitivity and threshold of activation are shifted to a higher level of arterial pressure. The cardiovascular reflexes involve high-pressure arterial receptors in the aortic arch and carotid sinus and low-pressure atrial receptors. In response to decreases in arterial pressure or vascular volume, increased sympathetic stimulation participates in shortterm control of arterial pressure. This increased stimulation does

Norepinephrine

Adrenal medulla

Kidney ↓ RBF ↓ GFR ↑Reabsorption ↓Na+ excretion

Epinephrine

so by enhancing cardiac performance and stimulating vascular smooth muscle tone, leading to increased total peripheral resistance and decreased capacitance. The direct effects of the sympathetic nervous system on kidney function lead to decreased sodium excretion caused by decreases in filtered load and increases in tubular reabsorption [26]. The decreases in the glomerular filtration rate (GFR) and filtered sodium load are due to increases in both afferent and efferent arteriolar resistances and to decreases in the filtration coefficient (see Fig. 1-7). Sympathetic activation also enhances proximal sodium reabsorption by stimulating the sodium-hydrogen (Na+-H+) exchanger mechanism (see Fig. 1-16) and by increasing the net chloride reabsorption by the thick ascending limb of the loop of Henle. The indirect effects include stimulation of renin secretion and angiotensin II formation, which, as discussed next, also stimulates tubular reabsorption. I—change in impulse firing; P—change in pressure; DN—dorsal motor nucleus; NA—nucleus ambiguous; NTS—nucleus tractus solitarii; RBF—renal blood flow; TPR—total peripheral resistance. (Adapted from Vari and Navar [4].)

The Kidney in Blood Pressure Regulation

Angiotensinogen Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Val-Tyr-Ser-R Renin NaCl intake

Arterial pressure

ECF volume

Stress trauma

Angiotensin I Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu Angiotensinconverting enzyme, chymase (heart)

Macula densa mechanism Baroreceptor mechanism Sympathetic nervous system

Angiotensin II Juxtaglomerular apparatus Cytosolic Ca2+ cAMP

Renin release

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe Angiotensinases

Metabolites

AT1, AT2, AT? Receptor binding and Biologic actions

Angiotensin (1–7) Angiotensin (2–8) Angiotensin (3–8) Inactive fragments

FIGURE 1-21 Renin-angiotensin system. The renin-angiotensin system serves as one of the most powerful regulators of arterial pressure and sodium balance. In response to various stimuli that compromise blood volume, extracellular fluid (ECF) volume, or arterial pressure—or those associated with stress and trauma—three major mechanisms are activated. These mechanisms stimulate renin release by the cells of the juxtaglomerular apparatus that act on angiotensinogen to form angiotensin I. Angiotensinogen is an 2 globulin formed primarily in the liver and to a lesser extent by the kidney. Angiotensin I is a decapeptide that is rapidly converted by angiotensin-converting enzyme (ACE) and to a lesser extent by chymase (in the heart) to angiotensin II, an octapeptide. Recent studies have indicated that other angiotensin metabolites such as angiotensin (2–8), angiotensin (1–7), and angiotensin (3–8) have biologic actions.

Angiotensin II and/or active metabolites

Adrenal cortex

Aldosterone Distal nephron reabsorption

Kidney

Intestine

Peripheral nervous system

Central nervous system

Proximal and distal sodium + water Reabsorption by intestine

Vascular smooth muscle

Adrenergic facilitation Sympathetic discharge

Vasoconstriction transport effects

Thirst, salt appetite

Heart

Growth factors

Contractility Proliferation

Vasoconstriction

Vasopressin release Water reabsorption

Maintain or increase extracellular fluid volume

FIGURE 1-22 Multiple actions of angiotensin. Angiotensin II and some of the other angiotensin II metabolites have a myriad of actions on many different vascular beds and organ systems. Angiotensin II exerts short- and long-term actions, including vasoconstriction and stimulation of aldosterone release. Angiotensin II also

Total peripheral resistance

1.13

Cardiac output

Hypertrophy

interacts with the sympathetic nervous system by facilitating adrenergic transmission and has long-term actions on vascular smooth muscle proliferation by interacting with growth factors. Angiotensin II exerts several important effects on the kidney that contribute to sodium conservation. (Adapted from Navar [3].)

1.14

Hypertension and the Kidney Enhance proximal tubular reabsorption PT

BS

Decrease Kf

GC

EA

PC

FIGURE 1-23 Angiotensin II actions on renal hemodynamics. Systemic and intrarenal angiotensin II exert powerful vasoconstrictive actions on the kidney to decrease renal blood flow and sodium excretion. At the level of the glomerulus, angiotensin II is a vasoconstrictor of both afferent (AA) and efferent arterioles (EA) and decreases the filtration coefficient Kf. Angiotensin II also directly inhibits renin release by the juxtaglomerular apparatus. Increased intrarenal angiotensin II also is responsible for the increased sensitivity of the tubuloglomerular feedback mechanism that occurs with decreased sodium chloride intake (see Fig. 1-9) [17,27,28]. BS—Bowman’s space; GC—glomerular capillaries; PC—peritubular capillaries; PT—proximal tubule; TAL—thick ascending limb; TGF—tubuloglomerular feedback mechanism. (Adapted from Arendshorst and Navar [17].)

Inhibit renin release

Efferent arteriolar vasoconstriction

Afferent arteriolar vasoconstriction TAL

Increased sensitivity of TGF mechanism AA

Angiotensin

Angiotensin

G PLA

H+ Tubule lumen

_ +

Na+

_

+

HCO3 Na+

cAMP

K+ Na+

_

FIGURE 1-24 Angiotensin II actions on tubular transport. Angiotensin II receptors are located on both the luminal and basolateral membranes of the proximal and distal nephron segments. The proximal effect has been studied most extensively. Activation of angiotensin II-AT1 receptors leads to increased activities of the sodium-hydrogen (Na+-H+) exchanger and the sodium-bicarbonate (Na+-HCO-3) cotransporter. These increased activities lead to augmented volume reabsorption. Higher angiotensin II concentrations can inhibit the tubular sodium reabsorption rate; however, the main physiologic role of angiotensin II is to enhance the reabsorption rate [28]. cAMP—cyclic AMP; G—G protein; PLA—phospholipase A. (Adapted from Mitchell and Navar [28].)

The Kidney in Blood Pressure Regulation

1.15

SNGFR Enhancement of proximal reabsorption rate Stimulation of apical amiloride-sensitive Na-H exchanger Stimulation of basolateral Na-HCO3 cotransporter Sustained changes in distal volume and sodium delivery Increased sensitivity of afferent arteriole to signals from macula densa cells

Distal delivery

Glomerular pressure, mm Hg

Reabsorption 60 Proximal

A. SYNERGISTIC RENAL ACTIONS OF ANGIOTENSIN II

55 50 45 40 35 30 0

B

Glomerular pressure, mm Hg

Proximal reabsorption 60 SNGFR

Distal delivery

55 50 45 40 35 30 0

C

Lumen

10 20 30 End proximal fluid flow, nL/min

40

Principal cell Mitochondria

ATP

Na+ Proteins

3Na+ 2 K+

ADP

mRNA

K+ Nucleus

A

MR

Aldosterone _ Spironolactone

10 20 30 End proximal fluid flow, nL/min

40

FIGURE 1-25 A–C, Synergistic effects of angiotensin II on proximal reabsorption and tubuloglomerular feedback mechanisms. The actions of angiotensin II on proximal nephron reabsorption and the ability of angiotensin II to enhance the sensitivity of the tubuloglomerular feedback (TGF) mechanism prevent a compensatory increase in glomerular filtration rate caused by the reduced distal tubular flow. These actions allow elevated angiotensin II levels to exert a sustained reduction in sodium delivery to the distal nephron segment. This effect is shown here by the shift of operating levels to a lower proximal fluid flow under the influence of elevated angiotensin II [27]. The effects of angiotensin II to enhance TGF sensitivity allow the glomerular pressure (GP) and nephron filtration rate to be maintained at a reduced distal volume delivery rate that would occur as a consequence of the angiotensin II effects on reabsorption. SNGFR—single nephron glomerular filtration rate. (Panels B and C adapted from Mitchell et al. [27].) FIGURE 1-26 Effects of aldosterone on distal nephron sodium reabsorption. A, Mechanism of action of aldosterone. Angiotensin II also is a very powerful regulator of aldosterone release by the adrenal gland. The increased aldosterone levels synergize with the direct effects of angiotensin II to enhance distal tubule sodium reabsorption. Aldosterone increases sodium reabsorption and potassium secretion in the distal segments of the nephron by binding to the cytoplasmic mineralocorticoid receptor (MR). On binding, the receptor complex migrates to the nucleus where it induces transcription of a variety of messenger RNAs (mRNAs). The mRNAs encode for proteins that stimulate sodium reabsorption by increasing sodium-potassium ATPase (Na+-K+ ATPase) protein and activity at basolateral membranes, increasing mitochondrial ATP formation, and increasing the sodium and potassium channels at the luminal membrane [29]. Growing evidence also exists for nongenomic actions of aldosterone to activate sodium entry pathways such as the amiloride-sensitive sodium channel [30]. (Continued on next page)

1.16

Hypertension and the Kidney

14

Filtered sodium remaining, %

12 Aldosterone blockade

10

FIGURE 1-26 (Continued) B, The net effect of aldosterone is to stimulate sodium reabsorption along the distal nephron segment, decreasing the remaining sodium to only 2% or 3% of the filtered load. The direct action of aldosterone can be blocked by drugs such as spironolactone that bind directly to the mineralocorticoid receptor.

8 6 4

Normal

2 0 0

20

40 60 Distal nephron length, %

B

Lumen

80

100

Principal cell Mitochondria

Na+

ATP

Proteins ADP

3Na+ 2 K+

mRNA Aldosterone

MR

K+

Nucleus Cortisone

Cortisol II-β_OHSD defect or glycyrrhizic acid or carbenoxolone

Lumen

Principal cell Mitochondria ATP

3Na+

Na+ Proteins

ADP

mRNA

K+ Nucleus

2K+ Primary hyperaldosteronism Adrenal enzymatic disorder Adenoma Glucorticoid-remediable aldosteronism

MR Aldosterone

FIGURE 1-27 Syndrome of apparent mineralocorticoid excess and hypertension. Aldosterone increases sodium reabsorption and potassium secretion in the distal segments of the nephron by binding to the cytoplasmic mineralocorticoid receptor (MR). Cortisol, the glucocorticoid that circulates in plasma at much higher concentrations than does aldosterone, also binds to MR. However, cortisol normally is prevented from this by the action of 11--hydroxysteroid dehydrogenase (11-OHSD), which metabolizes cortisol to cortisone in mineralocorticoid-sensitive cells. A deficiency or defect in this enzyme has been found to be responsible for a rare form of hypertension in persons with the hereditary syndrome of apparent mineralocorticoid excess. In these persons, cortisol binds to the MR receptor, causing sodium retention and hypertension [31]. This enzyme also is blocked by glycyrrhizic acid (in some forms of licorice) and carbenoxolone. The diuretic spironolactone acting by way of inhibition of MR is able to block this excessive action of cortisol on the MR receptor.

FIGURE 1-28 Hyperaldosteronism and glucocorticoid-remediable aldosteronism. Hypertension can result from increased aldosterone or from increases in other closely related steroids derived from abnormal adrenal metabolism (11--hydroxylase deficiency and 17-hydroxylase deficiency). The most common cause is an aldosterone-producing adenoma; bilateral hyperplasia of the adrenal zona glomerulosa is the next most common cause. In glucocorticoid-remediable aldosteronism, a DNA crossover mutation results in a chimeric gene in which aldosterone production is regulated by adrenocorticotropic hormone (ACTH). Increases in aldosterone also can result secondarily from any state of increased renin such as renal artery stenosis, which leads to increased circulating concentrations of angiotensin II and stimulation of aldosterone release [31]. MR—mineralocorticoid receptor; mRNA—messenger RNA.

The Kidney in Blood Pressure Regulation

Lumen Cell Liddle's syndrome Na+

δ δ

pp pp

α α

pp

β β

ATP ADP

Liddle's syndrome

3Na+ 2 K+

K+

1.17

FIGURE 1-29 Excess epithelial sodium channel activity in Liddle’s syndrome. The epithelial sodium channel responsible for sodium reabsorption in much of the distal portions of the nephron is a complex of three homologous subunits, , , and  each with two membrane-spanning domains. Liddle’s syndrome, an autosomal dominant disorder causing low renin-aldosterone hypertension often with hypokalemia, results from mutated  or  subunits. These mutations increase the sodium reabsorptive rate by way of these channels by keeping them open longer, increasing sodium channel density on the membranes, or both. The specific problem appears to reside with proline (P)-rich domains in the carboxyl terminal region of  or  that are involved in regulation of the channel membrane localization or activity. The net result is excess sodium reabsorption and a reduced capability to increase sodium excretion in response to volume expansion [31,32].

Extracellular fluid volume Blood volume

Intrathoracic blood volume

Atrial stretch receptors

Na Cl

Gitleman's syndrome

Sodium excretion

Aldosterone Renin Tubular sodium reabsorption

Vascular resistance

Vasodilation

Na+

B

L Na+2Cl _ Cl K+ K+

Pseudohypoaldosteronism

Bartter's syndrome

FIGURE 1-30 Syndromes of diminished sodium reabsorption and hypotension. Recently, a variety of syndromes associated with salt wasting, and usually hypotension, have been attributed to specific molecular defects in the distal nephron. Bartter’s syndrome, which usually is accompanied by metabolic alkalosis and hypokalemia, has been found to be associated with at least three separate defects (the three transporters shown) in the thick ascending limb. These defects are at the level of the sodium-potassium-2chloride (Na+-K+-2Cl-) cotransporter, apical potassium channel, and basolateral chloride channel (see Fig. 1-17). Malfunction in any of these three proteins results in diminished sodium chloride reabsorption similar to that occurring with administration of loop diuretics. Gitelman’s syndrome, which was originally described as a variant of Bartter’s syndrome, represents a defect in the sodium chloride cotransport mechanism in the distal tubule. Pseudohypoaldosteronism results from a defect in the apical sodium channels in the collecting ducts. In contrast to Bartter’s and Gitelman’s syndromes, hyperkalemia may be present. These rare disorders illustrate that defects in sodium chloride reabsorptive mechanisms can result in abnormally low blood pressure as a consequence of excessive sodium excretion in the urine. Although these conditions are rare, similar but more subtle defects of the heterozygous state may contribute to protection from hypertension in some persons [31]. B—basolateral side; L—lumen of tubule.

Atrial natriuretic peptide

FIGURE 1-31 Atrial natriuretic peptide (ANP). In response to increased intravascular volume, atrial distention stimulates the release of ANP from the atrial granules where the precursor is stored. Extracellular fluid volume expansion is associated with increased ANP levels, whereas reductions in vascular volume and dehydration elicit decreases in plasma ANP levels. ANP participates in arterial pressure regulation by sensing the degree of vascular volume expansion and exerting direct vasodilator actions and natriuretic effects. ANP has been shown to markedly increase the slope of the pressure natriuresis relationship (see Figs. 1-5 and 1-6). The vasorelaxant and transport actions are mediated by stimulation of membrane-bound guanylate cyclase, leading to increased cyclic GMP levels. ANP also inhibits renin release, which reduces circulating angiotensin II levels [33–35]. Related peptides, such as brain natriuretic peptides, have similar effects on sodium excretion and renin release [36].

1.18

Hypertension and the Kidney

Membrane phospholipids Phospholipase A2 COOH

Arachidonic acid Cytochrome P450 monooxygenases

Cyclooxygenase Endoperoxides

PGI2/PGE2 (vasodilation, natriuresis)

EETs (vasodilation )

Lipoxygenases HPETEs

HETEs (vasoconstriction)

Leukotrienes (vasoconstriction)

TXA2/PGH2 (vasoconstriction)

HETEs Lipoxins

FIGURE 1-32 Arachidonic acid metabolites. Several eicosanoids (arachidonic acid metabolites) are released locally and exert both vasoconstrictor and vasodilator effects as well as effects on tubular transport [16,37]. Phospholipase A2 catalyzes formation of arachidonic acid (an unsaturated 20-carbon fatty acid) from membrane phospholipids. The cyclooxygenase pathway and various prostaglandin synthetases are responsible for the formation of endoperoxides (PGH2), prostaglandins E2 (PGE2) and I2 (PGI2), and thromboxane (TXA2) [38,39].

Kallikrein-kinin system Low molecular weight kininogen

High molecular weight kininogen

Tissue kallikrein

Plasma kallikrein Bradykinin Kininase II (ACE) NEP

Kininase I Des Arg-bradykinin

B1-receptor

Kinin degradation products B2-receptor Endothelium-dependent Nitric oxide PGE2

Vasodilation natriuresis

States of volume depletion and hypoperfusion stimulate prostaglandin synthesis [16,17,38]. The vasodilator prostaglandins attenuate the influence of vasoconstrictor substances during activation of the renin-angiotensin system, sympathetic nervous system, or both [33]. These prostaglandins also have transport effects on renal tubules through activation of distinct prostaglandin receptors [40]. In some pathophysiologic conditions, enhanced production of TXA2 and other vasoconstrictor prostanoids may occur. The vasoconstriction induced by TXA2 appears to be mediated primarily by calcium influx [17,40]. Leukotrienes are hydroperoxy fatty acid products of 5-hydroperoxyeicosatetraenoic acid (HPETE) that are synthesized by way of the lipoxygenase pathway. Leukotrienes are released in inflammatory and immunologic reactions and have been shown to stimulate renin release. The cytochrome P450 monooxygenases produce several vasoactive agents [16,37,41,42] usually referred to as EETs and hydroxy-eicosatetraenoic acids (HETEs). These substances exert actions on vascular smooth muscle and epithelial tissues [16,41,42]. (Adapted from Navar [3].)

FIGURE 1-33 Kallikrein-kinin system. Plasma and tissue kallikreins are functionally different serine protease enzymes that act on kininogens (inactive 2 glycoproteins) to form the biologically active kinins (bradykinin and lysyl-bradykinin [kallidin]). Kidney kallikrein and kininogen are localized in the distal convoluted and cortical collecting tubules. Release of kallikrein into the tubular fluid and interstitium can be stimulated by prostaglandins, mineralocorticoids, angiotensin II, and diuretics. B1 and B2 are the two major bradykinin receptors that exert most of the vascular actions. Although glomerulus and distal nephron segments contain both B1 and B2 receptors, most of the renal vascular and tubular effects appear to be mediated by B2-receptor activation [16,17,43,44]. Bradykinin and kallidin elicit vasodilation and stimulate nitric oxide, prostaglandin E2 (PGE2) and I2 (PGI2), and renin release [45,46]. Kinins are inactivated by the same enzyme that converts angiotensin I to angiotensin II, angiotensin-converting enzyme (ACE). The kallikrein-kinin system is stimulated by sodium depletion, indicating it serves as a mechanism to dampen or offset the effects of enhanced angiotensin II levels [47,48]. Des Arg— bradykinin; NEP—neutral endopeptidase.

The Kidney in Blood Pressure Regulation

Plasma vasopressin, pg/mL

10

FIGURE 1-34 Vasopressin. Vasopressin is synthesized by the paraventricular and supraoptic nuclei of the hypothalamus. Vasopressin is stored in the posterior pituitary gland and released in response to osmotic or volume-dependent baroreceptor stimuli, or both. Atrial filling inhibits vasopressin release. Increases in plasma osmolality increase vasopressin release; however, the relationship is shifted by the status of extracellular fluid (ECF) volume, with decreases in the ECF volume increasing the sensitivity of the relationship. Stress and trauma also increase vasopressin release [15]. Therefore, when ECF volume and blood volume are diminished, vasopressin is released to help guard against additional losses of body fluids. (Adapted from Navar [8].)

Normal ECF volume

Decreased ECF volume

8 6

Increased ECF volume

4 2 0 260

340

280 300 320 Plasma osmolality, mOsm/kg

Collecting duct principal cell

Plasma membrane

Adenylate cyclase

Tubule lumen ATP cAMP + PPi

GTP

Protein kinase A

Gα G Gα G

Circulating vasopressin V2

1.19

H 2O Aquaporin 2 water channels

GTP

GDP

Aquaporin 2

FIGURE 1-35 Vasopressin receptors. Vasopressin exerts its cellular actions through two major receptors. Activation of V1 receptors leads to vascular smooth muscle constriction and increases peripheral resistance. Vasopressin stimulates inositol 1,4,5-triphosphate and calcium ion (Ca2+) mobilization from cytosolic stores and also increases Ca2+ entry from extracellular stores as shown in Figure 1-10. The vasoconstrictive action of vasopressin helps increase total peripheral resistance and reduces medullary blood flow, which enhances the concentrating ability of the kidney. V2 receptors are located primarily on the basolateral side of the principal cells in the collecting duct segment. Vasopressin activates heterotrimeric G proteins that activate adenylate cyclase, thus increasing cyclic AMP levels. Cyclic AMP (cAMP) activates protein kinase A, which increases the density of water channels in the luminal membrane. Water channels (aquaporin proteins) reside in subapical vesicles and on activation fuse with the apical membrane. Thus, vasopressin markedly increases the water permeability of the collecting duct and allows conservation of fluid and excretion of a concentrated urine. An intact vasopressin system is essential for the normal regulation of urine concentration by the kidney that, in turn, is the major mechanism for coupling the solute to solvent ratio (osmolality) of the extracellular fluid. As discussed in Figure 1-4, this tight coupling allows the confluence of homeostatic mechanisms regulating sodium balance with those regulating extracellular fluid volume. G and G—proteins; PPi— inorganic pyrophosphate. (Adapted from Vari and Navar [4].)

1.20

Hypertension and the Kidney

Hypertensinogenic Process Initial increase in vascular resistance

Initial increase in volume

Neurogenic or humoral stimuli

Volume

Renal volume retention

Vasoconstrictor effects

Effective blood volume

Cardiac output Tissue blood flow Autoregulatory resistance adjustments

Capacitance Increased vascular resistance Increased arterial blood pressure

FIGURE 1-36 Overview of mechanisms mediating hypertension. From a pathophysiologic perspective, the development of hypertension requires either a sustained absolute or relative overexpansion of the blood volume, reduction of the capacitance of the cardiovascular system, or both [4,49,50]. One type of hypertension is due primarily to overexpansion of either the actual or the effective blood volume compartment. In such a condition of volume-dependent hypertension,

Cumulative sodium balance, mmol/kg BW

Mean arterial pressure, mm Hg

180 Angiotensin II + Aldosterone

160 140

Aldosterone

120 100 80 14 12 10 8 6 4 2 0

Renal perfusion pressure Reduce renal perfusion pressure

Angiotensin II + Aldosterone

Aldosterone

0

1 2 3 4 Reduced renal pressure, d

5

either one or more of the physiologic mechanisms described in this chapter fails to respond appropriately to intravascular expansion or some pathophysiologic process causes excess production of one or more sodium-retaining factors such as mineralocorticoids or angiotensin II [51,52]. Through mechanisms delineated earlier, overexpansion leads to increased cardiac output that results in overperfusion of tissues; the resultant autoregulatory-induced increases in peripheral resistance contribute further to an increase in total peripheral resistance and elevated arterial pressure [2,53,54]. Hypertension also can be initiated by excess vasoconstrictor influences that directly increase peripheral resistance, decrease cardiovascular capacitance, or both. Examples of this type of hypertension are enhanced activation of the sympathetic nervous system and overproduction of catecholamines such as that occurring with a pheochromocytoma [45,54,55]. When hypertension caused by a vasoconstrictor influence persists, however, it must also exert significant renal vasoconstrictor and sodium-retaining actions. Without a renal effect the elevated arterial pressure would cause pressure natriuresis, leading to a compensatory reduction in extracellular fluid volume and intravascular volume. Thus, the elevated systemic arterial pressure would not be sustained [2,8,54]. Derangements that activate both a vasoconstrictor system and produce sodium-retaining effects, such as inappropriate elevations in the activity of the renin-angiotensin-aldosterone system, lead to an even more powerful hypertensinogenic mechanism that is not easily counteracted [27]. These dual mechanisms are why the reninangiotensin system has such a critical role in the cause of many forms of hypertension, leaving only the option to increase arterial pressure and elicit a pressure natriuresis. (Adapted from Navar [3].)

FIGURE 1-37 Predominance of the renin-angiotensin-aldosterone mechanisms. Collectively, the various mechanisms discussed provide overlapping influences responsible for the highly efficient regulation of sodium balance, extracellular fluid (ECF) volume, blood volume, and arterial pressure. Nevertheless, the synergistic actions of the renin-angiotensin-aldosterone system on both vasoconstrictor as well as sodium-retaining mechanisms exert a particularly powerful influence that is not easily counteracted. In a recent study by Seeliger and coworkers [56], renal perfusion pressure was lowered to 90 to 95 mm Hg. The angiotensin II and aldosterone levels were not allowed to decrease and were fixed at normal levels by continuous infusions. The results demonstrated that all compensatory mechanisms (such as increased release of atrial natriuretic peptide and reduced activity of the sympathetic system) could not overcome the hypertensinogenic influence of maintained aldosterone or aldosterone plus angiotensin II as long as renal perfusion pressure was not allowed to increase. Thus, under conditions of increased activity of the renin-angiotensin system, an increased renal arterial pressure seems essential to reestablish sodium balance. In conclusion, regardless of the specific intrarenal mechanism involved, the net effect of a long-term hypertensinogenic derangement is a reduced capability for sodium excretion at normotensive arterial pressures that cannot be completely compensated by other neural, humoral, or paracrine mechanisms, leaving only the option to increase arterial pressure and elicit a pressure natriuresis. (Adapted from Seeliger et al. [56].)

The Kidney in Blood Pressure Regulation

1.21

References 1. Guyton AC: Blood pressure control: special role of the kidneys and body fluids. Science 1991, 252:1813–1816. 2. Cowley AW Jr: Long-term control of arterial blood pressure. Physiol Rev 1992, 72:231–300. 3. Navar LG: The kidney in blood pressure regulation and development of hypertension. Med Clin North Am 1997, 81:1165–1198. 4. Vari RC, Navar LG: Normal regulation of arterial pressure. In Principles and Practice of Nephrology, edn 2. Edited by Jacobson HR, Striker GE, Klahr GE. St. Louis: Mosby-Yearbook; 1995:354–361. 5. Luke RG: Essential hypertension: a renal disease? A review and update of the evidence. Hypertension 1993, 21:380–390. 6. Freedman BI, Iskandar SS, Appel RG: The link between hypertension and nephrosclerosis. Am J Kidney Dis 1995, 25:207–221. 7. Tepel M, Zidek W: Hypertensive crisis: pathophysiology, treatment and handling of complications. Kidney Int 1998, 53(suppl 64):S-2–S-5. 8. Navar LG: Regulation of body fluid balance. In Edema. Edited by Staub NC, Taylor AE. New York: Raven Press; 1984:319–352. 9. Navar LG, Majid DSA: Interactions between arterial pressure and sodium excretion. Curr Opin Nephrol Hypertens 1996, 5:64–71. 10. Rettig R, Schmitt B, Pelzl B, Speck T: The kidney and primary hypertension: contributions from renal transplantation studies in animals and humans. J Hypertens 1993, 11:883–891. 11. Folkow B: Pathophysiology of hypertension: differences between young and elderly. J Hypertens 1993, 11(suppl 4):S21–S24. 12. Nichols WW, Nicolini FA, Pepine CJ: Determinants of isolated systolic hypertension in the elderly. J Hypertens 1992, 10(suppl 6):S73–S77. 13. Guyton AC, Hall JE: Integration of renal mechanisms for control of blood volume and extracellular fluid volume. In Textbook of Medical Physiology, edn 9. Philadelphia: WB Saunders; 1994:367–383. 14. Bankir L, Bouby N, Trinh-Trang-Tan M-M: The role of the kidney in the maintenance of water balance. In Bailliere’s Clinical Endocrinology and Metabolism. Water and Salt Homeostasis in Health and Disease. Edited by Baylis PH. London: Bailliere; 1989:249–311. 15. Baylis PH: Regulation of vasopressin secretion. In Bailliere’s Clinical Endocrinology and Metabolism: International Practice and Research. Edited by Baylis PH. London: Bailliere Tindall; 1989:313–330. 16. Navar LG, Inscho EW, Majid DSA, et al.: Paracrine regulation of the renal microcirculation. Physiol Rev 1996, 76:425–536. 17. Arendshorst WJ, Navar LG: Renal circulation and glomerular hemodynamics. In Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little-Brown; 1997:59–106. 18. Braam B, Mitchell KD, Koomans HA: Navar LG: Relevance of the tubuloglomerular feedback mechanism in pathophysiology. J Am Soc Nephrol 1993, 4:1257–1274. 19. Briggs JP, Schnermann J: Control of renin release and glomerular vascular tone by the juxtaglomerular apparatus. InHypertension: Pathophysiology, Diagnosis, and Management, edn 2. Edited by Laragh JH, Brenner BM. New York: Raven Press, 1995:1359–1385. 20. Carmines PK, Inscho EW, Gensure RC: Arterial pressure effects on preglomerular microvasculature of juxtamedullary nephrons. Am J Physiol (Renal Fluid Electrolyte Physiol 27) 1990, 258:F94–F102. 21. Casellas D, Navar LG: In vitro perfusion of juxtamedullary nephrons in rats. Am J Physiol (Renal Fluid Electrolyte Physiol 15) 1984, 246:F349–F358. 22. Carmines PK, Navar LG: Disparate effects of Ca channel blockade on afferent and efferent arteriolar responses to ANG II. Am J Physiol (Renal Fluid Electrolyte Physiol 25) 1989, 256:F1015–F1020. 23. Navar LG, Inscho EW, Imig JD, Mitchell KD: Heterogenous activation mechanisms in the renal microvasculature. Kidney Int 1998, 54(suppl 67):S17–S21.

24. Stoos BA, Garcia NH, Garvin JL: Nitric oxide inhibits sodium reabsorption in the isolated perfused cortical collecting duct. J Am Soc Nephrol 1995, 6:89–94. 25. Stoos BA, Carretero OA, Garvin JL: Endothelial-derived nitric oxide inhibits sodium transport by affecting apical membrane channels in cultured collecting duct cells.J Am Soc Nephrol 1994, 4:1855–1860. 26. DiBona GF, Kopp UC: Neural control of renal function.Physiol Rev 1997, 77:75–197. 27. Mitchell KD, Braam B: Navar LG: Hypertensinogenic mechanisms mediated by renal actions of renin-angiotensin system. Hypertension 1992, 19(suppl I):I-18–I-27. 28. Mitchell KD, Navar LG: Intrarenal actions of angiotensin II in the pathogenesis of experimental hypertension. In Hypertension: Pathophysiology, Diagnosis, and Management, edn 2. Edited by Laragh JH, Brenner BM. New York: Raven Press; 1995:1437–1450. 29. O’Neil RG: Aldosterone regulation of sodium and potassium transport in the cortical collecting duct. Sem Nephrol 1990, 10:365–374. 30. Wehling M, Eisen C, Christ M: Membrane receptors for aldosterone: a new concept of nongenomic mineralocorticoid action. NIPS 1993, 8:241–244. 31. Lifton RP: Molecular genetics of human blood pressure variation. Science 1996, 272:676–680. 32. Warnock DG: Liddle syndrome: an autosomal dominant form of human hypertension. Kidney Int 1998, 53:18–24. 33. Jamison RL, Canaan-Kuhl S, Pratt R: The natriuretic peptides and their receptors. Am J Kidney Dis 1992, 20:519–530. 34. Paul RV, Kirk KA, Navar LG: Renal autoregulation and pressure natriuresis during ANF-induced diuresis. Am J Physiol 1987, 253:F424–F431. 35. Knepper MA, Lankford SP, Terada Y: Renal tubular actions of ANF. Can J Physiol Pharmacol 1991, 69:1537–1545. 36. Jensen KT, Carstens J, Pedersen EB: Effect of BNP on renal hemodynamics, tubular function and vasoactive hormones in humans. Am J Physiol (Renal Fluid Electrolyte Physiol 43) 1998, 274:F63–F72. 37. Capdevila JH, Falck JR, Estabrook RW: Cytochrome P450 and the arachidonate cascade. FASEB J 1992, 6:731–736. 38. Smith WL: Prostanoid biosynthesis and mechanisms of action. Am J Physiol (Renal Fluid Electrolyte Physiol 32) 1992, 263:F181–F191. 39. Frazier LW, Yorio T: Eicosanoids: their function in renal epithelia ion transport. Proceedings of the Society for Experimental Biology and Medicine 1992, 201:229–243. 40. Breyer MD, Jacobson HR, Breyer RM: Functional and molecular aspects of renal prostaglandin receptors. J Am Soc Nephrol 1996, 7:8–17. 41. McGiff JC: Cytochrome P-450 metabolism of arachidonic acid. Ann Rev Pharmacol Toxicol 1991, 31:339–369. 42. Imig JD, Zou A-P, Stec DE, et al.: Formation and actions of 20hydroxyeicosatetraenoic acid in rat renal arterioles. Am J Physiol (Regulat Integrative Comp Physiol 39) 1996, 270:R217–R227. 43. Bhoola KD, Figueroa CD, Worthy K: Bioregulation of kinins: kallikreins, kininogens, and kininases. Pharmacol Rev 1992, 44:1–80. 44. El-Dahr SS: Development biology of the renal kallikrein-kinin system. Pediatr Nephrol 1994, 8:624–631. 45. Carretero OA, Scicli AG: Local hormonal factors (intracrine, autocrine, and paracrine) in hypertension. Hypertension 1991, 18 (suppl I):I-58–I-69. 46. Siragy HM, Jaffa AA, Margolius HS: Bradykinin B2 receptor modulates renal prostaglandin E2 and nitric oxide. Hypertension 1997, 29:757–762. 47. Margolius HS: Kallikreins and kinins: molecular characteristics and cellular and tissue responses. Diabetes 1996, 45:S14–S19.

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48. Siragy HM: Evidence that intrarenal bradykinin plays a role in regulation of renal function. Am J Physiol (Endocrinol Metab28) 1993, 265:E648–E654. 49. Ploth DW, Navar LG: Physiologic control of arterial blood pressure and mechanisms of hypertension. In Clinical Approaches to High Blood Pressure in the Young. Edited by Kotchen TA, Kotchen JM. Boston: John Wright, PSG; 1983:23–78. 50. Guyton AC, Manning RA, Normon RA, et al.: Current concepts and perspectives of renal volume regulation in relationship to hypertension. J Hypertens 1986, 4(suppl 4):S49–S56. 51. DeWardener HE: The primary role of the kidney and salt intake in the aetiology of essential hypertension: part II. Clin Sci 1990, 79:289–297. 52. Hamlyn JM, Blaustein MP: Sodium chloride, extracellular fluid volume, and blood pressure regulation. Am J Physiol (Renal Fluid Electrolyte Physiol 20) 1986, 251:F563–F575.

53. Coleman TG, Guyton AC: Hypertension caused by salt loading in the dog. Circ Res 1969, XXV:153–160. 54. Guyton AC, Hall JE, Coleman TG, et al.: The dominant role of the kidneys in long-term arterial pressure regulation in normal and hypertensive states. In Hypertension: Pathophysiology, Diagnosis, and Management, edn 2. Edited by Laragh JH, Brenner BM. New York: Raven Press; 1995, 78:1311–1326. 55. Julius S, Nesbitt S: Sympathetic overactivity in hypertension: a moving target. Am J Hypertens 1996, 9:113S–120S. 56. Seeliger E, Boemke W, Corea M, et al.: Mechanisms compensating Na and water retention induced by long-term reduction of renal perfusion pressure. Am J Physiol (Regulat Integrative Comp Physiol 42) 1997, 273:R646–R654.

Renal Parenchymal Disease and Hypertension Stephen C. Textor

H

ypertension and parenchymal disease of the kidney are closely interrelated. Most primary renal diseases eventually disturb sodium and volume control sufficiently to produce clinical hypertension. Both on theoretical and practical grounds, many authors argue that any sustained elevation of blood pressure depends ultimately on disturbed renal sodium excretion, ie, altered pressure natriuresis. Hence, some investigators argue that a clinical state of hypertension represents de facto evidence of disturbed (or “reset”) renal function even before changes in glomerular filtration can be measured. Many renal insults further induce inappropriate activation of vasoactive systems such as the renin-angiotensin system, adrenergic sympathetic nerve traffic, and endothelin. These mechanisms may both enhance vasoconstriction and act as mediators of additional tissue injury by altering the activity of inflammatory cytokines and promoters of interstitial fibrosis. Arterial hypertension itself accelerates many forms of renal disease and hastens the progression to advanced renal failure. Recent studies have firmly established the importance of blood pressure reduction as a means to slow the progression of many forms of renal parenchymal injury, particularly those characterized by massive proteinuria. Over the long term, damage to the heart and cardiovascular system resulting from hypertension represents the major causes of morbidity and mortality for patients with end-stage renal disease. Here are illustrated the roles of renal parenchymal disease in sustaining hypertension and of arterial pressure reduction in slowing the progression of renal injury. As discussed, parenchymal renal disease may refer to either unilateral (uncommon) or bilateral conditions.

CHAPTER

2

2.2

Hypertension and the Kidney

FORMS OF UNILATERAL RENAL PARENCHYMAL DISEASE RELATED TO HYPERTENSION Renal artery stenosis Atherosclerosis and fibromuscular lesions (Chapter X) Small vessel disease Vasculitis Atheroembolic renal infarction Thrombosis and infarction Traumatic injury Renal fracture Perirenal fibrosis (“Page” kidney) Radiation injury Arteriovenous malformation or fistulas Other diseases Renal carcinoma Enlarging renal cyst Multiple renal cysts Renin-secreting tumors (rare)

FIGURE 2-1 Forms of unilateral renal parenchymal diseases related to hypertension. Many unilateral abnormalities, such as congenital malformations, renal agenesis, reflux nephropathy, and stone disease, do not commonly produce hypertension. However, some unilateral lesions can produce blood pressure elevation. Data for each of these are based primarily on demonstrating unilateral secretion of renin and resolution with unilateral nephrectomy. It should be emphasized that unilateral renal disease does not reduce the overall glomerular filtration rate beyond that expected in patients with a solitary kidney. It follows that additional reductions in the glomerular filtration rate must reflect bilateral renal injury.

FIGURE 2-2 Angiogram and nephrogram of a persistent fractured kidney. The kidney damage shown here produced hypertension in a young woman 2 years after a motor vehicle accident. Measurement of renal vein renins confirmed unilateral production of renin from the affected side. Blood pressure control was achieved with blockade of the renin-angiotensin system using an angiotensin II receptor antagonist (losartan). Many traumatic injuries to the kidney produce temporary hypertension when a border of viable but underperfused renal tissue remains.

Prevalence of Hypertension in Chronic Renal Disease FIGURE 2-3 Prevalence of hypertension in chronic renal parenchymal disease. Most forms of renal disease are associated with hypertension. This association is most evident with glomerular diseases, including diabetic nephropathy (DN) and membranoproliferative glomerulonephritis (MPGN), in which 70% to 80% of patients are affected. Minimal change nephropathy (MCN) is a notable exception. Tubulointerstitial disorders such as analgesic nephropathy, medullary cystic diseases, and chronic reflux nephropathies are less commonly affected. APKD—adult-onset polycystic kidney disease; CIN—chronic interstitial nephritis; FSGN—focal segmental glomerulonephritis; MGN— membranous glomerulonephritis. (Data from Smith and Dunn [1].)

Prevalence of hypertension, %

80 70 60 50 40 30 20 10 0 CIN

APKD

MCN

IgA

MGN

DN

MPGN FSGN

Renal Parenchymal Disease and Hypertension

100 90

40 30 20 10 0

MDRD: Study B*

NHANES estimates

50

Mean GFR=39 mL/min/1.73 m2

%

60

Mean GFR=18.5 mL/min/1.73 m2

80 70

*n=255 patients

MDRD: Study A

FIGURE 2-4 Prevalence of hypertension requiring therapy as a function of the degree of chronic renal failure in the Modification of Diet in Renal Disease (MDRD) trial on progressive renal failure. The mean age of these patients was 52 years, with glomerular disease (25%) and polycystic disease (24%) being the most common renal diagnoses in this trial. In Study B, more than 90% of patients were treated with antihypertensive agents, including diuretics, to achieve an overall average blood pressure of 133/81 mm Hg. In general, the more severe the level of renal dysfunction, the more antihypertensive therapy is required to achieve acceptable blood pressures. Patients with glomerular filtration rates (GRFs) below 10 mL/min were hypertensive in 95% of cases. NHANES—National Health and Nutrition Examination Survey. (Data from Klahr and coworkers [2].)

US Population

Early Late

80 Prevalence of hypertension, %

2.3

70 60 50 40 30

FIGURE 2-5 Hypertension in acute renal disease. Acute renal failure is defined as transient increases in serum creatinine above 5.0 mg/dL. During the course of acute renal failure, worsening of preexisting levels or newly detected hypertension (>140/90 mm Hg) is common and almost universally observed in patients with acute glomerulonephritis (GN). Many of these patients have lower pressures as the course of acute renal injury subsides, although residual abnormalities in renal function and sediment may remain. Blood pressure returns to normal in some but not all of these patients. Overall, 39% of patients with acute renal failure develop new hypertension. IN—interstitial nephritis. (Adapted from RodriguezIturbe and coworkers [3]; with permission.)

20 10 0 Acute GN

Acute IN

FIGURE 2-6 (see Color Plate) Micrograph of an onion skin lesion from a patient with malignant hypertension.

2.4

Hypertension and the Kidney

Pathophysiology of Hypertension in Renal Disease

Increased vasoconstriction Increased adrenergic stimuli Inappropriate renin-endothelin release Increased endothelin-derived contracting factor Increased thromboxane

Decreased vasodilation Decreased prostacyclin Decreased nitric oxide

7

6

6

Intake and output of water and salt (x normal)

7

5 4

D

High intake

E s se n hyp tial erte nsio n

3 2 Normal intake

1

Low intake

0 0

50

A

B

4 3

High intake

F

ass lm na e r of ss D Lo C

E

2 Normal intake

1

Low intake

C

100 150 Arterial pressure, mm Hg

5

kid G o ld ne blat t ys

Systemic vascular resistance

Al do ste ron e-s tim ula ted

Increased contraction Increased adrenergic activation

Normal

Intake and output of water and salt (x normal)

Increased extracellular fluid volume Decreased glomerular filtration rate Impaired sodium excretion Increased renal nerve activity Ineffective natriuresis, eg, atrial natriuretic peptide resistance

A

x

Cardiac output

Normal

Blood pressure =

FIGURE 2-7 Pathophysiologic mechanisms related to hypertension in parenchymal renal disease: schematic view of candidate mechanisms. The balance between cardiac output and systemic vascular resistance determines blood pressure. Numerous studies suggest that cardiac output is normal or elevated, whereas overall extracellular fluid volume is expanded in most patients with chronic renal failure. Systemic vascular resistance is inappropriately elevated relative to cardiac output, reflecting a net shift in vascular control toward vasoconstricting mechanisms. Several mechanisms affecting vascular tone are disturbed in patients with chronic renal failure, including increased adrenergic tone and activation of the reninangiotensin system, endothelin, and vasoactive prostaglandins. An additional feature in some disorders appears to depend on reduced vasodilation, such as in impaired production of nitric oxide.

A

B H

G

0 200

FIGURE 2-8 A, The relationship between renal artery perfusion pressure and sodium excretion (which defines “pressure natriuresis”) has been the subject of extensive research. Essential hypertension is characterized by higher renal perfusion pressures required to achieve daily sodium balance. B, Distortion of this relationship routinely occurs in patients with parenchymal renal disease, illustrated here

0

B

50

100 150 Arterial pressure, mm Hg

200

as “loss of renal mass.” Similar effects are observed in conditions with disturbed hormonal effects on sodium excretion (aldosterone-stimulated kidneys) or reduced renal blood flow as a result of an arterial stenosis (“Goldblatt” kidneys). In all of these instances, higher arterial pressures are required to maintain sodium balance.

2.5

Renal Parenchymal Disease and Hypertension

35

30

122

118

Cumulative daily sodium intake

0 Cumulative urinary sodium loss

–400 Sodium, mEq

Percentage of body weight, kg

126

40

Total blood volume, mL/cm

200 Hemodialysis

130

–800

–1200 F

S

S

M

T

W TH Days

F

S

S

Sodium losses during hemodialysis or ultrafiltration Net sodium loss

M –1600

Total net loss of sodium=1741 mEq

A

Blood pressure, mm Hg

Plasma renin activity, mg/mL/h

10.0 Uremic control subjects

5.0

F

B

180 Captopril, 25 mg

140

100

FIGURE 2-9 Sodium expansion in chronic renal failure. The degree of sodium expansion in patients with chronic renal failure can be difficult to ascertain. A, Shown are data regarding body weight, plasma renin

Blood pressure, mm Hg

Angiotensin II inhibitor, µg/kg/min 5 10 50 100 10 10 Saline infusion L40

200

150

Plasma renin Cumulative sodium balance, mEq activity, ng/mL/hr

100 200

100 0 100 50 0 0

1

11 35 38 41 Hours

65 67

S

S

M T

W TH F Days

S

S M

T

activity, and blood pressure (before and after administration of an ACE inhibitor) over 11 days of vigorous fluid ultrafiltration. Sequential steps were undertaken to achieve net negative sodium and volume losses by means of restricting sodium intake (10 mEq/d) and initiating ultrafiltration to achieve several liters of negative balance with each treatment. A negative balance of nearly 1700 mEq was required before evidence of achieving dry weight was observed, specifically a reduction of blood pressure. Measured levels of plasma renin activity gradually increased during sodium removal, and blood pressure became dependent on the renin-angiotensin system, as defined by a reduction in blood pressure after administration of the angiotensin-converting enzyme inhibitor captopril. Achieving adequate reduction of both extracellular fluid volume and sodium is essential to satisfactory control of blood pressure in patients with renal failure. B, Daily and cumulative sodium balance.

FIGURE 2-10 Interaction between sodium balance and angiotensin-dependence in malignant hypertension. Studies in a patient with renal dysfunction and accelerated hypertension during blockade of the renin-angiotensin system using Sar-1-ala-8-angiotensin II demonstrate the interaction between angiotensin and sodium. Reduction of blood pressure induced by the angiotensin II antagonist was reversed during saline infusion with a positive sodium balance and reduction in circulating plasma renin activity. Administration of a loop diuretic (L40 [furosemide], 40 mg intravenously) induced net sodium losses, restimulated plasma renin activity, and restored sensitivity to the angiotensin II antagonist. Such observations further establish the reciprocal relationship between the sodium status and activation of the renin-angiotensin system [5]. (From Brunner and coworkers [5]; with permission.)

2.6

Hypertension and the Kidney

15 s

Normal person

Hemodialysis, bilateral nephrectomy

Hemodialysis, no nephrectomy

Neurogram

Electrocardiogram 3s

A

Systolic blood pressure, mm Hg

200

Sham Renal denervated

190 180 170 160 150 140 130 120 110

NS

0

B

NS

<0.01 <0.001 <0.001 <0.01 <0.05 <0.05 <0.05

NS

5 10 15 20 25 30 Deoxycorticosterone acetate–salt administration, d

35

FIGURE 2-11 A, Sympathetic neural activation in chronic renal disease. Adrenergic activity is disturbed in chronic renal failure and may participate in the development of hypertension. Microneurographic studies in patients undergoing hemodialysis demonstrate enhanced neural traffic (panel A) that relates closely to peripheral vascular tone [6]. Studies in patients in whom native kidneys are removed by nephrectomy demonstrate normal levels of neural traffic, suggesting that afferent stimuli from the kidney modulate central adrenergic outflow. B, Delayed onset hypertension in denervated rats. Panel B shows evidence from experimental studies in denervated animals subjected to deoxycorticosterone–salt hypertension. The role of the renal nerves in modifying the development of hypertension is supported by studies of renal denervation that show a delayed onset of hypertension, although no alteration in the final level of blood pressure was achieved. NS—not significant. (Panel A from Converse and coworkers [6]; with permission. Panel B from Katholi and coworkers [7]; with permission.)

2.7

Renal Parenchymal Disease and Hypertension

MAJOR CANDIDATE MECHANISMS THAT MAY ELEVATE PERIPHERAL VASCULAR RESISTANCE IN RENAL PARENCHYMAL DISEASE Increased vasoconstrictors

Impaired or relatively inadequate vasodilators

Renin-angiotensin system Endothelin Prostanoids: thromboxane Arginine vasopressin Endogenous digitalis-like substance: ouabain (?)

Nitric oxide: inadequate compensation Vasodilator prostaglandins: prostacyclin 2 Natriuretic peptides: atrial natriuretic peptide Kallikrein-kinin system

FIGURE 2-12 Major candidate mechanisms that may elevate peripheral vascular resistance in renal parenchymal disease. Some data support each of these pathways, although rarely does one mechanism predominate. Experimental studies suggest that endothelin-1 may magnify interstitial fibrosis and contribute to hypertension in some models; however, rarely is the effect major [8,9]. Most levels of vasodilators, including nitric oxide, prostacyclin, and atrial natriuretic peptide, are normal or elevated in patients with renal disease. The vasodilators appear to buffer the vasoconstrictive actions of angiotensin II, which may be increased abruptly if the vasodilator is removed, as occurs with inhibition of cyclo-oxygenase with the use of nonsteroidal antiinflammatory drugs.

Urinary endothelin, ng/d

80

Mean ±SEM *P<0.01 vs pretransplantation †P<0.01 vs normal subjects

*†

60

*†

40 † 20

Normal

Urinary endothelin excretion, pg/d

Sham-operated rats

Rats with renal mass reduction

Horizontal bars=mean values P<0.01 vs basal

160 120

*

80 40 0

0

A

200

Pretransplantation

12 mo

24 mo

FIGURE 2-13 Urinary endothelin in renal disease. A, Urinary endothelin levels in patients with cyclosporine-induced renal dysfunction and hypertension before and after liver transplantation. These patients had near-normal kidney function before liver transplantation, after which their glomerular filtration rates decreased from 85 to 55 mL/min, on average. These data underscore the observation that the kidney itself is a rich source of vasoactive materials and that renal excretion of substances such as endothelin is independent of circulating blood levels [10]. Endothelin has properties that both facilitate vasoconstriction and enhance mitogenic and fibrogenic responses, perhaps accelerating interstitial fibrosis in the kidney. Early withdrawal of cyclosporine leads to reversal of a

B

Basal

Day 45

Basal

Day 45

diminished glomerular filtration rate. With time, however, these changes lose the feature of reversibility [11]. B, Renal ablation. Urinary endothelin levels in rats exposed to reduced renal mass achieved by 5/6 nephrectomy. As in humans, plasma levels of endothelin were dissociated from urinary levels, and injected endothelin was not excreted. These results suggest that urinary levels were of renal origin. These studies further support the concept that the diminished nephron number elicits production of potent vasoactive and inflammatory materials that may accelerate irreversible parenchymal injury. (Panel A from Textor and coworkers [10]; with permission. Data in panel B from Benigni and coworkers [12].)

2.8

Hypertension and the Kidney

PHARMACOLOGIC AGENTS THAT COMMONLY AGGRAVATE OR INDUCE HYPERTENSION IN PARENCHYMAL RENAL DISEASE

Renal parenchymal disease

Decreased afferent resistance Decreased efferent resistance

Increased angiotensin Increased norepinephrine Increased endothelin Systemic hypertension

Impaired autoregulation

Increased glomerular pressure

Increased cytokine Increased growth factors Cellular proliferation

Over-the-counter sympathomimetic agents, eg, phenylpropanolamine Supplements containing ephedrine Oral contraceptives (less common with low-dose forms) Amphetamines and stimulants, eg, methylphenidate hydrochloride and cocaine

FIGURE 2-15 Many pharmacologic agents affect blood pressure levels or the effectiveness of antihypertensive therapy. Shown here are several agents that commonly lead to worsening hypertension and are likely to be administered to patients with renal disease.

160

120

150

90

Control 10 µg L–NAME 50 µg L–NAME

*

*

140

60

*

*

130

30

120

1 min

280

L-Arginine

100 mg kg-1

300 mg kg-1

FIGURE 2-16 Increase in arterial pressure induced by inhibition of nitric oxide. A, Intra-arterial pressure in rabbits during N-nitro-L-arginine methyl ester (L-NAME) infusion. B, Decrease in renal plasma flow and glomerular filtration rate in the blood pressures of rats during nitric oxide inhibition. (Continued on next page)

Glomerular filtration rate, mL/min

L-NAME

Renal plasma flow, mL/min

110

240 200

*

Mean arterial pressure, mL/min

Blood pressure, mm Hg

FIGURE 2-14 Mechanisms of glomerular injury in hypertension and progressive renal failure. This schematic diagram summarizes the general mechanisms by which disturbances linked to elevated arterial pressure in patients with parenchymal renal disease may lead to further tissue injury. Hemodynamic changes lead to increased glomerular perfusion pressures, whereas local activation of growth factors, angiotensin, and probably several other factors both worsen peripheral resistance and increase tissue fibrotic mechanisms. (From Smith and Dunn [1].)

Heart rate, bpm

Corticosteroids Cyclosporine Erythropoietin Nonsteroidal anti-inflammatory drugs

Increased glomerular volume

Increased glomerular pressure

A

Other agents

B

Results=means±standard error *P<0.05 compared with controls

4.0 *

3.0

*

2.0

*

* *

*

*

120'

180'

*

1.0 1.2

* *

1.0

*

0.8 Control

60'

Renal Parenchymal Disease and Hypertension

Control 10 µg/kg/min L– NAME 50 µg/kg/min L– NAME

Urinary sodium excretion, µEq/min

21 19

*

15 * *

11 9 140 Urinary flow rate, mL/min

FIGURE 2-16 (Continued) C, Urine flow rate and urinary sodium excretion over time. Inhibition of nitric oxide synthesis from L-arginine by a competitive substrate such as L-NAME produces dose-dependent and widespread vasoconstriction, leading to an increase in blood pressure [13]. Within specific regional beds such as the kidney, inhibition of nitric oxide produces a decrease in renal plasma flow, diminished glomerular filtration, and sodium retention [14]. The magnitude of these changes in normal animals and humans suggests that tonic nitric oxide production is a major endothelial buffering mechanism preserving vascular tone. The degree to which renal parenchymal disease alters the production of nitric oxide is not known precisely. In some situations, such as nephrotoxicity associated with cyclosporine administration, endothelial production of nitric oxide appears to be substantially impaired [15]. (Panel A from Rees and coworkers [13]; with permission. Panel B from Lahera and coworkers [14]; with permission.)

17

13

Results=means±standard error *P<0.05 compared with controls

2.9

*

120 100 80 * 60

C

Control

60'

120'

180'

Clinical Features of Hypertension in Renal Disease A. HYPERTENSION IN PARENCHYMAL RENAL DISEASE: CLINICAL MANIFESTATIONS OF HYPERTENSIVE DISEASE Central nervous system

Progressive renal injury

Myocardial infarction Congestive heart failure Atherosclerotic vascular disease Claudication and limb ischemia Aneurysm

Stroke Intracerebral hemorrhage

End-stage renal disease Increased proteinuria

Percentage of total

Cardiovascular disease

100 90

Cardiac Vascular Infection Other

80 70 60 50 40 30 20 10 0

B FIGURE 2-17 A and B, Major target organ manifestations of hypertension producing cardiovascular morbidity and mortality in patients with renal disease. More than half of deaths are related to cardiovascular disease in both patients on dialysis and transplantation recipients. These observations underscore the major risk for cardiovascular morbidity and mortality associated with hypertension in the population with chronic renal failure. (From Whitworth [16]; with permission.)

Transplantation Dialysis

2.10

Hypertension and the Kidney

Left ventricular hypertrophy

40

Congestive heart failure

35 Percentage of total

Blood pressure

Death: Congestive heart failure Overall mortality

Blood pressure

A

30 25 20 15 10 5

FIGURE 2-18 Based on average blood pressure values, a strong direct relationship was found between arterial pressure and left ventricular hypertrophy, left ventricular chamber dilation (by echocardiography), and systolic dysfunction in patients undergoing dialysis for end-stage renal disease. After prolonged follow-up, blood pressures fell with the onset of congestive heart failure and manifest coronary artery disease. With the onset of cardiac failure, there appeared to be an inverse relationship between arterial pressure and mortality. From the outset, the strongest predictor of congestive heart failure was elevated blood pressure. (Adapted from Foley and coworkers [17].)

0 Left ventricular Systolic Left ventricular chamber dilation dysfunction hypertrophy

B

250 Blood pressure, mm Hg

Awake: 156/101 mm Hg

Nocturnal: 167/100 mm Hg

Blood pressure values Heart rate

200

150 140 100 90 50 MMMM

Rx F d

MMMM

Fd ZZZZZ

Rx

RxZZZ

ZZZZZZZZZZZZZZZZZZ

MMMM

0 0.0

10a

12n

2p

4p

6p

8p 10p 12m Real time data

2a

4a

6a

8a

FIGURE 2-19 Around-the-clock ambulatory blood pressure monitoring in a patient with renal disease. Loss of diurnal blood pressure patterns have been implicated in increased rates of target organ injury in patients with hypertension. In normal persons with essential hypertension, nocturnal pressures decreased by at least 10% and were associated with a decrease in heart rate. Several conditions have been associated with a loss of the nocturnal decrease in pressure, particularly chronic steroid administration and chronic renal failure. Such a loss in normal circadian rhythm, in particular loss of the nocturnal decrease in blood pressure is more commonly associated with left ventricular hypertrophy and lacunar strokes (manifested as enhanced T-2 signals in magnetic resonance images) and increased rates of microalbuminuria. Data from a single subject with end-stage renal disease studied with are depicted here.

2.11

1/Creatinine

Renal Parenchymal Disease and Hypertension

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 May 1979

FIGURE 2-20 (see Color Plate) Hypertension accelerates the rate of progressive renal failure in patients with parenchymal renal disease. A, Photomicrograph of malignant phase hypertension. Regardless of the cause of renal disease, untreated hypertension leads to more rapid loss of remaining nephrons and decline in glomerular filtration rates. A striking example of pressure-related injury may be observed in patients with malignant phase hypertension. This image is an open biopsy specimen obtained from a patient with papilledema, an expanding aortic aneurysm, and

Aug 1987

May 1990 Date

Jan 1993

Oct 1995

Jul 1998

blood pressure level at approximately 240/130 mm Hg. The biopsy specimen shows the following features of malignant nephrosclerosis: these patients develop vascular and glomerular injury, which can progress to irreversible renal failure. Before the introduction of antihypertensive drug therapy, patients with malignant phase hypertension routinely proceeded to uremia. Effective antihypertensive therapy can slow or reverse this trend in some but not all patients. B, Progressive renal failure in malignant hypertension over 8 years.

100 n=11,912 men P<0.001

White=300,645 Black=20,222

SBP>180

0.10 0.08 0.06 165<SBP≤180

0.04 0.02 SBP≤165

Incidence per 100,000 person-years, %

0.12

Proportion with ESRD

Nov 1984

B

A

0.00

80

83.1

N=332,544 men

60

37.21

40

32.37 27.34

20

26.18

15.83 5.43

14.22 5.41

9.1

0 0

A

Feb 1982

1

2

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Years from beginning therapy to ESRD

FIGURE 2-21 Blood pressure levels and rates of end-stage renal disease (ESRD). A, Line graph showing Kaplan-Meier estimates of ESRD rates; 15-year follow-up. B, Age-adjusted 16-year incidence of all-cause ESRD in men in the Multiple Risk Factor Intervention Trial (MRFIT). Largescale epidemiologic studies indicate a progressive increase in the risk for developing ESRD as a function of systolic blood pressure levels. Follow-up of nearly 12,000 male veterans in the United States established that systolic blood pressure above 165 mm Hg at the initial visit was predictive of progressively higher risk of ESRD over a 15-year

<117

B

117–123 124–130 131–140 Systolic blood pressure, mm Hg

>140

follow-up period [18]. Similarly, follow-up studies after 16 years of more than 300,000 men in MRFIT demonstrated a progressive increase in the risk for ESRD, most pronounced in blacks [19]. These data suggest that blood pressure levels predict future renal disease. However, it remains uncertain whether benign essential hypertension itself induces a primary renal lesion (hypertensive renal disease nephrosclerosis) or acts as a catalyst in patients with other primary renal disease, otherwise not detected at initial screening. SBP—systolic blood pressure. (Panel A from Perry and coworkers [18]; with permission.)

2.12

Hypertension and the Kidney

30 Chronic glomerulonephritis: Rates of progression over time decrease after reduction of BP from 149/102 mm Hg to treated level, 136/90 mm Hg.

20

mL/mmol-1

4

Cr-1/s,

0

0

–3

–3

–6

–6

40 Decrease in glomerular filtration rate, mL/min/y

Ccr, mL/min

50

–9

–12

3

–15

2

–18

–400

–200

Days

0

+200

–12 –15

Study A: mean GFR: 39 mL/min/1.73 m2 N=585: range: 25–55 mL/min

86 1

–9

Protein excretion, g/d 0–0.25 1.0–3.0 0.25–1 ≥3.0

92 98 Mean follow-up MAP, mm Hg

–18 107

+400

FIGURE 2-22 Rates of progression in glomeruloneophritis. The decrease in glomerular filtration rate is illustrated. The rates of decline decreased considerably with administration of antihypertensive drug therapy. Among other mechanisms, the decrease in arterial pressure lowers transcapillary filtration pressures at the level of the glomerulus [20]. This effect is correlated with a reduction in proteinuria and slower development of both glomerulosclerosis and interstitial fibrosis. A distinctive feature of many glomerular diseases is the massive proteinuria and nephron loss associated with high single-nephron glomerular filtration, partially attributable to afferent arteriolar vasodilation. The appearance of worsening proteinuria (>3 g/d) is related to progressive renal injury and development of renal failure. Reduction of arterial pressure can decrease urinary protein excretion and slow the progression of renal injury. Ccr—creatinine clearance rate; Cr-1/s—reciprocal creatinine, expressed as 1/creatinine. (From Bergstrom and coworkers [20]; with permission.)

FIGURE 2-23 Blood pressure, proteinuria, and the rate of renal disease progression: results from the Modification of Diet in Renal Disease (MDRD) trial. Shown are rates of decrease of glomerular filtration rate (GFR) for patients enrolled in the MDRD trial, depending on level of achieved treated blood pressure during the trial [21]. A component of this trial included strict versus conventional blood pressure control. The term strict was defined as target mean arterial pressure (MAP) of under 92 mm Hg. The term conventional was defined as MAP of under 107 mm Hg. The rate of decline in GFR increased at higher levels of achieved MAP in patients with significant proteinuria (>3.0 g/d). No such relationship was evident over the duration of this trial (mean, 2.2 years) for patients with less severe proteinuria. These data emphasize the importance of blood pressure in determining disease progression in patients with proteinuric nondiabetic renal disease. No distinction was made in this study regarding the relative benefits of specific antihypertensive agents. (From Peterson and coworkers [21]; with permission.)

Slope of 1/creatinine vs time, dL/mg mo

Effects of Antihypertensive Therapy on Renal Disease Progression

–0.006 –0.008 –0.010 –0.012 0 85–90 70–85 90–96 96–113 Range of diastolic blood pressure (mm Hg) for each quartile of the population

FIGURE 2-24 Blood pressure and rate of progressive renal failure. Rates of disease progression (defined as the slope of 1/creatinine) were determined in 86 patients who reached end-stage renal disease and dialytic therapy. The rates of progression were defined between mean creatinine levels of 3.8 mg/dL (start) and 11.4 mg/dL (end) over a mean duration of 33 months [22]. Brazy and coworkers [22] demonstrated that the slope of disease progression appeared to be related to the range of achieved diastolic blood pressure during this interval. Hence, these authors argue that more intensive antihypertensive therapy may delay the need for replacement therapy in patients with end-stage renal disease. As noted in the Modification of Diet in Renal Disease trial, such benefits are most apparent in patients with proteinuria over a shorter follow-up period. (From Brazy and coworkers [22]; with permission.)

Renal Parenchymal Disease and Hypertension

CLASSES OF ANTIHYPERTENSIVE AGENTS USED IN TREATMENT OF CHRONIC RENAL DISEASE Diuretics: Thiazide class Loop diuretics Potassium-sparing agents Adrenergic inhibitors Peripheral agents, eg, guanethidine Central -agonists, eg, clonidine, methyldopa, and guanfacine -Blocking agents, eg, doxazosin -Blocking agents Combined - blocking agents, eg, labetalol Vasodilators Hydralazine Minoxidil Classes of calcium-channel blocking agents Verapamil Diltiazem Dihydropyridine Angiotensin-converting enzyme inhibitors Angiotensin receptor blockers

50 45 40 35

Rate of change in GFR, mL/min/1.73 m2/y

Conventional Strict n=87 patients Bars=95% confidence intervals for GFR estimates

55 GFR, mL/min/1.73 m2/y

FIGURE 2-25 The current classification of agents applied for chronic treatment of hypertension as summarized in the report by the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure [23]. Attention must be given to drug accumulation and limitations of individual drug efficacy as glomerular filtration rates decrease in chronic renal disease. Potassium levels may increase during administration of potassium-sparing agents and medications that inhibit the renin-angiotensin system, especially in patients with impaired renal function [24].

4

60

30

3

Mean ±SEM

2

1

0 –1 –2

25

–3 –6

A

2.13

0

6

12

18

24 30 Time, mo

36

42

48

FIGURE 2-26 Strict blood pressure control and progression of hypertensive nephrosclerosis. Whether vigorous blood pressure reduction reduces progression of early parenchymal renal disease in blacks with nephrosclerosis is not yet certain. A and B, A randomized prospective trial comparing strict (panel A) blood pressure control (defined as diastolic blood pressure [DBP] <80 mm Hg) with conventional (panel B) levels of diastolic control between 85 and 95 mm Hg for more than 3 years could not identify a reduction in rates of disease progression [25]. Of patients, 68 of 87 were black. Rates of progression in

B

Strict Conventional Blood pressure control group

these patients were low. It should be emphasized that entry criteria excluded patients with diabetes and massive proteinuria. Initial studies from the African American Study of Kidney Disease trial confirm that biopsy findings in most patients with clinical features of hypertension were considered consistent with primary hypertensive disease [26]. Whether lower than normal levels of blood pressure in these patients will prevent progression to end-stage renal disease over longer time periods remains to be determined. GFR—glomerular filtration rate. (From Toto and coworkers [25]; with permission.)

2.14

Hypertension and the Kidney 100 90

Patients who died or needed dialysis or transplantation, %

80 70 60 50 P=0.002

40 30 20 10

P=0.14

0 0.5

1.0

1.5

Creatinine ≥1.5 mg/dL Placebo 49 48 Captopril 53 53

0.0

2.0 2.5 Years of follow-up

44 52

40 51

33 48

Creatinine <1.5 mg/dL Placebo 153 150 Captopril 154 154

148 152

146 150

138 147

3.0

3.5

4.0

23 36

16 25

7 17

1 8

98 104

84 78

52 47

25 29

2.6

FIGURE 2-27 Angiotensin-converting enzyme (ACE) inhibitors and chronic renal disease. Progression of type I diabetic nephropathy to renal failure was reduced in the ACE inhibitor arm of a trial comparing conventional antihypertensive therapy with a regimen containing the ACE inhibitor captopril. All patients in this trial had significant proteinuria (>500 mg/d). The most striking effect of the ACE inhibitor regimen was seen in patients with higher serum creatinine levels (>1.5 mg/dL) as shown in the top two lines. It should be noted that calcium channel blocking drugs were excluded from this trial and the ACE inhibitor arm had somewhat lower arterial pressures during treatment. These data offer support to the concept that ACE inhibition lowers intraglomerular pressures, reduces proteinuria, and delays the progression of diabetic nephropathy by more mechanisms than can be explained by pressure reduction alone. (Data from Lewis and coworkers [27].)

2.6 Benazepril: n=583 patients; creatinine=1.5–4.0 Placebo

Benazepril: n=583 patients; creatinine=1.5–4.0 Placebo

239

2.4

117

2.4 137

262

A

2.2

2.2

2.0

2.0

0

1

Years

2

3

FIGURE 2-28 Angiotensin-converting enzyme (ACE) inhibition in nondiabetic renal disease. A and B, Shown here are serum creatinine levels from the 12-month (panel A) and 36-month (panel B) cohorts followed in the benazepril trial. In this trial, 583 patients were randomized to therapy with or without benazepril [28]. Slight reductions in the rates of increase in creatinine and of stop points in the ACE inhibitor group occurred; however, these reductions were modest. Whereas these

B

0

1

Years

2

3

data support a role for ACE inhibition, the results are considerably less convincing than are those for diabetic nephropathy. These results argue that some groups may not experience major benefit from ACE inhibition over the short term. Preliminary reports from recent studies limited to patients with proteinuria suggest that rates of progression were substantially reduced by treatment with ramipril [29]. (From Maschio and coworkers [28]; with permission.)

Renal Parenchymal Disease and Hypertension

CONCLUSIONS AND RECOMMENDATIONS OF THE SIXTH REPORT OF THE JOINT NATIONAL COMMITTEE ON PREVENTION, DETECTION, EVALUATION AND TREATMENT OF HIGH BLOOD PRESSURE, 1997 1. Hypertension may result from renal disease that reduces functioning nephrons. 2. Evidence shows a clear relationship between high blood pressure and end-stage renal disease. 3. Blood pressure should be controlled to ≤130/85 mm Hg (<125/75 mm Hg) in patients with proteinuria in excess of 1 g/24 h. 4. Angiotensin-converting enzyme inhibitors work well to lower blood pressure and slow progression of renal failure.

2.15

FIGURE 2-29 Conclusions and Recommendations of the Sixth Report of the Joint National Committee (JNC) on Prevention, Detection, Evaluation and Treatment of High Blood, 1997 [23]. The JNC Committee has emphasized the importance of vigorous blood pressure control with any agents needed, rather than specific classes of medication. Angiotensin-converting enzyme inhibitors in proteinuric disease are the exception.

References 1. Smith MC, Dunn MJ: Hypertension in renal parenchymal disease. In Hypertension: Pathophysiology, Diagnosis and Management. Edited by Laragh JH, Brenner BM. New York: Raven Press; 1995:2081–2102. 2. Klahr S, Levey AS, Beck GJ, et al.: The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. N Engl J Med 1994, 330:877–884. 3 Rodriguez-Iturbe B, Baggio B, Colina-Chouriao J, et al.: Studies on the renin-aldosterone system in the acute nephritic syndrome. Kidnet Int 1981, 445–453 4. Curtiss JJ, Luke RG, Dustan HP, et al.: Remission of essential hypertension after renal transplantation. N Engl J Med 1983, 309:1009–1015. 5. Brunner HR, Gavras H, Laragh JH: Specific inhibition of the reninangiotensin system: a key to understanding blood pressure regulation. Prog Cardiovasc Dis 1974; 17:87–98. 6. Converse RL, Jacobsen TN, Toto RD, et al.: Sympathetic overactivity in patients with chronic renal failure. N Engl J Med1992, 327:1912–1918. 7. Katholi RE, Nafilan AJ, Oparil S: Importance of renal sympathetic tone in the development of DOCA-salt hypertension in the rat. Hypertension 1980, 2:266–273. 8. Benigni A, Zoja C, Cornay D, et al.: A specific endothelin subtype A receptor antagonist protects against injury in renal disease progression. Kidney Int 1993, 44:440–444. 9. Levin ER: Mechanisms of disease: endothelins. N Engl J Med 1995, 333:356–363. 10. Textor SC, Burnett JC, Romero JC, et al.: Urinary endothelin and renal vasoconstriction with cyclosporine or FK506 after liver transplantation. Kidney Int 1995, 47:1426–1433. 11. Sandborn WJ, Hay JE, Porayko MK, et al.: Cyclosporine withdrawal for nephrotoxicity in liver transplant recipients does not result in sustained improvement in kidney function and causes cellular and ductopenic rejection. Hepatology 1994, 19:925–932. 12. Benigni A, Perico N, Gaspari F, et al.: Increased renal endothelin production in rats with renal mass reduction. Am J Physiol 1991, 260:F331–F339. 13. Rees DD, Palmer RMJ, Moncada S: Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci U S A 1989, 86:3375–3378. 14. Lahera V, Salom MG, Miranda-Guardiola F, et al.: Effects of N-nitroL-arginine methyl ester on renal function and blood pressure. Am J Physiol 1991, 261:F1033–F1037. 15. Gaston RS, Schlessinger SD, Sanders PW, et al.: Cyclosporine inhibits the renal response to L-arginine in human kidney transplant recipients. J Am Soc Nephrol 1995, 5:1426–1433.

16. Whitworth JA: Renal parenchymal disease and hypertension. In Clinical Hypertension. Edited by Robertson JIS. Amsterdam: Elsevier, 1992:326–350. 17. Foley RN, Parfrey PS, Harnett JD, et al.: Impact of hypertension on cardiomyopathy, morbidity and mortality in end-stage renal disease. Kidney Int 1996, 49:1379–1385. 18. Perry HM, Miller JP, Fornoff JR, et al.: Early predictors of 15-year end-stage renal disease in hypertensive patients. Hypertension 1995, 25(part 1):587–594. 19. Klag MJ, Whelton PK, Randall BL, et al.: End-stage renal disease in African-American and White men. JAMA 1997, 277:1293–1298. 20. Bergstrom J, Alvestrand A, Bucht H, Guttierrez A: Progression of chronic renal failure in man is retarded with more frequent clinical follow-ups and better blood pressure control. Clin Nephrol 1986, 25:1–6. 21. Peterson JC, Adler S, Burkart JM, et al.: Blood pressure control, proteinuria and the progression of renal disease. Ann Intern Med 1995; 123:754–762. 22. Brazy PC, Stead WW, Fitzwilliam JF: Progression of renal insufficiency: role of blood pressure. Kidney Int 1989, 35:670–674. 23. JNC Committee: Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Bethesda, MD: National Institutes of Health Publication; 1997. 24. Textor SC: Renal failure related to ACE inhibitors. Semin Nephrol 1997, 17:67–76. 25. Toto RD, Mitchell HC, Smith RD, et al.: “Strict” blood pressure control and progression of renal disease in hypertensive nephrosclerosis. Kidney Int 1995, 48:851–859. 26. Fogo A, Breyer JA, Smith MC, et al.: Accuracy of the diagnosis of hypertensive nephrosclerosis in African-Americans: a report from the African American Study of Kidney Disease (ASSK) trial. Kidney Int 1997; 51:244–252. 27. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensinconverting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993, 329:1456–1462. 28. Maschio G, Alberti D, Janin G, et al.: Effect of the angiotensin-converting enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 1996, 334:939–945. 29. Ruggenenti P, Perna A, Mosconi M, et al.: The angiotensin converting enzyme inhibitor ramipril slows the rate of GFR decline and the progression to end-stage renal failure in proteinuric, non-diabetic chronic renal diseases [abstract]. J Am Soc Nephrol 1997, 8:147A. 30. Giatras I, Lau J, Levey AS: Effect of angiotensin-converting enzyme inhibitors on the progression of non-diabetic renal disease: a metaanalysis of randomized trials. Ann Intern Med 1997, 127:345.

Renovascular Hypertension and Ischemic Nephropathy Marc A. Pohl

T

he major issues in approaching patients with renal artery stenosis relate to the role of renal artery stenosis in the management of hypertension, ie, “renovascular hypertension,” and to the potential for vascular compromise of renal function, ie, “ischemic nephropathy.” Ever since the original Goldblatt experiment in 1934, wherein experimental hypertension was produced by renal artery clamping, countless investigators and clinicians have been intrigued by the relationship between renal artery stenosis and hypertension. Much discussion has focused on the pathophysiology of renovascular hypertension, the renin angiotensin system, diagnostic tests to detect presumed renovascular hypertension, and the relative merits of surgical renal revascularization (SR), percutaneous transluminal renal angioplasty (PTRA), and drug therapy in managing patients with renal artery stenosis and hypertension. Hemodynamically significant renal artery stenosis, when bilateral or affecting the artery to a solitary functioning kidney, can also lead to a reduction in kidney function (ischemic nephropathy). This untoward observation may be reversed by interventive maneuvers, eg, surgical renal revascularization, PTRA, or renal artery stenting. The syndrome of “ischemic renal disease” or “ischemic nephropathy” now looms as an important clinical condition and has attracted the fascination of nephrologists, vascular surgeons, and interventional cardiologists and radiologists. The detection of renal artery stenosis in a patient with hypertension usually evokes the assumption that the hypertension is due to the renal artery stenosis. However, renal artery stenosis is not synonymous with “renovascular hypertension.” On the basis of autopsy studies and clinical angiographic correlations, high-grade atherosclerotic renal artery stenosis (ASO-RAS) in patients with mild blood pressure elevation or in patients with normal arterial pressure is well recognized. The vast majority of patients with ASO-RAS who have hypertension have essential hypertension, not renovascular hypertension. These hypertensive patients with ASO-RAS are rarely cured of their hypertension by interventive procedures that either bypass or

CHAPTER

3

3.2

Hypertension and the Kidney

dilate the stenotic lesion. Thus, it is critical to distinguish between the anatomic presence of renal artery stenosis, in which a stenotic lesion is present but not necessarily causing hypertension, and the syndrome of renovascular hypertension in which significant arterial stenosis is present and sufficient to produce renal tissue ischemia and initiate a pathophysiologic sequence of events leading to elevated arterial pressure. In the final analysis, proof that a patient has the entity of “renovascular hypertension” rests with the demonstration that the hypertension, presumed to be “renovascular,” can be eliminated or substantially ameliorated following removal of the stenosis by surgical or endovascular intervention, or by removing the kidney distal to the stenosis. Although the great majority of patients diagnosed as having renovascular hypertension have this syndrome because of main renal artery stenosis, hypertension following unilateral renal trauma,

CLASSIFICATION OF RENAL ARTERY DISEASE Disease

Incidence, %*

Atherosclerosis Fibrous dysplasia Medial (30%) Perimedial (5%) Intimal (5%)

chronic subcapsular hematoma, and unilateral ureteral obstruction may also be associated with hypertension that is relieved when the affected kidney is removed. These clinical analogues of the experimental Page kidney reflect the syndrome of renovascular hypertension (RVHT), but without main renal artery stenosis. Takayasu’s arteritis and atheroembolic renal disease are additional examples of RVHT without main renal artery stenosis. Accordingly, the anatomic presence of renal artery stenosis should not be equated with renovascular hypertension and the syndrome of RVHT need not reflect renal artery stenosis. This chapter reviews the types of renal arterial disease associated with RVHT, the pathophysiology of RVHT, clinical features and diagnostic approaches to renal artery stenosis and RVHT, evolving concepts regarding ischemic nephropathy, and management considerations in patients with renal artery stenosis, presumed RVHT, and ischemic renal disease.

FIGURE 3-1 Classification of renal artery disease. Two main types of renal arterial lesions form the anatomic basis for renal artery stenosis. Atherosclerotic renal artery disease (ASO-RAD) is the most common cause of renal artery disease, accounting for 60% to 80% of all renal artery lesions. The fibrous dysplasias are the other major category of renal artery disease, and as a group account for 20% to 40% of renal artery lesions. Arterial aneurysm and arteriovenous malformation are rarer types of renal artery disease.

60–80 20–40

*Percent of renal artery lesions.

A

B

FIGURE 3-2 Angiographic examples of atherosclerotic renal artery disease (ASO-RAD). A, Aortogram demonstrating severe nonostial atherosclerotic renal artery disease of the left main renal artery. B, Intra-arterial digital subtraction aortogram showing severe proximal right renal artery stenosis (ostial lesion) and moderately severe narrowing of the left renal artery due to atherosclerosis.

Atherosclerotic renal artery disease is typically associated with atherosclerotic changes of the abdominal aorta (see panel B). ASORAD predominantly affects men and women in the fifth to seventh decades of life but is uncommon in women under the age of 50. Anatomically, the majority of these patients demonstrate atherosclerotic plaques located in the proximal third of the main renal artery. In the majority of cases (70% to 80%), the obstructing lesion is an aortic plaque invading the renal artery ostium (ostial lesion). Twenty to 30 percent of patients with ASORAD demonstrate atherosclerotic narrowing 1 to 3 cm beyond the takeoff of the renal artery (nonostial lesion). Nonostial lesions are technically more amenable to percutaneous transluminal renal angioplasty (PTRA) than ostial ASO-RAD lesions, which are technically difficult to dilate and have a high restenosis rate after PTRA. Renal artery stenting has gained wide acceptance for ostial lesions. Endovascular intervention for nonostial lesions includes both PTRA and stents. Surgical renal revascularization is used for both ostial and nonostial ASO-RAD lesions. (From Pohl [1]; with permission.)

3.3

Renovascular Hypertension and Ischemic Nephropathy

NATURAL HISTORY OF ATHEROSCLEROTIC RENOVASCULAR DISEASE: REPORTS OF SERIAL ANGIOGRAMS First author

Year

Months of follow-up, n/n

Patients, n

Progression, n (%)

Total occlusion

Wollenweber Meaney Dean Schreiber Tollefson

1968 1968 1981 1984 1991

12/88 6/120 6/102 12/60 15/180

30 39 35 85 48

21 (70) 14 (36) 10 (29) 37 (44) 34 (71)

NA 3 (8) 4 (11) 14 (I6) 7 (15)

237

116 (49)

28 (14)

Total

FIGURE 3-3 Natural history of atherosclerotic renovascular disease. Retrospective studies, based on serial renal angiograms, suggest that atherosclerotic renal artery disease (ASO-RAD) is a progressive disorder. This figure summarizes retrospective series on the natural history of ASO-RAD. A large series from the Cleveland Clinic in nonoperated patients indicated progression of renal artery obstruction in 44%; progression to total occlusion occurred in 16% of these patients. Reduction in ipsilateral renal size is associated with angiographic evidence of progression in contrast to patients with nonprogressive (angiographically) ASO-RAD. Zierler and coworkers have prospectively studied the progression of ASO-RAD by sequential duplex ultrasonography. The

cumulative incidence of progession of lesions with less than 60% reduction in lumen diameter progressing to more than 60% reduction in lumen diameter was 30% at 1 year, 44% at 2 years, and 48% at 3 years. Progression to total occlusion occurred only in arteries with a baseline reduction in lumen diameter of more than 60%. The cumulative incidence of progression to total occlusion in patients with baseline stenosis of 60% or greater was 4% at 1 year, 4% at 2 years, and 7% at 3 years. Blood pressure control and serum creatinine were not predictors of progression. The risk of renal parenchymal atrophy over time in kidneys with ASO-RAD has also been described. (Table adapted from Rimmer and Gennari [2]; with permission.)

FREQUENCY AND NATURAL HISTORY OF FIBROUS RENAL ARTERY DISEASES Lesion Intimal fibroplasia and medial hyperplasia Perimedial fibroplasia Medial fibroplasia

Frequency, %*

Risk of progression

Threat to renal function

10

++++

++++

10–25 70–85

++++ ++

++++ —

*Frequency relates to frequency of only the fibrous renal artery diseases.

FIGURE 3-4 Frequency and natural history of fibrous renal artery diseases. There are four types of fibrous renal artery disease (fibrous dysplasias): medial fibroplasia, perimedial fibroplasia, intimal fibroplasia, and medial hyperplasia. Although the true incidence of these specific types of fibrous renal artery disease is not clearly defined, medial fibroplasia is the most common, estimated to account for 70% to 85% of fibrous renal artery disease. The majority of patients with medial fibroplasia are almost exclusively women who are diagnosed between the ages of 25 to 50 years. Although medial fibroplasia progresses to higher degrees of stenosis in about one third of cases, complete arterial occlusion or ischemic atrophy of the involved kidney is rare. Intervention on this type of fibrosis dysplasia is for relief of hypertension because the threat of progressive medial fibroplasia to renal function is negligible. Perimedial fibroplasia is

the second most common type of fibrous dysplasia, accounting for 10% to 25% of fibrous renal artery lesions. This lesion also occurs predominantly in women, is diagnosed between the ages of 15 and 30, is frequently bilateral and highly stenotic, and may progress to total arterial occlusion. These patients should undergo surgical renal revascularization to relieve hypertension and to avoid loss of renal function. Intimal fibroplasia and medial hyperplasia (usually indistinguishable angiographically) are not common, accounting for only 5% to 10% of fibrous renal artery lesions. Intimal fibroplasia occurs primarily in children and adolescents. Medial hyperplasia is found predominantly in adolescents; angiographically it appears as a smooth linear stenosis that may extend into the primary renal artery branches. Medial hyperplasia, like intimal fibroplasia, is a progressive lesion and is associated with ipsilateral renal atrophy. Surgical renal revascularization is recommended for patients with either intimal fibroplasia or medial hyperplasia to avoid lifelong antihypertensive therapy and to avert renal atrophy.

3.4

Hypertension and the Kidney

B

A

A

B

FIGURE 3-5 Arteriogram and schematic diagrams of medial fibroplasia. A, Right renal arteriogram demonstrating weblike stenosis with interposed segments of dilatation (large beads) typical of medial fibroplasia (“string of beads” lesion). B, Schematic diagram of medial fibroplasia. The lesion of medial fibroplasia characteristically affects the distal half of the main renal artery, frequently extending into the branches, is often bilateral, and angiographically gives the appearance of multiple aneurysms (“string of beads”). Histologically, this beaded lesion is characterized by areas of proliferation of fibroblasts of the media surrounded by fibrous connective tissue (stenosis) alternating with areas of medial thinning (aneurysms). Inspection of the renal angiogram in panel A indicates that the width of areas of aneurysmal dilatation is wider than the nonaffected proximal renal artery, an angiographic clue to medial fibroplasia. (Panel A from Pohl [1]; with permission.) FIGURE 3-6 Arteriogram and schematic diagram of perimedial fibroplasia. A, Selective right renal arteriogram shows a tight stenosis in the mid portion of the renal artery with a small string of beads appearance, typical of perimedial fibroplasia. B, Schematic diagram of perimedial fibroplasia. Perimedial fibroplasia, accounting for 10% to 25% of the fibrous renal artery diseases, is also observed almost exclusively in women. The stenotic lesion occurs in the mid and distal main renal artery or branches and may be bilateral. Angiographically, serial stenoses are observed with small beads, which are smaller in diameter than the unaffected portion of the renal artery. This highly stenotic lesion may progress to total occlusion; collateral blood vessels and renal atrophy on the involved side are frequently observed. Pathologically, the outer layer of the media varies in thickness and is densely fibrotic, producing a severe reduction in lumen diameter (panel B). Renal artery dissection and/or thrombosis are common. (Panel A from Pohl [1]; with permission.)

Renovascular Hypertension and Ischemic Nephropathy

B

A

ATHEROSCLEROTIC RENAL ARTERY DISEASE VERSUS MEDIAL FIBROPLASIA Atherosclerotic

Medial fibroplasia

Men and women Age >50–55 y

Women Age 20–40 y

Total occlusion common Ischemic atrophy common

Total occlusion rare Ischemic atrophy rare

Surgical intervention or angioplasty: Mediocre cure rates of the hypertension Less amenable to PTRA

Surgical intervention or angioplasty: Good cure rates of the hypertension More amenable to PTRA

FIGURE 3-8 A comparison of atherosclerotic renal artery disease and medial fibroplasia. The most common types of renal artery disease (atherosclerotic renal artery disease [ASO-RAD] and medial fibroplasia) are compared here. In general, ASO-RAD is observed in men and women older than 50 to 55 years of age, whereas medial fibroplasia is observed primarily in younger white women. Total occlusion of the renal artery and, hence, atrophy of the

3.5

FIGURE 3-7 Arteriogram and schematic diagram of intimal fibroplasia. A, Selective right renal arteriogram demonstrating a localized, highly stenotic, smooth lesion involving the distal renal artery, from intimal fibroplasia. B, Schematic diagram of intimal fibroplasia. Intimal fibroplasia occurs primarily in children and adolescents and angiographically gives the appearance of a localized, highly stenotic, smooth lesion, with poststenotic dilatation. It may occur in the proximal portion of the renal artery as well as in the mid and distal portions of the renal artery, is progressive, and is occasionally associated with dissection or renal infarction. Pathologically, idiopathic intimal fibroplasia is due to a proliferation of the intimal lining of the arterial wall. Intimal fibroplasia of the renal artery may also occur as an event secondary to atherosclerosis or as a reactive intimal fibroplasia consequent to an inciting event such as prior endarterectomy or balloon angioplasty. (Panel A from Pohl [1]; with permission.) kidney beyond the stenosis are relatively common with ASO-RAD, but ischemic atrophy of the kidney ipsilateral to the medial fibroplasia lesion is rare. Surgical intervention or pecutaneous transluminal renal angioplasty (PTRA) typically produce good cure rates for the hypertension in medial fibroplasia and these lesions are technically quite amenable to PTRA. In contrast, ASO-RAD is, technically, much less amenable to PTRA (particularly ostial lesions), and surgical intervention or PTRA produce mediocre-to-poor cure rates of the hypertension. ASO-RAD and medial fibroplasia may cause hypertension and when the hypertension is cured or markedly improved following intervention, the patient may be viewed as having “renovascular hypertension.” This sequence of events is far more likely to occur in patients with medial fibroplasia than in patients with ASO-RAD. ASO-RAD and medial fibroplasia involve both main renal arteries in approximately 30% to 40% of patients.

3.6

Hypertension and the Kidney

Pathophysiology of Renovascular Hypertension

Stenotic kidney

Contralateral kidney

Ischemia Renin

• Supressed renin • Pressure natriuresis

Angiotensin II Vasoconstriction

Aldosterone

• Intrarenal hemodynamics • Sodium retention

FIGURE 3-9 Schematic representation of renovascular hypertension. Renovascular hypertension may be defined as the secondary elevation of blood pressure produced by any of a variety of conditions that interfere with the arterial circulation to kidney tissue and cause renal ischemia. Almost always, renovascular hypertension is caused by obstruction of the renal artery or its branches, and demonstration of causality between the renal artery lesion and the hypertension is essential to this definition.

This diagram shows the classic model of two-kidney, one clip (2K,1C) Goldblatt hypertension, wherein one renal artery is constricted and the contralateral kidney is left intact. In the presence of hemodynamically sufficient unilateral renal artery stenosis, the kidney distal to the stenosis is rendered ischemic, activating the renin angiotensin system, and producing high levels of angiotensin II, causing a “vasoconstrictor” type of hypertension. Numerous studies have established the causal relationship between angiotensin II–mediated vasoconstriction and hypertension in the early phase of this experimental model. In addition, the high levels of angiotensin II stimulate the adrenal cortex to elaborate larger amounts of aldosterone such that the “stenotic kidney” demonstrates sodium retention. This secondary aldosteronism also produces hypokalemia. The degree of renal artery stenosis necessary to produce hemodynamically significant reductions in perfusion, triggering renal ischemia and activation of the renin angiotensin system, generally does not occur until a reduction of 80% or more in both lumen diameter and cross-sectional area of the renal artery takes place. Lesser degrees of renal artery constriction do not initiate this sequence of events. This model of 2K,1C Goldblatt hypertension implies that the contralateral (nonaffected) kidney is present, and that its renal artery is not hemodynamically significantly narrowed. As illustrated, the “contralateral kidney” demonstrates suppressed renin production and undergoes a pressure natriuresis, presumably because of angiotensin II–initiated vasoconstriction and sodium retention, leading to systemic elevation of blood pressure that then results in suppression of renin release and enhanced excretion of sodium (pressure natriuresis) by the “contralateral kidney.”

Renovascular Hypertension and Ischemic Nephropathy

Clip

I

Phase II

III

Blood pressure

Renin Change in blood pressure on removing clip

FIGURE 3-10 Sequential phases in two-kidney, one-clip (2K,1C) experimental renovascular hypertension. The schematic representation of renovascular hypertension depicted in Figure 3-9 is an oversimplification. In fact, the course of experimental 2K,1C hypertension may be divided into three sequential phases. In phase I, renal ischemia and activation of the renin angiotensin system are of fundamental importance, and in this early phase of experimental hypertension, the blood pressure elevation is renin- or angiotensin II–dependent. Acute administration of angiotensin II antagonists, administration of angiotensin-converting enzyme (ACE) inhibitors, removal of the renal artery stenosis (ie, removal of the clip in the experimental animal or removal of the “stenotic kidney”) promptly normalizes blood pressure. Several days after renal artery clamping, renin levels fall, but blood pressure remains elevated. This second phase of experimental 2K,1C hypertension may be viewed as a pathophysiologic transition phase that, depending on the experimental model and species, may last from a few days to several weeks. During this transition phase (phase II), salt and water retention are observed as a consequence of the effect of hypoperfusion of the stenotic kidney;

Two-kidney hypertension

Blood pressure

Renin

Volume

High

Normal

One-kidney hypertension

Blood pressure

Renin

Volume

Normal

High

3.7

augmented proximal tubular reabsorption of sodium and water and angiotensin II–induced stimulation of aldosterone secretion contribute to this sodium and water retention. In addition, the high levels of angiotensin II stimulate thirst, which further augments expansion of the extracellular fluid volume. The expanded extracellular fluid volume results in a progressive suppression of peripheral renin activity. During this transition phase, the hypertension is still responsive to removal of the unilateral renal artery stenosis, to angiotensin II blockade, or unilateral nephrectomy, although these maneuvers do not normalize the blood pressure as promptly and consistently as in the acute phase. After several weeks, a chronic phase (phase III) ensues wherein unclipping the renal artery of the experimental animal does not lower the blood pressure. This failure of “unclipping” to lower the blood pressure in this chronic phase (III) of 2K,1C hypertension is due to widespread arteriolar damage to the “contralateral kidney,” consequent to prolonged exposure to high blood pressure and high levels of angiotensin II. In this chronic phase of 2K,1C renovascular hypertension, extracellular fluid volume expansion and systemic vasoconstriction are the main pathophysiologic abnormalities. The pressure natriuresis of the “contralateral kidney” blunts the extracellular fluid volume expansion caused by the “stenotic kidney;” but as the contralateral kidney suffers vascular damage from extended exposure to elevated arterial pressure, its excretory function diminishes and extracellular fluid volume expansion persists. In this third phase of experimental 2K,1C hypertension, acute blockade of the renin angiotensin system fails to lower blood pressure. Sodium depletion may ameliorate the hypertension but does not normalize it. The clinical surrogate of phase III experimental 2K,1C hypertension is duration of hypertension. Widespread clinical experience indicates that major improvements in blood pressure control or cure of the hypertension following renal revascularization or even removal of the kidney ipsilateral to the renal artery stenosis are rarely observed in patients with a long duration (ie, >5 years) of hypertension. (Adapted from Brown and coworkers [3]; with permission.) FIGURE 3-11 Schematic representation of two types of experimental hypertension. The discussion so far of the pathophysiology of renovascular hypertension has focused on the two-kidney, one-clip model of renovascular hypertension (“two-kidney hypertension”), wherein the artery to the “contralateral kidney” is patent and the “contralateral” nonaffected kidney is present. Elevated peripheral renin activity, normal plasma volume, and hypokalemia are typically associated with the elevated arterial pressure. There is another type of “renovascular hypertension” known as “one-kidney” hypertension, wherein in the experimental model, one renal artery is constricted and the contralateral kidney is removed. Although there is an initial increase in renin release responsible for the early rise in blood pressure in “one-kidney” hypertension as in “two-kidney” hypertension, the absence of an unclipped contralateral kidney allows for sodium retention early in the course of this one-kidney, one-clip (1K,1C) model. Renin levels are suppressed to normal levels in conjunction with high blood pressure which is maintained by salt and water retention. Thus, extracellular fluid volume expansion is a prime feature of “one-kidney” hypertension.

3.8

Hypertension and the Kidney

A. LESIONS PRODUCING THE SYNDROME OF RENOVASCULAR HYPERTENSION (“TWO-KIDNEY HYPERTENSION”)* Unilateral atherosclerotic renal arterial disease Unilateral fibrous renal artery disease Renal artery aneurysm Arterial embolus Arteriovenous fistula (congenital and traumatic) Segmental arterial occlusion (traumatic) Pheochromocytoma compressing renal artery Unilateral perirenal hematoma or subcapsular hematoma (compressing renal parenchyma) *Implies contralateral (nonaffected) kidney present.

B. LESIONS PRODUCING THE SYNDROME OF RENOVASCULAR HYPERTENSION (“ONE-KIDNEY HYPERTENSION”)* Stenosis to a solitary functioning kidney Bilateral renal arterial stenosis Aortic coarctation Vasculitis (polyarteritis nodosa and Takayasu’s arteritis) Atheroembolic disease

FIGURE 3-12 Lesions producing the syndrome of renovascular hypertension. A, Two-kidney hypertension. The most common clinical counterpart to “two-kidney” hypertension is unilateral renal artery stenosis due to either atherosclerotic or fibrous renal artery disease. Unilateral renal trauma, with development of a calcified fibrous capsule surrounding the injured kidney causing compression of the renal parenchyma, may produce renovascular hypertension; this clinical situation is analogous to the experimental Page kidney, wherein cellophane wrapping of one of two kidneys causes hypertension, which is relieved by removal of the wrapped kidney. B, One-kidney hypertension. Clinical counterparts of experimental one-kidney, one-clip (“one kidney”) hypertension include renal artery stenosis to a solitary functioning kidney, bilateral renal arterial stenosis, aortic coarctation, Takayasu’s arteritis, fulminant polyarteritis nodosa, atheroembolic renal disease, and renal artery stenosis in a transplanted kidney. In some parts of the world, eg, China and India, Takayasu’s arteritis is a frequent cause of renovascular hypertension.

*Implies total renal mass ischemic.

STEPS IN MAKING THE DIAGNOSIS OF RENOVASCULAR HYPERTENSION 1. Demonstration of renal arterial stenosis by angiography 2. Determination of pathophysiologic significance of the stenotic lesion 3. Cure of the hypertension by intervention, ie, revascularization, percutaneous transluminal angioplasty, nephrectomy

FIGURE 3-13 Steps in making the diagnosis of renovascular hypertension (RVHT). With the exception of oral contraceptive use and alcohol ingestion, RVHT is the most common cause of potentially remediable secondary hypertension. RVHT is estimated to occur with a prevalence of 1% to 15%. Some hypertension referral clinics have estimated a prevalence of RVHT as high as 15%, whereas other prevalence data suggest that less than 1% to 2% of the hypertensive population has RVHT.

Although elderly atherosclerotic hypertensive individuals often have atherosclerotic renal artery disease, their hypertension is usually essential hypertension, not RVHT. On balance, the prevalence of RVHT in the general hypertensive population is probably no more than 2% to 3%. The particular appeal of diagnosing RVHT centers around its potential curability by an interventive maneuver such as surgical revascularization, percutaneous transluminal renal angioplasty (PTRA), or renal artery stenting. Whether or not to use these interventions for the goal of improving blood pressure depends on the likelihood such intervention will improve the blood pressure. The overwhelming majority of patients with RVHT will have this syndrome because of main renal artery stenosis. Therefore, the first step in making the diagnosis of RVHT is to demonstrate renal artery stenosis by one of several imaging procedures and, eventually, by angiography. The second step in establishing the probability that the renal artery stenosis is instrumental in promoting hypertension is to determine the pathophysiologic significance of the stenotic lesion. Finally, the hypertension, presumed to be renovascular in origin, is proven to be RVHT when the elevated blood pressure is cured or markedly ameliorated by an interventive maneuver such as surgical revascularization, PTRA, renal artery stent, or nephrectomy.

Renovascular Hypertension and Ischemic Nephropathy

DIAGNOSIS OF RENAL ARTERIAL STENOSIS Clinical clues

Diagnostic tests

Age of onset of hypertension <30 y or >55 y Abrupt onset of hypertension Acceleration of previously well-controlled hypertension Hypertension refractory to an appropriate three-drug regimen Accelerated retinopathy Systolic-diastolic abdominal bruit Evidence of generalized atherosclerosis obliterans Malignant hypertension Flash pulmonary edema Acute renal failure with use of angiotensin-converting enzyme inhibitors or angiotensin II receptor-blockers

Duplex ultrasonography Radionuclide renography Captopril renography Captopril provocation test Intravenous digital subtraction angiography Rapid sequence IVP Magnetic resonance angiography Spiral CT angiography CO2 angiography Conventional (contrast) angiography

FIGURE 3-14 Diagnosis of renal artery stenosis. Clinical clues suggesting renal artery stenosis, some of which suggest that the stenosis is the cause of the hypertension, are listed on the left. The well-documented age of onset of hypertension in an individual under the age of 30 or over age 55 years, particularly if the hypertension is severe and requiring three antihypertensive drugs, is a strong clinical clue to renal artery stenosis and predicts that the stenosis is causing the hypertension. The patient with a long history of mild hypertension, easily controlled with one or two drugs, who, particularly in older age, develops severe and refractory hypertension, is likely to have developed atherosclerotic renal artery stenosis as a contributor to underlying

3.9

longstanding essential hypertension. Grade III hypertensive retinopathy, malignant hypertension, and flash pulmonary edema all suggest renal artery stenosis with or without renovascular hypertension. The observation of a diastolic bruit in the abdomen of a young white women suggests fibrous renal artery disease and, further, is a reliable clinical clue that the hypertension will be helped substantially by surgical renal revascularization or percutaneous transluminal renal angioplasty. The diagnostic tests listed along the right side are used mainly to detect renal artery stenosis (ie, the anatomic presence of disease). Captopril renography is also used to predict physiologic significance of the stenotic lesion. The popularity of these diagnostic tests in detecting renal artery stenosis varies from institution to institution; correlations with percent stenosis by comparative angiography are widely variable. A substantial fall in blood pressure following initiation of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker suggests RVHT. With the exception of a diastolic abdominal bruit and accelerated retinopathy, no clear-cut physical findings definitely discriminate patients with RVHT from the larger pool of patients with essential hypertension.

FIGURE 3-15 Renal duplex ultrasound for diagnosis of renal artery stenosis. Duplex ultrasound scanning of the renal arteries is a noninvasive screening test for the detection of renal artery stenosis. It combines direct visualization of the renal arteries (B-mode imaging) with measurement of various hemodynamic factors in the main renal arteries and within the kidney (Doppler), thus providing both an anatomic and functional assessment. Unlike other noninvasive screening tests (eg, captopril renography), duplex ultrasonography does not require patients to discontinue any antihypertensive medications before the test. The study should be performed while the patient is fasting. The white arrow indicates the aorta and the black arrow the left renal artery, which is stenotic. Doppler scans (bottom) measure the corresponding peak systolic velocities in the aorta and in the renal artery. The peak systolic velocity in the left renal artery was 400 cm/s, and the peak systolic velocity in the aorta was 75 cm/s. Therefore, the renalaortic ratio was 5.3, consistent with a 60% to 99% left renal artery stenosis. (From Hoffman and coworkers [4]; with permission.)

3.10

Hypertension and the Kidney

COMPARISON OF DUPLEX ULTRASOUND WITH ARTERIOGRAPHY

Percent stenosis by ultrasound 0–59 60–99 100 Total

Percent stenosis by arteriogram 0–59

60–79

80–99

100

Total

62 1 0 63

0 31 1 32

1 67 1 69

1 0 22 23

64 99 24 187

Sensitivity, 0.98. Specificity, 0.98. Positive predictive value, 0.99. Negative predictive value, 0.97.

DETERMINATION OF PATHOPHYSIOLOGIC SIGNIFICANCE OF THE STENOTIC LESION Duration of hypertension <3–5 y Appearance of lesion on angiogram (>75% stenosis) Systolic-diastolic bruit in abdomen Renal vein renin ratio >1.5 Positive captopril provocation test or captopril renogram Abnormal rapid sequence IVP Hypokalemia

FIGURE 3-17 Determination of pathophysiologic significance of the stenotic lesion. The second step in making the diagnosis of renovascular hypertension (RVHT) is to determine the pathophysiologic significance of the stenotic lesion demonstrated by angiography. The likelihood of cure of the hypertension by an interventive maneuver is greatly enhanced when one or more of the items listed here are present. A positive captopril provocation test, abnormal rapid sequence intravenous pyelogram (IVP), or positive captopril

FIGURE 3-16 Comparison of duplex ultrasound with arteriography. A total of 102 consecutive patients with both duplex ultrasound scanning of the renal arteries and renal arteriography were prospectively studied. All patients in this study had difficult-to-control hypertension, unexplained azotemia, or associated peripheral vascular disease, giving them a high pretest likelihood of renovascular hypertension. Sixty-two of 63 arteries that showed less than 60% stenosis by formal arteriography, were identified by duplex ultrasound scanning. Twenty-two of 23 arteries with total occlusion on arteriography were correctly identified by duplex ultrasound. Thirty-one of 32 arteries with 60% to 79% stenosis using arteriography were identified as having 60% to 99% stenosis on duplex ultrasound and 67 of 69 arteries with 80% to 99% stenosis on arteriography were detected to have 60% to 99% stenosis on ultrasound. A current limitation of duplex ultrasound is the inability to consistently distinguish between more than and less than 80% stenosis (considered to be the magnitude of stenosis required for hemodynamic significance of the lesion). Nevertheless, duplex ultrasound is currently highly sensitive and specific in patients with a high likelihood of renovascular disease in detecting patients with more or less than 60% renal artery stenosis. Accessory renal arteries are difficult to identify by ultrasound and remain a limitation of this test. (Adapted from Olin and coworkers [5]; with permission.) renogram not only suggest the anatomic presence of renal artery stenosis but also imply that the stenosis is instrumental in producing the hypertension. Reductions of lumen diameter of less than 70% to 80% generally do not initiate renal ischemia or activation of the renin angiotensin system; thus, before recommending a renal revascularization procedure, severe renal artery stenosis (>75% reduction in lumen diameter) should be observed on the renal angiogram. A lateralizing renal vein renin ratio (a comparison of renin harvested from the renal vein ipsilateral to the renal artery stenosis with the renin level from renal vein of the contralateral kidney), particularly when renin production from the contralateral kidney is suppressed, suggests that an intervention on the renal artery stenosis will cure or markedly ameliorate the hypertension in about 90% of cases. Conversely, cure or marked improvement in blood pressure following renal revascularization has been reported in nearly 50% of cases in the absence of lateralizing renal vein renins. Hypokalemia, in the absence of diuretic therapy, strongly suggests that the hypertension is renovascular in origin, consequent to secondary aldosteronism. The sensitivity of an IVP in detecting unilateral RVHT is relatively poor (about 75%) and the overall sensitivity in detecting patients with bilateral renal artery disease is only about 60%. Because RVHT has a low prevalence in the general population, a negative IVP provides strong evidence (98% to 99% certainty) against RVHT.

3.11

Renovascular Hypertension and Ischemic Nephropathy

RENIN CRITERIA FOR CAPTOPRIL TEST THAT DISTINGUISH PATIENTS WITH RVHT FROM THOSE WITH ESSENTIAL HYPERTENSION Stimulated PRA of 12 ng/mL/h or more Absolute increase in PRA of 10 ng/mL/h or more Percent increase in PRA Increase in PRA of 150% if baseline PRA >3 ng/mL/h Increase in PRA of 400% if baseline PRA <3 ng/mL/h

FIGURE 3-18 The captopril test: renin criteria that distinguish patients with renovascular hypertension from those with essential hypertension. The captopril provocation test evolved because the casual measurement of peripheral plasma renin activity (PRA) has been of little

value as a diagnostic screening test for renovascular hypertension (RVHT). The notion that patients with high PRA, even in the face of high urinary sodium excretion, might turn out to have RVHT has not been supported by numerous clinical observations. However, the short-term (60- to 90-minute) response of blood pressure and PRA to an oral dose (25 to 50 mg) of captopril has gained recent popularity as a screening test for presumed RVHT. Preparation of patients for this test is vital; ideally patients should discontinue their antihypertensive medications, maintain a diet adequate in salt, and have good renal function. A baseline blood pressure and PRA are obtained after which captopril is administered; 60 minutes after captopril administration, a “postcaptopril” PRA is obtained along with repeat measurements of blood pressure. Early reports with this test indicated a high sensitivity and specificity (95% to 100%) in identifying RVHT if all three of the renin criteria listed here were met. Subsequent reports have not been as encouraging such that the overall sensitivity of this captopril test is only about 70%, with a specificity of approximately 85%. (Adapted from Muller and coworkers [6]; with permission.)

1.0

1.0

0.8 Relative acidity

Relative acidity

0.8

0.6

0.4

0.2

0.4

0.2

Bladder Right kidney Left kidney

Bladder Right kidney Left kidney

0

0 0

A

0.6

8

16

24 Time, min

32

40

48

FIGURE 3-19 Captopril renography. A, TcDPTA time-activity curves during baseline. B, TcDPTA time-activity curves after captopril administration. These curves represent a captopril renogram in a patient with unilateral left renal artery stenosis. This diagnostic test has been used to screen for renal artery stenosis and to predict renovascular hypertension. Captopril renography appears to be highly sensitive and specific for detecting physiologically significant renal artery stenosis. Scintigrams and time-activity curves should both be analyzed to assess renal perfusion, function, and size. If the renogram following captopril administration is abnormal (panel B, demonstrating delayed time to maximal activity and retention of the radionuclide in the right kidney), another renogram may be obtained without captopril for comparison. The diagnosis of renal artery stenosis is based on

B

0

8

16

24 Time, min

32

40

48

asymmetry of renal size and function and on specific, captoprilinduced changes in the renogram, including delayed time to maximal activity (≥11 minutes), significant asymmetry of the peak of each kidney, marked cortical retention of the radionuclide, and marked reduction in the calculated glomerular filtration rate of the kidney ipsilateral to the stenosis. One must interpret the clinical and renographic data with caution, as protocols are complex and diagnostic criteria are not well standardized. Nevertheless, captopril renography appears to be an improvement over the captopril provocation test, with many reports indicating sensitivity and specificity from 80% to 95% in predicting an improvement in blood pressure following intervention. (Adapted from Nally and coworkers [7]; with permission.)

3.12

Hypertension and the Kidney

Suggested work-up for renovascular hypertension Index of clinical suspicion

Low (<1%)

PRA

Low

High (>25%)

Moderate (≈5%–15%) Normal or high

?

Captopril test, or captopril renogram, or stimulated renal vein renins, or (?) duplex ultrasound

No further work-up

Negative

Positive

Arteriogram + renal vein renins

FIGURE 3-20 Suggested work-up for renovascular hypertension. Because the prevalence of renovascular hypertension (RVHT) among hypertensive persons in general is approximately 2% or less, widespread screening for renovascular disease is not justified. Despite the proliferation of diagnostic tests

now available to detect renal artery stenosis and several tests designed to predict the physiologic significance of the stenotic lesion, the index of clinical suspicion for RVHT remains the focal point of the work-up for RVHT. A brief duration of moderately severe hypertension is the most important clue directing subsequent work-up for RVHT. If the index of clinical suspicion (see Fig. 3-14) is high, it is reasonable to proceed directly to formal renal arteriography with renal vein renin determination. Alternatively, in patients highly suspected to have RVHT, a captopril renogram followed by a renal arteriogram may be recommended. Strong arguments against RVHT include 1) long duration (more than 5 years) of hypertension, 2) old age, 3) generalized atherosclerosis, 4) increased serum creatinine, and 5) a normal serum potassium concentration. For these patients, particularly if the blood pressure is only minimally elevated or easily controlled with one or two antihypertensive medications, further work-up for RVHT is not indicated. (Adapted from Mann and Pickering [8]; with permission.)

Ischemic Nephropathy FIGURE 3-21 Aortogram in a 62-year-old white woman demonstrating subtotal occlusion of the left main renal artery supplying an atrophic left kidney and high-grade ostial stenosis of the proximal right renal artery from atherosclerosis. This patient presented in 1977 with a recent appearance of hypertension and a blood pressure of 170/115 mm Hg. Three years previously, when diagnosed with polycythemia vera, an IVP was normal. She was followed closely between 1974 and 1977 by her physician and was always normotensive until the hypertension suddenly appeared. A repeat rapid sequence IVP demonstrated a reduction in the size of the left kidney from 14 cm in height (1974) to 11.5 cm in height (1977). The serum creatinine was 2.6 mg/dL. The renal arteriogram shown here indicates high-grade bilateral renal artery stenosis with the left kidney measuring 11.5 cm in height, and the right kidney measuring 14.5 cm in height. Renal vein renins were obtained and lateralized strongly to the smaller left kidney. The blood pressure was well controlled with inderal and chlorthalidone. Right aortorenal reimplantation was undertaken solely to preserve renal function. Postoperatively the serum creatinine fell to 1.5 mg/dL and remained at this level for the next 13 years. Blood pressure continued to require antihypertensive medication, but was controlled to normal levels with inderal and chlorthalidone.

Renovascular Hypertension and Ischemic Nephropathy

3.13

12.0 11.0 10.0 9.0

Serum creatinine, mg/dL

8.0 Pt. 7

Pt. 8

7.0 6.0

Pt. 3

5.0

A

Pt. 6

4.0 3.0

Pt. 2 Pt. 1 Pt. 4

2.0

Pt. 3

1.0 0 Admission

Medical therapy

Surgery or angioplasty

FIGURE 3-22 Effects of medical therapy and surgery or angioplasty on serum creatinine levels. This figure describes eight patients hospitalized because of severe hypertension and renal insufficiency. With medical management of the hypertension (antihypertensive drug therapy), four of the eight patients developed substantial worsening of their renal function as measured by serum creatinine; three of these four patients demonstrated improvement following surgery or angioplasty. The other four patients (patients one to four) did not demonstrate a worsening serum creatinine level with medical therapy; but three of these four patients showed improved renal function following surgery or angioplasty. (Adapted from Ying and coworkers [9]; with permission.)

B FIGURE 3-23 Improved renal function demonstrated by intravenous pyelography following left renal revascularization. A, preoperative IVP (5-minute film) in a 65-year-old white man with a 15-year history of hypertension; serum creatinine 2.6 mg/dL. Note poorly functioning left kidney, which measured 11.5 cm in height. B, post operative IVP (5-minute film) obtained following left aortorenal saphenous vein bypass grafting to the left kidney. Note the prompt function and increased height (14.0 cm) of the revascularized left kidney versus the preoperative IVP. (From Novick and Pohl [10]; with permission.) The clinical story of the patient in Figure 3-21, the benefits of surgical renal revascularization or pecutaneous transluminal renal angioplasty (Fig. 3-22), and the radiographic evidence of improved renal function after renal revascularization (Fig. 3-23) are examples of ischemic nephropathy. Two definitions of ischemic nephropathy are suggested herein: 1) clinically significant reduction in renal function due to compromise of the renal circulation; and 2) clinically significant reduction in glomerular filtration rate due to hemodynamically significant obstruction to renal blood flow, or renal failure due to renal artery occlusive disease.

3.14

Hypertension and the Kidney

ATHEROSCLEROTIC RENAL ARTERY STENOSIS IN 395 PATIENTS WITH GENERALIZED ATHEROSCLEROSIS OBLITERANS AND IN PATIENTS WITH CORONARY ARTERY DISEASE

Patients, n

Percent of patients with >50% stenosis

109 21 189 76 76 817

38 33 39* 70† 29† 20‡

Abdominal aortic aneurysm Aorto-occlusive disease Lower extremity disease Suspected renal artery stenosis Coronary artery disease

*50% in diabetic patients. †Data from Vetrovec and coworkers [12]. ‡Data from Harding [13].

CLINICAL PRESENTATIONS OF ISCHEMIC RENAL DISEASE Acute renal failure, frequently precipitated by a reduction in blood pressure (ie, angiotensin-converting enzyme inhibitors plus diuretics) Progressive azotemia in a hypertensive patient with known renal artery stenosis treated medically Progressive azotemia in a patient (usually elderly) with refractory hypertension Unexplained progressive azotemia in an elderly patient Hypertension and azotemia in a renal transplant patient

FIGURE 3-24 Atherosclerotic renal artery stenosis in patients with generalized atherosclerosis obliterans and in patients with coronary artery disease (CAD). Atherosclerotic renal artery stenosis is common in older patients with and without hypertension simply as a consequence of generalized atherosclerosis obliterans. Approximately 40% of consecutively studied patients undergoing arteriography for routine evaluation of abdominal aortic aneurysm, aorto-occlusive disease, or lower extremity occlusive disease have associated renal artery stenosis (more than 50% unilateral renal artery stenosis) and nearly 30% of patients undergoing coronary angiography may have incidentally detected unilateral renal artery stenosis. Approximately 4% to 13% of patients with CAD or peripheral vascular disease have more than 75% bilateral renal artery stenosis. Correlations of hypercholesterolemia and cigarette smoking with renal artery atherosclerosis are not unequivocally clear, but they probably represent risk factors for renal artery atherosclerosis just as they represent risk factors for atherosclerosis in other vascular beds. (Adapted from Olin and coworkers [11]; with permission.)

FIGURE 3-25 Clinical presentations of ischemic renal disease. The clinical presentation of a patient likely to develop renal failure from atherosclerotic ischemic renal disease is that of an older (more than 50 years) individual demonstrating progressive azotemia in conjunction with antihypertensive drug therapy, risk factors for generalized atherosclerosis obliterans, known renal artery disease, refractory hypertension, and generalized atherosclerosis. Acute renal failure precipitated by a reduction in blood pressure below a “critical perfusion pressure,” and particularly with the use of angiotensin convertingenzyme inhibitors (ACEI) or angiotensin II receptor blockers plus diuretics, strongly suggests severe intrarenal ischemia from arteriolar nephrosclerosis and/or severe main renal artery stenosis. Unexplained progressive azotemia in an elderly patient with clinical signs of vascular disease with minimal proteinuria and a bland urinary sediment also suggest ischemic nephropathy. (Adapted from Jacobson [14]; with permission.)

Renovascular Hypertension and Ischemic Nephropathy

A

FIGURE 3-26 Mild stenosis (less than 50%) due to atherosclerotic disease of the left main renal artery (panel A) that has progressed to high-grade (75% to 99%) stenosis on a later arteriogram (panel B). Underlying the concept of renal revascularization for preservation of renal function is the notion that atherosclerotic renal artery disease (ASO-RAD) is a progressive disorder. The sequential angiograms in Figures 3-26 and 3-27 show angiographic progression of ASO-RAD over time. In patients demonstrating progressive renal artery stenosis by serial angiography, a decrease in kidney function as measured by serum creatinine and a decrease in ipsilateral kidney size correlate significantly with progressive occlusive disease. Patients demonstrating more than 75% stenosis of a renal artery are at highest risk for progression to complete occlusion. (From Novick [15]; with permission.)

B

A FIGURE 3-27 A, Normal right main renal artery and minimal atherosclerotic irregularity of left main renal artery on initial (1974) aortogram. B, Repeat aortography (1978) showed progression to moderate

3.15

B stenosis of the right main renal artery (arrow) and total occlusion of left main renal artery (arrow). (From Schreiber and coworkers [16]; with permission.)

3.16

Hypertension and the Kidney

CLINICAL CLUES TO BILATERAL ATHEROSCLEROTIC RENOVASCULAR DISEASE Generalized atherosclerosis obliterans Presumed renovascular hypertension Unilateral small kidney Unexplained azotemia Deterioration in renal function with BP reduction and/or ACE inhibitor therapy Flash pulmonary edema

FIGURE 3-28 Clinical clues to bilateral atherosclerotic renovascular disease. The patient at highest risk for developing renal insufficiency from renal artery stenosis (ischemic nephropathy) has sufficient arterial stenosis to threaten the entire renal functioning mass. These highrisk patients have high-grade (more than 75%) arterial stenosis to a solitary functioning kidney or high-grade (more than 75%) bilateral renal artery stenosis. Patients with two functioning kidneys with only unilateral renal artery stenosis are not at significant risk for developing renal insufficiency because the

PREDICTORS OF KIDNEY SALVAGEABILITY

Kidney size >9 cm (laminography) Function on either urogram or renal flow scan Filling of distal renal arteries (by collaterals) angiographically, with total proximal occlusion Glomerular histology on renal biopsy

FIGURE 3-29 Predictors of kidney salvageability. In evaluating patients as candidates for renal revascularization to preserve or improve renal function, some determination should be made of the

entire renal functioning mass is not threatened by large vessel occlusive disease. Clinical clues to the high-risk patient are similar to the clinical presentations of ischemic renal disease shown in Figure 3-25. Nearly 75% of adults with a unilateral small kidney have sustained this renal atrophy due to large vessel occlusive disease from atherosclerosis. One third of these patients with a unilateral small kidney have high-grade stenosis of the artery involving the contralateral normalsized kidney. Flash pulmonary edema is another clue to bilateral renovascular disease or high-grade stenosis involving a solitary functioning kidney. These patients, usually hypertensive and with documented coronary artery disease and underlying hypertensive heart disease, present with the abrupt onset of pulmonary edema. Left ventricular ejection fractions in these patients are not seriously impaired. Flash pulmonary edema is associated with atherosclerotic renal artery disease and may occur with or without severe hypertension. Renal revascularization to preserve kidney function or to prevent life-threatening flash pulmonary edema may be considered in patients with high-grade arterial stenosis to a solitary kidney or high-grade bilateral renal artery stenosis. Pecutaneous transluminal renal angioplasty (PTRA), renal artery stenting, or surgical renal revascularization may be employed. Patients with chronic total renal artery occlusion bilaterally or in a solitary functioning kidney are candidates for surgical renal revascularization, but are not candidates (from a technical standpoint) for PTRA or renal artery stents. potential for salvable renal function. Clinical clues suggesting renal viability include 1) kidney size greater than 9 cm (pole-topole length) by laminography (tomography); 2) some function of the kidney on either urogram or renal flow scan; 3) filling of distal renal arteries (by collaterals) angiographically, when the main renal artery is totally occluded proximally (see Fig. 3-30); and 4) well-preserved glomeruli with minimal interstitial scarring (see Fig. 3-31) on renal biopsy. Patients with moderately severe azotemia, eg, serum creatinine more than 3-4 mg/dL, are likely to have severe renal parenchymal scarring (see Fig. 3-32), which renders improvement in renal function following renal revascularization unlikely. Exceptions to this observation are cases of total main renal artery occlusion wherein kidney viability is maintained via collateral circulation (see Figure 3-30). A kidney biopsy may guide subsequent decision making regarding renal revascularization for the goal of improving kidney function. FIGURE 3-30 This abdominal aortogram reveals complete occlusion of the left main renal artery (panel A) with filling of the distal renal artery branches from collateral supply on delayed films (panel B). The observation of collateral circulation when the main renal artery is totally occluded proximally suggests viable renal parenchyma. (From Novick and Pohl [10]; with permission.)

A

B

Renovascular Hypertension and Ischemic Nephropathy

FIGURE 3-31 Renal biopsy of a solitary left kidney in a 67-year-old woman who had been anuric and on chronic dialysis for 9 months. The biopsy shows hypoperfused retracted glomeruli consistent with ischemia. There is no evidence of active glomerular proliferation or glomerular sclerosis. Note intact tubular basement membranes and negligible interstitial scarring. Left renal revascularization resulted in recovery of renal function and discontinuance of dialysis with improvement in serum creatinine to 2.0 mg/dL. (From Novick [15]; with permission.)

3.17

FIGURE 3-32 Pathologic specimen of kidney beyond a main renal artery occlusion in a patient with severe bilateral renal artery stenosis and a serum creatinine of 4.5 mg/dL. The biopsy demonstrates glomerular sclerosis, tubular atrophy, and interstitial fibrosis. The magnitude of glomerular and interstitial scarring predict irreversible loss of kidney viability. (From Pohl [1]; with permission.)

FIGURE 3-33 Severe atherosclerosis involving the abdominal aorta, renal, and iliac arteries. This abdominal aortogram demonstrates a ragged aorta, total occlusion of the right main renal artery, and subtotal occlusion of the proximal left main renal artery. Such patients are at high-risk for atheroembolic renal disease following aortography, selective renal arteriography, pecutaneous transluminal renal angioplasty, renal artery stenting, or surgical renal revascularization.

FIGURE 3-34 (see Color Plate) “Purple toe” syndrome reflecting peripheral atheroembolic disease in the patient in Figure 3-33 (ragged aorta), following an abdominal aortogram.

3.18

Hypertension and the Kidney FIGURE 3-35 Pathologic specimen of kidney demonstrating atheroembolic renal disease (AERD). Microemboli of atheromatous material are readily identified by the characteristic appearance of cholesterol crystal inclusions that appear in a biconvex needle-shaped form. In routine paraffin-embedded histologic sections, the cholesterol is not seen because the methods used in preparing sections dissolve the crystals; the characteristic biconvex clefts in the glomeruli (or blood vessels) persist, allowing easy identification. Several patterns of renal failure in patients with AERD are recognized: 1) insult (eg, abdominal aortogram) leads to end-stage renal disease (ESRD) over weeks to months; 2) insult leads to chronic stable renal insufficiency; 3) multiple insults (repeated angiographic procedures) lead to a step-wise rise in serum creatinine eventuating in end-stage renal failure; and 4) insult leading to ESRD over several weeks to months with recovery of some renal function allowing for discontinuance of dialysis. FIGURE 3-36 Renal biopsy demonstrating severe arteriolar nephrosclerosis. Arteriolar nephrosclerosis is intimately associated with hypertension. The histology of the kidney in arteriolar nephrosclerosis shows considerable variation in intensity and extent of the arteriolar lesions. Thickening of the vessel wall, edema of the smooth muscle cells, hypertrophy of the smooth muscle cells, and hyaline degeneration of the vessel wall may be apparent depending on the severity of the nephrosclerosis. In addition to the vascular lesions of arteriolar nephrosclerosis there are abnormalities of glomeruli, tubules, and interstitial areas that are believed to be secondary to the ischemia that results from arteriolar insufficiency. Arteriolar nephrosclerosis is observed in patients with longstanding hypertension; the more severe the hypertension, the more severe the arteriolar nephrosclerosis. Arteriolar nephrosclerosis may also be seen in elderly normotensive individuals and is frequently observed in elderly patients with generalized atherosclerosis or essential hypertension.

Atherosclerosis

Nephrosclerosis

Atheroembolism

FIGURE 3-37 Schematic representation of ischemic nephropathy. Patients with atherosclerotic renal artery disease (ASO-RAD) often have coexisting renal parenchymal disease with varying degrees of nephrosclerosis (small vessel disease) or atheroembolic renal disease. Whether or not the renal insufficiency is solely attributable to renal artery stenosis, nephrosclerosis, or atheroembolic renal disease is difficult to determine. The term “ischemic nephropathy” is more complex than being simply due to atherosclerotic renal artery stenosis. In addition, in the azotemic patient with ASORAD, one should exclude other potential or contributing causes of renal insufficiency such as obstructive uropathy, primary glomerular disease (suggested by heavy proteinuria), drug-related renal insufficiency (eg, nonsteroidal anti-inflammatory drugs), and uncontrolled blood pressure.

Renovascular Hypertension and Ischemic Nephropathy 4% Miscellaneous

FIGURE 3-38 Distribution of endstage renal disease diagnoses. Atherosclerotic renal artery disease (ASORAD) has been claimed to contribute to the ESRD population. This diagram from the US Renal Data System Coordinating Center 1994 report indicates that 29% of calendar year 1991 incident patients entered ESRD programs because of “hypertension (HBP).” No renovascular disease diagnosis is listed. Crude estimates of the percentage of patients entering ESRD programs because of ASO-RAD range from 1.7% to 15%. Precise bases for making these estimates are both unclear and confounded by the high likelihood of coexisting arteriolar nephrosclerosis, type II diabetic nephropathy, and atheroembolic renal disease. ASO-RAD as a major contributor to the ESRD population is probably small on a percentage basis, occupying some portion of the ESRD diagnosis “hypertension (HBP).” For dialysis-dependent patients with ASO-RAD, predictors of recovery of renal function following renal revascularization and allowing for discontinuance of dialysis (temporary or permanent) include 1) bilateral (vs unilateral) renal artery stenosis, 2) a relatively fast rate of decline of estimated glomerular filtration rate (less than 6 months) prior to initiation of dialysis; and 3) mild-tomoderate arteriolar nephrosclerosis angiographically.

11% Other

12% CGN

5% Urology 3% Cyst

3.19

36% DM 29% High blood pressure

Treatment of Renovascular Hypertension and Ischemic Nephropathy TREATMENT OPTIONS FOR RENOVASCULAR HYPERTENSION AND ISCHEMIC NEPHROPATHY Pharmacologic antihypertensive therapy PTRA Renal artery stents Surgical renal revascularization

INCREASING COMORBIDITY IN PATIENTS UNDERGOING RENOVASCULAR SURGERY Comorbidity, % Condition Angina Prior MI CHF Cerebrovascular disease Diabetes Claudication *P <0.001.

1970–1980

1980–1993

21.4 16.3 12.2 11.2 7.1 35.7

29.9 27.0 23.7* 24.8* 18.1* 56.4*

FIGURE 3-39 Treatment options for renovascular hypertension and ischemic nephropathy. The main goals in the treatment of renovascular hypertension or ischemic nephropathy are to control the blood pressure, to prevent target organ complications, and to avoid the loss of renal function. Although the issue of renal function may be viewed as mutually exclusive from the issue of blood pressure control, uncontrolled hypertension may hasten a decline in renal function, and renal insufficiency may produce worsening hypertension. Even in the presence of excellent blood pressure control, progressive arterial stenosis might worsen renal ischemia and promote renal atrophy and fibrosis. Therapeutic options include pharmacologic antihypertensive therapy, percutaneous transluminal renal angioplasty (PTRA), renal artery stents, and surgical renal revascularization. Pharmacologic antihypertensive therapy is covered in more detail separately in this Atlas. FIGURE 3-40 Comorbidity in patients undergoing renovascular surgery. Patients presenting for renovascular surgery or endovascular renal revascularization are at high-risk for complications during intervention because of age, and frequently associated coronary, cerebrovascular, or peripheral vascular disease. As the population ages, the percentage of patients being considered for interventive maneuvers on the renal artery has increased significantly. Approximately 30% of patients currently undergoing interventive approaches to renal artery disease have angina, or have had a previous myocardial infarction. Congestive heart failure, cerebrovascular disease (eg, carotid artery stenosis), diabetes mellitus, and claudication are frequent comorbid conditions in these patients. Their aortas are often laden with extensive atherosclerotic plaque (Fig. 3-33), making angiographic investigation or endovascular renal revascularization hazardous. (Adapted from Hallet and coworkers [17]; with permission.)

3.20

Hypertension and the Kidney

DIMINISHED OPERATIVE MORBIDITY AND MORTALITY FOLLOWING SURGICAL REVASCULARIZATION FOR ATHEROSCLEROTIC RENOVASCULAR DISEASE Preoperative screening and correction of coronary and carotid artery disease Avoidance of operation on severely diseased aorta Unilateral revascularization in patients with bilateral renovascular disease

FIGURE 3-41 Diminished operative morbidity and mortality following surgical revascularization for atherosclerotic renovascular disease. Operative morbidity and mortality in patients undergoing surgical revascularization have been minimized by selective screening and/or correction of significant coexisting coronary and/or carotid artery disease before undertaking elective surgical renal revascularization for atherosclerotic renal artery disease. Screening tests for carotid artery disease include carotid ultrasound and carotid arteriography. Screening tests for coronary artery disease include thallium stress testing, dipyridamole stress testing, dobutamine echocardiography, and coronary arteriography. Aortorenal

bypass with saphenous vein grafting is a frequently used surgical approach in patients with nondiseased abdominal aortas. Severe atherosclerosis of the abdominal aorta may render an aortorenal bypass or renal endarterectomy technically difficult and potentially hazardous to perform. Effective alternate bypass techniques include splenorenal bypass for left renal revascularization, hepatorenal bypass for right renal revascularization, ileorenal bypass, bench surgery with autotransplantation, and use of the supraceliac or lower thoracic aorta (usually less ravaged by atherosclerosis). Simultaneous aortic replacement and renal revascularization are associated with an increased risk of operative mortality in comparison to renal revascularization alone. Some surgeons advocate unilateral renal revascularization in patients with bilateral renovascular disease. FIGURE 3-42 Schematic diagram of alternate bypass procedures. A, Hepatorenal bypass to right kidney. B, Splenorenal bypass to left kidney. C, Ileorenal bypass to left kidney. D, Autotransplantation.

A

B

C

D

Renovascular Hypertension and Ischemic Nephropathy

A

3.21

B

FIGURE 3-43 Percutaneous transluminal renal angioplasty (PTRA) of the renal artery. A, High-grade (more than 75%) nonostial atherosclerotic stenosis of the left main renal artery in a patient with a solitary functioning kidney (right renal artery totally occluded). Note gradient of 170 mm Hg across the stenotic lesion. B, Balloon angioplasty of the left main renal artery was successfully performed with reduction in the gradient across the stenotic lesion from 170 mm Hg pre-PTRA to 15 mm Hg post-PTRA. Repeat aortogram 3 years later demonstrated patency of the left renal artery.

PTRA of the renal artery has emerged as an important interventional modality in the management of patients with renal artery stenosis. PTRA is most successful and should be the initial interventive therapeutic maneuver for patients with the medial fibroplasia type of fibrous renal artery disease (eg, Fig.3-5A). Excellent technical success rates have also been attained for nonostial atherosclerotic lesions of the main renal artery, as shown here.

FIGURE 3-44 High-grade atherosclerotic renal artery stenosis at the ostium of the right main renal artery in a 68-year-old man with a totally occluded left main renal artery. Several attempts at balloon dilatation were unsuccessful. Over the subsequent 10 days, severe renal insufficiency developed (serum creatinine increasing from 2.0 to 12.0 mg/dL) requiring dialysis. Renal function never improved and the patient remained on dialysis.

FIGURE 3-45 Palmaz stent, expanded. Because percutaneous transluminal renal angioplasty (PTRA) has suboptimal long-term benefits for atherosclerotic ostial renal artery stenosis, endovascular stenting has gained wide acceptance. Renal artery stenting may be performed at the time of the diagnostic angiogram, or at some time thereafter, depending on the physician’s preference and the risk to the patient of repeated angiographic procedures. From a technical standpoint, indications for renal artery stenting include 1) as a primary procedure for ostial atherosclerotic renal artery disease (ASO-RAD), 2) technical difficulties in conjunction with attempted PTRA, 3) post-PTRA dissection, 4) post-PTRA abrupt occlusion, and 5) restenosis following PTRA. It is unclear what the long-term patency and restenosis rates will be for renal artery stenting for ostial disease. Preliminary observations suggest that the 1-year patency rate for stents is approximately twice that for PTRA.

3.22

Hypertension and the Kidney FIGURE 3-46 Abdominal aortogram in a 63-year-old male, 6 months following placement of a Palmaz stent. Note wide patency of the left main renal artery.

A. SURGICAL REVASCULARIZATION VERSUS PTRA FOR ATHEROSCLEROTIC RENAL ARTERY DISEASE

Lesion Nonostial (20%) Ostial (80%)

Successful PTRA, %

Successful surgical revascularization, %

80–90

90

25–30

90

FIGURE 3-47 Surgical revascularization vs percutaneous transluminal renal angioplasty (PTRA) for renal artery disease. A, Success rates for atherosclerotic renal artery disease (ASO-RAD). B, Success rates for fibrous renal artery disease. Success of either PTRA or surgical renal revascularization is viewed in terms of “technical” success and “clinical” success. For PTRA, technical success reflects a lumen patency with less than 50% residual stenosis (ie, successful establishment of a patent lumen). For surgical revascularization, technical success is the demonstration of good blood flow to the revascularized kidney determined during surgery, or postoperatively by DPTA renal scan or other immediate postoperative imaging procedures. Technical success with either PTRA or surgical revascularization is rarely defined by postoperative angiography. “Clinical” success may be defined as improved blood pressure or improvement in kidney function, and/or resolution of flash pulmonary edema. Technical and clinical successes do not necessarily occur together because technical success may be apparent, but without improvement in blood pressure or renal function.

B. SURGICAL REVASCULARIZATION VERSUS PTRA FOR FIBROUS RENAL ARTERY DISEASE

Lesion

Successful PTRA, %

Successful surgical revascularization, %

Main (50%) Branch (50%)

80–90

90

NA

90

The “percent success” for PTRA and surgical revascularization depicted above are estimates, and reflect primarily “technical” success for both nonostial and ostial lesions in ASO-RAD. Technical success rates for surgical revascularization are high, approximating 90%, with little difference in the technical success rates between ostial and nonostial lesions. For PTRA, technical success rates are much higher for nonostial lesions. There is a high rate of restenosis at 1 year (≈50% to 70%) for ostial ASO-RAD, which has promoted the use of renal artery stents for these lesions. The success rates of surgical renal revascularization and PTRA for stenosis of the main renal artery in fibrous renal artery disease are comparable, approximately 90%. Hypertension is more predictably improved with surgical revascularization and PTRA in fibrous renal artery disease in comparison with ASO-RAD. Technical success rates with surgical renal revascularization are high for branch fibrous renal artery disease, but long-term technical and clinical success rates are not available for PTRA of branch lesions due to fibrous dysplasia. NA—not available. (Adapted from Pohl [18]; with permission.)

Renovascular Hypertension and Ischemic Nephropathy

COMPLICATIONS OF TRANSLUMINAL ANGIOPLASTY OF THE RENAL ARTERIES Contrast-induced ARF (mild or severe) Atheroembolic renal failure Rupture of the renal artery Dissection of the renal artery Thrombotic occlusion of the renal artery Occlusion of a branch renal artery Balloon malfunction (may lead to inability to remove balloon) Balloon rupture Puncture site hematoma, hemorrhage, or vessel tear Median nerve compression (axillary approach) Renal artery spasm Mortality (≤1%)

FIGURE 3-48 Complications of transluminal angioplasty of the renal arteries. The more common complications of PTRA are contrast-induced acute renal failure (ARF) and atheroembolic renal failure. Dissection of the renal artery, occlusion of a branch renal artery, and occasionally thrombotic occlusion of the main renal artery may occur. In experienced hands, rupture of the renal artery is rare. Minor complications relate primarily to the puncture site. When the axillary approach is used (because of severe iliac and lower abdominal aortic atherosclerosis), median nerve compression may transpire. Some of these complications of percutaneous transluminal renal angioplasty, particularly atheroembolic renal failure and/or contrast-induced acute renal failure (ARF) may also be observed with renal artery stent procedures.

3.23

FACTORS TO CONSIDER IN SELECTION OF TREATMENT FOR PATIENTS WITH RENAL ARTERY DISEASE Is renal artery disease causing hypertension? Severity of hypertension Specific type of renal artery disease and threat to renal function General medical condition of patient Relative efficacy and risk of medical antihypertensive therapy, PTRA, renal artery stenting, surgical revascularization

FIGURE 3-49 Selection of treatment for patients with renal artery disease. In selecting treatment options for patients with renal artery disease, there are several factors to consider: what is the likelihood that the renal artery disease is causing the hypertension? For patients with fibrous renal artery disease the likelihood is high; for patients with atherosclerotic renal artery disease (ASO-RAD), the likelihood for a cure of hypertension is small. The more severe the hypertension, the greater the inclination to intervene with either surgery or balloon angioplasty. For children, adolescents, and younger adults, most of whom will have fibrous renal artery disease, intervention is usually recommended to avoid lifelong antihypertensive therapy. Cardiovascular comorbidity is high for patients with ASO-RAD and appropriate caution in approaching these patients is warranted, weighing the relative efficacy and risk of medical antihypertensive therapy, percutaneous transluminal renal angioplasty (PTRA), renal artery stenting, and surgical revascularization. Local experience and expertise of the treating physicians must be considered as well in selection of treatment options for these patients.

References 1. Pohl MA: Renal artery stenosis, renal vascular hypertension and ischemic nephropathy. In Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown & Co; 1997: 1367–1427. 2. Rimmer JM, Gennari FJ: Atherosclerotic renovascular disease and progressive renal failure. Ann Intern Med 1993, 118:712–719. 3. Brown JJ, Davies DL, Morton JJ, et al.: Mechanism of renal hypertension. Lancet 1976, 1:1219–1221. 4. Hoffmann U, Edwards JM, Carter S, et al.: Role of duplex scanning for the detection of atherosclerotic renal artery disease. Kidney Int 1991, 39:1232–1239. 5. Olin JW, Piedmonte MR, Young JR, et al.: The utility of duplex ultrasound scanning of the renal arteries for diagnosing significant renal artery stenosis. Ann Intern Med 1995, 122:833–838. 6. Muller FB, Sealey JE, Case DB, et al.: The captopril test for identifying renovascular disease in hypertensive patients. Am J Med 1986, 80:633–644. 7. Nally JV, Olin JW , Lammert MD: Advances in noninvasive screening for renovascular hypertension disease. Cleve Clin J Med 1994, 61:328–336. 8. Mann SJ, Pickering TG: Detection of renovascular hypertension: state of the art: 1992. Ann Intern Med 1992, 117:845–853. 9. Ying CY, Tifft CP, Gavras H, Chobanian AV: Renal revascularization in the azotemic hypertensive patient resistant to therapy. N Engl J Med 1984, 311:1070–1075. 10. Novick AC, Pohl MA: Atherosclerotic renal artery occlusion extending into branches: successful revascularization in situ with a branched saphenous vein graft. J Urol 1979, 122:240–242.

11. Olin JW, Melia M, Young JR, et al.: Prevalence of atherosclerotic renal artery stenosis in patients with atherosclerosis elsewhere. Am J Med 1990, 88:46N–51N. 12. Vetrovec GW, Landwehr DM, Edwards VL: Incidence of renal artery stenosis in hypertensive patients undergoing coronary angiography. J Intervent Cardiol 1989, 2:69–76. 13. Harding MB, Smith LR, Himmelstein SI, et al.: Renal artery stenosis: prevalence and associated risk factors in patients undergoing routine cardiac catheterization. J Am Soc Nephrol 1992, 2:1608–1616. 14. Jacobson HR: Ischemic renal disease: an overlooked clinical entity? [clinical conference]. Kidney Int 1988, 34:729–743. 15. Novick AC: Patient selection for intervention to preserve renal function in ischemic renal disease. In Renovascular Disease. Edited by Novick AC, Scoble J, Hamilton G. London: WB Saunders; 1996:323–335. 16. Schreiber MJ, Pohl MA, Novick AC: The natural history of atherosclerotic and fibrous renal artery disease. Urol Clin North Am 1984, 11:383–392. 17. Hallett JW Jr, Textor SC, Kos PB, et al.: Advanced renovascular hypertension and renal insufficiency: trends in medical comorbidity and surgical approach from 1970 to 1993. J Vasc Surg 1995, 21:750–759. 18. Pohl MA: Renovascular hypertension: An internist’s point of view. In Hypertension. Edited by Punzi HA, Flamenbaum W. Mt. Kisco, NY: Futura Publishing Co Inc; 1989:367–393.

3.24

Hypertension and the Kidney

Selected Bibliography Goldblatt H, Lynch J, Hanzal RF, Summerville WW: Studies on experimental hypertension. I. The production of persistent elevation of systolic blood pressure by means of renal ischemia. J Exp Med 1934, 59:347–381. Morris GC Jr, DeBakey ME, Cooley MJ: Surgical treatment of renal failure of renovascular origin. JAMA 1962, 182:113–116. Novick AC, Ziegelbaum M, Vidt DG, et al.: Trends in surgical revascularization for renal artery disease: ten years’ experience. JAMA 1987, 257:498–501. Dustan HP, Humphries AW, DeWolfe VG, et al.: Normal arterial pressure in patients with renal arterial stenosis. JAMA 1964, 187:1028–1029. Holley KE, Hunt JC, Brown ALJ, et al.: Renal artery stenosis: a clinicalpathological study in normotensive and hypertensive patients. Am J Med 1964, 34:14–22. Page IH: The production of persistent arterial hypertension by cellophane perinephritis. JAMA 1939, 113:2046–2048. McCormack LJ, Poutasse EF, Meaney TF, et al.: A pathologic-arteriographic correlation of renal arterial disease. Am Heart J 1966, 72:188–198.

Mailloux LU, Napolitano B, Bellucci AG, et al.: Renal vascular disease causing end-stage renal disease, incidence, clinical correlates, and outcomes: a 20-year clinical experience. Am J Kidney Dis 1994, 24:622–639. Appel RG, Bleyer AJ, Reavis S, Hansen KJ: Renovascular disease in older patients beginning renal replacement therapy. Kidney Int 1995, 48:171–176. Hansen KJ, Thomason RB, Craven TE, et al.: Surgical management of dialysisdependent ischemic nephropathy. J Vasc Surg 1995, 21:197–209. Hallett JW Jr, Fowl R, O’Brien PC, et al.: Renovascular operations in patients with chronic renal insufficiency: do the benefits justify the risks? J Vasc Surg 1987, 5:622–627. Conlon PJ, Athirakul K, Kovalik E, et al.: Survival in renal vascular disease. J Am Soc Nephrol 1998, 9:252–256. Textor SC, McKusick MA, Schirger AA, et al.: Atherosclerotic renovascular disease in patients with renal failure. Adv Nephrol Necker Hosp 1997, 27:281–295.

Pohl MA, Novick AC: Natural history of atherosclerotic and fibrous renal artery disease: clinical implications. Am J Kidney Dis 1985, 5:A120–A130. Zierler RE, Bergelin RO, Davidson RC, et al.: A prospective study of disease progression in patients with atherosclerotic renal artery stenosis. Am J Hypertens 1996, 9:1055–1061. Caps MT, Zierler RE, Polissar NL, et al.: Risk of atrophy in kidneys with atherosclerotic renal artery stenosis. Kidney Int 1998, 53:735–742.

Novick AC, Straffon RA, Stewart BH, et al.: Diminished operative morbidity and mortality in renal revascularization. JAMA 1981, 246:749–753.

Goncharenko V, Gerlock AJ Jr, Shaff MI, Hollifield JW: Progression of renal artery fibromuscular dysplasia in 42 patients as seen on angiography. Radiology 1981, 139:45–51.

Novick AC, Stewart R: Use of the thoracic aorta for renal revascularization. J Urol 1990, 143:77–79.

Vaughan ED Jr, Carey RM, Ayers CR, et al.: A physiologic definition of blood pressure response to renal revascularization in patients with renovascular hypertension. Kidney Int 1979, 15:S83–S92. Textor SC: Renovascular hypertension. Curr Opin Nephrol Hyperten 1993, 2:775–783. Working Group on Renovascular Hypertension: Detection, evaluation, and treatment of renovascular hypertension. Final report. Arch Intern Med 1987, 147:820–829. Hughes JS, Dove HG, Gifford RW Jr, Feinstein AR: Duration of blood pressure elevation in accurately predicting surgical cure of renovascular hypertension. Am Heart J 1981, 101:408–413. Svetkey LP, Himmelstein SI, Dunnick NR, et al.: Prospective analysis of strategies for diagnosing renovascular hypertension. Hypertension 1989, 14:247–257. Setaro JF, Saddler MC, Chen CC, et al.: Simplified captopril renography in diagnosis and treatment of renal artery stenosis. Hypertension 1991, 18:289–298. Novick AC, Pohl MA, Schreiber M, et al.: Revascularization for preservation of renal function in patients with atherosclerotic renovascular disease. J Urol 1983, 129:907–912. Gifford RW Jr, McCormack LJ, Poutasse EF: The atrophic kidney: its role in hypertension. Mayo Clin Proc 1965, 40:834–852. Pickering TG, Herman L, Devereux RB, et al.: Recurrent pulmonary oedema in hypertension due to bilateral renal artery stenosis: treatment by angioplasty or surgical revascularisation. Lancet 1988, 2:551–552. United States Renal Data System Coordinating Center: Incidence and causes of treated ESRD. In The USRDS 1994 Annual Data Report. Edited by Agodoa LYC, Held PJ, Port FK. Bethesda: USRDS Coordinating Center; 1994:43–54.

Khauli RB, Novick AC, Ziegelbaum M: Splenorenal bypass in the treatment of renal artery stenosis: experience with sixty-nine cases. J Vasc Surg 1985, 2:547–551. Chibaro EA, Libertino JA, Novick AC: Use of the hepatic circulation for renal revascularization. Ann Surg 1984, 199:406–411.

Tarazi RY, Hertzer NR, Beven EG, et al.: Simultaneous aortic reconstruction and renal revascularization: risk factors and late results in eighty-nine patients. J Vasc Surg 1987, 5:707–714. Hollenberg NK: Medical therapy of renovascular hypertension: efficacy and safety of captopril in 269 patients. Cardiovasc Rev Rpts 1983, 4:852–879. Pohl MA: Medical management of renovascular hypertension. In Renal Vascular Disease. Edited by Novick AC, Scoble J, Hamilton G. London: WB Saunders; 1996, 339–349. Palmaz JC, Kopp DT, Hayashi H, et al.: Normal and stenotic renal arteries: Experimental balloon-expandable intraluminal stenting. Radiology 1987, 164:705–708. Blum U, Krumme B, Flugel P, et al.: Treatment of ostial renal-artery stenoses with vascular endoprostheses after unsuccessful balloon angioplasty. N Engl J Med 1997, 336:459–465. Harden PN, MacLeod MJ, Rodger RSC, et al.: Effect of renal-artery stenting on progression of renovascular renal failure. Lancet 1997, 349:1133–1136. Fiala LA, Jackson MR, Gillespie DL, et al.: Primary stenting of atherosclerotic renal artery ostial stenosis. Ann Vasc Surg 1998, 12:128–133. Canzanello VJ, Millan VG, Spiegel JE, et al.: Percutaneous transluminal renal angioplasty in management of atherosclerotic renovascular hypertension: results in 100 patients. Hypertension 1989, 13:163–172. Plouin PF, Chatellier G, Darne B, Raynaud A, for the Essai Multicentrique Medicaments vs. Angioplastie (EMMA) Study Group: Blood pressure outcome of angioplasty in atherosclerotic renal artery stenosis: a randomized trial. Hypertension 1998, 31:823–829. Textor SC: Revascularization in atherosclerotic renal artery disease [clinical conference]. Kidney Int 1998, 53:799–811.

Adrenal Causes of Hypertension Myron H. Weinberger

T

he adrenal gland is involved in the production of a variety of steroid hormones and catecholamines that influence blood pressure. Thus, it is not surprising that several adrenal disorders may result in hypertension. Many of these disorders are potentially curable or responsive to specific therapies. Therefore, identifying adrenal disorders is an important consideration when elevated blood pressure occurs suddenly or in a young person, is severe or difficult to treat, or is associated with manifestations suggestive of a secondary form of hypertension. Because these occurrences are relatively rare, it is necessary to have a high index of suspicion and understand the pathophysiology on which the diagnosis and treatment of these problems is based. Three general forms of hypertension that result from excessive production of mineralocorticoids, glucocorticoids, or catecholamines are reviewed in the context of their normal production, metabolism, and feedback systems. The organization of this chapter provides the background for understanding the normal physiology and pathophysiologic changes on which effective screening and diagnosis of adrenal abnormalities are based. Therapeutic options also are briefly considered. Primary aldosteronism, Cushing’s syndrome, and pheochromocytoma are discussed.

CHAPTER

4

4.2

Hypertension and the Kidney

Adrenal Hypertension PHYSIOLOGIC MECHANISMS IN ADRENAL HYPERTENSION Disorder

Cause

Pathophysiology

Pressure mechanism

Primary aldosteronism

Autonomous hypersecretion of aldosterone (hypermineralocorticoidism)

Extracellular fluid volume expansion, hypokalemia (?), alkalosis

Cushing’s syndrome

Hypersecretion of cortisol (hyperglucocorticoidism)

Pheochromocytoma

Hypersecretion of catecholamines

Increased renal sodium and water reabsorption, increased urinary excretion of potassium and hydrogen ions Increased activation of mineralocorticoid receptor (?), increased angiotensinogen (renin substrate) concentration Vasoconstriction, increased heart rate

FIGURE 4-1 The causes and pathophysiologies of the three major forms of adrenal hypertension and the proposed mechanisms by which blood pressure elevation results.

Extracellular fluid volume expansion (?), increased angiotensin II (vasoconstriction and increased peripheral resistance) Increased peripheral resistance, increased cardiac output

Histology of the Adrenal FIGURE 4-2 Histology of the adrenal. A cross section of the normal adrenal before (left) and after (right) stimulation with adrenocorticotropic hormone (ACTH) [1]. The adrenal is organized into the outer adrenal cortex and the inner adrenal medulla. The outer adrenal cortex is composed of the zona glomerulosa, zona fasciculata, and zona reticularis. The zona glomerulosa is responsible for production of aldosterone and other mineralocorticoids and is chiefly under the control of angiotensin II (see Figs. 4-3 and 4-5). The zona fasciculata and zona reticularis are influenced primarily by ACTH and produce glucocorticoids and some androgens (see Figs. 4-3 and 4-19). The adrenal medulla produces catecholamines and is the major source of epinephrine (in addition to the organ of Zuckerkandl located at the aortic bifurcation) (see Fig. 4-25.)

Capsule Zona glomerulosa

Zona fasciculata

Zona reticularis Medulla Normal human suprarenal gland

Human suprarenal gland after administration of crude ACTH

Adrenal Causes of Hypertension

4.3

Adrenal Steroid Biosynthesis 17α−Hydroxylase

CH3 C=O

HO

Pregnenolone

CH3 O

C=O OH

HO 17-Hydroxypregnenolone

HO

Dehydroepiandrosterone

3 β-OH-Dehydrogenase: ∆5 ∆4 Isomerase

O

CH3

CH3

C=O

C=O –OH

O 17-Hydroxypregnenolone

Pregnenolone 21-Hydroxylase OH2OH

CH2OH

C=O

C=O OH

O 11-Deoxycorticosterone

O

11-Deoxycortisol

11β-Hydroxylase CH2OH HO

O

HO O

Corticosterone

18-Hydroxylase 18-OH-Dehrydrogenase CH2OH HO

O

CH2OH

C=O

OHC C=O

Aldosterone

Cortisol

}

Zona glomerulosa only

C=O OH

O

O ∆4 Androstene 3,17-dione

FIGURE 4-3 Adrenal steroid biosynthesis. The sequence of adrenal steroid biosynthesis beginning with cholesterol is shown as are the enzymes responsible for production of specific steroids [2]. Note that aldosterone production normally occurs only in the zona glomerulosa (see Fig. 4-2). (From DeGroot and coworkers [2]; with permission.)

4.4

Hypertension and the Kidney

ACTH PRA

Aldosterone Cortisol Morning

6 AM

Noon

6 PM

Morning

FIGURE 4-4 Circadian rhythmicity of steroid production and major stimulatory factors. Aldosterone and cortisol and their respective major stimulatory factors, plasma renin activity (PRA) and adrenocorticotropic hormone (ACTH), demonstrate circadian rhythms. The lowest values for all of these components are normally seen during the sleep period when the need for active steroid production is minimal. ACTH levels increase early before awakening, stimulating cortisol production in preparation for the physiologic changes associated with arousal. PRA increases abruptly with the assumption of the upright posture, followed by an increase in aldosterone production and release. Both steroids demonstrate their highest values through the morning and early afternoon. Cortisol levels parallel those of ACTH, with a marked decline in the afternoon and evening hours. Aldosterone demonstrates a broader peak, reflecting the postural stimulus of PRA.

Kidney ↓Perfusion pressure

Kidney

Juxtaglomerular apparatus

1

↑Perfusion pressure

↓Sodium content

↑Sodium content 6

↑Extracellular fluid volume

Juxtaglomerular apparatus

9 12

Renin

Renin

2

Angiotensin II

5

↑Extracellular fluid volume 8

↑Sodium reabsorption

Adrenal complex

Aldosterone

Zona glomerulosa

4

10

Angiotensin II 11

↑Sodium reabsorption

Adrenal complex

Aldosterone

Zona glomerulosa

7

13

14

A

Normal

K+

ACTH

B

Primary aldosteronism

K+

ACTH

FIGURE 4-5 Control of mineralocorticoid production. A, Control of aldosterone production under normal circumstances. A decrease in renal perfusion pressure or tubular sodium content (1) at the level of the juxtaglomerular apparatus and macula densa of the kidney triggers renin release (2). Renin acts on its substrate angiotensinogen to generate angiotensin I, which is converted rapidly by angiotensin-converting enzyme to angiotensin II. Angiotensin II then induces peripheral vasoconstriction to increase perfusion pressure (6) and acts on the zona glomerulosa of the adrenal cortex (3) (see Fig. 4-2) to stimulate production and release of aldosterone (4). Potassium and adrenocorticotropic hormone (ACTH) also play a minor role in aldosterone production in some circumstances. Aldosterone then acts on the cells of the collecting duct of the kidney to promote reabsorption of sodium (and passively, water) in exchange for potassium and hydrogen ions excreted in the urine. This increased secretion promotes expansion of extracellular fluid volume and an increase in renal tubular sodium content (5) that further suppresses renin release, thus closing the feedback loop (servomechanism). B, Abnormalities present in primary aldosteronism. Autonomous hypersecretion of aldosterone (7) leads to increased extracellular fluid volume expansion and increased renal tubular sodium content. These elevated levels are a result of increased renal

sodium and water reabsorption (8) at the expense of increased potassium and hydrogen ion excretion in the urine. The increase in sodium and volume then increase systemic blood pressure and renal perfusion pressure and sodium content (9), thereby suppressing further renin release (10) and angiotensin II production (11). Thus, in contrast to the normal situation depicted in panel A, the levels of angiotensin II are highly suppressed and therefore do not contribute to an increase in systemic blood pressure (12). In primary aldosteronism, ACTH (13) has a dominant modulatory role in influencing aldosterone production and hypokalemia, resulting from increased urinary potassium exchange for sodium, which has a negative effect on aldosterone production (14).

4.5

Adrenal Causes of Hypertension

Aldosteronism TYPES OF PRIMARY ALDOSTERONISM Types

SCREENING TESTS FOR PRIMARY ALDOSTERONISM

Relative frequency, %

Solitary adrenal adenoma Bilateral adrenal hyperplasia Unilateral adrenal hyperplasia Glucocorticoid-remediable aldosteronism Bilateral solitary adrenal adenomas Adrenal carcinoma

Test Serum potassium ≤3.5 mEq/L Plasma renin activity ≤4 ng/mL/90 min Urinary aldosterone ≥20 µg/d Plasma aldosterone ≥15 ng/dL Plasma aldosterone–plasma renin activity ratio ≥15 Plasma aldosterone–plasma renin activity ratio ≥30

65 30 2 <1 <1 <1

FIGURE 4-6 Types of primary aldosteronism. (Data from Weinberger and coworkers [3].)

Sensitivity, % 75 >99 70 90 99.8 96

Specificity, % ≈20 40–60 60 60 98 100

FIGURE 4-7 Screening tests for primary aldosteronism. Serum potassium levels range from 3.5 to normal levels of patients with primary aldosteronism. Most hypertensive patients with hypokalemia have secondary rather than primary aldosteronism. The plasma aldosterone-to-plasma renin activity (PRA) ratio (disregarding units of measure) is the most sensitive and specific single screening test for primary aldosteronism. However, because of laboratory variability, normal ranges must be developed for individual laboratory values. A random peripheral blood sample can be used to obtain this ratio even while the patient is receiving antihypertensive medications, when the effects of the medications on PRA and aldosterone are considered. (Data from Weinberger and coworkers [3,4].)

LOCALIZING TESTS FOR PRIMARY ALDOSTERONISM Test Adrenal computed tomographic scan Adrenal isotopic scan Adrenal venography Adrenal magnetic resonance imaging Adrenal venous blood sampling with adrenocorticotropic hormone infusion

Sensitivity, %

Specificity, %

≈50 ≈50 ≈70 ? >92

≈60 ≈65 ≈80 ? >95

FIGURE 4-8 Localizing tests for primary aldosteronism. Adrenal venous blood sampling with determination of both aldosterone and cortisol concentrations during adrenocorticotropic hormone stimulation provides the most accurate way to identify unilateral hyperaldosteronism. This approach minimizes artefact owing to episodic steroid secretion and to permit correction for dilution of adrenal venous blood with comparison of values to those in the inferior vena cava. (see Fig. 4-12). (Data from Weinberger and coworkers [3].)

A FIGURE 4-9 Normal and abnormal adrenal isotopic scans. A, Normal scan. Increased bilateral uptake of I131-labeled iodo-cholesterol of normal adrenal tissue is shown above the indicated renal outlines. (Continued on next page)

4.6

Hypertension and the Kidney FIGURE 4-9 (Continued) B, Intense increase in isotopic uptake by the left adrenal (as viewed from the posterior aspect) containing an adenoma.

B FIGURE 4-10 Adrenal venography in primary aldosteronism. A, Typical leaflike pattern of the normal right adrenal venous drainage. B, In contrast, marked distortion of the normal venous anatomy by a relatively large (3-cmdiameter) adenoma of the left adrenal. Most solitary adenomas responsible for primary aldosteronism are smaller than 1 cm in diameter and thus usually cannot be seen using anatomic visualizing techniques.

A

B

Normal

Plasma aldosterone, ng/dL

60

Adenoma

Hyperplasia

50 40 30 20 10 0

8 AM Supine

A

Noon Upright

8 AM Supine

B

8 AM Supine

Noon Upright

Noon Upright

C

FIGURE 4-11 Changes in plasma aldosterone with upright posture. A–C, Depicted are individual data for persons showing temporal and postural changes in plasma aldosterone concentration in normal persons (panel A), and in patients with primary aldosteronism owing to a solitary adrenal adenoma (panel B) or to bilateral adrenal hyperplasia (panel C). Blood is sampled at 8 AM, while the patient is recumbent, and again at noon after 4 hours of ambulation.

In normal persons the increase in plasma renin activity associated with upright posture results in a marked increase in plasma aldosterone at noon compared with that at 8 AM (see Fig. 4-4). In adenomatous primary aldosteronism, the plasma renin activity is markedly suppressed and does not increase appreciably with upright posture. Moreover, aldosterone production is modulated by adrenocorticotropic hormone (which decreases from high levels at 8 AM to lower values at noon (see Fig. 4-4). Thus, these patients typically demonstrate lower levels of aldosterone at noon than they do at 8 AM. In patients with bilateral adrenal hyperplasia, the plasma renin activity tends to be more responsive to upright posture and aldosterone production also is more responsive to the renin-angiotensin system. Thus, postural increases in aldosterone usually are seen. Exceptions to these changes occur in both forms of primary aldosteronism, however, making the postural test less sensitive and specific [3].

4.7

AC TH

TH AC

TH AC

AC TH

Adrenal Causes of Hypertension

A C

A C A C

A C

A C

A

Bilateral aldosteronism

FIGURE 4-12 Adrenal venous blood sampling during infusion of adrenocorticotropic hormone (ACTH) [3]. A, Bilateral aldosteronism. A schematic representation of the findings in primary aldosteronism owing to bilateral adrenal hyperplasia is shown on the left. When blood is sampled from both adrenal veins and the inferior vena cava during ACTH infusion, the aldosterone-to-cortisol ratio is similar in both adrenal effluents and higher than that in the inferior vena cava. In such cases, medical therapy (potassium-sparing diuretic combinations such as hydrochlorothiazide plus triamterene, amiloride, or spirolactone and calcium channel entry blockers) usually is effective. B, Unilateral aldosteronism. On the right is depicted the findings in a patient with a unilateral right adrenal lesion. This lesion can be diagnosed by an elevated aldosterone-to-cortisol ratio in right adrenal

A C

B

Unilateral aldosteronism

venous blood compared with that of the left adrenal and the inferior vena cava. Even if the venous effluent cannot be accurately sampled from one side (as judged by the levels of cortisol during ACTH infusion), when the contralateral adrenal venous effluent has an aldosterone-to-cortisol ratio lower than that in the inferior vena cava, it can be inferred that the unsampled side is the source of excessive aldosterone production (unless there is an ectopic source). In such cases, surgical removal of the solitary adrenal lesion usually results in normalization of blood pressure and the attendant metabolic abnormalities. Medical therapy also is effective but often requires high doses of Aldactone® (GD Searle & Co., Chicago) (200 to 800 mg/d), which may be intolerable for some patients because of side effects. A—aldosterone; C—cortisol.

4.8

Hypertension and the Kidney FIGURE 4-13 (see Color Plate) A section of a typical adrenal adenoma in primary aldosteronism pathology. A relatively large (2-cm-diameter) adrenal adenoma with its lipid-rich (bright yellow) content is shown.

180

FIGURE 4-14 Glucocorticoid-remediable aldosteronism. A–C, Seen are the effects of dexamethasone and spironolactone on blood pressure in a father (panel A) and two sons, one aged 6 years (panel B) and the other aged 8 years (panel C). Blood pressure levels are shown before and after treatment with dexamethasone (left) or spironolactone (right) [5]. Note that the maximum blood pressure reduction with dexamethasone required more than 2 weeks of treatment. Similarly, the maximum response to spironolactone was both time- and dose-dependent.

Father

160 140 120 100 80

mg 200 100

60

A Son 1

Blood pressure

160

Dexamethasone

Spironolactone

140 120 100 80 60

B

200 100

40 Son 2

160 140 120 100 80 60

200 100

40

C

0

1

2

3 4 Weeks

5

6

0

2

4 6 Months

8

Adrenal Causes of Hypertension

Urinary aldosterone, µg/ 24 h

20 15 10 5

0

1

2

3

4

20 15 10

Dexamethasone

5

B

5

1.0

0

1

2

3

4

5

50

0.8 0.6 0.4 0.2

Serum potassium, mEq/L

A Plasma renin activity, ng AI/mL- 3hr

25

25

Plasma aldosterone, ng/100 mL

Plasma cortisol, µg/ 100 mL

Changes with dexamethasone

40 30 20 10

7 6 5 4 3

0

C

0

1

2

3

4

5

0

D

1

2

3

4

5

E

0

1

2

3

4

Weeks

FIGURE 4-15 Humoral changes in glucocorticoid-remediable aldosteronism with dexamethasone. A–E, Depicted are the changes in plasma cortisol (panel A), urinary aldosterone (panel B), plasma renin activity (PRA) (panel C), plasma aldosterone (panel D), and serum potassium (panel E) before and after dexamethasone administration in the patients in Figure 4-14. Note that before dexamethasone administration, serum cortisol was in the normal range and was markedly suppressed after treatment. Urinary aldosterone was completely normal and plasma aldosterone was

Glomerulosa

Glomerulosa

AII

AII Aldosterone

Aldosterone

ACTH

Aldosterone

ACTH Cortisol Chimeric Aldos

Fasciculata

A

Fasciculata

B

Aldosterone

Cortisol + Aldosterone + 18–OH cortisol + 18–OXO cortisol

4.9

elevated in only one patient before dexamethasone administration. The diagnosis was made by demonstrating that the plasma aldosterone concentration failed to suppress normally after intravenous saline infusion (2 L/4 h) [6]. After dexamethasone administration, both plasma and urinary aldosterone levels decreased markedly (except for one occasion when it is suspected that the patient did not comply with dexamethasone therapy). PRA, which was markedly suppressed before treatment, increased with dexamethasone. Note also that serum potassium levels were normal in two of the three patients before treatment with dexamethasone but increased with therapy in all three [5]. All of these changes reverted to control baseline values when dexamethasone therapy was discontinued.

FIGURE 4-16 Normal and chimeric aldosterone synthase in glucocorticoid-remedial aldosteronism (GRA). A, Normal relationship between the stimuli and site of adrenal cortical steroid production. Aldosterone synthase normally responds to angiotensin II (AII) in the zona glomerulosa, resulting in aldosterone synthesis and release (see Figs. 4-2 and 4-3). B, In GRA, a chimeric aldosterone synthase gene results from a mutation, which stimulates production of aldosterone and other steroids from the zona glomerulosa under the control of adrenocorticotropic hormone (ACTH) (Fig. 4-17). Thus, when ACTH production is suppressed by steroid administration, aldosterone production is reduced.

4.10

Hypertension and the Kidney FIGURE 4-17 Mutation of the (11-OHase) chimeric aldosterone synthase gene [8]. The unequal crossing over between aldosterone synthase and 11-hydroxylase genes resulting in the mutated gene responsible for glucocorticoid-remedial aldosteronism is described.

11–OHase 5'

3'

5'

3'

Unequal crossing over

5'

3'

Aldosterone synthase

5'

3'

5'

3'

5'

3'

5'

3'

Chimeric gene

11–OHase

Cushing’s Syndrome

B

A

FIGURE 4-18 (see Color Plate) Physical characteristics of Cushing’s syndrome. A, Side profile of a patient with Cushing’s syndrome demonstrating an increased cervical fat pad (so-called buffalo hump), abdominal obesity, and thin extremities and petechiae (on the wrist). The round (so-called moon) facial appearance, plethora, and acne cannot be seen readily here. B, Violescent abdominal striae in a patient with Cushing’s syndrome. Such striae also can be observed on the inner parts of the legs in some patients.

4.11

Adrenal Causes of Hypertension

Pituitary

Pituitary

Pituitary

CRF

(–) (–)

(–)

Cortisol

ACTH

↑ Cortisol

ACTH

↑ Cortisol

↑ ACTH

Adrenal cortex (zona fasciculata zona reticularis)

FIGURE 4-19 Normal pituitary-adrenal axis. Corticotropinreleasing factor (CRF) acts to stimulate the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH then stimulates the adrenal zona fasciculata and zona reticularis to synthesize and release cortisol (see Figs. 4-2 and 4-3). The increased levels of cortisol feed back to suppress additional release of ACTH. As shown in Figure 4-4, ACTH and cortisol have circadian patterns.

Adrenal cortex (zona fasciculata zona reticularis)

Adrenal cortex (zona fasciculata zona reticularis)

FIGURE 4-20 Pituitary Cushing’s disease. Pituitary Cushing’s disease results from excessive production of adrenocorticotropic hormone (ACTH), typically owing to a benign adenoma. Excess ACTH stimulates both adrenals to produce excessive amounts of cortisol and results in bilateral adrenal hyperplasia. The increased cortisol production does not suppress ACTH release, however, because the pituitary tumor is unresponsive to the normal feedback suppression of increased cortisol levels. The diagnosis usually is made by demonstration of elevated levels of ACTH in the face of elevated cortisol levels, particularly in the afternoon or evening, representing loss of the normal circadian rhythm (see Fig. 4-4). Radiographic studies of the pituitary (computed tomographic scan and magnetic resonance imaging) will likely demonstrate the source of increased ACTH production. When the pituitary is the source, surgery and irradiation are therapeutic options.

FIGURE 4-21 Adrenal Cushing’s syndrome. Adrenal Cushing’s syndrome typically is caused by a solitary adrenal adenoma (rarely by carcinoma) producing excessive amounts of cortisol autonomously. The increased levels of cortisol feed back to suppress release of adrenocorticotropic hormone (ACTH) and corticotropin-releasing factor. The finding of very low ACTH levels in the face of elevated cortisol values and a loss of the circadian pattern of cortisol confirm the diagnosis (see Fig. 4-4). Additional anatomic studies of the adrenal (computed tomographic scan and magnetic resonance imaging) usually disclose the source of excessive cortisol production. Surgical removal usually is effective.

4.12

Hypertension and the Kidney

Cushing's syndrome: ectopic etiology

SCREENING TESTS FOR CUSHING’S SYNDROME

Ectopic Tumor

Test Pituitary

Elevated PM serum cortisol Elevated urinary 17-hydroxy corticosteroids Elevated urinary free cortisol

Sensitivity, %

Specificity, %

≈75 >90 >95

≈60 ≈60 >95

(–)

Cortisol

ACTH ACTH

FIGURE 4-23 Screening tests for Cushing’s syndrome. Whereas elevated evening plasma cortisol levels typically indicate abnormal circadian rhythm, other factors such as stress also can cause increased levels late in the day. Urinary levels of 17-hydroxy corticosteroids may be increased in association with obesity. In such cases, repeat measurement after a period of dexamethasone suppression may be required to distinguish this form of increased glucocorticoid excretion from Cushing’s syndrome. The measurement of urinary-free cortisol is the most sensitive and specific screening test.

Adrenal cortex (zona fasciculata zona reticularis)

FIGURE 4-22 Ectopic etiology of Cushing’s syndrome. Rarely, Cushing’s syndrome may be due to ectopic production of adrenocorticotropic hormone (ACTH) from a malignant tumor, often in the lung. In such cases, hypercortisolism is associated with increased levels of ACTH-like peptide; however, no pituitary lesions are found. Patients with ectopic Cushing’s syndrome often are wasted and have other manifestations of malignancy.

FIGURE 4-24 Algorithm for differentiation of Cushing’s syndrome. The first step in the differentiation of Cushing’s syndrome after diagnosing hypercortisolism is measurement of plasma adrenocorticotropic hormone (ACTH) levels. Typically, these should be reduced after

the morning hours (see Fig. 4-4). In pituitary Cushing’s disease and ectopic forms of Cushing’s syndrome, elevated values are observed, especially in the afternoon and evening. The next step in differentiation is an anatomic evaluation of the pituitary. When no abnormality is found, the next step is a search for a malignancy, typically in the lung. The finding of low ACTH levels points to the adrenal as the source of excessive cortisol production, and anatomic studies of the adrenal are indicated. CT— computed tomography; MRI—magnetic resonance imaging.

Adrenal Causes of Hypertension

4.13

Catecholamines

FIGURE 4-25 Synthesis, actions, and metabolism of catecholamines. Depicted is the synthesis of catecholamines in the adrenal medulla [9]. Epinephrine is only produced in the adrenal and the organ of Zuckerkandl at the aortic bifurcation. Norepinephrine and dopamine can be produced and released at all other parts of the sympathetic nervous system. The kidney is the primary site of excretion of

catecholamines and their metabolites, as noted here. The kidney also can contribute catecholamines to the urine. The relative contributions of norepinephrine and epinephrine to biologic events is noted by the plus signs. BMR—basal metabolic rate; CNS—central nervous system; NEFA—nonesterified fatty acids; VMA—vanillylmandelic acid.

4.14

Hypertension and the Kidney

Pheochromocytoma Blood pressure taken at 2-min intervals 5-min intervals

150 100

240 230 220 210 190 180 170 160 140 130 120 110 90 80 70 60 40 30 20 10

0

50

Blood pressure, mm Hg

200

250

Calibrate

8:30

10

2

5:00

7:45

9

10

11

PM

PM

AM

AM

AM

AM

AM

AM

12 Noon

1 PM

During the attack: Blood pressure, 192/100 mm Hg Pulse 108 Respirations, 24

FIGURE 4-26 Paroxysmal blood pressure pattern in pheochromocytoma. Note the extreme variability of blood pressure in this patient with pheochromocytoma during ambulatory blood pressure monitoring [9]. Whereas most levels were within the normal

FIGURE 4-27 (see Color Plate) Neurofibroma associated with pheochromocytoma. Neurofibromas are sometimes found in patients with pheochromocytoma. These lesions are soft, fluctuant, and nontender and can appear anywhere on the surface of the skin. These lesions can be seen in profile in Figure 4-28.

range, episodic increases to levels of 200/140 mm Hg were observed. Such paroxysms can be spontaneous or associated with activity of many sorts. (Adapted from Manger and Gifford [9]; with permission.) FIGURE 4-28 Café au lait lesions in a patient with pheochromocytoma. These light-browncolored (coffeewith-cream-colored) lesions, sometimes seen in patients with pheochromocytoma, usually are larger than 3 cm in the largest dimension. In this particular patient, neurofibromas also are present and can be seen in profile.

4.15

Adrenal Causes of Hypertension

DISORDERS ASSOCIATED WITH PHEOCHROMOCYTOMA

FIGURE 4-29 Disorders associated with pheochromocytoma. In addition to the neurofibromas and café au lait lesions depicted in Figures 4-27 and 4-28, several other associated abnormalities have been reported in patients with pheochromocytoma. (From Ganguly et al. [9]; with permission.)

Cholelithiasis Renal artery stenosis Neurofibromas Café au lait lesions Multiple endocrine neoplasia, types II and III Von Hippel-Lindau syndrome (hemangioblastoma and angioma) Mucosal neuromas Medullary thyroid carcinoma

COMMON SYMPTOMS AND FINDINGS IN PHEOCHROMOCYTOMA Patients, % Symptoms Severe headache Perspiration Palpitations, tachycardia Anxiety Tremulousness Chest, abdominal pain Nausea, vomiting Weakness, fatigue Weight loss Dyspnea Warmth, heat intolerance Visual disturbances Dizziness, faintness Constipation Finding Hypertension: Sustained Paroxysmal Pallor Retinopathy: Grades I and II Grades III and IV Abdominal mass Associated multiple endocrine adenomatosis

82 67 60 45 38 38 35 26 15 15 15 12 7 7

61 24 44 40 53 9 6

FIGURE 4-30 Common symptoms and findings in pheochromocytoma. Note that severe hypertensive retinopathy, indicative of intense vasoconstriction, frequently is observed. (Adapted from Ganguly et al. [10].)

SCREENING AND DIAGNOSTIC TESTS IN PHEOCHROMOCYTOMA Test Elevated 24-h urinary catecholamines, vanillylmandelic acid, homovanillic acid, metanephrines Abnormal clonidine suppression test Elevated urinary “sleep” norepinephrine

Sensitivity, %

Specificity, %

≈85

≈80

≈75 >99

≈85 >99

FIGURE 4-31 Screening and diagnostic tests in pheochromocytoma. Drugs, incomplete urine collection, and episodic secretion of catecholamines can influence the tests based on 24-hour urine collections in a patient with a pheochromocytoma. The clonidine suppression test is fraught with false-negative and false-positive results that are unacceptably high for the exclusion of this potentially fatal tumor. The “sleep” norepinephrine test eliminates the problems of incomplete 24-hour urine collection because the patient discards all urine before retiring; saves all urine voided through the sleep period, including the first specimen on arising; and notes the elapsed (sleep) time [10]. The sleep period is typically a time of basal activity of the sympathetic nervous system, except in patients with pheochromocytoma (see Fig. 4-32).

4.16

Hypertension and the Kidney

Sleep urinary norepinephrine excretion, µg

1000

Patient I Patient II Patient III Patient IV Patient V Patient VI

100

FIGURE 4-32 Nocturnal (sleep) urinary norepinephrine. The values for urinary excretion of norepinephrine are shown for normal persons and patients with essential hypertension as mean plus or minus SD [10]. Values for patients with pheochromocytoma are indicated by symbols. Note that the scale is logarithmic and the highest value for patients with normal or essential hypertension was less than 30 µg, whereas the lowest value for a patient with pheochromocytoma was about 75 µg. Most patients with pheochromocytomas had values an order of magnitude higher than the highest value for patients with essential hypertension.

Maximum for normal Maximum for hypertensive

10

Hypertensive mean + SD

Normal mean + SD

0

LOCALIZATION OF PHEOCHROMOCYTOMA Test Abdominal plain radiograph Intravenous pyelogram Adrenal isotopic scan (meta-iodobenzoylguanidine) Adrenal computed tomographic scan

Sensitivity, %

Specificity, %

≈40 ≈60 ≈85

≈50 ≈75 ≈85

>95

>95

FIGURE 4-33 Localization of pheochromocytoma. Once the diagnosis of pheochromocytoma has been made it is very important to localize the tumor preoperatively so that the surgeon may remove it with a minimum of physical manipulation. Computed tomographic scan or MRI appears to be the most effective and safest techniques for this purpose [10]. The patient should be treated with -adrenergic blocking agents for 7 to 10 days before surgery so that the contracted extracellular fluid volume can be expanded by vasodilation.

FIGURE 4-34 Intravenous pyelogram in pheochromocytoma. Note the displacement of the left kidney (right) by a suprarenal mass.

Adrenal Causes of Hypertension

A

B

C

D

FIGURE 4-35 A–D, Computed tomographic scans in four patients with pheochromocytoma [10]. The black arrows identify the adrenal tumor in

A FIGURE 4-36 (see Color Plates) A and B, Pathologic appearance of pheochromocytoma before (panel A) and after (panel B) sectioning. This 3.5-cm-diameter

4.17

these four patients. Three patients have left adrenal tumors, and in one patient (panel B) the tumor is on the right adrenal.

B tumor had gross areas of hemorrhage noted by the dark areas visible in the photographs.

4.18

Hypertension and the Kidney

References 1.

Netter FH: Endocrine system and selected metabolic diseases. In Ciba Collection of Medical Illustrations, vol. 4; 1981:Section III, Plates 5, 26.

2.

DeGroot LJ, et al.: Endocrinology, edn 2. Philadelphia: WB Saunders; 1989:1544.

3.

Weinberger MH, Grim CE, Hollifield JW, et al.: Primary aldosteronism: diagnosis, localization and treatment. Ann Intern Med 1979, 90:386–395.

4.

Weinberger MH, Fineberg NS: The diagnosis of primary aldosteronism and separation of subtypes. Arch Intern Med 1993, 153:2125–2129.

5.

Grim CE, Weinberger MH: Familial, dexamethasone-suppressible normokalemic hyperaldosteronism. Pediatrics 1980, 65:597–604.

6.

Kem DC, Weinberger MH, Mayes D, Nugent CA: Saline suppression of plasma aldosterone and plasma renin activity in hypertension. Arch Intern Med 1971, 128:380–386.

7: Lifton RP, Dluhy RG, Powers M: Hereditary hypertension caused by chimeric gene duplications and ectopic expression of aldosterone synthase. Nat Genet 1992, 2:66–74. 8. Lifton RP, Dluhy RG, Powers M: A glucocorticoid-remediable aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992, 355:262–265. 9. Manger WM, Gifford RW Jr: Pheochromocytoma. New York: Springer-Verlag; 1977:97. 10. Ganguly A, Henry DP, Yune HY, et al.: Diagnosis and localization of pheochromocytoma: detection by measurement of urinary norepinephrine during sleep, plasma norepinephrine concentration and computed axial tomography (CT scan). Am J Med 1979, 67:21–26.

Insulin Resistance and Hypertension Theodore A. Kotchen

R

esistance to insulin-stimulated glucose uptake is associated with increased risk for cardiovascular disease [1]. Risk factors for cardiovascular disease tend to cluster within individuals, and insulin resistance may be the link between hypertension and dyslipidemia. Depending on the populations studied and methodologies used for defining insulin resistance, approximately 25% to 40% of nonobese nondiabetic patients with hypertension are insulin-resistant [2]. Insulin resistance also has been observed in genetic and acquired animal models of hypertension. A constellation of insulin resistance, reactive hyperinsulinemia, increased triglycerides, decreased high-density lipoprotein cholesterol, and hypertension was designated as syndrome X by Reaven in 1988 [3]. Although a number of putative mechanisms have been proposed, it is unclear whether insulin resistance or reactive hyperinsulinemia, or both, actually cause hypertension. The recent observations that insulinsensitizing agents attenuate the development of hypertension lend credence to this hypothesis [4]. As discussed subsequently, however, these agents may lower blood pressure by different mechanisms. Whatever mechanism may be involved, the observation that a single agent may have the capacity to both increase insulin sensitivity and lower blood pressure is potentially of considerable clinical significance. Non–insulin-dependent diabetes mellitus represents an extreme of insulin resistance. Among diabetics, a two- to threefold increased prevalence of hypertension exists. Hypertension is associated with a fourfold increase in mortality among patients with non–insulin-dependent diabetes, and antihypertensive drug therapy has a beneficial impact on both macrovascular and microvascular disease [5]. Despite the potential concern that diuretics may augment insulin resistance, diabetic patients benefit from antihypertensive therapy with diuretics. The renal protective effect of antihypertensive drugs varies among different classes of agents. Angiotensin-converting enzyme inhibitors decrease proteinuria and retard the progression of renal insufficiency in diabetic patients with normal blood pressure and hypertension.

CHAPTER

5

5.2

Hypertension and the Kidney

This benefit is independent of an effect on blood pressure and may be related specifically to the capacity of these agents to dilate the efferent renal arteriole. Results of studies evaluating the effects of calcium antagonists on the progression of diabetic nephropathy are varied. Some studies suggest that

Men

7.0

dihydropyridine calcium antagonists accelerate the progression of diabetic nephropathy, particularly in the short term. Additional studies are required to evaluate the antihypertensive potential of insulin-sensitizing agents in patients with non–insulin-dependent diabetes.

Women

Total cholesterol, mmol/L

50–54 y

6.5

40–49 y

6.0

30–39 y

B. NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY II

40–49 y

30–39 y

5.5 20–29 y

1. Persons with blood pressure >140/90 mm Hg or taking medication for hypertension: 40% have cholesterol >240 mg/dL 2. Persons with blood cholesterol >240 mg/dL: 46% have blood pressure >140/90 mm Hg

20–29 y

5.0 70

80

A

90 100 70 80 90 Diastolic blood pressure, mm Hg

100

FIGURE 5-1 Hyperlipidemia and hypertension. A, Epidemiologic studies document an association between serum cholesterol and blood pressure in men and women. B, Based on data from the National Health

Epidemiologic + clinical association Hereditary + acquired mechanisms

Obesity

Insulin-resistance Hyperinsulinemia

Glucose tolerance ↓ Diabetes type II

Dyslipidemia, hypertension

and Nutrition Examination Survey II, persons with hypertension have a high prevalence of hyperlipidemia and vice versa [6]. (Panel A from Bonna and Thelle [7]; with permission.)

B. HYPERTENSION AND INSULIN RESISTANCE Type II diabetes mellitus Obesity Essential hypertension Salt sensitive (?) Experimental hypertension Dahl-salt-sensitive rats Spontaneously hypertensive rats

FIGURE 5-2 Insulin resistance and hypertension. A, Genetic and nutritional factors contribute to insulin resistance and resultant hyperinsulinemia. In addition to obesity and type II diabetes, hyperlipidemia and hypertension also may be associated with insulin resistance. Insulin resistance may account for the association of hyperlipidemia with hypertension. B, Insulin resistance is associated with hypertension in a number of clinical and experimental settings. (Panel A from Ferrari and Weidmann [8]; with permission.)

5.3

Insulin Resistance and Hypertension

120

* 80

*

Control group

40

Plasma insulin, µU/mL

0 60 40

*

20 0 0

30

60 Time, min

90

120

FIGURE 5-3 Insulin resistance based on glucose and insulin responses to glucose load. In response to an oral glucose load of 75 g, compared with persons with normal blood pressure, patients with hypertension tend to have higher plasma glucose and insulin levels. These data suggest that patients with hypertension are insulin resistant. (From Ferrannini and coworkers [9]; with permission.)

10 Glucose, mmol/L

Hypertensive patients

1 mmol/l = 0.0555 mg/dL

8 6 Salt-sensitive Salt-resistant

4 0

30

400

*

200

0

30

Count

*

60 90 Time, min

120

150

FIGURE 5-4 Salt sensitivity. Persons who have salt-sensitive hypertension tend to be more insulinresistant than are those who are saltresistant. That is, patients who are saltsensitive have higher plasma glucose and insulin responses to a glucose load than do those who are salt-resistant. (From Bigazzi and coworkers [10]; with permission.)

FIGURE 5-5 Insulin sensitivity. Insulin sensitivity also may be assessed using the euglycemic insulin clamp technique. The frequency distribution for insulin-mediated glucose disposal during euglycemic insulin clamping (M value) differs in persons with normal blood pressure and those with hypertension. The percentage of persons with hypertension considered insulin-resistant depends on the definition of insulin resistance. In this study, 27% of patients with hypertension were classified as being insulin-resistant based on an M value over two SDs above the mean for persons with normal blood pressure. (From Lind and coworkers [2]; with permission.)

10 8 6 4 2 0 4

150

1 pmol/L = 7.175 µU/mL

12

2

120

0

Hypertensive subjects Control subjects

0

90

600

16 14

60

800 Insulin, pmol/L

Plasma glucose, mg/100 mL

140

6

8

10

12

14

M value at clamp, mg/kg/min

SYNDROME X AND ASSOCIATED CONDITIONS Hypertension Hyperinsulinemia Increased triglycerides Decreased high-density lipoprotein cholesterol Increased low-density lipoprotein cholesterol Decreased plasminogen activator Increased plasminogen activator inhibitor Increased blood viscosity Increased uric acid Increased fibrinogen (?)

FIGURE 5-6 As originally defined, syndrome X includes hypertension, hyperinsulinemia, increased plasma triglycerides, and decreased HDL cholesterol. The syndrome also may be associated with clustering of additional cardiovascular disease risk factors.

5.4

Hypertension and the Kidney

Obesity

Vascular growth

Antinatriuresis

Increased α1– adrenegic receptors

Endothelial injury

Increased endothelial superoxide anion production

Increased degradation of nitric oxide

Hyperglycemia Hyperlipidemia

Impaired endotheliumdependent vasodilation

FIGURE 5-8 Metabolic consequences of insulin resistance. These consequences also may affect peripheral vascular resistance. Hypercholesterolemia may result in vascular endothelial injury and, hence, impaired vasodilation.

Hypercholesterolemia (low-density lipoprotein, lipoprotein (a))

FIGURE 5-7 Hypertension associated with insulin resistance. It is unclear whether hyperinsulinemia associated with insulin resistance causes hypertension, although a number of potential mechanisms have been proposed.

Genetic predisposition

Resistance to insulin-stimulated glucose uptake

Compensatory hyperinsulinemia

Increased sympathetic nervous system activity

Nutrition

High glucose Decreased nitric oxide production

Protein kinase C activation Increased sodium-hydrogen antiport activity

FIGURE 5-9 Results of high glucose concentrations. High glucose concentrations may inhibit nitric oxide production and alter ion transport in vascular smooth muscle cells, favoring vasoconstriction.

Impaired endothelium-dependent vasodilation

Sulfonylureas

R1

Biguanides R1 R2

SO2 NH C NH R2

Thiazolidinediones

N C NH C NH2

CH2

R1 O

NH

NH

O C1

O C NH CH2CH2

H 3C

SO2 NH C NH

H 3C

O

S

O NH

N N C NH C NH2 NH

CH3CH2

CH2CH2 O

CH2

NH O

Glyburide

Metformin

Pioglitazone

Systolic blood pressure, mm Hg

O NH

FIGURE 5-11 Pioglitazone in the treatment of hypertension in rats. A, Systolic blood pressures in Dahl-salt-sensitive rats treated with either vehicle or pioglitazone (a thiazolidinedione) for 3 weeks. Pioglitazone attenuated development of hypertension in this animal model. Weight gain did not differ in the two groups.

160 Control Pioglitazone

140 120

(Continued on next page)

100 80 0

A

S

FIGURE 5-10 Effects of chemically distinct oral hypoglycemic agents on blood pressure. Sulfonylureas stimulate endogenous insulin secretion and do not lower blood pressure. In contrast, biguanides and thiazolidinediones increase insulin sensitivity without stimulating endogenous insulin secretion, and drugs in these classes lower blood pressure.

2

4

6

8

10

12 Day

14

16

18

20

22

5.5

Insulin Resistance and Hypertension

B. HEMODYNAMIC MEASUREMENTS IN DAHL-SALT-SENSITIVE RATS

Control group Group treated with pioglitazone

MODELS IN WHICH THIAZOLIDINEDIONES LOWER BLOOD PRESSURE

Mean intra-arterial pressure, mm Hg

Cardiac index, mL/min/100 g

Total peripheral resistance, mm Hg/mL/min/100 g

129 ±1 121 ±3*

51.4 ±1.6 59.1±1.7*

2.50 ±0.07 2.07 ±0.07*

*P<0.05

FIGURE 5-11 (Continued) B, Direct intra-arterial pressure and cardiac index (thermodilution) in these same chronically instrumented, conscious pioglitazone-treated and control rats. Compared with control animals, rats treated with pioglitazone had lower mean arterial pressure, higher cardiac index, and lower total peripheral resistance. Thus, attenuation of hypertension by pioglitazone is due to a reduction of peripheral resistance. (From Dubey and coworkers [11]; with permission.)

AGENTS THAT INCREASE INSULIN SENSITIVITY, DECREASE PLASMA LIPID CONCENTRATIONS, AND LOWER BLOOD PRESSURE IN ANIMAL MODELS AND PRELIMINARY STUDIES IN HUMANS Thiazolidinediones Metformin Spontaneously hypertensive rats Humans (?) Vanadyl sulfate Spontaneously hypertensive rats Fructose-fed rats

Etomoxir Spontaneously hypertensive rats Clofibrate Dahl-salt-sensitive rats Fenfluramine derivatives Fructose-fed rats Humans

Mean arterial pressure, mm Hg

200

Dahl-S rat 1-Kidney, 1-clip rat Obese Zucker rat Fructose-fed rat L-NNA–treated rat SHR Obese rhesus monkey Watanabe hyperlipidemic rabbit Obese human

FIGURE 5-12 Thiazolidinediones lower blood pressure in several models of experimental hypertension and in obese humans. FIGURE 5-13 Agents that increase insulin sensitivity, decrease plasma lipid concentrations, and lower blood pressure in animal models and preliminary studies in humans.

Lovastatin/pravastatin Dahl-salt-sensitive rats Spontaneously hypertensive rats Human (?)

EFFECT OF CHOLESTEROL REDUCTION ON BLOOD PRESSURE RESPONSE TO MENTAL STRESS IN PATIENTS WITH NORMAL BLOOD PRESSURE AND HIGH CHOLESTEROL

180 160 140 120 100 80 Clofibrate Vehicle Clofibrate Vehicle Dahl-S

Placebo group Group treated with lovastatin

Systolic blood pressure

Diastolic blood pressure

Baseline

Stress

Baseline

Stress

122 119

141 133*

69 67

78 75

Dahl-R

FIGURE 5-14 Clofibrate in prevention of hypertension in rats. Clofibrate prevents the development of hypertension in Dahl salt-sensitive rats. This agent does not affect blood pressure in Dahl salt-resistant rats. (From Roman and coworkers [12]; with permission.)

FIGURE 5-15 In humans with normal blood pressure who have high serum cholesterol concentrations, treatment with lovastatin lowers serum cholesterol and attenuates the systolic blood pressure response to mathematics-induced stress. (From Sung and coworkers [13]; with permission.)

5.6

Hypertension and the Kidney FIGURE 5-16 Insulin-sensitizing and lipid-lowering agents may lower blood pressure by a number of different mechanisms. Different agents may act through different mechanisms.

ANTIHYPERTENSIVE MECHANISMS OF INSULIN-SENSITIZING AGENTS Block agonist-induced calcium ion entry into vascular smooth muscle cells Inhibit agonist-mediated vasoconstriction Inhibit growth of vascular smooth muscle cells Augment endothelium-dependent vasodilation Direct effect Metabolic effect Natriuresis Increase 20-hydroxy-eicosatetraenoic acid production Increase renal medullary blood flow

0.95

R172 #1–8 + 20 ng/mL PDGF

0.90

0.95

Intracellular [Ca2+]i

0.90 0.85 0.80

350

0.85 0.80 0.75

(59)

* P<0.05

200 150

0.70

0.65

50

0.65

0.60

(286) (290)

*

0 0 100 200 300 400 500 600 700 800

B

*

250

100

Time, s

Control Metformin

(73)

300

0.70

0.75

0 100 200 300 400 500 600 700 800

A

Arginine vasopressin

R172 #31–41 + 2 ug/mL ciglitazone + 20 ng/mL PDGF

Basal 450

Time, s

FIGURE 5-17 Use of ciglitazone to abolish calcium concentration elevation. Ciglitazone, a thiazolidinedione, abolishes agonist-stimulated sustained elevations of intracellular calcium concentrations. Shown are time-dependent plots of changes in intracellular calcium (in arbitrary units; [Ca2+]i) induced by platelet-derived growth factor (PDGF) in human gliobastoma cells with and without preincubation with ciglitazone. A, Addition of PDGF to control cells is indicated by the vertical line. B, An identical experiment conducted on cells pretreated with ciglitazone. The capacity of this agent to shorten the duration of agonist-stimulated increases in intracellular calcium may result in attenuation of both growth of vascular smooth muscle cells and vasoconstriction. (From Pershadsingh and coworkers [14]; with permission.)

Peak

400

Thrombin (213)

350

(231)

*

Delta

* P<0.05

300 [Ca2+]i(nM)

Intracellular [Ca2+]i

1.00

[Ca2+]i(nM)

1.05

250 *

200 150

(286) (290)

100 50 0 Basal

Peak

Delta

FIGURE 5-18 Use of metformin to attenuate intracellular calcium concentration elevation. Metformin is a biguanide that attenuates agonist-stimulated increases of intracellular calcium concentrations in vascular smooth muscle. (From Bhalla and coworkers [15]; with permission.)

Insulin Resistance and Hypertension

Cell number (x104)

28 24

Insulin

20

Insulin + pioglitazone (days 0–6)

16 12 8

Insulin + pioglitazone

4

0.4% FCS

0 0

2

4

6 8 10 Days in culture

12

FIGURE 5-19 Effect of pioglitazone on insulin-induced proliferation of arterial smooth muscle cells. Inhibition of insulin-stimulated vascular hyperplasia and hypertrophy is one potential mechanism by which insulin-sensitizing and lipid-lowering agents may decrease peripheral resistance. Two kinds of evidence suggest that thiazolidinediones inhibit the growth of vascular smooth muscle cells in vitro. Shown here, pioglitazone inhibits insulin-stimulated proliferation of vascular smooth muscle cells. Pioglitazone also inhibits 3H-thymidine incorporation in vascular smooth muscle cells (Fig. 5-19). FCS—fetal calf serum. (From Dubey and coworkers [11]; with permission.)

14

FIGURE 5-20 Effect of pioglitazone on 3H-thymidine incorporation in vascular smooth muscle cells. 3H-thymidine incorporation is stimulated by insulin, fetal calf serum (FCS), and epidermal growth factor (EGF). Pioglitazone inhibits 3H-thymidine incorporation stimulated by each of these mitogens. Similar observations have been made with pravastatin and lovastatin. (From Dubey and coworkers [11]; with permission.)

120 100 80 60 40

Insulin = 1 mU/mL EGF = 100 mg/mL 5% FCS

20

3

H-Thymidine incorporation, % of control

5.7

0 0.001

0.01

0.1

1

10

100

Pioglitazone concentration, uM

Control Pioglitazone

40

50 Percent of change

Percent of change

50

30 20 10

40 30 20

FIGURE 5-21 Decreases in mean arterial pressure in rats treated with pioglitazone and control Dahl-salt-sensitive rats in response to graded infusions of norepinephrine and angiotensin II. In vivo, pressor responses to norepinephrine and angiotensin are II attenuated in Dahl-salt-sensitive rats treated with pioglitazone [16]. (From Kotchen and coworkers [16]; with permission.)

10

0

0 0

Norepinephrine x 10–8 (log M)

Control Pioglitazone

100 200 300 400 500 Norepinephrine, ng/kg/min

3

0

*

2 1

0 Control

Insulin Pioglitazone Insulin + pioglitazone

100 200 300 400 500 Angiotensin II, ng/kg/min

FIGURE 5-22 Half-maximal values for norepinephrine-induced contraction in aortic strips preincubated with insulin, pioglitazone, or both. In vitro, pressor responsiveness of aortic strips to norepinephrine-induced contraction is inhibited by preincubation with insulin plus pioglitazone [16]. The half-maximal value is increased for strips incubated with insulin plus pioglitazone (ie, higher concentrations of norepinephrine are required to achieve half-maximal contraction) but not in strips incubated with insulin alone or pioglitazone alone.

5.8

Hypertension and the Kidney FIGURE 5-23 Impaired endothelium-dependent vascular relaxation and insulin resistance. Insulin resistance is associated with impaired endothelium-dependent vascular relaxation, which is a defect that may be corrected by insulin-sensitizing agents. One approach to evaluating vascular endothelial function is to measure vascular relaxation in response to acetylcholine. EDRF—endothelium derived relaxing factor.

Substance P Bradykinin Acetylcholine B Sodium P Gq protein M nitroprusside Endothelium Gi protein Nitric oxide L-arginine synthase Nitric oxide EDRF-nitric oxide

5 60

4 3 2

*

1 0 Control

Insulin Pioglitazone Insulin + pioglitazone

FIGURE 5-24 Half-maximal values for acetylcholineinduced vasodilation in aortic strips preincubated with insulin, pioglitazone, or both. In the presence of insulin, pioglitazone augments endothelium-dependent vasodilation. In vitro, the half-maximal values for acetylcholineinduced vasodilation is less in aortic strips incubated with insulin plus pioglitazone (ie, the strips are more responsive to acetylcholine) than in control strips or strips incubated with insulin alone or pioglitazone alone [16].

BENEFITS OF CONTROL OF HYPERTENSION AND DIABETES Hypertension Decreased nephropathy Decreased retinopathy Decreased stroke, myocardial infarction Drug specific (?) Diabetes (type I) Decreased nephropathy Decreased retinopathy Decreased neuropathy

Protein, pmol/min/mg

Acetylcholine x 10–7 (log M)

Smooth muscle

50

20-Hydroxy-eicosotetraenoic acid * P<0.05 Control, n = 9 Clofibrate, n = 12 *

+

2 Cl– + Na + K

*

40 30 20 10

(+)

+

K

+

+

20-HETE +

K

R

PLC 3 Na

All bradykinin vasopressin + Ca2

+

2K

*

+

–

Cl

0 Cortex Outer medulla

+

Na K Ca2 Mg2 AA PLA

Liver

FIGURE 5-25 Effect of clofibrate on 20-hydroxy-eicosatetraenoic (20-HETE) production in Dahlsalt-sensitive rats. Insulin stimulates sodium reabsorption in the proximal tubule. Consequently, lowering plasma insulin concentrations by increasing insulin sensitivity would potentially result in less sodium retention. In addition, clofibrate induces renal P-450 fatty acid w-hydroxylase activity and, hence, increases metabolism of arachidonic acid to 20-HETE. (From Roman and coworkers [12]; with permission.)

FIGURE 5-26 20-Hydroxy-eicosotetraenoic acid inhibits chloride transport in the thick ascending limb of the loop of Henle. This inhibition results in a natriuretic effect in the Dahl-salt-sensitive rat. This may be the mechanism by which clofibrate prevents hypertension in this animal model.

FIGURE 5-27 Benefits of hypertension control and blood glucose controls are well established in diabetic patients. Noninsulin-dependent diabetes mellitus represents an extreme of insulin resistance, and hypertension is a major contributor to the cardiovascular complications of diabetes. Despite the potential concern that diuretics increase insulin resistance, overall cardiovascular disease morbidity and mortality are reduced in diabetic patients with hypertension by antihypertensive therapy with regimens that include diuretics.

5.9

Glomerular filtration rate, mL/min/1-73 m2

Mean arterial blood pressure, mm Hg

Insulin Resistance and Hypertension

Start of antihypertensive treatment

125 115 105 95 105 GFR: 0.94 (mL/min/mo)

95 85

GFR: 0.29 (mL/min/mo) GFR: 0.10 (mL/min/mo)

75 65 55

Albuminuria, µg/min

1250 750 250 –2 –1 0

1

2

3

4

5

6

FIGURE 5-28 Course of diabetic nephropathy during effective antihypertensive treatment in patients with overt diabetic nephropathy. Effective antihypertensive therapy with regimens that include diuretics also decreases the rate of progression of renal failure (both the glomerular filtration rate and albumin excretion) in patients with diabetic nephropathy. (From Parving and coworkers [17]; with permission.)

50 45 40 35 30 25 20 15 10 5 0

Insulin sensitivity Renal protection

Angiotensin-converting enzyme inhibitors Diuretics -Blockers 1-Blockers Calcium ion antagonists Dihydropyridines Others

+ ? 0 0

0 Increase

-? +?

0.5

Percent risk reduction = 48.5% (16–69) P = 0.007

Risk reduction = 50.5% P = 0.006

0.4 0.3 0.2

Placebo

0.1 Captopril

0.0 0.5

Increase Decrease Decrease Increase

FIGURE 5-29 Different antihypertensive agents have different effects on insulin sensitivity, and in diabetic patients, on renal function. Question mark indicates inconsistent study results; plus sign indicates a protective effect; minus sign indicates no protection.

Placebo Captopril

0.0

A

Agent

Proportion with event

Percent doubling of baseline creatinine

Time, y

EFFECT OF ANTIHYPERTENSIVE AGENTS ON INSULIN SENSITIVITY AND RENAL FUNCTION IN DIABETIC PATIENTS

1.0

1.5 2.0 2.5 Years of follow-up

3.0

3.5

0

4.0

FIGURE 5-30 Cumulative incidence of events in patients with diabetic nephropathy in captopril and placebo groups. A, Time to doubling of serum creatinine. B, Time to end-stage renal disease or death. In type I diabetic patients with nephropathy and either normal blood pressure or hypertension, treatment with angiotensin-converting enzyme inhibitors

B

1

2 3 Years from randomization

4

4.5

decreases proteinuria and retards the rate of progression of renal insufficiency. The cumulative incidence of doubling of serum creatinine concentrations over time and development of end-stage renal disease are less in patients treated with captopril than in those treated with placebo. (From Lewis and coworkers [18]; with permission.)

5.10

Hypertension and the Kidney

CHANGES OF MEAN BLOOD PRESSURE, PROTEINURIA, AND GLOMERULAR FILTRATION RATE IN TREATMENT WITH DIFFERENT ANTIHYPERTENSIVE AGENTS IN PATIENTS WITH INSULIN-DEPENDENT DIABETES MELLITUS AND NON–INSULIN-DEPENDENT DIABETES MELLITUS WHO HAVE MICROALBUMINURIA OR MACROALBUMINURIA Treatment type Placebo Conventional (diuretics and -blockers) Angiotensin-converting enzyme inhibitors Calcium antagonists: All except nifedipine and nitrendipine Nifedipine Nitrendipine

Patients, n

MBP, %

UProt, %

GFR, %

244 213 489

-2 -10 -16

+39 -20 -52

-8 -9 -1

63 63 39

-16 -12 -17

-42 +2 -48

+2 -48 +30

FIGURE 5-31 Despite similar control of hypertension, different classes of antihypertensive agents have different effects on renal function in patients with

diabetic nephropathy. GFR—glomerular filtration rate; MBP—mean blood pressure; Uprot—urine protein. (From Bretzel [19]; with permission.)

References 1. Kotchen TA, Kotchen JM, O’Shaughnessy IM: Insulin and hypertensive cardiovascular disease. Curr Opin Cardiol 1996, 11:483–489. 2. Lind L, Berne C, Lithell H: Prevalence of insulin resistance in essential hypertension. J Hypertens 1995, 17:1457–1462. 3. Reaven GM: Role of insulin resistance in human disease. Diabetes 1988, 37:1595–1607. 4. Kotchen TA: Attenuation of hypertension by insulin-sensitizing agents. Hypertension 1996, 28:219–223. 5. Nadig V, Kotchen TA: Insulin sensitivity, blood pressure and cardiovascular disease. Cardiol Rev 1997, 5:213–219. 6. National High Blood Pressure Education Program and National Cholesterol Education Program: Working Group Report on Management of Patients with Hypertension and High Blood Cholesterol. National Institutes of Health Publication No. 90-2361. National Institutes of Health, 1990. 7. Bonna KH, Thelle DJ: Association between blood pressure and serum lipids in a population: the Tromso study. Circulation 1991, 83:1305–1324. 8. Ferrari P, Weidmann P: Insulin, insulin sensitivity and hypertension. J Hypertens 1990, 8:491–500. 9. Ferrannini E, Buzzigoli E, Bonadonna R, et al.: Insulin resistance in essential hypertension. N Engl J Med 1987, 317:350–357. 10. Bigazzi R, Bianchi S, Baldari G, et al.: Clustering of cardiovascular risk factors in salt-sensitive patients with essential hypertension: role of insulin. Am J Hypertens 1996, 9:24–32.

11. Dubey RK, Zhang HY, Reddy SR, et al.: Pioglitazone attenuates hypertension and inhibits growth in renal arteriolar smooth muscle in rats. Am J Physiol 1993, 265:R726–R732. 12. Roman RJ, Ma Y-H, Frohlich B, et al.: Clofibrate prevents the development of hypertension in Dahl salt-sensitive rats. Hypertension 1993, 21:985–988. 13. Sung BH, Izzo JL, Wilson MF: Effects of cholesterol reduction on BP response to mental stress in patients with high cholesterol. Am J Hypertens 1997, 10:592–599. 14. Pershadsingh H, Szollosi J, Benson S, et al.: Effects of ciglitazone on blood pressure and intracellular calcium metabolism. Hypertension 1993, 21:1020–1023. 15. Bhalla RC, Toth KF, Tan EQ, et al.: Vascular effects of metformin: possible mechanisms for its antihypertensive action in the spontaneously hypertensive rat. Am J Hypertens 1996, 9:570–576. 16. Kotchen TA, Zhang HY, Reddy S, et al.: Effect of pioglitazone on vascular reactivity in vivo and in vitro. Am J Physiol 1996, 260:R660–R666. 17. Parving H-H, Andersen AR, Smidt UM, et al.: Effect of antihypertensive treatment on kidney function in diabetic nephropathy. Br Med J 1987, 294:1443–1447. 18. Lewis EJ, Hunsicker LG, Bain RP, et al.: The effect of angiotensinconverting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993, 329:1456–1462. 19. Bretzel RG: Effects of antihypertensive drugs on renal function in patients with diabetic nephropathy. Am J Hypertens 1997, 10:208S–217S.

The Role of Hypertension in Progression of Chronic Renal Disease Lance D. Dworkin Douglas G. Shemin

H

ypertension is a cause and consequence of chronic renal disease. Data from the United States Renal Data System (USRDS) identifies systemic hypertension as the second most common cause of end-stage renal disease, with diabetes mellitus being the first. Renal failure in patients with hypertension has many causes, including functional impairment secondary to vascular disease and hypertensive nephrosclerosis. Even in those in whom hypertension is not the primary process damaging the kidney, elevations in systemic blood pressure may accelerate the rate at which kidney function is lost. This accelerated loss of kidney function occurs particularly in patients with glomerular diseases and clinically evident proteinuria. Hypertension may damage the kidney by several mechanisms. Because autoregulation of glomerular pressure is impaired in chronic renal disease, elevations in systemic blood pressure also are associated with increased glomerular capillary pressure. Glomerular hypertension results in increased protein filtration and endothelial damage, causing increased release of cytokines and other soluble mediators that promote replacement of normal kidney tissue by fibrosis. An important factor contributing to progressive renal disease is activation of the renin-angiotensin system, which not only tends to increase blood pressure but also promotes cell proliferation, inflammation, and matrix accumulation. Numerous studies in experimental animals suggest that antihypertensive drugs can slow the progression of chronic renal disease. Drugs that inhibit the renin-angiotensin system may be more effective than are other agents in retarding renal disease progression. For many reasons, the effects of angiotensin II receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors may not

CHAPTER

6

6.2

Hypertension and the Kidney

be identical. Calcium channel blockers also are beneficial in some settings; however, this effect is critically dependent on the degree of blood pressure reduction. The relationship between hypertension and progression of chronic renal disease has been examined in a number of clinical trials. Individuals with systemic hypertension are at increased risk for developing end-stage renal disease. The rate at which kidney function is lost increases in patients with poorly controlled systemic hypertension. Antihypertensive therapy can slow the rate of loss of kidney function in patients with diabetic and nondiabetic renal disease. Studies suggest that ACE inhibitors are particularly useful in patients with hypertension and proteinuria of over 1g/24 h. Calcium channel blockers also may slow the progression of renal disease; however, whether all

classes of calcium channel blockers have equivalent renal protective effects is uncertain. Patients with hypertension and chronic renal disease should be treated aggressively. A 24-hour urine collection determines the extent of proteinuria. The patient who excretes more than 1 g/24 h of protein or who has diabetes mellitus should receive an ACE inhibitor. The target in this group of patients is to reduce the blood pressure to lower than 120/80 mm Hg. Most often, reaching this goal requires the use of combinations of antihypertensive agents, diuretics, or calcium channel blockers. Patients who excrete less than 1 g/24 h of protein may be treated according to standard recommendations with diuretics, beta blockers, ACE inhibitors, or other agents. The target blood pressure for this group of patients is lower than 130/85 mm Hg.

Hypertension and Kidney Damage Partial loss of function

Fibrosis apoptosis

Compensatory growth

Renin AII activation

Afferent vasodilation

Systemic hypertension Release of cytokines and growth factors

Increased wall tension

Capillary injury

Proteinuria

Glomerular hypertension

FIGURE 6-1 Hypothesis identifying systemic hypertension as a central factor contributing to the progression of chronic renal disease. After partial loss of kidney function resulting from an undefined primary renal disease, a number of secondary processes develop that promote progressive kidney failure. Activation of the renin-angiotensin system is a common event in patients with chronic renal disease. In these patients, renin levels are either elevated or at least not

appropriately suppressed for the degree of volume expansion, elevation in blood pressure, or both. Activation of the reninangiotensin system and the relative salt and water excess contribute to the development of systemic hypertension in most patients with chronic renal disease. Systemic hypertension and a decrease in preglomerular vascular resistance lead to an increase in hydraulic pressure within the glomerular capillaries. Glomerular hypertension has a number of adverse effects, including increased protein filtration, which promotes release of cytokines and growth factors by mesangial cells and downstream tubular epithelial cells. A partial loss of kidney function also is a potent stimulus for compensatory renal growth. Glomerular hypertrophy and hypertension combine to increase capillary wall tension, promoting endothelial cell activation and injury, again causing release of cytokines and growth factors and recruitment of inflammatory cells. These mediators stimulate processes such as apoptosis, causing loss of normal kidney cells and increased matrix production, which leads to glomerular and interstitial fibrosis and scarring. As additional nephrons are damaged secondarily the cycle is repeated and amplified, causing progression to endstage renal failure. AII—antiotensin II.

The Role of Hypertension in Progression of Chronic Renal Disease

FIGURE 6-2 Imaginary autoregulation curves in normal and diseased kidneys. Plotted on the y-axis are renal plasma flow (RPF), glomerular filtration rate (GFR), and glomerular capillary hydraulic pressure (PGC) with undefined units. Ordinarily, RPF, GFR, and PGC remain relatively constant over a wide range of perfusion pressures within the physiologic range, from approximately 80 to 140 mm Hg. Because autoregulatory ability is impaired in the kidneys of persons with chronic renal disease, these patients who develop systemic hypertension also are likely to have glomerular hypertension.

PGC, RPF, or GFR

Typical autoregulatory response in normal kidneys RPF, GRF, and PGC vary with perfusion pressure in chronic renal failure

40

60

80

100

120

6.3

140

160

180

Renal perfusion pressure, mm Hg

PGC = PGC

RE

MAP

↑MAP

RA Baseline

↓RE ↑RA

Increased perfusion pressure

A

B

PGC < PGC

MAP

↓RE ↓RA

↑MAP

Baseline

A

FIGURE 6-3 Mechanism of autoregulation of glomerular capillary pressure in a single glomerulus from a normal kidney. A, Baseline. B, Increased perfusion pressure. Glomerular pressure is determined by three factors: mean arterial pressure (MAP) or perfusion pressure, and the relative resistance of both the afferent and efferent arterioles. The initial response to an increase in MAP is an increase in afferent arteriolar resistance (RA), preventing transmission of the elevated systemic pressure to the glomerular capillaries. Efferent arteriolar resistance (RE) also may decline. This decrease decompresses the glomerulus, helping to limit the increase in glomerular capillary hydraulic pressure (PGC), and maintains constant renal plasma flow.

→RE ↓RA

Increased perfusion pressure

B

FIGURE 6-4 Mechanism of failure of autoregulation in a glomerulus from a damaged kidney. A, Baseline. B, Increased perfusion pressure. To compensate for a partial loss of function, surviving glomeruli undergo adaptive changes to increase the filtration rate. These include a reduction in afferent (RA) and efferent (RE) arteriolar resistances, tending to increase renal plasma flow and the glomerular filtration rate. In this setting, an increase in mean arterial pressure (MAP) is transmitted directly to the glomerular capillaries, resulting in glomerular capillary hypertension, increased protein filtration, and hemodynamically mediated capillary injury. PGC— glomerular capillary hydraulic pressure.

6.4

Hypertension and the Kidney

Effects of Antihypertensive Agents on Experimental Kidney Injury 60

Results of the linear regression analysis Effects of going from low to high dose of triple therapy

40

Change in sclerosis, %

20 0 -20 -40 Unx–SHR Remnant–HD Remnant–LD Doc–salt NSN

-60 -80 -100 -1

-2

-3

-4

-5

-6

-7

-8

-9

-10

Change in PGC, mm Hg

FIGURE 6-5 Effects of triple therapy on glomerular pressure and injury. Relationship between the change in glomerular capillary hydraulic pressure (PGC) and the extent of glomerular injury (sclerosis) in

400 No treatment Enalapril Low dose triple therapy High dose triple therapy

Glomerular injury score

350 300 250 200 150 100 50 0 80

100

120

140

160

180

200

Overall averaged systolic blood pressure at final 8 week, mm Hg

five separate studies. In these studies, rats with experimental renal disease were given similar antihypertensive agents. Studies were conducted in several different animal models of hypertension and renal disease, including the following: uninephrectomized spontaneously hypertensive rats (Unx SHR); rats with a remnant kidney given either relatively high-dose (remnant-HD) or low-dose (remnant-LD) drug therapy; rats with desoxycorticosteronesalt–induced hypertension (Doc-salt); and rats with nephrotoxic serum nephritis (NSN), an immune-mediated form of glomerular disease (NSN) [1–5]. In all these studies, untreated rats were compared with those receiving a combination of three antihypertensive agents (triple therapy), including hydralazine, reserpine, and a thiazide diuretic. In rats with remnant kidneys, separate studies examined the effects of low or high doses of these agents. A close correlation was revealed between the degree of reduction in glomerular capillary pressure produced by triple therapy and subsequent development of glomerular sclerosis. The data are consistent with the hypothesis that antihypertensive agents lessen glomerular injury by reducing glomerular capillary pressure. In the studies in rats with remnant kidneys, only a relatively high dose of the drugs was effective in reducing pressure and injury, suggesting that aggressive antihypertensive therapy is more likely to slow progression of renal disease. This finding is particularly true for antihypertensive combinations that include direct vasodilators, such as the triple-therapy regimen. By dilating the afferent arteriole, regimens such as these tend to further impair autoregulation of glomerular pressure in the setting of chronic renal disease. (From Weir and Dworkin [6]; with permission.) FIGURE 6-6 Correlation between systolic blood pressure and glomerular injury in rats with remnant kidneys. In these rats, blood pressure was continuously monitored by implanting a blood pressure sensor in the abdominal aorta connected telemetrically to a receiver. The timeaveraged blood pressure in rats with remnant kidneys that were untreated or given the angiotensin-converting enzyme inhibitor enalapril or triple therapy (combination of hydralazine, reserpine, and a thiazide diuretic) was correlated with morphologic evidence of glomerular injury. A close correlation was found between the average blood pressure and extent of glomerular injury that developed in these rats. It is proposed that, because of impaired autoregulation in chronic renal disease, elevations in systemic blood pressure are associated with glomerular hypertension in these rats. The higher the systemic pressure, the higher the glomerular pressure is predicted to be and the more glomerular injury is observed. These data provide additional evidence that systemic hypertension produces glomerular injury by causing elevation in glomerular pressure, and that antihypertensive therapy reduces injury by reducing glomerular capillary pressure. (From Griffen and coworkers [7]; with permission.)

The Role of Hypertension in Progression of Chronic Renal Disease

Tension=pressure x radius

RGC

RGC

PGC

PGC

T T

A

B

A

B

C

D

6.5

FIGURE 6-7 The wall tension hypothesis. A, Normal. B, Chronic renal failure. After a partial loss of kidney function, compensatory adaptations within surviving nephrons include renal vasodilation. Vasodilation leads to an increase in glomerular capillary pressure and compensatory renal growth associated with an increase in the radius of the glomerular capillaries. According to the LaPlace equation, wall tension in a blood vessel is equal to the product of the transmural pressure and the radius of the vessel. In a surviving glomerular capillary of a damaged kidney, therefore, wall tension increases not only because of the increase in glomerular pressure but also because of an increase in capillary radius. Elevations in wall tension contribute to progressive renal disease by damaging the endothelial and epithelial cells lining the glomerular capillaries. By reducing wall tension, maneuvers that decrease either glomerular pressure or glomerular capillary radius are predicted to be beneficial. PGC—glomerular capillary hydraulic pressure; RGC—glomerular capillary radius; T—tension. (From Dworkin and Benstein [8]; with permission.) FIGURE 6-8 Scanning electron micrographs of vascular casts of glomeruli from normal or uninephrectomized rats. A, A glomerulus from a rat having had a sham operation, showing a uniform capillary pattern. (Panels B–D display casts from uninephrectomized rats.) B, A uniform pattern with most capillaries being approximately the same size. C and D, Nonuniform patterns in which individual capillary loops (indicated by asterisks) are markedly dilated. In dilated capillary loops, wall tension is elevated and capillary wall damage is most likely to occur. The segmental nature of the capillary dilation may explain why glomerular sclerosis that eventually develops in remnant kidneys is also focal in early stages of the disease process. (Panels A–D ≈320.) (From Nagata and coworkers [9]; with permission.)

6.6

Hypertension and the Kidney

Role of the Renin Angiotensin System Release of cytokines and growth factors

Increased protein filtration

Hyperplasia and hypertrophy

A II

Systemic and glomerular hypertension

FIGURE 6-9 The central role of angiotensin II(AII) in promoting progressive kidney failure. Based on studies in which the renin-angiotensin system has been blocked and renal injury ameliorated, it has been suggested that activation of this system is a crucial factor promoting progressive kidney failure. Increased activity of the renin-angiotensin system also may help explain the association between hypertension

and progression of renal disease. AII may promote renal injury by several mechanisms. Activation of the renin-angiotensin system is one mechanism leading to an increase in systemic blood pressure, the result of peripheral vasoconstriction. Glomerular hypertension results not only from the increase in systemic blood pressure but also because of the ability of AII to constrict efferent arterioles, contributing to an increase in glomerular pressure. Glomerular hypertension damages the glomerular capillary wall and promotes injury by multiple mechanisms (see Fig. 6-1). An increase in glomerular pressure tends to increase protein filtration directly. In addition, evidence suggests that AII alters the permeability of the glomerular capillary wall to macromolecules, directly increasing protein filtration. By activating mesangial and epithelial cells, proteinuria itself is a factor promoting progressive kidney failure. Evidence also exists that AII directly stimulates production of various growth factors and cytokines by kidney cells, including fibrogenic cytokines such as transforming growth factor-beta and platelet-derived growth factor. Release of these factors has been linked to the development of glomerular sclerosis and interstitial fibrosis. AII also stimulates proliferation and growth of kidney cells that contribute to progression of renal disease.

80

*

60

*

*

40

60 40

20 20 0

0 Remnant

AC EI

Triple

Remnant

AC EI

Triple 30

Proteinuria, g/24 h

120 100

20

80 60

10

40 20

*

*

0 Remnant

AC EI

Triple

Remnant

AC EI

0 Triple

Glomerular injury, %

Mean arterial pressure, mm Hg

100

Glomerular pressure, mm Hg

80

120

FIGURE 6-10 Angiotensin-converting enzyme (ACE) inhibitors and low-dose triple therapy. The effects of ACE inhibitors are compared with those of low-dose triple therapy on systemic and glomerular pressure, proteinuria, and morphologic evidence of glomerular injury in rats with remnant kidneys. Both ACE inhibitors and triple therapy caused similar reductions in mean arterial pressure in rats with remnant kidneys; however, glomerular pressure declined only in the group treated with ACE inhibitors, by approximately 10 mm Hg. ACE inhibitor—induced reductions in systemic and glomerular pressure were associated with a reduction in proteinuria and morphologic evidence of glomerular injury. The data suggest that ACE inhibitors are superior to low-dose triple therapy in preventing glomerular injury in chronic renal disease. The data support the importance of increased glomerular pressure as a determinant of glomerular injury. ACE inhibitors may be more effective than are other agents, specifically because of their ability to reduce glomerular pressure. It should be noted, however, that significant reductions in glomerular pressure and injury may be achieved even with the triple-therapy regimen when significantly higher doses than those used in the current study are administered (see Figs. 6-5 and 6-6). Asterisk indicates P < 0.05 versus remnant. (Data from Anderson and coworkers [10].)

6.7

The Role of Hypertension in Progression of Chronic Renal Disease

volume flux

0.1

0.01

selective pores

0.1

0.01

0.001

Fractional

Large Large nonselective pores

nonselective pores

0.001

0.0001 0.0005

0.0001 0.0005 30

A

1

at CA=0

1 Fractional volume flux at CA=0

Small

Small selective pores

40

50 60 Effective pore radius, A

FIGURE 6-11 Effect of renal vein constriction on glomerular protein filtration. The role of angiotensin II (AII) in modulating macromolecular clearance across the glomerular capillary wall has been examined by Yoshioka and coworkers [11]. These authors used a model of renal vein constriction to increase glomerular pressure and markedly increase protein filtration. They calculated the volume flux through the small selective pores (effective pore radius, 40–50 Å) within the glomerular capillary wall and through the large nonselective pores. A, Volume fluxes under control conditions (hatched bars) and during renal vein

A

B

C

D

30

B

40 50 60 Effective pore radius,

A

constriction (open bars). Renal vein constriction causes an increase in filtration through large nonselective pores, which accounts for increased protein filtration. B, Effects of renal vein constriction were again examined, alone (open bars) and during administration of the AII receptor antagonist saralasin (hatched bars). Saralasin reduced volume flux through the large pores, indicating that increased endogenous AII action was largely responsible for proteinuria during renal vein constriction. (From Yoshioka and coworkers [11]; with permission.) FIGURE 6-12 (see Color Plate) Local activation of the renin-angiotensin system and production of fibrogenic cytokines in experimental chronic renal disease. In situ reverse transcriptase was performed in rats with remnant kidneys to examine the level of gene expression for angiotensinogen and transforming growth factor-beta (TGF-beta). Rats still had not developed widespread morphologic evidence of glomerular injury 24 days after subtotal nephrectomy. A, At this point in time (arrows), staining for angiotensinogen messenger RNA (mRNA) was observed along the wall of a dilated capillary loop (CL) and in an adjacent cluster of mesangial cells. B, TGFbeta mRNA was present in an identical pattern in a contiguous section (arrows). C and D, Staining for angiotensinogen (panel C) and TGF-beta (panel D) is examined in kidneys from rats treated with the angiotensin receptor antagonist losartan from the time of nephrectomy. Administration of losartan markedly reduced expression of both factors in remnant kidneys. The findings are consistent with the hypothesis that endothelial injury is associated with increased angiotensinogen production and local activation of the renin-angiotensin system, leading to increased expression of TGFbeta and progressive glomerular fibrosis. (From Lee and coworkers [12]; with permission.)

6.8

Hypertension and the Kidney

**

* P< 0.05 vs cells treated with A II alone ** P< 0.01 vs unstimulated controls

90

fg RANTES/ 104 cells

80

15 **

70 60 *

50

*

40

Migrated monocytes

100

* P<0.05 vs control medium ** P<0.05 vs A II medium without antibody *

*

10 ** 5

30 0

20

0

A

Control

A II

CGP

CGP+ A II

PD

PD + A II

los

los + A II

FIGURE 6-13 Angiotensin II (AII) may be a proinflammatory molecule. The effect of AII on production of the chemokine RANTES was examined in cultured glomerular endothelial cells. A, Effects of AII on secretion of RANTES by cultured glomerular endothelial cells. AII markedly stimulated RANTES secretion. Of note is that AII-induced RANTES secretion was prevented by incubation with the AT2 receptor antagonists SCP-42112A (CGP) or PD 1231777 (PD) but not by the AT1 receptor antagonist losartan (los). These finding suggest AT2 receptors mediate the increase in secretion of RANTES. B, Results of a chemotactic assay for human monocytes. Migration of monocytes

Renin-angiotensin systems Angiotensinogen Bradykinin Substance P Enkephalin

b m G Ab A II diu t Ig ES A -6 M TE S me NT goa N 0 l A A 1 a R A II + m ii-R ant EM ant nor DM +m m+ m+ u u i i m d d u di me me me A II trol A II Con

m trol Con

10

Renin Angiotensin I CAGE Cathepsin G Tonin

ACE

Inactive fragments

Angiotensin II Other proteases Angiotensin III and IV

tPA Cathepsin G Tonin

B

ediu

m

was assessed using a modified Boyden chamber. Migration of monocytes was stimulated by conditioned medium from glomerular endothelial cells that were exposed to AII. This effect was blocked by incubation of the medium with an anti-RANTES antibody but not by control serum. The anti-RANTES antibody alone was also without effect, as was AII in the absence of conditioned media. The findings are consistent with the hypothesis that AII promotes glomerular inflammation by binding to AT2 receptors, promoting RANTES secretion and infiltration of inflammatory monocytes and macrophages. fg—femtograms. (From Wolf and coworkers [13]; with permission.) FIGURE 6-14 Renin-angiotensin systems. For many reasons the effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (AII) type 1 AT1 receptor antagonists on the progression of chronic renal disease may not be identical. In the classic pathway, renin cleaves angiotensinogen to form AI, which is further cleaved by ACE to form biologically active AII. ACE inhibitors inhibit the renin-angiotensin system by reducing the activity of ACE and decreasing AII formation. ACE also catalyzes other important pathways, however, including the breakdown of vasodilator substances such as bradykinin, substance P, and enkephalin. Increased levels of these substances might account for some of the biologic effects of ACE inhibition. Levels of these substances would not increase after administration of an AT1 receptor antagonist. In contrast, inhibition of the reninangiotensin system by ACE inhibitors may be incomplete because other proteases may catalyze to conversion of angiotensinogen to AII (on the right). CAGE— chymostatin-sensitive angiotensin II–generating enzyme; t-PA—tissue plasminogen activator. (Adapted from Dzau and coworkers [14].)

The Role of Hypertension in Progression of Chronic Renal Disease

Vasoconstriction AT 1 Aldosterone Growth Angiotensin II

Proteases

Clearance Apoptosis

Angiotensin III and IV

Vasodilation AT 4

AT 2

FIGURE 6-15 Subclasses of angiotensin receptors. Another theoretic reason the actions of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (AII) receptor antagonists may differ. All of the AII receptor antagonists currently available for clinical use selectively block the AT1 receptor. This receptor appears to transduce most of the wellknown effects of AII, including vasoconstriction, stimulation of cell growth, and secretion of aldosterone. Increasingly, however, potentially important actions of other angiotensin receptors are being discovered. For example, AT2 receptors may be involved in regulation of apoptosis and modulation of inflammation by way of secretion of RANTES (see Fig. 6-13) [13,15]. AT4 receptors bind other angiotensins preferentially and may promote endothelially mediated vasodilatation [16]. Activity of all pathways is reduced after administration of ACE inhibitors, whereas only AT1 receptor–mediated events are blocked by drugs currently available. Whether these differences will have important consequences for progression of renal disease is currently unknown.

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS VERSUS ANGIOTENSIN II ANTAGONISTS IN EXPERIMENTAL RENAL DISEASE Angiotensin II antagonists equivalent to angiotensin-converting enzyme inhibitors

Angiotensin II antagonists inferior to angiotensin-converting enzyme inhibitors

Remnant kidney Passive Heymann nephritis Chronic rejection Two-kidney, one-clip hypertension Streptozocin-induced diabetes Puromycin aminonucleoside Obstructive uropathy Munich-Wistar Furth/Ztm rat

Uninephrectomized spontaneously hypertensive rats Obese Zucker rats Passive Heymann nephritis

MAP

PGC

Reduction, %

0 -20 -40 -60 -80

Nifedipine Felodipine Amlodipine

PROT

SCLER

6.9

FIGURE 6-16 Shown are results of studies comparing the effects of angiotensin II (AII) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors on experimental renal injury. AII receptor antagonists were as effective as were ACE inhibitors in the remnant kidney model; streptozotocin-induced diabetic rats; the puromycin aminonucleoside model of progressive glomerular sclerosis, preventing interstitial fibrosis associated with obstructive uropathy; and an inherited model of glomerular sclerosis, the Munich-Wistar Furth/Ztm rat [17–21]. In contrast, AII receptor antagonists were somewhat less effective than were ACE inhibitors in several other animal models of chronic renal disease, including uninephrectomized spontaneously hypertensive rats, obese Zucker rats, and the passive Heymann nephritis model of membranous glomerulonephritis [22–24]. Clinical trials are necessary to determine whether these classes of drugs will be equally effective in preventing progressive renal disease in humans.

FIGURE 6-17 Three calcium channel blockers and their effects in experimental animals. The results of several studies examining the effects of three different dihydropyridine calcium channel blockers on hemodynamics and injury in the uninephrectomized spontaneously hypertensive rat model of progressive glomerular sclerosis are summarized. The three drugs produced graded declines in mean arterial pressure (MAP), with nifedipine causing the greatest and amlodipine the least reduction in systemic pressure. Micropuncture determinations of glomerular capillary hydraulic pressure (PGC) revealed that only nifedipine and felodipine caused glomerular pressure to decline significantly. These drugs reduced both the protein excretion rate (PROT) and morphologic evidence of glomerular injury (SCLER). The data are consistent with the hypothesis that antihypertensive agents ameliorate renal damage by reducing glomerular pressure and that, for calcium channel blockers, significant reductions in PGC occur only when drug administration causes a marked decline in systemic pressure. (From Dworkin [25,26]; with permission.)

6.10

Hypertension and the Kidney

The Effect of Hypertension on Renal Disease 100

ROLE OF HYPERTENSION IN CHRONIC RENAL DISEASE

90

Contributors to disease progression

80

Renal artery stenosis or occlusion Atheroembolic disease Hypertensive nephrosclerosis

Diabetes mellitus Glomerulonephritis Tubulointerstitial disease (?) Adult-onset polycystic kidney disease (?)

70

FIGURE 6-18 The impact of hypertension on the incidence of end-stage renal disease (ESRD) is vastly underestimated if one considers only those patients in whom systemic hypertension is the primary process resulting in loss of kidney function. The group of patients in whom ESRD is attributed to hypertension undoubtedly includes persons with renal disease of several causes. Some of these causes are occlusive disease of the main renal arteries as a result of atherosclerotic disease, atheroembolic disease of the kidneys, and hypertensive nephrosclerosis. The exact incidence of these processes within the hypertensive population with chronic renal disease is unknown. Even more commonly, poorly controlled systemic hypertension accelerates the rate of loss of kidney function in many patients in whom the primary cause of renal injury is another process altogether. This fact is particularly true in patients with glomerular diseases such as diabetic nephropathy and chronic glomerulonephritis [27,28]. Whether systemic hypertension also contributes to loss of kidney function in patients with tubulointerstitial or cystic disease of the kidney is less certain [29].

Volume/ total body sodium excess

Stimulation of renin-angiotensin system

Augmented sympathetic tone

Hypertensive persons, %

Cause

60 50 40 30 20 10 0 0

10

20

30

40

50

60

Mean GFR, mL/min/1.73m

70

80

90

2

FIGURE 6-19 Hypertension prevalence corresponds with decreased glomerular filtration rate (GFR). Hypertension is common in glomerular, tubular, vascular, and interstitial renal disease and becomes increasingly prevalent as renal function declines. In almost 200 patients screened for the Modification of Diet in Renal Disease study, the prevalence of hypertension increased as the GFR decreased and hypertension was almost universal as the GFR approached 10 mL/min [29].

FIGURE 6-20 Multifactorial mechanisms for hypertension in clinical renal disease. An increased intravascular volume, owing to decreased renal excretion of sodium and water as the glomerular filtration rate declines, is probably the primary cause. Activation of sympathetic tone and involvement of the renin-angiotensin system, which is inappropriately stimulated in the setting of volume expansion, have been demonstrated in renal failure. Decreased activity of nitric oxide and other vasorelaxants and increased activity of endothelin and other endogenous vasoconstrictors also are probably contributory.

6.11

The Role of Hypertension in Progression of Chronic Renal Disease

1.0

(53) (30)

80

(18)

60

0.8

(17)

40

Probability of survival

Free of renal failure, %

100

(7) (2) Normotensive (n=79) Hypertensive (n=69)

20 0 0

5

10

Free of renal endpoints, %

80 P<0.001

60

40

<120 mm Hg >120 mm Hg 0 0

1 Time, y

2

NBP after age 35

0.4

0.2

FIGURE 6-21 Consistent relationship between hypertension and progressive renal disease. Analysis of the Modification of Diet in Renal Disease study, which involved patients with a heterogeneous miscellany of renal diagnoses, showed that the degree of elevation of the mean arterial blood pressure correlated with the decline in the glomerular filtration rate [30]. This finding has been confirmed in cohorts of patients with the same renal disease. In immunoglobulin A (IgA) nephropathy, eg, the presence of high blood pressure at diagnosis is a strong predictor for development of end-stage renal disease. In this study by Radford and coworkers [31] of 148 patients with IgA nephropathy, 69 patients with hypertension had a much higher risk of proceeding to renal failure than did the 79 patients who were normotensive.

100

HBP before age 35

15

Time since biopsy, y

Systolic blood pressure

0.6

0 0

10

20

30

40

50 Age, y

60

70

80

90

FIGURE 6-22 Relationship between hypertension and renal failure. Johnson and Gabow [32] studied over one thousand patients with autosomal dominant polycystic kidney disease. These authors demonstrated that the time of renal survival was much shorter for patients with hypertension compared with patients whose blood pressure was normal (see Fig. 6-21). Renal survival was defined as the time period before the need for dialysis. HBP–high blood pressure; NBP–normal blood pressure.

FIGURE 6-23 Hypertension accelerates progression of renal failure in children and adults. For 2 years, Wingen and coworkers [33] followed almost 200 children and adolescents with renal disease, aged 2 to 18 years. Here, renal survival is defined as stability of the creatinine clearance rate. Compared with patients with systolic blood pressures lower than 120 mm Hg, those with systolic blood pressures higher than 120 mm Hg had more rapid development of renal death. Renal death was defined as a decrease in the creatinine clearance rate by 10 mL/min/1.73 m2.

6.12

Hypertension and the Kidney

4.0

Optimal Normal but not optimal High normal Stage 1 hypertension Stage 2 hypertension Stage 3 hypertension Stege 4 hypertension

ESRD due to any cause, %

3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 0

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Years since screening

FIGURE 6-24 There long has been controversy over whether hypertension alone, without renal disease, can cause renal failure, especially in whites. Recent convincing epidemiologic evidence, however, links

Deteriorating renal function Stable renal function

Stable renal function

16%

Controlled diastolic blood pressure <90 min Hg

12%

Uncontrolled diastolic blood pressure <90 min Hg

Blood pressure

0 Decline in GFR mL/min

Deteriorating renal function

Low BP group Usual BP group

3 6 9 12 15 B3

F4

F12

F20 Time, mo

F28

F36

hypertension to later development of renal failure. In over 300,000 men screened for the Multiple Risk Factor Intervention Trial, Klag and coworkers [34] showed that a single blood pressure measurement was strongly correlated with the risk of endstage renal disease (ESRD) later in life. Even men with high-normal blood pressures (defined as a systolic pressure of 130 to 139 mm Hg or a diastolic blood pressure of 85 to 89 mm Hg) were at a statistically significant greater risk for ESRD than were men with blood pressures under 120/80 mm Hg. This risk increases sequentially with the higher stage of hypertension. This study used definitions of hypertension discussed in the Fifth Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC-5). Stage I hypertension is defined as a systolic pressure of 140 to 159 mm Hg and a diastolic pressure of 90 to 99 mm Hg. Stage II hypertension is defined as a systolic pressure of 160 to 179 mm Hg and a diastolic pressure of 100 to 109 mm Hg. Stage III hypertension is a systolic pressure of 180 to 209 mm Hg and a diastolic pressure of 110 to 119 mm Hg. Stage IV hypertension is a systolic pressure of 210 mm Hg or higher and a diastolic blood pressure of 120 mm Hg or greater. The highest relative risk for renal failure was among persons with stage III or IV hypertension. FIGURE 6-25 Hypertension and impact on progression of renal disease caused by hypertension. In a study of 94 patients with essential hypertension and an initially normal serum creatinine concentration, Rostand and coworkers [35] showed that hypertension control apparently had little impact on progression of renal disease. When patients were divided into those with diastolic blood pressures higher and lower than 90 mm Hg, the percentage whose renal function deteriorated was equivalent in both groups. Blacks were at especially high risk; 23% of black patients with diastolic blood pressures below 90 mm Hg had worsened renal function over time, compared with 11% of white patients with diastolic blood pressures lower than 90 mm Hg.

FIGURE 6-26 Lower-than-usual blood pressure (BP) target. The Modification of Diet in Renal Disease study [36] also prospectively examined the effect of a lower-than-usual BP target in a larger cohort of patients with renal insufficiency. Patients were randomized to two target BPs: a usual mean arterial pressure (MAP) target of 107 mm Hg, corresponding to a BP of 140/90 mm Hg; or a low MAP target of 92 mm Hg, corresponding to a BP of 125/75 mm Hg. The changes in the glomerular filtration rate (GFR) in the two groups over a 3year follow-up period are depicted. (The y-axis depicts the changes in GFR, and the x-axis represents months. For example, F36 means 36 months after initiation of the study.) Patients in the two groups had statistically equivalent declines in GFR. Over the last 6 months of the study, however, a trend toward greater stabilization in renal function occurred in the group randomized to the lower target.

6.13

The Role of Hypertension in Progression of Chronic Renal Disease

FIGURE 6-27 Two patient groups in the study of diet in renal disease. The Modification of Diet in Renal Disease (MDRD) study involved two patient groups. The group in which patients had moderate renal dysfunction (glomerular filtration rate [GFR] between 25 and 55 mL/min) was called Study 1. The other group, which included patients who had more severe renal dysfunction (with a GFR between 13 and 24 mL/min) was called Study 2. The effects of the lower blood pressure (BP) target on patients with proteinuria in Studies 1 and 2 are shown. The y-axis divides patients in Studies 1 and 2 into three groups, depending on urinary protein excretion. The x-axis represents the rate of GFR decline. In the subset of patients in the MDRD trial in both Studies 1 and 2 who had massive proteinuria (protein over 3 g/24 h), the lower blood pressure had an especially salutary effect: the decline in GFR was much slower [37].

Patients randomized to low BP target Patients randomized to the usual BP target

Mean rate of GFR decline, mL/min/y

Study 1

Study 2

0

0

4

4

8

8

12

n=420

n=101

n=54

n=136

<1

1–<3

3

<1

n=63

n=32

1–<3

12

3

Baseline urinary protein, g/d

Renal survival

100

1.00

90 0.95 Creatinine clearance, mL/min

80

0.90 0.85 0.80

Proteinuria: <1g/24h mean BP: <107 mm Hg

0.75

Proteinuria: <1g/24h mean BP: >107 mm Hg

0.70

Proteinuria: <1–3g/24h mean BP: <107 mm Hg

0.65

Proteinuria: <1–3g/24h mean BP: >107 mm Hg

70 60 50 40 30 20 10 -12

0.60

Group A 0

6

12

18 Time, mo

24

30

FIGURE 6-28 Proteinuria as a marker for progressive renal disease. Nephrotic proteinuria may be a more important and independent marker for progression of renal disease than is hypertension. That is, patients in whom massive proteinuria and hypertension coexist have the worst renal prognosis. In a study of over 400 patients with renal insufficiency followed over 2 years, Locatelli and coworkers [38] found that patients who had both a mean blood pressure (BP) higher than 107 mm Hg and protein excretion of 1 to 3 g/24 h had the lowest rates of renal survival.

-6

0

6

12

18

24

30

36

Group B Evolution of creatinine clearance

FIGURE 6-29 The effect of reduction of proteinuria on the stabilization of renal function. The observations that the potentially correctable factors of hypertension and proteinuria predict the decline of renal function lead to the hypothesis that antihypertensive agents in the angiotensin-converting enzyme (ACE) inhibitor class may be especially important in treatment of hypertension in renal disease. Praga and coworkers [39] investigated 46 patients with nondiabetic renal disease and massive proteinuria treated with the ACE inhibitor captopril. These authors found that proteinuria was decreased by about half. In patients with the greatest reduction in proteinuria (group A), a greater stabilization of renal function occurred over time when compared with those (group B) whose reduction in proteinuria was less.

6.14

Hypertension and the Kidney

50 1.6

40

Ramipril

35 1.4

Placebo

30

Mean rate of GFR, mL/min/mo

Percentage with doubling of baseline creatinine

45

25 20

P=0.007

15 10

Captopril

5 0 0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Placebo

1.2 1.0 0.8 0.6

Years of follow-up 0.4

FIGURE 6-30 Large study of patients with diabetes mellitus and renal disease randomly assigned to captopril or placebo. Lewis and coworkers [40] have studied the use of the angiotensin-converting enzyme inhibitor captopril in patients with type I diabetes mellitus who have diabetic nephropathy and proteinuria. Captopril provides strong protection against progression of renal disease. Those patients treated with captopril had a significant decrease in proteinuria and a slower rate of disease progression, as defined by the time to doubling of the serum creatinine, as compared with patients randomized to placebo.

0.2 0

Country Year

IT Zucchelli et al. [43] DEN Kamper et al. [44] Brenner (Unpublished data) USA Toto (Unpublished data) USA HOL van Essen et al. [45] Hannedouche et al. [46] FR AUS Bannister et al. [47] Himmelmann et al. [48] SW AUS Becker et al. and Ihle et al. [49,50] EUR Maschio et al. [51]

1992 1992 1993 1993 1994 1994 1994 1995 1996

121 70 112 124 103 100 51 260 70

1996 583

Overall 0.5 1

n=20

FIGURE 6-31 Study of patients with renal disease not associated with diabetes randomly assigned to ramipril or placebo. A study structured similarly to that in Figure 6-30 examined the use of the angiotensinconverting enzyme inhibitor ramipril in over 150 patients with nondiabetic renal disease [41]. The primary conclusion of the study is summarized. Blood pressure and proteinuria decreased more significantly in the patients treated with ramipril. This group had significantly lower rates of decline in glomerular filtration rate (GFR) over time. This effect was increasingly striking as the baseline level of proteinuria increased and was most pronounced in patients with a urinary protein excretion of over 7 g per 24 hours.

Patients, n

0.01 0.02 0.05 0.1 0.2

n=36

Baseline urinary protein excretion, 1g/24h

Favors ACE inhibitors Favors other drugs Reference

n=61

2

5

Relative risk for ESRD

10

20 50 100

FIGURE 6-32 Meta-analysis of over 1500 patients with renal insufficiency. A recent meta-analysis examined randomized studies comparing an angiotensin-converting enzyme inhibitor (ACE) to other antihypertensive agents [42]. None of the individual studies showed that the relative risk for development of end-stage renal disease (ESRD) was statistically lower in patients treated with ACE inhibitors. The pooled relative risk, incorporating data from all the studies, however, was lower in the cohort groups treated with ACE inhibitors.

6.15

The Role of Hypertension in Progression of Chronic Renal Disease

100

Glomerular basement membrane

80

No change in proteinuria

Renal survival, %

Podocytes

60 40 Captopril Nifedipine

20

Decreased proteinuria

0 0

6

12

18

24

30

36

42

Time, mo Dihydropyridine calcium channel blockers Nifedipine Amlodipine Felodipine Isradipine Nisolodipine

Non-dihydropyridine calcium channel blockers Diltiazem Verapamil

FIGURE 6-33 Calcium channel blockers. Calcium channel blockers are prescribed widely to patients with normal renal function and affect renal protein excretion variably. The general consensus is that the nondihydropyridine calcium channel blockers diltiazem and verapamil decrease proteinuria, whereas the dihydropyridine agents have minimal or minor effects on proteinuria.

FIGURE 6-34 The effect of calcium channel blockers on preservation of renal function. Most studies of angiotensin-converting enzyme (ACE) inhibitors versus other agents did not examine calcium channel blockers. In a paper by Zucchelli and coworkers [43], patients with nondiabetic renal diseases and hypertension initially were treated with adrenergic antagonists, diuretics, and vasodilators. These patients were then randomized to treatment with the dihydropyridine calcium entry antagonist nifedipine or to the ACE inhibitor enalapril. The rate of decline in renal function was most rapid in the pre-randomization phase in patients treated with conventional antihypertensive agents, mostly adrenergic antagonists. The rate of decline then slowed after randomization. No significant difference in rates of decline was seen in patients treated with nifedipine compared with those treated with captopril. (From Zucchelli and coworkers [43]; with permission.)

Creatinine clearance, mL/min/1.73 m2

60 Lisinopril

NDCCBs 40

Atenolol

20

Lisinopril NDCCBs Atenolol

1998 18 18 16

1989 18 18 16

1990 18 18 16

1991 18 17 15

1992 16 16 13

1993 16 15 11

1994 15 15 11

FIGURE 6-35 The effect of angiotensin-converting enzyme inhibitors and other antihypertensive agents on stabilization of renal function in non–insulin-dependent diabetes. Bakris and coworkers [52] studied patients with non–insulin-dependent diabetes mellitus, hypertension, proteinuria, and presumed diabetic nephropathy. These patients were randomized to treatment with the angiotensin-converting enzyme inhibitor lisinopril; the beta-blocker atenolol; or a nondihydropyridine calcium channel blocker (NDCCB), either verapamil or diltiazem. The primary conclusion of the study is summarized. The change in glomerular filtration rate as a function of time is depicted in groups of patients receiving lisinopril, calcium channel blockers, or atenolol. The creatinine clearance rate declined in all three groups. However, the slope of the decline was significantly greater in the group treated with atenolol and not significantly different between the groups treated with lisinopril and the calcium entry antagonist.

6.16

Hypertension and the Kidney 120 115

Mean BP, mm Hg

110 105 100 Atenolol Amiodipine Enalapril

95 90 0

Baseline GFR1

GFR2

RV

FV3

FV6

Time, mo

FIGURE 6-36 Race and ethnicity in choice of antihypertensive agents. Racial and ethnic differences also may be important in determining the choice of antihypertensive agent to delay progression of chronic renal disease. Blacks are at much higher risk than are whites for progression of renal disease. In addition, a more aggressive antihypertensive program may be beneficial to blacks. In the Modification of Diet in Renal Disease study, a trend toward a more gradual decline in renal function in blacks randomized to the low mean blood pressure target was seen [36]. Blacks tend to have a better blood pressure response to administration of diuretics than do whites. In a large study of patients with normal renal function, blacks also responded well to calcium channel blockers [53]. The AfricanAmerican Study of Kidney Disease and Hypertension (AASK), currently in progress, is examining the hypothesis that a lower-thanusual blood pressure goal will have a renal protective effect in renal disease with hypertension. A preliminary finding from the study is depicted. The study randomized blacks with hypertension to the beta-blocker atenolol, the dihydropyridine calcium channel blocker amlodipine, or the angiotensin-converting enzyme enalapril. In the initial 6 months of the study, the mean arterial blood pressure decreased most significantly in the short term with amlodipine [54]. GFR–glomerular filtration rate.

Management of Hypertension in Clinical Renal Disease Blood pressure:> 130/185 mm HG or higher with renal disease Blood pressure: 130/85 mm Hg or higher with renal disease Proteinuria: 1g/24h or less Proteinuria: 1G/24h or more Diabetic or primary glomerular disease Begin ACE inhibitor Target blood pressure: 125/75 mm Hg or lower

If hyperkalemia or acute renal failure develops, evaluate possible causes If no other precipitant, decrease ACE inhibitor dose Add diuretic, calcium channel blocker

A FIGURE 6-37 Treatment of patients with renal disease and high-normal or elevated blood pressure (BP). A, All patients should have a measurement of 24-hour protein excretion. If the protein excretion is over 1 g/24 h, an angiotensin-converting enzyme (ACE) inhibitor should be started. The goal of hypertension control in patients with azotemia who have massive proteinuria should be a blood pressure of 125/75 mm Hg or lower. It is unlikely that an ACE inhibitor alone will be able to decrease the blood pressure to this level before hyperkalemia or hemodynamically mediated acute renal failure intervenes. A diuretic and medications from other classes, such as a calcium channel blocker, should then be added.

Yes

No

Treatment with ACE inhibitor Target blood pressure: 125/75 mm Hg or lower

Treatment with diuretic, ACE inhibitor, or calcium channel blocker

B

B, When protein excretion is less than 1 g/24 h, the blood pressure should be lowered to at least 130/85 mm Hg. No conclusive evidence exists to support the use of one antihypertensive agent or class of agents over another. However, in patients at risk for progressive proteinuria (eg, diabetic patients with microalbuminuria), ACE inhibitors should be used. Given the importance of sodium retention in the hypertension in renal disease, a loop or thiazide diuretic is a reasonable initial treatment. An ACE inhibitor or calcium channel blocker should be added as a second-line agent.

The Role of Hypertension in Progression of Chronic Renal Disease

6.17

References 1. Dworkin LD, Grosser M, Feiner HD, et al.: Renal vascular effects of antihypertensive therapy in uninephrectomized spontaneously hypertensive rats. Kidney Int 1989, 35:790–798. 2. Anderson S, Meyer T, Rennke HG, Brenner BM: Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass. J Clin Invest 1985, 76:612–619. 3. Kakinuma Y, Kawamura T, Bills T, et al.: Blood pressure independent effect of angiotensin inhibition on the glomerular and nonglomerular vascular lesions of chronic renal failure. Kidney Int 1996, 42: 46–55. 4. Dworkin LD, Feiner HD, Randazzo J: Glomerular hypertension and injury in desoxycorticosterone-salt rats on antihypertensive therapy. Kidney Int 1987, 31:718–724. 5. Neugarten J, Kaminetsky B, Feiner H, et al.: Nephrotoxic serum nephritis with hypertension: amelioration by antihypertensive therapy. Kidney Int 1985, 28:135–139. 6. Weir MR, Dworkin LD: Antihypertensive drugs, dietary salt and renal protection: How low should you go and with which therapy. Am J Kidney Dis 1998, 32:1–22. 7. Griffen KA, Picken M, Bidani AK: Radiotelemetric BP monitoring, antihypertensives and glomeruloprotection in remnant kidney model. Kidney Int 1994, 46:1010–1018. 8. Dworkin LD, Benstein JA: Antihypertensive agents, glomerular hemodynamics and glomerular injury. In Calcium Antagonists and the Kidney. Edited by Epstein M, Loutzenhiser R. Philadelphia, Hanley & Belfus; 1990:155–176. 9. Nagata M, Scharer K, Kriz W: Glomerular damage after uninephrectomy in young rats. I. Hypertrophy and distortion of the capillary architecture. Kidney Int 1992, 42:136–147. 10. Anderson S, Rennke HG, Brenner BM: Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension. J Clin Invest 1986, 77:1993–2000. 11. Yoshioka T, Mitarai T, Kon V, et al.: Role for angiotensin II in an overt functional proteinuria. Kidney Int 1986, 30:538–545. 12. Lee LK, Meyer TM, Pollock AS, Lovett DH: Endothelial cell injury initiates glomerular sclerosis in the rat remnant kidney. J Clin Invest 1995, 96:953–964. 13. Wolf G, Ziyadeh FN, Thaiss F, et al.: Angiotensin II stimulates expression of the chemokine RANTES in rat glomerular endothelial cells. J Clin Invest 1997, 100:1047–1058. 14. Dzau VJ, Sasamura H, Hein L: Heterogeneity of angiotensin synthetic pathways and receptor subtypes: physiological and pharmacological implications. J Hypertension 1993, 11(suppl 3):S13–S18. 15. Yamada T, Horiuchi M, Dzau VJ: Angiotensin II type 2 receptor mediates programmed cell death. Proc Natl Acad Sci U S A 1996, 93:156–160. 16. Pörsti I, Bara AT, Busse R, Hecker M: Release of nitric oxide by angiotensin (1-7) from porcine coronary endothelium: implications for a novel angiotensin receptor. Br J Pharmacol 1994, 111:652–654. 17. Lafayette RA, Mayer G, Park SK, Meyer TM: Angiotensin II receptor blockade limits glomerular injury in rats with reduced renal mass. J Clin Invest 1992, 90:766–771. 18. Remuzzi A, Perico N, Amuchastegui CS, et al.: Short- and long-term effect of angiotensin II receptor blockade in rats with experimental diabetes. J Am Soc Nephrol 1993, 4:40–49. 19. Tanaka R, Kon V, Yoshioka T, et al.: Angiotensin converting enzyme inhibitor modulates glomerular function and structure by distinct mechanisms. Kidney Int 1994, 45:537–543. 20. Ishidoya S, Morrissey J, McCracken R, et al.: Angiotensin receptor antagonist ameliorates renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction. Kidney Int 1995, 47:1285–1294.

21. Remuzzi A, Malanchini B, Battaglia C, et al.: Comparison of the effects of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade on the evolution of spontaneous glomerular injury in male MWF/Ztm rats. Experimental Nephrol 1996, 4:19–25. 22. Anderson AE, Tolbert EM, Esparza AR, Dworkin LD: Effects of an ACE inhibitor vs. an AII antagonist on hemodynamics, growth and injury in spontaneously hypertensive rats. J Am Soc Nephrol 1996, 7:A3014. 23. Crary GS, Swan SK, O’Donnell MP, et al.: The angiotensin II receptor antagonist losartan reduces blood pressure but not renal injury in obese Zucker rats. J Am Soc Nephrol 1995, 6:1295–1299. 24. Hutchinson FN, Webster SK: Effect of ANGII receptor antagonist on albuminuria and renal function in passive Heymann nephritis. Am J Physiol 1992, 263:F311–F318. 25. Dworkin LD, Feiner HD, Parker M, Tolbert E: Effects of nifedipine and enalapril on glomerular structure and function in uninephrectomized spontaneously hypertensive rats. Kidney Int 1991, 39:1112–1117. 26. Dworkin LD, Tolbert E, Recht PA, et al.: Effects of amlodipine on glomerular filtration, growth, and injury in experimental hypertension. Hypertension 1996, 27:245–250. 27. Breyer JA, Bain RP, Evans JK, et al.: Predictors of the progression of renal insufficiency in patients with insulin-dependent diabetes and overt diabetic nephropathy. Kidney Int 1996, 50:1651–1658. 28. Gisen Group: Randomized placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997, 349:1857–1863. 29. Klahr S, Levey AS, Beck GJ, et al.: The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med 1994, 330:877–884. 30. Modification of Diet in Renal Disease Study Group: Predictors of the progression of renal disease in the modification of diet in renal disease study. Kidney Int 1997, 51:1908–1919. 31. Radford MG, Donadio JV, Bergstralh EJ, Grande JP: Predicting renal outcome in IgA nephropathy. J Am Soc Nephrol 1997, 8199–207. 32. Johnson AM, Gabow PA: Identification of patients with autosomal dominant polycystic kidney disease at highest risk for end-stage kidney disease. J Am Soc Nephrol 1997, 8:1560–1567. 33. Wingen A-M, Fabian-Bach C, Shaefer F, Mehls O for the European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood. Lancet 1997, 349:1117–1123. 34. Klag MJ, Whelton PK, Randall BL, et al.: Blood pressure and endstage renal disease in men. N Engl J Med 1996, 334:13–18. 35. Rostand SG, Brown G, Kirk KA, et al.: Renal insufficiency in treated essential hypertension. N Engl J Med 1989, 320:684–688. 36. Klahr S, Levey A, Beck GJ, et al. for the Modification of Diet in Renal Disease Study Group. N Engl J Med 1994, 330:877–884. 37. Peterson JC, Adler S, Burkart JM, et al. for the Modification of Diet in Renal Disease Study Group. Ann Intern Med 1995, 123:754–762. 38. Locatelli F, Marcelli D, Comelli M, et al. for the Northern Italian Cooperative Study Group: proteinuria and blood pressure as causal components of progression to end-stage renal failure. Nephrol Dial Transplant 1996, 11:461–467. 39. Praga M, Hernandez E, Montoyo C, et al.: Long-term beneficial effects of angiotensin-converting enzyme inhibition in patients with nephrotic proteinuria. Am J Kidney Dis 1992, 20:240–248. 40. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD for the Collaborative Study Group: The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993, 329:1456–1462.

6.18

Hypertension and the Kidney

41. Gruppo Italiano di Studi Epidemiologici in Nefrologia: Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997, 349:1857–1863. 42. Giatras I, Lau J, Levey AS for the Angiotensin-Converting Enzyme Inhibition and Progressive Renal Disease Study Group: Effect of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials. Ann Intern Med 1997, 127:337–345. 43. Zucchelli P, Zuccala A, Borghi M, et al.: Long-term comparison between captopril and nifedipine in the progression of renal insufficiency. Kidney Int 1992, 42:452–458. 44. Kamper AI, Strandgaard S, Leyssac PP: Effect of enalapril on the progression of chronic renal failure: a randomized controlled trial. Am J Hypertens 1992, 5:423–430. 45. van Essen GG, Apperloo AJ, Sluiter WJ, et al.: Is ACE inhibition superior to conventional antihypertensive therapy in retarding progression in non-diabetic renal disease? J Am Soc Nephrol 1996, 7:1400. 46. Hannedouche T, Landais P, Goldfarb B, et al.: Randomized controlled trial of enalapril and beta-blockers in non-diabetic chronic renal failure. BMJ 1994, 309:833–837. 47. Bannister KM, Weaver A, Clarkson AR, Woodroffe AJ: Effect of angiotensin-converting enzyme and calcium channel inhibition on progression of IgA nephropathy. Contrib Nephrol 1995, 111:184–193.

48. Himmelmann A, Hansson L, Hannson BG, et al.: ACE inhibition preserves renal function better than beta-blockers in the treatment of essential hypertension. Blood Pressure 1995, 4:85–90. 49. Becker GJ, Whitworth JA, Ihle BU, et al.: Prevention of progression in non-diabetic chronic renal failure. Kidney Int Suppl 1994, 45:S167–S170. 50. Ihle BU, Whitworth JA, Shahinfar S, et al.: Angiotensin-converting enzyme inhibition in nondiabetic progressive renal insufficiency: a controlled double-blind trial. Am J Kidney Dis 1996, 27:489–495. 51. Maschio G, Aliberti D, Janin G, et al.: Effect of the angiotensinconverting enzyme inhibitor benazepril on the progression of renal insufficiency. N Engl J Med 1996, 334:939–945. 52. Bakris GL, Copley JB, Vicknair N, et al.: Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int 1996, 50:1641–1650. 53. Materson BJ, Reda DJ, Cushman WC, et al.: Single-drug therapy for hypertensive men: a comparison of six antihypertensive agents with placebo. N Engl J Med 1993, 328:914–921. 54. Hall WD, Kusek JW, Kirk KA, et al. for the African-American Study of Kidney Disease and Hypertension Pilot Study Investigators. Am J Kidney Dis 1997, 29:720–728.

Pharmacologic Treatment of Hypertension Garry P. Reams John H. Bauer

T

his chapter reviews the currently available classes of drugs used in the treatment of hypertension. To best appreciate the complexity of selecting an antihypertensive agent, an understanding of the pathophysiology of hypertension and the pharmacology of the various drug classes used to treat it is required. A thorough understanding of these mechanisms is necessary to appreciate more fully the workings of specific antihypertensive agents. Among the factors that modulate high blood pressure, there is considerable overlap. The drug treatment of hypertension takes advantage of these integrated mechanisms to alter favorably the hemodynamic pattern associated with high blood pressure.

CHAPTER

7

7.2

Hypertension and the Kidney

Pathogenesis of Hypertension Pathogenesis of hypertension Autoregulation B LO O D PR E SSUR E = C AR D I AC O U T P U T × PE R IPHER AL VA SCUL AR RE SISTAN CE H y p er tens i o n = I n c re a s e d CO and/or I n c re a s e d P V R

↑ Preload

↑ Fluid volume

Functional constriction

Sympathetic nervous overactivity

Reninangiotensin excess

Structural hypertrophy

Volume redistribution

Renal sodium retention

Excess sodium intake

↑ Contractility

Decreased filtration surface

Genetic alteration

Stress

FIGURE 7-1 Pathogenesis of hypertension. Mean arterial pressure (MAP) is the product of cardiac output (CO) and peripheral vascular resistance

Cell membrane alteration

Hyperinsulinemia

Genetic alteration

Obesity

Endotheliumderived factors

(PVR). There are a large number of control mechanisms involved in every type of hypertension. (From Kaplan [1]; with permission.)

FIGURE 7-2 Blood pressure changes and diet. Many hypertensive patients appear to be sodium sensitive, as first suggested by studies in 19 hypertensive subjects who were observed after “normal” (109 mmol/d), “low” (9 mmol/d), and “high” (249 mmol/d) sodium intake [2]. This figure shows the percent increase in mean blood pressure in salt-sensitive (SS) and non–salt-sensitive (NSS) patients with hypertension when their diet was changed from low sodium to high sodium. Vertical lines indicate mean ± standard deviation. (From Kawasaki et al. [2]; with permission.)

Increase, %

20

10

0 SS

NSS Mean arterial pressure

20 19 18 17 16 15 6.0

33 %

4%

20 %

5.5

5%

5.0 16 14 12 10

Cardiac output, L/min

70 65 60 55 50

Total peripheral resistance, mm Hg/L/min

13 12 11 10

40 35 30 25 20 15

Arterial pressure, mm Hg

Pressure gradient Mean circulatory for venous filling pressure, return, mm Hg mm Hg

Blood volume, L

Extracellular fluid volume, L

Pharmacologic Treatment of Hypertension

150 140 130 120 110 100

60 % 20 %

35 %

44 %

40 %

5%

38 %

–11 % Set-point elevated 45 % 22.5 %

0

4

8 Days

12

16

7.3

FIGURE 7-3 Cardiac output. An increase in cardiac output has been suggested as a mechanism for hypertension, particularly in its early borderline phase [3,4]. Sodium and water retention have been theorized to be the initiating events. Sequential changes following salt loading are depicted [3]. The resultant high cardiac output perfuses the peripheral tissues in excess of their metabolic requirements, resulting in a normal autoregulatory (vasoconstrictor) pressure. The early phase of high cardiac output and normal peripheral vascular resistance gradually changes to the characteristic feature of the sustained hypertensive state: normal cardiac output and high peripheral vascular resistance. Shown here are segmental changes in the important cardiovascular hemodynamic variables in the first few weeks following the onset of short-term salt-loading hypertension. Note especially that the arterial pressure increases ahead of the increase in total peripheral resistance. (From Guyton and coworkers [3]; with permission.)

7.4

Hypertension and the Kidney

200

HR beats min–1

SAP

180

TPRI dyn s cm–5 m–2

4000

150

100

3000

2000

140

60

1000

70

10

120 DAP

100

CI L min–1 m–2

MAP

SI mL stroke–1 m–2

BP, mm Hg

160

50

5

30

500

1000

VO2 mL min–1 m–2

500

1000

VO2 mL min–1 m–2

FIGURE 7-4 Peripheral vascular resistance. Most established cases of hypertension are associated with an increase in peripheral vascular resistance [5]. These alterations may be related to a functional constriction, the type observed under the influence of circulating or tissue-generated vasoconstrictors, or may be a result of structural alterations in the blood vessel. Solid line indicates values at start of the study [9];

500

1000

VO2 mL min–1 m–2

dashed line indicates results after 10 years; dotted line indicates results after 20 years. BP—blood pressure; CI—cardiac index; DAP—diastolic arterial blood pressure; HR—heart rate; MAP—mean arterial pressure; SAP—systolic arterial blood pressure; SI—stroke index; TPRI—total peripheral resistance index; VO2—oxygen consumption. (From LundJohansen [5]; with permission.)

Pharmacologic Treatment of Hypertension

7.5

Classes of Antihypertensive Drugs and Their Side Effects FIGURE 7-5 Classes of antihypertensive drugs. There are 12 currently available classes of antihypertensive agents.

CLASSES OF ANTIHYPERTENSIVE DRUGS Diuretics: benzothiadiazides, loop, and potassium-sparing -adrenergic and 1/-adrenergic antagonists Central 2-adrenergic agonists Central/peripheral adrenergic neuronal-blocking agent Peripheral 1-adrenergic antagonists Moderately selective peripheral 1-adrenergic antagonist Peripheral adrenergic neuronal blocking agents Direct-acting vasodilators Calcium antagonists Angiotensin-converting enzyme inhibitors Tyrosine hydroxylase inhibitor Angiotensin II receptor antagonists

BP

PV ISF CO

CO TPR

TPR Rx

PRA Time

No Rx

FIGURE 7-6 Hemodynamic response to diuretics. Diuretics reduce mean arterial pressure by their initial natriuretic effect [6]. Acutely, this is achieved by a reduction in cardiac output mediated by a reduction in plasma and extracellular fluid volumes [7]. Initially, peripheral vascular resistance is increased, mediated in part by stimulation of the reninangiotensin system. During sustained diuretic therapy, cardiac output returns to pretreatment levels, probably reflecting restoration of plasma volume. Chronic blood pressure control now correlates with a reduction in peripheral vascular resistance. BP—blood pressure; CO—cardiac output; ISF—interstitial fluid; PRA—plasma renin activity; PV—plasma volume; Rx—treatment; TPR—total peripheral resistance. (Adapted from Tarazi [7].)

7.6

Hypertension and the Kidney

A. DIURETICS: BENZOTHIADIAZIDES (PARTIAL LIST) AND RELATED DIURETICS Generic (trade) name

First dose, mg

Hydrochlorothiazide (G) (Hydrodiuril, Microzide) Chlorthalidone (G) (Hygroton) Indapamide (Lozol) Metolazone (Mykrox)*; (Zaroxolyn)

Usual dose

Maximum dose

Duration of action, h

12.5

12.5–50 mg QD

100

6–12

12.5

12.5–50 mg QD

100

48–72

5

15–18

12–24 12–24

1.25

2.5–5.0 mg

0.5 2.5

0.5–1.0 2.5–10 mg QD

1 20

First dose, mg

Usual dose

Maximum dose

0.5

0.5–2 mg bid

10

4–6

25

25–50 mg bid

200

6–8

20

20–120 mg bid

600

6–8

5

5–50 mg bid

100

6–8

*Marketed only for treatment of hypertension. (G)—generic available.

B. DIURETICS: LOOP Generic (trade) name Bumetanide (G) (Bumex) Ethacrynic Acid (Edecrin) Furosemide (G) (Lasix) Torsemide (Demadex)

Duration of action, h

(G)—generic available.

C. DIURETICS: POTASSIUM-SPARING DIURETICS Generic (trade) name Spironolactone (G) (Aldactone) Amiloride (G) (Midamor) Triamterene (G) (Dyrenium)

First dose, mg

Usual dose

Maximum dose

25

50–1 00 mg QD

400

5

5–10 mg QD

20

50

50-100 mg bid

300

Duration of action, h 48–72 24 7–9

(G)—generic available.

FIGURE 7-7 A–C. Diuretics: benzothiadiazides and related agents, loop diuretics, and potassium-sparing agents. A partial list of benzothiadiazides and their related agents is given [6]. With the exception of indapamide and metolazone, their dose-response curves are shallow; they should not be used when the glomerular filtration rate is less than 30 mL/min/1.73 m2. The second group listed is loop

diuretics. Because of their steep dose-response curves and natriuretic potency, they are especially useful when the glomerular filtration rate is less than 30 mL/min/1.73 m2. The third group is the potassium-sparing diuretics. The major therapeutic use of these drugs is to attenuate the loss of potassium induced by the other diuretics.

7.7

Pharmacologic Treatment of Hypertension Lumen

Blood

Lumen

Blood

Na DCT diuretics

Na

3Na

Cl

~

2K

3Na

Na channel blockers

K

DCT

~

2K

PC

PT DT

Blood

Lumen HCO3

Na

3Na H

CAI

H2CO3 CA H2O + CO2

~

Lumen

2K

Blood

HCO3 H2CO3 CA H2O + CO2

Loop diuretics

CAI

Na K 2Cl

3Na

~

2K CD

PT TAL

LH

FIGURE 7-8 Mechanisms of action of diuretics. This figure depicts the major sites and mechanisms of action of diuretic drugs [8]. The diuretic/natriuretic action of benzothiadiazide-type diuretics is predicated on their gaining access to the luminal side of the distal convoluted tubule and inhibiting Na+ - Cl- cotransport by competing for the chloride site. The diuretic/natriuretic action of loop diuretics is predicated on their gaining access to the luminal side of the thick ascending limb of the loop of Henle and inhibiting Na+ - K+ -2Cl- electroneutral cotransport by competing for the chloride site.

The diuretic/natriuretic action of potassium-sparing diuretics is predicated on their gaining access to the luminal side of the principal cells located in the late distal tubule and cortical collecting duct and blocking luminal sodium channels. Because Na+ uptake is blocked, the lumen negative voltage is reduced, inhibiting K+ secretion. The potassium-sparing diuretic spironolactone does this indirectly by competing with aldosterone for its cytosolic receptor. CA—carbonic anhydrase; CAI—carbonic anhydrase inhibitor; CD—collecting duct; DCT—distal convoluted tubule; DT—distal tubule; LH—loop of Henle; PC—principal cell; PT—proximal tubule; TAL—thick ascending limb. (From Ellison [8]; with permission.)

7.8

Hypertension and the Kidney

THE SIDE EFFECT PROFILE OF DIURETIC THERAPY Side effects Thiazide-type diuretic Azotemia Hypochloremia, hypokalemia, metabolic alkalosis

Hypomagnesemia Hyponatremia Hypercalcemia Hyperuricemia Carbohydrate intolerance Hyperlipidemia Increased total triglyceride Increased total cholesterol Loop-type diuretics Ototoxicity Hypocalcemia Potassium-sparing diuretics Hyperkalemia Decreased sexual function, gynecomastia, menstrual irregularity, hirsutism Renal stone

Mechanisms Enhanced proximal fluid and urea reabsorption secondary to volume depletion Increased delivery of sodium to distal tubule facilitating Na+K+ and Na+-H+ exchange; increased net acid excretion; increased urinary flow rate; secondary aldosteronism Increase fractional Mg2+ excretion by inhibiting reabsorption in ascending limb of loop of Henle Impaired free water clearance (distal cortical diluting segment) May reflect an increased protein-bound fraction secondary to volume depletion Impair enhanced proximal fluid and urate reabsorption secondary to volume depletion Hypokalemia impairing insulin secretion; decreased insulin sensitivity May be due to extracellular fluid depletion

High plasma concentration of furosemide or ethacrynic acid Increase fractional excretion of calcium by interfering with reabsorption in loop of Henle Blocks potassium excretion Spironolactone only; lower circulatory testosterone levels by increasing metabolic clearance and/or preventing compensatory rise in testicular androgen production Triamterene only

FIGURE 7-9 The side effect profile of diuretic therapy. The complications of diuretic therapy are typically related to dose and duration of therapy, and they decrease with lower dosages. This table lists the most common side effects of diuretics and their proposed mechanism of action [6].

Pharmacologic Treatment of Hypertension

Adrenal gland

Heart ↓ CO

E NE

β2

Effector cell

Kidney

β-blockers

β1 BP

Blood vessels ↑ TPR +

NE

7.9

FIGURE 7-10 -adrenergic antagonists. -adrenergic antagonists attenuate sympathetic activity through competitive antagonism of catecholamines at both 1- and 2-adrenergic receptors [6,9]. In the absence of partial agonist activity (PAA), the acute systemic hemodynamic effects are a decrease in heart rate and cardiac output and an increase in peripheral vascular resistance proportional to the degree of cardiodepression; blood pressure is unchanged. Chronically, there is a gradual decrease in blood pressure proportional to the fall in peripheral vascular resistance, which is dependent on the degree of cardiac sympathetic drive. -adrenergic antagonists with sufficient partial agonist activity to maintain heart rate and cardiac output may not evoke acute reflex vasoconstriction: Blood pressure falls proportional to the decrease in peripheral resistance (see Fig. 7-11) [10]. BP—blood pressure; CO—cardiac output; E—epinephrine; NE— norepinephrine; TPR—total peripheral resistance.

MAP, %

Sympathetic neuron

FIGURE 7-11 Hemodynamic changes associated with -adrenergic blockade. Time course of hemodynamic changes after treatment with a -adrenergic blocker devoid of partial agonist activity (PAA) (solid line) as compared with hemodynamic changes after administration of a -adrenergic blocker with sufficient PAA to replace basal sympathetic tone (eg, pindolol) (broken line). MAP—mean arterial pressure. (From Man in’t Veld and Schalekamp [10]; with permission.)

100 90

Cardiac output, %

80 100 90 80

Vascular resistance, %

130 120 110 100 90 80 Time (hours to days)

7.10

Hypertension and the Kidney

A. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: NON-SELECTIVE (1 AND 2) ADRENERGIC ANTAGONISTS THAT LACK PARTIAL AGONIST ACTIVITY Generic (trade) name Nadolol (G) (Corgard) Propranolol (G) (Inderal) (Inderal LA) Timolol (G) (Blockadren)

First dose, mg

Usual daily dose, mg

Maximum daily dose, mg

Duration of action, h

40

40–240 QD

320

>24

40 80

40–120 bid 80–240 QD

480 480

>12 >12

10

10–30 bid

60

>12

G—generic available.

B. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: NON-SELECTIVE (1 AND 2) ADRENERGIC ANTAGONISTS WITH PARTIAL AGONIST ACTIVITY Generic (trade) name Pindolol (G) (Visken) Carteolol (Cartrol) Penbutolol (Levatol)

First dose, mg 5 2.5 10

Usual daily dose, mg

Maximum daily dose, mg

Duration of action, h

60

12

10

24

40

24

Maximum daily dose, mg

Duration of action, h

10–30 bid 2.5–10 QD 10–20 QD

G—generic available.

C: DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: 1-SELECTIVE ADRENERGIC ANTAGONISTS THAT LACK PARTIAL AGONIST ACTIVITY Generic (trade) name Atenolol (G) (Tenormin) Metoprolol Tartrate (G) (Lopressor) Metoprolol Succinate (Toprol-XL) Betaxolol (Kerlone) Bisoprolol (Zebeta)

First dose, mg

Usual daily dose, mg

50

50–100 QD

200

24

50

50–150 bid

400

12

50

100–300 QD

400

12

5

10–20 QD

40

>24

5

5–20 QD

40

12

G—generic available.

FIGURE 7-12 Dosing schedules for -adrenergic antagonists. A, Nonselective adrenergic antagonists that lack partial agonist activity. B, Nonselective

-adrenergic antagonists with partial agonist activity. C, 1-selective adrenergic antagonists that lack partial agonist activity. (Continued on next page)

7.11

Pharmacologic Treatment of Hypertension

D. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: 1-SELECTIVE ADRENERGIC ANTAGONISTS WITH WEAK PARTIAL AGONIST ACTIVITY Generic (trade) name Acebutolol (Sectrol)

First dose, mg

Usual daily dose, mg

Maximum daily dose, mg

Duration of action, h

200

400–800 QD

1200

24

Maximum daily dose, mg

Duration of action, h

E. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: 1-NONSELECTIVE -ADRENERGIC ANTAGONISTS LABETALOL (G) Generic (trade) name Labetalol (G) (Normodyne) (Trandate) Carvedilol (Coreg)

First dose, mg 100

6.25

Usual daily dose, mg 100-600 bid

6.25-25 bid

G—generic available.

FIGURE 7-12 (Continued) D, 1-selective adrenergic antagonists with weak partial agonist activity. E, 1-nonselective -adrenergic antagonists.

2400

12

50

6

7.12

Hypertension and the Kidney

PHARMACOKINETICS OF -ADRENERGIC ANTAGONISTS

Nadolol Propranolol Propranolol LA Timolol Pindolol Carteolol Penbutolol Atenolol Metoprolol tartrate Metoprolol succinate Betaxolol Bisoprolol Acebutolol Labetalol Carvedilol

Solubility

Absorption

Hydrophilic Lipophilic Lipophilic Lipophilic Lipophilic Hydrophilic Lipophilic Hydrophilic Lipophilic Lipophilic Lipophilic Equal Lipophilic Lipophilic Lipophilic

30%–40% >90% >90% >90% >90% >90% >90% 50–60% >90% >90% >90% >90% 70% >90% >90

First-pass hepatic metabolism

Peak concentration, h

<10% 60% 80% 50% <10% <10% <10% <10% 50% 50% <10% 20% 30% 60% 70–80%

2–4 1–3 6 1–2 1–2 1–3 2–3 2–4 1–2 7 1.5–6 2–4 2–4 1–2 1–2

Active metabolite

Plasma half-life, h

Dose reduction in renal failure

None Yes Yes None None Yes Yes None None None None None Yes None Yes

20–24 3–4 10 3–4 3–4 5–6 5 6–7 3–7 3–7 14–22 9–12 3–4 3–4 7–10

Yes No No No Yes Yes Yes Yes No No Yes Yes Yes No No

FIGURE 7-13 Pharmacokinetics of -adrenergic antagonists.

THE SIDE EFFECT PROFILE OF -ADRENERGIC ANTAGONISTS Side effects

Mechanisms

Bronchospasm Bradycardia Congestive heart failure; decrease in exercise tolerance Claudication Constipation, dyspepsia

Blockade of 2-adrenergic receptors; increased airway resistance Blockade of atrial 1/2-adrenergic receptors; decrease in heart rate Blockade of ventricular 1-adrenergic receptors Blockade of peripheral vascular 2-adrenergic receptors Blockade of gastrointestinal 1/2-adrenergic receptors; decreased motility and relaxation of sphincter tone Blockade of CNS 1/2-adrenergic receptors

Central nervous system manifestations (sleep disturbances, depression) Sexual dysfunction (impotence, decrease libido) Impaired glucose tolerance

Unknown

Prolonged insulin-induced hypoglycemia Hepatocellular necrosis Withdrawal syndrome Unstable angina Myocardial infarction Dyslipidemia Increased total triglycerides Decreased high-density lipoproteins cholesterol

Labetalol only, idiosyncratic reaction Acute overshoot in heart rate with increased myocardial oxygen demand due to increase in number and/or sensitivity of -adrenergic receptors during chronic blockade Increased -adrenergic tone; reduced lipoprotein lipase activity

Impaired 2-adrenergic–mediated islet cell insulin secretion; increase hepatic glucose, and/or decrease insulin-stimulated glucose disposal Block epinephrine-mediated counterregulatory mechanisms

FIGURE 7-14 The side effect profile of -adrenergic antagonists. The side effect profile of betablockers is related to the specific blockade of 1 or 2 receptors. This table lists the more common side effects and their proposed mechanism(s) of action [6,9].

7.13

Pharmacologic Treatment of Hypertension Phsysiologic effect of central α2-adrenergic agonists α-Methyldopa guanfacine guanabenz

Clonidine

Stimulates

Stimulates

Central α2 adrenoceptor

I1-Imidazoline receptor

NTS

RVLM

Nucleus tractus solitarii

FIGURE 7-15 Central 2-adrenergic agonists. Central 2-adrenergic agonists cross the blood-brain barrier and stimulate 2-adrenergic receptors in the vasomotor center of the brain stem [6,9]. Stimulation of these receptors decreases sympathetic tone, brain turnover of norepinephrine, and central sympathetic outflow and activity of the preganglionic sympathetic nerves. The net effect is a reduction in norepinephrine release. The central 2-adrenergic agonist clonidine also binds to imidazole receptors in the brain; activation of these receptors inhibits central sympathetic outflow. Central 2-adrenergic agonists may also stimulate the peripheral 2adrenergic receptors that mediate vasoconstriction; this effect predominates at high plasma drug concentrations and may precipitate an increase in blood pressure. The usual physiologic effect is a decrease in peripheral resistance and slowing of the heart rate; however, output is either unchanged or mildly decreased. Preservation of cardiovascular reflexes prevents postural hypotension.

Rostral ventrolateral medulla Inhibition of central sympathetic activity

Blood pressure reduction

CENTRAL 2-ADRENERGIC ANTAGONISTS Generic (trade) name

First dose, mg

Usual daily dose

Maximum daily dose

-Methyldopa (G) (Aldomet) Clonidine (G) (Catapres) Clonidine TTS (Catapres-TTS) Guanabenz (Wytensin) Guanfacine (Tenex)

250 0.1 2.5 mg (TTS-1) 4 1

250–1000 mg bid 0.1–0.6 mg bid/tid 2.5–7.5 mg (TTS–1 to TTS–3) qwk 4–16 mg bid 1–3 mg QD

3000 2.4 15 mg (TTS-3x2) 9 wk 64 3

Duration of action 24–48 h 6–8 h 7d 12 h 36 h

G—generic available; TTS—transdermal patch.

FIGURE 7-16 Central 2-adrenergic agonists. -Methyldopa is a methyl-substituted amino acid that is active only after decarboxylation and conversion to -methyl-norepinephrine. The antihypertensive effect results from accumulation of 2-adrenergic receptors, displacing and competing with endogenous catecholamines. Methyldopa is absorbed poorly (<50%); peak plasma concentrations occur in 2 to 4 hours. It is metabolized in the liver and excreted in the urine mainly as the inactive O-sulfate conjugate. The plasma half-life of methyldopa (1 to 2 hours) and its metabolites is prolonged in patients with renal insufficiency; dose reduction is required. Clonidine, an imidazoline derivative, acts by stimulating either central 2-adrenergic receptors or imidazole receptors. Clonidine may be administered orally or by a transdermal delivery system (TTS). When given orally, it is absorbed well (>75%); peak plasma concentrations occur in 3 to 5 hours. Clonidine is metabolized mainly in the liver; fecal excretion ranges from 15% to 30%, and 40% to 60% is excreted unchanged in the urine. In patients with renal

insufficiency, the plasma half-life (12 to 16 hours) may be extended to more than 40 hours; dose reduction is required. When clonidine is administered transdermally, therapeutic plasma levels are achieved within 2 to 3 days. Guanabenz, a guanidine derivative, is highly selective for central 2-adrenergic receptors. It is absorbed well (>75%); peak plasma levels are reached in 2 to 5 hours. Guanabenz undergoes extensive hepatic metabolism; less than 2% is excreted unchanged in the urine. The plasma half-life (approximately 6 hours) is not prolonged in patients with renal insufficiency. Guanfacine is a phenylacetyl-guanidine derivative with a longer plasma half-life than guanabenz. It is absorbed well (>90%); peak plasma concentrations are reached in 1 to 4 hours. The drug is primarily metabolized in the liver. Guanfacine and its metabolites are excreted primarily by the kidneys; 24% to 37% is excreted as unchanged drug in the urine. The plasma half-life (15 to 17 hours) is not prolonged in patients with renal insufficiency [6,9].

7.14

Hypertension and the Kidney FIGURE 7-17 The side effect profile of central 2-adrenergic agonists. The side effect profile of these agents is diverse [6,9].

THE SIDE EFFECT PROFILE OF CENTRAL 2-ADRENERGIC AGONISTS Side effects

Mechanisms

Sedation/drowsiness

Stimulation of 2-adrenergic receptors in the brain Centrally mediated inhibition of cholinergic transmission Reduced central dopaminergic inhibition of prolactin release (methyldopa only) Long-term tissue toxicity (methyldopa only)

Xerostoniia (dry mouth) Gynecomastia in men, galactorrhea in women Drug fever, hepatotoxicity, positive Coombs test with or without hemolytic anemia Sexual dysfunction, depression, decreased mental acuity “Overshoot hypertension” Restlessness Insomnia Headache Tremor Anxiety Nausea and vomiting A feeling of impending doom

Stimulation of 2-adrenergic receptor in the brain Acute excessive sympathetic discharge in the face of chronic downregulation of central 2-adrenergic receptors in an inhibitory circuit during chronic treatment when treatment is stopped

Indicates blockade Brain stem Preganglionic neuron Ganglion

NE

Postganglionic adrenergic nerve ending

NE

NE

NE

α1

β1

α2 Vascular smooth muscle cells

FIGURE 7-18 Central and peripheral adrenergic neuronal blocking agents. Rauwolfia alkaloids act both within the central nervous system and in the peripheral sympathetic nervous system [6,9]. They effectively deplete stores of norepinephrine (NE) by competitively inhibiting the uptake of dopamine by storage granules and by preventing the incorporation of norepinephrine into the protective chromaffin granules; the free catecholamines are destroyed by monoamine oxidase. The predominant pharmacologic effect is a marked decrease in peripheral resistance; heart rate and cardiac output are either unchanged or mildly decreased.

7.15

Pharmacologic Treatment of Hypertension

CENTRAL PERIPHERAL ADRENERGIC-NEURONAL BLOCKING AGENT Generic (trade) name Reserpine (G) (Serpasil)

First dose, mg

Usual daily dose, mg

Maximum daily dose, mg

Duration of action

0.1

0.1–.25 QD

0.5

2–3 wk

FIGURE 7-19 Central and peripheral adrenergic neuronal blocking agents. Reserpine is the most popular rauwolfia product used. It is absorbed poorly (approximately 30%); peak plasma concentrations occur in 1 to 2 hours. Catecholamine depletion begins within 1 hour of drug administration and is maximal in 24 hours. Catecholamines are restored slowly. Chronic doses of reserpine are cumulative. Blood

THE SIDE EFFECT PROFILE OF RESERPINE Side effects

Mechanisms

Altered CNS function Inability to concentrate Decrease mental acuity Sedation Sleep disturbance Depression Nasal congestion/rhinitis Increased GI motility, increased gastric acid secretion Increased appetite/weight gain Sexual dysfunction Impotence Decreased libido

Depletion of serotonin and/or catecholamine

pressure is maximally lowered 2 to 3 weeks after beginning therapy. Reserpine is metabolized by the liver; 60% of an oral dose is recovered in the feces. Less than 1% is excreted in the urine as unchanged drug. The plasma half-life (12 to 16 days) is not prolonged in patients with renal insufficiency.

Indicates blockade

Peripheral adrenergic nerve ending

NE

NE

NE

NE NE

Cholinergic effects Cholinergic effects NE

Unknown Unknown

NE α2

FIGURE 7-20 The side effect profile of the central and peripheral adrenergic neuronal blocking agents [10,13]. Reserpine is contraindicated in patients with a history of depression or peptic ulcer disease. CNS—central nervous system; GI—gastrointestinal.

β1

α1 Vascular smooth muscle cells

FIGURE 7-21 Peripheral 1-adrenergic antagonists. 1-Adrenergic antagonists induce dilation of both resistance (arterial) and capacitance (venous) vessels by selectively inhibiting postjunctional 1-adrenergic receptors [6,9]. The net physiologic effect is a decrease in peripheral resistance; reflex tachycardia and the attendant increase in cardiac output do not predictably occur. This is due to their low affinity for prejunctional 2-adrenergic receptors, which modulate the local control of norepinephrine release from sympathetic nerve terminals by a negative feedback mechanism (see Fig. 7-22) [11]. NE—norepinephrine.

7.16

Hypertension and the Kidney

Varicosity

Vesicle containing NA

Nerve impulse induces exocytotic NA release + Presynaptic β β-receptor

Sympathetic C-fiber Presynaptic α-receptor Synaptic cleft

– α

Postganglionic sympathetic neuron

NA Varicosities

α

Synaptic cleft

Postsynaptic α-receptor

Effector cell

Response

NA

Postsynaptic α- receptors

Target organ

FIGURE 7-22 Adrenergic synapse. Nerve activity releases the endogenous neurotransmitter noradrenaline (NA) and also adrenaline from the varicosities. Noradrenaline and adrenaline reach the postsynaptic -adrenoceptors (or -adrenoceptors) on the cell membrane of the target organ by diffusion. On receptor stimulation, a physiologic or pharmacologic effect is initiated. Presynaptic 2-adrenoceptors on the membrane (enlarged area), when activated by endogenous noradrenaline as well as by exogenous agonists, inhibit the amount of transmitter noradrenaline released per nerve impulse. Conversely, the stimulation of presynaptic 2-receptors enhances noradrenaline release from the varicosities. Once noradrenaline has been released, it travels through the synaptic cleft and reaches both - and -adrenoceptors at postsynaptic sites, causing physiologic effects such as vasoconstriction or tachycardia. (Adapted from Van Zwieten [11].)

PERIPHERAL 1-ADRENERGIC ANTAGONISTS Generic (trade) name

First dose, mg

Usual daily dose, mg

Maximum daily dose, mg

Prazosin (G) (Minipress) Terazosin (Hytrin) Doxazosin (Cardura)

1 1 1

2-6 bid/tid 2-5 QD/bid 2-4 QD

20 20 16

Duration of action 6-12 w 12-24 h 24 h

G—generic available.

FIGURE 7-23 Peripheral 1-adrenergic antagonists. Prazosin is a lipophilic highly selective 1-adrenergic antagonist. It is absorbed well (approximately 90%) but undergoes variable first-pass hepatic metabolism. Peak plasma concentrations occur in 2 to 3 hours. It is extensively metabolized by the liver and predominantly excreted in the feces. The plasma half-life of prazosin (2 to 4 hours) is not prolonged in patients with renal insufficiency. Terazosin is a water-soluble quinazoline analogue of prazosin with about one third of its potency. It is completely absorbed and undergoes minimal first-pass hepatic metabolism. Peak plasma concentrations occur in 1 to 2 hours. It is extensively

metabolized by the liver and predominantly excreted in the feces. The plasma half-life of terazosin (approximately 12 hours) is not prolonged in patients with renal insufficiency. Doxazosin is also a water-soluble quinazoline analogue of prazosin, with about half its potency. It is absorbed well but undergoes significant first-pass hepatic metabolism; bioavailability is approximately 65%. Peak concentrations occur in 2 to 3 hours. It is extensively metabolized by the liver and primarily eliminated in the feces. The plasma half-life of doxazosin (approximately 22 hours) is not prolonged in patients with renal insufficiency [6,9].

Pharmacologic Treatment of Hypertension

150

Lying Standing

Placebo

Mean BP, mm Hg

140 130 120 110 100

140

Day 0

Prazosin, 2 mg

130

Mean BP, mm Hg

120 110 100 90 80 70 60 50

140

Day 1

Prazosin, 2 mg

Mean BP, mm Hg

130 120 110 100 90 80

Day 4

0700

0900

1100 1300 Time, h

1500

1700

7.17

FIGURE 7-24 The side effect profile of the peripheral 1-adrenergic antagonists. 1-Adrenergic antagonists are associated with relatively few side effects [6,9]; the most striking is the “first-dose effect” [12]. It occurs 30 to 90 minutes after the first dose and is dose dependent. It is minimized by initiating therapy in the evening and by careful dose titration. The “first-dose effect” is exaggerated by fasting, upright posture, volume contraction, concurrent -adrenergic antagonism, or excessive catecholamine activity (eg, pheochromocytoma). (From Graham and coworkers [12]; with permission.)

7.18

Hypertension and the Kidney FIGURE 7-25 Moderately selective peripheral 1-adrenergic antagonists. Phenoxybenzamine is a moderately selective peripheral 1-adrenergic antagonist [6,9]. It is 100 times more potent at 1-adrenergic receptors than at 2-adrenergic receptors. Phenoxybenzamine binds covalently to -adrenergic receptors, interfering with the capacity of sympathomimetic amines to initiate action at these sites. Phenoxybenzamine also increases the rate of turnover of norepinephrine (NE) owing to increased tyrosine hydroxylase activity, and it increases the amount of norepinephrine released by each nerve impulse owing to blockade of presynaptic 2-adrenergic receptors [11]. The net physiologic effect is a decrease in peripheral resistance and increases in heart rate and cardiac output. Postural hypotension may be prominent, related to blockade of compensatory responses to upright posture and hypovolemia. The degree of vasodilation is dependent on the degree of adrenergic vascular tone.

Indicates blockade

Peripheral adrenergic nerve ending

NE

NE

NE

NE

α2

NE

NE

NE α2

β1

α1 Vascular smooth muscle cells

MODERATELY SELECTIVE PERIPHERAL 1-ADRENERGIC ANTAGONIST Generic (trade) name Phenoxybenzamine (Dibenzyline)

First dose, mg

Usual daily dose, mg

Maximum of action, mg

Duration of action

10

20-40 bid

120

3–4 d

FIGURE 7-26 Moderately selective peripheral 1-adrenergic antagonists. Phenoxybenzamine is the only drug in its class. Absorption is variable and incomplete (20% to 30%). Peak blockade occurs in 3 to 4 hours. Its plasma half-life is 24 hours. The duration of action is

approximately 3 to 4 days. Phenoxybenzamine is primarily used in the management of preoperative or inoperative pheochromocytoma. Efficacy is dependent on the degree of underlying excessive -adrenergic vascular tone [6,9].

Pharmacologic Treatment of Hypertension

THE SIDE EFFECT PROFILE OF PHENOXYBENZAMINE Side effects

Mechanisms

Nasal congestion Miosis Sedation Weakness, lassitude

-adrenergic receptor blockade -adrenergic receptor blockade Unknown Impairment of compensatory vasoconstriction producing orthostatic hypotension -adrenergic receptor blockade

Sexual dysfunction Inhibition of ejaculation Tachycardia

Indicates blockade

NE

NE

NE

NE

β1

FIGURE 7-27 The side effect profile of phenoxybenzamine. The common side effects are listed [6,9].

Uninhibited effects of epinephrine, norepinephrine and direct or reflex sympathetic nerve stimulation on the heart

Peripheral adrenergic nerve ending

α1

7.19

α2 Vascular smooth muscle cells

FIGURE 7-28 Peripheral adrenergic neuronal blocking agents. Peripheral adrenergic neuronal blocking agents are selectively concentrated in the adrenergic nerve terminal by an active transport mechanism, or “norepinephrine pump” [6,9]. They act by interfering with the release of norepinephrine (NE) from neuronal storage sites in response to nerve stimulation and by depleting norepinephrine from nerve endings. Acutely, cardiac output is reduced, caused by diminished venous return and by blockade of sympathetic -adrenergic effects on the heart; peripheral resistance is unchanged. Following chronic therapy, peripheral resistance is decreased, along with modest decreases in heart rate and cardiac output.

7.20

Hypertension and the Kidney

PERIPHERAL ADRENERGIC-NEURONAL BLOCKING AGENTS Generic (trade) name Guanethidine (Ismelin) Guanadrel (Hylorel)

First dose, mg

Usual daily dose, mg

Maximum daily dose, mg

Duration of action

10 5

25–75 QD 10–50 bid

150 150

7–21 d 4–14 h

FIGURE 7-29 Peripheral adrenergic neuronal blocking agents. Guanethidine is the prototype peripheral adrenergic neuronal blocking agent. Absorption is incomplete and variable; only 3% to 30% is absorbed over 12 hours. Peak plasma levels are reached in 6 hours. The drug rapidly leaves the plasma for extravascular storage sites, including sympathetic neurons. Guanethidine is eliminated with a plasma half-life of 4 to 8 days, a time course that corresponds with its antihypertensive effect. Approximately 24% of the drug is excreted unchanged in the urine; the remainder is metabolized by the liver into more polar, less active, metabolites that are excreted in the urine and feces. When therapy is initiated or the dosage is changed, three half-lives (approximately 15 days) are required to accumulate

87.5% of a steady-state level. By administering loading doses of guanethidine at 6-hour intervals (the nearly maximal effect from a single oral dose), blood pressure can be lowered in 1 to 3 days. In patients with severe renal insufficiency, drug excretion is decreased; dose reduction is required. Guanadrel is a guanethidine derivative with a short therapeutic half-life. Absorption is greater than 85%; peak plasma concentrations are reached in 1 to 2 hours. Guanadrel is metabolized by the liver. Elimination occurs through the kidney; approximately 40% of the drug is excreted unchanged in the urine. In patients with renal insufficiency, the plasma half-life (10 to 12 hours) is prolonged; dose reduction is required [6,9].

THE SIDE EFFECT PROFILE OF PERIPHERAL ADRENERGIC-NEURONAL BLOCKING AGENTS Side effects

Mechanisms

Decrease renal function (GFR) Fluid retention/weight gain

Decreased renal perfusion; effect is magnified in the upright position Decreased filtered load and fractional excretion of sodium; diuretic should be used in combination Postural hypotension accentuated by hot weather, alcohol ingestion, and/or physical exercise Unopposed parasympathetic activity, increasing gastrointestinal motility Inhibition of bladder neck closure, unknown

Dizziness/weakness Syncope Intestinal cramping/diarrhea Sexual dysfunction Retrograde ejaculation Impotence Decreased libido Sinus bradycardia Atrioventricular block Bronchospasm Congestive heart failure

Interferes with cardiac sympathetic compensating reflexes Catecholamine depletion aggravates airway resistance Decreased cardiac output

FIGURE 7-30 The side effect profile of peripheral adrenergic neuronal blocking agents. The specific side effects of this class are related to either excessive sympathetic blockade or a relative increase in parasympathetic activity. GFR— glomerular filtration rate.

7.21

Pharmacologic Treatment of Hypertension

Plasma membrane

VGC

Leak

ROC

Altered calcium metabolism (?)

Ca2+

VGC

Ca2+ Ca2+

Ca2+

SR

Ca2+

SR

FIGURE 7-31 Direct-acting vasodilators. Direct-acting vasodilators may have an effect on both arterial resistance and venous capacitance vessels; however, the currently available oral drugs are highly selective for resistance vessels [6,9]. Their specific mechanism of vascular relaxation and reason for selectivity are unknown. By altering cellular calcium metabolism, they interfere with the calcium movements responsible for initiating or maintaining a contractile state. The net physiologic effect is a decrease in peripheral vascular resistance associated with increases in heart rate and cardiac output. These increases in heart rate and cardiac output are related directly to sympathetic stimulation and indirectly to the baroreceptor reflex response. ROC—receptor-operated channel; SR—sarcoplasmic reticulum; VGC—voltage-gaited channels.

Activation of Myofilaments

Contraction of vascular smooth muscle

Hypertension

DIRECT-ACTING VASODILATORS Generic (trade) name Hydralazine (G) (Apresoline) Minoxidil (G) (Loniten)

First dose, mg

Usual daily dose, mg

Maximum daily dose, mg

Duration of action, h

10 5

50–100 bid/tid 10–20 QD/bid

300 80

10–12 75

G—generic available.

FIGURE 7-32 Direct-acting vasodilators. Hydralazine is the prototype of directacting vasodilators. Absorption is more than 90%. Peak plasma levels occur within 1 hour but may vary widely among individuals. This is because hydralazine is subject to polymorphic acetylation; slow acetylators have higher plasma levels and require lower drug doses to maintain blood pressure control compared with rapid acetylators. Bioavailability for slow acetylators ranges from 30% to 35%; bioavailability for rapid acetylators ranges from 10% to 16%. Hydralazine undergoes extensive hepatic metabolism; it is mainly excreted in the urine in the form of metabolites or as unchanged drug. The plasma half-life is 3 to 7 hours. Dose reduction may be required in the slow acetylator with renal insufficiency.

Minoxidil is a substantially more potent direct-acting vasodilator than hydralazine. Absorption is greater than 95%. Peak plasma levels occur within 1 hour. Following a single oral dose, blood pressure declines within 15 minutes, reaches a nadir between 2 and 4 hours, and recovers at an arithmetically linear rate of 30% per day. Approximately 90% is metabolized by conjugation with glucuronic acid and by conversion to more polar products. Known metabolites, which are less pharmacologically active than minoxidil, are excreted in the urine. The plasma half-life of minoxidil is approximately 4 hours; dose adjustments are unnecessary in patients with renal insufficiency. Minoxidil and its metabolites are removed by hemodialysis and peritoneal dialysis; replacement therapy is required [6,9].

7.22

Hypertension and the Kidney Side effects of direct-acting vasodilators ↑ Heart rate

VASODILATORS

↑ Myocardial contractility

↑ Sympathetic function

↓ Venous capacitance ↑ Peripheral vascular resistance

↓ Peripheral vascular resistance

↑ Plasma renin activity

↓ Arterial pressure

↑ Cardiac output

PROPRANOLOL

↑ Circulating angiotensin

↑ Aldosterone secretion

DIURETICS ↑ Plasma and extracellular fluid volume

↓ Sodium excretion

Plasma membrane

ROC

VGC

Ca2+

Ca2+ Ca2+

Ca2+

Myofilaments

SR

Ca2+

SR

VGC

FIGURE 7-33 The side effect profile of direct-acting vasodilators. The most common and most serious effects of hydralazine and minoxidil are related to their direct or reflex-mediated hemodynamic actions, including flushing, headache, palpitations, anginal attacks, and electrocardiographic changes of myocardial ischemia [6,9]. These effects may be prevented by concurrent administration of a -adrenergic antagonist. Sodium retention with expansion of extracellular fluid volume is a significant problem. Large doses of potent diuretics may be required to prevent fluid retention and the development of pseudotolerance [13]. (From Koch-Weser [13]; with permission.) Repeated administration of hydralazine can lead to a reversible syndrome that resembles disseminated lupus erythematosus. The incidence is dose dependent; it rarely occurs in patients receiving less than 200 mg/day. Hypertrichosis is a common troublesome but reversible side effect of minoxidil; it develops during the first 3 to 6 weeks of therapy in approximately 80% of patients.

FIGURE 7-34 Calcium antagonists. The calcium antagonists share a common antihypertensive mechanism of action: inhibition of calcium ion movement into smooth muscle cells of resistance arterioles through L-type (long-lasting) voltage-operated channels [6,9]. The ability of these drugs to bind to voltage-operated channels, causing closure of the gate and subsequent inhibition of calcium flux from the extracellular to the intracellular space, inhibits the essential role of calcium as an intracellular messenger, uncoupling excitation to contraction. Calcium ions may also enter cells through receptor-operated channels. The opening of these channels is induced by binding neurohumoral mediators to specific receptors on the cell membrane. Calcium antagonists inhibit the calcium influx triggered by the stimulation of either -adrenergic or angiotensin II receptors in a dose-dependent manner, inhibiting the influence of -adrenergic agonist and angiotensin II on vascular smooth muscle tone. The net physiologic effect is a decrease in vascular resistance. Although all the calcium antagonists share a basic mechanism of action, they are a highly heterogeneous group of compounds that differ markedly in their chemical structure, pharmacologic effects on tissue specificity, pharmacologic behavior side-effect profile, and clinical indications [6,9,14]. Because of this, calcium antagonists have been subdivided into several distinct classes: phenylalkamines, dihydropyridines, and benzothiazepines. ROC—receptor-operated channel; SR—sarcoplasmic reticulum; VGC—voltage-gaited channels.

7.23

Pharmacologic Treatment of Hypertension

A. DOSING SCHEDULES FOR CALCIUM ANTAGONISTS: PHENYLALKAMINE DERIVATIVE Generic (trade) name Verapamil (G) (Isoptin, Calan) Verapamil SR (Isoptin SR, Calan SR) Verapamil SR—pellet (Veralan) Verapamil COER-24 (Covera HS)

First dose, mg 80 90 120 180

Usual dose, mg

Maximum daily dose, mg

Duration of action, h

80–120 tid 90–240 bid 240–480 QD 180–480 qhs

480 480 480 480

8 12–24 24 24

G—generic available.

B. DOSING SCHEDULES FOR CALCIUM ANTAGONISTS: DIHYDROPYRIDINE DERIVATIVES Generic (trade) name Amlodipine (Norvasc) Felodipine (Plendil) Isradipine (DynaCirc) Isradipine CR (DynaCirc CR) Nicardipine SR (Cardine SR) Nifedipine Caps (G) (Procardia) Nifedipine ER (Adalat CC) Nifedipine GITS (Procardia XL) Nisoldipine (Sular)

First dose, mg

Usual dose, mg

5 5 2.5 5 30 10 30 30 20

5–10 QD 5–1 0 QD 2.5-5 bid 5–20 QD 30–60 bid 10–30 tid/qid 30–90 QD 30–90 QD 20–40 QD

Maximum daily dose, mg 10 20 20 20 120 120 120 120 60

Duration of action, h 24 24 12 24 12 4–6 24 24 24

G—generic available.

C. DOSING SCHEDULES FOR CALCIUM ANTAGONISTS: BENZODIAZEPINE DERIVATIVE Generic (trade) name Diltiazem (G) (Cardizem) Diltiazem SR (Cardizem SR) Diltiazem CD (Cardizem CD) Diltiazem XR (Dilacor XR) Diltiazem ER (Tiazac)

First dose, mg 60 180 180 180 180

Usual dose, mg 60–120 tid/qid 120–240 bid 240–480 QD 180–480 QD 180–480 QD

G—generic available.

FIGURE 7-35 A–C. Dosing schedules for calcium antagonists: phenylalkamine derivatives, dihydropyridine derivatives, and benzothiazepine derivatives.

Maximum daily dose, mg 480 480 480 480 480

Duration of action, h 8 12 24 24 24

7.24

Hypertension and the Kidney

PHARMACOKINETICS OF CALCIUM ANTAGONISTS Absorption, %

First-pass hepatic

Peak concentration

Verapamil

>90

70%–80%

Amlodipine Felodipine Isradipine

>90 >90 >90

Minimal Extensive Extensive

Nicardipine Nifedipine

>90 >90

Extensive 20%–30%

Nisoldipine Diltiazem

>85 >80

Extensive 50%

1–2 h (tablet) 5 h (SR caplet) 7–9 h (SR pellet) 11 h (COER) 6–12 h 2.5–5 h 1–2 h (tablet) 7–18 h (CR) 1–4 h (SR) <30 min (cap) 2.5–5 h (ER) 6 h GITS) 6–12 h 2–3 h (tablet) 6–11 h (SR) 10–14 h (CD) 4–6 h (XR) 7 h (ER)

Route of elimination Active metabolite Plasma half-life, h Dose reduction Liver

Yes

4–12 (tablet) 12 (SR pellet)

No

Liver Liver Liver

No No No

30–50 11–16 8

No No No

Liver Liver

No No

No No

Liver Liver

Yes Yes

8–9 2 24 24 7–12 4–6 5–7 5–8 5–10 4–10

No Yes

FIGURE 7-36 Pharmacokinetics of the calcium antagonists: phenylalkamine derivatives, dihydropyridine derivatives, and benzothiazepine derivatives.

THE SIDE EFFECTS PROFILE OF CALCIUM ANTAGONISTS Side effects

Mechanism

Dihydropyridine Headache, flushing, palpitation, edema Phenylalkylamine Constipation Bradycardia, AV block congestive heart failure Benzodiazepine Bradyarrhythmia, AV block congestive heart failure

Potent peripheral vasodilator Negative inotropic, dromotropic, chronotropic effects

Negative inotropic, dromotropic, chronotropic effects

FIGURE 7-37 The side effect profile of calcium antagonists [10,13,18]. AV—atrioventricular.

7.25

Pharmacologic Treatment of Hypertension ACE inhibition and angiotensin II type I receptor antagonists: mechanisms for decrease in peripheral vascular resistance +

–

+

Angiotensinogen (renin substrate) 1

Non-renin enzymes

AT1 receptor

Non-ACE enzymes

Renin Angiotensin I (decapeptide)

3

2

+

Remodeling, vascular smooth muscle

+

Blood pressure

Sympathetic activity (central and peripheral) Baroreceptor sensitivity

4

Inactive fragments

Bradykinin

Vasoconstriction, vascular smooth muscle

–

ACE

+

Aldosterone release

+

+

Angiotensin II (octapeptide)

Functions:: Renal tubular sodium reabsorption

AT2 receptor

? Function

Nitric oxide – Prostaglandin E2 Prostaglandin I2

– –

FIGURE 7-38 Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type I receptor antagonists. Angiotensin-converting enzyme inhibitors and angiotensin II type I receptor antagonists lower blood pressure by decreasing peripheral vascular resistance; there is usually little change in heart rate or cardiac output [6,9,15].

Mechanisms proposed for the observed decrease in peripheral resistance are shown [15]. Sites of pharmacologic blockade in the renin angiotensin system: 1) renin inhibitors, 2) ACE inhibitors, 3) angiotensin II type I receptor antagonists, 4) angiotensin II type II receptor antagonists.

7.26

Hypertension and the Kidney

A. DOSING SCHEDULES FOR SULFHYDRYL-CONTAINING ACE INHIBITOR Generic (trade) name

First dose, mg

Usual dose, mg

Maximum dose, mg

Duration of action, h

Captopril (G) (Capoten)

12.5

12.5–50 bid/tid

150

6–12

Maximum dose, mg

Duration of action, h

B. DOSING SCHEDULES FOR CARBOXYL-CONTAINING ACE INHIBITORS Generic (trade) name

First dose, mg

Benazepril (Lotensin) Enalapril (Vasotec) Lisinopril (Prinivil,Zestril) Moexipril (Univasc) Quinapril (Accupril) Ramipril (Altace) Trandolapril (Mavik)

10 5 10 7.5 5–10 2.5 1

Usual dose, mg 10–20 QD 5–10 QD/bid 20–40 QD 7.5–15 QD/bid 20–40 QD 2.5–20 QD/bid 2–4 QD

40 40 40 30 40 40 8

24 12–24 24 24 24 24 24

C. DOSING SCHEDULES FOR PHOSPHINIC ACID–CONTAINING ACE INHIBITOR Generic (trade) name Fosinopril (Monopril)

First dose, mg

Usual dose, mg

Maximum dose, mg

Duration of action, h

10

20–40 QD/bid

40

24

G—generic available.

FIGURE 7-39 A–C. Classification of and dosing schedule for angiotensin-converting enzyme (ACE) inhibitors. Angiotensin-converting enzyme inhibitors differ in prodrug status, ACE affinity, potency, molecular weight and

conformation, and lipophilicity [6,9]. They are generally classified into one of three main chemical classes according to the ligand of the zinc ion of ACE: sulfhydryl, carboxyl, or phosphinic acid.

7.27

Pharmacologic Treatment of Hypertension

PHARMACOKINETICS OF ACE INHIBITORS

Captopril Benazepril Enalapril Lisinopril Moexipril Quinapril Ramipril Trandolapril Fosinopril

Absorption, %

Prodrug

Peak concentration (active component), h

Route of elimination

Plasma half-life, h

Dose reduction (renal disease)

60–75 37 55–75 25 > 20 60 50–60 70 36

No Yes Yes Yes Yes Yes Yes Yes Yes

1 1–2 3–4 6–8 1–2 2 2–4 4–10 3

Kidney Kidney/liver Kidney Kidney Kidney Kidney Kidney/liver Kidney/liver Kidney/liver

2 10–11 11 12 2–9 25 13–17 16–24 12

Yes Yes Yes Yes Yes Yes Yes Yes No

FIGURE 7-40 Pharmacokinetics of angiotensin-converting enzyme (ACE) inhibitors: sulfhydrylcontaining, carboxyl-containing, and phosphinic acid–containing.

THE SIDE EFFECTS PROFILE OF ACE INHIBITORS Side effects

Mechanisms

Cough, angioedema Laryngeal edema Lightheadedness, syncope

Potentiation of tissue kinins Excessive hypotension in patients with high basal peripheral vascular resistance— high renin states, like volume contraction, impaired cardiac output Decreased aldosterone; potassium-containing salt substitutes and supplements should be avoided Extreme hypotension with impaired efferent arteriolar autoregulation

Hyperkalemia Acute renal failure

FIGURE 7-41 The side effect profile of angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors are well tolerated; there are few side effects [6,9].

7.28

Arterial pressure, mm Hg

Hypertension and the Kidney

Renal artery stenosis

230

FIGURE 7-42 Angiotensin-converting enzyme (ACE) inhibition in acute renal failure. ACE inhibitors may produce functional renal insufficiency in patients with essential hypertension and hypertensive nephrosclerosis, in patients with severe bilateral renal artery stenosis, or in patients with stenosis of the renal artery of a solitary kidney. The postulated mechanism for this effect is diminished renal blood flow (decrease in systemic pressure, compromising flow through a fixed stenosis) in combination with diminished postglomerular capillary resistance (ie, decrease in angiotensin II–mediated efferent arteriolar tone). In unilateral renal artery stenosis, a drop in the critical perfusion and filtration pressures may result in a marked drop in single-kidney glomerular filtration rate (GFR); however, the contralateral kidney may show an increase in both effective renal plasma flow (ERPF) and GFR due to attenuation of the intrarenal effects of angiotensin II on vascular resistance and mesangial tone. Thus, total “net” GFR may be normal, giving the false appearance of stability [16]. Although ACE inhibition may invariably decrease the GFR of the stenotic kidney, it is unlikely to cause renal ischemia owing to preservation of ERPF; GFR usually returns to pretreatment values following cessation of therapy. Shown is the effect of captopril (50 mg) on total clearances of 131I-sodium iodohippurate (ERPF) and 126I-thalamate (GFR) in 14 patients with unilateral renal artery stenosis and in 17 patients with essential hypertension. The effects after 60 minutes of captopril on systolic and diastolic intra-arterial pressure (P < 0.001) and of renin were significant. (From Wenting and coworkers [16]; with permission.)

Essential hypertension

190 150 110

Total glomerular filtration rate, mL/min

Total effective renal plasma flow, mL/min

70 440 360 280 110 100 90 80

Plasma renin, mU/L

1000

100

10

Captopril 50 mg

Captopril 50 mg

30

30

–15 0

60 –15 0 Time, min

60

Indicates blockade

Peripheral adrenergic nerve ending

Tyrosine Tyrosine hydroxylase Dihydroxyphenylalanine NE

α1

β1

α2 Vascular smooth muscle cells

FIGURE 7-43 Tyrosine hydroxylase inhibitor. Metyrosine (-methyl-para-tyrosine) is an inhibitor of tyrosine hydroxylase, the enzyme that catalyzes the conversion of tyrosine to dihydroxyphenylalanine [6,9]. Because this first step is rate limiting, blockade of tyrosine hydroxylase activity results in decreased endogenous levels of circulating catecholamines. In patients with excessive production of catecholamines, metyrosine reduces biosynthesis 36% to 79%; the net physiologic effect is a decrease in peripheral vascular resistance and increases in heart rate and cardiac output resulting from the vasodilation. The degree of vasodilation is dependent on the degree of blockade of adrenergic vascular tone. NE—norepinephrine.

7.29

Pharmacologic Treatment of Hypertension

TYROSINE HYDROXYLASE INHIBITOR Generic (trade) name Metyrosine (Demser)

First dose, mg

Usual daily dose, mg

Maximum dose, mg

Duration of action, h

250

25 qid

1000 qid

3–4

FIGURE 7-44 Tyrosine hydroxylase inhibitor. Metyrosine is the only drug in its class. The initial recommended dose is 1 g/d, given in divided doses. This may be increased by 250 to 500 mg daily to a maximum of 4 g/d. The usual effective dosage is 2 to 3 g/d. The maximum biochemical effect occurs within 2 to 3 days. In hypertensive patients in whom there is a response, blood pressure decreases progressively during the first days of therapy. In patients who are usually normotensive, the dose should be titrated to the amount that will reduce circulating or urinary catecholamines by 50% or more.

THE SIDE EFFECTS PROFILE OF METYROSINE Side effects

Mechanisms

CNS symptoms Sedation Extrapyramidal signs Drooling Speech difficulty Tremor Trismus Parkinsonian syndrome Psychic dysfunction Anxiety Depression Disorientation Confusion Crystalluria, uroliathiasis Diarrhea Insomnia (temporary)

Depletion of CNS dopamine

Poor urine solubility Direct irritant to bowel mucosa Following drug withdrawal

Following discontinuation of therapy, the clinical and biochemical effects may persist 2 to 4 days. Metyrosine is variably absorbed from the gastrointestinal tract; bioavailability ranges from 45% to 90%. Peak plasma concentrations are reached in 1 to 3 hours. The plasma half-life is 3 to 4 hours. Metyrosine is not metabolized; the unchanged drug is recovered in the urine. Drug dosage should be reduced in patients with renal insufficiency. Metyrosine is exclusively used in the management of preoperative or inoperative pheochromocytoma [6,9]. FIGURE 7-45 The side effect profile of metyrosine. The adverse reactions observed with metyrosine are primarily related to the central nervous system and are typically dose dependent [6,9]. Metyrosine crystalluria (needles or rods), which is due to the poor solubility of the drug in the urine, has been observed in patients receiving doses greater than 4 g/d. To minimize this risk, patients should be well hydrated. CNS—central nervous system.

7.30

Hypertension and the Kidney

ANGIOTENSIN II RECEPTOR ANTAGONISTS Generic (trade) name

First dose, mg

Usual dose, mg

Maximum dose, mg

Duration of action, h

50 80 150

50–100 QD/bid 80–160 QD 150–300 QD

100 320 300

12–24 24 24

Losartan (Cozaar) Valsartan (Diovan) Irbesaftan (Avapro)

FIGURE 7-46 Angiotensin II receptor antagonists. These drugs antagonize angiotensin II–induced biologic actions, including proximal sodium reabsorption, aldosterone release, smooth muscle vasoconstriction, vascular remodeling, and baroreceptor sensitivity. Antihypertensive efficacy appears dependent on an activated renin-angiotensin system; bilateral nephrectomy and volume expansion abolish their activity. Losartan is a nonpeptide, specific angiotensin II receptor antagonist acting on the antagonist AT1 subtype receptor. Peak response occurs within 6 hours of dosing. It is readily absorbed; peak plasma concentrations are achieved within 1 hour. It has a relatively short terminal half-life of 1.5 to 2.5 hours. Oral bioavailability is approximately 33%. Losartan undergoes extensive first-pass hepatic metabolism to the predominant circulatory form of the drug Exp-3174. This metabolite is 15 to 30 times more potent than losartan with a

THE SIDE EFFECTS PROFILE OF ANGIOTENSIN II RECEPTOR ANTAGONISTS Side effects

Mechanisms

Hyperkalemia

Blockade of angiotensin II Reduced aldosterone secretion Hypotension with impaired efferent anteriolar autoregulation

Acute renal dysfunction

longer half-life (between 4 and 9 hours). The metabolite is cleared equally by the liver and the kidney; there may be enhanced hepatic clearance in renal insufficiency [15]. Dose reduction is not required in patients with renal insufficiency. Valsartan is a nonpeptide, specific angiotensin II antagonist acting on the AT1 subtype receptor. Peak response occurs within 6 hours of dosing. Peak plasma concentrations are reached 2 to 4 hours after dosing. The average elimination half-life is about 6 hours. Oral bioavailability is approximately 25%. Dose reduction is not required in patients with renal insufficiency [15]. Irebsartan is a nonpeptide, specific angiotensin II antagonist acting on the AT1 subtype receptor. Peak response occurs in 4 to 8 hours. There is no active metabolite. Dose reduction is not required in patients with renal insufficiency [15]. FIGURE 7-47 The side effect profile of angiotensin II receptor antagonists. Angiotensin II receptor antagonists are well tolerated. In contrast to the angiotensin-converting enzyme (ACE) inhibitors, cough and angioedema are rarely (if at all) associated with this class of antihypertensive drug. Similar to ACE inhibitors, however, hyperkalemia and acute renal failure may occur in patients at risk [15].

Pharmacologic Treatment of Hypertension

7.31

Prevention and Treatment of High Blood Pressure JNC VI CLASSIFICATION OF HYPERTENSION Category* Optimal† Normal High normal Hypertension‡ Stage 1 Stage 2 Stage 3

Systolic (mm Hg)

Diastolic (mm Hg)

<120 <130 130–139

and and or

<80 <85 85–89

140/159 160/179 ≥-180

or or or

90/99 100/109 ≥110

*Not taking anithypertensive drugs and not acutely ill. When systolic and diastolic blood pressures fall into different categories, the higher category should be selected to classify the individual’s blood pressure status. For example, 160/92 mm Hg should be classified as stage 2 hypertension, and 174/120 mm Hg should be classified as stage 3 hypertension. Isolated systolic hypertension is defined as systolic blood pressure of 140 mm Hg or greater and diastolic blood pressure of less than below 90 mm Hg and staged appropriately (eg, 170/82 mm Hg is defined as stage 2 isolated hypertension). In addition to classifying stages of hypertension on the basis of average blood pressure levels, clinicians should specify presence of target organ disease and additional risk factors. This specifically is important for risk classification. †Optimal blood pressure with respect to cardiovascular risk is below 120/80 mm Hg. Unusually low readings should be evaluated for clinical significance. ‡Based on the average of two or more readings taken at each of two or more visits after an initial screening. JNC—Joint National Committee.

FIGURE 7-48 Prevention and treatment of high blood pressure. The aim of antihypertensive therapy is risk reduction. Since the relationship between blood pressure and cardiovascular risk is continuous, the goal of treatment might be the maximum tolerated reduction in blood pressure. There is controversy concerning what constitutes hypertension and how far systolic or diastolic blood pressure should be lowered, however. The Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) [17] provides a new classification of hypertension and recommends that risk stratification be used to determine if lifestyle modification or drug therapy with adjunctive lifestyle modification be initiated according to the patient’s blood pressure classification (see Fig. 7-50). Major risk factors include smoking, dyslipidemia, diabetes mellitus, an age of 60 or older, male sex or postmenopausal state for women, and a family history of cardiovascular disease in women younger than 65 and in men younger than 55. Target organ damage includes heart disease (left ventricular hypertrophy, angina pectoris, prior myocardial infarction, heart failure), stroke or transient ischemic attack, and nephropathy. Prevention and management of hypertension-related morbidity and mortality may best be accomplished by achieving a systolic blood pressure below 140 mm Hg and a diastolic blood pressure below 90 mm Hg; lower if tolerable. Recently, more aggressive blood pressure control has been advocated in patients with renal disease and hypertension, particularly in those patients with a urinary protein excretion of greater than 1 g/d. Blood pressure control in the range of 125/80 mm Hg (mean arterial pressure of 108 mm Hg) has been shown to slow the progression of renal disease [18,19]. This targeted blood pressure control may therefore be advisable in the majority of patients with hypertension. Regardless, each patient should be treated according to their cerebrovascular, cardiovascular, or renal risks; their specific pathophysiology or target organ damage; and their concurrent disease states. A uniform blood pressure goal (target) probably does not exist for all hypertensive patients, and lower may not always be better.

7.32

Hypertension and the Kidney

JNC VI DECISION ANALYSIS FOR TREATMENT

Blood pressure stages (mm Hg) High normal (130–139/85–89) Stage 1 (140–159/90–99) Stages 2 and 3 (>160/≥100)

Risk group A (no risk factors, no TOD/CCD)*

Risk group B (at least 1 risk factor, not including diabetes; no TOD/ CCD)

Risk Group C (TOD/CCD and/or diabetes, with or without other risk factors)†

Lifestyle modification

Lifestyle modification

Drug therapy‡

Lifestyle modification (up to 12 months) Drug therapy

Lifestyle modification (up to 6 months) Drug therapy

Drug therapy

FIGURE 7-49 Decision analysis for treatment based on the Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) [17].

Drug therapy

Lifestyle modification should be adjunctive therapy for all patients recommended for pharmacologic therapy. *TOD/CCD indicates target organ disease/clinical cardiovascular disease. †For patients with multiple risk factors, clinicians should consider drugs as initial therapy plus lifestyle modifications. ‡For those with heart failure, renal insufficiency, or diabetes.

CRITERIA FOR INITIAL DRUG THERAPY Reduce peripheral vascular resistance No sodium retention No compromise in regional blood flow No stimulation of the renin-angiotensin-aldosterone system Favorable profile with concomitant diseases Once a day dosing Favorable adverse effect profile Cost effective (low direct and indirect cost)

FIGURE 7-50 Selection of initial drug therapy. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) recommends that either a diuretic or a -blocker be chosen as initial drug therapy, based on numerous randomized controlled trials that show reduction in morbidity and mortality with these agents [17]. Not all authorities agree with this recommendation. In selecting an initial drug therapy to treat a hypertensive patient, several criteria should be met [6,9]. The drug should decrease peripheral resistance, the pathophysiologic hallmark of all hypertensive diseases. It should not produce sodium retention with attendant pseudotolerance. The drug should neither stimulate nor suppress the heart, nor should it compromise regional blood flow to target organs such as the heart, brain, or the kidney. It should not stimulate the renin-angiotensin-aldosterone axis. Drug selection should consider concomitant diseases such as arteriosclerotic cardiovascular and peripheral vascular disease, chronic obstructive pulmonary disease, diabetes mellitus, hypertensive cardiovascular disease, congestive heart failure, and hyperlipidemia. Drug dosing should be infrequent. The drug’s side effect profile, including its effect on physical state, emotional well-being, sexual and social function, and cognitive activity, should be favorable. Drug costs, both direct and indirect, should be reasonable. It is readily apparent that no current class of antihypertensive drug fulfills all these criteria.

7.33

Pharmacologic Treatment of Hypertension

CANDIDATES FOR INITIAL DRUG THERAPY OF MILD TO MODERATE HYPERTENSIVE DISEASE

Peripheral vascular resistance Sodium homeostasis Urinary sodium excretion Extracellular fluid volume Pseudotolerance Target organ function Heart rate, cardiac output Cerebral function Renal function (GFR) Renin-angiotensin-aldosterone Plasma renin activity Plasma angiotensin II Plasma aldosterone Concurrent disease efficacy Coronary disease Peripheral vascular disease Obstructive airway disease Diabetes mellitus Dyslipidemia Systolic dysfunction

ACE inhibitors

1-adrenergic antagonists

Angiotensin II type I receptor antagonists

1-adrenergic antagonists

Thiazide-type Calcium antagonists diuretics

Decrease

Decrease

Decrease

Decrease

Decrease

Decrease

Increase/no change No change No

May decrease May increase No

Increase/no change No change No

No change No change No

Increase/no change No change No

Increase Decrease No

No change Preserve No change/increase

May increase Preserve No change

No change Preserve No change

Decrease Preserve No change/decrease

Class specific Preserve No change/increase

No change Preserve No change

Increase Decrease Decrease/no change

No change No change No change

Increase Increase Decrease/no change

Decrease Decrease Decrease/no change

No change No change No change

Increase Increase Increase

No effect No effect No effect May benefit No effect Benefit

No effect No effect No effect No effect Benefit No effect

No effect No effect No effect May benefit No effect Benefit

Benefit May aggravate May aggravate May aggravate May aggravate May aggravate

Benefit May benefit No effect No effect No effect No effect

No effect No effect No effect May aggravate Aggravate Benefit

FIGURE 7-51 Options for monotherapy. Given the drugs that we have and their pharmacologic profiles, what are the best classes for initial drug therapy? Alphabetically, they include 1) angiotensin-converting enzyme (ACE) inhibitors, 2) 1-adrenergic antagonists, 3) angiotensin II type I receptor antagonists, 4) 1-adrenergic antagonists, 5) calcium antagonists, and

6) thiazide-type diuretics [6,9,15]. All these drugs, given as monotherapy, are effective in lowering blood pressure in 50% to 60% of patients with mild to moderate hypertension. 1-adrenergic antagonists, ACE inhibitors, and angiotensin II receptor antagonists are less efficacious in blacks than in whites.

7.34

Hypertension and the Kidney Options for subsequent antihypertensive therapy

Not at goal blood pressure (<140/<90 mm Hg); lower goal in patients with diabetes mellitus or renal disease

No response or troublesome side effects

Sustitute another drug from a different class

Inadequate response but well tolerated

Add a second agent from a different class (diuretic if not already used)

Not a goal blood pressure

FIGURE 7-52 Options for subsequent antihypertensive therapy. The majority of patients with mild to moderate hypertension can be controlled with one drug. If, after a 1- to 3-month interval, the response to the initial choice of therapy is inadequate, however, three options for subsequent antihypertensive drug therapy may be considered: 1) increase the dose of the initial drug, 2) discontinue the initial drug and substitute a drug from another class, or 3) add a drug from another class (combination therapy). Recommendations from the Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) are provided [17].

Continue adding agents from other classes Consider referral to a hypertension specialist

COMBINATION THERAPIES Mild to moderate (stage 1 or 2) hypertension Addition of low-dose thiazide-type diuretic to: ACE inhibitor 1-adrenergic antagonist 1-adrenergic antagonist Angiotensin III receptor antagonist Severe (Stage 3) hypertension Classic triple drug therapy Diuretic 1-adrenergic antagonist Direct-acting vasodilator ACE inhibitor plus calcium antagonist 1-adrenergic antagonist plus 1-adrenergic antagonist 1-adrenergic antagonist plus dihydropyridine calcium antagonist

FIGURE 7-53 Combination therapies. If a second drug is required, the addition of a low-dose thiazidetype diuretic to a nondiuretic drug will usually enhance the effectiveness of the first drug [6,9,17]. Newly developed formulations, using combinations of low doses of two agents from different classes, are available and effective and may minimize the likelihood of a dose-dependent adverse effect. The fixed doses used in these formulations were chosen to control mild to moderate (JNC VI stage 1 or 2) hypertension. More severe (JNC VI stage 3) cases of hypertension that are unresponsive to this therapeutic strategy may respond either to a variety of combination therapies given together as separate formulations or to classic triple-drug therapy (ie, diuretic, -adrenergic antagonist, and direct-acting vasodilator) [6,9]. ACE—angiotensin-converting enzyme; JNC—Joint National Committee.

Pharmacologic Treatment of Hypertension

JNC VI LIFE STYLE MODIFICATIONS Lose weight if overweight Limit alcohol intake to no more than 1 oz (30 mL) ethanol (eg, 24 oz [720 mL] beer, 10 oz [300 mL] wine, or 2 oz [60 mL] 100-proof whiskey) per day or 0.5 oz (15 mL) ethanol per day for women and lighter weight people Increase aerobic physical activity (30 to 45 minutes most days of the week) Reduce sodium intake to no more than 100 mmol/d (2.4 g sodium or 6 g sodium chloride) Maintain adequate intake of dietary potassium (approximately 90 mmol/d) Maintain adequate intake of dietary calcium and magnesium for general health Stop smoking and reduce intake of dietary saturated fat and cholesterol for overall cardiovascular health

CAUSES OF RESISTANT HYPERTENSION Patient’s failure to adhere to drug therapy Physician’s failure to diagnose a secondary cause of hypertension Renal parenchymal hypertension Renovascular hypertension Mineralocorticoid excess state (eg, primary aldosteronism) Pheochromocytoma Drug-induced hypertension (eg, sympathomimetic, cyclosporine) Illicit substances (eg, cocaine, anabolic steroids) Glucocortoid excess state (eg, Cushing’s syndrome) Coarctation of the aorta Hormonal disturbances (eg, thyroid, parathyroid, growth hormone, serotonin) Neurologic syndromes (eg, Guillain-Barré syndrome, porphyria, sleep apnea) Physician’s failure to recognize an adverse drug–drug interaction See Physician’s Desk Reference Physician’s failure to recognize the development of secondary drug resistance Sodium retention with pseudotolerance, secondary to diuretic resistance or excess sodium intake Increased heart rate, cardiac output secondary to drug-induced reflex tachycardia Increased peripheral vascular resistance secondary to drug-induced stimulation of the renin-angiotensin system

7.35

FIGURE 7-54 Follow-up in antihypertensive therapy. During follow-up visits, pharmacologic therapy should be reconfirmed or readjusted. As a rule, antihypertensive therapy should be maintained indefinitely. Cessation of therapy in patients who were correctly diagnosed as hypertensive is usually (but not always) followed by a return of blood pressure to pretreatment levels. After blood pressure has been controlled for 1 year and at least four visits, however, attempts should be made to reduce antihypertensive drug therapy “in a deliberate, slow, and progressive manner;” such “step-down therapy” may be successful in patients following lifestyle modification [17]. Patients for whom drug therapy has been reduced or discontinued should have regular follow-up, since blood pressure may increase again to hypertensive levels. JNC—Joint National Committee.

FIGURE 7-55 Resistant hypertension. Causes of failure to achieve or sustain control of blood pressure with drug therapy are listed [6,9].

7.36

Hypertension and the Kidney

DIURETIC RESISTANCE Problem

Mechanism

Solution

Limits active transport of diuretics Reduced renal blood flow Use of large doses of a diuretic and into proximal tubular fluid, reducing appropriate dosing interval to achieve inhibitory effect at a more distal a therapeutic tubular drug concentration intraluminal membrane site Reduced glomerular filtration rate Use loop diuretics with steep dose Limits absolute amount of sodium filtered response curve and/or block multiple sites of sodium reabsorption: loop diuretic with thiazide-like diuretic Secondary hyperaldosteronism Sodium recaptured at late distal Addition of a potassium-sparing diuretic tubule and collecting duct to above, to maintain urine sodium/potassium ratio > 1

FIGURE 7-56 Diuretic resistance. Diuretic resistance may result from patient noncompliance, impaired bioavailability in an edematous syndrome, impaired diuretic secretion by the proximal tubule, protein binding in the tubule lumen (eg, nephrotic syndrome), reduced glomerular filtration rate, or enhanced sodium chloride reabsorption [7,8]. Resultant fluid retention will attenuate the effectiveness of most antihypertensive drugs. Renal mechanisms, problems, and solutions are provided in this table [6,8,9].

References 1. Kaplan NM: Clinical Hypertension, edn 6. Baltimore: Williams & Wilkins; 1994:50. 2. Kawasaki T, Delea CS, Bartter FC, Smith H: The effect of high-sodium and low-sodium intakes on blood pressure and other related variables in human subjects with idiopathic hypertension. Am J Med 1978, 64:193–198. 3. Guyton AC, Coleman TG, Yang DB, et al.: Salt balance and long-term blood pressure control. Annu Rev Med 1980, 31:15–27. 4. Julius S, Krause L, Schork NJ: Hyperkinetic borderline hypertension in Tecumseh, Michigan. J Hypertens 1991, 9:77–84. 5. Lund-Johansen P: Cetra haemodynamics in essential hypertension at rest and during exercise: a 20-year follow-up study. J Hypertens 1989, 7(suppl 6): 552–555. 6. Bauer JH, Reams GP: Mechanisms of action, pharmacology, and use of antihypertensive drugs. In The Principles and Practice of Nephrology. Edited by Jacobson HR, Striker GE, Klahr S. St. Louis: Mosby; 1995:399–415. 7. Tarazi RC: Diuretic drugs: mechanisms of antihypertensive action. In Hypertension: Mechanisms and Management. The 26th Hahnemann Symposium. Edited by Oneti G, Kim KE, Moer JH. New York: Grune and Stratton; 1973:255. 8. Ellison DH: The physiologic basis of diuretic synergism: its role in treating diuretic resistance. Ann Intern Med 1991, 114:886–894. 9. Bauer JH, Reams GP: Antihypertensive drugs. In The Kidney, edn 5. Edited by Brenner BM. Philadelphia: W.B. Saunders Co.; 1995: 2331–2381. 10. Man in’t Veld AJ, Schalekamp MADH: How intrinsic sympathomimetic activity modulates the haemodynamic responses to -adrenoceptor antagonists: a clue to the nature of their antihypertensive mechanism. Br J Clin Pharmac 1982, 13:2455–2575.

11. Van Zwieten PA: Antihypertensive drug interacting with -and -adrenoceptors: a review of basic pharmacology. Drugs 1988, 35(suppl 6):6–19. 12. Graham RM, Thornell IR, Gain JM, et al.: Prazosin: the first dose phenomenon. Br Med J 1976, 2:1293–1294. 13. Koch-Weser J: Vasodilation drugs in the treatment of hypertension. Arch Intern Med 1974, 133:1017–1025. 14. Entel SI, Entel EA, Clozel J-P: T-type Ca2+ channels and pharmacological blockade: potential pathophysiological relevance. Cardiovasc Drugs Ther 1997, 11:723—739. 15. Bauer JH, Ream GP: The angiotensin II type 1 receptor antagonists. Arch Intern Med 1995, 155:1361–1368. 16. Wenting GJ, Tan-Tjiong HL, Derkx FMH, et al.: Split renal function after captopril in unilateral renal artery stenosis. Br Med J 1974, 288:886–890. 17. JNC VI: The Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1993, 153:154–183. 18. Peterson JC, Adler S, Burkart JM, et al.: Blood pressure control, proteinuria, and the progression of renal disease. Ann Intern Med 1995, 123:754–762. 19. Hebert LA, Kusek JW, Greene T, et al.: Effects of blood pressure control on progressive renal disease in blacks and whites. Hypertension 1997, 30 (part 1):428–435.

Hypertensive Crises Charles R. Nolan

M

ost patients with hypertension remain asymptomatic for many years, until complications from atherosclerosis, cerebrovascular disease, or congestive heart failure supervene. In some patients, this so-called benign course is punctuated by a hypertensive crisis. Hypertensive crisis is defined as the turning point in the course of an illness at which acute management of the elevated blood pressure plays a decisive role in the eventual outcome [1]. The haste with which blood pressure must be controlled varies with the type of hypertensive crisis. If the patient’s outcome is to be optimal, however, the crucial role of hypertension in the disease process must be identified and a plan for management of the blood pressure successfully implemented. The absolute level of the blood pressure clearly is not the most important factor in determining the existence of a hypertensive crisis. For example, in children, pregnant women, and other previously normotensive persons in whom mild to moderate hypertension develops suddenly, a hypertensive crisis can occur at a level of blood pressure that normally is well-tolerated by adults with chronic hypertension. Furthermore, a crisis can occur in adults with mild to moderate hypertension with the onset of acute end-organ dysfunction involving the heart or brain.

CHAPTER

8

8.2

Hypertension and the Kidney

HYPERTENSIVE CRISES Malignant hypertension (Hypertensive neuroretinopathy present) Benign (nonmalignant) hypertension with acute complications (Acute organ system dysfunction without hypertensive neuroretinopathy) Hypertensive encephalopathy (also common in malignant hypertension) Acute hypertensive heart failure (also common in malignant hypertension) Acute aortic dissection Central nervous system catastrophe Intracerebral hemorrhage Subarachnoid hemorrhage Severe head trauma Acute myocardial infarction or unstable angina Active bleeding, including postoperative bleeding Uncontrolled hypertension in patients requiring surgery Severe postoperative hypertension Post–coronary artery bypass hypertension Post–carotid endarterectomy hypertension Catecholamine excess states Pheochromocytoma Monoamine oxidase inhibitor–tyramine interactions Miscellaneous hypertensive crises Preeclampsia and eclampsia Scleroderma renal crisis Autonomic hyperreflexia in quadriplegic patients

FIGURE 8-1 Malignant hypertension is a clinical syndrome characterized by marked elevation of blood pressure, with widespread acute arteriolar injury (hypertensive vasculopathy). Funduscopy reveals hypertensive neuroretinopathy with flame-shaped hemorrhages, cottonwool spots (soft exudates), and sometimes papilledema. Regardless of the severity of blood pressure elevation, malignant hypertension cannot be diagnosed in the absence of hypertensive neuroretinopathy. Thus, hypertensive neuroretinopathy is an extremely important clinical finding, indicating the presence of a hypertension-induced arteriolitis that may involve the kidneys, heart, and central nervous system. In malignant hypertension, rapid and relentless progression to end-stage renal disease occurs if effective blood pressure control is not implemented. Mortality can result from acute hypertensive heart failure, intracerebral hemorrhage, hypertensive encephalopathy, or complications of uremia. Malignant hypertension represents a hypertensive crisis given that adequate control of blood pressure clearly prevents these morbid complications. Even in patients with so-called benign (nonmalignant) hypertension, in which hypertensive neuroretinopathy is absent, a hypertensive crisis may occur based on the development of concomitant acute end-organ dysfunction. Hypertensive crises caused by benign hypertension with acute complications include hypertension in the setting of hypertensive encephalopathy, acute hypertensive heart failure, acute aortic dissection, intracerebral hemorrhage, subarachnoid hemorrhage, severe head trauma, acute myocardial infarction or unstable angina, and active bleeding. Poorly controlled hypertension in patients requiring surgery increases the risk of intraoperative cerebral or myocardial ischemia and postoperative acute renal failure. Severe postoperative hypertension, including post–coronary artery bypass hypertension and post–carotid endarterectomy hypertension, increases the risk of postoperative bleeding, hypertensive encephalopathy, pulmonary edema, and myocardial ischemia. The various catecholamine excess states can cause a hypertensive crisis with hypertensive encephalopathy or acute hypertensive heart failure. Preeclampsia and eclampsia represent hypertensive crises unique to pregnancy. Scleroderma renal crisis is a hypertensive crisis because failure to adequately control blood pressure with a regimen that includes a converting enzyme inhibitor results in rapid irreversible loss of renal function. Hypertensive crises as a result of autonomic hyperreflexia induced by bowel or bladder distention also can occur in patients with quadriplegia. The sudden onset of hypertension in this setting can lead to hypertensive encephalopathy or acute pulmonary edema. Each hypertensive crisis is discussed in more detail in the figures that follow.

Hypertensive Crises

HYPERTENSIVE SYNDROMES SOMETIMES MISDIAGNOSED AS HYPERTENSIVE CRISES Severe uncomplicated hypertension (Severe hypertension without hypertensive neuroretinopathy or acute end-organ dysfunction, formerly known as urgent hypertension) Benign hypertension with chronic end-organ complications Chronic renal insufficiency from primary renal parenchymal disease Chronic congestive heart failure from systolic or diastolic dysfunction Atherosclerotic coronary vascular disease (previous myocardial infarction, stable angina) Cerebrovascular disease (history of transient ischemic attack or cerebrovascular accident)

8.3

FIGURE 8-2 Hypertensive syndromes sometimes misdiagnosed as hypertensive crises. It should be noted that the finding of severe hypertension does not always imply the presence of a hypertensive crisis. In patients with severe uncomplicated hypertension (formally known as urgent hypertension) in which severe hypertension is not accompanied by evidence of malignant hypertension or acute end-organ dysfunction, eventual complications due to stroke, myocardial infarction, or congestive heart failure tend to occur over months to years, rather than hours to days. Long-term control of blood pressure can prevent these eventual complications. However, a hypertensive crisis cannot be diagnosed because no evidence exists that acute reduction of blood pressure results in improvement in short- or long-term prognosis. Moreover, the presence of chronic hypertensive end-organ complications in a patient with nonmalignant hypertension does not imply the existence of a hypertensive crisis requiring rapid control of blood pressure. The category of benign hypertension with chronic complications includes hypertensive patients with chronic renal insufficiency due to underlying primary renal parenchymal disease, chronic congestive heart failure as a result of either systolic or diastolic dysfunction, atherosclerotic coronary vascular disease (stable angina or previous myocardial infarction), or chronic cerebrovascular disease (previous transient ischemic attacks or cerebrovascular accident). Long-term inadequate blood pressure control increases the risk of further deterioration of endorgan function in each of these conditions. However, no evidence exists that rapid control of blood pressure is necessary to prevent further complications. Therefore, a true hypertensive crisis does not exist.

8.4

Hypertension and the Kidney

Pathophysiology of malignant hypertension Renal parenchymal disease Renal artery stenosis Endocrine hypertension

Essential hypertension

Severe hypertension

Spontaneous natriuresis

Critical level or Rate of increase

Volume depletion

Forced vasodilation (sausage-string)

↑ Catecholamines ↑ Vasopressin ↑ Renin/Angiotensin II

Low potassium diet

Renal ischemia

Decreased prostacyclin Oral contraceptives Cigarette smoking

Vascular damage

Denudation of epithelium

↑ Endothelial permeability

Platelet adherence PDGF release

Extravasation Fibrinogen

Smooth muscle proliferation

Fibrin deposition Arteriolar wall

Deposition of mucopolysaccharide

Necrosis of smooth muscle

Musculomucoid intimal hyperplasia

Fibrinoid necrosis

Localized intravascular coagulation

Lumen

Narrowing of vascular lumen

Renal ischemia

Accelerated glomerular obsolescence

Tubular atrophy

Interstitial fibrosis

Chronic renal failure

FIGURE 8-3 Pathophysiology of malignant hypertension. The vicious cycle of malignant hypertension is best demonstrated in the kidneys. This cycle also applies equally well to the vascular beds of the retina, pancreas, gastrointestinal tract, and brain [1]. In this scheme, severe hypertension is central. Hypertension may be either essential or secondary to any one of a variety of causes. Because not all patients develop malignant hypertension despite equally severe hypertension, the interaction between the level of blood pressure and the adaptive capacity of the vasculature may be important. In this regard, chronic hypertension results

in thickening and remodeling of arteriolar walls that may be an adaptive mechanism to prevent vascular damage from the mechanical stress of hypertension. However, when the blood pressure increases suddenly or increases to a critical level, these adaptive mechanisms may be overwhelmed, resulting in vascular damage. As a result of the mechanical stress of increased transmural pressure, focal segments of the arteriolar vasculature become dilated, producing a sausage-string pattern. Endothelial permeability increases in the dilated segments, leading to extravasation of fibrinogen, fibrin deposition in the media, and necrosis of smooth muscle cells (fibrinoid necrosis). Platelet adherence to damaged endothelium with release of platelet-derived growth factor induces migration of smooth muscle cells to the intima where they proliferate (neointimal proliferation) and produce mucopolysaccharide. These cells also produce collagen, resulting in proliferative endarteritis, musculomucoid hyperplasia, and eventually, fibrotic obliteration of the vessel lumen. Occlusion of arterioles leads to accelerated glomerular obsolescence and end-stage renal disease. Other factors may synergize with hypertension to damage the arterial vasculature. Renal ischemia leads to activation of the renin-angiotensin system that can cause further elevation of blood pressure and progressive vascular damage. Spontaneous natriuresis early in the course of malignant hypertension leads to volume depletion with activation of the renin-angiotensin system or catecholamines that further elevates blood pressure. It also is possible that angiotensin II may be directly vasculotoxic. Activation of the clotting cascade within the lumen of damaged vessels may lead to fibrin deposition with localized intravascular coagulation. Thus, microangiopathic hemolytic anemia is a common finding in malignant hypertension. Cigarette smoking and oral contraceptive use may contribute to development of malignant hypertension by decreasing prostacyclin production in the vessel wall and thereby inhibiting repair of hypertensioninduced vascular injury. Low dietary intake of potassium may help promote vascular smooth muscle proliferation and therefore predisposes to the development of malignant hypertension in Blacks with severe essential hypertension. PDGF—plateletderived growth factor.

Hypertensive Crises

Vascular lesions in malignant hypertension Malignant hypertension

Fibrinoid necrosis

Proliferative endarteritis

Occlusion of vessels

Ischemia

Retinal Hemorrhages Cotton-wool spots Papilledema

CNS Intracerebral hemorrhage Hypertensive encephalopathy

Cardiac Left ventricular dysfunction

Renal Glomerulosclerosis Tubular atrophy Interstitial fibrosis

GI Hemorrhage Bowel necrosis

COMMON CAUSES OF MALIGNANT HYPERTENSION Primary (essential) malignant hypertension* Secondary malignant hypertension Primary renal disease Chronic glomerulonephritis* Chronic pyelonephritis* Analgesic nephropathy* Immunoglobulin A nephropathy* Acute glomerulonephritis Radiation nephritis Renovascular hypertension* Oral contraceptives Atheroembolic renal disease (cholesterol embolism) Scleroderma renal crisis Antiphospholipid antibody syndromes Chronic lead poisoning Endocrine hypertension Aldosterone-producing adenoma (Conn’s syndrome) Cushing’s syndrome Congenital adrenal hyperplasia Pheochromocytoma

*Most common causes of malignant hypertension.

FIGURE 8-5 Malignant hypertension is not a single disease entity but, rather, a syndrome in which the hypertension can be either primary (essential) or secondary to any one of a number of different causes [2]. Among Black patients the underlying cause is almost always essential hypertension that has entered a malignant phase. The most common secondary causes of malignant hypertension are primary renal parenchymal disorders. Chronic glomerulonephritis is thought to be the cause of malignant hypertension in up to 20% of cases. Unless a history of an acute nephritic episode or long-standing hematuria or proteinuria is available, the underlying glomerulonephritis may only

Pancreatic Necrosis Hemorrhage

8.5

FIGURE 8-4 Distribution of vascular lesions in malignant hypertension. Malignant hypertension is essentially a systemic vasculopathy induced by severe hypertension. Fibrinoid necrosis and proliferative endarteritis occur throughout the body in numerous vascular beds, leading to ischemic changes. In the retina, striate hemorrhages and cotton-wool spots develop. The finding of hypertensive neuroretinopathy is the clinical sine qua non of malignant hypertension. Vascular lesions in the gastrointestinal tract (GI) can lead to hemorrhage or bowel necrosis. Hemorrhagic pancreatitis also can occur. Cerebrovascular lesions can lead to cerebral infarction or intracerebral hemorrhage. Hypertensive encephalopathy also can develop as a result of failure of autoregulation with cerebral overperfusion and edema (Fig. 8-22). Vascular lesions also can develop in the myocardium; however, acute hypertensive heart failure is largely the result of acute diastolic dysfunction induced by the marked increase in afterload that accompanies malignant hypertension (Figs. 824 and 8-25). CNS—central nervous system.

become apparent when a renal biopsy is performed. Recently, immunoglobulin A (IgA) nephropathy has been reported as an increasingly frequent cause of malignant hypertension. In one series of 66 patients with IgA nephropathy, 10% developed malignant hypertension [3]. Chronic atrophic pyelonephritis in children, often a result of underlying vesicoureteral reflux, is the most common cause of malignant hypertension [4]. In Australia, malignant hypertension complicates up to 7% of cases of analgesic nephropathy [5]. Transient malignant hypertension responsive to volume expansion has been reported in analgesic nephropathy. It has been suggested that interstitial disease with salt-wasting is important in the pathogenesis by causing profound volume depletion with activation of the renin-angiotensin axis. Malignant hypertension is both an early and late complication of radiation nephritis that can occur up to 11 years after radiotherapy. Renovascular hypertension from either fibromuscular dysplasia or atherosclerosis is a well-recognized cause of malignant hypertension. In a series of 123 patients with malignant hypertension, renovascular hypertension was found in 43% of Whites and 7% of Blacks [6]. Among women of childbearing age, oral contraceptives can cause malignant hypertension [7]. In the absence of underlying renal disease, with discontinuation of the drug, long-term prognosis is excellent. Severe hypertension that may become malignant is a common complication of atheroembolic renal disease. In patients presenting with malignant hypertension in the weeks to months after an arteriographic procedure, a careful history and physical should be performed to look for evidence of atheroembolism. Scleroderma renal crisis is the most life-threatening complication of progressive systemic sclerosis. Scleroderma renal crisis is characterized by hypertension that may enter the malignant phase. Even in the absence of hypertensive neuroretinopathy suggesting malignant hypertension, the renal lesion in scleroderma renal crisis is virtually indistinguishable from primary malignant nephrosclerosis [8]. Patients with antiphospholipid antibody syndrome, either primary or secondary to systemic lupus erythematosus, can develop malignant hypertension with renal insufficiency as a result of thrombotic microangiopathy [9]. The endocrine causes of hypertension only rarely lead to malignant hypertension. Pheochromocytoma can cause hypertensive crises owing to hypertensive encephalopathy or acute hypertensive heart failure in the absence of hypertensive neuroretinopathy (malignant hypertension).

8.6

Hypertension and the Kidney

Tertiary hyperaldosteronism after treatment of malignant hypertension Malignant hypertension

Renal ischemia

Vascular lesions heal

Activation of reninangiotensin axis

Antihypertensive treatment with resolution of malignant hypertension

Renin levels decrease rapidly

Bilateral adrenal hyperplasia

Resolves slowly over 1 year after control of blood pressure

FIGURE 8-6 Tertiary hyperaldosteronism after treatment of malignant hypertension. The diagnosis of primary hyperaldosteronism must be made with caution in patients with a history of malignant hypertension. After successful treatment of malignant hypertension, plasma renin activity rapidly normalizes, whereas aldosterone secretion may remain elevated for up to a year. This phenomenon has been attributed to persistent adrenal hyperplasia induced by long-standing hyperreninemia during the malignant phase [10]. During this phase of tertiary hyperaldosteronism, despite suppressed renin activity, hypokalemia, metabolic alkalosis, and aldosterone levels that are not suppressible, mimic primary hyperaldosteronism. Adrenal imaging studies reveal bilateral nodular adrenal hyperplasia. With continued long-term control of blood pressure this hyperaldosteronism remits spontaneously.

Nonsuppressible aldosteronism

Renal potassium-wasting with hypokalemia

Metabolic alkalosis

RENAL CHANGES IN HYPERTENSION Retinal arteriosclerosis and arteriosclerotic retinopathy (benign hypertension) Focal or diffuse arteriolar narrowing Arteriovenous crossing changes Broadening of the light reflex Copper or silver wiring Perivasculitis (parallel white lines around the arteries) Solitary round hemorrhages Hard exudates Central or branch venous occlusion Hypertensive neuroretinopathy (malignant hypertension) Generalized arteriolar narrowing Striate (flame-shaped) hemorrhage* Cotton-wool spots* Papilledema* Star figure at the macula

*Features that distinguish hypertensive neuroretinopathy from retinal arteriosclerosis.

FIGURE 8-7 Funduscopic findings are pivotal in the diagnosis of malignant hypertension. Keith and Wagener [11] graded retinal findings in hypertensive patients as follows: grade I, arteriolar narrowing; grade II, arteriovenous crossing changes; grade III, hemorrhages and exudates; grade IV, the changes in grade III plus papilledema. Although this classification of hypertensive retinopathy is of great historical importance, its clinical utility has several limitations, eg, it is extremely difficult to quantify arteriolar narrowing. In this regard, a tendency exists for significant observer bias such that patients with mild hypertension and questionable narrowing are invariably assigned to grade I. More importantly, this classification does not distinguish the retinal changes of benign and malignant hypertension. For example, the clinical significance of a cottonwool spot appearing in the fundus of a young man with severe

hypertension (diagnostic of malignant hypertension) is quite different from the clinical significance of a hard exudate in the fundus of a 60-year-old man with moderate hypertension. The prognostic and therapeutic implications of these two types of exudates clearly are different, although both would be classified as grade III. For this reason, the Keith and Wagener classification has been supplanted by the more clinically useful classification of hypertensive retinopathy shown here. This classification system draws a distinction between retinal arteriosclerosis with arteriosclerotic retinopathy, which is characteristic of benign hypertension, and hypertensive neuroretinopathy, which defines the existence of malignant hypertension [12,13]. Retinal arteriosclerosis, which is characterized histologically by the accumulation of hyaline material in arterioles, occurs in elderly normotensive persons or in the setting of long-standing benign hypertension. Funduscopic findings reflecting retinal arteriosclerosis include arteriolar narrowing, arteriovenous crossing changes, perivasculitis, and changes in the light reflex with copper or silver wiring. Arteriosclerotic retinopathy manifests as solitary round hemorrhages in the periphery of the fundus and hard exudates. The finding of retinal arteriosclerosis is of no prognostic significance with regard to the risk of coronary atherosclerosis or cerebrovascular disease. The arteries visualized with the ophthalmoscope are technically arterioles with a diameter of 0.1 mm. Hyaline arteriolosclerosis of the retinal vessels is a process entirely distinct from the atherosclerotic process that affects larger muscular arteries. Thus, the finding of retinal arteriosclerosis cannot predict the presence of atherosclerosis of the coronary or cerebral vessels. This lack of clinical significance of retinal arteriosclerosis in hypertensive patients contrasts dramatically with the importance and prognostic significance of the finding of hypertensive neuroretinopathy. This finding is the clinical sine qua non of malignant hypertension. The appearance of striate hemorrhages or cottonwool spots with or without papilledema closely parallels the development of fibrinoid necrosis and proliferative endarteritis in the kidney and other organs. Thus, the presence of hypertensive neuroretinopathy predicts the development of end-stage renal disease, or other life-threatening hypertensive complications, within a year if adequate control of the blood pressure is not achieved.

Hypertensive Crises

8.7

FIGURE 8-8 (see Color Plate) Fundus photography of retinal arteriosclerosis in benign hypertension. Funduscopy in a 60-year-old man reveals the characteristic changes of retinal arteriosclerosis, including arteriolar narrowing, mild arteriovenous crossing changes, copper wiring, and perivasculitis (parallel white lines around blood columns). The striate hemorrhages, cotton-wool spots, and papilledema characteristic of malignant hypertension are absent.

FIGURE 8-9 (see Color Plate) Fundus photography of arteriosclerotic retinopathy in benign hypertension. Funduscopy in a 52-year-old woman with benign hypertension demonstrates a solitary round hemorrhage characteristic of arteriosclerotic retinopathy.

FIGURE 8-10 (see Color Plate) Fundus photography of striate hemorrhages in hypertensive neuroretinopathy. Funduscopic findings in a 53-year-old woman with secondary malignant hypertension as a result of underlying immunoglobulin A nephropathy, demonstrating striate or flame-shaped hemorrhages (arrows). The appearance of small striate hemorrhages often is the first sign that malignant hypertension has developed. These hemorrhages are most commonly observed in a radial arrangement around the optic disc. The retinal circulation is under autoregulatory control such that under normal circumstances as blood pressure increases, arterioles constrict to maintain constant retinal blood flow. The appearance of striate hemorrhages implies that autoregulation has failed. Striate hemorrhages are a result of bleeding from superficial capillaries in the nerve fiber bundles near the optic disc. These capillaries originate directly from arterioles so that when autoregulation fails, the high systemic pressure is transmitted directly to the capillaries. This process leads to breaks in the continuity of the capillary endothelium. The resultant hemorrhages extend along nerve fiber bundles parallel to the retinal surface. The hemorrhages often have a frayed distal border owing to extravasation of blood between nerve fiber bundles.

8.8

Hypertension and the Kidney FIGURE 8-11 (see Color Plate) Fundus photography of cotton-wool spots in hypertensive neuroretinopathy. Cotton-wool spots (arrows) are the most characteristic feature of malignant hypertension. They usually surround the optic disc and most commonly occur within three disc-diameters of the optic disc. Cotton-wool spots result from ischemic infarction of retinal nerve fiber bundles owing to arteriolar occlusion caused by proliferative arteriopathy in retinal vessels. Fluorescein angiography demonstrates that cotton-wool spots are areas of retinal nonperfusion. Embolization of pig retina with glass beads produces immediate neuronal cell edema followed by accumulation of mitochondria and other subcellular organelles in ischemic nerve fibers. It has been postulated that the normal axoplasmic flow of subcellular organelles is disrupted by retinal ischemia such that accumulation of organelles in ischemic nerve fiber bundles results in a visible white patch. Cotton-wool spots tend to distribute around the optic disc because nerve fiber bundles are most dense in this region. The detection of cotton-wool spots is a crucial clinical finding because they are the retinal manifestation of the malignant hypertension-induced systemic vasculopathy that also causes proliferative endarteritis and ischemia in the kidney and other organs. (This is the same patient as in Fig. 8-10.) FIGURE 8-12 (see Color Plate) Fundus photography of papilledema in hypertensive neuroretinopathy. Funduscopic findings in a 23-year-old Black man noted incidentally to be severely hypertensive during a routine dental clinic visit. Papilledema of the optic disc is apparent, with surrounding cotton-wool spots and striated hemorrhages. The pathogenesis of papilledema in hypertensive neuroretinopathy is unclear. Intracranial pressure is not always increased in patients with malignant hypertension and papilledema. Papilledema has been produced experimentally in Rhesus monkeys by occlusion of the long posterior ciliary artery that supplies the optic nerve. As in cotton-wool spots, indeed papilledema may result from hypertensive vasculopathy–induced ischemia of nerve fiber bundles in the optic disc. Thus, in hypertensive neuroretinopathy, papilledema essentially may represent a giant cotton-wool spot resulting from ischemia of the optic nerve. When papilledema occurs in malignant hypertension, it almost always is accompanied by striated hemorrhages and cotton-wool spots. When papilledema occurs alone, the possibility of a primary intracranial process such as tumor or cerebrovascular accident should be considered. FIGURE 8-13 (see Color Plate) Fundus photography of far-advanced hypertensive neuroretinopathy. Funduscopy in this 30-year-old man with malignant hypertension demonstrates all the characteristic features of hypertensive neuroretinopathy. These features include striate hemorrhages, cotton-wool spots, papilledema, and a star figure at the macula.

Hypertensive Crises

1–0 No papilledema Papilledema

Estimated survival

0–8

0–6

0–4 96 43

74 28

45 16

26 10

14 6

No. with papilledema No. without papilledema

0

2

4

6 Years

8

10

8.9

FIGURE 8-14 Prognosis in accelerated hypertension versus malignant hypertension. In the original Keith and Wagener [11] classification of hypertensive retinopathy, malignant hypertension (grade IV) was defined by the presence of papilledema, whereas the term accelerated hypertension (grade III) was used when hemorrhages and exudates occurred in the absence of papilledema. However, more recent studies indicate that the prognosis is the same in hypertensive patients with striate hemorrhages and cotton-wool spots whether or not papilledema is present. In this regard, the World Health Organization has recommended that accelerated hypertension and malignant hypertension be regarded as synonymous terms for the same disease. Demonstrated are the effects of the presence or absence of papilledema on survival among 139 hypertensive patients with hypertensive neuroretinopathy (striated hemorrhages and cotton-wool spots) [14]. By multivariate analysis, after controlling for age, gender, smoking habit, initial serum creatinine concentration, and initial and achieved blood pressure, the presence of papilledema did not influence prognosis. (From McGregor [14] et al.; with permission.)

0

FIGURE 8-15 (see Color Plate) Micrograph of fibrinoid necrosis in malignant hypertension. Fibrinoid necrosis of the afferent arterioles and interlobular arteries has traditionally been regarded as the hallmark of malignant hypertension. The characteristic finding is the deposition in the arteriolar wall of a granular material that is a bright-pink color on hematoxylin and eosin staining. On Masson trichrome staining, as illustrated, the granular fibrinoid material is bright red (arrow). The fibrinoid material usually is found in the media of the vessel; however, deposition in the intima also may occur. Whole or fragmented erythrocytes may be extravasated into the arteriolar wall. These hemorrhages account for the petechial hemorrhages that give rise to the peculiar flea-bitten appearance of the capsular surface of the kidney in malignant hypertension. Fibrinoid necrosis is thought to result from the mechanical stress placed on the vessel wall by severe hypertension. Forced vasodilation occurs when there is failure of autoregulation of renal blood flow, which leads to endothelial injury with seepage of plasma proteins into the vessel wall. Contact of plasma constituents with smooth muscle cells activates the coagulation cascade, and fibrin is deposited in the wall. Fibrin deposits then cause necrosis of smooth muscle cells (fibrinoid necrosis). (Masson trichrome stain, original magnification  100.)

8.10

Hypertension and the Kidney

SPECTRUM OF CLINICAL RENAL INVOLVEMENT IN MALIGNANT HYPERTENSION Progressive subacute deterioration of renal function to end-stage renal disease Transient deterioration of renal function with initial blood pressure control Oliguric acute renal failure Established renal failure

FIGURE 8-16 (see Color Plate) Micrograph of proliferative endarteritis in malignant hypertension (musculomucoid intimal hyperplasia). In malignant nephrosclerosis, the interlobular (cortical radial) arteries reveal characteristic lesions. These lesions are variously referred to as proliferative endarteritis, endarteritis fibrosa, musculomucoid intimal hyperplasia, or the onionskin lesion. The typical finding is marked thickening of the intima that obstructs the vessel lumen. In severely affected vessels the luminal diameter may be reduced to the caliber of a single erythrocyte. Occasionally, complete obliteration of the lumen by a superimposed fibrin thrombus occurs. Traditionally, three patterns of intimal thickening have been described [15]. (1) The onionskin pattern consists of pale layers of elongated concentrically arranged myointimal cells along with delicate connective tissue fibrils that give rise to a lamellar appearance. The media often appears as an attenuated layer stretched around the expanded intima. (2) In the mucinous pattern, intimal cells are sparse. Seen is an abundance of lucent, faintly basophilic-staining amorphous material. (3) In fibrous intimal thickening, seen are few cells with an abundance of hyaline deposits, reduplicated bands of elastica, and coarse layers of collagen. The renal histology in Blacks with malignant hypertension demonstrates a characteristic finding in the larger arterioles and interlobular arteries known as musculomucoid intimal hyperplasia, with an abundance of cells and a small amount of myxoid material (that is light blue in color on hematoxylin and eosin staining) between the cells [16, 17]. These various intimal findings may represent progression over time from an initially cellular lesion to fibrosis of the intima. Electron microscopy demonstrates that in each type of intimal thickening the most abundant cellular element is a modified smooth muscle cell. This cell is called a myointimal cell. Proliferative endarteritis is thought to occur as a result of phenotypic modulation of medial smooth muscle cells that dedifferentiate from the normal contractile phenotype to acquire a more embryologic proliferative-secretory phenotype. It has been proposed that the endothelial injury in malignant hypertension results in attachment of platelets with release of plateletderived growth factor (PDGF) that may induce the phenotypic change in smooth muscle cells. PDGF stimulates chemotaxis of medial smooth muscles to the intima, where they proliferate and secrete mucopolysaccharide and later collagen and other extracellular matrix proteins, resulting in proliferative endarteritis, musculomucoid hyperplasia, and ultimately fibrous intimal thickening. (Hematoxylin and eosin stain, original magnification  100.)

FIGURE 8-17 Malignant hypertension is a progressive systemic vasculopathy in which renal involvement is a relatively late finding. In this regard, patients with malignant hypertension can present with a spectrum of renal involvement ranging from normal renal function with minimal albuminuria to end-stage renal disease (ESRD) indistinguishable from that seen in primary renal parenchymal disease. In patients initially exhibiting preserved renal function, in the absence of adequate blood pressure control, it is common to observe subacute deterioration of renal function to ESRD over a period of weeks to months. Transient deterioration of renal function with initial control of blood pressure is a well-documented entity in patients initially exhibiting mild to moderate renal impairment. Occasionally, patients with malignant hypertension initially exhibit oliguric acute renal failure, necessitating initiation of dialysis within a few days of hospitalization. Because erythrocyte casts sometimes appear in the urine sediment, malignant nephrosclerosis initially may be misdiagnosed as a rapidly progressive glomerulonephritis or systemic vasculitis [18]. Careful examination of the fundus for evidence of hypertensive neuroretinopathy confirms the diagnosis of malignant hypertension. Patients with malignant hypertension can also present with established renal failure. Often, it is impossible to determine clinically whether a patient initially exhibiting hypertensive neuroretinopathy and renal failure has primary malignant hypertension or secondary malignant hypertension with underlying primary renal parenchymal disease. The presence of normal-sized kidneys on ultrasonography supports a diagnosis of primary malignant nephrosclerosis that potentially is reversible with long-term blood pressure control. However, a renal biopsy may be required for definitive diagnosis. All patients with malignant hypertension should receive aggressive antihypertensive therapy to prevent further renal damage, regardless of the degree of renal impairment. Control of blood pressure in patients with malignant hypertension and renal insufficiency often causes further deterioration of renal function, especially when the initial glomerular filtration rate (GFR) is less than 20 mL/min. However, a fall in GFR is not a contraindication to intensive blood pressure control aimed at normalization of blood pressure. Control of hypertension protects other vital organs, such as the heart and brain, whose function cannot be replaced. Moreover, with rigid blood pressure control, renal function may eventually recover over the ensuing months, even in patients with apparent ESRD owing to primary malignant nephrosclerosis [19,20].

Hypertensive Crises

8.11

FIGURE 8-18 (see Color Plate) Micrograph of hyaline arteriolar nephrosclerosis in benign hypertension. It is important to draw a clear distinction between malignant hypertension and benign hypertension with regard to renal histology and clinical renal involvement. In benign arteriolar nephrosclerosis caused by benign hypertension, the characteristic histologic lesion is hyaline arteriosclerosis. In hyaline arteriosclerosis there is expansion of the intima of afferent arterioles with hyaline material that stains a pale-pink color on periodic acid–Schiff staining (large arrow). Patchy (focal) ischemic atrophy of the glomeruli usually is seen. Many glomeruli appear normal, whereas some are completely hyalinized. Atrophic tubules (small arrows), sometimes filled with amorphous material, may be seen in the vicinity of ischemic glomeruli. The severity of the glomerular and tubular changes generally reflect the extent of vascular involvement with hyaline arteriosclerosis. On gross examination, the kidneys are small with a granular-appearing capsular surface (contracted granular kidney). The loss of renal mass primarily is due to a thinning of the cortex. In untreated malignant hypertension, relentless progression to end-stage renal disease (ESRD) occurs within a year. In contrast, in benign hypertension, without underlying renal disease or superimposed malignant hypertension, despite well-established folklore to the contrary, ESRD seldom develops [21,22]. In benign hypertension, there is a usually a long asymptomatic phase, with eventual complications resulting from cerebrovascular disease, atherosclerotic disease, or congestive heart failure, in the absence of significant renal impairment despite histologic evidence of benign nephrosclerosis. In this regard, patients classified as having ESRD owing to “hypertensive nephrosclerosis” typically exhibit advanced disease initially, making the original process that initiated the renal disease difficult to detect. Moreover, significant racial bias may occur in the clinical diagnosis of the cause of ESRD [23]. Nephrologists presented with identical case histories of hypothetical patients with ESRD and hypertension in which the race is arbitrarily stated to be Black or White, tend to diagnose hypertensive nephrosclerosis in Blacks and chronic glomerulonephritis in Whites. It has been proposed that many of the patients presumed clinically to have ESRD owing to benign hypertension, actually have occult intrinsic renal disease with chronic glomerulonephritis, unrecognized bilateral atherosclerotic renal artery stenosis with ischemic nephropathy, atheroembolic renal disease, or episodes of malignant hypertension that had gone undetected [21,22]. (Periodic acid–Schiff stain, original magnification  100.)

8.12

Hypertension and the Kidney

INDICATIONS FOR PARENTERAL THERAPY IN MALIGNANT HYPERTENSION Hypertensive encephalopathy Rapidly failing vision Pulmonary edema Intracerebral hemorrhage Rapid deterioration of renal function Acute pancreatitis Gastrointestinal hemorrhage or acute abdomen from mesenteric vasculitis Patients unable to tolerate oral therapy because of intractable vomiting

FIGURE 8-19 Malignant hypertension must be treated expeditiously to prevent complications such as hypertensive encephalopathy, acute hypertensive heart failure, and renal failure. The traditional approach to patients with malignant hypertension has been the initiation of potent parenteral agents. Listed are the settings in which parenteral antihypertensive therapy is mandatory in the initial management of malignant hypertension. Parenteral therapy generally should be used in patients with evidence of acute end-organ dysfunction or those unable to tolerate oral medications. Nitroprusside is the treatment of choice for patients requiring parenteral therapy. Diazoxide, employed in minibolus fashion to avoid sustained overshoot hypotension, may be advantageous in patients for whom monitoring in an intensive care unit is not feasible. It generally is safe to reduce the mean arterial pressure by 20% or to a level of 160 to 170 mm Hg systolic over 100 to 110 mm Hg diastolic. The use of a short-acting agent such as nitroprusside has obvious advantages because blood pressure can be stabilized quickly at a higher level if complications develop during rapid blood pressure reduction. When no evidence of vital organ hypoperfusion is seen during this initial reduction, the diastolic blood pressure can be lowered gradually to 90 mm Hg over a period of 12 to 36 hours. Oral antihypertensive agents should be initiated as soon as possible to minimize the duration of parenteral therapy. The nitroprusside infusion can be weaned as the oral agents become effective. The cornerstone of initial oral therapy should be arteriolar vasodilators such as calcium channel blockers, hydralazine, or minoxidil. Usually, -blockers are required to control reflex tachycardia, and a diuretic must be initiated within a few days to prevent salt and water retention, in response to vasodilator therapy, when the patient’s dietary salt intake increases. Diuretics may not be necessary as a part of initial parenteral therapy because patients with malignant hypertension often present with volume depletion (Fig. 8-20). Many patients with malignant hypertension definitely require initial parenteral therapy. However, some patients may not yet have evidence of cerebral or cardiac dysfunction or rapidly deteriorating renal function and therefore do not require instantaneous control of blood pressure. These patients often can be managed with an intensive oral regimen, often with a -blocker and minoxidil, designed to bring the blood pressure under control within 12 to 24 hours. After the immediate crisis has resolved and the patient’s blood pressure has been controlled with initial parenteral therapy, oral therapy, or both, lifelong surveillance of blood pressure is mandatory. If blood pressure control lapses, malignant hypertension can recur even after years of successful antihypertensive therapy. Triple therapy with a diuretic, -blocker, and a vasodilator often is required to maintain satisfactory long-term blood pressure control.

Hypertensive Crises

Role of diuretics to treat malignant hypertension

Malignant hypertension

Abrupt increase in blood pressure Pressure-induced natriuresis and diuresis

Intravascular volume depletion

Activation of the renin-angiotensin axis

Angiotensin II–mediated vasoconstriction

Vicious circle

8.13

FIGURE 8-20 Role of diuretics in the treatment of malignant hypertension. Traditionally, it had been taught that patients with malignant hypertension require potent parenteral diuretics in conjunction with potent vasodilator therapy during the initial phase of management of malignant hypertension. However, evidence now exists to suggest that parenteral diuretic therapy during the acute management phase actually may be deleterious. In experimental animals, spontaneous natriuresis appears to be the initiating event in the transition from benign to malignant hypertension, and treatment with volume expansion leads to resolution of the malignant phase [24]. Rapid weight loss often occurs in patients with malignant hypertension, which is consistent with a pressure-induced natriuresis. In analgesic nephropathy, profound volume depletion often accompanies malignant hypertension, perhaps owing to tubular dysfunction with salt-wasting [5]. In this setting, restoration of normal volume status actually lowers blood pressure and leads to resolution of the malignant phase. Thus, some patients with malignant hypertension may benefit from a cautious trial of volume expansion. Volume depletion should be suspected when there is exquisite sensitivity to vasodilator therapy with a precipitous decrease in blood pressure at relatively low infusion rates. Even patients with malignant hypertension complicated by pulmonary edema may not be total-body salt and water overloaded. Pulmonary congestion in this setting may result from acute hypertensive heart failure caused by an acute decrease in left ventricular (LV) compliance precipitated by severe hypertension. In this setting, pulmonary edema occurs owing to a high LV end-diastolic pressure with normal LV end-diastolic volume (Fig. 8-24). Thus, the need for diuretic therapy during the initial phases of management of malignant hypertension depends on a careful assessment of volume status. Unless obvious fluid overload is present, diuretics should not be given initially. Overdiuresis may result in deterioration of renal function owing to superimposed volume depletion. Moreover, volume depletion may further activate the renin-angiotensin system and other pressor hormone systems. Although vasodilator therapy will eventually result in salt and water retention by the kidneys, an increase in total body sodium content cannot occur unless the patient is given sodium. Eventually, during long-term treatment with oral vasodilators, the use of diuretics becomes imperative to prevent fluid retention and adequately control blood pressure.

8.14

Hypertension and the Kidney

Pathogenesis and treatment of hypertensive encephalopathy Malignant hypertension (hypertensive neuroretinopathy present)

Sudden or severe nonmalignant hypertension (hypertensive neuroretinopathy absent)

Sudden onset or severe hypertension

Failure of autoregulation of cerebral blood flow (breakthrough of autoregulation)

Forced vasodilation of cerebral arterioles

Endothelial damage (increased permeability to plasma proteins)

Cerebral hyperperfusion (increased capillary hydrostatic pressure)

Cerebral edema

Hypertensive encephalopathy (headache, vomiting, altered mental status, seizures)

Prompt blood pressure reduction with nitroprusside

New or progressive focal findings (suspect primary central nervous system process)

Dramatic clincal improvement (diagnostic of hypertensive encephalopathy)

FIGURE 8-21 Pathogenesis and treatment of hypertensive encephalopathy. Hypertensive encephalopathy is a hypertensive crisis in which acute cerebral dysfunction is attributed to sudden or severe elevation of blood pressure [25–27]. Hypertensive encephalopathy is one of the most serious complications of malignant hypertension. However, malignant hypertension (hypertensive neuroretinopathy) need not be present for hypertensive encephalopathy to develop. Hypertensive encephalopathy also can occur in the setting of severe or sudden hypertension of any cause, especially if an acute elevation of blood pressure occurs in a previously normotensive person, eg, from postinfectious glomerulonephritis, catecholamine excess states, or eclampsia. Under normal circumstances, autoregulation of the cerebral microcirculation occurs, and therefore, cerebral blood flow remains constant over a wide range of perfusion pressures. However, in the setting of sudden severe hypertension, autoregulatory vasoconstriction fails and there is forced vasodilation of cerebral arterioles with endothelial damage, extravasation of plasma proteins, and cerebral hyperperfusion with the development of cerebral edema. This breakthrough of cerebral autoregulation underlies the development of hypertensive encephalopathy. In patients with chronic hypertension, structural changes occur in the cerebral arterioles that lead to a shift in the autoregulation curve such that much higher blood pressures can be tolerated without breakthrough. This phenomenon may explain the clinical observation that hypertensive encephalopathy occurs at much lower blood pressure in previously normotensive persons than it does in those with chronic hypertension. Clinical features of hypertensive encephalopathy include severe headache, blurred vision or occipital blindness, nausea, vomiting, and altered mental status. Focal neurologic findings can sometimes occur. If aggressive blood pressure reduction is not initiated, stupor, convulsions, and death can occur within hours. The sine qua non of hypertensive encephalopathy is the prompt and dramatic clinical improvement in response to antihypertensive drug therapy. When a diagnosis of hypertensive encephalopathy seems likely, antihypertensive therapy should be initiated promptly without waiting for the results of time-consuming radiographic examinations. The goal of therapy, especially in previously normotensive patients, should be reduction of blood pressure to normal or near-normal levels as quickly as possible. Theoretically, cerebral blood flow could be jeopardized by rapid reduction of blood pressure in patients with chronic hypertension in whom the lower limit of cerebral blood flow autoregulation is shifted to a higher blood pressure. However, clinical experience has shown that prompt blood pressure reduction with the avoidance of frank hypotension is beneficial in patients with hypertensive encephalopathy [25]. Of the conditions in the differential diagnosis of hypertension with acute cerebral dysfunction, only cerebral infarction might be adversely affected by the abrupt reduction of blood pressure. Pharmacologic agents that have rapid onset and short duration of action such as sodium nitroprusside should be used so that the blood pressure can be titrated carefully, with close monitoring of the patient’s neurologic status. A prompt improvement in mental status with blood pressure reduction confirms the diagnosis of hypertensive encephalopathy. Conversely, when blood pressure reduction is associated with new or progressive focal neurologic deficits, the presence of a primary central nervous system event, such as cerebral infarction, should be considered.

Hypertensive Crises

CAUSES OF HYPERTENSIVE ENCEPHALOPATHY Malignant hypertension of any cause Acute glomerulonephritis, especially postinfectious Eclampsia Catecholamine-induced hypertensive crises Pheochromocytoma Monoamine oxidase inhibitor–tyramine interactions Abrupt withdrawal of centrally acting 2-agonists Phenylpropanolamine overdose Cocaine-hydrochloride or alkaloid (crack cocaine) intoxication Phencyclidine (PCP) poisoning Acute lead poisoning in children High-dose cyclosporine for bone marrow transplantation in children Femoral lengthening procedures Scorpion envenomation in children Acute renal artery occlusion from thrombosis or embolism Atheroembolic renal disease (cholesterol embolization) Recombinant erythropoietin therapy Transplantation renal artery stenosis Acute renal allograft rejection Paroxysmal hypertension in acute or chronic spinal cord injuries Post–coronary artery bypass or post–carotid endarterectomy hypertension

8.15

FIGURE 8-22 Hypertensive encephalopathy can complicate malignant hypertension of any cause. However, not all patients with hypertensive encephalopathy have hypertensive neuroretinopathy, indicating the presence of malignant hypertension. In fact, hypertensive encephalopathy most commonly occurs in previously normotensive persons who experience a sudden onset or worsening of hypertension. In acute postinfectious glomerulonephritis, the abrupt onset of even moderate hypertension may cause breakthrough of autoregulation of cerebral blood flow, resulting in hypertensive encephalopathy. Eclampsia can be viewed as a variant of hypertensive encephalopathy that complicates preeclampsia. Moreover, hypertensive encephalopathy is a common complication of catecholamine-induced hypertensive crises such as pheochromocytoma, monoamine oxidase inhibitor–tyramine interactions, clonidine withdrawal, phencyclidine (PCP) poisoning, and phenylpropanolamine overdose. Cocaine use also can induce a sudden increase in blood pressure accompanied by hypertensive encephalopathy. In children, acute lead poisoning, high-dose cyclosporine for bone marrow transplantation, femoral lengthening procedures, and scorpion envenomation may be accompanied by the sudden onset of hypertension with hypertensive encephalopathy. Acute renal artery occlusion resulting from thrombosis or renal embolism can induce hypertensive encephalopathy. Likewise, atheroembolic renal disease (cholesterol embolization) can cause a sudden increase in blood pressure complicated by encephalopathy. Recombinant erythropoietin therapy occasionally results in encephalopathy and seizures. This complication is unrelated to the extent or rate of increase in hematocrit; however, it is associated with a rapid increase in blood pressure, especially if the patient was normotensive previously. Transplantation renal artery stenosis or acute renal allograft rejection may cause sudden severe hypertension with encephalopathy. Hypertensive encephalopathy may complicate acute or chronic spinal cord injury. Sudden elevation of blood pressure occurs owing to autonomic stimulation by bowel or bladder distention or noxious stimulation in a dermatome below the level of the injury. Hypertensive encephalopathy also may complicate the rebound hypertension that follows coronary artery bypass procedures or carotid endarterectomy.

8.16

Hypertension and the Kidney

120

5.0

90 100

60 30

NF

0 NS Stroke work index, g m/m2 150

NS LVEDP, mm Hg 200

100

30 15

0 0 NS P<0.005 NS A Baseline hemodynamics in acute hypertensive heart failure (AHHF) vs no failure (NF)

60

AHHF: baseline AHHF: with nitroprusside No failure: baseline No failure: with nitroprusside

LVFP, mm Hg

50

40

30 20

10 0

C

NP

NP

50

120 160 LVEDV, mL/m2

200

240

Left ventricular compliance at baseline and with nitroprusside

FIGURE 8-23 Pathogenesis of acute hypertensive heart failure. Both malignant hypertension and severe benign hypertension can be complicated by acute pulmonary edema caused by isolated diastolic dysfunction. In acute hypertensive heart failure the compromise of left ventricular (LV) diastolic function occurs as a result of a decrease in LV compliance caused by an increased workload imposed on the heart by the marked elevation in systemic vascular resistance. Illustrated are the hemodynamic derangements in acute hypertensive heart failure in a study that compared five patients with severe essential hypertension complicated by acute pulmonary edema with a control group of five patients with equally severe hypertension but no pulmonary edema [28]. Patients

B

P<0.005

40 9 NP

6 3

B

B

NP

0

B

30 20 10

NP B NP

0 P<0.005

0

80

B

P<0.005 NS LVEDV, mL/m2

45

40

B

100

0

60

75

150

0

0

Cardiac output, L/min

AHHF

2.5

AHHF NF

200

LVEDP, mm Hg

200

Cardiac index, L/min/m2

Heart rate, beats/min

Mean arterial pressure, mm Hg

MAP, mm Hg

NS

P<0.005

P<0.025

Hemodynamic parameters at baseline (B) and during nitroprusside (NP) infusion

in both groups had electrocardiographic evidence of LV hypertrophy caused by long-standing hypertension. A, Baseline hemodynamic measurements before treatment revealed that the following measurements were the same in both groups: mean arterial pressure (MAP), heart rate, cardiac index, systemic vascular resistance, and stroke work index. Likewise, the LV end-diastolic volume (LVEDV) was similar in both groups. In fact, the only hemodynamic difference between the groups was a significant elevation of LV filling pressure (LVFP) (pulmonary capillary wedge pressure) in the group with pulmonary edema. In acute hypertensive heart failure the finding of elevated LV end-diastolic pressures (LVEDPs), despite normal ejection fraction and cardiac index, implies the presence of isolated diastolic dysfunction. The increased LV end-diastolic pressure (LVEDP), despite similar LVEDV, can only be explained by a decrease in LV compliance in patients with acute hypertensive heart failure. B, The importance of an acute decrease in LV compliance in the pathogenesis of acute hypertensive heart failure (AHHF) was confirmed in these patients by the hemodynamic response to vasodilator therapy. Sodium nitroprusside infusion resulted in prompt resolution of pulmonary edema in the group having AHHF, with the LVEDP decreasing from a mean of 43 to 18 mm Hg. C, The decrease in filling pressure during nitroprusside therapy in patients with AHHF was not caused by venodilation with decreased venous return because the LVEDV actually increased during nitroprusside infusion. Thus, the response to sodium nitroprusside therapy was mediated through a decrease in systemic vascular resistance that led to an immediate improvement in LV compliance and reduction in wedge pressure despite an increase in LVEDV. These findings suggest that the proximate cause of AHHF is an elevation of the systemic vascular resistance that precipitates acute diastolic dysfunction (decreased LV compliance) with elevated pulmonary capillary wedge pressure, resulting in pulmonary edema. NS— not significant. (Adapted from Cohn and coworkers [28]; with permission.)

Hypertensive Crises

50 40 Nitroprusside

30 HF

20

AH

Left ventricular end-diastolic pressure, mm Hg

60

No

10

rm

al

0 40

80

120

160

200

Left ventricular end-diastolic volume, mL/m2

240

8.17

FIGURE 8-24 Treatment of acute hypertensive heart failure. The left ventricular (LV) end-diastolic pressure-volume relationships (compliance curves) in acute hypertensive heart failure (AHHF) before and after treatment with sodium nitroprusside are represented schematically. In AHHF, the pressure-volume curve is shifted up and to the left, reflecting an acute decrease in LV compliance caused by severe systemic hypertension. In this setting, a higher than normal LV end-diastolic pressure (LVEDP) is required to achieve any given level of LV end-diastolic volume (LVEDV). Normal LV systolic function (ejection fraction and cardiac output) is maintained but at the expense of a very high wedge pressure that results in acute pulmonary edema. Treatment with sodium nitroprusside causes a reduction in the elevated systemic vascular resistance, with a concomitant decrease in impedance to LV ejection. As a result, LV compliance improves. Pulmonary edema resolves owing to a reduction in LVEDP, despite the fact that LVEDV actually increases during treatment. Sodium nitroprusside is the preferred drug for treatment of AHHF. There is no absolute blood pressure goal. The infusion should be titrated until signs and symptoms of pulmonary edema resolve or the blood pressure decreases to hypotensive levels. Rarely is it necessary to lower the blood pressure to this extent, however, because reduction to levels still within the hypertensive range is usually associated with dramatic clinical improvement. Although hemodynamic monitoring is not always required, it is essential in patients in whom concomitant myocardial ischemia or compromised cardiac output is suspected. After the hypertensive crisis has been controlled and pulmonary edema has resolved, oral antihypertensive therapy can be substituted as the patient is weaned from the nitroprusside infusion. As in the treatment of hypertensive patients with chronic congestive heart failure symptoms owing to isolated diastolic dysfunction, agents such as blockers, angiotension-converting enzyme inhibitors, or calcium channel blockers may represent logical first-line therapy. These agents directly improve diastolic function in addition to reducing systemic blood pressure. In patients with malignant hypertension or resistant hypertension, however, adequate control of blood pressure may require therapy with more than one drug. Potent directacting vasodilators such as hydralazine or minoxidil may be used in conjunction with a -blocker to control reflex tachycardia and a diuretic to prevent reflex salt and water retention.

8.18

Hypertension and the Kidney

Aortic dissection Transverse aortic arch

Descending aorta

Ascending aorta

Proximal (Type A)

Distal (Type B)

FIGURE 8-25 Aortic dissection. Classification of aortic dissection is based on the presence or absence of involvement of the ascending aorta [29]. The dissection is defined as proximal if there is involvement of the ascending aorta. The primary intimal tear in proximal dissection may arise in the ascending aorta, transverse aortic arch, or descending aorta. In distal dissections, the process is confined to the descending aorta without involvement of the ascending aorta, and the primary intimal tear occurs most commonly just distal to the origin of the left subclavian artery. Proximal dissections account for approximately 57% and distal dissections 43% of all acute aortic dissections. Acute aortic dissection is a hypertensive crisis requiring immediate antihypertensive treatment aimed at halting the progression of the dissecting hematoma. The three most frequent complications of aortic dissection are acute aortic insufficiency, occlusion of major arterial branches, and rupture of the aorta with fatal hemorrhage (location of rupture-hemorrhage: ascending aorta–hemopericardium with tamponade, aortic arch–mediastinum, descending thoracic aorta–left pleural space, abdominal aorta– retroperitoneum). Patients with acute dissection should be stabilized with intensive antihypertensive therapy to prevent life-threatening complications before diagnostic evaluation with angiography. The initial therapeutic goal is the elimination of pain that correlates with halting of the dissection, and reduction of the systolic pressure to the 100 to 120 mm Hg range or to the lowest level of blood pressure compatible with the maintenance of adequate renal, cardiac, and cerebral perfusion [30]. Even in the absence of systemic hypertension the blood pressure should be reduced. Antihypertensive therapy should be designed not only to lower the blood pressure but also to decrease the steepness of the pulse wave. The most commonly used treatment regimens consist of initial treatment with intravenous -blockers such as propranolol, metoprolol, or esmolol followed by treatment with sodium nitroprusside. After control of the blood pressure, angiography or transesophageal echocardiography, or both, should be performed. The need for surgical intervention is determined based on involvement of the ascending aorta. In proximal dissections, surgical therapy is clearly superior to medical therapy alone (70% vs 26% survival, respectively). In contrast, in patients with distal dissection, intensive drug therapy alone leads to an 80% survival rate compared with only 50% in patients treated surgically. The explanation for the advantage of surgical therapy in proximal dissection is probably that the risks of complications such as cerebral ischemia, acute aortic insufficiency, and cardiac tamponade are higher and managed more effectively with surgery. Because these complications do not occur in distal dissection, in the absence of occlusion of a major arterial branch or development of a saccular aneurysm during long-term follow-up, medical therapy is preferred. Patients with distal dissection tend to be elderly with more advanced aortic atherosclerosis and therefore are at higher risk of complications from operative intervention. (Adapted from Wheat [29]; with permission.)

Hypertensive Crises

Poorly controlled hypertension in surgical patients Postpone elective surgery until blood pressure adequately controlled for 2–3 weeks

Administer blood pressure and antianginal medications the morning of surgery

Manage intraoperative hypertension with sodium nitroprusside

Manage postoperative hypertension with nitroprusside in patients with complications or labetalol in patients without complications

Carefully institute oral antihypertensives at low-dose and titrate based on orthostatic blood pressure measurements

Inadequate preoperative blood pressure control (diastolic blood pressure >110 mm Hg or mild to moderate hypertension in patients with history of cerebrovascular accident, myocardial ischemia, heart failure, or renal insufficiency General anesthesia Decreased cardiac output (30%) Decreased systemic vascular resistance (27%) Hypotension (45% Decrease in mean arterial pressure) Increased risks of Cerebral ischemia Myocardial ischemia Acute renal failure Increased perioperative morbidity and mortality

FIGURE 8-26 Poorly controlled hypertension in the patient requiring surgery. Hypertension in the preoperative patient is a common problem. Poor control of preoperative hypertension, with a diastolic blood pressure higher than 110 mm Hg, is a relative contraindication to elective surgery. In such patients, perioperative morbidity and mortality are increased because of a higher incidence of intraoperative hypotension accompanied by myocardial ischemia and a heightened risk of acute renal failure [31]. Malignant hypertension clearly represents an excessive surgical risk and all but lifesaving emergency surgery should be deferred until the blood pressure can be controlled and organ function stabilized. Mild to moderate uncomplicated hypertension with diastolic blood pressure less than 110 mm Hg does not appear to increase the risk of surgery significantly and therefore is not an absolute indication to postpone elective surgery. However, patients with mild to moderate hypertension and preexisting complications such as ischemic heart disease, cerebrovascular disease, congestive heart failure, or chronic renal insufficiency, represent a subgroup with significantly increased perioperative risk. In these patients, adequate preoperative control of blood pressure

8.19

is imperative [32]. Even though the blood pressure in patients with severe or complicated hypertension usually can be controlled within hours using aggressive parenteral therapy, such precipitous control of blood pressure carries the risk of significant complications such as hypovolemia, electrolyte abnormalities, and marked intraoperative blood pressure lability. General anesthesia is accompanied by a 30% decrease in cardiac output. In normotensive persons and patients with adequately treated hypertension, anesthesia is not associated with a decrease in systemic vascular resistance. Therefore, the decrease in mean arterial pressure (MAP) is modest (25–30%). However, in patients with inadequate preoperative blood pressure control, anesthesia is associated with a concomitant decrease in systemic vascular resistance (SVR) of approximately 27%. The combined decrease in cardiac output and SVR leads to a profound decrease in MAP (45%) during anesthesia [33]. This intraoperative hypotension predisposes to myocardial ischemia, cerebrovascular accidents, and acute renal failure. Therefore, in patients with diastolic blood pressure over 110 mm Hg or these other high-risk groups, elective surgery should be postponed and blood pressure brought under control for a few weeks before surgery, if possible. Ideally, sustained adequate preoperative blood pressure control should be the goal in all hypertensive patients [34]. In patients with adequately treated hypertension, oral antihypertensive, and antianginal medications should be continued up to and including the morning of surgery, administered with small sips of water. Because hypovolemia increases the risk of intraoperative hypotension and postoperative acute renal failure, diuretics should be withheld for 1 to 2 days preoperatively except in patients with overt heart failure or fluid overload. Adequate potassium repletion should be given to correct hypokalemia well in advance of surgery. Continuation of -blockers to within a few hours of surgery does not impair cardiac function and has been shown to decrease the risks of dysrhythmia and myocardial ischemia during surgery. In patients with complications and a history of cardiovascular disease or heart failure, or after coronary artery bypass surgery, postoperative hypertension should be managed with short-acting agents such as nitroglycerin or nitroprusside. In patients without complications, intermittent intravenous infusions of labetalol may be useful for management of mild to moderate postoperative hypertension until the preoperative oral antihypertensive agents can be resumed. Many patients with long-standing hypertension, even if severe, require much smaller doses of antihypertensive medications in the early postoperative course. Thus, the preoperative regimen should not be restarted automatically. Measurement of orthostatic blood pressures should be used as a guide to dosage adjustment during the postoperative recovery period. In most instances, the need for antihypertensive medications will gradually increase over a few days to weeks to eventually equal the preoperative requirement.

8.20

Hypertension and the Kidney

Hypertensive crises after bypass surgery

Coronary artery bypass graft surgery Paradoxical hypertensive response to intravascular volume depletion

Increased sympathetic tone owing to activation or pressor reflexes from heart, coronary arteries, or great vessels

Increased systemic vascular resistance

Systemic hypertension

Increased risk of postoperative mediastinal bleeding

Increased impedance to left ventricular ejection

Treat with nitroprusside or intravenous nitroglycerin

Hypertensive encephalopathy (Fig. 8-21)

Acute diastolic dysfunction (decreased left ventricular compliance)

Increased left ventricular end-diastolic pressure

Impaired subendocardial perfusion causing myocardial ischemia

Acute hypertensive heart failure with pulmonary edema (Figs. 8-23 and 8-24)

FIGURE 8-27 Hypertensive crisis after coronary artery bypass surgery. Paroxysmal hypertension in the immediate postoperative period is a frequent and serious complication of cardiac surgery [35,36]. Paroxysmal hypertension is the most frequent complication of coronary artery bypass surgery, occurring in 30% to 50% of patients. It occurs just as often in normotensive patients as it does in those with a history of chronic hypertension. The increase in blood pressure usually occurs during the first 4 hours after surgery. The hypertension results from a dramatic increase in systemic vascular resistance (SVR) without a change in the cardiac output and is most commonly mediated by an increase in sympathetic tone owing to activation of pressor reflexes from the heart, great vessels, or coronary arteries. Hypervolemia, although often cited as a potential mechanism of postoperative hypertension, is a rare cause of postbypass hypertension except in patients with renal failure. In fact, increased SVR owing to marked sympathetic overreaction to volume depletion is a common, often unrecognized, cause of severe postoperative hypertension [37]. Patients with this paradoxical hypertensive response to hypovolemia are exquisitely sensitive to vasodilator therapy and

may develop precipitous hypotension with even low-dose infusions of nitroglycerin or nitroprusside. Hypertension in this setting should be treated using careful volume expansion with crystalloid solutions or blood if required. Post–coronary artery bypass hypertension represents a hypertensive crisis because the heightened SVR increases the impedance to left ventricular (LV) ejection (afterload) that can result in an acute decrease in ventricular compliance with elevation of LV end-diastolic pressure (LVEDP) and acute hypertensive heart failure with pulmonary edema (Figs. 8-23 and 8-24). The increase in LVEDP also impairs subendocardial perfusion and can cause myocardial ischemia. Moreover, the elevated blood pressure increases the risk of mediastinal bleeding in these recently heparinized patients. The initial management of postbypass hypertension should focus on attempts to ameliorate reversible causes of sympathetic activation, including patient agitation on emergence from anesthesia, tracheal or nasopharyngeal irritation from the endotracheal tube, pain, hypothermia with shivering, ventilator asynchrony, hypoxia, hypercarbia, and volume depletion. If these general measures fail to control the blood pressure, further therapy should be guided by measurement of systemic hemodynamics. Intravenous nitroglycerin or nitroprusside is the drug of choice to provide a controlled decrease in SVR and blood pressure. Nitroglycerin may be the preferred drug because it dilates intracoronary collateral arteries [35,36]. Therapy with -blockers is not indicated in this setting and may be detrimental because these drugs impair cardiac output and cause a further increase in SVR. Labetalol also has been shown to cause a significant reduction in cardiac output in postbypass hypertension. Postbypass hypertension is usually transient and resolves by 6 to 12 hours postoperatively, so that the vasodilatory therapy can be weaned. The hypertension usually does not recur after the initial episode in the immediate postoperative period.

Hypertensive Crises

Hypertensive crises after carotid endarterectomy Carotid endarterectomy

Postoperative hypertension (mechanism unknown)

Repair of high-grade stenosis

Sudden increase in perfusion pressure in arteriocapillary bed that was previously protected from hypertension

Failure of autoregulation of cerebral blood flow (breakthrough of autoregulation)

Overperfusion of cerebral circulation Vessel rupture (hemorrhage and infarction)

8.21

FIGURE 8-28 Hypertensive crisis after carotid endarterectomy. Hypertension in the immediate postoperative period occurs in up to 60% of patients after carotid endarterectomy [38]. A history of chronic hypertension, especially if the blood pressure is poorly controlled preoperatively, dramatically increases the risk of postoperative hypertension. The mechanism of post-endarterectomy hypertension is unknown. The incidence of hypertension is the same whether or not the carotid sinus nerve is preserved. Hypertension after endarterectomy is a hypertensive crisis because it is associated with increased risk of intracerebral hemorrhage and increases the postoperative mortality rate [39]. A mechanism for the development of post–carotid endarterectomy cerebral hemorrhage owing to postoperative hypertension has been proposed. In patients with high-grade carotid artery stenosis, the distal cerebral circulation has been relatively protected from systemic hypertension. In this regard, the autoregulatory curve may be shifted to a lower threshold to compensate for reduced perfusion pressure. After repair of the obstructing lesion, a relative increase in perfusion pressure occurs in the cerebral arteriocapillary bed. In the setting of systemic hypertension the increased blood flow and perfusion pressure may overwhelm the autoregulatory mechanisms. Overperfusion and rupture may then occur, resulting in hemorrhagic infarction. Because poor preoperative blood pressure control increases the risk of postoperative hypertension, strict blood pressure control is essential before elective carotid endarterectomy. Furthermore, intra-arterial pressure should be monitored in the operating room and in the immediate postoperative period. Ideally, the patient should be awake and extubated before reaching the recovery room so that serial neurologic examinations can be performed to assess for the development of focal deficits. When the systolic blood pressure exceeds 200 mm Hg, an intravenous infusion of sodium nitroprusside should be initiated to maintain the systolic blood pressure between 160 and 200 mm Hg. The use of a short-acting parenteral agent is imperative to avoid overshoot hypotension and cerebral hypoperfusion.

8.22

Hypertension and the Kidney

Risks of antihypertensive therapy in acute cerebral infarction Acute cerebral infarction

Reflex increase in systemic blood pressure Even with cautious blood pressure reduction using parenteral agents

Altered blood flow autoregulation in the ischemic penumbra surrounding the infarct

Exaggerated response to oral antihypertensives Spontaneous resolution within first week

Failure of autoregulation with worsening ischemia

Extension of infarct

FIGURE 8-29 Risks of antihypertensive therapy in acute cerebral infarction. Cerebral infarction results from partial or complete occlusion of an artery by an atherosclerotic plaque or embolization of atherothrombotic debris from a more proximal plaque. These atherothrombotic infarcts typically involve the cerebral cortex, cerebellar cortex, or pons; these infarcts are to be contrasted with hypertension-induced lipohyalinosis of the small penetrating cerebral end-arteries that is the principal cause of the small lacunar infarcts occurring in the basal ganglia, pons, thalamus, cerebellum, and deep hemispheric white matter. Hypertension occurs in up to 85% of patients with acute cerebral infarction, even in previously normotensive persons [40]. This early elevation of blood pressure probably represents a physiologic response to brain ischemia. Because of the known benefits of antihypertensive therapy with regard to stroke prevention, it previously had been assumed that acute reduction of blood pressure would also be of benefit in acute cerebral infarction. However, no evidence exists to suggest that acute reduction of blood pressure is beneficial in this setting. In fact, reports exist of worsening neurologic status, apparently precipitated by emergency treatment of hypertension in patients with cerebral infarction [41]. In the setting of acute cerebral

infarction, hypertension tends to be very labile and exquisitely sensitive to hypotensive therapy. Thus, even modest doses of oral antihypertensive agents can lead to profound and devastating overshoot hypotension with extension of the infarct [42]. An additional rationale for not treating hypertension in the acute setting is based on evidence that local autoregulation of cerebral blood flow is impaired in the so-called ischemic penumbra, which surrounds the area of acute infarction [43]. Without intact autoregulation, the regional blood flow in this marginal zone of ischemia becomes critically dependent on the perfusion pressure. Thus, the presence of mild to moderate systemic hypertension may actually be protective, and acute reduction of blood pressure may cause a regional reduction in blood flow with extension of the infarct. Thus, in most cases of cerebral infarction it is prudent to allow the blood pressure to seek its own level during the first few days to weeks after the event. In most cases the hypertension tends to resolve spontaneously, without any specific therapy, over the first week as brain function recovers. When hypertension persists for more than 3 weeks after a completed infarction, reduction of the blood pressure into the normal range with oral antihypertensives is appropriate. Although benign neglect of mild to moderate hypertension is prudent in acute cerebral infarction, there may be certain indications for active treatment of blood pressure. When the diastolic blood pressure is sustained at over 130 mm Hg, cautious reduction of blood pressure into the ranges of 160 to 170 mm Hg systolic and 100 to 110 mm Hg diastolic may be appropriate. In stroke patients requiring anticoagulation therapy, moderate control of severe hypertension also should be considered. Cautious blood pressure reduction is indicated when stroke is accompanied by other hypertensive crises such as acute myocardial ischemia or acute hypertensive heart failure. Stroke caused by carotid occlusion by a proximal aortic dissection mandates aggressive blood pressure reduction into the normal range to halt the dissection process. In the setting of sudden severe hypertension, it may be difficult to distinguish hypertensive encephalopathy with focal neurologic findings from cerebral infarction. Because rapid reduction of blood pressure is lifesaving in patients with hypertensive encephalopathy, a cautious diagnostic trial of blood pressure reduction may be warranted (Fig. 821). If blood pressure reduction is deemed necessary in patients with acute cerebral infarction, treatment should be initiated using small doses of a short-acting parenteral agent such as sodium nitroprusside. Use of oral or sublingual nifedipine is associated with excessive risk of prolonged overshoot hypotension. Oral clonidine loading also is contraindicated because of the risk of hypotension and because sedative side effects interfere with the assessment of mental status.

Hypertensive Crises

Hypertensive crises from intracerebral hemorrhage

Intracerebral hemorrhage

Reflex increase in blood pressure (Cushing's reflex) Hypertension may help maintain blood flow in ischemic areas Cerebral hyperperfusion with cerebral edema

Impairment of autoregulation of blood flow in ischemic area surrounding hematoma (shift of lower limit of autoregulation)

Increased risk of rebleeeding (expansion of hematoma)

Sodium nitroprusside Cautious blood pressure reduction by no more than 20% of presenting mean arterial pressure (intra-arterial and intracranial pressure monitoring to ensure adequate cerebral perfusion pressure)

FIGURE 8-30 Hypertensive crises due to intracerebral hemorrhage. Chronic hypertension is the major risk factor for intracerebral hemorrhage. The most common sites of hemorrhage are the small-diameter penetrating cerebral end-arteries in the basal ganglia, pons, thalamus, cerebellum, and deep hemispheric white matter. Lacunar infarcts arise from the same vessels and are similarly distributed. Intracerebral hemorrhage characteristically begins abruptly with headache and vomiting followed by steadily increasing focal neurologic deficits and alteration of consciousness [44]. More than 90% of hemorrhages rupture through brain parenchyma into the ventricles, producing bloody cerebrospinal fluid. Patients presenting with intracerebral hemorrhage are invariably hypertensive. In contrast to cerebral infarction, the hypertension does not tend to decrease spontaneously during the first week. The patient’s condition worsens steadily over a period of minutes to days until either the neurologic deficit stabilizes or the patient dies. When death occurs, most often it is due to herniation caused by the expanding hematoma and surrounding edema. Treatment of hypertension in the setting of intracerebral hemorrhage is controversial. An increase in intracranial pressure accompanied by a reflex increase in systemic blood pressure almost always occurs. Because cerebral perfusion pressure is a function of the difference between arterial pressure and intracranial pressure, reduction of blood pressure could compromise cerebral perfusion. Moreover, as in cerebral infarction, autoregulation is impaired in the area of marginal ischemia surrounding the hemorrhage. In contrast, cerebral vasogenic edema may be exacerbated by hypertension. Moreover, hypertension may increase the risk of rebleeding with expansion of the hematoma. Thus, in deciding to treat hypertension in the setting of intracerebral hemorrhage, a precarious balance must be struck between beneficial reduction in cerebral edema on the one hand, and deleterious reduction of cerebral blood flow on the other. Studies have shown that the lower limit of autoregulation after intracerebral hemorrhage is approximately 80% of the initial blood pressure; therefore, a 20% decrease in mean arterial pressure should be considered the maximal goal of blood pressure reduction during the acute stage [45]. Antihypertensive therapy should be undertaken only in conjunction with intracranial and intra-arterial pressure monitoring to allow for assessment of cerebral perfusion pressure. The short duration of action of nitroprusside makes its use preferable over other agents with a longer duration of action and the risk of sustained overshoot hypotension, despite the theoretic concern that nitroprusside treatment could lead to an increase in intracranial pressure by way of dilation of cerebral veins and arteries.

8.23

8.24

Hypertension and the Kidney

Hypertensive crisis with pheochromocytoma Pheochromocytoma Acute treatment with nitroprusside or phentolamine followed by β-blockers

Episodic release of catecholamines Paroxysmal hypertension

Pressure-induced natriuresis and diuresis Intravascular volume depletion

Intracerebral hemorrhage

Acute hypertensive heart failure with pulmonary edema (Figs. 8-23 and 8-24)

Hypertensive encephalopathy (Fig. 8-21)

Increased risk of intraoperative and postoperative hypotension

FIGURE 8-31 Hypertensive crisis with pheochromocytoma. In most patients, pheochromocytoma causes sustained hypertension that sometimes becomes malignant as evidenced by the presence of hypertensive neuroretinopathy. Paroxysmal hypertension is present in approximately 30% of patients. Spontaneous paroxysms consist of severe hypertension, headache, profuse diaphoresis, pallor, coldness of hands and feet, palpitations, and abdominal discomfort. Paroxysmal hypertension in pheochromocytoma represents a hypertensive crisis because it can lead to intracerebral hemorrhage, hypertensive encephalopathy, or acute hypertensive heart failure with pulmonary edema. Prompt control of the blood pressure is mandatory to prevent these life-threatening complications. Although the nonselective -blocker phentolamine often is cited as the treatment of choice for pheochromocytoma-related hypertensive crises, sodium nitroprusside is equally effective and easier to administer [46]. Only after blood pressure has been controlled with nitroprusside or phentolamine can intravenous -blockers, such as esmolol, labetalol, or propranolol, be used to control tachycardia or arrhythmias. After resolution of the hypertensive crisis, oral antihypertensive agents should be instituted as the parenteral agents are weaned. The nonselective -blocker phentolamine usually is administered orally for 1 to 2 weeks before elective surgery. After adequate -blockade is achieved, based on the presence of moderate orthostatic hypotension, oral -blocker therapy can be initiated as needed to control tachycardia. Oral or intravenous -blockers should never be administered before adequate -blockade. Doing so can precipitate a hypertensive crisis as the result of intense -adrenergic vasoconstriction that is no longer opposed by -adrenergic vasodilatory stimuli. Careful attention to volume status also is mandatory in the preoperative period. Catecholamine-induced hypertension induces a pressure natriuresis with volume depletion. Moreover, alleviation of the chronic state of vasoconstriction by -blockade results in increases in both arterial and venous capacitances. Preoperative volume expansion, guided by measurement of central venous pressure or wedge pressure often is advocated to reduce the risk of intraoperative hypotension [47]. During surgery, rapid and wide fluctuations in blood pressure should be anticipated. Careful intraoperative monitoring of intra-arterial pressure, cardiac output, wedge pressure, and systemic vascular resistance is mandatory to manage the rapid swings in blood pressure. Despite adequate preoperative -blockade with phenoxybenzamine, severe hypertension can occur during intubation or intraoperatively as a result of catecholamine release during tumor manipulation. Sodium nitroprusside is the treatment of choice for controlling acute hypertension owing to pheochromocytoma during surgery. At the opposite end of the spectrum, profound intraoperative hypotension can occur. Hypotension or even frank shock can supervene after isolation of tumor venous drainage from the circulation, with resultant abrupt decrease in circulating catecholamine levels. Volume expansion is the treatment of choice for intraoperative and postoperative hypotension [46]. Pressors only should be employed when hypotension is unresponsive to volume repletion.

Hypertensive Crises

Hypertension crises secondary to monoamine oxidase inhibitor–tyramine interactions Monoamine oxidase inhibitor therapy

Impaired degradation of intracellular amines (epinephrine, norepinephrine, dopamine) Accumulation of catecholamines in nerve terminal storage granules Increased circulating tyramine level

Massive release of catecholamines

Ingestion of tyramine-containing food

Hepatic monamine oxidase inhibition with decreased oxidative metabolism of tyramine

Tachyarrhythmias

Vasoconstriction (increased systemic vascular resistance)

Severe paroxysm of hypertension

Hypertensive encephalopathy (Fig. 8-21)

Acute hypertensive heart failure with pulmonary edema (Figs. 8-24 and 8-25)

Intracerebral hemorrhage

FIGURE 8-32 Hypertensive crises secondary to monoamine oxidase inhibitor–tyramine interactions. Severe paroxysmal hypertension complicated by intracerebral or subarachnoid hemorrhage, hypertensive encephalopathy, or acute hypertensive heart failure can occur in patients treated with monoamine oxidase (MOA) inhibitors after ingestion of certain drugs or tyraminecontaining foods [48,49]. Because MAO is required for degradation of intracellular amines, including epinephrine, norepinephrine, and dopamine, MAO inhibitors lead to accumulation of catecholamines within storage granules in nerve terminals. The amino acid tyramine is a potent inducer of neurotransmitter release from nerve terminals. As a result of inhibition of hepatic MAO, ingested tyramine escapes oxidative degradation in the liver. In addition, the high circulating levels of tyramine provoke massive catecholamine release from nerve terminals, resulting in vasoconstriction and a paroxysm of severe hypertension. A hyperadrenergic syndrome resembling pheochromocytoma then ensues. Symptoms include severe pounding headache, flushing or pallor, profuse diaphoresis, nausea, vomiting, and extreme prostration. The mean increase in blood pressure is 55 mm Hg systolic and 30 mm Hg diastolic [49]. The duration of the attacks varies from 10 minutes to 6 hours. Attacks can be provoked by the ingestion of foods known to be rich in tyramine: natural or aged cheeses, Chianti wines, certain imported beers, pickled herring, chicken liver, yeast, soy sauce, fermented sausage, coffee, avocado, banana, chocolate, and canned figs. Sympathomimetic amines in nonprescription cold remedies also can provoke neurotransmitter release in patients treated with an MAO inhibitor. Either sodium nitroprusside or phentolamine can be used to manage this type of hypertensive crisis. Because most patients are normotensive before onset of the crisis the goal of blood pressure treatment should be normalization of the blood pressure. After blood pressure control, intravenous -blockers may also be required to control heart rate and tachyarrhythmias. Because the MAO inhibitor–tyramine hypertensive crisis is self-limited, parenteral antihypertensive agents can be weaned without institution of oral antihypertensive agents.

8.25

8.26

Hypertension and the Kidney

Mechanism of action and metabolism of nitroprusside +

NO

CN-

CNFe++

CN-

CNCNNitroprusside

t1/2=3–4 min

Metabolized by direct combination with -SH groups in erythrocytes and tissues

Free cyanide (CN-)

Thiocyanate t1/2=1 wk

Combination of nitroso group with cysteine

Renal excretion

Nitrosocysteine

Activation of guanylate cyclase

cGMP accumulation in vascular smooth muscle

Venodilation (increased venous capacitance)

t1/2=2–3min

Metabolized by cGMP-specific phosphodiesterases

Dilation of arteriolar resistance vessels (decreased systemic vascular resistance)

Decreased blood pressure

Afterload reduction

FIGURE 8-33 Mechanism of action and metabolism of nitroprusside. Sodium nitroprusside is the drug of choice for management of virtually all hypertensive crises, including malignant hypertension, hypertensive encephalopathy, acute hypertensive heart failure, intracerebral hemorrhage, perioperative hypertension, catecholamine-related hypertensive crises, and acute aortic dissection (in combination with a -blocker) [1,50]. Sodium nitroprusside is a potent intravenous hypotensive agent with immediate onset and brief duration of action. The site of action is the vascular smooth muscle. Nitroprusside has no direct action on the myocardium, although it may affect cardiac performance indirectly through alterations in systemic hemodynamics. Nitroprusside is an iron (Fe) coordination complex with five cyanide moieties and a nitroso (NO) group. The nitroso group combines with cysteine to form nitrosocysteine and other short-acting S-nitrosothiols. Nitrosocysteine is a potent activator of guanylate cyclase, thereby causing cyclic guanosine monophosphate (cGMP) accumulation and relaxation of vascular smooth muscle [51,52]. Nitroprusside causes vasodilation of both arteriolar resistance vessels and venous capacitance vessels. Its hypotensive action is a result of a decrease in systemic vascular resistance. The combined decrease in preload and afterload reduces myocardial wall tension and myocardial oxygen demand. The net effect of nitroprusside on cardiac output and heart rate depends on the intrinsic state of the myocardium. In patients with left ventricular (LV) systolic dysfunction and elevated LV end-diastolic pressure, nitroprusside causes an increase in stroke volume and cardiac output as a result of afterload reduction and heart rate may actually decrease in response to improved cardiac performance. In contrast, in the absence of LV dysfunction, venodilation and preload reduction can result in a reflex increase in sympathetic tone and heart rate. For this reason, nitroprusside must be used in conjunction with a -blocker in acute aortic dissection. The hypotensive action of nitroprusside appears within seconds and is immediately reversible when the infusion is stopped. The cGMP in vascular smooth muscle is rapidly degraded by cGMP-specific phosphodiesterases. Nitroprusside is rapidly metabolized with a half-life (t1/2) of 3 to 4 minutes. Cyanide is formed as a short-lived intermediate product by direct combination with sulfhydryl (SH) groups in erythrocytes and tissues. The cyanide groups are rapidly converted to thiocyanate by the liver in a reaction in which thiosulfate acts as a sulfur donor. Thiocyanate is excreted by the kidneys, with a half-life of 1 week in patients with normal renal function. Thiocyanate accumulation and toxicity can occur when a high-dose or prolonged infusion is required, especially in patients with renal insufficiency. When these risk factors are present, thiocyanate levels should be monitored and the infusion stopped if the level is over 10 mg/dL. Thiocyanate toxicity is rare in patients with normal renal function requiring less than 3 µg/kg/min for less than 72 hours [50]. Cyanide poisoning is a very rare complication, unless hepatic clearance of cyanide is impaired by severe liver disease or massive doses of nitroprusside (over 10 µg/kg/min) are used to induce deliberate hypotension during surgery [50].

FIGURE 8-34 Sodium nitroprusside remains the treatment of choice in virtually all hypertensive crises requiring rapid blood pressure control with Minutes

Direct venodilation at low doses; combined venodilation and arteriolar dilation at higher doses Selective 1- and noncardioselective -blocker; arteriolar and venous dilation

Nonselective -blocker

Direct arteriolar vasodilation

2–4 h Decrease sympathetic nervous system activity via CNS 2 stimulation, decrease systemic vascular resistance 2–4 h Sympathetic dysfunction owing to central and peripheral catecholamine dysfunction; decreased SVR, decreased CO

Nitroglycerin

Phentolamine

Hydralazine

Methyldopa

parenteral therapy. However, other parenteral antihypertensive agents may be useful in certain circumstances. 2–4 h

4–6 h

30–60 min

5 min

5–50 min

Minutes

Advantages

Disadvantages

Side effects

2–8 h

4–6 h

3–9 h

15–30 min

16–18 h

Useful in catecholaminerelated crises

Short duration of action

Intramuscular: Initial, 0.5–1.0 mg 2–4 mg over 3 h 2–4 mg over 3–12 h

Contraindicated in pheochromocytoma, heart failure, asthma, heart block >1 degree, after coronary artery bypass graft surgery Nitroprusside equally efficacious in catecholaminerelated crises

Delayed onset Nasal congestion, None—not CNS sedation, recommended for of action, unpredictable bradycardia, use in hypertenhypotensive effect exacerbates pepsive crises tic ulcer disease, depression

Contraindicated in hypertensive encephalopathy, CNS catastrophe, cumulative hypotensive response

Contraindicated in hypertensive encephalopathy, CNS catastrophe

aortic dissection, atherosclerotic coronary vascular disease

Tachycardia, arrhythmias, nausea, vomiting, diarrhea, exacerbation of peptic ulcer disease Headache, angina Contraindicated in Delayed onset IV bolus: 5–10 mg over Proven efficacy of action, 20–30 min or continuand safety in ous infusion 400 µg/mL hypertensive crises unpredictable hypotensive effect solution Loading dose: of pregnancy 200–300 µg/min for 30–60 min Maintenance infusion: 50–150 µg/min Delayed onset Sedation IV of 250–500 mg None—not over 6–8 h recommended for of action, unpredictable use in hypertenhypotensive effect sive crises

IV bolus: 1–5 mg over 5 min

Fails to control BP Headache, nausea, Theoretic advanin some patients vomiting, tages over nitropalpitations, prusside in setting abdominal pain of myocardial ischemia -blockage can Nausea, vomiting, IV minibolus: Initial, 20 Continuous worsen congestive paresthesias, mg over 2 min Then monitoring not heart failure, headache, 40–80 mg over 10 min. required bronchospasm, bradycardia Maximum, 300 mg heart block

1–5 min after infusion Continuous infusion: stopped Initially, 5 µg/min Increase by 5 µg/min over 3–5 min

insufficiency and glaucoma; potentiates succinylcholine Dilates intracoronary collaterals

Comments

Discontinue if 2–3 min after infusion Continuous infusion: Precise titration of Monitoring in ICU Nausea, vomiting, required apprehension. stopped Initial, 0.5 µg/kg/min BP. Consistently thiocyanate level Thiocyanate toxic- >10 mg/dL Average, 3 µg/kg/min effective when ity with prolonged Maximum, 10 µg/kg/min other drugs fail. infusion, renal Parenteral agent insufficiency of choice for hypertensive crises Sustained Nausea, vomiting, Contraindicated in 4–24 h IV minibolus: 50–100 mg Long duration of hypotension with hyperglycemia, IV given rapidly over action. Constant aortic dissection, CNS and myocarmyocardial 5–10 min. Total dose, monitoring not cerebrovascular ischemia, uterine 150–600 mg required after ini- dial ischemic can disease, myocardial occur. Reflex sym- atony tial titration ischemia pathetic cardiac stimulation Dry mouth, blurred Tilt-bed enhances 5–10 min after infuContinuous infusion: Blocks barorecep- Parasympathetic blockade vision, urinary sion stopped Initial, 0.5 mg/min tor-mediated effect; tachyphylaxis retention, paralyt- after 24–48 h; Maximum, 5.0 mg/min sympathetic ic ileus, respiratocardiac stimulation contraindicated ry arrest in respiratory

Method of Duration of action administration

BP—blood pressure; CNS—central nervous system; CO—cardiac output; ICU—intensive care unit; IV—intravenous; SVR—systemic vascular resistance.

Reserpine

10–30 min

2–3 min

Minutes

Minutes Ganglionic blockage with venodilation and arteriolar vasodilation

Trimethaphan camsylate

Labetalol

10–15 min

1–2 min

Direct arteriolar vasodilation

Diazoxide

Minutes

Immediate

Onset of action Peak effect Instantaneous

Mechanism of action

Sodium Direct arteriolar nitroprusside vasodilation and venodilation

Drug

VARIOUS ANTIHYPERTENSIVE DRUGS FOR PARENTERAL USE IN THE MANAGEMENT OF MALIGNANT HYPERTENSION AND OTHER HYPERTENSIVE CRISES

Hypertensive Crises

8.27

8.28

Hypertension and the Kidney

Mean arterial pressure, mm Hg

200

Uncontrolled hypertensives (n=13) Controlled hypertensives (n=9) Normotensives (n=10)

150

100 79 72 ± 74 10% ± 29% ± 12%

50

0 Baseline mean arterial pressure

Lower limit of autoregulation

45 ± 6%

46 45 ± ± 16% 12%

Lowest tolerated mean arterial pressure

FIGURE 8-35 Risks of rapid blood pressure reduction in hypertensive crises. It has been argued over the years that rapid reduction of blood pressure in the setting of hypertensive crises may have a detrimental effect on cerebral perfusion because the autoregulatory curve of cerebral blood flow is shifted upward in patients with chronic hypertension. Conversely, this upward shift protects the brain from hypertensive encephalopathy in the face of severe hypertension. However, this autoregulatory shift could be deleterious when the blood pressure is reduced acutely because the lower limit of autoregulation is shifted to a higher level of blood pressure. Theoretically, aggressive reduction of the blood pressure in chronically hypertensive patients could induce cerebral ischemia. Nonetheless, in clinical practice, moderately controlled reduction of blood pressure in patients with hypertensive crises rarely causes cerebral ischemia. This clinical observation may be explained by the fact that even though the cerebral autoregulatory curve is shifted in patients with chronic hypertension, a considerable difference still exists between the initial blood pressure at presentation and the lower limit of autoregulation. Illustrated are the differences in the lower autoregulatory threshold during blood pressure reduction with trimethaphan in patients with uncontrolled hypertension and treated hypertension, and those in the control group [53]. At least eight of the 13 patients with uncontrolled hypertension had hypertensive neuroretinopathy consistent with malignant hypertension. The control groups included nine patients with a history of severe hypertension in the past whose blood pressure was effectively controlled at the time of study and a group of 10 normotensive persons. Baseline mean arterial pressures (MAPs) in the three groups were 145 ±17 mm Hg, 116 ±18 mm Hg, and 96 ±17 mm Hg, respectively. The lower limit of blood pressure at which autoregulation failed was 113 ±17 mm Hg in persons with uncontrolled hypertension, 96 ±17mm Hg in persons with treated hypertension, and 73 ±9 mm Hg in normotensive persons. Although the absolute level at which autoregulation failed was substantially higher in patients with uncontrolled hypertension, the percentage reduction in blood pressure from the baseline level required to reach the autoregulatory threshold was similar in each group. The numbers on the bars indicate the percentage reduction from the baseline

blood pressure required to reach the autoregulatory limit. Thus, a reduction in MAP of approximately 20% to 25% was required in each group to reach the threshold. This result indicates that a considerable safety margin exists for blood pressure reduction before cerebral autoregulation of blood flow fails, even in patients with severe untreated hypertension. Moreover, symptoms of cerebral ischemia did not develop until the blood pressure was reduced substantially below the autoregulatory threshold because even in the face of reduced blood flow, cerebral metabolism can be maintained and ischemia prevented by an increase in oxygen extraction by the tissues. The lowest tolerated MAP, defined as the level at which mild symptoms of brain hypoperfusion developed (ie, yawning, nausea, and hyperventilation), was 65 ±10 mm Hg in patients with uncontrolled hypertension, 53 ±18 mm Hg in persons with treated hypertension, and 43 ±8 mm Hg in normotensive persons. The numbers on the bars illustrate that these MAP values were approximately 45% of the baseline blood pressure level in each group. Thus, symptoms of cerebral hypoperfusion did not occur until the MAP was reduced by an average of 55% from the presenting level. In the reported cases of neurologic sequelae sustained during rapid reduction of blood pressure in patients with hypertensive crises, the MAP was reduced by more than 55% of the presenting blood pressure. This frank hypotension was sustained for a period of hours to days, mostly as a result of treatment with bolus diazoxide, which has long duration of action [54]. The general guideline for acute blood pressure reduction in the treatment of hypertensive crises is reduction of systolic blood pressure to 160 to 170 mm Hg and diastolic pressure to 100 to 110 mm Hg, which equates to MAPs of 120 to 130 mm Hg. Alternatively, the initial goal of antihypertensive therapy can be a 20% reduction of the MAP from the patient’s initial level at presentation. This level should be above the predicted autoregulatory threshold. Once this goal is obtained the patient should be evaluated carefully for evidence of cerebral hypoperfusion. Further reduction of blood pressure can then be undertaken in a controlled fashion based on the overall clinical status of the patient. Of course, in previously normotensive persons in whom hypertensive crises develop, such as patients with acute glomerulonephritis complicated by hypertensive encephalopathy, the autoregulatory curve should not yet be shifted. Therefore, the initial goal of therapy should be normalization of blood pressure. In terms of avoiding sustained overshoot hypotension in the treatment of hypertensive crises, the use of potent parenteral agents with short duration of action, such as sodium nitroprusside or intravenous nitroglycerin, has obvious advantages. If neurologic sequelae develop during blood pressure reduction with these agents, these sequelae can be reversed quickly by tapering the infusion and allowing the blood pressure to stabilize at a higher level. Agents with a long duration of action have an inherent disadvantage in that excessive reduction of blood pressure cannot be reversed easily. Thus, bolus diazoxide, labetalol, minoxidil, hydralazine, converting enzyme inhibitors, calcium channel blockers, and central 2-agonists should be used with extreme caution in patients requiring rapid but controlled blood pressure reduction in the setting of hypertensive crises. (Adapted from Strandgaard [53]; with permission.)

Hypertensive Crises

Severe uncomplicated hypertension Severe hypertension (diastolic blood pressure > 115 mm Hg)

Hypertensive neuroretinopathy present (striate hemorrhages, cotton-wool spots with or without papilledema) Treat malignant hypertension (Fig. 8-20)

Hypertensive neuroretinopathy absent

No acute end-organ dysfunction

Acute end-organ dysfunction Treat as hypertensive crisis (see preceding figures)

Severe uncomplicated hypertension Step 1 Patient education regarding the chronic nature of hypertension and importance of long-term compliance and blood pressure control to prevent complications

Step 2

Step 3

Evaluate reason for inadequate blood pressure control and adjust maintenance antihypertensive drug regimen

Noncompliant

Arrange outpatient follow-up to document adequate blood pressure control over the ensuing days to weeks and change drug treatment regimen as required

Compliant with current blood pressure regimen

"Ran out" of medications

Drug side effects

Cannot afford drugs

Restart

Switch to drug of another class

Switch to generic thiazide diuretic

Add low-dose thiazide diuretic to existing monotherapy with CCB, CEI, β-blocker, α2-agonist

FIGURE 8-36 Severe uncomplicated hypertension. The benefits of acute reduction in blood pressure in the setting of true hypertensive crises are obvious. Fortunately, true hypertensive crises are relatively rare events that almost never affect hypertensive patients. Another type of presentation that is much more common than are true hypertensive crises is that of the patient who initially exhibits severe hypertension (diastolic blood pressure >115 mm Hg) in the absence of hypertensive neuroretinopathy or acute end-organ damage that would signify a true crisis. This entity, known as severe uncomplicated hypertension, is very commonly seen in the emergency department or other acute-care settings. Of patients with severe uncomplicated hypertension, 60% are entirely asymptomatic and present for prescription refills or routine blood pressure checks, or are found to have elevated pressure during routine physical examinations. The other 40% of patients initially exhibit nonspecific findings such as headache, dizziness, or weakness in the absence of evidence of acute end-organ dysfunction. In the past, this entity was referred to as urgent hypertension, reflecting the erroneous notion that acute reduction of blood pressure, over a few hours before discharge from the acute-care facility, was essential to minimize the risk of short-term complications from severe hypertension. Commonly employed treatment regimens included oral clonidine loading or sublingual nifedipine. However, in recent years the practice of acute blood pressure reduction in severe uncomplicated hypertension has been questioned [55,56]. In the Veterans Administration Cooperative Study of patients with severe hypertension, there were 70 placebo-treated patients who had an average diastolic blood pressure of 121 mm Hg at entry. Among these untreated patients, 27 experienced morbid events at a mean of 11 ± 8 months of follow-up. However, the earliest morbid event occurred only after 2 months [57]. These data suggest that in patients with severe uncomplicated hypertension in which severe hypertension is not accompanied by evidence of malignant hypertension or acute end-organ dysfunction, eventual complications from stroke, myocardial infarction, or congestive

8.29

heart failure tend to occur over months to years, rather than hours to days. Although long-term control of blood pressure clearly can prevent these eventual complications, a hypertensive crisis cannot be diagnosed because no evidence exists that acute reduction of blood pressure results in an improvement in short- or long-term prognosis. Acute reduction of blood pressure in patients with severe uncomplicated hypertension with sublingual nifedipine or oral clonidine loading was once the de facto standard of care. This practice, however, often was an emotional response on the part of the treating physician to the dramatic elevation of blood pressure or motivated by the fear of medico-legal repercussions in the unlikely event of a hypertensive complication occurring within hours to days [55]. Although observing and documenting the dramatic decrease in blood pressure is a satisfying therapeutic maneuver, there is no scientific basis for this approach. At present, no literature exists to support the notion that some goal level of blood pressure reduction must be achieved before the patient with severe uncomplicated hypertension leaves the acute-care setting [58]. In fact, acute reduction of blood pressure often is counterproductive because it can produce untoward side effects that render the patient less likely to comply with long-term drug therapy. Instead, the therapeutic intervention should focus on tailoring an effective welltolerated maintenance antihypertensive regimen with patient education regarding the chronic nature of the disease process and the importance of long-term compliance and medical follow-up. If the patient has simply run out of medicines, reinstitution of the previously effective drug regimen should suffice. If the patient is thought to be compliant with an existing drug regimen, a sensible change in the regimen is appropriate, such as an increase in a suboptimal dosage of an existing drug or the addition of a drug of another class. In this regard, addition of a low dose of a thiazide diuretic as a second-step agent to existing monotherapy with converting enzyme inhibitor (CEI), angiotensin II receptor blocker, calcium channel blocker (CCB), -blocker, or central 2-agonist often is remarkably effective. Another essential goal of the acute intervention should be to arrange suitable outpatient follow-up within a few days. Gradual reduction of blood pressure to normotensive levels over the next few days to a week should be accomplished in conjunction with frequent outpatient visits to modify the drug regimen and reinforce the importance of lifelong compliance with therapy. Although less dramatic than acute reduction of blood pressure in the acute-care setting, this type of approach to the treatment of chronic hypertension is more likely to prevent long-term hypertensive complications and recurrent episodes of severe uncomplicated hypertension.

8.30

Hypertension and the Kidney

References 1. Nolan CR, Linas SL: Malignant hypertension and other hypertensive crises. In Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown; 1997:1475–1554. 2. Derow HA, et al.: The nature of malignant hypertension. Ann Intern Med 1941, 14:1768. 3. Perez-Fontan M, et al.: Idiopathic IgA nephropathy presenting as malignant hypertension. Am J Nephrol 1986, 6:482. 4. Holland NH, et al.: Hypertension in children with chronic pyelonephritis. Kidney Int 1975, 8(suppl):S234. 5. Nanra RS, et al.: Analgesic nephropathy: etiology, clinical syndrome, and clinicopathologic correlations in Australia. Kidney Int 1978, 13:79. 6. Davis BA, et al.: Prevalence of renovascular hypertension in patients with grade III or grade IV hypertensive neuroretinopathy. N Engl J Med 1979, 301:1273. 7. Lim K, et al.: Malignant hypertension in women of childbearing age and its relation to the contraceptive pill. Br Med J 1987, 294:1057. 8. Traub YM, et al.: Hypertension and renal failure (scleroderma renal crisis) in progressive systemic sclerosis. Medicine 1983, 62:335. 9. Cacoub P, et al.: Malignant hypertension with antiphospholipid syndrome without overt lupus nephritis. Clin Exp Rheumatol 1993, 11:479–485. 10. McAllister RG, et al.: Malignant hypertension: effect of therapy on renin and aldosterone. Circ Res 1971, 28(suppl II):II–160. 11. Keith NM, Wagener HP, Barker NW: Some different types of essential hypertension: their course and prognosis. Am J Med Sci 1939, 197:332. 12. Kirkendall WM: Retinal changes of hypertension. In The Eye in Systemic Disease. Edited by Mausolf FA. St Louis: Mosby; 1975:212–222. 13. Dollery CT: Hypertensive retinopathy. In Hypertension: Pathophysiology and Treatment. Edited by Genest O, Kuchel O, Hamet P. New York: McGraw-Hill; 1983:723–732. 14. McGregor E, Isles CG, Jay JL, et al.: Retinal changes in malignant hypertension. Br Med J 1986, 292:233–234. 15. Sinclair RA, Antonovych TT, Mostofi FL: Renal proliferative arteriopathies and associated glomerular changes: a light and electron microscopy study. Hum Pathol 1976, 7:565. 16. Pitcock JA, et al.: Malignant hypertension in blacks: malignant intrarenal arterial disease as observed by light and electron microscopy. Hum Pathol 1976, 7:33. 17. Jones DB: Arterial and glomerular lesions associated with severe hypertension. Lab Invest 1974, 31:303. 18. Mattern WD, Sommers SC, Kassiere JP: Oliguric acute renal failure in malignant hypertension. Am J Med 1972, 52:187. 19. Isles CG, McLay A, Boulton-Jones JM: Recovery in malignant hypertension presenting as acute renal failure. Q J Med 1984, 53:439. 20. Bacon BR, Ricanatie ES: Severe and prolonged renal insufficiency. Reversal in a patient wit malignant hypertension. JAMA 1978, 239:1159. 21. Shirley D, et al.: Clinical documentation of end-stage renal disease due to hypertension . Am J Kidney Dis 1994, 23:655. 22. Freedman BI, Iskander SS, Appel RG: The link between hypertension and nephrosclerosis. Am J Kidney Dis 1995, 25:207. 23. Rerneger TV, et al.: Diagnosis of hypertensive end-stage renal disease: effect of patient’s race. Am J Epidemiol 1995, 141:10. 24. Möhring J, et al.: Effects of saline drinking on the malignant course of renal hypertension in rats. Am J Physiol 1976, 230:849. 25. Gifford RW Jr, et al.: Hypertensive encephalopathy: mechanisms, clinical features, and treatment. Progr Cardiovasc Dis 1974, 17:115. 26. Dinsdale HB: Hypertensive encephalopathy. Neurol Clin 1983, 1:83. 27. Ziegler DK, et al.: Hypertensive encephalopathy. Arch Neurol 1965, 12:472. 28. Cohn JN, Rodriguera E, Guiha NH: Left ventricular function in hypertensive heart disease. In Hypertension Mechanisms and Management. Edited by Onesti O, Kim KE, Moyer JH. New York: Grune & Stratton; 1973:191–197. 29. Wheat MW Jr: Acute dissecting aneurysms of the aorta: diagnosis and treatment, 1979. Am Heart J 1980, 99:373. 30. DeSanctis RW, et al.: Aortic dissection. N Engl J Med 1987, 317:1060.

31. Goldman L, Caldera DL: Risks of general anesthesia and elective operation in the hypertensive patient. Anesthesiology 1979, 50:285. 32. Breslin DR, et al.: Elective surgery in hypertensive patients: preoperative considerations. Surg Clin North Am 1970, 50:585. 33. Prys-Roberts C: Hypertension and anesthesia: fifty years on. Anesthesiology 1979, 50:281. 34. Reichgott MJ: Hypertension in the perioperative patient. In Medical Care of the Surgical Patient: A Problem-Oriented Approach to Management. Edited by Goldman DR, Brown FH, Levy KW et al. Philadelphia: Lippincott; 1982:78–86. 35. Estafanous RG, Tarazi RC: Systemic arterial hypertension associated with cardiac surgery. Am J Cardiol 1980, 46:685. 36. Fouad FM, et al.: Hemodynamics of postmyocardial revascularization hypertension. Am J Cardiol 1978, 41:564. 37. Cohn JN: Paroxysmal hypertension and hypovolemia. N Engl J Med 1966, 275:643. 38. Skydell JL, et al.: Incidence and mechanism of post-carotid endarterectomy hypertension. Arch Surg 1987, 122:1153. 39. Towne JB, Bernhard VM: The relationship of postoperative hypertension to complications after carotid endarterectomy. Surgery 1980, 88:575. 40. Wallace JD, et al.: Blood pressure after stroke. JAMA 1981, 246:2177. 41. Britton M, et al.: Hazards of therapy for excessive hypertension in acute stroke. Acta Med Scand 1980, 207:253. 42. Lavin P: Management of hypertension in patients with acute stroke. Arch Intern Med 1986, 146:66. 43. Meyer JS, et al.: Impaired neurogenic cerebrovascular control and dysautoregulation after stroke. Stroke 1973, 4:169. 44. Cuneo RA, et al.: The neurologic complications of hypertension. Med Clin North Am 1977, 61:565. 45. Kaneko T, et al.: Lower limit of blood pressure in treatment of acute hypertensive intracranial hemorrhage. J Cerebral Blood Flow Metab 1983, 3(suppl 1):S51. 46. Shapiro B, Rig LM: Management of pheochromocytoma. Endocrinol Metab Clin North Am 1989, 18:443. 47. Pinaud M, et al.: Preoperative acute volume loading in patients with pheochromocytoma. Care Med 1985, 13:460. 48. Glazener RS, et al.: Pargyline, cheese, and acute hypertension. JAMA 1964, 188:754. 49. Blackwell B, et al.: Hypertensive interactions between monoamine oxidase inhibitors and foodstuffs. Br J Psychiatry 1967, 113:349. 50. Palmer RF, Lasseter KC: Sodium nitroprusside. N Engl J Med 1975, 292:294. 51. Gruetter CA, et al.: Relationship between cyclic guanosine 3’:5’ monophosphate formation and relaxation of coronary arterial smooth muscle by glyceryl trinitrate, nitroprusside, nitrite and nitric oxide. J Pharmacol Exp Ther 1981, 219:181. 52. Ignarro IJ, et al.: Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside, and nitric oxide. J Pharmacol Exp Ther 1981, 218:739. 53. Strandgaard S: Autoregulation of cerebral blood flow in hypertensive patients. Circulation 1976, 53:720. 54. Franklin SS: Hypertensive emergencies: the case for more rapid lowering of blood pressure. In Controversies in Nephrology and Hypertension. Edited by Narins RG. New York: Grune & Stratton; 1973:191–197. 55. Fagan TC: Acute reduction of blood pressure in asymptomatic patients with severe hypertension. An idea whose time has come–and gone. Arch Intern Med 1989, 149:2169. 56. Ferguson RK, Vlasses PH: Hypertensive emergencies and urgencies. JAMA 1986, 255:1607. 57. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension. Result in patients with diastolic blood pressure averaging 115 through 129 mm Hg. JAMA 1967, 202:1028. 58. Zeller KR, et al.: Rapid reduction of severe asymptomatic hypertension. Arch Intern Med 1989, 149:2186.

Diabetic Nephropathy: Impact of Comorbidity Eli A. Friedman

T

hroughout the industrialized world, diabetes mellitus is the leading cause of end-stage renal disease (ESRD), surpassing glomerulonephritis and hypertension. Both the incidence and the prevalence of ESRD caused by diabetes have risen each year over the past decade, according to reports from European, Japanese, and North American registries of patients with renal failure. Illustrating the dominance of diabetes in ESRD is the 1997 report of the United States Renal Data System (USRDS), which noted that of 257,266 patients receiving either dialytic therapy or a kidney transplant in 1995 in the United States, 80,667 had diabetes [1], a prevalence rate of 31.4%. Also, during 1995 (the most recent year for which summative data are available), of 71,875 new (incident) cases of ESRD, 28,740 (40%) patients were listed as having diabetes. In America, Europe, and Japan, the form of diabetes is predominantly type II; fewer than 8% of diabetic Americans are insulinopenic, C-peptide-negative persons with type I disease. It follows that ESRD in diabetic persons reflects the demographics of diabetes per se [2]: 1) The incidence is higher in women [3], blacks [4], Hispanics [5], and native Americans [6]. 2) The peak incidence of ESRD occurs from the fifth to the seventh decade. Consistent with these attack rates is the fact that blacks older than the age of 65 face a seven times greater risk of diabetes-related renal failure than do whites. Within our Brooklyn and New York state hospital ambulatory hemodialysis units in October 1997, 97% of patients had type II diabetes. Despite widespread thinking to the contrary, vasculopathic complications of diabetes, including hypertension, are at least as severe in type II as in type I diabetes [7,8]. When carefully followed over a decade or longer, cohorts of type I and type II diabetic individuals have equivalent rates of proteinuria, azotemia, and ultimately ESRD. Both types of diabetes show strong similarities in their rate of renal functional deterioration [9] and onset of comorbid complications. Initial nephromegaly as well as both glomerular hyperfiltration and microalbuminuria (previously thought to be limited to type I) is now recognized as equally in type II [10].

CHAPTER

1

1.2

Systemic Diseases and the Kidney

Overview and Prevalence DIABETIC NEPHROPATHY Epidemiology IDDM vs. NIDDM Natural history Intervention measures ESRD options Promising strategies

FIGURE 1-1 Diabetic neuropathy topics. People with diabetes and progressive kidney disease are more difficult to manage than age- and gender-matched nondiabetic persons because of extensive, often life-threatening extrarenal (comorbid) disease. Diabetic patients manifesting end-stage renal disease (ESRD) suffer a higher death rate than do nondiabetic patients with ESRD owing to greater incidence rates for cardiac decompensation, stroke, sepsis, and pulmonary disease. Concurrent extrarenal disease—especially blindness, limb amputations, and cardiac disease—limits and may preempt their rehabilitation. For most diabetic patients with ESRD, the difference between rehabilitation and heartbreaking invalidism hinges on attaining a renal transplant as well as comprehensive attention to comorbid conditions. Gradually, over a quarter century, understanding of the impact of diabetes on the kidney has followed elucidation of the epidemiology, clinical course, and options in therapy available for diabetic individuals who progress to ESRD. For each of the discussion points listed, improvement in patient outcome has been contingent on a simple counting (point prevalence) of the number of individuals under consideration. For example, previously the large number of diabetic patients with ESRD were excluded from therapy owing to the belief that no benefit would result. A reexamination of exactly why dialytic therapy or kidney transplantation failed in diabetes, however, was stimulated. IDDM—insulin dependent diabetes mellitus; NIDDM—non–insulin-dependent diabetes mellitus. FIGURE 1-2 Maintenance hemodialysis. In the United States, the large majority (more than 80%) of diabetic persons who develop end-stage renal disease (ESRD) will be treated with maintenance hemodialysis. Approximately 12% of diabetic persons with ESRD will be treated with peritoneal dialysis, while the remaining 8% will receive a kidney transplant. A typical hemodialysis regimen requires three weekly treatments lasting 4 to 5 hours each, during which extracorporeal blood flow must be maintained at 300 to 500 mL/min. Motivated patients trained to perform self-hemodialysis at home gain the longest survival and best rehabilitation afforded by any dialytic therapy for diabetic ESRD. When given hemodialysis at a facility, however, diabetic patients fare less well, receiving significantly less dialysis than nondiabetic patients, owing in part to hypotension and reduced blood flow [11]. Maintenance hemodialysis does not restore vigor to diabetic patients, as documented by Lowder and colleagues [12]. In 1986, they reported that of 232 diabetics on maintenance hemodialysis, only seven were employed, while 64.9% were unable to conduct routine daily activities without assistance [12]. Approximately 50% of diabetic patients begun on maintenance hemodialysis die within 2 years of their first dialysis session. Diabetic hemodialysis patients sustained more total, cardiac, septic, and cerebrovascular deaths than did nondiabetic patients. When initially applied to diabetic patients with ESRD in the 1970s, maintenance hemodialysis was associated with a first-year mortality in excess of 75%, with inexorable loss of vision in survivors. Until the at-first-unappreciated major contribution of type II diabetes to ESRD became evident, kidney failure was incorrectly viewed as predominantly limited to the last stages of type I (juvenile, insulin-dependent) diabetes. Illustrated here is a blind 30-year-old man undergoing maintenance hemodialysis after experiencing 20 years of type I diabetes. A diabetic renal-retinal syndrome of blindness and renal failure was thought to be inevitable until the salutary effect of reducing hypertensive blood pressure became evident. Without question, reduction of hypertensive blood pressure levels was the key step that permitted improvement in survival and reduction in morbidity.

Diabetic Nephropathy: Impact of Cormorbidity

FIGURE 1-3 Statistical increase in diabetes. In the past 20 years, since the diabetic patient with endstage renal disease (ESRD) is no longer excluded from dialytic therapy or kidney transplantation, there has been a steady increase in the proportion of all patients with ESRD who have diabetes. In the United States, according to the 1997 report of the United States Renal Data System (USRDS) for the year 1995, more than 40% of all newly treated (incident) patients with ESRD have diabetes. For perspective, the USRDS does not list the actual incidence of a renal disease but rather tabulates those individuals who have been enrolled in federally reimbursed renal programs. The distinction may be important in that a relaxation in policy for referral of diabetic kidney patients would be indistinguishable from a true increase in incidence.

Diabetes 40%

28,740

43,135 All other 60%

Prevalence of diabetes, %

25

Country of origin United States

20

18

15

5

PERCENTAGE OF PATIENTS WITH END-STAGE RENAL DISEASE WITH TYPE II DIABETES

23 19

18 16

15

15

14

10

7

Country Japan Germany United States Pima Indians

10

9

1.3

8

Percentage 99 90 95

5

4

0 Black Mexican Puerto Rican

Japanese Filipinos Chinese

Koreans

FIGURE 1-4 Prevalence of diabetes mellitus in minority populations. Attack rates (incidence) for diabetes are higher in nonwhite populations than in whites. Type II diabetes accounts for more than 90% of all patients with end-stage renal disease (ESRD) with diabetes. As studied by Carter and colleagues [13], the effect of improved nutrition on expression of diabetes is remarkable. The American diet not only induces an increase in body mass but also may more than double the expressed rate of diabetes, especially in Asians. (From Carter and coworkers [13]; with permission.)

Infrequent feeding

Insulin resistance

Overfeeding

Obesity

Fat in muscle NIDDM

FIGURE 1-6 Thrifty gene. In addition to the artificial increase in incident patients with end-stage renal disease (ESRD) and diabetes that followed relaxation of acceptance criteria, industrialized nations have experienced a real increase in type II diabetes that correlates with an increase in body mass attributed to overfeeding. Formerly

FIGURE 1-5 Percent of diabetic ESRD. Noted first in United States inner-city dialysis programs, type II diabetes is the predominant variety noted in those individuals undergoing maintenance hemodialysis. Our recent survey of hemodialysis units in Brooklyn, New York, found that 97% of the mainly African-American patients had type II diabetes. Thus, there has been a reversal of the previously held impression that uremia was primarily a late manifestation of type I diabetes. (From Ritz and Stefanski [14] and Nelson and coworkers [15]; with permission.)

termed non–insulin-dependent diabetes mellitus (NIDDM) or maturity-onset diabetes, the variety of diabetes observed in industrialized overfed populations is now classified as type II disease. According to the Thrifty Gene hypothesis, the ability to survive extended fasts in prehistoric populations that hunted to survive selected genes that in time of excess caloric intake are expressed as hyperglycemia, insulin resistance, and hyperlipidemia (type II diabetes). A study by Ravussin and colleagues of American and Mexican Pima Indian tribes illustrates the effect of overfeeding on a genetic predisposition to type II diabetes. Separated about 200 years ago, Indians with the same genetic makeup began living in different areas with different lifestyles and diets. In the Arizona branch of the Pimas, who were fed surplus food and restrained to a reservation that restricted hunting and other activities, the prevalence of type II diabetes progressively increased to 37% in women and 54% in men. In contrast, Pimas living in Mexico with shorter stature, lower body mass, and lower cholesterol had a lower prevalence of type II diabetes (11% in women and 6% in men). (From Shafrir [16] and Schalin-Jantti [17]; with permission.)

1.4

Systemic Diseases and the Kidney

Type I and Type II Classified Type II

Insulin requiring Type II decreased insulin secretion/sensitvity

C-PEPTIDE CRITERIA

Type I

Type I β-cell destruction

FIGURE 1-7 Type I and type II compared. Differentiating type I from type II diabetes may be difficult, especially in young nonobese adults with minimal insulin secretion. Furthermore, with increasing duration of type II diabetes, beta cells may decrease their insulin secretion, sometimes to the range diagnostic of type I diabetes. Shown here is a modification of the schema devised by Kuzuya and Matsuda [18] that suggests a continuum of diabetes classification based on amount of insulin secreted. Lacking in this construction is the realization of the genetic determination of type I diabetes (all?) and the clear hereditary predisposition (despite inconstant genetic analyses) of many individuals with type II diabetes. At present, classification of diabetes is pragmatic and will likely change with larger-population screening studies. IGT—impaired glucose tolerance. (From Kuzuya and Matsuda [18]; with permission.)

70 Proportion on insulin, %

IGT

60

60 50 40

33

30 20

Type I (90% concordence between clinical criteria and C-peptide testing) Basal C-peptide <0.17 pmol/mL Increment above basal at 6 min <0.07 pmol/mL

13

10 0 0–5

5–10 10–15 Years of NIDDM

FIGURE 1-8 Increasing insulin treatment in non–insulindependent diabetes mellitus (NIDDM). A decision to treat diabetes with insulin does not necessarily equate with establishing a diagnosis of type I diabetes. Terms such as “insulin-requiring” do not help because the need for insulin is physician-determined and will vary from clinician to clinician. After 10 to 15 years of metabolic regulation of type II diabetes, treatment with insulin has been initiated in more than half of individuals with this disorder. Even in patients with type II diabetes treated with insulin, measured secretion of insulin may fall in the normal range. (From Clauson and coworkers [19]; with permission.)

TERMINOLOGY IN DIABETIC NEPHROPATHY Hyperfiltration A supernormal glomerular filtration rate associated with hyperglycemia during the early years of diabetes Microalbuminuria Urinary albumin excretion of 30 to 300 mg/day or 20 to 200 g/min—a predictor of nephropathy Mesangial expansion An increase in mesangial matrix often but not always associated with basement membrane thickening

FIGURE 1-9 C-peptide criteria. Multiple strategies have been proposed to distinguish type I from type II diabetes. Each has limitations. Service and colleagues [20] employed baseline and stimulated C-peptide levels to differentiate between the two. They found satisfactory differentiation of type I from type II diabetes with minimal overlap using the screening levels shown. (From Service and coworkers [20]; with permission.)

FIGURE 1-10 Terminology. Clarification of the course of both types of diabetes was made possible by recognizing two functional perturbations: microalbuminuria and glomerular hyperfiltration. Additionally, early glomerular mesangial expansion was noted to be a constant finding in diabetic nephropathy.

Diabetic Nephropathy: Impact of Cormorbidity

1.5

Clinical Features of Diabetic Kidney FIGURE 1-11 Diabetic kidney characteristics. The diabetic kidney is about 140% greater in length, width, and weight. Morphologic findings on histologic examination of the kidney in diabetes include increased size of glomeruli and tubules. Physiologic assessment of renal function is supernormal in diabetes, as shown by increases of about 150% in renal plasma flow and glomerular filtration rate in initial phases of diabetic nephropathy. In the induced-diabetic rat and in limited observations of type I diabetes, establishing euglycemia will return enlarged kidneys and abnormal renal function test results to normal, suggesting that hyperglycemia is the cause of nephromegaly.

A

B FIGURE 1-12 Mesangial expansion. Expansion of the mesangium is depicted in light and electron microscopic views of a kidney biopsy specimen from a patient with type I diabetes with a urinary albumin concentration of 500 mg/dL. A, Electron microscopic view of a greatly expanded mesangium in a glomerulus is shown. B, Less advanced changes are seen on a silver stain. C, Progression to nodular intercapillary glomerulosclerosis is shown.

C

1.6

Systemic Diseases and the Kidney

A

B

C

D

FIGURE 1-13 Glomerular basement membrane thickening. B and D, Glomerular basement membrane thickening is a constant abnormality in diabetic nephropathy, as seen in these photomicrographs from a biopsy specimen in type I diabetes. Note the loss of epithelial foot processes in

panel B. In panel D, a mesangial nodule (MN) is present. A and C, Electron photomicrographs from a normal kidney. BM—basement membrane; C—capillary; E—epithelial cell; MN—mesangial nodule; M—mesangial cell.

FIGURE 1-14 Diabetic nephropathy is a microvasculopathy. Microaneurysms are visible in the retina and occasionally in glomerular capillaries. A microaneurysm in a biopsy specimen from a 42-year-old woman with type I diabetes is shown.

FIGURE 1-15 Key pathologic findings. Nondiabetic renal disorders (eg, amyloidosis, cryoglobulinemia, nephrosclerosis) may simulate the nodular and diffuse intercapillary glomerulosclerosis of diabetes (both type I and type II). When associated with afferent and efferent arteriolosclerosis, nodular and diffuse intercapillary glomerulosclerosis is pathognomonic for diabetic nephropathy. A—afferent artery arteriosclerosis; D—diffuse intercapillary glomerulosclerosis; E—efferent artery arteriosclerosis; N—nodular intercapillary glomerulosclerosis.

Diabetic Nephropathy: Impact of Cormorbidity

FIGURE 1-16 Diabetic nodules. Diabetic nodules are characterized by clear centers with cells along the periphery of the nodule, as shown here in a kidney biopsy specimen from a 44-year-old man with type II diabetes (hematoxylin and eosin stain).

1.7

FIGURE 1-17 Nodular size variability. Great variability in nodular size in diabetic nodular glomerulosclerosis is usual, as illustrated in this totally obliterated glomerulus obtained by biopsy from a 65-year-old woman with type II diabetes (periodic acid–Schiff stain).

>4 4.0

Urinary albumin, g/d

3.5 3.0 2.5 2.0 1.5

Clinical nephropathy

1.0 0.5 0 0

A

3

6

9

12 15 18 Hyperglycemia, y

21

24

27

FIGURE 1-18 A and B, Progression of nephropathy. Microalbuminuria, the excretion of minute quantities of albumin in the urine (more than 20 mg/day), is a marker of subsequent renal deterioration in diabetic nephropathy.

B Typically, proteinuria increases to the nephrotic range, leading to edema of the extremities and subsequent anasarca, which are often the presenting complaints in diabetic nephropathy.

1.8

Systemic Diseases and the Kidney

180

Type 2 diabetes Type 1 diabetes

10

160 140

Cumulative incidence chronic renal failure, %

GFR, mL/min

(13)

Clinical nephropathy

120 100 80 60 40

(69)

5

(205)

(447)

20

(1,377)

(1,832)

0

0 0

3

6

9

12

15

18

21

24

(112)

(75)

(49)

0

5

10

15

1

2

3

4

5 6 Time, y

25

30

35

FIGURE 1-20 Renal failure cumulative incidence. Before careful studies of the natural history of type II diabetes were reported, it was not appreciated that diabetic nephropathy was a real endpoint risk. Older diabetic individuals with a “touch of sugar” are now known to be subject to the same microvascular and macrovascular complications that afflict individuals with type I disease. Population studies indicate that the rate of loss of glomerular filtration is superimposable in type I and type II diabetes. Humphrey and colleagues [21] documented the development of end-stage renal disease in diabetic subjects in Rochester, Minnesota. They showed that chronic renal failure was as likely to develop at a superimposable rate in both diabetic subsets. Numbers in parentheses indicate number of patients for each line. (From Humphrey and coworkers [21]; with permission.)

Creatinine clearance, mL/min

Creatinine clearance, mL/min

Type I diabetic patients

0

20

Years from diagnosis of diabetes

FIGURE 1-19 Hyperfiltration. Almost immediately after the onset of hyperglycemia (signaling the onset of diabetes), glomerular filtration rate (GFR) increases to the limit of renal reserve function (hyperfiltration). Over subsequent years of hyperglycemia, a steady decline in glomerular filtration rate ensues in the 20% to 40% of diabetic individuals destined to manifest diabetic nephropathy. There is great variability in the rate of decline of GFR, from as rapid as 20 mL/min/year to 1 to 2 mL/min/year (usually seen in aging). Projection of future loss of GFR on the basis of the slope of the curve of prior decline in function contains errors as high as 37%. The importance of an inconstant and thus unpredictable decline in GFR lies in interpretation of interventive studies designed to protect kidney function. Careful attention to both selection of sufficient untreated controls and a “run-in” period is vital.

A

(30)

(812)

(136)

27

Hyperglycemia, y

130 120 110 100 90 80 70 60 50 40 30 20 10

(12)

7

8

9

10

Type II diabetic patients

0

11

FIGURE 1-21 Creatinine clearance. Further evidence of the similarity in course of diabetic nephropathy in type I (A) and type II (B) diabetes was presented in Ritz and Stefansky’s study [22] of equivalent deterioration

130 120 110 100 90 80 70 60 50 40 30 20 10

B

1

2

3

4

5 6 Time, y

7

8

9

10

11

in creatinine clearance over the course of a decade in subjects with either type of diabetes in Heidelberg, Germany. (From Ritz and Stefanski [22]; with permission.)

1.9

Diabetic Nephropathy: Impact of Cormorbidity

14 Hyperfiltration

>4

3.5

3.5 3.0

3.0 Clinical nephropathy

2.5

2.5 2.0

2.0 1.5

1.5

Clinical nephropathy

1.0

1.0

12

0.5

0.5 Microalbuminuria

0 0

3

6

9

12 15 18 Hyperglycemia, y

24

Doubling of base-line creatinine, %

Placebo P=0.007

20 15 Captopril

0 0.0 Placebo 202 Captopril 207

0.5

1.0

1.5

184 199

173 190

161 180

2.0 2.5 Follow-up, y 142 167

99 120

6 4 2 15

30

45

60

75

90

105 120

135

150 165

Creatinine clearance, mL/min

50

10 5

Window for conservative management

8

0

27

FIGURE 1-22 Diabetic nephropathy in types I and II. Whereas microalbuminuria and glomerular hyperfiltration are subtle pathophysiologic manifestations of early diabetic nephropathy, transformation to overt clinical diabetic nephropathy takes place over months to many years. In this figure, the curve for loss of glomerular filtration rate is plotted together with the curve for transition from microalbuminuria to gross proteinuria, affording a perspective of the course of diabetic nephropathy in both types of diabetes. While not all microalbuminuric individuals progress to proteinuria and azotemia, the majority are at risk for end-stage renal disease due to diabetic nephropathy. GFR—glomerular filtration rate.

45 40 35 30 25

10

0

0 21

Serum creatinine, mg/dL

4.0 Urinary albumin, g/d

GFR, mL/min

>4 4.0

3.0

3.5

4.0

75 82

45 50

22 24

FIGURE 1-23 Clinical recognition of diabetic nephropathy. The timing of renoprotective therapy in diabetes is a subject of current inquiry. Certainly, hypertension, poor metabolic regulation, and hyperlipidemia should be addressed in every diabetic individual at discovery. Discovery of microalbuminuria is by consensus reason to start treatment with an angiotensin-converting enzyme inhibitor in either type of diabetes, regardless of blood pressure elevation. As is true for other kidney disorders, however, nearly the entire course of renal injury in diabetes is clinically silent. Medical intervention during this “silent phase,” however (comprising blood pressure regulation, metabolic control, dietary protein restriction, and administration of angiotensin-converting enzyme inhibitors), is renoprotective, as judged by slowed loss of glomerular filtration. FIGURE 1-24 Renoprotection with enzyme inhibitors. Streptozotocin-induced diabetic rats manifest slower progression to proteinuria and azotemia when treated with angiotensin-converting enzyme inhibitors than with other antihypertensive drugs. The consensus supports the view that angiotensin-converting enzyme inhibitors afford a greater level of renoprotection in diabetes than do other classes of antihypertensive drugs. Large long-term direct comparisons of antihypertensive drug regimens in type II diabetes are now in progress. In the study shown here by Lewis and colleagues [23], treatment with captopril delayed the doubling of serum creatinine concentration in proteinuric type I diabetic patients. Trials of different angiotensin-converting enzyme inhibitors in both types of diabetes confirm their effectiveness but not their unique renoprotective properties in humans. For patients who cannot tolerate angiotensin-converting enzyme inhibitors because of cough, hyperkalemia, azotemia, or other side effects, substitution of an angiotensin-converting enzyme receptor blocker (losartan) may be renoprotective, although clinical trials of its use in diabetes are uncompleted. (From Lewis and coworkers [23]; with permission.)

1.10

Systemic Diseases and the Kidney

Microalbuminuric

Normoalbuminuric

10

70

AER, µg/min

50 6

40

4

30

AER, µg/min

60

8

20 2

Lisinopril

0 n n

10

Placebo

0 6

0

12 18 24 0 6 12 Time from randomization, m

227 202 201 179 213 196 179 170

120

193 34 191 45

33 37

29 34

18

24

25 32

32 37

FIGURE 1-26 Restricting protein. Dietary protein restriction in limited trials in small patient cohorts has slowed renal functional decline in type I diabetes. Because long-term compliance is difficult to attain, the place of restricted protein intake as a component of management is not defined. A, Normal diet. B, Protein-restricted diet. Dashed line indicates trend line slope. (From Zeller and colleagues [25]; with permission.)

Normal diet

Glomerular filtration rate, mL/min/1.73 m2

100 80 60 40 20 0 0

10

20

A

30

40

50

40

50

Time, mo 120

Protein-restricted diet

Glomerular filtration rate, mL/min/1.73 m2

100 80 60 40 20 0 0

B

FIGURE 1-25 Albumin excretion rate. In the recently completed Italian Euclid multicenter study, both microalbuminuric and normalbuminuric type I diabetic patients showed benefit from treatment with lisinopril, an angiotensin-converting enzyme inhibitor. Although microalbuminuria, with or without hypertension, is now sufficient reason to start treatment with an angiotensin-converting enzyme inhibitor, the question of whether normalbuminuric, normotensive diabetic individuals should be started on drug therapy is unanswered. AER—albumin excretion rate. (From Euclid study [24]; with permission.)

10

20

30 Time, mo

1.11

Diabetic Nephropathy: Impact of Cormorbidity

125

80

Rate of change in AER, % /year

Rate of change in AER, % /year

100

75

50

25

0

60

40

20

0 0

A

10

12

14

6

8

10

B

Mean Hb A1, %

FIGURE 1-27 Metabolic regulation studies. Multiple studies of the strict metabolic regulation of type I and type II diabetes all indicate that reduction of hyperglycemic levels to near normal slows the rate of renal functional deterioration. In this study, the albumin excretion rate (AER)— another way of expressing albuminuria—correlates directly with

Function

Pathology

Hyperfiltration

Mesangial expansion

Microalbuminuria

12

14

Mean Hb A1, %

hyperglycemia, as indicated by hemoglobin A1 (Hb A1) levels in both type I (A) and type II (B) diabetes. As for other studies using different markers, the courses of both types of diabetes over time were found to be equivalent. (From Gilbert and coworkers [26]; with permission.) FIGURE 1-28 Stages of nephropathy. The interrelationships between functional and morphologic markers of the stages of diabetic nephropathy are shown. Additional pathologic studies are needed to time with precision exactly when glomerular basement membrane (GBM) thickening and glomerular mesangial expansion take place. ESRD—endstage renal disease.

GBM thickening

Proteinuria

Glomerulosclerosis

ESRD

DIABETIC NEPHROPATHY: COMPLICATIONS Rate of GFR Loss Course of proteinuria Nephropathology Comorbidity Progression to ESRD

FIGURE 1-29 Type I and II nephropathic equivalence. A summation about the equivalence of type I and type II diabetes in terms of nephropathy is listed. Both types have similar complications. ESRD—endstage renal disease; GFR—glomerular filtration rate.

Hyperglycemia Normotension Euglycemia Protein restriction

Glomerulosclerosis

FIGURE 1-30 Major therapeutic maneuvers to slow loss of glomerular filtration rate are shown. Recent recognition of the adverse effect of hyperlipidemia is reason to include dietary and, if necessary, drug treatment for elevated blood lipid levels.

1.12

Systemic Diseases and the Kidney

PROGRESSION OF COMORBIDITY IN TYPE II DIABETES* Complication Retinopathy Cardiovascular Cerebrovascular Peripheral vascular

Initial, %

Subsequent, %

50 45 30 15

100 90 70 50

COMORBIDITY INDEX Persistent angina or myocardial infarction Other cardiovascular problems Respiratory disease Autonomic neuropathy Musculoskeletal disorders Infections including AIDS Liver and pancreatic disease Hematologic problems Spinal abnormalities Vision impairment Limb amputation Mental or emotional illness

*Creatinine clearance declined from 81 mL/min over 74 (40—119) mo. Endpoint: dialysis or death.

FIGURE 1-31 Comorbidity in type II. In both type I and type II diabetes, comorbidity, meaning extrarenal disease, makes every stage of progressive nephropathy more difficult to manage. In the long-term observational study in type II diabetes done by Bisenbach and Zazgornik [27], the striking impact of eye, heart, and peripheral vascular disease was noted in a cohort over 74 months. (From Bisenbach and Zazgornik [27]; with permission.)

A

Score 0 to 3: 0 = absent; 1 = mild; 2 = moderate; 3 = severe. Total = Index.

FIGURE 1-32 Comorbidity index. We devised a Comorbidity Index to facilitate initial and subsequent evaluations of patients over the course of interventive studies. Each of 12 areas is rated as having no disease (0) to severe disease (3). The total score represents overall illness and can be both reproduced by other observers and followed for years to document improvement or deterioration.

B

FIGURE 1-34 Heart disease and renal transplants. A, Pretransplantation. B, Five years after kidney transplation. Experienced clinicians managing renal failure in diabetes rapidly reach the conclusion that quality of life following successful kidney transplantation is far superior to that attained during any form of dialytic therapy. In the most favorable series, as illustrated by a singlecenter retrospective review of all kidney transplants performed between 1987 and 1993, there is no significant difference in actuarial 5-year patient or kidney graft survival between diabetic and nondiabetic recipients overall or when analyzed by donor source. It is equally encouraging that no difference in mean serum creatinine levels at 5 years was noted between diabetic and nondiabetic recipients [28]. Remarkably superior survival following kidney transplantation compared with survival after peritoneal dialysis and hemodialysis is documented in the 1997

HEART DISEASE Hyperlipidemia Hypertension Volume overload ACE inhibitor Erythropoietin

FIGURE 1-33 Heart disease. Heart disease is the leading cause of morbidity and death in both type I and type II diabetes. Throughout the course of diabetic nephropathy, periodic screening for cardiac integrity is appropriate. We have elicited symptomatic improvement in angina and work tolerance by using erythropoietin to increase anemic hemoglobin levels. ACE—angiotensin-converting enzyme.

report of the United States Renal Data System (USRDS) [1]. Fewer than five in 100 diabetic patients with end-stage renal disease (ESRD) treated with dialysis will survive 10 years, while cadaver donor and living donor kidney allograft recipients fare far better. Rehabilitation of diabetic patients with ESRD is incomparably better following renal transplantation compared with dialytic therapy. The enhanced quality of life permitted by a kidney transplant is the reason to prefer this option for newly evaluated diabetic persons with ESRD who are younger than the age of 60. More than half of diabetic recipients of a kidney transplant in most series live at least 3 years: many survivors return to occupational, school, and home responsibilities. Failure to continue monitoring of cardiac integrity may have disastrous results, as in this relatively young type I diabetic recipient of a cadaver renal allograft for diabetic nephropathy Although her allograft maintained good function, coronary artery disease progressed silently until a myocardial infarction occurred We now perform annual cardiac testing in all diabetic patients who have ESRD and are receiving any form of treatment.

Diabetic Nephropathy: Impact of Cormorbidity

RETINOPATHY Hyperglycemia Hypertension Volume overload Photocoagulation Erythropoietin

1.13

FIGURE 1-35 Retinopathy. Blindness due to the hemorrhagic and fibrotic changes of diabetic retinopathy is the most dreaded extrarenal complication feared by diabetic kidney patients. The pathogenesis of proliferative retinopathy reflects release by retinal and choroidal cells of growth (angiogenic) factors triggered by hypoxemia, which is caused by diminished blood flow. The interrelationship among hyperglycemia, hypertension, hypoxemia, and angiogenic factors is now being defined. There is reason to hope that specifically designed interdictive measures may halt progression of loss of sight.

FIGURE 1-36 Retinopathic changes. Proliferative retinopathy, microcapillary aneurysms, and dot plus blot hemorrhages are present in this funduscopic photograph taken at the time of initial renal evaluation of a nephrotic 37-year-old woman with type I diabetes. After prescription of a diuretic regimen, immediate consultation with a laser-skilled ophthalmologist was arranged.

A FIGURE 1-37 Panretinal photocoagulation (PRP). A, PRP is the therapeutic technique performed for proliferative retinopathy using an argon laser to deliver approximately 1500 discrete retinal burns, avoiding the fovea and disk (IA
B of proliferative retinopathy were attained with PRP, as shown in this fundus, photographed 6 weeks after the one shown in panel A. Vision stabilized, and sight has been retained through the past 6 years of observation. If applied before retinal traction and detachment supervene, PRP is effective in preserving sight in more than 90% of diabetic patients undergoing dialytic therapy or kidney transplantation.

1.14

AMPUTATION Inspection Shoes Socks Nails Prompt treatment

Systemic Diseases and the Kidney FIGURE 1-38 Amputation. After blindness, no comorbid complication limits rehabilitation in diabetic kidney patients more than lower limb amputation. A combination of macrovascular and microvascular disease in the limb, loss of pain perception due to sensory nephropathy, and impaired resistance to infection converts any minor insult to the foot into a major threat to the limb and life. Previously regarded as unavoidable in as many as 30% of patients with end-stage renal disease treated with dialysis or kidney transplantation, programs that emphasize prophylactic foot care as a component of preventive medicine have reduced the incidence of limb amputation to about 5% after 3 years.

B

A

FIGURE 1-40 Charcot’s joint. Diabetic neuropathy may involve the proprioceptive nerves, removing limitation of joint stretching and resulting in bone shifts and joint destruction, as seen in the Charcot’s joint shown here. An insensitive deformed foot with a compromised blood supply is at risk of ulceration, with slow or absent healing after minor trauma.

FIGURE 1-39 Genesis of foot problems. The genesis of diabetic foot problems includes peripheral neuropathy, peripheral vascular disease, impaired vision (nail cutting), edema (heart and kidney), and slow wound healing. A, Note the demarcated hair line indicative of peripheral vascular insufficiency. B, The foot radiograph shows a Charcot’s joint. (From Shaw and Boulton [29]; with permission.)

FIGURE 1-41 Ulcers. A collaborating podiatrist stationed within the renal clinic adds a level of protection for diabetic kidney patients. Common lesions, like this pressure ulcer overlying the head of the first metatarsal, are managed easily with shoe pads that shift weightbearing. The recent introduction of genetically engineered human skin holds promise for closing formerly unhealable diabetic foot ulcers.

Diabetic Nephropathy: Impact of Cormorbidity

CLINICAL STRATEGY Main Collaborators

Consultants

Opththalmologist Podiatrist Cardiologist Nutritionist Nurse educator

Neurologist Vascular surgeon Endocrinologist Gastroenterologist Urologist

FIGURE 1-42 Team management of neuropathy. Proper management of diabetic kidney patients requires a skilled team including collaborating specialists. Depending on the qualifications of the patient’s primary physician, other professionals are recruited as needed. A nurse educator can ease the interface between otherwise independent specialists. Without such a team mentality, the diabetic patient is often set adrift, forced to cope with conflicting instructions and unneeded repetition of tests. Especially helpful as renal function declines toward end-stage renal disease, patient education facilitates the choice of uremia therapy and, if appropriate, interaction with the renal transplant service.

NEPHROTIC SYNDROME Precedes renal failure May arrest or revert (15±%) Confused with cardiac failure Intensifies risk to feet Management: ACEi + metolazone + furosemide

ANASARCA Hypoproteinemia (renal loss, liver disease) Glycated albumin (more permeable) Heart failure (coronary disease) Management includes Daily weight Metolazone + furosemide Cardiac compensation

AUTONOMIC NEUROPATHY Cardiovascular (rate, QT, R-R) Orthostatic hypotension Gastroparesis Cystopathy Diarrhea, obstipation

FIGURE 1-43 Autonomic neuropathy. Autonomic neuropathy accompanies advanced diabetic nephropathy. While an unvarying R-R interval may have minimal clinical importance, diabetic cystopathy and reduced bowel motility, including gastroparesis, may seriously impede quality of life. Questioning to discern the presence of travel-limiting diarrhea, obstipation, and gastroparesis should be included in each initial evaluation of a diabetic kidney patient. (From Spallone and Menzinger [30]; with permission.)

1.15

GASTROPARESIS IN DIABETIC NEPHROPATHY Prevalent in majority, often silent Correlates with autonomic neuropathy Symptoms not linked to delayed emptying Management includes Prokinetic agents: cisapride, erythromycin, metoclopramide, domperidone Serotoninergic (5-HT-3) antagonists

FIGURE 1-44 Gastroparesis. Incomplete and inconstant gastric emptying due to diabetic autonomic neuropathy (gastroparesis) may preempt good glucose regulation because of an inability to match insulin dosing with food ingestion. The diagnosis can be established by having the patient ingest a test meal with a radioisotope tracer. Satisfactory drug treatment for gastroparesis is usually able to minimize the problem. (From Enck and Frieling [31] and Savkan and coworkers [32]; with permission.)

FIGURE 1-45 Nephrotic syndrome. Proteinuria in diabetic nephropathy typically progresses more than 3.5 g/day (nephrotic range), leading to hypoproteinemia, hyperlipidemia, and extracellular fluid accumulation (nephrotic syndrome). Management of a nephrotic diabetic patient includes minimizing protein loss using an angiotensin-converting enzyme inhibitor (ACEi) and promoting diuresis with a combination of loop diuretics (furosemide) and thiazide diuretics (metolazone). Distinction between congestive heart failure and nephrotic edema requires assessment of cardiac function. (From Herbert et at. [33] and Gault and Fernandez [34]; with permission.)

FIGURE 1-46 Anasarca. Anasarca is a long-term management problem in diabetic nephropathy. As renal reserve decreases, the balance between volume overload and excessive diuresis may be difficult to maintain. Having the patient measure and record weight daily as a guide for each day’s dose of diuretics (metolazone plus furosemide) is a workable strategy. Once the creatinine clearance falls below 10 mL/min, ambulatory dialysis may be the only means of continuing life outside the hospital.

1.16

Systemic Diseases and the Kidney

0

90

30

5 10

s tic be D ia

15

5

Creatinine clearance, mL/min 75

45

60

FIGURE 1-47 Uremia therapy, conservative management. Although enthusiastically favored in Canada and Mexico, in the United States peritoneal dialysis sustains the life of only about 12% of diabetic patients with end-stage renal disease (ESRD) [1]. Continuous ambulatory

PLANNING FOR ESRD Expose patient to treatment options Establish vascular or peritoneal access Encourage intrafamilial kidney donation Schedule visit with transplant surgeon Monitor creatinine, general well being Err on side of early dialysis start

Nondiabetic

peritoneal dialysis (CAPD) affords the advantages of freedom from a machine, ability to be performed at home, rapid training, minimal cardiovascular stress, and avoidance of heparin [35]. Some enthusiasts believe CAPD to be “a first choice treatment” for diabetic patients with ESRD [36]. Consistent with the author’s view, however, is the report of Rubin and colleagues [37]. They found that in a largely black diabetic population, only 34% of patients continued CAPD after 2 years, and at 3 years, only 18% remained on CAPD. In fairness, comparisons of either mortality or comorbidity in patients receiving hemodialysis versus peritoneal dialysis suffer from the limitations of starting with unequal cohorts reflecting selection bias. Data subsets from the United States Renal Data System (USRDS) report for 1997 [1] show that in diabetic patients, all cohorts have a higher risk of death with CAPD than with hemodialysis. Furthermore, patients receiving peritoneal dialysis in the United States have a 14% greater risk of hospitalization than do patients undergoing hemodialysis [38]. Benefits of peritoneal dialysis, including freedom from a machine and electrical outlets and ease of travel, stand against the disadvantages of unremitting attention to fluid exchange, constant risk of peritonitis, and disappearing exchange surface. There are no absolute criteria for abandoning conservative management in favor of initiating maintenance hemodialysis or peritoneal dialysis. As a generalization, diabetic individuals with progressive renal disease decompensate with uremic symptoms earlier than nondiabetic individuals. A decision to start dialysis is usually the culmination of unsuccessful efforts to regain compensation after episodic dyspnea due to volume overload or nausea and a reversed sleep pattern characteristic of renal failure. Sometimes, both physician and patient appreciate that lassitude and decreasing activity in a catabolic patient signal the need to begin dialysis. FIGURE 1-48 Treatment for end-stage renal disease (ESRD). Ideally, treatment for ESRD should be selected without stress or urgency on the basis of prior thought and planning. Discussions with representatives of patient self-help groups, such as the American Association of Kidney Patients, and institutional transplant coordinators aid in communicating the information required by patients to enable them to select from available options for uremia therapy.

Diabetic 40–64 y

51.5% Center hemo

71.5% Center hemo Transplant 13.0%

Transplant 36.3%

Center hemo Home hemo CAPD CCPD Transplant

FIGURE 1-49 Management with dialysis. As tabulated in the 1997 report of the United States Renal Data System [1], diabetic patients with end-stage renal disease (ESRD) are less likely than nondiabetic patients with ESRD to receive a kidney transplant and are most often managed with maintenance hemodialysis (center hemo). A greater proportion of diabetic patients with ESRD are managed with continuous ambulatory peritoneal dialysis (CAPD) or machine-based continuous cyclic peritoneal dialysis (CCPD) than are nondiabetic patients with ESRD.

1.17

Diabetic Nephropathy: Impact of Cormorbidity

Nondiabetic transplant Nondiabetic dialysis

26.2

100

Diabetic transplant Diabetic dialysis

100 94.9 91.2

80 Surviving, %

24.1 205.4

90.3 84.3 75.3

76.3

60

64.7

57.9

36.9

40

26.5

279.9

20.1

20 0

50

100

150

200

250

300

3.9

0 0

Deaths per 1000 Patient Years

1

2

5

10

Time after initiatling treatment, y

FIGURE 1-50 Survival rates of diabetics and nondiabetics. As tabulated in the 1997 report of the United States Renal Data System [1], there are sharp differences in survival between diabetic and nondiabetic patients with end-stage renal disease (ESRD) as well as between treatment by dialysis versus kidney transplantation. The highest death rate is suffered by diabetic dialysis patients (combined peritoneal dialysis and hemodialysis), while the best survival is experienced by nondiabetic renal transplant recipients. Selection bias in choosing more fit ESRD patients for kidney transplantation while leaving a residual pool of sicker patients for dialysis accounts for some of the difference in mortality. Other variables, especially extrarenal comorbidity, are probably more important in defining the less favorable course in diabetes.

FIGURE 1-51 Survival rates of diabetic ESRD patients. After a decade of treatment, the remarkable superiority of renal transplantation over dialysis (combined peritoneal dialysis and hemodialysis, lower curve) is starkly evident in these survival curves drawn from the 1997 report of the United States Renal Data System [1]. Fewer than 1 in 20 diabetic patients with end-stage renal disease (ESRD) treated with any form of dialysis will live a decade. In contrast, kidney transplantation from a living donor (upper curve) or a cadaver donor (middle curve) permits substantive cohorts to survive.

42.4

Deaths per 1000 Patient Years

USRDS 1996 Ages 45–64

Transplant Hemodialysis Peritoneal dialysis

40 30.9 30 21.5

19

20 15.1

14.5

10

8.7

7.5 7.5

6.3 2.4 1.4

6.8

4.5

3.7

2.0

1.8

0.4

1.6

0 MI Nondiab

MI Diab

CVA Nondiab

CVA Diab

FIGURE 1-52 Comorbidity in ESRD. Death of diabetic patients with end-stage renal disease (ESRD) relates to comorbidity, as shown in this table abstracted from the 1997 report of the United States Renal Data System (USRDS) [1]. Representative subsets of patients with ESRD with and without diabetes treated by peritoneal dialysis, hemodialysis, or renal transplantation are shown. Note that for each comorbid

Cancer Nondiab

Cancer Diab

3.0 1.6

0.1 +]

[K Nondiab

4.0

0.1 [K+] Diab

cause of death, rates are higher in patients receiving peritoneal dialysis than in those receiving hemodialysis and are lowest in renal transplant recipients. For undetermined reasons, deaths due to cancer are less frequent in diabetic than in nondiabetic patients with ESRD. CVA—cerebrovascular accident; Diab—diabetes; K+—potassium; MI—myocardial infarction.

Systemic Diseases and the Kidney

COMPLICATIONS IN PATIENTS RECEIVING HEMODIALYSIS Inadequate vascular access “Steal,” thrombosis/infection Interdialytic hypotension Progressive eye disease Progressive vascular disease Minimal rehabilitation

COMPLICATIONS IN PATIENTS RECEIVING PERITONEAL DIALYSIS Peritonitis “Tunnel” infection Abdominal/back pain Retinopathy Progressive vascular disease Minimal rehabilitation

FIGURE 1-53 Complications prevalent in diabetic hemodialysis patients.

FIGURE 1-54 Complications prevalent in diabetic peritoneal dialysis patients.

Infections: bacterial (AFB), fungal viral (CMV); genitourinary, lung, skin, wound Cancer: skin, lymphoma, solid organ Drug induced: gout, cataracts Allograft rejection: acute/chronic Recurrent diabetic nephropathy Progressive eye, vascular disease

FIGURE 1-55 Frequent complications reported in diabetic kidney transplant recipients. AFB—acid fast bacteria; CMV—cytomegalovirus.

Rehabilitation 100

OPTIONS IN DIABETES WITH ESRD

First-year survival Survival >10 y Diabetic complications Rehabilitation Patient acceptance

COMPLICATIONS IN PATIENTS UNDERGOING KIDNEY TRANSPLANTATION

CAPD/CCPD

Hemodialysis

Transplantation

75% <5% Progress Poor Fair

75% <5% Progress Poor Fair

>90% >25% Slow progression Fair to excellent Good to excellent

FIGURE 1-56 Options in diabetes with ESRD. Comparing outcomes of various options for uremia therapy in diabetic patients with end-stage renal disease (ESRD) is flawed by the differing criteria for selection for each treatment. Thus, if younger, healthier subjects are offered kidney transplantation, then subsequent relative survival analysis will be adversely affected for the residual pool treated by peritoneal dialysis or hemodialysis. Allowing for this caveat, the table depicts usual outcomes and relative rehabilitation results for continuous ambulatory peritoneal dialysis (CAPD), continuous cyclic peritoneal dialysis (CCPD), hemodialysis, and transplantation.

Kidney transplant Karnofsky score

1.18

Hemodialysis 50

Peritoneal dialysis

Withdrawal 0

Death

FIGURE 1-57 Karnofsky scores in rehabilitation. Graphic depiction of rehabilitation in diabetic patients with end-stage renal disease (ESRD) as judged by Karnofsky scores. Few diabetic patients receiving hemodialysis or peritoneal dialysis muster the strength to resume fulltime employment or other gainful activities. Originally devised for use by oncologists, the Karnofsky score is a reproducible, simple means of evaluating chronic illness from any cause. A score below 60 indicates marginal function and failed rehabilitation.

Diabetic Nephropathy: Impact of Cormorbidity

1.19

FIGURE 1-58 Complications of the hemodialysis regimen are more frequent in diabetic than in nondiabetic patients. A, Axillary vein occlusion proximal to an arteriovenous graft used for dialysis access is shown. B, Balloon angioplasty proffers only temporary respite owing to a high rate (70% in 6 months) of restenosis in diabetic patients. The value of an intraluminal stent prosthesis is being studied.

A

B

76.2 75

USRDS 1996 PD + Hemo

74

Surviving, %

72.6

74.4

LIFE PLAN FOR DIABETIC NEPHROPATHY

73.1 Explore and endorse treatment goals Enlist patient as key team member Prepare patient for probable course Prioritize ESRD options

70.9 70 68.9 67.7 65.9

66.2

66.4

65 1983

1984 1985

1986

1987

1988 1989

1990

1991

1992

1993

FIGURE 1-59 Improving one year survival with dialysis. The summative effect of multiple incremental improvements in management of diabetic patients with end-stage renal disease (ESRD) is reflected in a continuing increase in survival. Shown here, abstracted from the 1977 report of the United States Renal Data System (USRDS), is the increasing first-year survival rates for hemodialysis (hemo) plus peritoneal dialysis (PD) patients with diabetes.

FIGURE 1-60 Life plan. Given the concurrent involvement of multiple consultants in the care of diabetic individuals with end-stage renal disease (ESRD), there is a need for a defined strategy, here termed a “Life Plan.” Switching from hemodialysis to peritoneal dialysis (or the reverse) and deciding on a midcourse kidney transplant are common occurrences that ought not to provoke anxiety or stress. Reappraisal and reconstruction of the Life Plan should be performed by patient and physician at least annually.

1.20

Systemic Diseases and the Kidney

References 1. United States Renal Data System: USRDS 1997 Annual Data Report. Bethesda, MD: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; April, 1997. 2. Zimmet PZ: Challenges in diabetes epidemiology—from West to the rest (Kelly West Lecture 1991). Diabetes Care 1992, 15:232–252. 3. Harris M, Hadden WC, Knowles WC, and colleagues: Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in U.S. population aged 20-74 yr. Diabetes 1987, 36:523–534. 4. Stephens GW, Gillaspy JA, Clyne D, and colleagues: Racial differences in the incidence of end-stage renal disease in types I and II diabetes mellitus. Am J Kidney Dis 1990, 15:562–567. 5. Haffner SM, Hazuda HP, Stern MP, and colleagues: Effects of socioeconomic status on hyperglycemia and retinopathy levels in Mexican Americans with NIDDM. Diabetes Care 1989, 12:128–134. 6. National Diabetes Data Group: Diabetes in America. Bethesda, MD: NIH Publication No. 85-1468; August, 1985. 7. Mauer SM, Chavers BM: A comparison of kidney disease in type I and type II diabetes. Adv Exp Med Biol 1985, 189:299–303. 8. Melton LJ, Palumbo PJ, Chu CP: Incidence of diabetes mellitus by clinical type. Diabetes Care 1983, 6:75–86. 9. Biesenback G, Janko O, Zazgornik J: Similar rate of progression in the predialysis phase in type I and type II diabetes mellitus. Nephrol Dial Transplant 1994, 9:1097–1102. 10. Wirta O, Pasternack A, Laippala P, Turjanmaa V: Glomerular filtration rate and kidney size after six years disease duration in noninsulin-dependent diabetic subjects. Clin Nephrol 1996, 45:10–17. 11. Cheigh J, Raghavan J, Sullivan J, and colleagues: Is insufficient dialysis a cause for high morbidity in diabetic patients [abstract]? J Am Soc Nephrol 1991, 317. 12. Lowder GM, Perri NA, Friedman EA: Demographics, diabetes type, and degree of rehabilitation in diabetic patients on maintenance hemodialysis in Brooklyn. J Diabet Complications 1988, 2:218–226. 13. Carter JS, et al.: Non-insulin-dependent diabetes mellitus in minorities in the United States. Ann Intern Med 1996, 125:221–232. 14. Ritz E, Stefanski A: Diabetic nephropathy in type II diabetes. Am J Kidney Dis 1996, 27:167–194. 15. Nelson RG, Pettitt DJ, Carraher MJ, et al.: Effect of proteinuria on mortality in NIDDM. Diabetes 1988, 37:1499–1504. 16. Shafrir E: Development and consequences of insulin resistance: lessons from animals with hyperinsulinemia. Diabetes Metab 1996, 22:122–131. 17. Schalin-Jantii C, et al.: Polymorphism of the glycogen synthase gene in hypertensive and normotensive subjects. Hypertension 1996, 27:67–71. 18. Kuzuya T, Matsuda A: Classification of diabetes on the basis of etiologies versus degree of insulin deficiency. Diabetes Care 1997, 20:219–220. 19. Clausson P, Linnarsson R, Gottsater A, et al.: Relationships between diabetes duration, metabolic control and beta-cell function in a representative population of type 2 diabetic patients in Sweden. Diabet Med 1994, 11:794–801. 20. Service FJ, Rizza RA, Zimmerman BR, et al.: The classification of diabetes by clinical and C-peptide criteria: a prospective populationbased study. Diabetes Care 1997, 20:198–201.

21. Humphrey LL, et al.: Chronic renal failure in non-insulin-dependent diabetes mellitus: a population-based study in Rochester, Minnesota. Ann Intern Med 1989, 111:788–796. 22. Ritz E, Stefanski A: Diabetic nephropathy in type II diabetes. Am J Kidney Dis 1996, 27:167–194. 23. Lewis EJ, et al.: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy: the Collaborative Study Group. N Engl J Med 1993, 329:1456–1462. 24. The Euclid Study Group: Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Lancet 1997, 349:1787–1792. 25. Zeller K, et al.: Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus. N Engl J Med 1991, 324:78–84. 26. Gilbert RE, Tsalamandris C, Bach LA, et al.: Long-term glycemic control and the rate of progression of early diabetic kidney disease. Kidney Int 1993, 44:855–859. 27. Biesenbach G, Zazgornik J: High mortality and poor quality of life during predialysis period in type II diabetic patients with diabetic nephropathy. Ren Fail 1994, 16:263–272. 28. Shaffer D, Simpson MA, Madras PN, et al.: Kidney transplantation in diabetic patients using cyclosporine. Five-year follow-up. Arch Surg 1995, 130:287–288. 29. Shaw JE, Boulton AJ: The pathogenesis of diabetic foot problems: an overview. Diabetes 1997, 46 (suppl 2): S58–S61. 30 Spallone V, Menzinger G: Diagnosis of cardiovascular autonomic neuropathy in diabetes. Diabetes 1997, 46 (suppl 2):S67–S76. 31. Enck P, Frieling T: Pathophysiology of diabetic gastroparesis. Diabetes 1997, 46 (suppl 2):S77–S81. 32. Soykan I, et al.: The effect of chronic oral domperidone therapy on gastrointestinal symptoms, gastric emptying, and quality of life in patients with gastroparesis. Am J Gastroenterol 1997, 92:976–980. 33. Hebert LA, Bain RP, Verme D, Cattran Det al.: Remission of nephrotic range proteinuria in type I diabetes: Collaborative Study Group. Kidney Int 1994, 46:1688–1693. 34. Gault MH, Fernandez D: Stable renal function in insulin-dependent diabetes mellitus 10 years after nephrotic range proteinuria. Nephron 1996, 72:86–92. 35. Lindblad AS, Nolph KD, Novak JW, Friedman EA: A survey of the NIH CAPD Registry population with end-stage renal disease attributed to diabetic nephropathy. J Diabet Complications 1988, 2:227-232. 36. Legrain M, Rottembourg J, Bentchikou A, et al.: Dialysis treatment of insulin dependent diabetic patients: ten years experience. Clin Nephrol 1984, 21:72-81 37. Rubin J, Hsu H: Continuous anbulatory peritoneal dialysis: ten years at one facility. Am J Kidney Dis 1991, 17: 165-169. 38. Habach G, Bloembergen WE, Mauger EA, et al.: Hospitalization among United States dialysis patients: hemodialysis versus peritoneal dialysis. J Am Soc Nephrol 1995, 11:1940-1948.

Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener’s Granulomatosis, HenochSchönlein Purpura) J. Charles Jennette Ronald J. Falk

T

he kidneys are affected by a variety of systemic vasculitides [1,2]. This is not surprising given the numerous and varied types of vessels in the kidneys. The clinical manifestations and even the pathologic expressions of vasculitis often are not specific for a particular diagnostic category of vasculitis. An accurate precise diagnosis usually requires the integration of many different types of data, including clinical signs and symptoms, associated diseases (eg, asthma, systemic lupus erythematosus, rheumatoid arthritis, hepatitis virus, polymyalgia rheumatica), vascular distribution (ie, types and locations of involved vessels), histologic pattern of inflammation (eg, granulomatous versus necrotizing), immunopathologic features (eg, presence and composition of vascular immunoglobulin deposits), and serologic findings (eg, cryoglobulins, hypocomplementemia, hepatitis B antibodies, hepatitis C antibodies, antineutrophil cytoplasmic autoantibodies, anti–glomerular basement membrane [GBM] antibodies, antinuclear antibodies). Specific diagnosis of a vasculitis is very important because the prognosis and appropriate therapy vary substantially among different types of vasculitis. A general overview of the major categories of vasculitis that affect the kidneys is presented. The focus is primarily on polyarteritis nodosa, Henoch-Schönlein purpura, Wegener’s granulomatosis, and microscopic polyangiitis.

CHAPTER

2

2.2

Systemic Diseases and the Kidney

Overview SELECTED CATEGORIES OF VASCULITIS Large vessel vasculitis Giant cell arteritis Takayasu arteritis Medium-sized vessel vasculitis Polyarteritis nodosa Kawasaki disease Small vessel vasculitis ANCA small vessel vasculitis Microscopic polyangiitis Wegener’s granulomatosis Churg-Strauss syndrome Immune complex small vessel vasculitis Henoch-Schönlein purpura Cryoglobulinemic vasculitis Lupus vasculitis Serum sickness vasculitis Infection-induced immune complex vasculitis Anti–GBM small vessel vasculitis Goodpasture’s syndrome

Distribution of renal vascular involvement Small vessel vasculitis

Large vessel vasculitis

Medium-sized vessel vasculitis

FIGURE 2-1 Many different approaches to categorizing vasculitis exist. We use the approach adopted by the Chapel Hill International Consensus Conference on the Nomenclature of Systemic Vasculitis [3]. The Chapel Hill System divides vasculitides into those that have a predilection for large arteries (ie, the aorta and its major branches), medium-sized vessels (ie, main visceral arteries), and small vessels (predominantly capillaries, venules, and arterioles, and occasionally, small arteries). However, there is so much overlap in the size of the vessel involved by different vasculitides that other criteria are very important for precise diagnosis, especially when distinguishing among the different types of small vessel vasculitis. ANCA—antineutrophil cytoplasmic antibody.

FIGURE 2-2 Predominant distributions of renal vascular involvement. This diagram depicts the predominant distributions of renal vascular involvement by large, medium-sized, and small vessel vasculitides [2]. Note that all three categories may affect arteries, although arteries are least often affected by the small vessel vasculitides and often are not involved at all by this category of vasculitis. By the Chapel Hill definitions, glomerular involvement (ie, glomerulonephritis) is confined to the small vessel vasculitides, which provides a concrete criterion for separating the diseases in this category from those in the other two categories [3].

Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener’s Granulomatosis, Henoch-Schönlein Purpura)

RENAL INJURY CAUSED BY DIFFERENT CATEGORIES OF VASCULITIS Large vessel vasculitis Ischemia causing renovascular hypertension (uncommon) Medium-sized vessel vasculitis Renal infarcts (frequent) Hemorrhage (uncommon) and rupture (rare) ANCA small vessel vasculitis Pauci-immune crescentic glomerulonephritis (common) Arcuate and interlobular arteritis (occasional) Medullary angiitis (uncommon) Interstitial granulomatous inflammation (rare) Immune complex small vessel vasculitis Immune complex proliferative or membranoproliferative glomerulonephritis with or without crescents (common) Arteriolitis and interlobular arteritis (rare) Anti–GBM small vessel vasculitis Crescentic glomerulonephritis (common) Extraglomerular vasculitis (only with concurrent ANCA disease)

2.3

FIGURE 2-3 The type of renal vessel involved by a vasculitis determines the resultant renal dysfunction. Large vessel vasculitides cause renal dysfunction by injuring the renal arteries and the aorta adjacent to the renal artery ostia. These injuries result in reduced renal blood flow and resultant renovascular hypertension. Medium-sized vessel vasculitis most often affects lobar, arcuate, and interlobular arteries, resulting in infarction and hemorrhage. Small vessel vasculitides most often affect the glomerular capillaries (ie, cause glomerulonephritis), but some types (especially the antineutrophil cytoplasmic antibody vasculitides) may also affect extraglomerular parenchymal arterioles, venules, and capillaries. Anti-GBM disease is a form of vasculitis that involves only capillaries in glomeruli or pulmonary alveoli, or both. This category of vasculitis is considered in detail seperately in this Atlas.

Large Vessel Vasculitis NAMES AND DEFINITIONS FOR LARGE VESSEL VASCULITIS Giant cell arteritis

Takayasu arteritis

Granulomatous arteritis of the aorta and its major branches, with a predilection for the extracranial branches of the carotid artery. Often involves the temporal artery. Usually occurs in patients older than aged 50 years and often is associated with polymyalgia rheumatica. Granulomatous inflammation of the aorta and its major branches. Usually occurs in patients younger than aged 50 years.

FIGURE 2-4 The two major categories of large vessel vasculitis, giant cell (temporal) arteritis and Takayasu arteritis, are both characterized pathologically by granulomatous inflammation of the aorta, its major branches, or both. The most reliable criterion for distinguishing between these two disease is the younger age of patients with Takayasu arteritis compared with giant cell arteritis [3]. The presence of polymyalgia rheumatica supports a diagnosis of giant cell arteritis. Clinically significant renal disease is more commonly associated with Takayasu arteritis than giant cell arteritis, although pathologic involvement of the kidneys is a frequent finding with both conditions [4,5].

2.4

Systemic Diseases and the Kidney

Medium-sized Vessel Vasculitis NAMES AND DEFINITIONS FOR MEDIUM VESSEL VASCULITIS Polyarteritis nodosa

Kawasaki disease

Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules. Arteritis involving large, medium-sized, and small arteries, and associated with mucocutaneous lymph node syndrome. Coronary arteries are often involved. Aorta and veins may be involved. Usually occurs in children.

FIGURE 2-5 The medium-sized vasculitides are confined to arteries by the definitions of the Chapel Hill Nomenclature System [3,6]. By this approach the presence of evidence for involvement of vessels smaller than arteries (ie, capillaries, venules, arterioles), such as glomerulonephritis, purpura, or pulmonary hemorrhage, would point away from these diseases and toward one of the small vessel vasculitides. Both polyarteritis nodosa and Kawasaki disease cause acute necrotizing arteritis that may be complicated by thrombosis and hemorrhage. The presence of mucocutaneous lymph node syndrome distinguishes Kawasaki disease from polyarteritis nodosa.

FIGURE 2-6 Photograph of kidneys showing gross features of polyarteritis nodosa. The patient died from uncontrollable hemorrhage of a ruptured aneurysm that bled into the retroperitoneum and peritoneum. The cut surface of the left kidney and external surface of the right kidney are shown. The upper pole of the left kidney has three large aneurysms filled with dark thrombus. These aneurysms are actually pseudoaneurysms because they are not true dilations of the artery wall but rather are foci of necrotizing erosion through the artery wall into the perivascular tissue. These necrotic foci predispose to thrombosis with distal infarction, and if they erode to the surface of a viscera they can rupture and cause massive hemorrhage. The kidneys also have multiple pale areas of infarction with hemorrhagic rims, which are seen best on the surface of the right kidney.

A

B

FIGURE 2-7 Antemortem abdominal CAT scans showing polyarteritis nodosa (A–E). These are the same kidneys shown in Figure 2-6. Demonstrated are echogenic oval defects in both kidneys corresponding to the

C aneurysms (pseudoaneurysms), and a perirenal hematoma adjacent to the right kidney (left sides of panels) that resulted from rupture of one of the aneurysms. (Continued on next page)

Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener’s Granulomatosis, Henoch-Schönlein Purpura)

2.5

FIGURE 2-7 (Continued) Antemortem abdominal CAT scans showing polyarteritis nodosa.

D

E

FIGURE 2-8 (see Color Plate) Micrograph of transmural fibrinoid necrosis of an arcuate artery in acute polyarteritis nodosa. The fibrinoid necrosis results from lytic destruction of vascular and perivascular tissue with spillage of plasma constituents, including the coagulation proteins, into the zone of destruction. The coagulation system, as well as other mediator systems, is activated and fibrin forms in the zone of necrosis, thus producing the deeply acidophilic (bright red) fibrinoid material. Marked perivascular inflammation is seen, which is the basis for the archaic term for this disease, ie, periarteritis nodosa. Note that the glomerulus is not inflamed. (Hematoxylin and eosin stain, 200.)

FIGURE 2-9 Micrograph of extensive destruction and sclerosis of an arcuate artery in the chronic phase of polyarteritis nodosa. Severe necrotizing injury, probably with thrombosis as well, has been almost completely replaced by fibrosis. A few small residual irregular foci of fibrinoid material can be seen. Extensive destruction to the muscularis can be discerned. Infarction in the distal vascular distribution of this artery was present in the specimen. (Hematoxylin and eosin stain, 150.)

2.6

Systemic Diseases and the Kidney

Small Vessel Vasculitis NAMES AND DEFINITIONS FOR SMALL VESSEL VASCULITIS Henoch-Schönlein purpura Cryoglobulinemic vasculitis Wegener’s granulomatosis Churg-Strauss syndrome Microscopic polyangiitis

Vasculitis with IgA-dominant immune deposits affecting small vessels, ie, capillaries, venules, or arterioles. Typically involves skin, gut and glomeruli, and is associated with arthralgias or arthritis. Vasculitis with cryoglobulin immune deposits affecting small vessels, ie, capillaries, venules, or arterioles, and associated with cryoglobulins in serum. Skin and glomeruli are often involved. Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to medium-sized vessels, eg, capillaries, venules, arterioles, and arteries. Necrotizing glomerulonephritis is common. Eosinophil-rich and granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small to medium-sized vessels, and associated with asthma and blood eosinophilia Necrotizing vasculitis with few or no immune deposits affecting small vessels, ie, capillaries, venules, or arterioles. Necrotizing arteritis involving small and medium-sized arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs.

FIGURE 2-10 The small vessel vasculitides have the highest frequency of clinically significant renal involvement of any category of vasculitis. This is not surprising given the numerous small vessels in the kidneys and their critical roles in renal function. The renal vessels most often involved by all small vessel vasculitides are the glomerular capillaries, resulting in glomerulonephritis. Glomerular involvement in immune complex vasculitis typically results in proliferative or membranoproliferative glomerulonephritis, whereas ANCA disease usually causes necrotizing glomerulonephritis with extensive crescent formation. Involvement of renal vessels other than glomerular capillaries is rare in immune complex vasculitis but common in ANCA vasculitis.

Diagnostic categorization of small vessel vasculitis with glomerulonephritis Signs and symptoms of small vessel vasculitis (eg, nephritis, purpura, mononeuritis multiplex, pulmonary hemorrhage, abdominal pain, arthralgias, myalgias)

Pauci-immune crescentic glomerulonephritis on renal biopsy

Cryoglobulins in blood

IgA nephropathy on renal biopsy

Type 1 MPGN on renal biopsy

No granulomatous inflammation or asthma

Granulomatous inflammation but no asthma

Granulomatous inflammation, asthma, and eosinophilia

Henoch-Schönlein purpura

Cryoglobulinemic vasculitis

Microscopic polyangiitis

Wegener's granulomatosis

Churg-Strauss syndrome

FIGURE 2-11 Algorithm for differentiating among the major categories of small vessel vasculitis that affect the kidneys. In a patient with signs and symptoms of small vessel vasculitis, the type of glomerulonephritis is useful for categorization. Identification of IgA nephropathy is indicative of Henoch-Schönlein purpura. Type I membranoproliferative glomerulonephritis (MPGN) suggests cryoglobulinemia and/or hepatitis C infection, and pauci-immune necrotizing and crescentic glomerulonephritis suggest some form of ANCA-associated vasculitis [1,2]. The different forms of ANCA vasculitis are distinguished by the presence or absence of certain features in addition to the necrotizing vasculitis, ie, granulomatous inflammation in Wegener’s granulomatosis, asthma and blood eosinophilia in Churg-Strauss syndrome, and neither granulomatous inflammation nor asthma in microscopic polyangiitis. Approximately 80% of patients with active untreated Wegener’s granulomatosis or microscopic polyangiitis have ANCA, but it is important to realize that a small proportion of patients with typical clinical and pathologic features of these diseases do not have detectable ANCA.

2.7

Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener’s Granulomatosis, Henoch-Schönlein Purpura)

APPROXIMATE FREQUENCY OF ORGAN SYSTEM INVOLVEMENT IN SMALL VESSEL VASCULITIS

Organ system Renal Cutaneous Pulmonary Gastrointestinal Ear, nose, and throat Musculoskeletal Neurologic

Henoch-Schönlein purpura, % 50 90 <5 60 <5 75 10

Cryoglobulinemic vasculitis, % 55 90 <5 30 <5 70 40

FIGURE 2-12 All of the small vessel vasculitides share signs and symptoms of small vessel injury in multiple different tissues; however, the frequency of involvement varies among the different diseases [1]. Combined renal and pulmonary involvement (pulmonary-renal syndrome) is most common in ANCA vasculitis, whereas combined renal and dermal involvement (dermal-renal syndrome) is most common in immune complex vasculitis. The cutaneous involvement in small vessel vasculitides usu-

Microscopic polyangiitis, % 90 40 50 50 35 60 30

Wegener’s granulomatosis, % 80 40 90 50 90 60 50

Churg-Strauss syndrome, % 45 60 70 50 50 50 70

ally manifests as purpura caused by venulitis, but occasionally is more nodular or necrotizing secondary to arteritis or granulomatous inflammation. Nodular cutaneous lesions, as well as neuropathies, abdominal pain, and musculoskeletal symptoms also can be caused by medium sized vessel vasculitis (eg, polyarteritis nodosa), and thus these clinical manifestations are not specific for a small vessel vasculitis; whereas glomerulonephritis, purpura, or alveolar capillaritis are.

Henoch-Schönlein Purpura

FIGURE 2-13 Cutaneous purpura in a patient with Henoch-Schönlein purpura. This clinical appearance could be caused by any of the small vessel vasculitides, and thus is not specific for Henoch-Schönlein purpura. Henoch-Schönlein purpura is the most common small vessel vasculitis in children [7]. In a young child with purpura, nephritis and abdominal pain, the likelihood of Henoch-Schönlein purpura is approximately 80%; however, in an older adult with the same clinical presentation, the likelihood of Henoch-Schönlein purpura is very low and the patient has an approximately 80% chance of having an ANCA-associated vasculitis.

FIGURE 2-14 Skin biopsy from a patient with small vessel vasculitis demonstrating the typical dermal leukocytoclastic angiitis pattern of venulitis that results in vasculitic purpura. This histologic lesion is nonspecific and can be a component of any of the small vessel vasculitides. Additional immunohistologic, serologic, and clinical observations are required to determine what is causing the leukocytoclastic angiitis (Figs. 2-9 and 2-10). (Hematoxylin and eosin stain.)

2.8

Systemic Diseases and the Kidney

FIGURE 2-15 Direct immunofluorescence microscopy demonstrating granular IgA-dominant immune complex deposits in dermal vessels, which is indicative of Henoch-Schönlein purpura. This procedure typically would show vascular IgM, IgG, and C3 cryoglobulinemic vasculitis, and little or no staining for immunoglobulins in a specimen from a patient with an ANCA vasculitis (a paucity of staining for immunoglobulins in vessel walls indicates pauci-immune vasculitis).

FIGURE 2-16 Direct immunofluorescence microscopy demonstrating granular, predominantly mesangial IgA-dominant immune complex deposits in a glomerulus. This is indicative of some form of IgA nephropathy, including the form that occurs as a component of HenochSchönlein purpura.

FIGURE 2-17 Electron micrograph showing mesangial dense deposits representative of the pattern of deposition seen in patients with HenochSchönlein purpura glomerulonephritis. The dense deposits are immediately beneath the paramesangial basement membrane.

FIGURE 2-18 Severe crescentic proliferative glomerulonephritis in a patient with Henoch-Schönlein purpura and rapidly progressive glomerulonephritis (Masson trichrome stain). Approximately half of patients with Henoch-Schönlein purpura have mild nephritis with hematuria and proteinuria, but less than a quarter develop renal insufficiency, and rapidly progressive glomerulonephritis is rare. Less than 10% of patients have persistent renal disease that progresses to end-stage renal disease.

Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener’s Granulomatosis, Henoch-Schönlein Purpura)

2.9

FIGURE 2-19 Fibrinoid necrosis obliterating the wall of an arteriole in a renal biopsy specimen from a patient with Henoch-Schönlein purpura (hematoxylin and eosin). Involvement of renal vessels other than glomeruli is rare in Henoch-Schönlein purpura.

ANCA Small Vessel Vasculitis FIGURE 2-20 (see Color Plate) C-ANCA staining pattern of ethanol-fixed normal human neutrophils in an indirect immunofluorescence assay of serum. Approximately 90% of C-ANCA are specific for proteinase 3 (PR3-ANCA) in specific immunochemical assays, such as enzyme immunoassay (EIA) [8–10].

FIGURE 2-21 (see Color Plate) P-ANCA staining pattern of ethanol-fixed normal human neutrophils in an indirect immunofluorescence assay of serum. Approximately 90% of P-ANCA in patients with nephritis or vasculitis are specific for myeloperoxidase (MPO-ANCA) in specific immunochemical assays, such as EIA. P-ANCA in patients with other types of inflammatory disease, such as inflammatory bowel disease are typically not specific for MPO. Using ethanol-fixed neutrophils as substrate, nuclear staining caused by anti-nuclear antibodies (ANA) cannot be distinguished confidently from nuclear staining caused by P-ANCA. Using formalin-fixed neutrophils as substrate, P-ANCA stain the cytoplasm but ANA do not. The difference in staining pattern between ethanol and formalin fixed cells is due to the artifactual diffusion of solubilized cationic ANCAantigens to the nucleus during substrate preparation of the ethanolfixed cells, as opposed to immobilization of the antigens in the cytoplasm by covalent crosslinking during formalin fixation.

2.10

Systemic Diseases and the Kidney

Pauci-immune crescentic glomerulonephritis Microscopic polyangiitis Wegener's granulomatosis P-ANCA/MPO-ANCA

C-ANCA/PR3-ANCA

FIGURE 2-22 Approximate relative frequency of P-ANCA/MPO-ANCA versus CANCA/PR3-ANCA in patients with pauci-immune necrotizing and crescent glomerulonephritis without systemic vasculitis (“renal-limited vasculitis”), microscopic polyangiitis, and Wegener’s granulomatosis. Note that most patients with renal-limited disease have PANCA/MPO-ANCA, most patients with Wegener’s granulomatosis have C-ANCA/PR3-ANCA, and patients with microscopic polyangiitis do not have a major preponderance of either ANCA specificity.

FIGURE 2-24 Glomerulus from a patient with ANCA and a pauci-immune necrotizing and crescentic glomerulonephritis showing a large circumferential crescent and segmental lysis of glomerular basement membranes (combined Jones silver and hematoxylin and eosin stain). Also note the adjacent tubulointerstitial inflammation, which often is pronounced in ANCA disease. This pattern of glomerular injury can be seen with any of the ANCA-small vessel vasculitides.

FIGURE 2-23(see Color Plate) Early segmental fibrinoid necrosis and infiltration by neutrophils in an ANCA-positive patient with Wegener’s granulomatosis (Masson trichrome stain). There also is fibrin (red/fuchsinophilic material) in Bowman’s space, which is a precursor event to crescent formation.

FIGURE 2-25(see Color Plate) Direct immunofluorescence microscopy demonstrating intense staining of a crescent and adjacent segmental glomerular fibrinoid necrosis with an antiserum specific for fibrin in a renal biopsy from a patient with ANCA small vessel vasculitis. There was no staining of glomeruli in this specimen with antisera specific for IgG, IgA, or IgM.

Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener’s Granulomatosis, Henoch-Schönlein Purpura)

2.11

FIGURE 2-26 Chronic ANCA-associate glomerulonephritis with effacement of the architecture of a glomerulus by extensive sclerosis. Bowman’s capsule has been destroyed and there is periglomerular fibrosis and chronic inflammation.

FIGURE 2-27 Necrotizing arteritis involving an interlobular artery in a renal biopsy specimen from a patient with ANCA-positive microscopic polyangiitis (hematoxylin and eosin). There is focal transmural fibrinoid necrosis with intense perivascular inflammation. This pattern of arteritis is nonspecific, and could be seen, for example, in a patient with polyarteritis nodosa, microscopic polyangiitis, or Wegener’s granulomatosis. The presence of ANCA or glomerulonephritis in the patient would exclude polyarteritis nodosa.

FIGURE 2-28 Direct immunofluorescence microscopy demonstrating intense staining of the fibrinoid necrosis in the wall of an interlobular artery with an antiserum specific for fibrin in a renal biopsy from a patient with microscopic polyangiitis.

FIGURE 2-29 Medullary leukocytoclastic angiitis involving vasa recta in a patient with Wegener’s granulomatosis (hematoxylin and eosin). When this process is severe, papillary necrosis may result. The frequency of this process is unknown because the medulla often is not sampled in renal biopsy specimens.

2.12

Systemic Diseases and the Kidney

FIGURE 2-30 Poorly defined focus of necrotizing granulomatous inflammation in the cortex in a renal biopsy obtained from a patient with ANCA-positive Wegener’s granulomatosis (hematoxylin and eosin). Granulomatous inflammation is only very rarely observed in renal biopsy specimens.

FIGURE 2-31 Necrotizing granulomatous inflammation in a wedge biopsy of lung from a patient with Wegener’s granulomatosis (hematoxylin and eosin). Note the scattered large multinucleated giant cells on the left side and the extensive necrosis and neutrophilic infiltration on the right side. The granulomatous inflammation of acute Wegener’s granulomatosis has much more neutrophilic infiltration and liquefactive necrosis than most other forms of granulomatous inflammation, which is why the lesions in the lung tend to cavitate, and why the lesions in the nose and sinuses tend to destroy bone.

P-ANCA (MPO-ANCA) disease Systemic small vessel vasculitis (eg, MPA) Pulmonary– renal vasculitic syndrome

FIGURE 2-32 Hemorrhagic alveolar capillaritis in a wedge biopsy from the lung of a patient with microscopic polyangiitis (hematoxylin and eosin). Note the neutrophils within alveolar capillaries and the massive hemorrhage into the air spaces. This pattern of injury can be seen in both microscopic polyangiitis and Wegener’s granulomatosis. The pulmonary hemorrhage of anti-GBM disease usually does not have conspicuous neutrophils in alveolar capillaries.

Glomerulonephritis alone

Wegener's granulomatosis

Anti-GBM disease

C-ANCA (PR3-ANCA) disease

FIGURE 2-33 Categorization of patients with crescentic glomerulonephritis with respect to both the immunopathologic category of disease (immune complex versus anti-GBM versus ANCA) and the clinicopathologic expression (glomerulonephritis alone versus Wegener’s granulomatosis versus Goodpasture’s syndrome versus other small vessel vasculitis) [11]. Note that most patients with ANCA have some expression of systemic vasculitis rather than glomerulonephritis alone. Most patients with Wegener’s granulomatosis have C-ANCA/PR3-ANCA but some have P-ANCA/MPO-ANCA. Also note that some patients with anti-GBM and some patients with immune complex disease also are ANCA positive. (Adapted from Jennette [11]).

Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener’s Granulomatosis, Henoch-Schönlein Purpura)

2.13

References 1.

Jennette JC, Falk RJ: Small vessel vasculitis. N Engl J Med 1997, 337:1512–1523.

7. Dillon MJ, Ansell BM: Vasculitis in children and adolescents. Rheum Dis Clin North Am 1995, 21:1115–1136.

2.

Jennette JC, Falk RJ: The pathology of vasculitis involving the kidney. Am J Kidney Dis 1994, 24:130–141.

3.

Jennette JC, Falk RJ, Andrassy K, et al.: Nomenclature of systemic vasculitides: the proposal of an international consensus conference. Arthritis Rheum 1994, 37:187–192.

8. Gross WL, Schmitt WH, Csernok E: ANCA and associated diseases: immunodiagnostic and pathogenetic aspects. Clin Exp Immunol 1993, 91:1–12.

4.

Klein RG, Hunder GG, Stanson AW, et al.: Larger artery involvement in giant cell (temporal) arteritis. Ann Intern Med 1975, 83:806–812.

5.

Arend WP, Michel BA, Bloch DA, et al.: The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 1990, 33:1129–1134.

6.

Lhote F, Guillevin L: Polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome. Rheum Dis Clin North Am 1995, 21:911–947.

9. Kallenberg CGM, Brouwer E, Weening JJ, Cohen Tervaert JW: Anti-neutrophil cytoplasmic antibodies: current diagnostic and pathophysiologic potential. Kidney Int 1994, 46:1–15. 10. Jennette JC, Falk RJ: Anti-neutrophil cytoplasmic autoantibodies: discovery, specificity, disease associations and pathogenic potential. Adv Pathol Lab Med 1995, 8:363–377. 11. Jennette JC: Anti-neutrophil cytoplasmic autoantibody-associated disease: a pathologist’s perspective. Am J Kidney Dis 1991, 18:164–170.

Amyloidosis Robert A. Kyle Morie A. Gertz

T

he word amyloid was first coined in 1838 by Schleiden, a German botanist, to describe a normal constituent of plants. Virchow [1] observed the similarity of the staining properties of the amyloid to those of starch and named it amyloid. All forms of amyloid appear homogeneous when viewed under a light microscope and are pale pink when stained with hematoxylin-eosin. Under polarized light, amyloid stained with Congo red dye produces the characteristic apple-green birefringence. The modification of alkaline Congo red dye by Puchtler and Sweat [2] is used most often. The amorphous hyalinelike appearance of amyloid is misleading because it is a fibrous protein. On electron microscopy, amyloid deposits are composed of rigid, linear, nonbranching fibrils 7.5- to 10-nm wide and of indefinite length. The fibrils aggregate into bundles. The deposits occur extracellularly and ultimately lead to damage of normal tissue. In primary amyloidosis (AL) the fibrils consist of the variable portions of monoclonal () or () immunoglobulin light chains or, very rarely, heavy chains. In secondary amyloidosis (AA) the fibrils consist of protein A, a nonimmunoglobulin. In familial amyloidosis (AF) the fibrils are composed of mutant transthyretin (prealbumin) or, rarely, fibrinogen or apolipoprotein. In senile systemic amyloidosis the fibrils consist of normal transthyretin. The amyloid fibrils associated with long-term dialysis (A 2M dialysis arthropathy) consist of 2-microglobulin. Amyloid P component is a glycoprotein composed of 10 identical glycosylated polypeptide subunits, each with a molecular weight of 23,500 and arranged as two pentamers. The liver produces human serum amyloid P (SAP) component. SAP is present in healthy persons and shows 50% to 60% homology with C-reactive protein. SAP is bound to the amyloid fibrils; it is not an integral part of the fibrillar structure. It is found in all types of amyloid, including the vessel walls in patients with Alzheimer’s disease. The physiologic function of SAP and its pathologic role in amyloidosis are unknown. Glycosaminoglycans are present in amyloid deposits. Their role also is unknown. Catabolism or breakdown of the fibrils is an important factor in pathogenesis; however, little is known of the process [3]. No obvious predisposing condition is associated with primary amyloidosis. Secondary amyloidosis is associated with an inflammatory process, malignancy, and many other conditions. No monoclonal protein exits in the serum or urine.

CHAPTER

3

3.2

Systemic Diseases and the Kidney

Microscopic Appearance and Classification

FIGURE 3-1 (see Color Plate) Blood vessel from a bone marrow biopsy specimen indicating primary amyloidosis. The specimen was stained with Congo red dye and viewed with a polarizing light source, producing the characteristic apple-green birefringence. In more than half of patients, results of bone marrow testing are positive for amyloidosis. (From Kyle [4]; with permission.)

FIGURE 3-2 Electron photomicrograph showing the fibrillar character of amyloidosis. The fibrils are 7.5- to 10-nm wide and of indefinite length. The fibrils are deposited extracellularly, are insoluble, and generally resist proteolytic digestion. They ultimately lead to disorganization of tissue architecture and loss of normal tissue elements.

CLASSIFICATION OF AMYLOIDOSIS Amyloid type

Classification

Major protein component

Primary amyloidosis (AL) Secondary amyloidosis (AA) Familial amyloidosis (AF)

Primary, including multiple myeloma Secondary Familial Neuropathic: Portugal, Sweden, Japan, and other countries Cardiopathic: Denmark and Appalachia in the United States Nephropathic: familial Mediterranean fever Senile cardiac Dialysis arthropathy

 or  light chain Protein A

Senile systemic amyloidosis (AS) Dialysis amyloidosis (AD)

Transthyretin mutant (prealbumin) Transthyretin mutant (prealbumin) Protein A Transthyretin normal (prealbumin) 2-microglobulin

FIGURE 3-3 Classification of amyloidosis. The fibrils in primary amyloidosis consist of monoclonal  or  light chains. Rarely, monoclonal heavy chains are responsible. The major component of the amyloid fibril in secondary amyloidosis is protein A. It has a molecular weight of 8.5 kD

and contains 76 amino acids. It is derived from serum amyloid A, which is an acutephase protein. The level of serum amyloid A is increased in patients with rheumatoid arthritis and Crohn’s disease. In familial amyloidosis the Portuguese, Swedish, and Japanese variants are characterized by substitution of methionine for valine at residue 30 (Met-30) in the transthyretin molecule. This mutation is characterized by the development of peripheral neuropathy. Cardiomyopathy from a transthyretin mutation has been reported in Denmark (Met-111) and in the Appalachian area of the United States (Ala-60). Familial renal amyloid from a mutation of the fibrinogen -chain (Leu-554 or Glu-526) or mutations of lysozyme have been reported. Amyloidosis associated with familial Mediterranean fever consists of protein A. Senile systemic amyloidosis involving the heart results from the deposition of normal transthyretin. Long-term dialysis often results in systemic amyloidosis from 2microglobulin deposition.

3.3

Amyloidosis

SYSTEMIC AMYLOIDOSIS Amyloid type

Amyloid stains

Primary (AL) Secondary (AA) FMF Associated with long-term hemodialysis Familial (AF) Senile systemic (AS)

Congo red

 or 

Serum amyloid A

2-microglobulin

Transthyretin (prealbumin)

+ + + +

+ -

+ + -

+

-

+ +

-

-

-

+ +

FIGURE 3-4 Systemic amyloidosis. Types of proteins constituting the amyloid fibrils. In primary amyloidosis the fibrils consist of monoclonal  or  light chains. In secondary amyloidosis the fibrils consist of protein A. Systemic amyloidosis associated with long-term hemodialysis consists

Secondary (AA), 3.5% (5)

Familial, 3.5% (5) Senile, 2% (2) Localized, 8% (11)

Primary (AL), 83% (112)

of 2-microglobulin. The amyloid fibrils consist of mutated transthyretin or, rarely, fibrinogen  or lysozyme in familial amyloidosis. Senile systemic amyloidosis is characterized by the deposition of normal transthyretin in the heart. (From Kyle and Gertz [5]; with permission.)

FIGURE 3-5 Distribution of forms of amyloidosis seen in patients at the Mayo Clinic in 1996. Of the 135 patients with amyloidosis, 83% had the primary form. Familial, secondary, and senile amyloidosis accounted for less than 10% of patients. Localized amyloid is limited to the involved organ and never becomes systemic. In localized amyloidosis, the fibrils consist of an immunoglobulin light chain; however, the patients do not have a monoclonal protein in their serum or urine. Most localized amyloidosis occurs in the respiratory tract, genitourinary tract, or skin.

n=135

Primary Systemic Amyloidosis FIGURE 3-6 Pattern of primary systemic amyloidosis in patients during an 11year study at the Mayo Clinic. From 1981 to 1992, of the 474 patients seen within 30 days of diagnosis the median age was 64 years. Only 1% were younger than 40 years, and males were affected more often than were females. (From Kyle and Gertz [5]; with permission.)

50

Patients, %

40

Male: 69% (n=327) Female: 31% (n=147) Median age: 64 y (n=474) Age range: 32–90 y

37

30 23

22

20 10

10 0

7 1

<40

40–49

50–59 60–69 Age, y

70–79

≥80

3.4

Systemic Diseases and the Kidney

70 Range: 4–200 lb Median: 23 lb

62

60 With symptoms, %

52

50 40 30 20

15

10 0

5

Fatigue

Weight loss Purpura Symptoms

FIGURE 3-7 Symptoms of primary systemic amyloidosis in patients during an 11-year study at the Mayo Clinic. Weakness or fatigue and weight loss were the most frequent initial symptoms seen within 30 days of diagnosis. Weight loss occurred in more than half of patients. The median weight loss was 23 lb; five patients lost more than 100 lb each. Purpura, particularly in the periorbital and facial areas, was noted in about one sixth of patients. Gross bleeding was reported initially in only 3%. Skeletal pain was a major symptom in only 5% and usually was related to lytic lesions or fractures associated with multiple myeloma. Dyspnea, pedal edema, paresthesias, light-headedness, and syncope were noted. (From Kyle and Gertz [5]; with permission.)

Bone pain

FIGURE 3-8 Macroglossia in a man with primary systemic amyloidosis. Macroglossia occurs initially in about 10% of patients. Note the imprint of the teeth on the dorsum of the tongue. This patient was unable to close his mouth and complained of drooling. Macroglossia may cause obstruction of the airway, sometimes necessitating a tracheostomy. (From Kyle [4]; with permission.)

FIGURE 3-9 Nodules causing occlusion of the auditory canal in a patient with primary systemic amyloidosis. The external auditory canal may be occluded completely by nodules of amyloid. This condition frequently produces deafness, which may be the initial symptom. (From Gertz and Kyle [6]; with permission.)

FIGURE 3-10 Shoulder pad sign in a woman with primary systemic amyloidosis. Infiltration of the periarticular tissues with amyloid may produce this sign. The shoulder pad sign causes pain and limitation of motion and is very difficult to treat. (From Kyle [4]; with permission.)

3.5

Amyloidosis

FIGURE 3-11 Hypertrophic form of primary systemic amyloidosis in a 39-year-old man with prominent and firm muscles. Despite the muscular appearance, results of a biopsy revealed displacement of muscle fibers with amyloid. Patients often exhibit stiffness or limitation of movement. (From Kyle and Greipp [7]; with permission.)

FIGURE 3-12 Signs of primary systemic amyloidosis in patients during an 11-year study at the Mayo Clinic. The liver was palpable in about one fourth of patients seen within 30 days of diagnosis. Hepatomegaly is due to infiltration of amyloid or congestion from heart failure. The spleen is palpable in only 5% of patients and rarely extends more than 5 cm below the left costal margin. Lymphadenopathy occurs infrequently. (Adapted from Kyle and Gertz [5]; with permission.)

30

Patients, %

25

24

20 15 10

9 5

5 0

3

Liver palpable

Spleen palpable Lymphadenopathy Signs of primary amyloidosis

Macroglossia

HEMOGLOBIN AND PLATELET VALUES WITHIN 30 DAYS OF DIAGNOSIS OF PRIMARY SYSTEMIC AMYLOIDOSIS, MAYO CLINIC, 1981–1992

≥2.0 20% n=473

Factor Hemoglobin, g/dL (<10 g/dL in 11%) Platelets,  109/L (>500  109/L in 9%)

Median

Range

12.9 288

6.6–18.6 4–953

FIGURE 3-13 Hemoglobin and platelet values within 30 days of diagnosis of primary systemic amyloidosis. Anemia was not a prominent feature. When present, it usually is due to multiple myeloma, renal insufficiency, or gastrointestinal bleeding. Thrombocytosis was relatively common; in 9% of patients the platelet count was over 500  109/L. Functional hyposplenism from amyloid replacement of the spleen may occur [8]. Hyposplenism is manifested by the presence of HowellJolly bodies and occurs in about one fourth of patients. (Adapted from Kyle and Gertz [5].)

1.3–1.9 25%

<1.2 55%

Median: 1.1 Range: 0.4–14.6

FIGURE 3-14 Serum creatinine (mg/dL) in patients at diagnosis of primary systemic amyloidosis. Renal insufficiency was present in almost half of patients. Proteinuria was present in about 75% of patients.

3.6

Systemic Diseases and the Kidney

Polyclonal 1% Hypogammaglobulinemia 20% β band 10%

IgM 5%

IgD 1% ≥ 6.0 20%

κ only 9% Negative 28%

λ only 15%

γ band 38%

Normal 31%

n=463

IgA 10%

IgG 32%

<1.0 45%

3.0–5.9 16%

n=430

Median:1.2 g/d Range: 0.1–24.1 g/d

1.0–2.9 19%

n=443

FIGURE 3-15 Results of serum protein electroplasmaphoresis in patients at diagnosis of primary systemic amyloidosis. The serum protein electrophoretic pattern showed hypogammaglobulinemia in 20% of patients. Only half of patients had a localized band or spike in the  or  areas of the electrophoretic pattern. The median size of the M spike was 1.4 g/dL. In the remaining patients the pattern was normal.

S+, U– 16% S–, U– 11%

κ 23% λ 50% Negative 27%

FIGURE 3-16 Serum monoclonal (M-) protein in patients at diagnosis of primary systemic amyloidosis in an 11-year study at the Mayo Clinic. Immunoelectrophoresis or immunofixation of the serum showed an M-protein in 72% of patients. IgG was most common, followed by IgA. Twenty-four percent of patients had monoclonal immunoglobulin light chains in the serum (Bence Jones proteinemia). (Adapted from Kyle and Gertz [5]; with permission.)

n=429

S–, U+ 17%

FIGURE 3-17 Urine total protein values in patients at diagnosis of primary systemic amyloidosis in an 11-year study at the Mayo Clinic. More than one third of patients exhibited 24-hour urine total protein values of 3.0 g/d or more. Over half of patients had a urine protein value of more than 1 g/d. The electrophoretic pattern showed mainly albumin. (Adapted from Kyle and Gertz [5]; with permission.)

S+, U+ 56%

n=408

FIGURE 3-18 Urine monoclonal (M-) protein in patients at diagnosis of primary systemic amyloidosis in an 11-year study at the Mayo Clinic. Almost three fourths of patients had monoclonal light chains in their urine on immunoelectrophoresis or immunofixation. In contrast to the type of protein found in multiple myeloma,  is twice as common as is . The 24-hour total amount of monoclonal (M-) protein in the urine was less than 0.5 g/d in more than half of patients. (From Kyle and Gertz [5]; with permission.)

FIGURE 3-19 Serum (S) and urine (U) proteins in patients with primary systemic amyloidosis in an 11-year study at the Mayo Clinic. Immunoelectrophoresis or immunofixation of serum and appropriate concentrations in urine showed a monoclonal protein in nearly 90% of patients. In the absence of monoclonal protein, one must search for a monoclonal population of plasma cells in the bone marrow or perform immunohistochemical staining to identify the type of amyloid. (From Kyle and Gertz [5]; with permission.)

FIGURE 3-20 Enlarged kidney in primary systemic amyloidosis. Involvement of the kidneys is the most common presenting feature. The kidney is frequently normal in size, but in some instances small kidneys have been found.

Amyloidosis

3.7

100

Survival, %

80 60 40 20 0 0

1

2

3

Years after dialysis

FIGURE 3-21 (see Color Plate) Photomicrograph showing a renal biopsy specimen stained with Congo red dye taken from a patient with primary systemic amyloidosis. Note the homogeneous deposition of amyloid in the glomerulus. Results of kidney biopsy are positive in about 95% of patients.

FIGURE 3-22 Survival analysis of patients with primary systemic amyloidosis. The median survival from the onset of dialysis was 8.2 months in 37 patients. No difference exists between patients treated with hemodialysis and those treated with peritoneal dialysis. Biopsy results were used to make the diagnosis in 211 patients. The most important predictors of which patients would ultimately require dialysis were the 24-hour urinary protein loss and serum creatinine values at the time of diagnosis. None of the patients who had a normal serum creatinine value and a urine protein value of less than 2 g/d at diagnosis required dialysis during follow-up. Of the 37 patients who received dialysis, 31 died, and 21 of the 31 died as a result of extrarenal progression of their systemic amyloidosis. Half of the deaths were caused by cardiac amyloidosis [9].

FIGURE 3-23 Gross specimen of a liver in primary systemic amyloidosis. The liver is grossly enlarged.

FIGURE 3-24 Photomicrograph showing extensive amyloid deposition in the liver in primary systemic amyloidosis.

3.8

Systemic Diseases and the Kidney

ALKALINE PHOSPHATASE, ASPARTATE AMINOTRANSFERASE, AND BILIRUBIN VALUES WITHIN 30 DAYS OF DIAGNOSIS OF PRIMARY SYSTEMIC AMYLOIDOSIS, MAYO CLINIC, 1981–1992

PROTHROMBIN TIME, CAROTENE, AND B12 VALUES WITHIN 30 DAYS OF DIAGNOSIS OF PRIMARY SYSTEMIC AMYLOIDOSIS, MAYO CLINIC, 1981–1992

Factor Factor

Normal value

Values above normal, n (%)

Alkaline phosphatase

≤250 U/L

Aspartate aminotransferase

≤30 U/L

>250 (26) ≥500 (11) >30 (34) ≥100 (3) >1.1 (11) ≥5 (1)

Total bilirubin

≤1.1 mg/dL

FIGURE 3-25 Alkaline phosphatase, aspartate aminotransferase, and bilirubin values within 30 days of diagnosis of primary systemic amyloidosis. The serum alkaline phosphatase level was increased in one fourth of 474 patients at the time of diagnosis. The aspartate aminotransferase value was increased in one third of patients but rarely reached 100 U/L. Hyperbilirubinemia was an infrequent finding but when present was associated with short survival [5]. (Adapted from Kyle and Gertz [5].)

Patients, %

Prothrombin time >13 s Carotene <48 µg/dL Serum B12 <150 pg/mL

16 6 3

FIGURE 3-26 Prothrombin time, carotene, and vitamin B12 values within 30 days of diagnosis of primary systemic amyloidosis. The prothrombin time was increased in one sixth of patients at the time of diagnosis. It has been shown that prolongation of thrombin time occurs in 40% of patients [10]. A deficiency in factor X occurs in 15% but is not associated with bleeding. Malabsorption as manifested by a low carotene or serum B12 level occurs infrequently. (Adapted from Kyle and Gertz [5].)

PERCENTAGE OF BONE MARROW PLASMA CELLS WITHIN 30 DAYS OF DIAGNOSIS OF PRIMARY SYSTEMIC AMYLOIDOSIS, MAYO CLINIC, 1981–1992

FIGURE 3-27 Bone marrow aspirate specimen from a patient with primary systemic amyloidosis. This specimen contains an increase in plasma cells.

Plasma cells, % (median = 7%)

Patients, % (n = 391)

≤5 6–9 10–19 ≥20

44 16 22 18

FIGURE 3-28 Percentage of bone marrow plasma cells within 30 days of diagnosis of primary systemic amyloidosis. Almost half of patients had 5% or fewer plasma cells in the bone marrow at the time of diagnosis. About one fifth of patients had bone marrow plasmacytosis of 20% or more. Multiple myeloma must be considered in this setting. The plasma cells are monoclonal  or . (From Kyle and Gertz [5]; with permission.)

3.9

Amyloidosis FIGURE 3-29 Radiograph showing marked cardiac enlargement in a patient with primary systemic amyloidosis. Overt congestive heart failure is present in about one sixth of patients at the time of diagnosis. Pleural effusion is common.

FIGURE 3-30 Electrocardiogram in a patient with primary systemic amyloidosis, showing low voltage in the limb leads or loss of anterior septal forces that mimics the findings in myocardial infarction. However, ischemic heart disease is not present. Arrhythmias may include atrial fibrillation, junctional tachycardia, premature ventricular complexes, or heart block.

≥20 mm 11% 15–19 mm 36%

Survival, %

≤11 mm 24%

100

P=0.0003

75 < 15 mm (n=64)

50 25

12–14 mm 29% n=121

FIGURE 3-31 Echocardiogram of a patient with primary systemic amyloidosis showing marked thickness of the ventricular wall. Results on echocardiogram are abnormal in two thirds of patients at the time of diagnosis. LV–left ventricle; RV–right ventricle. (From Gertz and Kyle [3]; with permission.)

FIGURE 3-32 Septal thickness on echocardiography in patients with primary systemic amyloidosis. Almost half of patients had septal thickness of 15 mm or more on echocardiography at the time of diagnosis. Only 24% had no increased septal thickness.

≥ 15 mm (n=57)

0 0

1

2

3 Time, y

4

5

FIGURE 3-33 Analysis of the association between septal thickness and survival in patients with primary systemic amyloidosis in an 11-year study at the Mayo Clinic. An increase in septal thickness is associated with shorter survival. Patients with a septal thickness of 15 mm or more had a median survival of 7 months, whereas in those with a septal thickness less than 15 mm the median survival was 26 months. (From Kyle and Gertz [5]; with permission.)

3.10

Systemic Diseases and the Kidney FIGURE 3-34 Cross section of the heart showing marked thickening of the left ventricular wall and septum in primary systemic amyloidosis. The ventricular cavity is greatly reduced in volume. (From Gertz and Kyle [3]; with permission.)

40

Patients, %

30

FIGURE 3-35 Analysis of previously unexplained syndromes in patients with primary systemic amyloidosis at the time of diagnosis in an 11-year study at the Mayo Clinic. Nephrotic syndrome or renal failure was present in 28% of patients, congestive heart failure (CHF) in 17%, and carpal tunnel syndrome in 21%. Peripheral neuropathy and orthostatic hypotension also were common features. The possibility of primary systemic amyloidosis must be considered in every patient who has monoclonal protein in the serum or urine and who has unexplained nephrotic syndrome, CHF, sensorimotor peripheral neuropathy, carpal tunnel syndrome, hepatomegaly, or malabsorption. (Adapted from Kyle and Gertz [5]; with permission.)

At diagnosis During follow-up n=474

2 5

0.5

20

0.5 1.5

10 0

28

17

21

Nephrotic/ renal failure (142)

CHF

Carpal tunnel (102)

(104)

17

11

Peripheral Orthostatic neuropathy hypotension (58) (81)

Symptoms (number of patients)

100

Positive, %

80 60

94

90

86

Skin

Sural nerve (21)

83

82

80

100

97

75 56

40 20 0

Abdominal Bone Rectum Kidney Carpal ligament fat marrow (20) (212) (394) (194) (81)

Liver (32)

Small intestine (23)

Presence of amyloid in tissue (number of patients)

(19)

Heart (16)

FIGURE 3-36 Diagnosis of primary systemic amyloidosis based on the presence of amyloid in tissue in an 11-year study at the Mayo Clinic. The initial diagnostic procedure should be an abdominal fat aspirate [11]. The diagnosis will be confirmed in 80% of patients. Experience in the staining technique and interpretation of the fat aspirate is important before routine use. A bone marrow aspirate and bone marrow biopsy specimen should be obtained to determine the degree of plasmacytosis, and results of amyloid stains are positive in more than half of patients. Either the abdominal fat aspirate or bone marrow biopsy specimen is positive in 90% of patients. When amyloid is still suspected and the test results of these tissues are negative, one should proceed to performing a rectal biopsy, which is positive in approximately 80% of patients. The specimen must include the submucosa. When the test results for these sites are negative, tissue should be obtained from an organ with suspected involvement. (From Kyle and Gertz [5]; with permission.)

3.11

Amyloidosis

100

Nephrotic/renal failure (n=114) Congestive heart failure (n=80) Orthostatic hypotension (n=41)

Survival, %

75

Peripheral neuropathy (n=40) Total (n=474)

50

25

0 0

FIGURE 3-37 (see Color Plate) Aspirate of subcutaneous abdominal fat from a patient with primary systemic amyloidosis. The specimen shows the characteristic apple-green birefringence when stained with Congo red dye and viewed with a polarizing light source.

1

2

3

4 Time, y

5

6

7

8

FIGURE 3-38 Analysis of median survival in patients with primary systemic amyloidosis in an 11-year study at the Mayo Clinic. The median survival of 474 patients seen within 1 month of diagnosis was 13.2 months. The median duration of survival was 4 months for the 80 patients who exhibited congestive heart failure on presentation. (From Kyle and Gertz [5]; with permission.)

FIGURE 3-39 Causes of death in patients with primary systemic amyloidosis in an 11-year study at the Mayo Clinic. Of the 285 patients who died, death was attributed to cardiac involvement from congestive heart failure or arrhythmias in 48%. The actual percentage of cardiacrelated deaths was probably higher because some patients whose death was attributed to primary amyloidosis almost certainly had terminal cardiac arrhythmia. (Adapted from Kyle and Gertz [5]; with permission.)

Infection 8% Renal 6%

Other 8% Cardiac 48%

Unknown 13% "Primary amyloidosis" 17% n=285

100 Arm MP MPC C

Patients, %

80 60

Months 18 17 8.5

P<0.001

40 20 0 0

1

2

3

4

5 6 Survival, y

7

8

9

10

FIGURE 3-40 Survival curves in patients with primary systemic amyloidosis. Because amyloid fibrils consist of monoclonal immunoglobulin light chains, treatment with alkylating agents that are effective against plasma cell neoplasms is warranted. We treated 220 patients who had positive results on biopsy. The patients were randomized to receive colchicine (C, 72 patients), melphalan and prednisone (MP, 77), or melphalan, prednisone, and colchicine (MPC, 71). Patients were stratified according to their chief clinical manifestations: renal disease (105 patients), cardiac involvement (46), peripheral neuropathy (19), or other (50). The median duration of survival after randomization was 8.5 months in the colchicine group; 18 months in the group assigned to melphalan and prednisone; and 17 months in the group assigned to melphalan, prednisone, and colchicine (P < 0.001). In patients who had a reduction in serum or urine monoclonal protein at 12 months, the overall duration of survival was 50 months; whereas among those without a reduction in monoclonal protein at 12 months, the duration of survival was 36 months (P < 0.003). Thirty-four patients (15%) survived for 5 years or longer. (Adapted from Kyle et al. [12]; with permission.)

3.12

Systemic Diseases and the Kidney FIGURE 3-41 Other therapy for primary amyloidosis. High-dose dexamethasone has been reported to be beneficial in treating patients with primary systemic amyloidosis [13]. More intensive therapy consisting of high-dose chemotherapy followed by rescue with peripheral stem cells shows promise [14]. The introduction of 4-iodo-4-deoxydoxorubicin, which has an affinity for amyloid fibrils, may be an important treatment option [15].

OTHER THERAPY FOR PRIMARY AMYLOIDOSIS High-dose dexamethasone Stem cell transplantation 4’-iodo-4’-deoxydoxorubicin

Secondary Amyloidosis CAUSES OF SECONDARY AMYLOIDOSIS Cause

PRESENTING CLINICAL FEATURES OF SECONDARY AMYLOIDOSIS

Patients, n Feature

Rheumatic disease Rheumatoid arthritis Ankylosing spondylitis Other Total Infection Inflammatory bowel disease Bronchiectasis Osteomyelitis Other Total Malignancy None

Proteinuria or renal insufficiency Diarrhea, obstipation, or malabsorption Goiter Hepatomegaly Neuropathy or carpal tunnel syndrome Lymphadenopathy Hematuria Cardiac amyloidosis

31 5 6 42 6 5 5 3 19 2 1

FIGURE 3-42 Causes of secondary amyloidosis. Rheumatoid arthritis is the most frequent cause of secondary amyloidosis. In our study of 64 patients, rheumatoid arthritis was present for a median of 18 years before the diagnosis was made [16]. Inflammatory bowel disease, bronchiectasis, and osteomyelitis are not uncommon causes of secondary amyloidosis. (From Gertz and Kyle [16]; with permission.)

19

Patients, n

17 14

15 10

17

17 14

14

7

5 0 1–3 3–8 >8 0 24-h urinary protein, g/d n=55

91 22 9 5 3 2 2 0

FIGURE 3-43 Presenting features of secondary amyloidosis. Proteinuria is the most frequent laboratory finding in patients with secondary amyloidosis. Involvement of the gastrointestinal tract as manifested by diarrhea, obstipation, or malabsorption occurred in one fifth of our patients. Treatment of secondary amyloidosis depends on the underlying disease. Familial Mediterranean fever frequently is associated with secondary amyloidosis unless the patient is treated with colchicine. (From Gertz and Kyle [16]; with permission.)

FIGURE 3-44 Proteinuria and renal insufficiency in patients with secondary amyloidosis. The clinical target organ was the kidney in 91% of patients. (From Gertz and Kyle [16]; with permission.)

25 20

Patients, %

≤1 1.1–2 2.1–4 >4 Serum creatinine, mg/dL n=64

Amyloidosis

100 Creatinine <2.0 mg/dL, n=32 Creatinine ≥2.0 mg/dL, n=32 P=0.003

Survival, %

80

3.13

FIGURE 3-45 Association between serum creatinine levels and survival in patients with secondary amyloidosis. A serum creatinine value of 2 mg/dL or more was associated with a shorter survival than was a value of less than 2 mg/dL. (From Gertz and Kyle [16]; with permission.)

60 40 20 0 0

24

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Not studied for variant transthyretin Met-30 Ala-60 Tyr-77 His-58 Leu-33 Studied—no variant transthyretin found Leu-64

3

FIGURE 3-46 Wide geographic distribution of familial amyloidosis. Familial or hereditary amyloidosis has an autosomal dominant pattern of inheritance. It accounts for 3.5% of our cases of amyloidosis. In our practice, the geographic distribution is wide and not associated with clustering. Frequently, a family history of amyloidosis was not obtained until after amyloidosis was diagnosed [17]. More than 50 transthyretin mutations have been recognized [18]. (Adapted from Gertz et al. [17]; with permission.)

3.14

Systemic Diseases and the Kidney

CLASSIFICATION OF FAMILIAL AMYLOIDOSIS Classification

Major protein component

Neuropathic: Portugal, Japan, Sweden, and other countries Cardiopathic: Denmark and Appalachia in the United States Nephropathic: familial Mediterranean fever

Transthyretin (prealbumin) Transthyretin (prealbumin) Protein A

FIGURE 3-47 Classification of familial amyloidosis. Clinically, familial amyloidosis can be classified most easily as neuropathic, cardiopathic, or nephropathic. The neuropathic form is characterized by a sensorimotor peripheral neuropathy beginning in the lower extremities. Disturbances

of bladder and gastrointestinal function are common. Late onset may occur with the development of symptoms in the seventh or eighth decade of life. The nephropathic form is most often caused by familial Mediterranean fever. This form affects persons of Mediterranean descent and is characterized by recurrent episodes of fever and abdominal pain that begin in childhood. Familial amyloidosis involving the kidneys has been reported by Ostertag [19] and others [20–22]. Families with apolipoprotein A1 mutation, as well as mutations in the fibrinogen -chain gene, have been recognized. On presentation, patients with renal involvement exhibit hypertension and mild renal insufficiency that progresses to endstage renal failure. The amyloid deposits have mutations in the fibrinogen -chain gene. This form of amyloidosis is autosomal dominant. No peripheral neuropathy develops, and the onset of renal disease occurs in the fifth to seventh decades of life. The mutation consists of the substitution of glutamic acid for valine at position 526 of the fibrinogen chain. A mutation in fibrinogen has been described at position 554 [23,24]. A rare form of inherited secondary amyloidosis produces nephropathy, deafness, and urticaria. This form has been referred to as the Muckle-Wells syndrome [25]. (Adapted from Kyle and Gertz [26].)

Dialysis-Associated Amyloidosis RATE OF AMYLOIDOSIS (2-MICROGLOBULIN) WITH DIALYSIS Years of dialysis 10 15 >20

FIGURE 3-48 Radiograph showing carpal tunnel syndrome in a patient with dialysis-associated amyloidosis. Long-term hemodialysis often results in carpal tunnel syndrome with pain involving the shoulders, hands, wrists, hips, and knees. Cystic radiolucencies are common in the carpal bones. Pathologic fractures have occurred from large amyloid deposits. The major component of the amyloid is 2-microglobulin. (From Gertz and Kyle [3]; with permission.)

Patients with amyloidosis, % 20 30–50 80–100

FIGURE 3-49 Amyloidosis (2-microglobulin) with dialysis. The duration of dialysis is directly associated with the incidence of amyloidosis. Dialysisassociated amyloidosis will develop in more than 80% of patients after 20 years of dialysis. It occurs with both hemodialysis and peritoneal dialysis. The amyloid deposition is systemic; however, involvement of visceral organs is usually modest [27,28]. Renal transplantation often leads to dramatic improvement in joint symptoms. A 2microglobulin–absorbent column may be useful in therapy [29].

Amyloidosis

3.15

References 1. Virchow R: Cited by Schwartz P: Amyloidosis: Cause and Manifestation of Senile Deterioration. Springfield, IL: Charles C Thomas; 1970. 2. Puchtler H, Sweat F: Cited by Elghetany MT, Saleem A: Methods for staining amyloid in tissues: a review. Stain Technol 1988, 63:201–212. 3. Gertz MA, Kyle RA: Amyloidosis. In Neoplastic Diseases of the Blood, edn 3. Edited by Wiernik PH, Canellos GP, Dutcher JP, et al. New York: Churchill Livingstone; 1996:635–677.

15. Gianni L, Bellotti V, Gianni AM, et al.: New drug therapy of amyloidoses: resorption of AL-type deposits with 4-iodo-4-deoxydoxorubicin. Blood 1995, 86:855–861. 16. Gertz MA, Kyle RA: Secondary systemic amyloidosis: response and survival in 64 patients. Medicine 1991, 70:246–256.

4. Kyle RA: Amyloidosis. In Hematology: Basic Principles and Practice. Edited by Hoffman R, Benz EJ Jr, Shattil SJ, et al. New York: Churchill Livingstone; 1991:1038–1047.

17. Gertz MA, Kyle RA, Thibodeau SN: Familial amyloidosis: a study of 52 North American-born patients examined during a 30-year period. Mayo Clin Proc 1992, 67:428–440. 18. Saraiva MJM: Molecular genetics of familial amyloidotic polyneuropathy. J Peripheral Nerv Syst 1996, 1:179–188.

5. Kyle RA, Gertz MA: Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995, 32:45–59.

19. Ostertag B: Demonstration einer eigenartigen familiaren “paraamyloidose” [abstract]. Zentralbl Allg Pathol 1932, 56:253–254.

6. Gertz MA, Kyle RA: Primary systemic amyloidosis: a diagnostic primer. Mayo Clin Proc 1989, 64:1505–1519.

20. Weiss SW, Page DL: Amyloid nephropathy of Ostertag with special reference to renal glomerular giant cells. Am J Pathol 1973, 72:447–460.

7. Kyle RA, Greipp PR: Amyloidosis (AL): clinical and laboratory features in 229 cases. Mayo Clin Proc 1983, 58:665–683. 8. Gertz MA, Kyle RA, Greipp PR: Hyposplenism in primary systemic amyloidosis. Ann Intern Med 1983, 98:475–477.

21. Lanham JG, Meltzer ML, De Beer FC, et al.: Familial amyloidosis of Ostertag. Q J Med 1982, 51:25–32.

13. Dhodapkar M, Jagannath S, Vesole D, et al.: Efficacy of pulse dexamethasone (DEX) plus maintenance alpha interferon (IFN) in primary systemic amyloidosis (AL) [abstract]. Blood 1995, 86(suppl 1):442A.

22. Mornaghi R, Rubinstein P, Franklin EC: Familial renal amyloidosis: case reports and genetic studies. Am J Med 1982, 73:609–614. 23. Benson MD, Liepnieks J, Uemichi T, et al.: Hereditary renal amyloidosis associated with a mutant fibrinogen alpha-chain. Nat Genet 1993, 3:252–255. 24. Uemichi T, Liepnieks JJ, Benson MD: Hereditary renal amyloidosis with a novel variant fibrinogen. J Clin Invest 1994, 93:731–736. 25. Muckle TJ: The “Muckle-Wells” syndrome. Br J Dermatol 1979, 100:87–92. 26. Kyle RA, Gertz MA: Amyloidosis of the liver. In Schiff’s Diseases of the Liver, edn 8. Edited by Schiff ER, Sorrell MF, Maddrey WC. Philadelphia: Lippincott-Raven; in press. 27. Gejyo F, Arakawa M: 2-microglobulin-associated amyloidoses. J Intern Med 1992, 232:531–532. 28. Kay J: 2-Microglobulin amyloidosis. Int J Exp Clin Invest 1997, 4:187–211.

14. Comenzo RL, Vosburgh E, Sarnacki DL, et al.: High-dose melphalan with blood stem-cell support for AL amyloidosis [abstract]. Blood 1995, 86 (suppl 1):206A.

29. Gejyo F, Homma N, Hasegawa S, et al.: A new therapeutic approach to dialysis amyloidosis: intensive removal of 2-microglobulin with adsorbent column. Artif Organs 1993, 17:240–243.

9. Gertz MA, Kyle RA, O’Fallon WM: Dialysis support of patients with primary systemic amyloidosis: a study of 211 patients. Arch Intern Med 1992, 152:2245–2250. 10. Gastineau DA, Gertz MA, Daniels TM, et al.: Inhibitor of the thrombin time in systemic amyloidosis: a common coagulation abnormality. Blood 1991, 77:2637–2640. 11. Gertz MA, Li C-Y, Shirahama T, Kyle RA: Utility of subcutaneous fat aspiration for the diagnosis of systemic amyloidosis (immunoglobulin light chain). Arch Intern Med 1988, 148:929–933. 12. Kyle RA, Gertz MA, Greipp PR, et al.: A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med 1997, 336:1202–1207.

Sickle Cell Disease L.W. Statius van Eps

H

errick [1] was the first to discover sickle cell hemoglobin (2 S2) with sickle-shaped erythrocytes. In 1910, he described the case of a young black student from the West Indies with severe anemia characterized by “peculiar elongated and sickle-shaped red blood corpuscles.” Herrick also noted a slightly increased volume of urine of low specific gravity and thus observed the most frequent feature of sickle cell nephropathy: inability of the kidney to concentrate urine normally.

CHAPTER

4

4.2

Systemic Diseases and the Kidney

Sickle Cell Nephropathy The term sickle cell nephropathy encompasses all the structural and functional abnormalities of the kidneys seen in sickle cell disease. These renal defects are most pronounced in homozygous sickle cell anemia (Hb SS), double heterozygous sickle cell hemoglobin C disease (Hb SC), sickle cell hemoglobin D dis-

ease, sickle cell hemoglobin E disease (SE) disease, and sickle cell -thalassemia. Identification of this familial autosomal codominant disorder as an abnormality of the hemoglobin molecule was made in 1949 by Pauling and coworkers [2].

Sickle Cell Anemia In 1959, Ingram [3] discovered the exact nature of the defect: substitution of valine for glutamic acid at the sixth residue of the  chain, establishing sickle cell anemia as a disease of molecular structure, “a molecular disease” based on one point mutation. It is most fascinating that one substitution in the gene encoding, with the resulting replacement of 6 glutamic acid by valine, leads to the protean and devastating clinical manifestations of sickle cell disease. The structural and functional abnormalities in the kidneys of patients with sickle cell disease, all resulting from that one point mutation, are described and discussed. When sickle hemoglobin (Hb S) is deoxygenated the replacement of 6 glutamic acid with valine has as a consequence a hydrophobic interaction with another hemoglobin molecule (reproduced schematically in Fig. 4-3). One of the two  subunits forms a hydrophobic contact with an acceptor site on a  subunit of a neighboring  chain. An aggregation into large polymers is triggered. The twisted ropelike structure to the right is a polymer composed of 14 strands. In a concentrated solution of deoxygenated Hb S, large polymers and free tetramers are demonstrated readily. However, species of intermediate size cannot be detected. This means

polymerization of Hb S occurs easily and can be regarded as a simple crystal solution equilibrium [4]. As a rule, renal hemodynamics are either normal or supernormal in patients with Hb SS and who are less than 30 years of age. The filtration fraction (glomerular filtration rate/effective renal plasma flow) has been found to be decreased (mean, 14% to 18%; normal, 19% to 22%). It has been suggested that selective damage of the juxtamedullary glomeruli might result in a lower filtration fraction because these nephrons appear to have the highest filtration fractions. Microradioangiographic studies lend support to this suggestion [5]. Speculation exists as to the possible mechanisms responsible for the decline in renal hemodynamics with age, sometimes ending in renal failure with shrunken end-stage kidneys. This decline could be the result of the loss of medullary circulation, as suggested by the microradioangiographic studies. Another possible mechanism is the relationship between supernormal hemodynamics, hyperfiltration, and glomerulosclerosis [6]. An inability to achieve maximally concentrated urine has been the most consistent feature of sickle cell nephropathy.

Sickle Cell Disease

4.3

Molecular Pathogenic Mechanisms and Sickling EF1

EF F'

β2

β1

F1 A9

H23

E'

F

A

H15

E7

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H'

H9 G9

FG4

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B9

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B

E7

E7

E

F8

H

F

H15

E'

A12

A

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α2

A'

F8

H

B1

FIGURE 4-1 Three-dimensional drawing of a hemoglobin molecule. Shown are the interrelationship of the two  and two  chains, localization of the helices, amino acids in the chains, and iron molecules in the porphyria structure. Of the 1 and 2 chains the helical and nonhelical segments can be identified easily. The individual amino acids are marked as circles and connected to each other. The dark rectangles represent the heme group, and within their center is the iron molecule. These heme groups are localized between the E and F helices. The helices in a hemoglobin molecule are designated by letters from A to H, starting from the amino end. The whole molecule has a spherical form with a three-dimensional measurement of 64 by 55 by 50 Å. (Adapted from Dickerson and Geis [7]; with permission.)

α1

A1

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EF1

Respiratory Movement of the Hemoglobin Molecule Shift of β chains F

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B

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G

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Oxyhemoglobin

C

GH

A F

F

B

D H

F'

G

Deoxyhemoglobin

α2

FIGURE 4-2 Respiratory movement of a hemoglobin molecule. From a functional point of view the so-called respiratory movement of the hemoglobin molecule is of great importance. When the four oxygen atoms bind to oxyhemoglobin, the firmly bound 1-1 and 1-2 move away from each other slightly. After full oxygenation the heme groups of the  chains are 7 Å closer to each other (R configuration). After deoxygenation the opposite occurs (T configuration). This “respiratory movement” (R indicates the relaxed and T the tense configuration) is of great importance in our understanding of the pathogenesis of sickling: polymerization occurs when the T configuration takes place. (Adapted from Dickerson and Geis [7]; with permission.)

4.4

Systemic Diseases and the Kidney

β

α

β

α

α

β

α

β

FIGURE 4-3 Schematic representation of the interactions of sickle red cells. Sickle red cells (dark circles) traverse the microcirculation, releasing oxygen from oxyhemoglobin, and change into deoxyhemoglobin (light circles). Deoxygenation of hemoglobin S induces a change in conformation in which the  subunits move away from each other. The hydrophobic patch at the site of the 6 where the valine replacement has occurred (shown as a projection) can bind to a complementary hydrophobic site of the 6 valine replacement (shown as an indentation). This mechanism is important for the formation of a polymer (see Fig. 4-4). The diagram to the right shows the assembly of deoxyhemoglobin S into a helical 14-strand fiber: a polymer is formed (see Fig. 4-5). As the deoxyhemoglobin S polymerizes and fibers align, the erythrocyte is transformed into a “sickle” shape, observed at the bottom by scanning electron micrography. (Adapted from Bunn [4]; with permission).

O2

β β

α

β

α

α

α α

β β

β

α

β

β

α

α

β

β

α

α

β

α α

β

Cell Polymer

Nucleation

Alignment

Growth

FIGURE 4-4 Polymerization of sickle cell hemoglobin. This polymerization occurs in three stages: 1) nucleation, 2) fiber growth, and 3) fiber alignment. The end stage is a complicated structure for a helical fiber: four inner fibers surrounded by 10 outer filaments. Sickling, the process of polymerization, occurs under three different circumstances: 1) deoxygenation, 2) acidosis, and 3) extracellular hyperosmolality. These circumstances produce shrinking of the erythrocytes that causes elevation of the intracellular hemoglobin concentration. This mechanism occurs in the inner medulla of the kidney and renal papillae as a result of countercurrent multiplication. Extracellular osmolality increases with the results previously mentioned [8].

Sickle Cell Disease

4.5

Electron Microscopy and Three-Dimensional Reconstruction of a Polymerized Fiber of Hemoglobin FIGURE 4-5 Structures of polymerized fibers. A, Electron microscopy of a polymerized fiber of hemoglobin S. B–D, Structures of a three-dimensional reconstruction of such a fiber. Each small sphere represents a Hb S tetramer. B, A complete fiber, consisting of 14 grouped filaments in helical structure. C, The inner core of four filaments. D, A combination of inner and outer filaments. (From Edelstein [9]; with permission.)

A

B

C

D

Polymerization of Hemoglobin S

A FIGURE 4-6 Polymerization of hemoglobin S. Polymerization of deoxygenated hemoglobin S is the primary event in the molecular pathogenesis of sickle cell disease, resulting in a distortion of the shape of the erythrocyte and a marked decrease in its deformability. These rigid cells are responsible for the vaso-occlusive phenomena that are the hallmark of the disease [4]. Interesting shapes of variable forms result depending

B on the localization of the polymers in the cell. A collection of electron microscopy scans of sickle cells undergoing intracellular polymerization is shown here. The slides were created in different laboratories. A, Characteristic peripheral blood smear from a patient with sickle cell anemia. Extreme sickled forms and target cells are seen. B, Electron microscopy scan of normal erythrocytes. (Continued on next page)

4.6

Systemic Diseases and the Kidney

C

D

F

G

H

I

E

J FIGURE 4-6 (Continued) C, Electron microscopy scan of a normal erythrocyte and a sickle cell. D–L, This series of sickle cells show many possible formations of sickled erythrocytes. The variety of shapes results from the intracellular localization of the polymers. In bananaor sickle-shaped cells the polymers have formed bundles of fibers oriented along the long axis of the cell. In cells with a hollyleaf shape (panel E), the hemoglobin fibers point in different directions.

K

L

Sickle Cell Disease

4.7

Types of Sickle Cells and Released Membrane Structures

A

B

C

D

E

FIGURE 4-7 Types of sickle cells and released membrane structures. Franck and coworkers [10] reported that the normal membrane phospholipid organization is altered in sickled erythrocytes. These authors presented evidence of enhanced trans-bilayer movement of phosphatidylcholine in deoxygenated reversibly sickled cells and put forward the hypothesis that these abnormalities in phospholipid organization are confined to the characteristic protrusions of these cells. Scanning electron micrographs of various types of sickle cells and released membrane structures are shown. A, Deoxygenated despicular red sickle cells (RSC). B, Deoxygenated native RSC. C, Oxygenated irreversibly sickled cell. D, Spicules. E, Purified microvesicles. The free spicules released from RSC by repeated sickling and unsickling as well as the remnant despicular cells were studied by following the fate of 14C-labeled phosphatidylcholine. The results are shown in Figure 4-8. The free spicules have the same lipid composition as do the native cell but are deficient in spectrin. These spicules markedly enhance the rate of thrombin and prothrombin formation, explaining the prethrombotic state of the patient with sickle cell disease and the tendency toward the occurrence of crises. The prethrombotic state, also present in the renal circulation, stimulates sickle cell formation occurring in the inner renal medulla and papillae where hyperosmosis also contributes to sickling and microthrombi formation in the vasa recta. (From Franck and coworkers. [10]; with permission.)

4.8

Systemic Diseases and the Kidney

Penetration and Deconstruction of the Erythrocyte Membrane Spicule formation in sickled erythrocyte

Spicule formation in sickled erythrocyte

A

B

Band 3

C

Actin

Band 4.1

Spectrin

Ankyrin

FIGURE 4-8 Penetration and destruction of the erythrocyte membrane. A, The membrane is penetrated and destroyed by the intracellular formation of polymers, resulting in spicule formation. B, Interruption of the binding between the membrane and protein skeleton results in a massive exchange of lipids between the inside and outside of the cell. This process is called flip-flop. An abnormal membrane skeleton causes an increased flip-flop. The result in the spicule is a change of the chemical structure, increasing the tendency toward coagulation of sickle cell blood (prethrombotic state). C, The relationship between the protein skeleton of the erythrocyte and lipid membrane is shown. (Adapted from Franck [11]; with permission.)

Sickle Cell Disease

B

A

D

C

E

FIGURE 4-9 Macroscopy and microradioangiographs of sickle cell kidneys. The kidneys of patients with sickle cell disease usually are of near normal size, and most kidneys show no significant gross alterations. Abnormalities can be expected in the renal medulla as erythrocytes form sickles more readily in the relatively hypoxic and hyperosmotic renal medulla than in other capillary circulations. Formation of microthrombi causes further impairment of the vasa recta circulation. A and B, Injection microradioangiographs of the kidney in a person without hemoglobinopathy are shown: the entire kidney (panel A) and a detailed view (panel B). C and D, Injection microradioangiographs of the kidney in a patient with sickle cell disease are shown: the entire kidney (panel C) and a detailed view (panel D). E, Injection microradioangiograph of a kidney in a patient with sickle cell hemoglobin C disease . In the normal kidney (panel A), vasa recta are visible radiating into the renal papilla. In sickle cell anemia (panel D), vasa recta are virtually absent. Those vessels that are present show abnormalities: they are dilated, form spirals, end bluntly, and many appear to be obliterated. In the patient with hemoglobin SC (panel E) changes are seen intermediately between patients with hemoglobin SC and normal persons. (From van Eps et al. [5]; with permission.)

4.9

4.10

Systemic Diseases and the Kidney

Renal Concentrating Mechanism in a Normal Person Juxtamedullary nephron

600

Cortex

Urine osmolality, mosmol/kg

1200

400

0 5 10 50 100 Urine arginine vasopressin, pg min–1 C –1osm

500

FIGURE 4-10 A–H, Models to demonstrate the principle of countercurrent multiplier in creating high urine concentration. The first panel illustrates the relation between urine osmolality and arginine vasopressin excretion. The long loops of Henle and their accompanying vasa recta reaching the papillae comprise only 15% of the total nephron population but are necessary for producing concentrated urine [12]. As seen, the mechanisms of countercurrent multiplication and countercurrent exchange create an increase in osmolality in the kidney from 280 mOsm at the cortex to about 1200 mOsm/kg H2O in the inner medulla and papillae. Reabsorption in the collecting ducts results in production of highly concentrated urine.

Medulla

1

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Thin segment

Vasa recta

(Continued on next page) B

Sickle Cell Disease FIGURE 4-10 (Continued)

Urine concentration and dilution: countercurrent multiplier

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4.11

4.12

Systemic Diseases and the Kidney FIGURE 4-10 (Continued)

Urine concentration and dilution: countercurrent diffusion (exchange)

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Sickle Cell Disease FIGURE 4-10 (Continued) Urine concentration and dilution: diluting kidney

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4.13

4.14

Systemic Diseases and the Kidney FIGURE 4-10 (Continued)

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Sickle Cell Disease

4.15

Relationship Between Maximal Urinary Osmolality and Age Maximum osmolality, mosm/kg H2O

Hemoglobin AA

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ACo CCo

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20 40 60 80

FIGURE 4-11 Relationship between maximal urinary osmolality and age in normal subjects and in patients with hemoglobinopathies. Results of an investigation into a large group of normal persons and those with homozygotous hemoglobin disease (Hb SS; Hb SS + Hb F),

heterozygotous hemoglobin disease (Hb AS), sickle cell hemoglobin C disease (SC), hemoglobin C trait (AC), and hemoglobin C disease (Hb CC). Normal persons have a mean maximal urinary osmolality of 1058 ±SD 128 mOsm/kg H2O. The most marked impairment in concentrating capacity occurs in Hb SS disease. Maximal urinary osmolality decreases significantly in the first decade of life and stabilizes in patients over 10 years of age at a mean of 434 ±SD 21 mOsm/kg H2O. The measurement has been designated the fixed maximum of sickle cell nephropathy. In patients with Hb AS and Hb SC, a progressive decrease in maximal urinary osmolality can be observed with age. C hemoglobin alone (AC or CC) does not impair the concentrating ability of the kidneys. The renal concentrating capacity of the heterozygote (Hb AS) also is affected, but only later in life. (Adapted from van Eps et al. [13]; with permission.)

Relationship Between Nephron with Long Loops and Those with Short Loops of Henle

Cortex

Subcortex

Outer medulla

Inner medulla

FIGURE 4-12 Relationship between nephron with long loops and those with short loops of Henle. In the normal human kidney, approximately 85% of the nephrons have short loops of Henle restricted to the outer medullary zone. These nephrons may be largely responsible for achieving the interstitial osmolality of about 450 mOsm/kg H2O that exists at the transition of the outer and inner medulla. The remaining 15% of human nephrons are juxtamedullary nephrons with long loops of Henle, extending into the inner medullary zone and renal papillae. Together with the parallel hairpin vasa recta, these units are responsible for further increasing interstitial osmolality during antidiuresis to about 1200 mOsm/kg H2O at the tip of the papillae. In experiments with rats, selectively removing the papillae destroys only nephrons originating in the juxtamedullary cortex. In such animal preparations, a severe loss of concentrating capacity during fluid deprivation has been observed. Thus, juxtamedullary nephrons are necessary for achieving a maximal urine osmolality. These pathophysiologic mechanisms help clarify the abnormal findings in sickle cell nephropathy. On the basis of these mechanisms, the concentrating defect in sickle cell disease can be explained as a consequence of the sickling process per se and the resultant ischemic changes in the medullary microcirculation [5]. It has been demonstrated that Hb SS erythrocytes form sickle erythrocytes within seconds when placed in surroundings as hyperosmotic as is the renal medulla during hydropenia [8]. Sickling of renal blood cells causes a significant increase in blood viscosity that could interfere with the normal circulation through the vasa recta, preventing both active and passive accumulation of solute in the papillae necessary to achieve maximally concentrated urine. Increased viscosity of blood and intravascular aggregations of Hb SS erythrocytes could also produce local hypoxia and eventually infarction of the renal papillae.

4.16

Systemic Diseases and the Kidney

Relationship Between Concentrating Capacity and Patient Age Aug. Sept. 31 10

20

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Nov. 10

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W.J. 4 y. Red blood cellsuspension 175 mL Hemoglobin, Hb % content, g%

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CInuline , CCreatinine , Urine osmolality, mL/min mL/min mosm/kg H2O

100 0

Filtration fraction, %

S

F

20

Mar. 1

FIGURE 4-13 A–E, Relationship between concentrating capacity and patient age. Over a prolonged period, we investigated the effect of multiple transfusions of hemoglobin A erythrocytes into children and adults with sickle cell anemia (4, 7, 11, 15, and 40 years). In the first panel, the effects of multiple transfusions of normal blood given to a 4-yearold boy with homozygotic sickle cell anemia. A significant improvement in concentrating capacity can be observed. This diminishes in older patients. (Continued on next page)

900 700 500 200 50 200

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4.17

Sickle Cell Disease

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4.18

Systemic Diseases and the Kidney FIGURE 4-13 (Continued)

Dec. Feb. '62 '65 Apr. May June July 29 25 22 30 10 20 30 10 20 30 10 20 M.K. 15 y.

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Sickle Cell Disease

4.19

Relationship Between Age and Ability to Reverse the Defect in Urinary Concentration by Blood Transfusions 8 patients; van Eps [12]

1100

Maximal urinary osmolality, mosm

FIGURE 4-14 Relationship between age and ability to reverse the defect in urinary concentration by blood transfusions in patients with sickle cell disease. A, The maximal urinary osmolality achieved before transfusion (lower point of each vertical line) and after multiple transfusions with normal blood (upper point of each vertical line) in 14 patients with sickle cell disease, ranging in age from 2 to 40 years. B, The percentage of increase in maximal urinary osmolality resulting from transfusion. Maximal urinary osmolality before transfusion is depressed at all ages; significant improvement after transfusion occurs only in children and adolescents. (From van Eps et al. [13]; with permission.)

6 patients; Keitel [13]

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Length of the Loops of Henle in Animals Correlated with Kidney Concentrating Capacity Sickle cell kidney Beaver kidney Long loops of Henle not functioning or absent

Normal kidney 14% juxtamedullary nephrons with long loops Medulla Inner zone

Outer

Cortex

Sickle cell trait: Progressive loss in 70 y of inner medullary concentrating function Sickle cell anemia: A. Up to about 15 y: reversible concentrating defect B. Over 15 y: complete and irreversible loss of inner medullary concentrating function

A

FIGURE 4-15 Length of the loops of Henle in animals correlated with kidney concentrating capacity. A, Investigations of animal species [14] with different lengths of the loops of Henle and correlation with the concentrating capacity of their kidneys reveal their relationship. B, Desert animals with very long loops of Henle can produce highly concentrated urine; in contrast, beavers living in water-rich surroundings have only short loops of Henle and cannot produce urine concentrate over 450 mOsm. (Continued on next page)

4.20

Systemic Diseases and the Kidney

B

Beaver

Rabbit

FIGURE 4-15 (Continued) In sickle cell disease the long loop of Henle has been obliterated and the concentrating capacity of the kidney is not higher than

Psammomys

400 mosm, much as in beavers. An overview has been reproduced. (From van Eps and De Jong [15]; with permission.)

Urinary Acidification SS Anemia 70

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FIGURE 4-16 A, Urinary acidification. Patients with hemoglobin SS or SC demonstrate an incomplete form of renal tubular acidosis. In response to a short-duration acid load, all of the patients studied by Goossens and coworkers [16] with otherwise normal renal function were unable to decrease urine pH below 5.3, whereas normal persons achieve a urinary pH of 5.0 or lower. Titrateable acid (TA) and total hydrogen ion excretion are lower in patients with Hb SS or Hb SC; however, in most cases, ammonia excretion is appropriate for the coexisting urine pH. The acidification defect has been classified as distal rather than proximal, because no associated wasting of bicarbonate occurs, and the acidification defect is characterized by failure to achieve a normal minimal urinary pH during acid loading. Investigators from several centers have found no evidence of metabolic acidosis in the absence of a sickle cell crisis; however, they have found changes consistent with mild chronic respiratory alkalosis [15].

2

4

6 Time, h

8

10

Sickle Cell Disease

FIGURE 4-16 (Continued) B, Relationship between renal concentrating and acidifying capacity in Hb AS, SC, and SS and in normal persons [16].

SC SS

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4.21

Maximal urinary osmolality

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FIGURE 4-17 Relationship between Cp/glomerular filtration rate and serum phosphate. Closed circles represent values for patients who had fasted from food and drink; open circles are values obtained when UpV was 0.032 mmol/min. The continuous line shows the mean of the values in patients with sickle cell anemia, and the hatched area indicates the range for normal persons. Cp—clearance of phosphate; TmP/GFR—tubular maximum reabsorption of phosphate/ glomerular filtration rate. (Adapted from De Jong and coworkers [17]; with permission.)

4.22

Systemic Diseases and the Kidney

Blood Pressure in Sickle Cell Disease Male

180

Female

ns

ns

ns

ns

<0.05

<0.01

<0.01

<0.01

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ns

<0.02

<0.05

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160 140

mm Hg

FIGURE 4-18 Blood pressure and sickle cell anemia. Mean standard deviation of systolic and diastolic blood pressure in control subjects (dotted lines) and patients with sickle cell anemia (closed lines) who are matched for age and gender. (From De Jong and van Eps [20].)

120

Diastolic

100 80 60

15–24 25–34 35–44 45–54

<0.05 P

15–24 25–34 35–44 45–54 Age, y

References 1. Herrick JB: Peculiar elongated and sickle shaped red blood corpuscles in a case of severe anemia. Arch Intern Med 1910, 6:517. 2. Pauling L, et al.: Sickling cell anemia, molecular disease. Science 1949, 110:543. 3. Ingram VM: Gene mutations in human hemoglobin: the chemical difference between normal and sickle cell hemoglobin. Nature 1959, 180:326. 4. Bunn HF: Mechanisms of disease: pathogenesis and treatment of sickle cell disease. N Engl J Med 1997, 337:762–769. 5. Statius van Eps LW, Pinedo Veels C, De Vries H, De Koning J: Nature of concentrating defect in sickle cell nephropathy, microradioangiographic studies. Lancet 1970, 1:450. 6. Hostetter TH, et al.: Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am J Physiol 1981, 241:F85. 7. Dickerson RE, Geis I: The Structure and Action of Proteins. New York: Harper and Row, 1969, 1971. 8. Perillie PE, Epstein, FH: Sickling phenomenon produced by hypertonic solutions: a possible explanation for the hyposthenuria of sicklemia. J Clin Invest 1963, 42:570. 9. Edelstein SJ: Structure of the fibers of hemoglobin S: human hemoglobins and hemoglobinopathies: a review to 1981. Galveston: University of Texas; 1981. 10. Franck PF, Bevers EM, Lubin BH, et al.: Uncoupling of the membrane skeleton from the lipid bilayer: the cause of accelerated phospholipid flip-flop leading to an enhanced procoagulant activity of sickled cells. J Clin Invest 1985, 75:183–190.

11. Frank PFH: Studies on the phospolid organization in membranes of abnormal erythrocytes [PhD thesis]. Utrecht: State University of Utrecht; 1984. 12. Statius van Eps LW, Schouten H, Ter Haar Romeny Wachter CCh, la Porte-Wijsman LW: The relation between age and renal concentrating capacity in sickle cell disease and hemoglobin C disease. Clin Chim Acta 1970, 27:501. 13. Statius van Eps LW, Schouten H, la Porte-Wijsman LW, Struyker Boudier AM: The influence of red blood cell transfusions on the hyposthenuria and renal hemodynamics of sickle cell anemia. Clin Chim Acta 1967, 17:449. 14. Schmidt-Nielsen B, O’Dell R: Structure and concentrating mechanism in the mammalian kidney. Am J Physiol 1961, 200:1119. 15. Keitel HG, et al.: Hyposthenuria in sickle cell anemia: a reversible renal defect. J Clin Invest 1956, 35:998. 16. Statius van Eps LW, De Jong PE: Sickle cell disease. In Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown; 1997:2201. 17. Goossens JP, Statius van Eps LW, Schouten H, Gieterson AL: Incomplete renal tubular acidosis in sickle cell disease. Clin Chim Acta 1972, 41:149. 18. De Jong PE, et al.: The tubular reabsorption of phosphate in sickle cell nephropathy. Clin Sci 1978, 55:429. 19. De Jong PE, Landman H, Statius van Eps LW: Blood pressure in sickle cell disease. Arch Intern Med 1982, 142:1239. 20. De Jong PE, Statius van Eps LW: Sickle cell nephropathy: new insights into its pathophysiology. Editorial review. Kidney Int 1985, 27:711.

Renal Involvement in Malignancy Richard E. Rieselbach A. Vishnu Moorthy Marc B. Garnick

P

atients with malignancy are particularly vulnerable to development of renal abnormalities [1]. Additionally, patients with renal abnormalities who have undergone kidney transplantation are at increased risk for malignancy, which may involve the kidney [2]. Malignancy may directly involve the urinary tract. More commonly, however, the many systemic manifestations of cancer and the toxicity of its treatment are involved in the pathogenesis of diverse clinical syndromes involving the kidney [3]. Malignant neoplasms directly involving the renal parenchyma, renal pelvis, or ureter may be primary or secondary in origin. Metastatic neoplasms are the cause of renal malignancy more frequently than primary tumors. These secondary lesions are usually asymptomatic, however, and most often are discovered incidentally only at postmortem examination [4]. Additionally, extrarenal malignancy may involve the kidney by producing obstruction of urine flow via extrinsic compression of the urinary tract. This occurs most often with gynecologic and other pelvic neoplasms in women and with prostatic cancer in men. Systemic manifestations of cancer may involve the kidney via formation of immune complexes, which may produce glomerulonephritis [5]. Also, paraproteins generated by multiple myeloma and other lymphoid neoplasms may produce renal dysfunction [6]. In addition to tumor products, malignancy-induced metabolic abnormalities, such as hypercalcemia and hyperuricemia, may impair renal function. Finally, a high percentage of cancer patients are candidates for aggressive chemotherapy or radiation therapy, or both. Nephrotoxicity due to chemotherapy may manifest as acute renal failure, chronic renal failure, or specific tubular dysfunction causing fluid and electrolyte imbalance [7]. The nephrotoxicity of radiation therapy may be synergistic with that of chemotherapy in some settings, or radiation therapy may by itself produce significant renal damage.

CHAPTER

5

5.2

Systemic Diseases and the Kidney

CLINICAL SYNDROMES OF RENAL INVOLVEMENT IN MALIGNANCY Acute renal failure Prerenal Intrinsic Postrenal Hematuria and/or nephrotic syndrome Chronic renal failure Specific tubular dysfunction and associated fluid and electrolyte disorders Malignancy in the renal transplant patient

FIGURE 5-1 Clinical syndromes of renal involvement in malignancy. Renal involvement in malignancy may present as one or more of four clinical syndromes. Additionally, the incidence of a broad spectrum of malignancies is increased in the renal transplant patient, and the malignancy may directly involve the transplanted kidney.

Prerenal Acute Renal Failure CAUSES OF PRERENAL ACUTE RENAL FAILURE Clinical syndrome

Cause

ECF volume contraction (hypovolemia)

External fluid loss (skin, gastrointestinal, renal, hemorrhage) Internal fluid loss (peritonitis, bowel obstruction, acute pancreatitis, hemorrhage, malignant effusion) Sepsis Anaphylaxis Anesthesia Drug overdose Myocardial infarct, failure Arrhythmia Pericardial tamponade Pulmonary embolus Arterial Venous Hepatorenal syndrome Drugs that inhibit prostaglandin synthesis

Peripheral vasodilation

Impaired cardiac function

Bilateral extrarenal vascular occlusion Functional disorders of intrarenal circulation

FIGURE 5-2 Causes of prerenal failure (ARF). Prerenal ARF is encountered frequently in the cancer patient, particularly in association with depletion of the extracellular fluid (ECF) volume, which is

caused by excessive loss from the gastrointestinal tract due to vomiting or diarrhea induced by cancer or its therapy. Also, hypovolemia may occur owing to internal fluid loss due to translocation of ECF volume with sequestration in third spaces, as seen in peritonitis, bowel obstruction, malignant effusion, or interleukin-2 therapy [8]. A decrease in effective intravascular volume may occur owing to peripheral vasodilation, as frequently noted in sepsis. A decrease in cardiac output due to cardiac tamponade secondary to malignant pericardial disease also may produce prerenal ARF. Hepatobiliary disease may cause alterations in intrarenal hemodynamics with resultant hepatorenal syndrome, as seen in hepatic veno-occlusive disease following bone marrow transplantation (see Fig. 5-3). The administration of nonsteroidal anti-inflammatory agents for analgesia in the cancer patient may lead to ARF by elimination of the prostaglandin-mediated intrarenal vasodilatation. This homeostatic mechanism represents a critical hemodynamic adjustment necessary for maintaining glomerular filtration rate in a patient with cancer in whom renal blood flow may be decreased owing to a variety of causes.

Renal Involvement in Malignancy 60 50 Azotemia

Patients, %

40 30 20

Tumor Stored lysis marrow syndrome toxicity

HUS CSA

ARF

10 0 –10 0 Conditioning

7

14

21 Time, d

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FIGURE 5-3 Time distribution and frequency of renal syndromes in the setting of bone marrow transplantation (BMT). The solid line depicts the approximate frequency of renal insufficiency, as defined by at least a doubling of the baseline serum creatinine concentration (azotemia); the dotted line represents the frequency of dialysis required because of acute renal failure (ARF). During the period of conditioning, tumor lysis syndrome and stored marrow-infusion toxicity are most common; 10 to 28 days after transplantation, the peak incidence of ARF is observed, most notably due to a hepatorenal-like syndrome associated with veno-occlusive disease (VOD). After 1 month, the hemolyt-

CAUSES OF INTRINSIC ACUTE RENAL FAILURE Glomerular abnormalities Tubular abnormalities

Interstitial abnormalities

Abnormalities of intrarenal blood vessels

Glomerulonephritis Hemolytic-uremic syndrome Ischemic acute tubular necrosis (ATN) Exogenous nephrotoxins Antineoplastic agents Antimicrobials Radiocontrast media Anesthetic agents Endogenous nephrotoxins Myoglobin Hemoglobin Immunoglobulins and light chains Calcium and phosphorus Uric acid and xanthine Drug-induced acute tubulointerstitial nephritis Acute pyelonephritis Tumor infiltration Radiation nephropathy Disseminated intravascular coagulation Hemolytic-uremic syndrome Malignant hypertension Vasculitis

FIGURE 5-4 The four major causes of malignancy-associated intrinsic acute renal failure (ARF). With glomerular abnormalities, the pathologic process most frequently involves diffuse proliferative or crescentic glomeru-

5.3

ic-uremic syndrome (HUS) can be observed. As noted, the greatest risk for development of ARF occurs 10 to 21 days after BMT, with the usual cause at this time being prerenal acute renal failure due to hepatic veno-occlusive disease. This causes a syndrome very similar to the hepatorenal syndrome (HRS). There are five clinical similarities between the two syndromes: 1) jaundice and portal hypertension precede the onset of ARF, 2) a very low fractional excretion of sodium always occurs, 3) the blood urea nitrogen (BUN)/creatinine ratio is very high, 4) mild hyponatremia and a decrease in systemic arterial blood pressure are usually present, and 5) postmortem examination of patients dying of this syndrome fails to reveal any structural or morphologic basis for ARF, suggesting a hemodynamic cause [9]. In contrast to the very high incidence of hepatic VOD in patients undergoing allogeneic BMT, autologous hematopoietic support is associated with a much lower incidence. A recent study evaluating renal function in 232 women treated with high-dose chemotherapy and autologous hematopoietic support for high-risk breast cancer revealed a frequency of hepatic VOD of 4.7 %, as compared with a reported incidence ranging from 22% to 53% in various series of patients undergoing allogeneic bone marrow transplantation [10]. In this series of autologous transplants, 21% of patients developed severe renal dysfunction, which correlated most significantly with sepsis, liver, and pulmonary disease. The major incidence of renal failure occurred during chemotherapy, before the initiation of hematopoietic cell support, thereby primarily incriminating the cytoreductive therapy rather than hematopoietic cell support [10]. CSA—cell surface antigen. (From Zager [9]; with permission.) lonephritis. Although immune-complex–mediated glomerular disease is not uncommon in patients with cancer [11], glomerular disease causing ARF in the cancer patient has been reported in only a few cases [12]. Hemolytic-uremic syndrome with vascular endothelial injury in both the glomeruli and the intrarenal blood vessels may occur in patients with disseminated malignancy or after chemotherapy for malignancy. With respect to tubular abnormalities, ARF may arise either on the basis of ischemia or as a result of exposure to exogenous or endogenous nephrotoxins. Renal ischemia is usually the initiating factor when ATN follows sepsis or shock or when it arises as a postsurgical complication. Cancer patients are particularly vulnerable to ARF induced by exogenous nephrotoxins in view of their frequent exposure to a wide variety of nephrotoxic drugs. The indicated nephrotoxins of endogenous origin are encountered with increasing frequency in the cancer patient. The most frequent cause of interstitial abnormalities is acute tubulointerstitial nephritis, which may be induced in cancer patients via hypersensitivity to various drugs. These patients frequently receive the analgesics and antimicrobials associated with this form of ARF. Immunosuppressed cancer patients may be particularly vulnerable to severe acute bacterial pyelonephritis. ARF may occur in this setting, even in the absence of urinary tract obstruction or another underlying renal disease [13]. Tumor infiltration of the kidney may involve the interstitium but rarely causes ARF [14]. Finally, radiation nephropathy may occur following radiation therapy for cancer and has been associated with ARF [15], although when it occurs, it more frequently produces chronic renal failure. The fourth major cause of intrinsic ARF is abnormalities of intrarenal blood vessels. Disseminated intravascular coagulation may occur in association with sepsis in the cancer patient [16]. In addition, because the cancer patient is more often older, atheroembolic disease or malignant hypertension must be considered as a possible cause of intrarenal vascular occlusion in the presence of ARF. Finally, vasculitis is a consideration, particularly in the presence of hepatitis B antigenemia.

5.4

Systemic Diseases and the Kidney

A

B

FIGURE 5-5 (see Color Plate) Hemolytic-uremic syndrome (HUS). A 46-year-old woman with metastatic carcinoma of the lung and congestive heart failure developed renal insufficiency over a 12-week period. A percutaneous renal biopsy revealed that several glomeruli had the acute changes of swelling and detachment of endothelial cells and luminal occlusion (panel A, periodic acid–Schiff stain). The arterioles and arteries showed intimal cellular swelling and hyperplasia and fibrin deposition. Immunofluorescence microscopy revealed glomerular fibrin deposition (panel B). Hemolytic-uremic syndrome is a thrombotic microangiopathy presenting as an acute illness characterized by renal failure, thrombocytopenia, and microangiopathic hemolytic anemia. Vascular and endothelial cell injury leads to microvascular thrombosis and ischemic organ damage. HUS can occur in diverse clinical settings, including metastatic carcinoma, particularly of the stomach, breast, or lung [17]. The initiating factor is presumably tumor emboli. These patients have an extremely poor prognosis and often die within a few weeks of diagnosis [18]. HUS also has been reported after chemotherapy for cancer. This form of chemotherapy-related HUS is mainly associated with mitomycin C but has also been noted after therapy with bleomycin and platinum-containing

agents. The risk of developing mitomycin C–induced HUS is 2% to 10%, and cumulative doses larger than 60 mg are often associated with the disease [19]. The patients with cancer are often in remission at the time of diagnosis. The mortality rate has been as high as 70%, usually in the first 2 months, and is related to renal failure and sepsis. The diagnosis of HUS should be considered in the clinical setting of acute renal failure associated with thrombocytopenia and microangiopathic hemolytic anemia with schistocytes (seen on a peripheral blood smear). The renal biopsy results show a variety of glomerular and vascular changes, such as endothelial cell swelling, detachment of thrombi, and thrombotic occlusion of the lumen. Fibrin is noted in the walls of blood vessels of glomeruli on immunofluorescence microscopy. On electron microscopy, endothelial cell swelling and detachment from the basement membrane, subendothelial granular material, and luminal thrombi may be seen in the glomeruli. Treatment is generally supportive, including dialysis. Hemolytic-uremic syndrome with vascular endothelial injury both in the glomeruli and in the intrarenal blood vessels may occur in patients with disseminated malignancy or after chemotherapy for malignancy.

FIGURE 5-6 Renal changes in humans following cisplatin administration. The proximal convoluted tubules are dilated and show coagulation necrosis of the epithelium and epithelial nuclear atypia. The tubular lumens contain eosinophilic material [20]. Cisplatin is the most frequently used antineoplastic agent for the treatment of solid tumors, and the pathogenesis of its nephrotoxicity has been studied extensively. Cisplatin-induced acute renal failure

(ARF) is dose related, nonoliguric, and usually reversible. The serum creatinine level may increase immediately after administration and often peaks in 3 to 10 days; dialysis is rarely required. Treatment protocols involving prehydration and vigorous diuresis with saline and mannitol have greatly decreased the incidence of ARF. A commonly used protocol involves initiating diuresis 12 to 24 hours before cisplatin administration. Cisplatin is then infused in isotonic saline over a 3-hour period, followed by an isotonic saline or mannitol infusion for 24 hours thereafter. Cisplatin is usually administered in daily divided doses for 5 days until the maximum dose is attained, usually not to exceed 120 mg/m2 of body surface area [7]. When this dose is exceeded, an unacceptable degree of nephrotoxicity may occur regardless of prophylactic protocols [21]. Hypomagnesemia is frequent in patients receiving cisplatin and may be severe (0.3 to 0.5 mEq/L). It is due to induction of a tubular reabsorptive defect [22]. Magnesium wasting may be present for many months but usually remits when cisplatin is discontinued. Associated hypocalcemia and hypokalemia may persist unless hypomagnesemia has been corrected. In recent years in some settings, cisplatin has been replaced with carboplatin, which is not nephrotoxic in usual doses (400 to 600 mg/m2). Transient ARF has been noted in patients receiving very high doses (1600 to 2400 mg/m2), however. (From Rieselbach and Garnick [1]; with permission.)

Renal Involvement in Malignancy

FIGURE 5-7 Methotrexate (MTX) nephrotoxicity. Renal biopsy specimen from a patient treated with 3 g/m2 of MTX followed by leucovorin who became dehydrated and developed acute renal failure. Precipitated material in the tubules (arrow) strongly reacted with a fluorescinated

CAUSES OF RENAL FAILURE IN MULTIPLE MYELOMA Cause

Pathogenesis

Light-chain cast nephropathy AL amyloidosis

Intratubular precipitation of light chains Deposition of amyloid fibers composed of light chains (Congo red positive) Nodular glomerulosclerosis with granular deposits (Congo red negative) of light chains along the basement membrane Often incidental finding at autopsy Rare cause of renal dysfunction Tubular toxicity of light chains

Light-chain deposition disease

Plasma cell infiltration of the kidney Fanconi’s syndrome and other tubular dysfunction Hypercalcemic nephropathy Acute uric acid nephropathy Radiocontrast nephropathy

Bone resorption causing hypercalcemia Renal tubular precipitation of uric acid following tumor lysis Interaction between light chains and radiocontrast agents

FIGURE 5-8 Renal failure in multiple myeloma. The patient with multiple myeloma is at increased risk for the development of acute renal failure [27]. In up to 25% of patients with multiple myeloma,

5.5

rabbit anti-MTX antibody [23]. MTX nephrotoxicity may occur with high-dose therapy (1 to 15 g/m2); at conventional doses, MTX does not produce nephrotoxicity. Before the importance of maintaining a high urinary volume and pH was realized, renal toxicity was noted in approximately 30% of treatment courses and was responsible for 20% of drug-related deaths during high-dose MTX-leucovorin rescue therapy [24]. MTX is excreted primarily by the kidneys by means of glomerular filtration and tubular secretion; more than 90% of an intravenous dose appears unchanged in the urine following conventional doses [25]. During high-dose infusions, urinary MTX levels exceed solubility and therefore drug precipitation occurs, as illustrated previously. At physiologic systemic pH, MTX is completely ionized; however, the un-ionized moiety predominates at the more acidic pH usually encountered within the distal nephron, with solubility being markedly reduced. Thus, patients receiving high-dose MTX therapy may be more prone to development of nephrotoxicity if they are dehydrated and excreting an acidic urine. The 7-OH metabolite of MTX also may precipitate within the nephrons. This metabolite may account for as much as 7% to 33% of the MTX appearing in the urine 24 to 48 hours after intravenous administration; its solubility is only 25% of that observed for MTX [26]. (From Rieselbach and Garnick [1]; with permission.) acute renal failure may be present at the time of initial diagnosis. In others, it may occur at any time during the disease. Renal failure can be due to diverse mechanisms. The light chains produced by the monoclonal B lymphocytes may be nephrotoxic [28]. While the toxicity of the light chains leads to a variety of tubular transport disorders, including Fanconi’s syndrome, the intratubular precipitation of these proteins causes light-chain cast nephropathy and acute renal failure. The light chains (usually lambda) may be transformed into Congo-red–positive amyloid fibrils and deposited diffusely throughout the body [29]. Deposition of amyloid in renal tissue results in the nephrotic syndrome and, often, renal failure. Biopsy of the kidney, abdominal fat pad, or rectal mucosa is useful in the diagnosis of AL amyloidosis. Light chains may also be deposited in a granular pattern along the basement membranes of blood vessels in a variety of organs. In the kidney, these deposits are noted in the glomeruli, causing an expansion of the mesangium, and appear as nodular glomerulosclerosis. This condition is referred to as light-chain deposition disease (LCDD) [30]. Other causes of renal failure in a patient with multiple myeloma include metabolic disturbances such as hypercalcemia and hyperuricemia. Hypercalcemia may be due to direct bone erosion by the malignant cells or to the elaboration of cytokines, which activate osteoclasts. The administration of radiocontrast agents to patients with multiple myeloma may lead to interaction with light chains and tubular precipitation, thereby causing acute renal failure. The prognosis for recovery from acute renal failure in a patient with multiple myeloma is generally poor unless reversible factors such as hypercalcemia or dehydration are responsible [27].

5.6

Systemic Diseases and the Kidney FIGURE 5-9 Light-chain cast nephropathy. The kidney at autopsy of a 68-yearold man with multiple myeloma who died 2 years after diagnosis owing to sepsis and renal failure. Note the dense, lamellated, and fractured casts in the renal tubules surrounded by multinucleated giant cells. There is also interstitial fibrosis.

FIGURE 5-10 Nephrocalcinosis in a patient with multiple myeloma. Irregular fractured hematoxylinophilic deposits of calcium are seen in this fibrotic renal tissue. Hypercalcemia may produce serious structural changes in the kidney, resulting in acute or chronic renal failure. Hypercalcemia is a relatively common complication of malignancy. Increased bone reabsorption is most often responsible owing to bone metastases or to the release of humoral substances such as parathyroid hormone–like peptide or cytokines such as transforming growth factor- [32]. Secretion of calcitriol, the active form of vitamin D, also may occur in some lymphomas [33]. Renal dysfunction in the setting of hypercalcemia results from both calcium-induced constriction of the afferent arteriole and the deposition of calcium in the tubules and interstitium, leading to intratubular obstruction and secondary tubular atrophy and interstitial fibrosis [34]. Prompt treatment generally restores renal function, but irreversible damage can occur with long-standing hypercalcemia [35]. Recovery of the glomerular filtration rate varies inversely with the extent of nephrocalcinosis, interstitial scarring, associated obstructive uropathy, infection, and hypertension. All the foregoing reflect the duration and severity of hypercalcemia. (From Skarin [31]; with permission.)

FIGURE 5-11 Acute uric acid nephropathy (AUAN). Intrarenal obstruction caused by uric acid precipitation in collecting ducts produces severe tubular dilatation (DeGalantha stain). This patient, who received chemotherapy for acute lymphocytic leukemia before allopurinol was available, had a plasma urate concentration of 44 mg/dL at the time of death. Acute uric acid nephropathy is most frequently encountered in patients with a large tumor burden (often due to rapidly proliferating lymphoma or leukemia) in whom aggressive radiation or chemotherapy has been recently initiated. If rapid lysis of tumor cells occurs, massive quantities of uric acid precursors (and often other tumor products) are released. This induces a marked increase in synthesis of uric acid and thus acute hyperuricemia. The subsequent renal uricosuric response may be of sufficient magnitude to exceed solubility limits for uric acid in the distal nephron, particularly in the presence of dehydration or metabolic acidosis. The resultant intrarenal obstruction produces a characteristic pattern of acute renal failure [36]. In the setting of particularly extensive disease with rapid cell lysis, profound hyperkalemia, hyperphosphatemia, and hypocalcemia (due to precipitation of calcium phosphate) may be observed. This is termed acute tumor lysis syndrome [37]. This syndrome usually occurs after treatment of poorly differentiated lymphoma or leukemia; if it arises spontaneously, hyperphosphatemia is not prominent because phosphate is incorporated into rapidly proliferating tumor cells. Rarely, xanthine nephropathy can occur during tumor lysis when allopurinol is used to prevent the production of uric acid. The resultant xanthine oxidase inhibition can produce a marked increase in blood and urine xanthine and hypoxanthine concentrations. Xanthine, like uric acid, is poorly soluble in an acidic urine; xanthine crystalluria occurs when its concentration exceeds its solubility, thereby causing obstructive nephropathy [38].

Renal Involvement in Malignancy

PROPHYLAXIS AND TREATMENT OF ACUTE URIC ACID NEPHROPATHY AND ACUTE TUMOR LYSIS SYNDROME Prophylaxis A. Patients presenting (before chemotherapy) with evidence of large, rapidly proliferating tumor burden and hyperuricemia 1. Correct initial electrolyte and fluid imbalance, and azotemia, if possible; dialysis as indicated for established renal failure or unresponsive electrolyte or metabolic abnormalities 2. Maintain adequate hydration and urine output (>3 L/d). May require 4 to 5 L/24 h of intravenous hypotonic saline or bicarbonate; diuretics as indicated 3. Give Allopurinol* (300 mg/m2) at least 3 days before therapy if possible 4. Alkalinize urine to pH >7.0 (hypotonic NaHCO3 infusion; Diamox if necessary) 5. Postpone chemotherapy (if possible) until uric acid and electrolytes are reasonably normalized 6. Continuous-flow leukapheresis might be indicated for patients with a high circulating blast count (white cell count >100,000/mm3) B. Patients presenting (before chemotherapy) with normouricemia, but still at risk 1. Allopurinol* 300 mg/m2; at least 2 days before therapy if possible 2. 4 to 5 L/d of intravenous fluid as described above 3. Urinary alkalinization as described above Treatment C. Patients presenting (usually after chemotherapy) with renal failure 1. Same as for patients with tumor and hyperuricemia if sufficient renal function remains. If dialysis is necessary, continuous hemodialysis or hemofiltration may be preferable if severe hyperuricemia or hyperkalemia is present 2. Discontinue urine alkalinization when uric acid homeostasis is achieved (to avoid Ca3[PO412]precipitation) 3. Treat symptomatic hypocalcemia after correction of hyperphosphatemia

5.7

FIGURE 5-12 Prevention and management of acute uric acid nephropathy (AUAN) and the acute tumor lysis syndrome (ATLS). The metabolic consequences of rapid malignant cell lysis are many, ranging from moderate hyperuricemia to death from hyperkalemia. The measures employed for prevention and management vary according to the type and extent of the tumor and whether cytolytic therapy has been initiated. In recent years, with appropriate prophylaxis and dialytic therapy, AUAN and ATLS rarely represent life-threatening problems. When acute renal failure (ARF) does occur, prognosis is excellent. The approach to AUAN and ATLS is divided into two stages. The first is to prevent or minimize the metabolic consequences, and the second involves treatment if prophylaxis has not been successful. The approach to both prophylaxis and treatment includes inhibition of xanthine oxidase, forced diuresis, and urinary alkalinization. If treatment is not successful and ARF develops, these patients respond very well to hemodialysis, with morbidity and mortality usually related to the underlying disease process [39].

*Allopurinol dosage must be adjusted for level of renal function.

N

C

C

N C–H

H

C

OH

OH

OH

C N

N

Xanthine oxidase HO

N

C

C

N C–H

C

C N

N

N

C N

H

C

C N

OH

H C

N

H Allopurinol (4-Hydroxypyrazolo pyrimidine)

C

C

Xanthine oxidase HO

N

C

N C–OH

C

C N

N H

Uric acid

Xanthine

Hypoxanthine

C

HO

N

H

H

OH

Xanthine oxidase

H C

C N

C

C N

N

H Oxypurinol (Alloxanthine) (4,6-Dihydroxypyrazolo pyrimidine)

FIGURE 5-13 Allopurinol structure and metabolism. Allopurinol is a crucial component of therapy for the prevention and management of acute uric acid nephropathy and acute tumor lysis syndrome. Its

metabolism and pharmacology must be considered to avoid life-threatening toxicity [40]. Allopurinol is a structural analogue of hypoxanthine. The product of the enzymatic oxidation of allopurinol is the xanthine analogue oxypurinol. Both allopurinol and oxypurinol act as xanthine oxidase inhibitors. Allopurinol is rapidly absorbed from the gastrointestinal tract and is not protein bound. It has a half-life of just 2 to 3 hours because it has a clearance equal to the glomerular filtration rate and is rapidly converted to oxypurinol via enzymatic oxidation. By contrast, oxypurinol has a half-life of 18 to 30 hours because it undergoes extensive tubular reabsorption and is dependent on renal excretion for elimination. Thus, allopurinol dosage must be modified according to renal function. Serious toxicity may occur in the presence of a sustained increase in oxypurinol concentration. Oxypurinol may be removed effectively with dialysis, since it is not protein bound. (From Rieselbach and Garnick [1]; with permission.)

5.8

Systemic Diseases and the Kidney

FIGURE 5-14 Interstitial tumor infiltration due to leukemia. Leukemic infiltrates in this case of acute myelocytic leukemia are diffusely present

throughout the cortex of the kidney. The pelvic and parenchymal hemorrhages are secondary to severe thrombocytopenia. Microscopically, many myeloblasts are seen in the interstitial infiltrates. Interstitial infiltration by hematologic neoplasms is usually bilateral, diffuse, and more prominent in the cortex [14]. Renal failure is unusual. When it does occur, affected patients generally present with relatively acute renal failure and a benign urinalysis. The kidneys are grossly enlarged, as may be demonstrated by renal ultrasound, by CT scan, or in some cases even by physical examination. The differential diagnosis in this setting includes obstruction and other tubulointerstitial disorders. The presence of large kidneys without hydronephrosis on ultrasonography in a patient with lymphoma or leukemia, however, is highly suggestive of tumor infiltration. The renal prognosis is dependent on the responsiveness of the tumor to radiation or chemotherapy. A rapid reduction in renal size and return of renal function toward the baseline level may be seen within a few days with responsive tumors. (From Skarin [31]; with permission.)

B A FIGURE 5-15 Renal involvement in lymphoma. A, Renal involvement in a patient with diffuse large cell lymphoma. There is little remaining parenchyma in this specimen, which exhibits many large, gray-white nodules of tumor. Although primary renal lymphoma is rare, 5% to 10% of patients with disseminated lymphoma exhibit clinically detectable renal involvement. At autopsy, the incidence of renal involvement by lymphoma has been estimated by several series to be more than 30% [41]. The incidence was higher in patients with lymphosarcoma or histiocytic lymphoma than in those having Hodgkin’s disease, with its occurrence in mycosis fungoides being intermediate in frequency. The majority of patients had involvement of both kidneys. Lymphoma may involve the kidney by multinodular or diffuse infil-

tration or occasionally by the presence of a large solitary tumor. Renal failure due to parenchymal infiltration by lymphoma cells is extremely rare. In one large series, uremia resulting from lymphomatous replacement of kidney tissue was the cause of death in only 0.7% of patients [42]. As with leukemia, when lymphoma has caused renal failure, chemotherapy and radiation therapy have led to improvement in kidney function. B, Lymphoma with renal infiltration. A 65-year-old-man presented with left flank pain and microscopic hematuria of 6 weeks’ duration. He had a left renal mass demonstrable on abdominal ultrasound. Left renal perihilar and retroperitoneal lymph node enlargement was noted on a CT scan. He was normotensive and had a serum creatinine level of 1.2 mg/dL. A needle biopsy of the renal mass, under CT guidance, revealed renal parenchymal infiltration with lymphoid cells with neoplastic characteristics. (Panel A from Skarin [31]; with permission.)

Renal Involvement in Malignancy

5.9

Postrenal Acute Renal Failure CAUSES OF POSTRENAL ACUTE RENAL FAILURE Anatomic site

Cause

Urethral obstruction Bladder neck obstruction

Prostatic hypertrophy Prostatic or bladder cancer Functional: neuropathy or drugs Extraureteral Cancer of prostate or uterine cervix Periureteral fibrosis Accidental ureteral ligation during pelvic surgery for cancer Intraureteral Uric acid crystals or stones Blood clots Pyogenic debris Edema Necrotizing papillitis

Bilateral ureteral obstruction (or unilateral obstruction with single kidney)

Nodal obstruction

Uterus

Bladder ulceration Stricture

Uretovaginal fistula

Bladder Vesicovaginal fistula Vagina

FIGURE 5-16 The etiology of postrenal failure involves obstruction at various anatomic sites by tumors of the urinary tract or surrounding tissues. Some of the more common causes of bladder neck obstruction in the cancer patient include prostatic hypertrophy [43] and prostatic or bladder cancer [44]. Postrenal acute renal failure may also be produced by bilateral obstruction of both ureters (or unilateral ureteral obstruction in the presence of a single kidney). This may be caused by invasion of the ureters by bladder neoplasms or, more commonly, by retroperitoneal spread of malignancies, particularly of colon, prostate, bronchus, or breast origin.

FIGURE 5-17 Urinary tract obstruction. Obstruction is a prominent feature of urinary tract involvement in gynecologic cancers [45]. The ureters may be invaded by tumor or compressed by the tumor mass or tumor-filled lymph nodes. Ureteral stricture may be the cause of obstruction following radiation therapy or surgery. Also, the bladder may be subject to direct extension of tumor with occlusion of ureteral orifices. In this figure, the anterior wall of the bladder is cut away to illustrate these as well as other forms of urinary tract involvement by gynecologic cancers. In this setting, obstruction may produce either acute or chronic renal failure depending on the location of the obstruction and the rapidity of tumor growth. (Adapted from Rieselbach and Garnick [1].)

5.10

Systemic Diseases and the Kidney Diagnostic approach to acute renal failure STEP I ACUTE Normal recent function Normal renal size on ultrasound Normal HCT

CHRONIC Prior renal dysfunction Small kidneys on ultrasound Anemia

STEP II History, physical exam Prerenal Edema CHF Cirrhosis ECFV contraction Drugs

Postrenal Distended bladder Pelvic mass ( ) Enlarged kidney(s) Flank pain Prostatism ( )

Intrinsic renal Hypotension Nephrotoxins Systemic symptoms Trauma/surgery STEP III Urinalysis

RBC casts and/or dysmorphic RBCs

Eosinophils

Acute tubulointerstitial Glomerulonephritis nephritis or vasculitis

Dipsticknegative proteinuria

Epithelial cells Granular, pigmented casts

Light-chain cast nephropathy Acute tubular necrosis

Gallium scan

Renal biopsy

UPE Bone marrow biopsy

Uric acid crystals

Benign

Acute uric acid nephropathy

Orthotolidine positive on dipstick but RBC negative in sediment

Prerenal or postrenal Myoglobin Hemoglobun

STEP IV

Blood chemistries ↑BUN/creatinine ratio ↑Calcium ↑Uric acid ↑Phoshorus ↑CPK, aldolase

Other blood studies SPE→M spike ↓ C3/C4 (complement) ↓ Haptoglobin Eosinophilia

STEP V Urinary diagnostic indicies Prerenal or glomerulonephritis

Acute uric acid nephropathy

Light chain nephropathy

ATN or obstruction

UNA<20, FENA<1% UOSM>500

Urine uric acid/ creatinine >1.0

Urine positive for light chains

UNA>40, FENA>3% UOSM<350

Anuria

Renal biopsy

Glomerulonephritis

Obstruction

Bilateral cortical necrosis

Exclude obstruction Ultrasound CT scan Retrograde pyelogram

Bilateral renal artery or vein occlusion Magnetic resonance angiography Duplex ultrasonography Digital subtraction angiography Renal arteriography/venography

FIGURE 5-18 Diagnostic approach to acute renal failure. Acute renal failure developing in a patient with malignancy may be due to diverse causes. It is important to employ an organized diagnostic approach to define the specific cause in a costeffective manner. The approach outlined in this figure involves five steps. Step I addresses the distinction between acute and chronic renal failure, and step II lists the various causes of prerenal, intrinsic, and postrenal acute renal failure (see Figs. 5-2, 5-4, and 5-16) according to data obtained from the history and physical examination. Urinalysis is very useful in the workup of a patient with acute renal failure, particularly due to intrinsic renal disease, as outlined in step III. The presence of red blood cell (RBC) casts or dysmorphic RBCs in the urine sedi-

ment is suggestive of glomerulonephritis, while eosinophiluria is indicative of acute interstitial nephritis. Step IV involves obtaining blood chemistries and other blood studies, abnormalities that may strongly support a given diagnosis. Step V is employed in the presence of oliguric acute renal failure. Urinary diagnostic indices are used to distinguish between prerenal acute renal failure and glomerulonephritis, as opposed to acute tubular necrosis or acute obstruction. Evaluation of the urine is also helpful in detecting the presence of light chains of immunoglobulins, which may be diagnostic of multiple myelomainduced acute renal failure. Also, an increased urinary uric acid/creatinine ratio may indicate acute uric acid nephropathy. In the patient who is anuric (<50 mL of urine per day), it is particularly important to rule out obstruction. Bilateral cortical necrosis or glomerulonephritis must be considered in this setting; a renal biopsy may be necessary for definitive diagnosis. If bilateral renal artery or vein occlusion is a consideration, angiography may be indicated. ATN—acute tubular necrosis; BUN— blood urea nitrogen; CHF—congestive heart failure; CPK—creatine phosphokinase; ECFV— extracellular fluid volume; FENa—fractional extraction of sodium; Hct—hematocrit; SPE— serum protein electrophoresis; Una—urine sodium; Uosm—urine osmolality; UPE—urine protein electrophoresis.

Renal Involvement in Malignancy

5.11

Hematuria and/or the Nephrotic Syndrome CAUSES OF HEMATURIA AND/OR THE NEPHROTIC SYNDROME Paraneoplastic glomerulonephritis Membranous glomerulonephritis Minimal change nephrotic syndrome Crescentic glomerulonephritis Membranoproliferative glomerulonephritis Primary or metastatic renal cancer Chemotherapy agents causing nephrotic syndrome Mitomycin C Gemcitabine Interferon

A FIGURE 5-20 Membranous glomerulonephritis and the nephrotic syndrome in a patient with bronchogenic carcinoma. A 76-year-old veteran presented with ankle edema and weight gain of 8 weeks’ duration. He was noted to have the nephrotic syndrome with 5 grams of proteinuria per day. A chest radiograph revealed a perihilar mass. A bronchoscopic biopsy of the mass was diagnostic of malignancy. He was managed conservatively with diuretics and radiotherapy for the

FIGURE 5-19 Causes of hematuria and/or the nephrotic syndrome. Hematuria and/or the nephrotic syndrome may occur in association with malignancy without causing acute or chronic renal failure. Causes may include one of the many paraneoplastic types of glomerulonephritis, with proteinuria and often the nephrotic syndrome resulting from the glomerular injury; hematuria is also noted in some cases. In contrast, isolated hematuria is the predominant feature when primary or metastatic renal cancer erodes the intrarenal vasculature. Proteinuria, and in some cases the nephrotic syndrome, may be the presenting nephrotoxicity of cancer chemotherapy agents.

B chest mass. He died 10 months later. Membranous glomerulonephritis and bronchogenic carcinoma were diagnosed at autopsy. A, Light microscopic study of the kidney of this patient. Note the thickening of capillary walls and spikes (PAM stain). B, Immunofluorescence microscopy of renal tissue showing peripheral glomerular capillary deposition of IgG in a granular pattern indicative of immune-complex-mediated glomerulonephritis. (Continued on next page)

5.12

Systemic Diseases and the Kidney

C FIGURE 5-20 (Continued) C, Electron microscopy of the glomerulus showing subepithelial electron-dense deposits along the capillary walls. There is effacement of the epithelial cell foot processes, which is a common finding in patients with nephrotic syndrome. D, Bronchogenic carcinoma noted at autopsy in this patient (hematoxylin and eosin stain). Membranous glomerulonephritis is an immune-complex–mediated glomerular disease, often resulting in nephrotic syndrome as a clinical manifestation. In adults older than the age of 50, a coexisting malignancy, usually a carcinoma, may be present in up to 10%

A FIGURE 5-21 Minimal change nephrotic syndrome in Hodgkin’s disease. A, Light microscopic study of a renal biopsy specimen from a 57-year-old man with nephrotic syndrome of 3 months’ duration. Urine protein excretion was 7.1 g/d. The serum creatinine concentration was 1.3 mg/dL. The patient also had cervical lymphadenopathy, biopsy of which revealed Hodgkin’s disease of the mixed cellularity type. He was treated with irradiation to the upper mantle region with resolution of the lymphadenopathy. Proteinuria also declined to 2 g/d in 2 weeks and was absent in 8 weeks. The glomerulus was normocellular with delicate capillary walls diagnostic of minimal change nephrotic syndrome (PAM stain). B, Electron microscopy of a glomerulus from the same patient showing glomerular capillaries with extensive effacement of the epithelial foot processes but without electron-dense deposits. In patients with Hodgkin’s disease and other malignancies arising from lymph nodes as well as different types of chronic leukemias, the

D of cases [5]. Although a variety of malignancies have been observed to be associated with membranous glomerulonephritis, the most common sites are the breast, the lung, and the colon. In some instances, the tumor antigen or antitumor antibodies have been detected in the glomeruli. Development of the nephrotic syndrome has been temporally related to the malignancy in several instances, and successful cure of the malignancy has led to a remission in the nephrotic syndrome. Relapses have been associated with reappearance of proteinuria [46].

B occurrence of glomerular diseases has been noted [5,46]. Several histologic types of glomerular diseases have been documented in these instances; the most common type has been minimal change nephrotic syndrome [47]. The glomeruli of these patients are normal on light microscopic study and are devoid of hypercellularity or capillary wall thickening. No immunoglobulins are noted in the glomeruli on immunofluorescence microscopy. On electron microscopy, effacement of the epithelial cell foot processes is the only abnormality present. Proteinuria has been noted to remit with cure of lymphoma (with use of surgery, radiotherapy, or chemotherapy) in some cases; relapses in nephrotic syndrome occur with recurrence of the tumor. This has been documented to occur several times in some patients [47]. The pathogenesis of minimal change nephrotic syndrome in patients with malignancy remains unknown. It is possible that a cytokine or tumor cell product may be responsible for the increase in glomerular permeability with resultant proteinuria [48].

Renal Involvement in Malignancy

5.13

A. COMPARISON OF PARAPROTEINEMIAS Diagnosis

Frequency*

Clinical Findings

Renal Lesions

Diagnostic Means

Multiple myeloma

Yes

Light-chain cast nephropathy Acute tubular necrosis

Immunoelectrophoresis or bone marrow Light chains in urine

AL amyloidosis

Yes

Deposits of amyloid fibrils in the kidney

Light-chain deposition disease

No

Proteinuria (light chain) Acute renal failure Hypercalcemia Proteinuria Nephrotic syndrome Proteinuria Nephrotic syndrome Chronic renal failure

Renal or rectal biopsy Immunoelectrophoresis Renal biopsy Bone marrow biopsy Immunoelectrophoresis

Waldenström’s macroglobulinemia

Rarely

No renal symptoms or minimal proteinuria

Monoclonal gammopathy of unknown significance (MGUS)

Rarely

Proteinuria Nephrotic syndrome

Nodular glomerulosclerosis with granular deposition of light chains along the glomerular and tubular basement and membrane; usually kappa light chains Intraglomerular “coagula” of IgM Proliferative glomerulonephritis in some case

Immunoelectrophoresis Bone marrow biopsy Immunoelectrophoresis Bone marrow biopsy Renal biopsy

* Frequency of renal involvement.

B FIGURE 5-22 (see Color Plate) A, Paraprotein abnormalities as a cause of nephrotic syndrome. This table compares the characteristics of various paraproteinemias. Paraproteins are abnormal immunoglobulins or abnormal immunoglobulin fragments produced by B lymphocytes. They are monoclonal, appear in the serum or urine (or both), and cause renal damage by several different mechanisms. Paraproteinemias comprise a group of disorders characterized by overproduction of different paraproteins. Multiple myeloma is a common type of paraproteinemia. The overproduction of immunoglobulins or light chains, or both, causes

renal toxicity, directly affecting the tubular cells or forming casts after precipitation in the tubular lumen. The light chains may be transformed into amyloid fibrils and deposited in various tissues, including the kidney. Amyloidosis is diagnosed by performing a biopsy of the involved organ and staining the tissue with Congo red stain. On occasion, the light chains do not form fibrils but are deposited as granules along the basement membrane of blood vessels and glomeruli. Kappa chains often behave in this manner. This entity is called light-chain deposition disease [6] (panel B). Paraproteins composed of IgM are noted in Waldenström’s macroglobulinemia. Renal dysfunction is uncommon in this condition [49]. Hyperviscosity is present. On rare occasions, thrombi composed of IgM may be noted in the glomeruli of these patients. In the most common form of paraproteinemia, monoclonal protein is detected in the serum of an otherwise healthy person. This condition is referred to as monoclonal gammopathy of unknown significance (MGUS) and may on occasion progress to multiple myeloma or amyloidosis [50]. B, Light-chain deposition disease (LCDD) in a patient with multiple myeloma. A light microscopic study of a renal biopsy specimen from a 65-year-old man with recently diagnosed multiple myeloma who was found to have an elevated serum creatinine concentration (2.6 mg/dL) and proteinuria of 3 g/d. Note the nodular mesangial lesions, capillary wall thickening, and hypercellularity resembling diabetic nodular glomerulosclerosis. Immunofluorescence staining was positive for kappa light chains but negative for lambda light chains.

5.14

Systemic Diseases and the Kidney

FIGURE 5-23 Renal cell carcinoma. With massive invasion by tumor, the renal vein may become occluded by adherent tumor thrombus. Renal adenocarcinoma is the most common tumor of the kidney [51]. In the past, many of these tumors achieved large sizes before being detected and hence were advanced in their stage and limited in their curability by surgical resection. Today, many renal cancers are often detected with routine abdominal computed tomography for nonrelated indications. Once called “the internist’s tumor”

PRESENTING SIGNS AND SYMPTOMS OF RENAL CELL CARCINOMA Feature Hematuria Pain Flank or abdominal mass Weight loss Symptoms from distant metastatic spread Fever Classic triad (pain, hematuria, mass) Polycythemia Acute varicocele

Frequency, % 40–65 20–50 20–40 30 10 15–20 10 <5 <5

because of the myriad paraneoplastic signs and symptoms, now renal cancer is often termed “the radiologist’s tumor” [51,52]. Most forms of renal cancer arise from the cells of the proximal tubular epithelium, not from adrenal rests of cells. Thus, the term hypernephroma (ie, tumor arising from above the kidney) should not be employed to describe this lesion. Risk factors for the development of renal cancer include cigarette smoking, occupational exposure to cadmium, obesity, excessive exposure to analgesics, acquired cystic disease in dialysis patients, adult polycystic kidney disease, and other industrial exposures, such as to asbestos, leather tanning, and certain petroleum products. Genetic and familial forms of the disease occur, most notably with von Hippel-Lindau disease, an autosomal dominant disorder characterized by the development of multiple tumors of the central nervous system, pheochromocytomas, and bilateral renal carcinomas. Several families have been reported also to have a high incidence of renal cancer. Genetic analyses of these patients demonstrate a balanced translocation between the short arm of chromosome 3 and either chromosome 6 or 8. Other abnormalities have been reported as well [52]. It should be noted that other primary tumors of the kidneys in the adult include transitional cell carcinoma of the renal pelvis and other neoplasms, such as angiomyolipoma and oncocytoma. Metastatic lesions of the kidney include those arising from the common epithelial cancers such as breast, lung, colon, and infiltrative lesions secondary to lymphoma and leukemias. (From Skarin [31]; with permission.) FIGURE 5-24 Presenting signs and symptoms of renal cell carcinoma. Patients with renal cell cancer present with symptoms produced by the local neoplasm, with signs and symptoms of paraneoplastic phenomena, or with other aspects of systemic disease. Alternatively, the patient may be totally asymptomatic and may be diagnosed from a radiologic abnormality detected on ultrasound or abdominal CT scanning. Fewer than 10% of patients present with the classic triad of hematuria, abdominal mass, and flank pain. The most common features include hematuria (70%), flank pain (50%), palpable mass (20%), fever (15%), and erythrocytosis (infrequent). Other features may include acute onset of lower extremity edema, or, in males, the presence of a left-sided varicocele, indicating obstruction of the left gonadal vein at its point of entry into the left renal vein by a tumor thrombus [53,54].

Renal Involvement in Malignancy

FREQUENCY OF SYSTEMIC EFFECTS IN PATIENTS WITH RENAL CELL CARCINOMA Symptom

Incidence, %

Elevated ESR Anemia Hypertension Cachexia Pyrexia Abnormal liver function Elevated alkaline phosphatase Hypercalcemia Polycythemia Neuromyopathy Amyloidosis

362/6.51 (55.6) 409/991 (41.3) 89/237 (37.6) 338/979 (34.5) 164/954 (17.2) 60/400 (15.0) 64/434 (14.7) 33/577 (5.7) 33/903 (3.7) 13/400 (3.3) 12/573 (2.1)

Stage I

Vena cava

Stage III

Aorta

Stage II

Stage I: Confined to kidney Stage II: Including renal vein involvement Stage III: Lymph node and caval involvement Stage IV: Adjacent organ metastases

Stage IV

5.15

FIGURE 5-25 Frequency of systemic effects. The most frequent systemic manifestations of renal cell cancer are noted [55]. Other paraneoplastic and systemic manifestations include liver function abnormalities, high-output congestive heart failure, and manifestations of the secretion of substances such as prostaglandins, renin, glucocorticoids, and cytokines (eg, interleukin-6). At presentation, a small percentage of tumors are bilateral, while nearly a third of patients have demonstrable metastatic disease, which may occur in virtually any organ. Most common sites of metastases include lung, bone, liver, and brain. ESR—erythrocyte sedimentation rate. (From Chisholm and Roy [55]; with permission.)

FIGURE 5-26 The staging of renal adenocarcinoma. Renal cell cancer can be staged using one of two systems in common use. The TNM (tumor, node, metastasis) system has the advantage of being more specific but the disadvantage of being cumbersome; a modification of the Robson staging system (as illustrated here) is more practical and more widely used in the United States. In this system, stage I represents cancer that is confined to the kidney capsule; stage II indicates invasion through the renal capsule, but not beyond Gerota’s fascia; stage III reflects involvement of regional lymph nodes and the ipsilateral renal vein or the vena cava; and stage IV indicates the presence of distant metastases [57]. With regard to pathologic assessment, previously renal carcinomas were classified according to cell type and growth pattern. The former included clear cell, spindle cell, and oncocytic carcinoma, while the latter included acinar, papillary, and sarcomatoid varieties. Recently, this classification has undergone a transformation to reflect more accurately the morphologic, histochemical, and molecular basis of differing types of adenocarcinoma [58]. Based on these studies, five distinct types of carcinoma have been identified: clear cell, chromophilic, chromophobic, oncocytic, and collecting duct. Each of these types has a unique growth pattern, cell of origin, and cytogenetic characteristics [59,60]. (From Brenner and Rector [56].)

5.16

Systemic Diseases and the Kidney

Dialysate Serum

Osmolality, mOsm/L

360

340 Osmotic equilibrium

320

300

C

0

1

2 Dwell time, h

3

4

ADK-vol05 chap04 fig07c24p6 x 14 p au:Khanna art:Weischedel

FIGURE 5-27 Diagnostic evaluation of and therapeutic approach to primary renal cancer—an algorithm for diagnosis and management of a renal mass. The discovery of evidence during the history or physical examination that suggests a renal abnormality should be followed by either an intravenous pyelogram or an abdominal ultrasound. With increasing frequency, however, evidence of a space-occupying lesion in the kidney is found incidentally during radiographic testing for other unrelated conditions. Renal ultrasonography may help distinguish simple cysts from more complex abnormalities. A simple cyst is defined sonographically by the lack of internal echoes, the presence of smooth borders, and the transmission of the ultrasound wave. If these three features are present, the cyst is most likely benign. At one time, cyst puncture was used, but it seems to be unnecessary today in the asymptomatic patient without hematuria. Periodic repetition of the ultrasound is suggested for follow-up. If a change in the lesion occurs, cyst puncture, needle aspiration, or CT scanning should be considered to evaluate the lesion further.

If the sonographic criteria for a simple cyst are not met or the intravenous pyelogram suggests a solid or complex mass, a CT scan should be performed. If a renal neoplasm is demonstrated on CT scanning, renal vein or vena caval involvement should be assessed with CT scanning or magnetic resonance imaging. Although used frequently in the past, selective renal arteriography has assumed a more limited use, mainly in further evaluating the renal vasculature in patients who are to undergo partial nephrectomy (nephron-sparing surgery). CT scanning is also very helpful in determining the presence of lymphadenopathy. The differential diagnosis of a renal mass detected on CT scanning includes primary renal cancers, metastatic lesions of the kidney, and benign lesions. The latter include angiomyolipomas (renal hamartomas), oncocytomas, and other rare or unusual growths. If a renal cancer is considered based on the radiographic studies of the kidney, the patient should undergo a preoperative staging evaluation to assess the presence of metastases in the lung, bone, or brain. (Continued on next page)

Renal Involvement in Malignancy (Continued) The operative and diagnostic approach is dictated according to the preoperative stage of the patient. For example, the patient who presents with stage IV disease by virtue of a positive bone scan may need only a needle biopsy of either the kidney lesion or the bone lesion to establish the tissue diagnosis and thus avoid more extensive surgery on the kidney. In contrast, a patient with an isolated pulmonary lesion may be considered for both nephrectomy and pulmonary nodulectomy at one operative intervention. The standard therapy for localized renal cell carcinoma is radical nephrectomy, which includes removal of the kidney, Gerota’s fascia, the ipsilateral adrenal gland, and regional hilar lymph nodes. The value of an extended hilar lymphadenectomy seems to be its ability to provide prognostic information, since there is rarely a therapeutic reason for performing this portion of the operation. In the past, the removal of the ipsilateral adrenal gland was done routinely; today, most data suggest that it is involved less than 5% of the time, more frequently with large upper-pole lesions. Thus, today, ipsilateral adrenalectomy is reserved for those patients with abnormal-appearing glands or enlarged glands on CT scan or those with large upperpole lesions, in which the probability of direct extension of the tumor to the adrenal gland is more likely [61]. Partial nephrectomy (nephron-sparing surgery) has become more popular, especially for patients with small tumors, for those at risk for developing bilateral tumors, or for patients in whom the contralateral kidney is at risk for other systemic diseases, such as diabetes or hypertension [62]. The main concern associated with partial nephrectomy is the likelihood of tumor recurrence in the operated kidney, since many renal cancers may be multicentric. Local recurrence rates of 4% to 10% have been reported; lower rates have been reported when partial nephrectomy was performed for smaller lesions (< 3 cm) with a normal contralateral kidney. Lesions that are centrally located, however, still require radical nephrectomy. Frequent follow-up, usually with CT scanning or ultrasonography, will be necessary in those patients who undergo partial nephrectomy. Inferior vena caval involvement with renal cancer occurs more frequently with rightsided tumors and is usually associated with metastases in nearly 50% of patients. Vena caval obstruction may lead to the diagnosis; it may present with abdominal distention from ascites, hepatic dysfunction, nephrotic syndrome, abdominal wall venous collaterals, varicocele, malabsorption, or pulmonary embolus. The anatomic location of the caval thrombus is important prognostically; supradiaphragmatic lesions, which may involve the heart, can be resected, but the prognosis is poor. Subdiaphragmatic lesions enjoy a better 5-year survival, but the survival rate is usually less than 50% [63]. In the surgical management of these patients, a team of specialists is required, especially if a cardiac tumor thrombectomy is contemplated. The role of surgery in the management of metastatic disease either at initial presentation or later remains controversial. Although most data that support nephrectomy plus metastatectomy are anecdotal, many patients with synchronous renal cell cancer and an isolated pulmonary nodule may be considered for surgical resection of both lesions. Likewise, patients who develop an isolated lesion in the liver or lung some time following the removal of the kidney also may be considered for surgical removal of the metastasis. Nevertheless, even when such vigorous surgery is carried out, most patients do poorly. Additional controversy surrounds the practice of performing nephrectomy in patients with widespread metastatic disease as a means of potentially improving their response to systemic therapy. Many investigative programs require such resection, but at this writing, the practice should be considered investigational. A patient who does experience an excellent response to systemic therapy should be

5.17

considered for nephrectomy following the response, however. Finally, since many renal tumors can become quite large, consideration should be given to palliative nephrectomy (in the setting of metastatic disease), especially if the patient experiences uncontrollable hematuria or pain or is catabolic secondary to the sheer mass of the tumor. The medical management of patients with either locally advanced renal cancer or metastatic disease provides a great challenge to physicians and clinical investigators. Although chemotherapy and hormonal treatments have been studied extensively in patients with metastatic renal cancer, no single treatment protocol or program has been uniformly effective. Therefore, most physicians treating the disease usually rely on novel modalities of treatment, including biologic response modifiers, investigational anticancer agents, differentiation agents (such as retinoic acid), vaccines, and gene therapy. Interferon therapy with interferon-, -, or - has led to responses in approximately 15% to 20% of treated patients [64]. Interferons demonstrate antiproliferative activity against renal cell cancers in vitro, stimulate immune cell function, and can modulate the expression of major histocompatibility complex molecules. Although responses have been seen in cancers involving many different anatomic areas, patients who have had a prior nephrectomy with isolated pulmonary metastases and who are otherwise well may enjoy a higher response rate [65]. Duration of response is usually less than 2 years; longer lasting remissions have been noted in a few selected patients. Interferons have been combined with other immune modifiers as well as with chemotherapy agents with no real improvement in patient outcome in larger-scale trials. Several smaller trials have combined interferon with interleukin-2 or chemotherapy agents (eg, 5-fluorouracil) with some encouraging preliminary results. Interleukin 2 (Il-2) has received a great deal of attention as a potential advance in the treatment of renal cell cancer. This agent enhances both proliferation and functioning of lymphocytes involved in antigen recognition and tumor elimination. Initial studies used very high doses of Il-2 in association with ex vivo populations of lymphoid cells grown and matured under the influence of Il-2 [66]. These programs resulted in substantial toxicity, including patient deaths, but nevertheless had early and encouraging therapeutic results. Unfortunately, the initial encouraging results were not consistently observed in larger-scale trials. Efforts are now directed at selectively manipulating the immune-enhancing features of the treatment, with modification of the toxic effects. In several recent studies, the use of lower doses of Il-2 without the cellular components has resulted in comparable results with less toxicity. The toxicity of Il-2 is related to alterations in vascular permeability, leading to a capillary leak type of syndrome. Although the drug is approved by the Food and Drug Administration for the management of patients with metastatic renal cell cancer, its use should be restricted to those patients who can tolerate the side effect profile and those patients with acceptable cardiac, renal, pulmonary, and hepatic function. Investigational therapies continue to be studied for renal cell cancer. These include novel cytokines such as interleukin-12, combinations of biologics with or without chemotherapeutic agents, circadian timing of chemotherapy administration, vaccine therapy, various forms of cellular therapy, and gene therapy [67]. Although all these approaches have a solid scientific preclinical rationale, none, unfortunately, can be considered standard treatment. The sobering fact still remains that nearly 50% of all patients diagnosed with renal cell cancer die of their disease within 5 years of diagnosis, and a substantial proportion have advanced stages of cancer spread at initial presentation.

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Systemic Diseases and the Kidney FIGURE 5-28 Metastatic malignant melanoma involving the kidney. The urinary tract is a common site of melanoma metastases. If not amelanotic, the metastatic nodules are brownish black. Metastatic infiltration of the kidneys is often an incidental finding at autopsy but is a rare cause of functional impairment [68]. Most renal metastases are multiple and bilateral. Glomeruli tend to be spared, possibly because of their lack of lymphatic channels. Pulmonary carcinoma is the most commonly reported form of metastatic solid tumor involving the kidneys, followed by metastatic stomach and breast carcinoma [69]. Metastatic melanoma is an example of a tumor that may be transplanted at the time of cadaver kidney transplantation, with subsequent rapid proliferation in the immunosuppressed recipient; tumor rejection may occur with cessation of immunosuppressive therapy [70] (see Fig. 5-37). The presence of renal metastases is often overlooked during life due to the absence of any specific physical or laboratory findings. The laboratory finding most likely to occur is hematuria due to tumor erosion of intrarenal vessels. (From Skarin [31]; with permission.)

Chronic Renal Failure CAUSES OF CHRONIC RENAL FAILURE Glomerular abnormalities

Tubulointerstitial abnormalities

Renovascular disease

Obstruction

Glomerulonephritis Amyloidosis Primary renal cancer Antineoplastic agents Immunoglobulins or light chains Radiation nephropathy Leukemic infiltration Lymphomatous infiltration Metastatic infiltration Chronic pyelonephritis Antineoplastic agents Hypertension due to malignancy Peripheral vascular involvement by renal or nonrenal cancer Renal vein thrombosis Hemolytic-uremic syndrome Cancer Prostate Cervix Bladder Retroperitoneal lymphoma Primary renal Uric acid or calcium stones Periureteral fibrosis

FIGURE 5-29 Causes of chronic renal failure. The glomerular abnormalities listed may be associated with cancer but most often do not cause a significant degree of chronic renal failure; their clinical expression most often involves hematuria or the nephrotic syndrome. Disordered immunoglobulin production associated with multiple myeloma is a frequent cause of interstitial abnormalities, producing chronic renal failure in association with cancer. Renal failure has been reported to develop in up to half of patients with myeloma at some time during their illness and is associated with a significantly worse prognosis [71]. The multiple causes of renal failure in myeloma have been previously reviewed (see Fig. 5-8). Radiation nephropathy may produce chronic renal failure owing to interstitial abnormalities and may be associated with severe hypertension. Interstitial involvement by metastatic infiltration of the kidneys or by hematologic neoplasms may rarely cause chronic renal failure. The immunosuppressed status of many cancer patients serves to increase their susceptibility to bacterial and fungal invasion of the renal interstitium. Thus, chronic pyelonephritis may be a cause of chronic renal failure in the cancer patient, particularly in association with chronic obstruction. With regard to renal vascular disease, hypertension due to malignancy may produce nephrosclerosis. Hypertension may be associated with the hypercalcemia of malignancy and is observed frequently in patients with renal carcinoma. Perirenal vascular involvement may be observed with primary renal cancer or nonrenal cancer; renal vein thrombosis or occlusion may occur because of external compression by tumor or direct extension of tumor. When obstruction is present at any level of the urinary tract, the continued production of urine results in an increase in volume and pressure proximal to the obstruction. If the obstruction persists, the kidney may be damaged progressively with resultant chronic renal failure. The causes in obstruction causing chronic renal failure in association with cancer are similar to those noted in Figure 5-16 in the production of postrenal acute renal failure.

Renal Involvement in Malignancy

A

B

C

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FIGURE 5-30 (see Color Plate) Amyloidosis. A, Light microscopic study of a renal biopsy specimen from a patient with multiple myeloma and AL amyloidosis showing eosinophilic, fluffy amyloid deposits in the glomerulus. (Periodic acid–Schiff stain.) B, When stained with Congo red and viewed under polarized light, the amyloid deposits show applegreen birefringence. C, The amyloid fibrils viewed by means of electron microscopy. Amyloidosis is a generic term for a group of disorders in which there is extracellular deposition of insoluble fibrillar proteins in a characteristic B-pleated sheet configuration [29]. Although the proteins may be different, they all bond to Congo red stain. When the stained tissue is viewed under polarized light, it displays apple-green birefringence. In 10% to 15% of patients with multiple myeloma, AL amyloidosis (composed of light chains) may occur in association with the nephrotic syndrome and renal insufficiency. There is no specific therapy for renal amyloidosis. Some patients have experienced remission of the nephrotic syndrome with chemotherapy for myeloma, however. Dialysis (hemodialysis or peritoneal dialysis) and transplantation have been of value in a small number of patients with AL amyloidosis and end-stage renal disease [72].

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Systemic Diseases and the Kidney

POTENTIALLY NEPHROTOXIC CHEMOTHERAPEUTIC AGENTS Risk Drug Alkylating agents Cisplatin Carboplatin Cyclophosphamide Ifosfamide Streptozotocin Semistine (methyl-CCAU) Carmustine (BCNU) Antimetabolites Methotrexate† Cytosine arabinoside (Ara-A) 5-Fluorouracil (5-FU)‡ 5-Azacitidine 6-Thiognanine Antitumor antibiotics Mitomycin§ Mithramycin¶ Doxorubicin Biologic agents Interferons Interleukin-2

High

Intermediate

Type of renal failure Low

X X X X X

Acute

Chronic

Specific tubular damage

Immediate

Delayed

X X

X X

X X X X X

X X X X

X X

X X

X

X X X X

X X X X X

X X X

X X

X X X X X

X

X X

X X X

X X

X

X

Time Course

X X X X

X X X

X

X X

X

*Fanconi’s syndrome as the most severe manifestation. †Only seen with intermediate to high dose regimens. ‡Only seen when given in combination with mitomycin C. §Hemolytic-uremic syndrome as the most severe manifestation. ¶Frequent with antineoplastic doses, rare in doses used for hypercalcemia.

FIGURE 5-31 Toxic therapeutic agents. Nephrotoxicity due to antineoplastic agents may result in chronic renal failure but also may manifest as acute renal failure, specific tubular dysfunction, or the nephrotic syndrome. Nephrotoxicity has been observed with use of alkylating agents, antimetabolites, antitumor antibiotics, and biologic agents, as outlined in the table. These neoplastic agents

may induce nephrotoxicity soon after initiation of therapy or only after long-term administration. The risk of nephrotoxicity varies with each agent. This table summarizes the risk of nephrotoxicity, time of onset, and type of functional impairment produced by each agent. (From Massry and Glassock [73]; with permission.) FIGURE 5-32 Semustine nephropathy. A, Photomicrograph of the late stages of semustine nephrotoxicity in a specimen obtained at autopsy. (Continued on next page)

A

Renal Involvement in Malignancy

FIGURE 5-32 (Continued) B, Photomicrograph of a renal biopsy specimen from a patient with advanced semustine nephrotoxicity. Semustine (methyl-CCNU) is a lipidsoluble nitrosourea that is structurally similar to carmustine (BCNU) and lomustine (CCNU). Because of the ability of these agents to cross the blood-brain barrier due to their high lipid solubility, and because of their broad spectrum of antitumor activity and ease of administration, they have been used widely. Nephrotoxicity has been a factor limiting more widespread use, however. Semustine has proved to be the most nephrotoxic of these compounds. The degree of toxicity appears to be dose dependent. Evidence of renal damage often is not apparent until 18 to 24 months following the completion of therapy [74]. When it occurs, renal failure is usually progressive and irreversible. As noted in this figure, toxicity involves glomerulosclerosis, focal tubular atrophy, and varying degrees of interstitial fibrosis on light microscopic examination. (From Harmon and coworkers [74]; with permission.)

B

A

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B

FIGURE 5-33 Radiation nephritis is the basis for the atrophy of the superior portion of the left kidney shown in this intravenous pyelogram. The right kidney shows straightening of its medial border due to irradiation atrophy. A, Preirradiation pyelogram; B, film showing radiation field. Radiation nephropathy refers to damage to the kidney parenchyma and vasculature as a result of ionizing radiation [14]. Fortunately, this disease is relatively uncommon. It was more prevalent before meticulous detail to abdominal organ shielding was widely practiced or understood. Historically, patients receiving whole abdominal radiation therapy for lymphoma, seminoma, or other retroperitoneal tumors were the most likely to suffer the consequences of this disorder. Doses greater than 30 to 35 gray and single large fractions were likely to cause damage. Pathologically, the disease is characterized by damage to the microvasculature, proliferation of fibrous tissue, and disruption of the renal capillaries and arterioles. Clinically, the disease manifests predominantly with renal dysfunction and hypertension. Hematuria, oliguria, fatigue, and gradually developing renal atrophy are common manifestations. The chronic form of radiation nephropathy may occur 10 to 15 years after the radiation treatments. (From Rieselbach and Garnick [1]; with permission.)

FIGURE 5-34 Bilateral ureteral obstruction by diffuse large-cell lymphoma. Extensive retroperitoneal involvement is evident. Confluent adenopathy of retroperitoneal lymph nodes has led to bilateral encasement and compression of the ureters by pink-tan, fleshy tumor. This may produce chronic renal failure if tumor involvement is slowly progressive or involves predominantly one ureter. (From Skarin [31]; with permission.)

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Systemic Diseases and the Kidney

Specific Renal Tubular Dysfunction and Associated Fluid and Electrolyte Disorders RENAL TUBULAR DYSFUNCTION IN MALIGNANCY Cause Tumor-induced inappropriate hormone concentrations PTH-like substances Excess ADH Deficient ADH Adrenocortical excess Adrenocortical insufficiency Tumor products or metabolites Lysozyme (AML) Immunoglobulin light chains (MM) Hypercalcemia (MM, osseous metastases) Reabsorptive urate transport inhibitor (Hodgkin’s, solid tumors) Intrinsic Amyloid deposits in collecting ducts (MM) Partial intrarenal obstruction (MM cast nephropathy) Antineoplastic agents Cyclophosphamide Ifosfamide Vincristine Cisplatin Streptozocin

Clinical presentation Hypercalcemia Hypophosphatemia Hyponatremia (SIADH) Hypernatremia (central DI) Hypokalemia Hyperkalemia Hypokalemia Fanconi’s syndrome Renal tubular acidosis Fanconi’s syndrome Urinary concentrating defect Multiple transport defects Hypouricemia Nephrogenic DI Nephrogenic DI SIADH Fanconi’s syndrome SIADH Hypomagnesemia Renal tubular acidosis Hypophosphatemia Fanconi’s syndrome

FIGURE 5-35 Renal tubular dysfunction. Specific tubular dysfunction may be encountered in association with the four major causes listed. Normal renal tubular function is controlled by a delicate balance of humoral mediators. Thus, a tumor-induced inappropriate concentration of a hormone that normally contributes to the modulation of this balance may result in a profound disturbance of tubular function, thereby causing impairment of fluid and electrolyte balance as well as other homeostatic defects. A tumor product appears to be the basis for renal phosphate loss in some cases, in that the resultant hypophosphatemia regresses when the tumor is removed [75]. Hyponatremia occurs frequently in the patient with cancer; it is frequently caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Bronchogenic carcinoma is the most frequent cause of this syndrome. A number of other tumors have also been reported to cause SIADH. Disappearance of the syndrome on removal of the tumor or improvement following successful chemotherapy has been observed frequently [76]. Cancer is a common cause of central diabetes insipidus; metastatic lesions have been reported to cause 5% to 20% of all cases, with breast cancer being the primary malignancy in more than half the cases reported [77]. Adrenocortical steroid excess may be associated with malignancies and often manifests with hypokalemia and metabolic alkalosis due to excessive mineralocorticoid effect in the distal nephron. Adrenal insufficiency may develop owing to metastatic lesions of the adrenal glands, producing hyperkalemia and hyponatremia due

to mineralocorticoid deficiency and affecting tubular transport at the same site. Hypercalcemia is the most common setting in which tumor products or metabolites can cause specific tubular defects. In this case, profound tubular dysfunction is observed involving impairment of bicarbonate or sodium transport, urinary concentration, hydrogen ion secretion, or the renal handling of potassium, phosphorus, or magnesium [35]. Massive lysozymuria may be associated with renal damage, leading to kaliuresis and hypokalemia [78]. Elevations of lysozyme levels are seen with acute myelogenous leukemia. In this setting, proximal tubular defects in urate, phosphate, and amino acid reabsorption have also been noted [79]. Isolated hypouricemia has been reported in patients with advanced Hodgkin’s disease; these patients have increased renal clearance of urate despite decreased serum urate levels. Abnormal urate clearance was corrected by successful treatment of the underlying Hodgkin’s disease, suggesting a humoral basis for this tubular defect. Hypouricemia, in association with other types of proximal tubular dysfunction, has been associated with a variety of solid tumors. In multiple myeloma, the proliferation of abnormal plasma cells produces large quantities of a variety of immunoglobulins. These may produce changes in tubular function, which result from tubular reabsorption of the freely filtered low-molecular-weight tumor products. These in turn interfere with normal metabolism of proximal tubular cells after their reabsorption. This toxicity produces Fanconi’s syndrome, which is a complex proximal tubulopathy associated with multiple reabsorption defects, and renal tubular acidosis, which may be of the proximal or distal variety. Intrinsic renal lesions produced by cancer may cause nephrogenic diabetes insipidus, in which the kidney is unresponsive to the action of antidiuretic hormone (ADH), with resultant formation of inappropriately dilute urine. This may be seen in multiple myeloma, in which causative intrinsic lesions could include intratubular obstruction by myeloma proteins or amyloid deposition in collecting ducts. Various antineoplastic agents produce a wide array of tubular dysfunction, with defective reabsorptive transport of magnesium constituting the defect of greatest clinical significance. AML—acute myelogenous leukemia; DI—diabetes insipidus; MM—multiple myeloma; PTH—parathyroid hormone.

Renal Involvement in Malignancy

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Malignancy in the Renal Transplant Patient MALIGNANCY IN THE RENAL TRANSPLANT PATIENT Cancer of the skin and lips Squamous cell carcinoma Basal cell carcinoma Malignant melanoma Malignant lymphoma Non-Hodgkin’s lymphoma Reticulum cell sarcoma B-cell lymphoproliferative syndromes (Epstein-Barr virus) Kaposi’s sarcoma Cutaneous form Visceral and cutaneous form Genitourinary cancer Carcinoma of the native kidney (acquired cystic kidney disease) Carcinoma of the transplanted kidney Renal cell carcinoma Malignant melanoma Carcinoma of the urinary bladder (cyclophosphamide associated) Uroepithelial tumors (associated with analgesic abuse) Gynecologic cancer Carcinoma of the cervix Ovarian cancer

FIGURE 5-36 Malignancy in the renal transplant patient. In patients with end-stage renal disease with an adequately functioning renal allograft, there is an increased incidence of malignancy at various sites [80]. The most common form of malignancy is skin cancer. Its incidence may be as high as 24% in countries such as Australia where excessive exposure to the sun occurs. Other forms of cancer also occur with increased incidence in the transplant recipient. Malignant lymphoma, especially at extranodal sites (such as the central nervous system), occurs with increased frequency. Women with renal transplants have been observed to have an increased incidence of cervical cancer. Kaposi’s sarcoma can account for 5% to 10% of posttransplant neoplasms. This tumor may be confined to the skin or may involve the viscera. Several factors contribute to the increased risk of cancer in the immunosuppressed renal transplant recipient. These include loss of immune surveillance, chronic antigenic stimulation, oncogenic potential of the immunosuppressant agents, and viral infections leading to neoplasia. Epstein-Barr virus has been implicated in the polyclonal B-cell lymphoproliferative disease in these patients. Lymphoproliferative disorders have been noted to occur after a median period of 56 months when azathioprine and prednisone are used as immunosuppressive therapy. After the introduction of cyclosporine, lymphoproliferative disorders develop sooner, with a median interval of only 6 months [81]. The prognosis for patients with skin cancer remains good. Preventive measures such as avoiding sun exposure, utilization of sun-blocking creams, and careful periodic skin examinations are important. Patients with Kaposi’s sarcoma confined to the skin may have remission rates of up to 50% with cessation of immunosuppression or with chemotherapy. Patients with Kaposi’s sarcoma involving the viscera or with other lymphoproliferative disorders do poorly, with a more rapid course than seen in nontransplant patients with malignancy. Even those patients responding to chemotherapy tend to have only short remissions and a poor outcome. FIGURE 5-37 Malignant lymphoma in the transplanted kidney. A 55-year-old man with end-stage renal disease due to diabetic nephropathy received a cadaveric renal transplant. He was managed with prednisone, azathioprine, and antilymphocyte globulin (ALG). The allograft functioned poorly despite therapy a week later with OKT3. Results of a percutaneous renal biopsy were suspicious for a lymphoproliferative disorder in the renal allograft. He had a transplant nephrectomy 5 weeks after the original surgery. Pathologic study of the allograft showed extensive infiltration of the interstitium, renal pelvis, and blood vessels with large round and ovoid lymphocytes with many nucleoli and scant cytoplasm, diagnostic of a malignant lymphoma. Special studies revealed the lymphoid cells to be polyclonal in nature, and the patient’s serologic testing was positive for Epstein-Barr virus. Immunosuppression was stopped, and therapy with ganciclovir was started.

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Systemic Diseases and the Kidney

References 1. Rieselbach RE, Garnick MB (eds): Cancer and the Kidney. Philadelphia: Lea & Febiger, 1982. 2. Marple JT, MacDougall M: Development of malignancy in the endstage renal disease patient. Semin Nephrol 1993, 13:306–314. 3. Flombaum C: Electrolyte and renal abnormalities. In Critical Care of the Cancer Patient, edn 2. Edited by Groeger JS. St. Louis: Mosby Year Book; 1991:140–164. 4. Garnick MB, Richie JP: Primary neoplasms of the kidney and renal pelvis. In Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown; 1997:779–802. 5. Norris SH: Paraneoplastic glomerulopathies. Semin Nephrol 1993, 13:258–272. 6. Sanders PW, Herrera GA: Monoclonal immunoglobulin light chainrelated renal disorders. Semin Nephrol 1993, 13:324–341. 7. Safirstein RL: Renal diseases induced by antineoplastic agents. In Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown; 1996:1153–1165. 8. Guleria AS, Yang JC, Topalian SL, et al.: Renal dysfunction associated with the administration of high-dose interleukin-2 in 199 consecutive patients with metastatic melanoma or renal cell carcinoma. J Clin Oncol 1994, 12:2714–2722. 9. Zager RA: Acute renal failure in the setting of bone marrow transplantation. Kidney Int 1994, 46:1443–1458. 10. Merouani A, Shpall EJ, Jones RB, et al.: Renal function in high dose chemotherapy and autologous hematopoietic cell support treatment for breast cancer. Kidney lnt 1996, 50:1026–1031. 11. Zimmerman SW, Moorthy AV, Burkholder PM, Jenkins PG: Glomerulopathies associated with neoplastic disease. In Cancer and the Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Lea & Febiger; 1982. 12. Jenkins PG, Rieselbach RE: Acute renal failure: diagnosis, clinical spectrum, and management. In Cancer and the Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Lea & Febiger; 1982. 13. Baker LRJ, Cattell WR, Fry IK, Mallison WJ: Acute renal failure due to bacterial pyelonephritis. Q J Med 1979, 48:603. 14. Mayer RJ: Infiltrative and metastatic disease of the kidney. In Cancer and the Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Lea & Febiger; 1982. 15. Greenberger JS, Weichselbaum RR, Cassady JR: Radiation nephropathy. In Cancer and the Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Lea & Febiger; 1982. 16. Lodish JR, Boxer RJ: Urinary tract hemorrhage. In Cancer and the Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Lea & Febiger; 1982. 17. Murgo AJ: Thrombotic microangiopathy in the cancer patient including those induced by chemotherapeutic agents. Semin Hematol 1987, 24:161–174. 18. D’Elia JA, Aslani M, Schermer S, et al.: Hemolytic-uremic syndrome and acute renal failure in metastatic adenocarcinoma treated with mitomycin: case report and literature review. Renal Failure 1987, 170:107–113. 19. Remuzzi G, Ruggenenti P: The hemolytic-uremic syndrome. Kidney Int 1995, 47:2–19. 20. Gonzalez-Vitale JC, et al.: The renal pathology in clinical trials of cisplatinum (II) diamminedichloride. Cancer 1977, 39:1362.21. Bhuchar VK, Lanzotti VJ: High-dose cisplatin for lung cancer. Cancer Treat Rep 1982, 66:375. 21. Bhuchar VK, Lanzotti VJ: High-dose cisplatin for lung cancer. Cancer Treat Rep 1982, 66:375. 22. Schilsky RL, Anderson T: Hypomagnesemia and renal magnesium wasting in patients receiving cisplatin. Ann Intern Med 1979, 90:929.

23. Garnick MB, Mayer RJ: Management of acute renal failure associated with neoplastic disease. Oncologic Emergencies. Edited by Yarbo J, Bornstein R. New York: Grune and Stratton; 1981:247. 24. Von Hoff DD, Penta JS, Helman LJ, Slavik M: Incidence of drugrelated deaths secondary to high-dose methotrexate and citrovorum factor administration. Cancer Treat Rep 1977, 61:745. 25. Hande KR, Donehower RC, Chabner BA: Pharmacology and pharmokinetics of high dose methotrexate in man. In Clinical Pharmacology of Antineoplastic Drugs. Edited by Pinedo HM. New York: Elsevier/North Holland; 1978. 26. Jacobs SA, Stoller RG, Chabner BA, Johns DG: 7-Hydroxy methotrexate as a urinary metabolite in human subjects and rhesus monkeys receiving high dose methotrexate. J Clin Invest 1976, 57:534. 27. Johnson WJ, Kyle RA, Pineda AA, et al.: Treatment of renal failure associated with multiple myeloma. Arch Intern Med 1990, 50:863–869. 28. Solomon A, Weiss DT, Kattine AA: Nephrotoxic potential of BenceJones proteins. N Engl J Med 1991, 324:1845–1851. 29. Kyle RA, Gertz MA: Systemic amyloidosis. Crit Rev Oncol Hematol 1990, 10:49–87. 30. Preud’homme JL, Aucouturier P, Striker L: Monoclonal immunoglobulin deposition disease (Randall type): relationship with structural abnormalities of immunoglobulin chains. Kidney Int 1994, 46:965–972. 31. Skarin AT: Atlas of Diagnostic Oncology. New York: Gower Medical Publishing; 1991. 32. Rosol TJ, Capen CC: Mechanisms of cancer-induced hypercalcemia. Lab Invest 1992, 67:680–702. 33. Seymour JF, Gagel RF: Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin’s disease and non-Hodgkin’s lymphomas. Blood 1993, 82:1383–1394. 34. Benabe JE, Martinez-Maldonado M: Hypercalcemic nephropathy. Arch Intern Med 1978, 138:777–779. 35. Coe FL, Favus MJ, Kathpalia SC, et al.: Calcium and phosphorus metabolism in cancer: hypercalcemic nephropathy. In Cancer and the Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Lea & Febiger; 1982. 36. Rieselbach RE, Sorensen LB: Uric acid metabolism in cancer: hyperuricemic nephropathy. In Cancer and the Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Lea & Febiger; 1982. 37. Bishop MR, Coccia PF: Tumor lysis syndrome. In Clinical Oncology. Edited by Abeloff MD, Armitage JO, Lichter AS, Niederhuber JR. New York: Churchill Livingstone; 1995:557–561. 38. Band PR, Silverberg DS, Henderson JF, et al.: Xanthine nephropathy in a patient with lymphosarcoma treated with allopurinol. N Engl J Med 1970, 2283:354. 39. Pichette V, Leblanc M, Bonnardeaux A, et al.: High dialysate flow rate continuous arteriovenous hemodialysis: a new approach for the treatment of acute renal failure and tumor lysis syndrome. Am J Kidney Dis 1994, 23:591. 40. Hande KR, Noone RM, Stone WJ: Severe allopurinol toxicity: Description and guidelines for prevention in patients with renal insufficiency. Am J Med 1984, 76:47–56. 41. Obrador GT, Price B, O’Meara Y, Salant DJ: Acute renal failure due to lymphomatous infiltration of the kidneys. J Am Soc Nephrol 1997, 8:1348–1354. 42. Richmond J, Sherman RS, Diamond HD, Craver LF: Renal lesions associated with malignant lymphomas. Am J Med 1962, 32:184–207.

Renal Involvement in Malignancy 43. Gutmann FD, Boxer RJ: Pathophysiology and management of urinary tract obstruction. In Cancer and the Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Lea & Febiger; 1982. 44. Boxer RJ, Garnick MB, Anderson T: Extrarenal cancer of the genitourinary tract. In Cancer and the Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Lea & Febiger; 1982. 45. Kearney GP, Knapp RC: Genitourinary complications of gynecologic cancers. In Cancer and the Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Lea & Febiger; 1982. 46. Eagen JW, Lewis EJ: Glomerulopathies of neoplasia. Kidney Int 1977, 11:297–306. 47. Moorthy AV, Zimmerman SW, Burkholder PM: Nephrotic syndrome in Hodgkin’s disease: evidence for pathogenesis alternative to immune complex deposition. Am J Med 1976, 61:471–477. 48. Shalhoub RJ: Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 1974, 2:556–560. 49. Tsuji M, Ochiai S, Taka T, et al.: Nonamyloidotic nephrotic syndrome in Waldenstrom’s macroglobulinemia. Nephron 1990, 54:176–178. 50. Kyle RA: “Benign” monoclonal gammopathy—after 20-35 years of follow-up. Mayo Clin Proc 1993, 68:26–36. 51. Garnick MB: Bladder, renal and testicular cancer. Scientif Am Med 1995: 12:ixB 1–5. 52. Shapiro CL, Garnick MB, Kantoff PW: Tumors of the kidney, ureter, and bladder. In Cecil Textbook of Medicine, edn 20. Edited by Bennett JC. Philadelphia: WB Saunders; 1996:867. 53. McDougal WS, Garnick MB: Clinical signs and symptoms of kidney cancer. In Comprehensive Textbook of Genitourinary Oncology. Edited by Vogeizang NJ, Scardino PT, Shipley WU, et al. Baltimore: Williams & Wilkins; 1996:P546. 54. Motzer RJ, Bander NH, Nanus DM: Renal-cell carcinoma. N Engl J Med 1996, 335:8665–8875. 55. Chisholm GD, Roy RR: The systemic effects of malignant renal tumors. Br J Urol 1971, 43:687–700. 56. Brenner B, Rector F: The Kidney, edn 5. Philadelphia: WB Saunders Co.; 1996. 57. Beahrs OH, Henson DE, Hutter RVP, et al.: Handbook for the Staging of Cancer: From the Manual for Staging Cancer, edn 4. 1993, Philadelphia: J.B. Lippincott; 1993. 58. Storkel S, van den Berg E: Morphologic classification of renal cancer. World J Urol 1995, 13:153–158. 59. Latif F, Tory K, Gnarra J, et al.: Identification of the von HippelLindau tumor suppressor gene. Science 1993, 260:1317–1320. 60. Storkel S, Stearata PV, Drenckhain D, Thoenes W: The human chromophobe cell renal carcinoma: its probable relation to intercalated cells of the collecting duct. Virchows Arch B Cell Pathol 1989, 56:237–245. 61. Shalev M, Cipolia B, Guille F, et al.: Is ipsilateral adrenalectomy a necessary component of radical nephrectomy? J Urol 1995, 153:1415–1417. 62. Licht MR, Novick AC, Goormastic M: Nephron sparing surgery in incidental versus suspected renal cell carcinoma. J Urol 1994, 152:39–42. 63. Thrasher JB, Paulson DF: Prognostic factors in renal cancer. Urol Clin North Am 1993, 20:247–262.

5.25

64. Nanus DM, Pfeffer LM, Bander NH, et al.: Antiproliferative and antitumor effects of alpha-interferon in renal cell carcinomas: correlation with the expression of a kidney-associated differentiation glycoprotein. Cancer Res 1990, 50:4190–4194. 65. Minasian LM, Motzer RJ, Gluck L, et al.: Interferon alfa-2a in advanced renal cell carcinoma: treatment results and survival in 159 patients with long-term follow-up. J Clin Oncol 1993, 11:1368–1375. 66. Law TM, Motzer RJ, Mazumdar M, et al.: Phase III randomized trial of interleukin-2 with or without lymphokine activated killer cells in the treatment of patients with advanced renal cell carcinoma. Cancer 1995, 76:824–832. 67. Wigginton JM, Komschlies KL, Back TC, et al.: Administration of interleukin-12 with pulse interleukin-2 and the rapid and complete eradication of murine renal carcinoma. J Natl Cancer Inst 1996, 88:38–43. 68. Manning EC, Belenko MI, Frauenhoffer EE, Ahsan N: Acute renal failure secondary to solid tumor renal metastases: case report and review of the literature. Am J Kidney Dis 1996, 27:284–291. 69. Wagle DG, Moore RH, Murphy GP: Secondary carcinomas of the kidney. J Urol 1975, l 14:30–32. 70. Wilson RE, Hager EB, Hampers CL, et al.: Immunologic rejection of human cancer transplanted with a renal allograft. N Engl J Med 1968, 278:479–483. 71. Sharland A, Snowdon L, Joshua DE, et al.: Hemodialysis: an appropriate therapy in myeloma-induced renal failure. Am J Kidney Dis 1997, 30:786–792. 72. Gertz MA, Kyle RA, Greipp PR: Response rates and survival in primary systemic amyloidosis. Blood 1991, 77:257–262. 73. Massry, Glassock: Textbook of Nephrology, edn 3. Baltimore: Williams & Wilkins; 1995. 74. Harmon WC, Cohen HJ, Schneeberger E, et al.: Chronic renal failure in children treated with methyl CCNU. N Engl J Med 1979, 300:1200–1203. 75. Daniels RA, Weisenfeld I: Tumorous phosphaturic osteomalacia: report of a case associated with multiple hemangiomas of bone. Am J Med 1979, 67:155–159. 76. Simpson DP, Wen SF, Chesney RW: Fluid and electrolyte abnormalities due to tumors, their products, or metabolites. In Cancer and the Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Lea & Febiger; 1982. 77. Hauck WA, Olson KB, Horton J: Clinical features of tumor metastasis to the pituitary. Cancer 1970, 26:656. 78. Pickering TG, Catovsky D: Hypokalemia and raised lysozyme level in acute myeloid leukemia: Q J Med 1973, 42:677–682. 79. Bennett JS, et al.: Hypouricemia in Hodgkin’s disease. Ann Intern Med 1972, 76:751–756. 80. Chan L, Kam I, Spees EK: Outcome and complications of renal transplantation. In Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown; 1997:2713–2769. 81. Stone RM, Mark EJ, Ferry JA: Case records of the Massachusetts General Hospital: Weekly clinicopathological exercises. A 67-year-old renal-transplant recipient with anemia, leukopenia, and pulmorary lesions. N Engl J Med 1997, 337:1065–1074.

Renal Involvement in Tropical Diseases Rashad S. Barsoum Magdi R. Francis Visith Sitprija

T

ropical nephrology is no longer a regional issue. With the enormous expansion of travel and immigration, the world has become a global village. Today, a health problem in a particular region has worldwide repercussions. Typical examples are the acquisition of malaria in European airports, renal disease associated with herbal medications, and increasing encounters of parasitic infections in immunocompromised persons [1–3]. Lessons learned from the study of tropical diseases have considerably enriched worldwide medical knowledge of the basic and clinical aspects of nontropical diseases. Examples include better understanding of macrophage function in vitro, the role of cytokines in acute renal failure, and the importance of immunoglobulin A deposits in the progression of glomerular disease [4–7]. The so-called typical tropical nephropathies are broadly classified as infective or toxic. Infective nephropathies include renal diseases associated with endemic bacterial, viral, fungal, and parasitic infections. Toxic tropical nephropathies include exposure to poisons of animal origin, such as snake bites, scorpion stings, and intake of raw carp bile, and plant origin, such as certain mushrooms and the djenkol bean [3]. Tropical bacterial infections often are associated with renal complications that vary according to the causative organism, severity of infection, and individual susceptibility. The principal acute infections reported to affect the kidneys are salmonellosis, shigellosis, leptospirosis, melioidosis, cholera, tetanus, scrub typhus, and diphtheria [8–16]. Renal involvement in mycobacterial infections such as tuberculosis and leprosy usually pursues a subacute or chronic course [17–19].

CHAPTER

6

6.2

Systemic Diseases and the Kidney

The clinical spectrum of renal involvement extends all the way from asymptomatic proteinuria or urinary sediment abnormalities to fatal acute renal failure. The respective renal pathologies include glomerular, microvascular, and tubulointerstitial lesions. The pathogenesis of renal complications in tropical bacterial infections is multifactorial. The principal factors are direct tissue invasion by the causative organisms and remote cellular and humoral effects of bacterial antigens and endotoxins. The relative significance of the different pathogenetic mechanisms varies with the causative organism. In tropical zones many viral nephropathies are endemic, such as those associated with human immunodeficiency virus and hepatitis A, B, and C viruses. These are addressed in Chapter 7. Here the focus is on an important viral disease endemic in Southeast Asia that often causes minor epidemics in Africa and other tropical countries, dengue hemorrhagic fever.

Mycotic infections are described in detail elsewhere. Discussed here is a fairly common mycotic infection, mucormycosis, which occurs in underdeveloped tropical regions, particularly among immunocompromised patients. Also described is ochratoxin, a fungal toxin often incriminated in the pathogenesis of Balkan nephropathy. Ochratoxin also contributes to progressive interstitial nephropathy in Africa [20]. Three ways exist by which parasitic infections cause renal disease: 1) direct physical invasion of the kidneys or urinary tract, as in schistosomiasis, echinococcosis, and filariasis; 2) renal injury as a consequence of the acute systemic effects of parasitic infection, eg, falciparum malaria; and 3) immunemediated renal injury resulting from the concomitant host-parasite interaction, eg, schistosomiasis, malaria, filariasis, leishmaniasis, trichinosis, echinococcosis, toxoplasmosis, and trypanosomiasis [21–32].

Infective Tropical Nephropathies Bacterial Infections CLINICAL MANIFESTATIONS OF TROPICAL BACTERIAL NEPHROPATHIES Disease Salmonellosis Shigellosis Leptospirosis Melioidosis Cholera Tetanus Scrub typhus Diphtheria Tuberculosis Leprosy

Abnormal sediment

Proteinuria

ARF

CRF

HUS

Hemolysis

DIC

Jaundice

+++

++++

++++

++++

+ + ++++

-

+ ++* +

+ + +

+ + +

+ + ++++

+++++

+

+ + + ++ ++

++++ ++ + +/+++ +++

++ + +++ + +

+ +

+

+

Commonly associated features Gastrointestinal Neurologic† Hemorrhagic tendency Polyuria‡ Hyponatremia§ Hypokalemia, acidosis Sympathetic overflow

+ Myocarditis, polyneuritis Retroperitoneal nodes Lepromas

*Associated with Shigella serotype I endotoxin [33]. †Visual disturbances, drowsiness, seizures, and coma in 40% of cases [34]. ‡In 90% of cases [12]. §Nephrogenic diabetes insipidus [35]. ARF—acute renal failure; CRF—chronic renal failure; DIC—disseminated intravascular coagulation; HUS—hemolytic uremic syndrome; +—<10%; ++—10%–24%; +++—25%–49%; ++++—50%–80%; +++++—>80%. Dash indicates not reported.

FIGURE 6-1 Clinical manifestations of tropical bacterial nephropathies. Note the wide spectrum of clinical manifestations that may ultimately reflect on the kidneys [33–35].

6.3

Renal Involvement in Tropical Diseases

SPECTRUM OF RENAL PATHOLOGY IN TROPICAL BACTERIAL INFECTIONS

Disease

Salmonellosis Shigellosis Leptospirosis Melioidosis Cholera Tetanus Scrub typhus Diphtheria Tuberculosis Leprosy

Glomerulonephritis

MPGN

EXGN

++ + + +

++*

MCGN

MN

NG

CGN

Vasculitis

Amyloid

G,M,A,C3,Ag† +

+

+

M,C3

+¶

ATN

++

+ + +++ + ++ ++ + +/++

Other tubular changes

Deposits of immunoglobulins, complement, and antigen

+

+/+++

AIN

+ +

G,M,A,C3

+ +

++ +++

+ ++ + +

+/+++**

Cloudy swelling Cloudy swelling Cloudy swelling Vacuolation‡ Cloudy swelling Degeneration§ Functional defects

*When associated with Schistosoma mansoni infection in Egypt [9]. †Vi antigen deposits [8]. ‡Hypokalemic nephropathy [36]. §Exotoxin-induced inhibition of protein synthesis in tubule cells [37]. ¶Usually complicates amyloidosis: 2.4%–8.4% [18]. **63% in lepromatous leprosy; 2% in nonlepromatous types [38]. AIN—acute interstitial nephritis; ATN—acute tubular necrosis; CGN—crescentic glomerulonephritis; EXGN—exudative glomerulonephritis; MCGN—mesangiocapillary glomerulonephritis; MN—membranous glomerulopathy; NG—necrotizing glomerulitis; +—<10%; ++—10%–24%; +++—25%–50%.

FIGURE 6-2 Spectrum of renal pathology in tropical bacterial infections [36–38].

A FIGURE 6-3 Glomerular lesions associated with tropical bacterial infections. A, Simple proliferative glomerulonephritis in a

B patient with shigellosis. B, Exudative glomerulonephritis in a patient with salmonellosis. (Continued on next page)

6.4

Systemic Diseases and the Kidney

C

D

FIGURE 6-3 (Continued) C, Necrotizing vasculitis in a patient with leptospirosis. D, Membranous nephropathy associated with leprosy. (Hematoxylin-eosin stain  150.) FIGURE 6-4 Glomerular amyloid deposits in a patient with leprosy. (Hematoxylin-eosin stain  200.)

FIGURE 6-5 Acute tubular pathology associated with bacterial infections. A, Acute tubular necrosis with erythrocyte aggregates in the tubular lumina in a patient with leptospirosis. (Hematoxylin-eosin stain  250.) B, Cortical necrosis in a child with severe shigellosis and hemolytic uremic syndrome. (Hematoxylin-eosin stain  200.)

A

B

Renal Involvement in Tropical Diseases

6.5

FIGURE 6-6 Extensive vacuolation of the proximal tubules (hypokalemic nephropathy) in a patient with cholera. (Hematoxylin-eosin stain  300.) (From Sinniah and coworkers [39]; with permission.)

A

B

C

D

FIGURE 6-7 Interstitial lesions associated with bacterial infections. A, Acute interstitial nephritis in a patient with diphtheria. (Hematoxylin-eosin stain  100.) B, Perivenular monocytic infiltration in a patient with scrub typhus. (Hematoxylin-eosin

stain  100.) C, Renal abscess in a patient with septicemic melioidosis. (Hematoxylin-eosin stain  75.) D, Microabscesses in a patient with typhoid fever [40]. (Hematoxylineosin stain  75.)

6.6

Systemic Diseases and the Kidney

FIGURE 6-8 Low-power electron micrograph. Here leptospires (arrow) in the peritubular cortical interstitial space are seen in a patient with leptospirosis. (Magnification  12,000.)

FIGURE 6-9 Renal tuberculosis. Seen here are multiple tuberculous granulomata with Langhans’ giant cells. Diffuse interstitial tuberculosis without definite granulomatous formation also has been described. (Hematoxylin-eosin stain  200.)

Bacterial infection

Direct invasion

Monocyte activation

Endothelial injury

Nonspecific inflammatory effects

T-cell response

Monokines

Humoral

B-cell response

IL-1,6 TNF-α NO ROM

Complement/coagulation

Antibodies

Hematologic

Platelets

Erythrocytes

DIC

Hemolysis

Hypovolemia

Cholestasis

Adhesion molecules Immune complexes

Abscess

Glomerulonephritis

Endothelin Renal ischemia

Interstitial nephritis

ATN

Jaundice

FIGURE 6-10 Common pathogenetic mechanisms of renal injury in tropical bacterial infections. Depending on the bacterial species and strain, as well as on the host’s resistance and genetic background, bacteria may directly invade the renal parenchyma, induce an immune reaction, injure the capillary endothelium or provoke a nonspecific humoral or hematologic response. The subsequent evolution of these pathways may lead to different forms of renal injury. The asterisk indicates that the role of hemolysis is augmented in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. ATN—acute tubular necrosis; DIC—disseminated intravascular coagulation; IL—interleukin; NO—nitric oxide; ROM—reactive oxygen molecules; TNF-—tumor necrosis factor-.

6.7

Renal Involvement in Tropical Diseases

PATHOGENETIC MECHANISMS IN ACUTE TUBULAR NECROSIS Disease

Monokines

Hypovolemia

Hemolysis

Rhabdomyolysis

Disseminated intravascular coagulation

Complement activation

+ + ++ + + ++ + + +

+ ++ + + +++ + + + -

+ + +

+ +

+ + +

++

Salmonellosis Shigellosis Leptospirosis Melioidosis Cholera Tetanus Scrub typhus Diphtheria Leprosy

+ ++*

+ +

+

*Elevated creatine phosphokinase in 88%, myoglobinuria in 39% of cases [14]. +—<10%; ++—10%–24%; +++—24%–50%.

FIGURE 6-11 Pathogenetic mechanisms in acute tubular necrosis associated with bacterial infections. Note the multiplicity of factors depending on the bacterial species and their host targets.

Viral Infections FIGURE 6-12 Clinical manifestations of renal involvement in dengue hemorrhagic fever. Note that proteinuria and abnormal urinary sediment are the most common manifestations. Also note the high incidence of hyponatremia, like with many other tropical infections [40,41].

90

Incidence, %

80 70 60 50 40 30 20 10 0

Urinary sediment abnormalities

Proteinuria Hyponatremia

Lactic acidosis

Selected important features

Acute renal failure

6.8

Systemic Diseases and the Kidney FIGURE 6-13 Renal lesions in a patient with dengue hemorrhagic fever. A, Mesangial proliferative glomerulonephritis, which usually is associated with deposits of immunoglobulins G and M and complement 3. (Hematoxylineosin stain  200.) B, Acute tubular necrosis, which is associated with interstitial edema and mononuclear cell infiltration. (Hematoxylin-eosin stain  175.)

A

B

Mycotic Infections

FIGURE 6-14 Section from a patient with mucormycosis, showing extensive tissue necrosis, weak inflammatory cellular infiltration, and fungal hyphae branching at right angles. (Hematoxylin-eosin stain  150.)

FIGURE 6-15 Ochratoxin-A–induced interstitial fibrosis, showing marked intertubular scarring with patchy atrophy and collapse of tubules. This patient’s serum ochratoxin-A and urinary ochratoxin-A levels were 5.18 and 3.87 ng/mL, respectively (the means for a control group were 1.6 and 1.85 ng/mL, respectively) [20]. (Masson trichrome stain  200.)

Renal Involvement in Tropical Diseases

6.9

Parasitic Infections Schistosoma hemalobium Schistosoma mansoni

Echinococcosis Plasmodium falciparum

Quartan malaria

FIGURE 6-16 Global distribution of important parasitic nephropathies. Note the high prevalence of schistosomal, malarial, filarial, and echinococcal renal complications in Africa; S. mansoni and hydatid in South America; falciparum malaria and filariasis in South East Asia and filariasis in India [3].

Schistosoma mansoni

Filariasis

FIGURE 6-17 Urinary schistosomiasis. A, A sheet of Schistosoma haematobium ova in tissues. (Silver stain  350.) B, S. haematobium granuloma. Shown is a delayed hypersensitivity reaction of the host to soluble oval antigens released from the ova through micropores in their shells. The granuloma is composed of mononuclear cells, a few neutrophils, eosinophils, and fibroblasts, surrounding a distorted egg. (Hematoxylineosin stain  300.)

A

B

6.10

A

Systemic Diseases and the Kidney

B

C

FIGURE 6-18 Cystoscopic appearances of different bladder lesions associated with Schistosoma haematobium infection. A, Bilharzial (schistosomal) pseudotubercles. B, Bilharzial submucous mass covered by pseudotubercles. C, Bilharzial ulcer surrounded by pseudotubercles. D, Bilharzial ulcer surrounded by sandy patches. (Courtesy of N. Makar, MD.)

D FIGURE 6-19 Postmortem specimen showing advanced bilharzial involvement of the urinary tract. Note the dirty bladder mucosa, fibrosed muscle layer, and neoplastic growth (histologically a squamous cell carcinoma) cut through transversely. The ureters are dilated, with a clear stricture at the lower end of the right ureter. Also seen in this patient are bilateral hydroureters with submucous cystic lesions (bilharzial ureteritis cystica). The kidneys show considerable scarring, with the right kidney also showing chronic back pressure changes.

FIGURE 6-20 Filariasis of the abdominal lymphatics. Lymphangiogram shows the dilated retroperitoneal lymphatics in a patient with filarial chyluria.

Renal Involvement in Tropical Diseases

6.11

Antigens Merozoites

Erythrocyte Monocyte

Hemolysis Cell membrane changes

TH1

CIC

TNF-α

Platalet

CD8+

Endothelial activation Hemodynamic changes Acute tubular necrosis

TH2

Acute inflammatory

Tubulointerstitial nephropathy

B

Immunoglobulins

Immune complex disease

Acute glomerulonephritis

Proliferative glomerulonephritis

FIGURE 6-21 The pathogenesis of falciparum malarial renal complications. Note the infection triggers two initially independent pathways: red cell parasitization and monocyte activation. These subsequently interact, as the infected red cells express abnormal proteins that induce an immune reaction by their own right, in addition to providing sticky points (knobs) for clumping and adherence to platelets and capillary endothelium. TNF- released from the activated monocytes shares in the endothelial activation. As both pathways proceed and interact, a variety of renal complications develop, including acute tubular necrosis, acute interstitial nephritis and acute glomerulonephritis. B—B-lymphocyte; CD8—cytotoxic T cell; CIC—circulating immune complexes; TH—T-helper cells (1 and 2); TNF-—tumor necrosis factor-.

FIGURE 6-22 Erythrocyte knobs in a patient with falciparum malaria [43]. These erythrocyte knobs contain novel proteins, mainly Plasmodium falciparum erythrocyte membrane protein (PfEMP), histidine-rich protein 1, and histidine-rich protein 2, that are synthesized under the influence of the DNA of the parasite [44–46]. These proteins constitute the sticky points (arrows) by which parasitized erythrocytes aggregate and adhere to blood platelets and endothelial cells [47,48]. EN—electron microphotograph. (Magnification  12,000.)

B

A

FIGURE 6-23 Renal lesions in a patient with falciparum malaria. A, Proliferative and exudative glomerulonephritis, an immune-complex–mediated lesion that may lead to an acute nephritic syndrome, which usually is reversible by antimalarial treatment. (Hematoxylin-eosin stain  175.) B, Acute tubular necrosis (ATN) associated with interstitial mononuclear cell infiltration. ATN is seen in 1% to 4% of patients with falciparum malaria and in up to 60% of those with malignant malaria. (Hematoxylin-eosin stain  200.) (Continued on next page)

6.12

Systemic Diseases and the Kidney FIGURE 6-23 (Continued) C, Subendothelial and mesangial malarial antigen deposits seen on immunofluorescence. Often, complement 3, immunoglobulins M and G, and fibrinogen also are seen. (Hematoxylin-eosin stain  200.)

C

CDCT ACDC

+ ADCC

–

Parasite

Eosinophil +

–

+

+

+ + Neutrophil Complement

Antigen

+

CIC IL-5,13

IL-2

IgM,E,G,A

FIGURE 6-24 The broad lines of the immune response to parasitic infections. Note the pivotal role of the monocyte, activated by exposure to parasitic antigens, in stimulating both T-helper 1 (TH1) and T-helper 2 (TH2) cells. The different cytokine mediators and parasite elimination mechanisms are shown. B—B-lymphocyte; -IFN—-interferon; CIC—circulating immune complexes; GM-CSF—granulocytemacrophage colony-stimulating factor; Ig—immunoglobulin; IL—interleukin.

IL-1,6,12 GM-CSF + TH2

TH1

+

γ-IFN

B

+

IL-2 IL-4,5,10

Active monocytes TH2, CD8 cells IgG1,2,3 IL-1,6;+γIFN

Initial events

Inactive monocytes TH2 ,CD8 cells IgM,IgG4,IgA IL-4,5,10

Late events

FIGURE 6-25 The T-helper1–T-helper 2 (TH1-TH2) cell balance that determines the clinical expression of different parasitic nephropathies. TH1 predominance leads to either reversible acute proliferative glomerulonephritis or acute interstitial nephritis. TH2 predominance tends to lessen the severity of the lesions and may lead to chronic glomerulonephritis in the presence of copathogenic factors such as concomitant infection (malaria, schistosomiasis), autoimmunity (malaria, filariasis, schistosomiasis), or immunoglobulin A (IgA) switching (Schistosoma mansoni) [7, 9, 49–52]. CD4—T-helper cells; CD8—cytotoxic cells; -INF—-interferon; IL—interleukin.

Renal Involvement in Tropical Diseases

6.13

FIGURE 6-26 Leishmaniasis. A, Amastigotes in peripheral blood monocytes. Amastigotes downregulate the host cells that show no attempt at eradicating the parasite. (Hematoxylineosin stain  450.) B, Interstitial nephritis representing a TH1 predominant state, which is self-limited owing to the parasiteinduced monocyte inhibition [53]. (Hematoxylin-eosin stain  175.)

A

B FIGURE 6-27 Trichinosis. A, Here Trichinella spiralis is encysted in the muscle tissue of a patient. (Hematoxylin-eosin stain  75.) B, Associated proliferative glomerulopathy in a patient. This lesion usually is subclinical but may be manifested as an acute nephritic syndrome that can be resolved with antiparasitic treatment. This lesion represents a TH1 predominant state. (Hematoxylineosin stain  150.)

A

B

6.14

Systemic Diseases and the Kidney

B

A FIGURE 6-28 Echinococcosis. A, Mesangiocapillary type III glomerulonephritis. (Hematoxylin-eosin stain  200.) B, Electron micrograph showing subepithelial deposits. (Hematoxylin-eosin stain  25,000.) C, Peripheral part of a hydatid cyst showing the daughter cysts in a patient. (Hematoxylineosin stain  75.)

C FIGURE 6-29 Onchocercosis. A, The parasite Onchocerca volvulus deposits lesions in tissues. (Hematoxylin-eosin stain  150.) B, Associated mesangial proliferative lesion. This lesion represents a TH1 predominant state. Some patients, however, develop an autoimmune reaction that leads to progressive glomerulonephritis. (Hematoxylin-eosin stain  175.)

A

B

Renal Involvement in Tropical Diseases

6.15

FIGURE 6-30 Quartan malarial nephropathy. A, Proliferative glomerulonephritis with capillary wall thickening. (Hematoxylin-eosin stain  200.) B, Subendothelial deposits with splitting of the basement membrane. (Silver stain  500.) This lesion occurs under TH2 predominance and usually is encountered in genetically predisposed persons. This lesion also is associated with autoimmunity or concomitant viral infection.

A

B

A

B

FIGURE 6-31 Intestinal schistosomiasis. A, Pair of adult Schistosoma mansoni worms in colonic mucosa. (Hematoxylin-eosin stain  75.) B, Colonic granuloma around a viable ovum. (Hematoxylin-eosin stain  150.)

FIGURE 6-32 Patient with hepatosplenic schistosomiasis, complicating intestinal mansoniasis. Note the shrunken liver and very large spleen, surface marked on the abdominal wall by black ink. Of these patients, 15% develop clinically overt glomerular lesions. Half of the 15% become hypertensive, most become nephrotic at some stage, and almost all progress to end-stage disease [54].

6.16

Systemic Diseases and the Kidney FIGURE 6-33 Early glomerular lesion in a patient with schistosomiasis. A, Mesangial proliferation. (Hematoxylin-eosin stain  200.) B, Schistosomal gut antigen deposits in the mesangium. Other immunofluorescent deposits at this stage include immunoglobulins M and G and complement C. This lesion may be encountered in infection by Schistosoma mansoni, S. haematobium, or S. japonicum. The lesion does not necessarily progress any further. (Hematoxylin-eosin stain  300.)

A

B

A

B

C

D

FIGURE 6-34 Histologic lesions in a patient with progressive Schistosoma mansoni glomerulopathy. A, Mesangial proliferative glomerulonephritis. (Hematoxylin-eosin stain  150.) B, Exudative glomerulonephritis, often encountered with concomitant Salmonella paratyphi A infection [9]. (Hematoxylin-eosin stain  150.) C, Mesangial proliferation with areas of mesangiocapillary changes. (Hematoxylin-eosin stain  150.) D, Focal and

segmental glomerulosclerosis. (Masson trichrome stain  150.) The two lesions in panels C and D are associated with advanced hepatic fibrosis, impaired macrophage function, and predominant immunoglobulin A mesangial deposits [7,55]. The lesions shown are categorized, respectively, as classes I to IV schistosomal glomerulopathy according to the classification system of the African Association of Nephrology [54].

Renal Involvement in Tropical Diseases Pathogenesis of S. mansoni glomerulotherapy Adult worms in the portal vein Egg granulomata in the portal tracts

Autoimmunity

IgG,M,E Periportal fibrosis

Egg granulomata in the colonic mucosa

Antigens

Mucosal breach

Switching

IgA

Immune complexes

Impaired macrophage function Portosystemic collaterals

FIGURE 6-35 Pathogenesis of Schistosoma mansoni glomerulopathy. Note the crucial role of hepatic fibrosis, which 1) induces glomerular hemodynamic changes; 2) permits schistosomal antigens to escape into the systemic circulation, subsequently depositing in the glomerular mesangium; and 3) impairs clearance of immunoglobulin A (IgA), which apparently is responsible for progression of the glomerular lesions. IgA synthesis seems to be augmented through B-lymphocyte switching under the influence of interleukin-10, a major factor in late schistosomal lesions [7].

Glomerular deposits

B

A

C

FIGURE 6-36 (see Color Plate) Renal amyloidosis in schistosomiasis. A, Schistosomal granuloma (top), three glomeruli with extensive amyloid deposits (bottom), and dense interstitial infiltration and fibrosis in a patient with massive Schistosoma haematobium infection. (Hematoxylin-eosin stain  75.) B, Amyloid deposition in the mesangium associated with mild mesangial cellular proliferation in a patient with S. mansoni glomerulopathy (African Association of Nephrology class V). (Hematoxylin-eosin stain  175.) C, Early amyloid deposits seen as green (birefringent) deposits in a glomerulus with considerable mesangial proliferation in a patient with hepatosplenic schistosomiasis. (Congo red stain  200, examined under polarized light.)

6.17

6.18

Systemic Diseases and the Kidney Pathogenesis of schistoma-associated amyloidosis Interleukin-1,6

+

Hepatocyte

Antigen Uptake

AA protein

FIGURE 6-37 Pathogenesis of schistosoma-associated amyloidosis. The monocyte continues to release interleukin-1 and interleukin-6 under the influence of schistosomal antigens. These antigens stimulate the hepatocytes to release AA protein, which has a distinct chemoattractant function. The monocyte is the normal scavenger of serum AA protein, a function that is impaired in hepatosplenic schistosomiasis. Serum AA protein accumulates and tends to deposit in tissue.

Matrix adhesion

Chemoattraction

Tissue deposition

Toxic Tropical Nephropathies Toxins of Animal Origin NEPHROPATHIES ASSOCIATED WITH EXPOSURE TO ANIMAL TOXINS Acute renal failure Snake bite Scorpion sting Insect stings Jelly fish sting Spider bite Centipede bite Raw carp bile

+++ + + + + + ++

Vasculitis Subnephrotic proteinuria +

Nephrotic syndrome

+ (MPGN) ++ (MCD, MPGN, MN)

MCD—minimal change disease; MN—membranous glomerulonephritis; MPGN—mesangial proliferative glomerulonephritis; +—<10%; ++—10%–24%; +++—25%–50%.

FIGURE 6-38 Nephropathies associated with exposure to toxins of animal origin. Note that acute renal failure is the most common and important renal complication. Vascular and glomerular lesions are occasionally encountered with specific exposures [56–62].

Renal Involvement in Tropical Diseases Pathogenetic mechanisms in snake venom nephrotoxicity Snake venom Immunologic reaction

Direct toxicity

Disseminated intravascular coagulation

Hemolysis Rhabdomyolysis

Cytokines Mediators

Hemodynamic changes

Mesangiolysis

6.19

FIGURE 6-39 Pathogenetic mechanisms in snake venom nephrotoxicity. The immediate effect of exposure is attributed to direct hematologic toxicity involving the coagulation system and red cell membranes. The massive release of cytokines and rhabdomyolysis also contribute. Late effects may be encountered as a consequence of the immune response to the injected antigens.

Vasculitis

Renal ischemia Acute glomerulonephritis

Acute tubular necrosis

Glomerulonephritis

Toxins of Plant Origin NEPHROPATHIES ASSOCIATED WITH EXPOSURE TO PLANT TOXINS Acute renal failure

Hypertension

Proteinuria

Hematuria

+++ + +++ +

++

+++ +

++++

Djenkol bean Mushroom poisoning Callilepis laureola Semecarpus anacardium

FIGURE 6-40 Nephropathies associated with exposure to toxins of plant origin. Note that with the exception of Djenkol bean nephrotoxicity, most plant toxins lead to acute renal failure due to hemodynamic effects [63–66].

+—<10%; ++—10%–24%; +++—25%–49%; ++++—50%–80%.

Acknowledgment The authors acknowledge the help of Professor Amani Amin Soliman, Chairperson of the Parasitology Department, Cairo

University, for providing very valuable material included in this work.

References 1. 2.

3.

Giacomini T, Toledano D, Baledent F: The severity of airport malaria. Bull Soc Pathol Exot Faliales 1988, 81:345–350. Vanherweghem JL: A new form of nephropathy secondary to the absorption of Chinese herbs. Bull Mem Acad R Med Belg 1994, 149:128–135. Barsoum R, Sitprija V: Tropical nephrology. In Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown and Company; 1997:2221–2268.

4.

5.

Prina E, Lang T, Glaichenhaus N, et al.: Presentation of the protective parasite antigen LACK by Leishmania-infected macrophages. J Immunol 1996, 156: 4318–4327. Persat F, Vincent C, Schmitt D, et al.: Inhibition of human peripheral blood mononuclear cell proliferative response by glycosphingolipids from metacestodes of Echinococcus multilocularis. Infect Immun 1996, 64:3682–3687.

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Systemic Diseases and the Kidney

6. Clark IA: Suggested importance of monokines in pathophysiology of endotoxin shock and malaria. Klin Wochenschr 1982, 60:756–758.

31. Ginsburg BE, Wasserman J, Huldt G, et al.: A case of glomerulonephritis associated with acute toxoplasmosis. Br Med J 1974, 3:664–665.

7. Barsoum RS, Nabil M, Saady G, et al.: Immunoglobulin A and the pathogenesis of schistosomal glomerulopathy. Kidney Int 1996, 50:920–928.

32. Lindsley HB, Nagle RB, Werner PA, et al.: Variable severity of glomerulonephritis in inbred rats infected with Trypanosoma rhodesiense: correlation with immunoglobulin class-specific antibody responses to trypanosomal antigens and total IgM levels. Am J Trop Med Hyg 1980, 29:348–357. 33. Srivastava RN, Mocedgil A, Bagga A, et al.: Hemolytic uremic syndrome in children in northern India. Pediatr Nephrol 1991, 5:284–288.

8. Khajehdehi P, Tastegar A, Karazmi A: Immunological and clinical aspects of kidney disease in typhoid fever in Iran. Q J Med 1984, 209:101–107. 9. Bassily S, Farid Z, Barsoum RS, et al.: Renal biopsy in schistosomasalmonella associated nephrotic syndrome. J Trop Med Hyg 1976, 79:256–258. 10. Benish ML, Harris JR, Wojtyniak BJ , et al.: Death in shigellosis: incidence and risk factors in hospitalized patients. J Infect Dis 1990, 161:500–506. 11. Sitprija V: Leptospirosis. Med Int 1992, 106:4476–4479. 12. Susaengrat W, Dhiensiri T, Sinavatana P, et al.: Renal failure in melioidosis. Nephron 1987, 46:167–169. 13. World Health Organization: Cholera in Africa. WHO Weekly Epidemiol Rec 1997, 72:89–92. 14. Martinelli R, Matos CM, Rocha H: Tetanus as a cause of acute renal failure: possible role of rhabdomyolysis. Rev Soc Bras Med Trop 1993, 26:1–4. 15. Hsu GJ, Young T, Peng MY, et al.: Acute renal failure associated with scrub typhus, report of a case. J Formosan Med Assoc 1993, 92:475–477. 16. Singh M, Saidali A, Bakhtiar A: et al.: Diphtheria in Afghanistan: review of 155 cases. J Trop Med Hyg 1985, 88:373–376. 17. Latimer JK: Renal tuberculosis. N Engl J Med 1975, 273:208–214. 18. Chugh KS, Damle PB, Kaur S: Renal lesions in leprosy amongst North Indian patients. Postgrad Med J 1983, 59:707–711. 19. Madiwale CV, Mittal BV, Dixit M , et al.: Acute renal failure due to crescentic glomerulonephritis complicating leprosy. Nephrol Dial Transplant 1994, 9:178–179. 20. Saadi MG, Abdulla E, Fadel F, et al.: Prevalence of ochratoxin-A (OTA) among Egyptian children and adults with different renal diseases [abstract]. Second International Congress on Geographic Nephrology, Hurghada, Egypt; 1993:22. 21. Barsoum RS: Schistosomiasis. In Oxford Textbook of Clinical Nephrology. Oxford: Oxford University Press; Edited by Cameron S, Davidson A, Grunfeld JP, et al. 1992:1729–1741. 22. Beyribey S, Cetinkaya M, Adsan O, et al.: Treatment of renal hydatid disease by pedicled omentoplasty. J Urol 1995, 154:25–27. 23. Addiss DG, Dimock KA, Eberhard ML, et al.: Clinical, parasitologic and immunologic observations of patients with hydrocele and elephantiasis in an area with endemic lymphatic filariasis. J Infect Dis 1995, 171:755–758. 24. Sitprija V: Nephrology forum: nephropathy in falciparum malaria. Kidney Int 1988, 34:867–877. 25. Sobh M, Moustafa F, El-Arbagy A, et al.: Nephropathy in asymptomatic patients with active Schistosoma mansoni infection. Int Urol Nephrol 1990, 22:37–43. 26. Hendrickse RG, Adeniyi A: Quartan malarial nephrotic syndrome in children. Kidney Int 1979, 16:64–74. 27. Waugh DA, Alexander JH, Ibels LH: Filarial chyluria–associated glomerulonephritis and therapeutic consideration in the chyluric patient. Aust N Z J Med 1980, 10:559–562. 28. Ayachi R, Ben Dhia N, Guediche N, et al.: The nephrotic syndrome in kala-azar. Arch Fr Pediatr 1988, 45:493–495. 29. Sitprija V, Keoplung M, Boonpucknavig V, et al.: Renal involvement in human trichinosis. Arch Intern Med 1980, 140:544–546. 30. Okelo GBA, Kyobe J: A three-year review of human hydatid disease seen at Kenyata National Hospital. East Afr Med J 1981, 58:695–701.

34. O’Riordan T, Kavanagh P, Mellotte G, et al.: Haemolytic uraemic syndrome in shigella. Irish Med J 1990, 83:72–73. 35. Magaldi AJ, Yasuda PN, Kudo LH, et al.: Renal involvement in leptospirosis: a pathophysiologic study. Nephron 1992, 62:332–339. 36. Sinniah R, Churg J, Sobin LH (eds.): Renal Disease: Classification and Atlas of Infectious and Tropical Diseases. Chicago: ASCP Press; 1988. 37. Melby EI, Jacobsen J, Olsnes S, et al.: Entry of protein toxins in polarized epithelial cells. Cancer Res 1993, 53:1753–1760. 38. Nigam P, Pant KC, Kapoor KK, et al.: Histo-functional status of kidney in leprosy. Indian J Lepr 1986, 58:567–575. 39. American Society of Clinical Pathologists: Renal Disease: Classification and Atlas of Infection and Tropical Diseases. Edited by Sinniah R, Chugh J, Sobin LH. Chicago: ASCP Press; 1988:137. 40. Baker NM, Mills AE, Rachman I, et al.: Hemolytic uremic syndrome in typhoid fever. Br Med J 1974, 2:84–87. 41. Sitprija V, Boonpucknavig W: The kidney in dengue. Proceedings of the 11th Asian Colloquium of Nephrology. Singapore; 1996:260–265. 42. Boonpucknavig V, Bhamarapravati N, Boonpucknavig E, et al.: Glomerular changes in dengue hemorrhagic fever. Arch Pathol Lab Med 1976, 100:206–212. 43. Kilejian A, Abati A, Trager W: Plasmodium falciparum and Plasmodium coatney: immunogenicity of knoblike protrusions on infected erythrocyte membrane. Exp Parasitol 1977, 42:157. 44. Kojima S: Molecular biology of malaria. XIV International Congress on Nephrology, Sydney; 1997:S5. 45. Leech JH, Barnwell JW, Aikawa M, et al.: Plasmodium falciparum malaria: association of knobs on the surface of infected erythrocytes with a histidine-rich protein and the erythrocyte skeleton. J Cell Biol 1984, 98:1256. 46. Parra ME, Evans CB, Taylor DW: Identification of Plasmodium falciparum histidine-rich protein 2 in the plasma of humans with malaria. J Clin Microbiol 1991, 29:1629–1634. 47. Butthep P, Bunyaratvej A: An unusual adhesion between red cells and platelets in falciparum malaria. J Med Assoc Thai 1992, 75(suppl 1):195–202. 48. Udeinya IJ, Schmidt JA, Aikawa M, et al.: Falciparum malaria infected erythrocytes specifically bind to cultured human endothelial cells. Science 1981, 213:555. 49. Wedderburn N, Ochs HD, Clark EA, et al.: Glomerulonephritis in common marmosets infected with Plasmodium brazilianum and Epstein-Barr virus. J Infect Dis 1988, 148:289. 50. Yahya TM, Benedict S, Shalabi A, et al.: Antineutrophil cytoplasmic antibody (ANCA) in malaria is directed against cathepsin G. Clin Exp Immunol 1997, 110:41–44. 51. Meilof JF, Van der Lelij A, Rokeach LA, et al.: Autoimmunity and filariasis: autoantibodies against cytoplasmic cellular proteins in sera of patients with onchocerciasis. J Immunol 1993, 151:5800–5809. 52. Thomas MA, Frampton G, Isenberg DA, et al.: A common anti-DNA antibody idiotype and anti-phospholipid antibodies in sera from patients with schistosomiasis and filariasis with and without nephritis. J Autoimmune 1989, 2:803–811. 53. Prina E, Lang T, Glaichenhaus N, et al.: Presentation of the protective parasite antigen LACK by Leishmania-infected macrophages. J Immunol 1996, 156:4318–4327.

Renal Involvement in Tropical Diseases 54. Barsoum RS: Schistosomal glomerulopathies. Kidney Int 1993, 44:1–12. 55. Barsoum RS, Sersawy G, Haddad S, et al.: Hepatic macrophage function in schistosomal glomerulopathy. Nephrol Dial Transplant 1988, 3:612–616. 56. Chugh KS: Snake bite induced renal failure in India. Kidney Int 1989, 194. 57. Waterman J: Some notes on scorpion poisoning in Trinidad. Trans R Soc Trop Med Hyg 1993, 32:607. 58. Barss P: Renal failure and death after multiple stings in Papua New Guinea. Ecology, prevention and management of attacks by vespid wasps. Med J Aust 1989, 151:659. 59. Spielman FJ, Bowe EA, et al.: Acute renal failure as a result of Physalia physalis sting. South Med J 1982, 75:1425. 60. Kibukamusoke JW, Chugh KS, Sakhuja V: Renal effects of envenomation. In Tropical Nephrology. Edited by Kibukamusoke JW. Canberra, Australia: Citforge Pty; 1984:170.

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61. Logan JL, Ogden DA: Rhabdomyolysis and acute renal failure following the bite of the giant desert centipede, Scolopendra heros. West J Med 1985, 142:549. 62. Lin CT, Huang PC, Yen TS, et al.: Partial purification and some characteristic nature of a toxic fraction of the grass carp bile. Clin Biochem Soc 1977, 6:1. 63. Eiam-Ong S, Sitprija V, Saetang P, et al.: Djenkol bean nephrotoxicity in Southern Thailand. Proceedings of the First Asia Pacific Congress on Animal, Plant and Microbial Toxins. Singapore; 1989:628. 64. McClain JL, Hause DW, Clark MA: Amanita phalloides mushroom poisoning: a cluster of four fatalities. J Forensic Sci 1989, 34:83. 65. Bye BN, Coetzer TH, Dutton MF: An enzyme immunoassay for atractyloside, the nephrotoxin of Callilepis laureola (Impila). Toxicology 1990, 28:997. 66. Matthai TP, Date A: Renal cortical necrosis following exposure to sap of the marking nut tree (Semecarpus anacardium). Am J Trop Med Hyg 1979, 28:773.

Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Virus Jacques J. Bourgoignie T.K. Sreepada Rao David Roth

I

nfection with hepatitis B virus (HBV) may be associated with a variety of renal diseases. In the past, HBV was the major cause of viral hepatitis in patients with end-stage renal disease (ESRD). Introduction of rigorous infection-control strategies has led to a remarkable decline in the spread of HBV infection in dialysis units. Physicians also are increasingly recognizing the association between chronic hepatitis C virus (HCV) infection and glomerular disease, both in native kidneys and renal allografts. Liver disease caused by HCV is a major factor in morbidity and mortality among patients with ESRD treated with dialysis and transplantation. The first part of this chapter focuses mainly on issues related to HCV infection. The second part of this chapter examines the renal complications in patients with human immunodeficiency virus (HIV) infection. Our knowledge about HIV has increased greatly, and dramatic advances have occurred in the treatment of patients with acquired immunodeficiency syndrome (AIDS). For the first time since the discovery of the disease, deaths are decreasing. Nevertheless, in the United States, as of June 30, 1997, there were over 600,000 cumulative cases of HIV infection, with over 400,000 deaths. Worldwide, the HIV epidemic continues to spread; an estimated 20 million persons are infected with HIV. Recent advances in the clinical management of these patients result from better understanding of the replication kinetics of HIV, assays to measure viral load, availability of

CHAPTER

7

7.2

Systemic Diseases and the Kidney

new effective drugs against HIV, and demonstration that aggressive protocols combining antiviral drugs substantially reduce HIV replication. Thus, prolonged survival of patients

with HIV infection now is common. The incidence of renal complications in this population is expected to increase further as patients live longer.

Hepatitis B and C Virus RENAL DISEASE ASSOCIATED WITH HEPATITIS B VIRUS INFECTION Lesion

Clinical presentations

Pathogenesis

Membranous nephropathy

Nephrotic syndrome

Polyarteritis nodosa

Vasculitis, nephritic

Membranoproliferative glomerulonephritis

Nephrotic, nephritic

Deposition of HBeAg with anti-HBeAb Deposition of circulating antigen-antibody complexes Deposition of complexes containing HBsAg and HBeAg

HBeAg—hepatitis B antigen; HBsAg—hepatitis B surface antigen.

RENAL DISEASE ASSOCIATED WITH HEPATITIS C VIRUS INFECTION Disease

Renal manifestations

Mixed cryoglobulinemia [6–11]

Hematuria, proteinuria Positive cryoglobulins; (often nephrotic), rheumatoid factor variable renal insufficiency often present Hematuria, proteinuria Hypocomplementemia; (often nephrotic) rheumatoid factor and cryoglobulins may be present Proteinuria Complement levels normal; (often nephrotic) rheumatoid factor negative

Membranoproliferative glomerulonephritis [13]

Membranous nephropathy [14,15]

Serologic testing

FIGURE 7-2 Renal disease associated with hepatitis C. Hepatitis C virus (HCV) infection is associated with parenchymal renal disease. Chronic HCV infection has been associated with three different types of renal disease. Type II or essential mixed cryoglobulinemia has been strongly linked with HCV infection in almost all patients with this disorder [6–11]. The clinical manifestations of this renal disease include hematuria, proteinuria that is often in the nephrotic range, and a variable degree of renal insufficiency. Essential mixed cryoglobulinemia had been considered an idiopathic disease; however,

FIGURE 7-1 Renal disease associated with hepatitis B. Infection with hepatitis B virus (HBV) may be associated with a variety of renal diseases [1,2]. Many patients are asymptomatic, with plasma serology positive for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), and hepatitis B antigen (HBeAg). The pathogenetic role of HBV in these processes has been documented primarily by demonstration of hepatitis B antigen-antibody complexes in the renal lesions [1,3,4]. Three major forms of renal disease have been described in HBV infection. In membranous nephropathy, it is proposed that deposition of HBeAg and anti-HBe antibody forms the classic subepithelial immune deposits [1,3–5]. Polyarteritis nodosa is a medium-sized vessel vasculitis in which antibody-antigen complexes may be deposited in vessel walls [1,2]. Finally, membranoproliferative glomerulonephritis is characterized by deposits of circulating antigen-antibody complexes in which both HBsAg and HBeAg have been implicated [3]. recent studies have noted one or more of the following features in over 95% of patients with this disorder: circulating anti-HCV antibodies; polyclonal immunoglobulin G anti-HCV antibodies within the cryoprecipitate; and HCV RNA in the plasma and cryoprecipitate [6,7]. Furthermore, evidence exists suggesting direct involvement of HCV-containing immune complexes in the pathogenesis of this renal disease [6]. Sansono and colleagues [12] demonstrated HCV-related proteins in the kidneys of eight of 12 patients with cryoglobulinemia and membranoproliferative glomerulonephritis (MPGN) by indirect immunohistochemistry. Convincing clinical data exist suggesting that HCV is responsible for some cases of MPGN and possibly membranous nephropathy [13–15]. In one report of eight patients with MPGN, purpura and arthralgias were uncommon and cryoglobulinemia was absent in three patients [13]. Circulating anti-HCV antibody and HCV RNA along with elevated transaminases provided strong evidence of an association with HCV infection. Establishing the diagnosis of HCV infection in these diseases is important because of the potential therapeutic benefit of -interferon treatment [13]. A number of reports exist that demonstrate a beneficial response to chronic antiviral therapy with -interferon [6,13,16,17]. Even more compelling evidence for a beneficial effect of -interferon in HCV-induced mixed cryoglobulinemia was demonstrated in a randomized prospective trial of 53 patients given either conventional therapy alone or in combination with -interferon [18]. Because of the likely recurrence of viremia and cryoglobulinemia with cessation of -interferon therapy after conventional treatment (3  106 U three times weekly for 6 mo), extended courses of therapy (up to 18 mo) and higher dosing regimens are being studied [19–21].

Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Virus

FIGURE 7-3 Membranoproliferative glomerulonephritis with hepatitis C. Micrograph of a biopsy showing membranoproliferative glomerulonephritis (MPGN) in a patient with hepatitis C virus (HCV) infection. A lobulated glomerulus with mesangial proliferation and an increase in the mesangial matrix are seen. Although still an idiopathic disease in many cases, HCV appears to be responsible for some cases of MPGN [13,16]. It has been suggested that the decline in the incidence of idiopathic type 1 MPGN may be partly a result of more careful screening by blood banks, leading to a decrease in the overall incidence of HCV infection and subsequent glomerulonephritis [16].

Envelope Capsid glycoproteins 341 Nucleotides Open-reading frame

C

E1

E2

Protein helicase NS2

Replicase

C200 Epitope

C22-3 Epitope

FIGURE 7-4 Electron microscopy of membranoproliferative glomerulonephritis from the biopsy specimen shown in Figure 7-3. Mesangial cell interposition is noted with increased mesangial matrix. Abundant subendothelial immunocomplex deposits are noted. Fusion of the epithelial cell foot processes also is seen.

WORLDWIDE PREVALENCE OF ANTI–HEPATITIS C AMONG PATIENTS ON DIALYSIS

NS3 NS4a NS4b NS5a NS5b 5-1-1

SA2 ELI BA2 RI

7.3

RIBA

2 C33c C100-3 Epitope Epitope

RIBA2

Continent

2 ELISA

North America [25–29] South America [30] Europe [31–41] Asia [42–49] New Zealand and Australia [50,51]

ELISA RIBA1+2 2

ELISA-1 positive, % 8–36 39 1–54 17–51 1.2–10

3000 Amino acids

5'

Genomic HCV RNA

3'

FIGURE 7-5 Diagnostic tests for HCV infection. In 1989, hepatitis C virus (HCV) was cloned and identified as the major cause of parenterally transmitted non-A, non-B hepatitis [22]. The first serologic test for HCV employed an enzyme-linked immunosorbent assay (ELISA-1) that detected a nonneutralizing antibody (anti-HCV) to a single recombinant antigen. Limitations of the sensitivity and specificity of this test led to development of second-generation tests, ELISA-2 and a recombinant immunoblot assay (RIBA-2) [23]. The standard for identifying active HCV infection remains the detection of HCV RNA by reverse transcriptase polymerase chain reaction. (Adapted from Roth [24].)

ELISA-1—enzyme-linked immunosorbent assay-1.

FIGURE 7-6 Prevalence of anti-HCV among dialysis patients. Patients receiving dialysis clearly are at greater risk for acquiring hepatitis C virus (HCV) infection than are healthy subjects, based on the seroprevalence of anti-HCV antibodies among patients with end-stage renal disease. These results of ELISA-1 testing likely underestimate true positivity because studies have demonstrated a nearly twofold increase in seropositivity when screening dialysis patients with the ELISA-2 assay [52]. Additional studies have demonstrated that most patients receiving dialysis who have anti-HCV seropositive test results have circulating HCV RNA by polymerase chain reaction analysis, indicating active viral replication.

7.4

Systemic Diseases and the Kidney

RISK FACTORS IN THE POPULATION WITH END-STAGE RENAL DISEASE AND HEPATITIS C VIRUS INFECTION Transfusions [24,27,30,32,54–57] Duration of end-stage renal disease [29,30,32,35,37,53–61] Mode of dialysis [60–70] Prevalence of hepatitis C virus infection in the dialysis unit [71,72]

TRANSMISSION OF HEPATITIS C VIRUS IN HEMODIALYSIS UNITS Breakdown in universal precautions [73,74] Dialysis adjacent to an infected patient [71,75] Dialysis equipment [46,60] Type of dialyzer membrane [76–78] Reuse [71,72]

Pericentral fibrosis 3% Other 6%

Cirrhosis 9%

Hemosiderosis 15%

FIGURE 7-7 Risk of HCV in the ESRD population. Numerous studies have demonstrated a strong association between the prevalence of hepatitis C virus (HCV) infection among patients receiving dialysis and both the number of transfusions received and duration of dialysis [53,61]. Although these two variables are related, the prevalence of anti-HCV in these patients has been shown to be independently associated with both factors by regression analysis. In contrast to patients receiving hemodialysis, patients receiving peritoneal dialysis consistently have a lower prevalence of anti-HCV antibody [60–70]. Moreover, units with a low prevalence of anti-HCV have been shown to have a lower seroconversion rate [71]. The latter two observations coupled with the independent association of duration of dialysis with seropositivity argue in favor of nosocomial transmission of HCV in hemodialysis units. This conclusion is further supported by data showing a decreased incidence of HCV seroconversion in dialysis units employing isolation and dedicated equipment for patients who test positive for HCV infection [72].

FIGURE 7-8 Transmission of HCV during dialysis. Convincing data are available that demonstrate an increased risk of anti-HCV seroconversion associated with both a failure to strictly follow infection control procedures and the performance of dialysis at a station immediately adjacent to that of a patient testing positive for anti-HCV [71–75]. Units using dedicated machines have shown a decreased incidence of seroconversion [51]. The literature provides conflicting data on the likelihood of passage of HCV RNA into dialysis ultrafiltrate and the risk of contamination by reprocessing filters [71,72,76–78]. At this time the Centers for Disease Control does not recommend that patients who are HCV positive be isolated or dialyzed on dedicated machines and has no official policy concerning reuse of machines in these patients [79].

Chronic active hepatitis 42%

Reactive hepatitis 18%

Chronic persistent hepatitis 6%

FIGURE 7-9 Liver disease among anti-HCV–positive dialysis patients. Serum alanine aminotransferase levels are elevated in only 24% to 67% of dialysis patients who test positive for the anti-hepatitis C virus (HCV) [80]. Caramelo and colleagues [81] evaluated liver biopsies from 33 patients on hemodialysis who tested positive using ELISA-2 and found a variety of histologic patterns; however, over 50% of these patients had chronic hepatitis or cirrhosis. No correlation has been found between mean levels of serum aminotransferase and severity of liver disease [81]. At this time, liver biopsy is the only reliable method to determine the extent of hepatic injury in patients with end-stage renal disease infected with HCV. Liver function tests and HCV serology testing may help identify patients who are at risk for liver disease. However, a liver biopsy should be obtained before initiating therapy or as part of the evaluation before transplantation. Liver biopsy can identify patients with advanced histologic liver injury who may not be good candidates for transplantation or can be used as a baseline before starting -interferon therapy. (From Caramelo and colleagues [81]; with permission.)

Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Virus

FIGURE 7-10 Liver disease after kidney transplant. Biochemical abnormalities reflecting liver injury have been reported in 7% to 34% of kidney recipients in the early period after transplantation [23,82–86]. Morbidity and mortality associated with liver disease, however, are rarely seen until the second decade after transplantation [87]. Liver dysfunction can be secondary to viral infections, such as hepatitis B and C, herpes simplex virus, Epstein-Barr virus, and cytomegalovirus, in addition to the hepatotoxicity associated with several immunosuppressive agents (azathioprine, tacrolimus, and cyclosporine) [88]. However, hepatitis C virus infection has been demonstrated convincingly to be the primary cause of posttransplantation liver disease in renal allograft recipients [89,90].

PREVALENCE OF LIVER DISEASE AFTER KIDNEY TRANSPLANTATION First decade, %

Second decade, %

Acute liver disease: 5–65 Chronic liver disease: 5–15

Chronic liver disease: 5–40 Death from liver failure: 10–30

TRANSMISSION OF HEPATITIS C VIRUS INFECTION BY CADAVERIC DONOR ORGANS Posttransplantation HCV infection status Reference

Anti-HCV, n/n (%)

HCV RNA, n/n (%)

Pereira et al. [91,92] Roth et al. [93] Tesi et al. [94] Vincente et al. [95] Wreghtt et al. [96]

16/24(67) 10/31(32) 15/43(35) 1/7(14) 6/15(40)

23/24(96) Not available 21/37(57) 1/7(14) 12/14(86)

Recipient 3a (Donor 1a)

5 Recipient 1b (Donor 1a)

Recipient strain Donor strain Both strains

Patient, n

4 Recipient 2b (Donor 3a)

3 Recipient 2b (Donor 3a)

2 Recipient 2b (Donor 3a)

1 Pretransplant 0

3

6 9 12 15 18 Months after transplant

21

24

7.5

27

FIGURE 7-11 Organ donor hepatitis C virus (HCV) transmission. Most recipients of a kidney from a donor positive for hepatitis C virus RNA will become infected with HCV if the organ is preserved in ice. ELISA1 testing of serum samples from 711 cadaveric organ donors identified 13 donors positive for anti-HCV infection; 29 recipients of organs from these donors were followed [91,92]. The prevalence of HCV RNA in these allograft recipients increased from 27% before transplantation to 96% after transplantation. In contrast, studies from centers using pulsatile perfusion of the kidney during preservation have confirmed transmission of HCV in only about 56% of cases [93,94]. Several factors might explain the discrepancy in transmission rates. One possibility may involve differences in organ preservation. Zucker and colleagues [97] demonstrated that pulsatile perfusion removed 99% of the estimated viral burden in the kidney, and centers using pulsatile perfusion have consistently reported lower transmission rates than do centers preserving organs on ice. Additional factors could include geographic variation in HCV quasi-species and the magnitude of the circulating viral titer in the donor at the time of harvesting. FIGURE 7-12 Patterns of hepatitis C virus (HCV) infection after transplantation of a kidney from a positive donor into a positive recipient. In a simple but important study, Widell and colleagues [98] demonstrated three differing virologic patterns of HCV infection emerging after kidney transplantation from a donor infected with HCV into a recipient infected with HCV. Superinfection with the donor strain, persistence of the recipient strain, or long-term co-infection with both the donor and recipient strain may result. The clinical significance of infection with more than one HCV strain has not been determined in the transplantation recipient with immunosuppression, although no data exist to suggest that co-infection confers a worse outcome. For this reason, many centers will transplant a kidney from a donor who was infected with HCV into a recipient infected with HCV rather than discard the organ. (Data from Widell and colleagues [98]; with permission.)

7.6

Systemic Diseases and the Kidney

IMPACT ON OUTCOME OF HEPATITIS C VIRUS INFECTION CONTRACTED BEFORE TRANSPLANTATION After transplantation* Reference Fritche et al. [99] Pereira et al. [100] Roth et al. [90] Ynares et al. [101]

Anti–hepatitis C virus infection

Actuarial graft survival, % Actuarial patient survival, %

ELISA-2 positive ELISA-2 negative ELISA-2 positive ELISA-2 negative RIBA-2 positive RIBA-2 negative ELISA-1 positive ELISA-1 negative

32(10) 53(10) 50 59 81(5) 80(5) 33(10) 25(10)

58(8) 82(8) 59 85 63(5) 63(5) 53(10) 54(10)

FIGURE 7-13 Pretransplant HCV infection effect on outcome. Reports have varied from different centers concerning the impact of pretransplantation hepatitis C virus (HCV) infection on outcome after transplantation. Patient survival and graft survival were significantly worse among patients with anti-HCV infection in some studies [99,100]; in other studies a measurable impact could not be detected [90,101]. Some of these differences could be attributed to geographic variation in the prevalence of various HCV genotypes, differing immunosuppressive protocols, and length of follow-up after transplantation.

ELISA—enzyme-linked immunosorbent assay; RIBA—recombinant immunoblot assay. *Numbers in parentheses indicate years after transplatation.

GLOMERULAR DISEASE IN KIDNEY RECIPIENTS INFECTED WITH HEPATITIS C VIRUS

Reference Cockfield and Prieksaitis [102] Huraib et al. [103] Morales et al. [104] Roth et al. [105] Morales et al. [106]

Number of anti–HCVpositive patients

Histologic diagnosis MGN MPGN DPGN

CGN

Total cases of GN

51

–

–

–

–

11*

30 166 98 409

0 7 0 15

5 0 5 0

1 0 0 0

1 0 0 0

7 7 5 15

CGN—crescentic glomerulonephritis; DPGN—diffuse proliferative GN; MGN—membranous GN; MPGN—membranoproliferative GN. *No specific diagnosis.

FIGURE 7-14 Glomerular disease in HCV positive recipients. Chronic hepatitis C virus (HCV) infection has been associated with several different immune-complex–mediated diseases in the renal allograft, including membranous and membranoproliferative glomerulonephritis (MPGN)

[102–106]. From a cohort of 98 renal allograft recipients with HCV, Roth and colleagues [105] detected de novo membranoproliferative glomerulonephritis in the biopsies of five of eight patients with proteinuria of over 1 g/24 h [105]. Compared with a control group of nonproteinuric kidney recipients infected with HCV, patients with MPGN had viral particles present in greater amounts in the high-density fractions of sucrose density gradients associated with significant amounts of IgG and IgM. Thus, deposition of immune complexes containing HCV genomic material may be involved in the pathogenesis of this form of MPGN. The differential diagnosis for significant proteinuria in a patient infected with HCV after transplantation should include immune-complex glomerulonephritis. Similarly, if the renal allograft biopsy shows immune-complex glomerulonephritis, the patient should be tested for HCV infection without regard to serum alanine aminotransferase levels.

Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Virus

INTERFERON THERAPY FOR PATIENTS IN END-STAGE RENAL DISEASE WITH HEPATITIS C VIRUS INFECTION Reference

Study population Patients, n Clearing of HCV RNA, % Comments

Pol et al. [107]

HD

19

53

Casanovas et al. [108]

HD

10

10

Koenig et al. [109]

HD

37

65

Duarte et al. [110]

HD

5

NA

Raptopoulou-Gigi et al. [111]

HD

19

77

Magnone et al. [112]

TX

7

NA

6/7 (86%) rejection

Rostaing et al. [113]

TX

16

33

6/16 (37%) acute renal failure

Harihara et al. [114]

TX

3

0

3/3(100%) renal failure

Thervet et al. [115]

TX

13

0

2/3 (67%) acute renal failure

Izopet et al. [116]

TX

15

0

5/15 (33%) acute renal failure

Ozgur et al. [117]

TX

5

NA

All with improved liver histology

HD—hemodialysis; NA—not available; TX—transplantation.

7.7

FIGURE 7-15 Interferon in HCV-positive end-stage renal disease (ESRD) and transplant patients. Interferon therapy in patients infected with hepatitis C virus (HCV) who have ESRD has been studied in both patients receiving dialysis and transplantation recipients. Some studies have reported encouraging early responses [107–111]. Relapses are common after cessation of treatment, however, and many transplantation recipients have experienced deterioration in allograft function [112–116]. Based on the poor outcomes reported in transplantation recipients, additional studies are needed. These studies would evaluate the long-term benefits of a strategy in which infected patients who have ESRD are treated with -interferon while on dialysis in an effort to clear viremia before the planned transplantation. Further study of protocols using extended treatment periods coupled with differing dosing regimens are necessary to determine the optimal therapy for the patient infected with HCV who has ESRD.

Human Immunodeficiency Virus RENAL COMPLICATIONS OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION Acid-base and electrolyte disturbances Acute renal failure Human immunodeficiency virus–associated nephropathies Renal infections and tumors

PATHOGENESIS OF HYPONATREMIA IN PATIENTS WITH ACQUIRED IMMUNODEFICIENCY SYNDROME Hypovolemia Tubular dysfunction Mineralocorticoid deficiency Syndrome of inappropriate antidiuretic hormone Hemodilution

FIGURE 7-16 Renal complications of HIV. Renal complications are frequent, and these rates are expected to increase as patients with HIV live longer. Many renal diseases are incidental and are the consequences of opportunistic infections, neoplasms, or the treatment of these infections and tumors. The renal diseases include a variety of acidbase and electrolyte disturbances, acute renal failure having various causes, specific HIV-associated nephropathies, and renal infections and tumors.

FIGURE 7-17 Hyponatremia pathogenesis in AIDS. Single and mixed acid-base disturbances, as well as all types of electrolyte disorders, can be observed in patients with AIDS. These disturbances and disorders develop spontaneously in patients with complications of AIDS or follow pharmacologic interventions and usually are not associated with structural lesions in the kidneys unless renal failure also is present. Hyponatremia is the most prevalent electrolyte abnormality, occurring in 36% to 56% of patients hospitalized with AIDS [118–122]. In the absence of an evident source of fluid loss, volume depletion may be related to renal sodium wasting as a result of Addison’s disease or hyporeninemic hypoaldosteronism [123–125]. In euvolemic patients, hyponatremia is compatible with nonosmolar inappropriate secretion of antidiuretic hormone [120,121,126]. Hyponatremia in patients with hypervolemia is dilutional in origin as a result of excessive free water intake in a context of renal insufficiency [122].

7.8

Systemic Diseases and the Kidney

ELECTROLYTE COMPLICATIONS OF DRUGS USED TO TREAT ACQUIRED IMMUNODEFICIENCY SYNDROME Hypernatremia: foscarnet, rifampin, amphotericin B Hyperkalemia: pentamidine, ketoconazole, trimethoprim Hypokalemia: rifampin, didanosine, amphotericin B, foscarnet Hypomagnesemia: pentamidine, amphotericin B Hypocalcemia: foscarnet, pentamidine, didanosine Hypercalcemia: foscarnet Hypouricemia: rifampin Hyperuricemia: didanosine, pyranzinamide, ethambutol Tubular acidosis: amphotericin B, trimethoprim, cidofovir, rifampin, foscarnet

FIGURE 7-18 Drugs causing electrolyte complications. A number of drugs used in the treatment of patients with AIDS can induce acid-base or electrolyte abnormalities from direct renal toxicity (didanosine,

CAUSES OF ACUTE RENAL FAILURE Prerenal azotemia, acute tubular necrosis Allergic interstitial nephritis Obstructive nephropathy Rhabdomyolysis, myoglobinuric acute renal failure Thrombotic thrombocytopenic purpura, hemolytic uremic syndrome Rapidly progressive glomerulonephritis

30%, most often in patients with AIDS and prerenal azotemia from hypovolemia, hypotension, severe hypoalbuminemia, superimposed sepsis, or drug nephrotoxicity (radiocontrast dyes, foscarnet, acyclovir, pentamidine, cidofovir, amphotericin B, nonsteroidal anti-inflammatory drugs, and antibiotics) [129–138]. The clinical presentation, laboratory findings, and course of acute tubular necrosis do not differ in patients with AIDS and those in other clinical settings. Prevention includes correction of fluid and electrolyte abnormalities and dosage adjustments of potentially nephrotic drugs. Identification and withdrawal of the offending agents usually result in recovery of renal function. Dialysis may be needed before renal function improves. Less frequent causes of acute renal failure include allergic acute interstitial nephritis; complicating treatments with trimethoprim and sulfamethoxazole, rifampin, or acyclovir; and acute obstructive nephropathy, resulting from the intrarenal precipitation of crystals of sulfadiazine, acyclovir, urate, or protease inhibitors [134,139–146]. Obstructive uropathy without hydronephrosis also may develop in patients with lymphoma as a result of lymphomatous ureteropelvic infiltration or retroperitoneal fibrosis [147–149]. Rhabdomyolysis with myoglobinuric acute renal failure usually occurs in the setting of cocaine use [150]. Instances of acute renal failure associated with intravascular coagulation related to thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS) have been reported (vide infra). Rare causes of acute renal failure include disseminated microsporidian infection or histoplasmosis [151,152]. A clinical presentation of acute renal failure also can be seen in patients with acute immunocomplex postinfectious glomerulonephritis, crescentic glomerulonephritis, or fulminant HIV-associated glomerulosclerosis.

2.4 1.4 0.4

7 6 5 4 3 2 1 0

7 6 5 4 3 2 1 0 1

2

3

4

5 Day

6

7

8

Urine volume, L/d

-0.6

Serum creatinine, mg/dL

Acyclovir, g/d IV

FIGURE 7-19 Causes of acute renal failure. Acute renal failure is related to complications of AIDS, its treatment, or the use of diagnostic agents in about 20% of patients [129,130]. Acute tubular necrosis occurs with a prevalence of 8% to

foscarnet, pentamidine, cidofovir, rifampin, and amphotericin B), other organ toxicity (didanosine, foscarnet, and rifampin), or interference with uric acid metabolism. Hypernatremia may be the result of drug-induced diabetes insipidus. Hyperkalemia can occur in 16% to 24% of patients with AIDS, even in the absence of renal insufficiency. Hypokalemia is associated with tubular nephrotoxicity. Hypocalcemia may result from urinary losses of magnesium and hypomagnesemia (pentamidine and amphotericin B) or from drug-induced pancreatitis (pentamidine, didanosine, and foscarnet). Hypercalcemia occurs in association with granulomatous disorders, disseminated cytomegalovirus infection, lymphoma, human T-cell leukemia (HTLV) related to HTLV-I infection or foscarnet administration. Hypouricemia was described in 22% of patients as a result of an intrinsic tubular defect in urate transport unrelated to drug therapy. In contrast, hyperuricemia usually is the result of drug interference with purine metabolism (didanosine) or tubular urate secretion (pyrazinamide and ethambutol). In the absence of clinical manifestations that readily explain acid-base or electrolyte disturbances, a careful review of the pharmacopeia used to treat patients with HIV infection is mandated. Extensive reviews of the complications associated with drugs are available [127,128].

FIGURE 7-20 Acyclovir nephrotoxicity. Drugs may induce acute renal failure by more than one mechanism. For instance, acute renal failure may complicate the use of acyclovir as a result of intrarenal precipitation of acyclovir crystals, acute interstitial nephritis, or acute tubular necrosis [139,144,153]. An example of nonoliguric acute tubular necrosis associated with administration of large doses of intravenous acyclovir is illustrated, which was readily reversible on decreasing the dose of acyclovir from 2.4 to 0.4 g/24 h. Patients infected with HIV can exhibit a broad spectrum of conditions that may affect the kidneys. Renal biopsy is useful for diagnostic and prognostic purposes when the cause of acute renal failure is not clinically evident. In a recent study of 60 patients with acute renal failure, a percutaneous renal biopsy yielded a pathologic diagnosis in 13% that was not expected clinically [154].

Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Virus

MANAGEMENT OF SEVERE ACUTE RENAL FAILURE

Conservative Recovered Needing dialysis Not initiated Initiated Recovered

HIV

Non-HIV

20 (14%) 85% 126 42% 73 56%

42 (14%) 83% 264 22% 207 47%

NS 0.003 NS

7.9

FIGURE 7-21 Acute renal failure management. Rao and Friedman [155] compared the course of 146 patients with severe acute renal failure (serum creatinine >6 mg/dL) infected with HIV with a group of 306 contemporaneous persons not infected with HIV but with equally severe acute renal failure. The patients infected with HIV were younger than those in the group not infected (mean age 38.4 and 55.2 years, respectively; P<0.001) and were more often septic (52% and 24%, respectively; P<0.001). Over 80% of patients in each group recovered renal function when conservative therapy alone was sufficient. When dialysis intervention was needed, it was not initiated more often in the group with HIV than in the control group (42% and 24%, respectively; P<0.003). In those patients in whom dialysis was initiated, recovery occurred in about half in each group. Overall, the mortality in patients with severe acute renal failure was not significantly different in those with HIV infection from those in the group not infected with HIV (immediate mortality, 60% and 56%, respectively; mortality at 3 months, 71% and 60%, respectively).

NS— not significant.

NEPHROPATHIES ASSOCIATED WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION Focal segmental or global glomerulosclerosis Diffuse and global mesangial hyperplasia Minimal change disease Others: Immune-complex glomerulopathies Hemolytic uremic syndrome, thrombotic thrombocytopenic purpura

100

Percent

75

FIGURE 7-22 Nephropathies associated with HIV. The literature refers to the glomerulosclerosis associated with human immunodeficiency virus (HIV) as HIV-associated nephropathy. However, HIVassociated nephropathies may include a spectrum of renal diseases, including HIV-associated glomerulosclerosis, HIV-associated immune-complex glomerulonephritis (focal or diffuse proliferative glomerulonephritis, immunoglobulin A nephropathy) and HIV-associated hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP). Diffuse mesangial hyperplasia and minimal change disease also may be associated with HIV, particularly in children. Therefore, the nomenclature of HIV-associated nephropathies should be amended to list the associated qualifying histologic feature [156]. All types of glomerulopathies have been observed in patients with HIV-infection. Their prevalence and severity vary with the population studied. Focal segmental or global glomerulosclerosis is most prevalent in black adults. In whites, proliferative and other types of glomerulonephritis predominate. In children with perinatal acquired immunodeficiency syndrome, glomerulosclerosis, diffuse mesangial hyperplasia, and proliferative glomerulonephritis are equally prevalent.

Glomerulosclerosis Diff. mesangial hyperplasia Other

50

25

0 Caribbean blacks (n=22)

American blacks (n=11)

Whites (n=12)

FIGURE 7-23 Glomerulosclerosis associated with HIV. In the United States, HIVassociated focal segmental or global glomerulosclerosis was described originally in 1984 in large East Coast cities, particularly New York and Miami [157–159]. This entity initially was considered with skepticism because it was not seen in San Francisco, where most patients testing seropositive were white homosexuals [160,161]. In New York, patients with glomerulosclerosis were

largely black intravenous (IV) drug abusers, a group of patients in whom heroin nephropathy was prevalent. Thus, concern existed that this entity merely represented the older heroin nephropathy now seen in HIV-infected IV drug abusers. However, in a Miamibased population of adult non-IV drug users with glomerular disease and HIV infection, 55% of Caribbean and American blacks had severe glomerulosclerosis, 9% had mild focal glomerulosclerosis, and 27% had diffuse mesangial hyperplasia. In contrast, two of 12 (17%) whites had a mild form of focal glomerulosclerosis, 75% had diffuse mesangial hyperplasia, and none had severe glomerulosclerosis. These morphologic differences were reflected in more severe clinical presentations, with blacks more likely to manifest proteinuria in the nephrotic range (>3.5 g/24 h) and renal insufficiency (serum creatinine concentration (>3 mg/dL). Whites often had proteinuria under 2 g/24 h and serum creatinine values less than 2 mg/dL [162]. In blacks, glomerulosclerosis has been described in all groups at risk for HIV infection, including IV drug users, homosexuals, patients exposed to heterosexual transmission or to contaminated blood products, and children infected perinatally [163,164]. Subsequent reports confirmed the unique clinical and histopathologic manifestations of HIV-associated glomerulosclerosis and its striking predominance in blacks independent of IV drug abuse [165]. Racial factors explain the absence of HIV-associated glomerulosclerosis in whites and Asians. The cause of this strong racial predilection is unknown.

7.10

Systemic Diseases and the Kidney

TWO CASE HISTORIES OF PATIENTS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION ASSOCIATED WITH GLOMERULOSCLEROSIS 41-year-old black Jamaican woman

28-year-old black Haitian man

October 1985: Viral syndrome. 135 lbs; proteinuria, 1+; serum creatinine, 0.5 mg/dL; blood pressure, 130/70 mm Hg December 1986: Fever, fatigue, cough. 120 lbs; proteinuria, 1+; interstitial pneumonia; serum creatinine, 1.5 mg/dL; ex-husband used intravenous drugs; 11-cm, echogenic kidneys February 1987: 3+ edema. 116 lbs; proteinura, 12.7 g/24 h; serum creatinine, 11.4 mg/dL; albumin, 2.5 g/dL; blood pressure, 150/86; renal biopsy showed focal segmental glomerulosclerosis May 1987: 100 lbs; patient died after 3 months of hemodialysis from sepsis and cryptococcal meningitis

A dockworker until 3 months before admission, when fevers began to occur. No identifiable risk factor. He presented with a blood pressure of 110/80 mm Hg, periorbital and trace ankle edema, interstitial pneumonia, and diffuse adenopathies. Serum creatinine increased from 5.3 to 9 mg/dL in 6 days; albumin, 1.6 g/dL; proteinuria, 6.9 g/24 h; 15-cm, echogenic kidneys. Renal biopsy showed focal segmental glomerulosclerosis. Lymph node biopsy showed Mycobacterium gordonae. This patient returned to Haiti after six hemodialyses.

FIGURE 7-24 These two patients illustrate typical presenting features of HIV-associated glomerulosclerosis, ie, proteinuria, usually in the nephrotic range; normal-sized or large echogenic kidney; and renal insufficiency rapidly progressing to endstage renal disease (ESRD). The onset of the nephropathy is often abrupt, with uremia and massive nonselective proteinuria (sometimes in excess of 20 g/24 h). These fulminant lesions may present as acute renal failure in patients who were well only a few weeks or months before hospitalization. In other patients, minimal proteinuria and azotemia at presentation increase insidiously over a period of several months until a nephrotic syndrome becomes evident, with rapid evolution thereafter to uremia and ESRD. Hypertension and peripheral edema may be absent even in the context of advanced renal insufficiency or severe nephrotic syndrome. The status of the patient’s HIV infection rather than the presence of renal disease per se has the greatest impact on survival.

PATHOLOGIC FEATURES OF GLOMERULOSCLEROSIS ASSOCIATED WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION Collapsed glomerular capillaries Visceral glomerular epitheliosis Microcystic tubules with variegated casts Focal tubular simplification Interstitial lymphocytic infiltration Endothelial reticular inclusions

FIGURE 7-25 Ultrasonography of a hyperechogenic 15-cm kidney in a patient with HIV-associated glomerulosclerosis, nephrotic syndrome, and renal failure.

FIGURE 7-26 Pathologic features of glomerulosclerosis. None of the features listed is pathognomonic. The concomitant presence of glomerular and tubular lesions with tubuloreticular inclusions in the glomerular and peritubular capillary endothelial cells, however, is highly suggestive of glomerulosclerosis associated with human immunodeficiency virus infection [134,166–171].

Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Virus

FIGURE 7-27 Glomerulosclerosis. Micrograph of segmental glomerulosclerosis with hyperplastic visceral epithelial cells (arrows).

FIGURE 7-29 Collapsing glomerulosclerosis. Micrograph of global collapsing glomerulosclerosis. No patent capillary lumina are present. In the same patient, normal glomeruli, glomeruli with segmental sclerosis, and glomeruli with global sclerosis may be found [172].

7.11

FIGURE 7-28 More advanced glomerulosclerosis. Micrograph of a more advanced stage of glomerulosclerosis with large hyperplastic visceral epithelial cells loaded with hyaline protein droplets, interstitial infiltrate, and tubules filled with proteinaceous material.

FIGURE 7-30 Dilated microcystic tubules. Micrograph of massively dilated microcystic tubules filled with variegated protein casts adjacent to normal-sized glomeruli. These casts contain all plasma proteins. The tubular epithelium is flattened. The tubulointerstitial changes likely play an important role in the pathogenesis of the renal insufficiency and offer one explanation for the rapid decrease in renal function.

7.12

Systemic Diseases and the Kidney FIGURE 7-31 Diffuse mesangial hyperplasia and nephrotic syndrome. Micrograph of diffuse mesangial hyperplasia in a child with perinatal AIDS and nephrotic syndrome. Both diffuse and global mesangial hyperplasia are identified in 25% of children with perinatal AIDS and proteinuria. The characteristic microcystic tubular dilations and the kidney enlargement of glomerulosclerosis associated with human immunodeficiency virus infection are absent in patients with diffuse mesangial hyperplasia.

FIGURE 7-32 Tubuloreticular cytoplasmic inclusions. Micrograph of tubuloreticular cytoplasmic inclusions in glomerular endothelial cell. The latter are virtually diagnostic of nephropathy associated with HIV infection, provided systemic lupus erythematosus has been excluded. On immunofluorescent examination, findings in the glomeruli are nonspecific and similar in HIV-associated glomerulosclerosis and idiopathic focal segmental glomerulosclerosis. These findings consist largely of immunoglobulin M and complement C3 deposited in a segmental granular pattern in the mesangium and capillaries. The same deposits also occur in 30% of patients with AIDS without renal disease [134,163,167].

HIV infection

HIV in glomerular, tubular epithelial cells

Cytopathic effects

HIV gene products

HIV in lymphocytes, monocytes

Cytokines, growth factors

Glomerular epithelial cell proliferation Tubular epithelial cell apoptosis and proliferation

Glomerulosclerosis

Tubular microcysts

FIGURE 7-33 Possible pathogenic mechanisms of glomerulosclerosis associated with HIV infection. HIV-associated glomerulosclerosis is not the result of opportunistic infections. Indeed, the nephropathy may be the first manifestation of HIV infection and often occurs in patients before opportunistic infections develop. HIV-associated glomerulosclerosis also is not an immune-complex-mediated glomerulopathy because immune deposits are generally absent. Three mechanisms have been proposed: direct injury of renal epithelial cells by infective HIV, although direct renal cell infection has not been demonstrated conclusively and systematically; injury by HIV gene products; or injury by cytokines and growth factors released by infected lymphocytes and monocytes systemically or intrarenally or released by renal cells after uptake of viral gene products. The variable susceptibility to glomerulosclerosis also suggests that unique viral-host interactions may be necessary for expression of the nephropathy [132,156,166,173–175].

Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Virus

Transplantation of kidneys between normal mice and mice transgenic of noninfectious HIV

Transgenic kidney in normal mouse

Normal kidney in transgenic mouse

Kidney develops glomerulosclerosis

Kidney remains disease-free

FIGURE 7-34 HIV proteins in glomerulosclerosis. HIV-associated glomerulosclerosis has been viewed as a complication that occurs either as a direct cellular effect of HIV infection or HIV gene products in the kidney, as an indirect effect of the dysregulated cytokine milieu existing in patients with acquired immunodeficiency syndrome, or both. Studies involving reciprocal transplantation of kidneys between normal and mice transgenic of noninfectious HIV clearly show that the pathogenesis of HIV-glomerulosclerosis is intrinsic to the kidney [176]. In these studies, HIV-glomerulosclerosis developed in kidneys of transgenic mice transplanted into nontransgenic littermates, whereas kidneys from normal mice remained disease-free when transplanted into HIV-transgenic mice [176]. These findings suggest that HIV gene proteins, rather than infective HIV, may induce the nephropathy either through direct effects on target cells or indirectly through the release of cytokines and growth factors.

7.13

TREATMENT OPTIONS OF GLOMERULOSCLEROSIS ASSOCIATED WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION Antiretroviral therapy Corticosteroids Cyclosporine Angiotensin-converting enzyme inhibitors Dialysis

FIGURE 7-35 Treatment of glomerulosclerosis. There have been no prospective controlled randomized trials of any therapy in patients with nephropathy associated with HIV infection. Thus, the optimal treatment is unknown. Individual case reports and studies, often retrospective, on a small number of patients suggest a beneficial effect of monotherapy with azidothymidine (AZT) on progression of renal disease [177–179]. No reports exist on the effects of double or triple antiretroviral therapy on the incidence or progression of renal disease in patients with HIV who have modest proteinuria or nephrotic syndrome. The incidence of HIV-associated glomerulosclerosis may be declining as a result of prophylaxis with AZT, trimethoprim and sulfamethoxazole, or other drugs. Using logistic regression analysis, Kimmel and colleagues [180] demonstrated an improved outcome related specifically to antiretroviral therapy. Steroids usually have been ineffective on proteinuria or progression of renal disease in adults and children. Recently, 20 adult patients with HIV-associated glomerulosclerosis or mesangial hyperplasia with proteinuria over 2 g/24 h and serum creatinine over 2 mg/dL were studied. These patients showed impressive decreases in proteinuria and serum creatinine when given 60 mgd of prednisone for 2 to 6 weeks [181]. Complications of steroid therapy, however, were common. These include development of new opportunistic infections, steroid psychosis, and gastrointestinal bleeding. The short-term improvement in renal function may correlate with an improvement in tubulointerstitial mononuclear cell infiltration [182]. In a single report of three children with perinatal AIDS, HIV-associated glomerulosclerosis, and normal creatinine clearance, cyclosporine induced a remission of the nephrotic syndrome [183]. This report has not been confirmed, and the use of cyclosporine in adults with HIV-associated glomerulosclerosis has not been studied.

Serum creatinine, mg/dL

7.14

Systemic Diseases and the Kidney

4.0 3.5 4.0 3.5

P=0.006 Fosinopril Control

3.0 2.5 2.0 1.5 1.0 0.5 0 0 9

Urinary protein, g/24 h

8 7

4

8

12 Week

16

20

24

8

12 Week

16

20

24

P=0.006 Fosinopril Control

6 5 4

FIGURE 7-36 Effect of angiotensin-converting enzyme (ACE) inhibitors on progression of glomerulosclerosis associated with HIV infection. Serum ACE levels are increased in patients with HIV infection [184]. Kimmel and colleagues [180], using captopril, and Burns and colleagues [185], using fosinopril, demonstrated a renoprotective effect of ACE inhibitors in patients with biopsy-proven HIV-associated glomerulosclerosis. In the former study, the median time to end-stage renal disease was increased from 30 to 74 days in nine patients given 6.25 to 25 mg captopril three times a day. In the latter study, 10 mg of fosinopril was given once a day to 11 patients with early renal insufficiency (serum creatinine <2 mg/dL). Serum creatinine and proteinuria remained stable during 6 months of treatment with fosinopril. In contrast, patients not treated with fosinopril exhibited progressive and rapid increases in serum creatinine and proteinuria. Similar outcomes prevailed in patients with proteinuria in the nephrotic range and serum creatinine levels less than 2 mg/dL. Captopril also is beneficial to the progression of the nephropathy in HIV-transgenic mice [186]. The mechanism(s) of the renoprotective effects of ACE inhibitors are unclear and may include hemodynamic effects, decreased expression of growth factors, or an effect on HIV protease activity. Renal biopsy early in the course of the disease is important to define the renal lesion and guide therapeutic intervention.

3 2 1 0 0

4

SURVIVAL OF PATIENTS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION RECEIVING CHRONIC HEMODIALYSIS Reference

Year

Patients

Rao et al. [187] Ortiz et al. [188]

1987 1988

Feinfeld et al. [189]

1989

Ribot et al. [190]

1990

Schrivastava et al. [191] Kimmel et al. [192] Ifudu et al. [193]

1992 1993 1997

79 AIDS 17 AIDS 12 carriers 5 AIDS 10 carriers 8 AIDS 28 carriers 44 AIDS 23 AIDS 34 AIDS

Mean survival, mo <3 3 16 13 16 88% <12 96% >12 41% >15 14.7 57

FIGURE 7-37 Survival rates in dialysis patients. Once end-stage renal disease (ESRD) develops and supportive maintenance dialysis is needed, the complications of HIV are the dominant factor in patient survival, as they are in patients with HIV infection without renal involvement. Asymptomatic patients on chronic hemodialysis survive longer than do patients with AIDS on chronic hemodialysis. Patients with AIDS also may develop malnutrition, wasting, and failure to thrive that are unresponsive to intensive nutritional support [131]. Recent studies, however, show that the survival of patients with AIDS maintained on chronic hemodialysis is improving. Enhanced survival has been attributed to antiviral drugs, better prophylaxis, and aggressive treatment of opportunistic infections. We have seen four patients with HIV infection survive for more than 10 years on hemodialysis. Chronic hemodialysis and chronic ambulatory peritoneal dialysis are equally appropriate treatments for patients with HIV infection and ESRD. Universal precautions should be used for peritoneal dialysis and hemodialysis alike, because infectious HIV is present in peritoneal effluent and blood.

Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Virus

PREDICTORS OF SURVIVAL OF PATIENTS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION RECEIVING CHRONIC HEMODIALYSIS

CD4 Blood pressure, systolic Infection rate Proteinuria Edema +/ Antiretroviral therapy +/-

R

P

0.668 0.496 0.519 0.537 14.5 vs 6.1 mo 15.2 vs 62. mo

<0.001 <0.02 <0.01 <0.02 <0.01 <0.01

RECOMMENDED ANTIRETROVIRAL THERAPY Combination of two reverse transcriptase inhibitors Aggressive triple therapy, including a protease inhibitor for patients who are Symptomatic of acquired immunodeficiency syndrome Asymptomatic with CD4 <500 cells/µL Asymptomatic with CD4 >500 cells/µL but viral load > 20,000

OTHER NEPHROPATHIES ASSOCIATED WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION Immune-complex glomerulopathies Proliferative glomerulonephritis Membranous glomerulonephritis Lupus-like nephropathy Immunoglobulin A nephropathy Hemolytic uremic syndrome, thrombotic thrombocytopenic purpura

FIGURE 7-40 Other nephropathies associated with HIV. A variety of immune-complex-mediated glomerulopathies have been documented in patients with HIV infection. Some represent glomerular diseases associated with HIV infection, whereas others may be incidental or manifestations of associated diseases.

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FIGURE 7-38 Predictors of survival. Perinbasekar and colleagues [194] analyzed those factors associated with better survival in patients infected with HIV receiving chronic hemodialysis. A low CD4 lymphocyte count, low systolic blood pressure, increased infection rate, nephrotic range proteinuria, lack of edema, and lack of antiretroviral therapy are associated with decreased survival.

FIGURE 7-39 Antiretroviral therapy. Recommended antiretroviral therapy for patients with HIV infection without renal disease includes therapies with two drugs for all patients, combining two reverse transcriptase inhibitors. Aggressive early intervention with triple antiviral drugs, one of which is a protease inhibitor, should be offered to patients symptomatic of AIDS, asymptomatic patients with CD4 counts under 500/µL, and asymptomatic patients with CD4 counts over 500/µL and plasma HIV RNA levels over 20,000 copies/mL [195]. Reduced dosages are required for reverse transcriptase inhibitors in renal insufficiency. Although the clearance information on these drugs is limited, additional dosing is not necessary in patients receiving maintenance dialysis. No dosage reduction is needed for protease inhibitors.

Proliferative glomerulonephritides represent instances of postinfectious glomerulonephritis or manifestations of hepatitis C co-infection [196–199]. Alternatively, proliferative glomerulonephritides may result from renal depository of preformed circulating immune complexes with specificity for HIV proteins and are HIV-associated [199]. In patients infected with HIV, membranous glomerulonephritis has been associated with hepatitis B, hepatitis C, syphilis, and systemic lupus erythematosus [198,200–203]. Lupus-like nephritis has been reported in children and adults with HIV infection in association with membranous, mesangial, and intracapillary proliferative glomerular lesions [204]. IgA nephropathy has been reported in association with HIV infection. The occurrence of IgA nephropathy may not be coincidental and is HIV-associated. Indeed, circulating immune complexes composed of idiotypic IgA antibody reactive with anti-HIV IgG or IgM were identified in two patients, and the identical immune complex was eluted from the renal biopsy tissue of one patient studied [199,205]. Unlike HIV-associated glomerulosclerosis, HIV-associated IgA nephropathy has been reported exclusively in white patients with early HIV infection exhibiting microscopic or macroscopic hematuria, absent or modest azotemia, and slowly progressive disease [206]. Instances of intravascular coagulation related to TTP or HUS are recognized with increased frequency and may be the first manifestation of HIV infection, although most develop at a late stage of the disease. The cause of hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) in patients infected with HIV is unknown. Plasma tissue plasminogen activator is increased in patients infected with HIV who have thrombotic microangiopathy [207]. There is no association with Escherichia coli 0154:H7 infection, and intercurrent infections have been demonstrated in only one third of patients. Renal involvement in TTP usually is minimal, whereas vascular and glomerular involvement are more frequent and extensive in HUS and can lead to renal cortical necrosis. Therapy with plasmapheresis, using fresh frozen plasma replacement, should be instituted as soon as the diagnosis of HIV-related HUS/TTP is made [208].

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Systemic Diseases and the Kidney

RENAL INFECTIONS AND TUMORS ASSOCIATED WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION Pathogens

Neoplasms

Cytomegalovirus Candida Nocardia Cryptococcus Pneumocystis Mycobacterium Toxoplasma Histoplasma Aspergillus Herpes

Kaposi’s sarcoma Carcinoma Lymphoma Myeloma

FIGURE 7-41 Other renal findings in patients with AIDS include infections and tumors. Almost all opportunistic infections seen in patients with AIDS may localize in the kidneys as manifestations of systemic disease. However, rarely are these infections expressed clinically, and often they are found at autopsy. Cytomegalovirus infection is the most common [209]. Referrals to a urologist are reported for renal and perirenal abscesses with uncommon organisms (Candida, Mucor mycosis, Aspergillus, and Nocardia). Nephrocalcinosis can occur in association with pulmonary granulomatosis, Mycobacterium avium–intracellulare infection, or as a manifestation of extrapulmonary pneumocystis infection. Renal tuberculosis is a manifestation of miliary disease. Non-Hodgkin’s lymphoma and Kaposi’s sarcoma are the most frequently found renal neoplasms in patients with AIDS, usually as a manifestation of disseminated involvement.

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150. Roth D, Alarcon FJ, Fernandez JA, et al.: Acute rhabdomyolysis associated with cocaine intoxication. N Engl J Med 1988, 319:673–677. 151. Aarons EJ, Woodrow D, Hollister WS, et al.: Reversible renal failure caused by a microsporidian infection. AIDS 1994, 8:1119–1121. 152. Clinicopathologic Conference: Fever and acute renal failure in a 31-year-old male with AIDS. Am J Med 1997, 102:310–315.

128. Berns JS, Cohen RM, Rudnick MR, et al.: Renal aspects of antimicrobial therapy for HIV infection. In Renal and Urologic Aspects of HIV Infection. Comtemp Issues Nephrol 1996, 29:195–235.

153. Becker BN, Fall P, Hall C, et al.: Rapidly progressive acute renal failure due to acyclovir: case report and review of the literature. Am J Kidney Dis 1993, 22:611–615.

129. Valeri A, Neusy AJ: Acute and chronic renal disease in hospitalized AIDS patients. Clin Nephrol 1991, 35:110–118.

154. Peraldi MN, Ovali N, Rondeau E, et al.: Is biopsy useful in HIVJinfected patients with acute renal failure? A retrooperative study. J Am Soc Nephrol 1997, 8:130A.

130. Genderini A, Bertoli S, Scorza D, et al.: Acute renal failure in patients with acquired immune deficiency syndrome. J Nephrol 1991, 1:45–47. 131. Rao TK, Friedman EA: Renal syndromes in the acquired immunodeficiency syndrome (AIDS): lessons learned from analysis over 5 years. Artif Organs 1988, 12:206–209. 132. Bourgoignie JJ: Renal complications of human immunodeficiency virus type 1. Kidney Int 1990, 37:1571–1584. 133. Cantor ES, Kimmel PL, Bosch JP: Effect of race on expression of acquired immunodeficiency syndrome–associated nephropathy. Arch Intern Med 1991, 151:125–128. 134. D’Agati V, Cheng JI, Carbone L, et al.: The pathology of HIVnephropathy: a detailed morphologic and comparative study. Kidney Int 1989, 35:1358–1370. 135. Polis MA, Spooner KM, Baird BF, et al.: Anticytomegaloviral activity and safety of cidofovir in patients with human immunodeficiency virus infection and cytomegalovirus viruria. Antimicrob Agents Chemother 1995, 39:882–886. 136. Seidel EA, Koenig S, Polis MA: A dose escalation study to determine the toxicity and maximally tolerated dose of foscarnet. AIDS 1993, 7:941–945. 137. Rao TKS, Berns JS: Acute renal failure in patients with HIV infections. Contemp Issues Nephrol 1996, 29:41–57. 138. Jabs DA, David MD, Kuriniji et al.: Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: the HPMC peripheral cytomegalovirus retinitis trial. A randomized controlled trial. Ann Intern Med 1997, 126:264–275. 139. Rashed A, Azadeh B, Abu Romeh SH: Acyclovir-induced acute tubulo-interstitial nephritis. Nephron 1990, 56:436–438.

155. Rao TK, Friedman EA: Outcome of severe acute renal failure in patients with acquired immunodeficiency syndrome. Am J Kidney Dis 1995, 25:390–398. 156. Bourgoignie J: Glomerulosclerosis associated with HIV infection. Contemp Issues Nephrol 1996, 29:59–75. 157. Rao TK, Filippone EJ, Nicastri AD, et al.: Associated focal and segmental glomerulosclerosis in the acquired immunodeficiency syndrome. N Engl J Med 1984, 310:669–673. 158. Pardo V, Aldana M, Colton RM, et al.: Glomerular lesions in the acquired immunodeficiency syndrome. Ann Intern Med 1984, 101:429–434. 159. Gardenswartz MH, Lerner CW, Seligson GR, et al.: Renal disease in patients with AIDS: a clinicopathologic study. Clin Nephrol 1984, 21:197–204. 160. Mazbar SA, Schoenfeld PY, Humphreys MH: Renal involvement in patients infected with HIV: experience at San Francisco General Hospital. Kidney Int 1990, 37:1325–1332. 161. Humphreys MH: Human immunodeficiency virus–associated nephropathy: east is east and west is west? Arch Intern Med 1990, 150:253–255. 162. Bourgoignie JJ, Ortiz-Interian C, Green DF, et al.: The epidemiology of human immunodeficiency virus–associated nephropathy. In Nephrology, vol 1. Edited by Hatano M. Tokyo: Springer-Verlag; 1991:484–492. 163. Pardo V, Meneses R, Ossa L, et al.: AIDS-related glomerulopathy: occurrence in specific risk groups. Kidney Int 1989, 31:1167–1173.

140. Christin S, Baumelou A, Bahri S, et al.: Acute renal failure due to sulfadiazine in patients with AIDS. Nephron 1990, 55:233–234.

164. Strauss J, Abitbol C, Zilleruelo G, et al.: Renal disease in children with the acquired immunodeficiency syndrome. N Engl J Med 1989, 321:625–630.

141. Carbone LG, Bendixen B, Appel GB: Sulfadiazine-associated obstructive nephropathy occurring in a patient with the acquired immunodeficiency syndrome. Am J Kidney Dis 1988, 12:72–75.

165. Nochy D, Gotz D, Dosquet P, et al.: Renal disease associated with HIV infection: a multicentric study of 60 patients from Paris hospitals. Nephrol Dial Transplant 1993, 8:11–19.

142. Molina JM, Belenfant X, Doco-Lecompte T, et al.: Sulfadiazineinduced crystalluria in AIDS patients with toxoplasma encephalitis. AIDS 1991, 5:587–589.

166. D’Agati V, Appel GB: HIV infection and the kidney. J Am Soc Nephrol 1997, 8:138–152.

143. Becker K, Jablonowski H, Haussinger D: Sulfadiazine-associated nephrotoxicity in patients with the acquired immunodeficiency syndrome. Medicine 1996, 75:185–194. 144. Sawyer MH, Webb DE, Balow JE, et al.: Acyclovir-induced acute renal failure. clinical course and histology. Am J Med 1988, 84:1067–1071. 145. Tashima KT, Horowitz JD, Rosen S: Indinavir nephropathy [letter]. N Engl J Med 1997, 336:138–139. 146. Kopp JB, Miller KD, Micam JAM, et al.: Crystoalluria and urinary tract abnormalities associated with Indinovir. Ann Intern Med 1997, 127:119–125. 147. Spector DA, Katz RS, Fuller H, et al.: Acute non-dilating obstructive renal failure in a patient with AIDS. Am J Nephrol 1989, 9:129–132. 148. Comiter S, Glasser J, Al-Askari S: Ureteral obstruction in a patient with Burkitt’s lymphoma. Urology 1992, 39:277–289. 149. Kuhlman JE, Browne D, Shermak M, et al.: Retroperitoneal and pelvic CT of patients with AIDS: primary and secondary involvement of the genitourinary tract. Radiographics 1991, 11:473–483.

167. Cohen AH, Nast CC: HIV-associated nephropathy: a unique combined glomerular, tubular and interstitial lesion. Modern Pathol 1988, 1:87–97. 168. Soni A, Agarwal A, Chander P, et al.: Evidence for an HIV-related rephropathy: a clinicopathological study. Clin Nephrol 1989, 31:12–17. 169. Bourgoignie JJ, Pardo V: The nephropathology in human immunodeficiency virus (HIV-1) infection. Kidney Int 1991, 35:S19–S23. 170. Cohen AH: Renal pathology of HIV-associated nephropathy. Contemp Issues Nephrol 1996, 27:155–180. 171. Pardo V, Strauss J, Abitbol C: Renal disease in children with HIV infection. Contemp Issues Nephrology 1996, 29:135–154. 172. Langs C, Gallo GR, Schacht RG, et al.: Rapid renal failure in AIDSassociated focal glomerulosclerosis. Arch Intern Med 1990, 150:287–292. 173. Humphreys MH: Human immunodeficiency virus–associated glomerulosclerosis. Kidney Int 1995, 48:311–320. 174. Shuka RR, Kimmel PL, Jumar A: Molecular biology of HIV-1 and kidney disease. Contemp Issues Nephrol 1996, 29:329–389.

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175. Barisoni L, Bruggeman L, Schwartz E, et al.: Pathogenesis of HIV-associated nephropathy in transgenic mice. J Am Soc Nephrol 1997, 8:492A. 176. Bruggeman LA, Dikman S. Meng C, et al.: Nephropathy in human immunodeficiency virus-1 transgenic mice is due to renal transgene expression. J Clin Invest 1997, 100:84–92. 177. Babut-Gay ML, Echard M, Kleinknecht D, et al.: Zidovudine and nephropathy with human immunodeficiency virus (HIV) infection [letter]. Ann Intern Med 1989, 111:856–857. 178. Harrer T, Hunzelmann N, Stoll R, et al.: Therapy for HIV-1 related nephritis with zidovudine. AIDS 1990, 4:815–817. 179. Ifudu O, Rao TK, Tan CC, et al.: Zidoudine is beneficial in human immunodeficiency virus associated nephropathy. Am J Nephrol 1995, 15:217–221. 180. Kimmel PL, Mishkin GJ, Umana WO: Captopril and renal survival in patients with human immunodeficiency virus nephropathy. Am J Kidney Dis: 1996, 28:202–208. 181. Smith MC, Austen JL, Carey JT, et al.: Prednisone improves renal function and proteinuria in human immunodeficiency virus-associated nephropathy. Am J Med 1996, 101:41–48. 182. Watterson MK, Detwiler RD, Bolin P Jr: Clinical response to prolonged corticosteroids in a patient with human immunodeficiency virus-associated nephropathy. Am J Kidney Dis 1997, 29:624–626. 183. Ingulli E, Tejani A, Fikrig S, et al.: Nephrotic syndrome associated with acquired immunodeficiency syndrome in children. J Pediatr 1991, 119:710–716. 184. Ouelette DR, Kelly JW, Anders JT: Serum angiotensin converting enzyme level is elevated in patients with HIV-infection. Arch Intern Med 1992, 152:321–324. 185. Burns G, Paul SK, Sivak SL, et al.: Effect of angiotensin-converting enzyme inhibition in HIV-associated nephropathy. J Am Soc Nephrol 1997, 8:1140–1146. 186. Bird JE, Kopp JB, Gitlitz P, et al.: Captopril intervention is of benefit in HIV-transgenic mice. J Am Soc Nephrol 1997, 8:611A. 187. Rao TKS, Friedman EA, Micastri AD: The types of renal disease in human acquired immunodeficiency syndrome. N Engl J Med 1987, 316:1062–1068. 188. Ortiz C, Meneses R, Jaffe D, et al.: Outcome of patients with human immunodeficiency virus on maintenance hemodialysis. Kidney Int 1988, 34:248–253. 189. Feinfeld DA, Kaplan R, Dressler R, et al.: Survival of human immunodeficiency virus infected patients on maintenance dialysis. Clin Nephrol 1989, 32:221–224. 190. Ribot S, Dean D, Goldblat M, et al.: Prognosis of HIV positive dialysis patients [abstract]. Kidney Int 1990, 37:315. 191. Schrivastava D, Delano BG, Lundin P, et al.: Factors affecting survival of HIV+ patients undergoing maintenance hemodialysis [abstract]. J Am Soc Nephrol 1992, 3:320.

192. Kimmel PL, Umana WO, Simmens SJ, et al.: Continuous ambulatory peritoneal dialysis and survival of HIV infected patients with endstage renal disease. Kidney Int 1993, 44:373–378. 193. Ifudu O, Mayers JD, Matthew JJ, et al.: Uremia therapy in patients with end-stage renal disease and human immunodeficiency virus infection: Has the outcome changed in the 1990s? Am J Kidney Dis 1997, 29:549–552. 194. Perinbasekar S, Brod-Miller S, Pal S, et al.: Predictors of survival in HIV-infected patients on hemodialysis. Am J Nephrol 1996, 16:280–286. 195. Carpenter C, Fischl M, Hammer S, et al.: Antiretroviral therapy for HIV infection in 1996. JAMA 1996, 276:146–154. 196. Casanova S, Mazzucco G, Barbiano di Belgiojoso G, et al.: Pattern of glomerular involvement in human immunodeficiency virus-infected patients: an Italian study. Am J Kidney Dis 1995, 26:446–453. 197. Korbet SM, Schwartz MM: Human immunodeficiency virus infection and nephrotic syndrome. Am J Kidney Dis 1992, 20:97–103. 198. Stokes MB, Chawla H, Brody RI, et al.: Immune complex glomerulonephritis in patients co-infected with human immunodeficiency virus and hepatitis C virus. Am J Kidney Dis 1997, 29:514–525. 199. Kimmel PL, Phillips TM: Immune-complex glomerulonephritis associated with HIV infection. Contemp Issues Nephrol 1996, 29:77–110. 200. Guerra IL, Abraham AA, Kimmel PL, et al.: Nephrotic syndrome associated with chronic persistent hepatitis B in an HIV antibody positive patient. Am J Kidney Dis: 1987, 10:385–388. 201. Schectman JM, Kimmel PL: Remission of hepatitis B–associated membranous glomerulonephritis in human immunodeficiency virus infection. Am J Kidney Dis 1991, 17:716–718. 202. Kusner DJ, Ellner JJ: Syphilis, a reversible cause of nephrotic syndrome in HIV infection [letter]. N Engl J Med 1991, 324:341–342. 203. D’Agati V, Seigle R: Coexistence of AIDS and lupus nephritis: a case report. Am J Nephrol 1990, 10:243–247. 204. Contreras G, Green DF, Pardo V, et al.: Systemic lupus erythematosus in two adults with human immunodeficiency virus. Am J Kidney Dis 1996, 28:292–295. 205. Kimmel PL, Phillips TM, Farkas-Szallasi T, et al.: Idiotypic IgA nephropathy in patients with HIV infection. N Engl J Med 1992, 327:702–706. 206. Bourgoignie JJ, Pardo V: Human immunodeficiency virus: associated nephropathies [editorial]. N Engl J Med 1992, 327:729–730. 207. Peraldi MN, Berrou J, Flahaut A, et al.: Elevated plasma tissue type plasminogen activator (tPA) in HIV-infected patients with thrombotic microangiopathy [abstract]. J Am Soc Nephrol 1996, 7:1377. 208. Berns JS: Hemolytic uremic syndrome and thrombotic thrombocytopenic purpura associated with HIV infection. Contemp Issues Nephrol 1996, 29:111–133. 209. Nadasdy T, Miller KW, Johnson LD, et al.: Is cytomegalovirus associated with renal disease in AIDS patients? Modern Pathol 1992, 5:277–282.

Renal Involvement in Sarcoidosis Garabed Eknoyan

S

arcoidosis is a clinicopathologic syndrome resulting from dispersed organ involvement by a noncaseating granulomatous process of unknown cause. The clinical manifestations of sarcoidosis are protean, depending on the affected organs; however, the principal targets of sarcoidosis are the lungs and thoracic lymph nodes, which almost always are involved. As a rule, it is a disease of insidious onset that pursues a chronic course, with episodic remissions and exacerbations. The severity and diversity of its clinical manifestations depend on the extent of infiltrating granulomatous lesions of the involved organs and that of the number of affected organs. When diffuse and widespread the disease may pursue an acute fulminant course. Diagnosis depends on demonstration of the characteristic pathologic lesion of noncaseating granulomas within the affected organ. Sarcoidosis is a common (1 to 40 cases per 100,000 population) disease of the relatively young (mean age 40 years), with a proclivity for racial (3.5 times more in blacks), ethnic (Scandinavian), and seasonal occurrence (summer rather than winter). Reports of community outbreaks, work-related risks, familial clustering, occurrence after organ transplantation, and experimental induction in animals by injection of affected tissue homogenates from humans strongly suggests an infective cause that remains to be identified. Two associated metabolic abnormalities of diagnostic and clinical import are elevated levels of calcitriol (1,25-dihydroxy-vitamin D3) and angiotensin-converting enzyme (ACE). Neither is unique to sarcoidosis. Elevated levels of calcitriol are consequent to the capacity of the infiltrating macrophages of the granulomas to synthesize calcitriol. Elevated levels of ACE are consequent to that of the multinucleated giant and epithelioid cells that ultimately develop in the granulomas, along with that of the infiltrating macrophages, to produce ACE. Of these, the elevated levels of calcitriol are the more important because they account for the abnormal calcium metabolism that occurs in most patients. Elevated levels of ACE are of no known clinical consequence

CHAPTER

8

8.2

Systemic Diseases and the Kidney

and are of limited value in diagnosis; however, they can be useful in follow-up of the course of the disease and patient response to treatment. In symptomatic cases, steroids are highly effective in suppressing the cellular inflammatory reaction of sarcoidosis and in reversing most forms of organ dysfunction caused by granulomatous infiltration. Therapy with prednisone (30 to 40 mg/d) for 8 to 12 weeks, with gradual tapering of the dose (10 to 20 mg/d) over 6 to 12 months, is usually sufficient. Persistent dysfunction can result from residual fibrosis after reversal of

the active granulomatous lesions. Close monitoring of patients is essential during tapering and after discontinuation of steroid therapy, because 25% of treated patients experience relapse. Other drugs that have been used in cases unresponsive to steroids are methotrexate, chloroquine, azathioprine, and cyclophosphamide. Of these, methotrexate seems to be more effective. The prognosis is worse in blacks, the elderly, and those patients who fail to respond to steroids or have extensive multiorgan involvement.

Pathophysiology and Diagnosis

A

B

C

D

FIGURE 8-1 (see Color Plate) Pathology of granulomatous lesions in lungs affected by sarcoidosis. The diagnosis of sarcoidosis depends on demonstration of the characteristic lesion of noncaseating granulomas within the affected organs. As with other epithelioid granulomas, the more commonly involved organs are the lungs and liver. A, A section of a normal lung is shown. (Pentachrome stain  10.) B, Multiple noncaseating granulomas and areas of mononuclear cell infiltration of the lung interstitium charac-

teristic of sarcoidosis are shown. (Hematoxylin-eosin stain  10.) C and D, Lesions in the lung are illustrated, showing their course from a cellular inflammatory response, which may be asymptomatic (panel C), to that of the fibrotic resolution (panel D). The fibrotic response usually accounts for the permanent loss of normal parenchyma and organ function. (Hematoxylin-eosin stain  10 and pentachrome  10, respectively.) (From Newman et al. [1]; with permission.)

Renal Involvement in Sarcoidosis Pathogenesis of granulomatous lesions Mononuclear cell infiltration

Macrophage aggregation

↑ Synthesis of 1,25-dihydroxy-vitamin D3

Epithelioid and multinucleated giant cells

↑ Synthesis of angiotensin-converting enzyme

Encapsulating rim CD4>CD8 (except in rare cases) B cells, few Fibroblasts Mast cells

CYTOKINES IMPLICATED IN PERPETUATING GRANULOMAS

FIGURE 8-2 Pathogenesis of granulomatous lesions. Mononuclear cell infiltration is the initial step in the sequence of events that leads to granuloma formation. Recruited macrophages then differentiate into epithelioid and multinucleated giant cells. Activated lymphocytes are interspersed in the evolving lesion and come to form a rim around the granulomas. In time, fibroblasts, mast cells, and collagen fibers begin to encapsulate the mature sarcoid granuloma. Cultured granulomatous homogenates exhibit 1-hydroxylase activity and are capable of converting 25-hydroxy-vitamin D3 to its active 1,25-dihydroxylated form, calcitriol. This capacity resides in the infiltrating macrophages and is not unique to sarcoidosis but a feature of most other granulomatous disorders. Although lacking in specificity to be of diagnostic merit, radioactive gallium scans can be used as noninvasive methods of assessing the activity of sarcoid granulomas. The uptake of radioactive gallium by the macrophages and lymphocytes reflects the activity of the infiltrating cells in affected organs.

SARCOIDOSIS FREQUENCY OF ORGAN INVOLVEMENT Patients, %

Interferon- Interleukin-2, 6, and 1 Chemoattractants Adhesion molecules Tumor necrosis factor-

FIGURE 8-3 Cytokines implicated in perpetuating granulomas. Cytokines released by the infiltrating mononuclear cells and T-cell lymphocytes initiate the cascade of inflammatory reaction that results in subsequent formation of the noncaseating granulomas that characterize sarcoidosis. It is the loss of the otherwise balanced ability of cytokines to modulate the inflammatory response that accounts for the progression of the initial inflammatory reaction to granulomatous formation, and ultimately to the more detrimental process of fibrosis. Macrophages are critical in inducing fibroblasts to proliferate and deposit fibronectin and collagen in the extracellular matrix.

8.3

Thoracic Stage I: hilar adenopathy Stage II: hilar adenopathy plus pulmonary infiltration Stage III: pulmonary infiltration Dermatologic Erythema nodosum, lupus pernio, papules, macules, plaques Ophthalmic Uveitis, iritis, conjunctivitis Nervous system Peripheral neuropathy, Bell’s palsy Central nervous system Gastrointestinal Liver Spleen Cardiac Renal Musculoskeletal Polyarthritis, lower > upper

90–100

25 25 10

40–70

5–10 1–20 10–15

FIGURE 8-4 Frequency of organ involvement. Sarcoidosis is a multisystem disease. Parenchymal involvement by granulomatous lesions is most common in the lungs, whereas that of renal involvement is relatively rare.

8.4

Systemic Diseases and the Kidney

DIFFERENTIAL DIAGNOSIS OF PULMONARY SARCOIDOSIS Sarcoidosis Beryllium exposure Hypersensitivity pneumonitis Idiopathic pulmonary fibrosis Mycobacterial infection Fungal infections Methotrexate-induced pneumonitis Wegener’s granulomatosis

LABORATORY FINDINGS IN SARCOIDOSIS Hyperglobulinemia Abnormal liver function tests Anergy Leukopenia Hyperuricemia Hypercalciuria Hypercalcemia Elevated calcitriol (1,25-dihydroxy-vitamin D3) Elevated angiotensin-converting enzyme Cryoglobulinemia

FIGURE 8-5 Differential diagnosis of pulmonary sarcoidosis. The lungs are the principal organs involved in sarcoidosis. Pulmonary involvement may or may not be associated with hilar lymphadenopathy. In contrast to the pulmonary diseases listed, pulmonary symptoms may be absent in sarcoidosis even in the presence of extensive pulmonary lesions seen on chest radiographs. Pulmonary symptoms develop when the disease is in its late fibrotic phase and are associated with airway obstruction.

FIGURE 8-6 Laboratory findings in sarcoidosis. The diagnosis of sarcoidosis depends on the demonstration of the characteristic pathologic lesion of noncaseating granulomas within the affected organs. Several laboratory abnormalities characterize sarcoidosis and are useful in supporting but not establishing the diagnosis. Hyperglobulinemia is a principal feature, being present in two thirds of cases. About half of patients have liver involvement, with some abnormality of liver function tests; anergy is present in about half of patients; leukopenia is present in 25% to 30%. Hypercalciuria is common because of increased levels of calcitriol. In 50% to 60% of patients levels of angiotensin-converting enzymes are elevated. Fever is present in about one third of patients.

RENAL INVOLVEMENT IN SARCOIDOSIS Patients, % Calcium metabolism Hypercalciuria Hypercalcemia Nephrolithiasis Nephrocalcinosis Tubulointerstitial nephritis Granulomatous Fibrotic Glomerulopathy Membranous Proliferative Focal segmental glomerulosclerosis Arteritis Granulomatous angiitis Obstructive nephropathy Retroperitoneal lymphadenopathy Retroperitoneal fibrosis

50–60 10–20 ≈10 5–10 15–40 10–20 Rare

Rare Rare

FIGURE 8-7 Renal involvement in sarcoidosis. The principal manifestations of renal involvement in sarcoidosis are the functional abnormalities resulting from the altered metabolism of calcium as a result of the increased synthesis of 1,25-dihydroxy-vitamin D3 by the macrophages of the granulomatous lesions. The consequent increased calcium absorption from the gastrointestinal tract results in the hypercalciuria that can be detected in more than half of patients. The frequency of hypercalciuria depends on the extent of granulomatous lesions and on the time of the year, being more common in spring and summer when exposure to the sun is greatest. Hypercalcemia is less common and usually depends on coexistent deterioration of renal function when the capacity of the kidney to excrete calcium is compromised. In most patients, hypercalciuria is asymptomatic. Its principal manifestations are inability to concentrate the urine and polyuria. Nephrolithiasis occurs in about 10% of patients; another 10% develop nephrocalcinosis.

Renal Involvement in Sarcoidosis Abnormal calcium metabolism and pathophysiology of renal involvement in sarcoidosis Sarcoid granulomas

↓ Parathyroid hormone secretion

↑ Levels of calcitriol

↑ Intestinal calcium absorption and ↑ bone resorption ↓ Tubular calcium absorption

Hypercalciuria

↑ Calcium load for renal excretion

Renal calcium deposition

↓Renal Function

Outflow tract parenchymal

↓ Total calcium excretion

Nephrolithiasis

Nephrocalcinosis

Hypercalcemia

FIGURE 8-8 Abnormal calcium metabolism and pathophysiology of renal involvement in sarcoidosis. Increased synthesis of calcitriol (1,25-dihydroxy-vitamin D3) by the macrophages of the granulomatous lesions of sarcoidosis are at the core of the abnormal calcium metabolism that accounts for the principal manifestations of renal involvement of sarcoidosis (gray boxes). Patients with hypercalciuria, which by far is the most common, may remain asymp-

8.5

tomatic, and the disease may go undetected. Polyuria and a reduced capacity to concentrate the urine are its main manifestations. Either of these two features may be the result of tubulointerstitial nephritis caused by sarcoidosis, and can be present in the absence of any altered calcium metabolism. Nephrocalcinosis also may be asymptomatic. In contrast, nephrolithiasis presents as renal colic or hematuria. Hypercalcemia develops only when the load of calcium to be excreted exceeds the ability of the kidneys to excrete the calcium load, either because of reduced renal function or, less commonly, when the amount of calcium absorbed is excessive. The magnitude of hypercalcemia determines its symptomatology. The circulating level of parathyroid hormone should be determined in patients with hypercalcemia. An increase in the prevalence of parathyroid adenomas seems to occur in sarcoidosis. In hypercalcemia caused by elevated levels of calcitriol and by reduced renal excretion of calcium, parathyroid hormone levels should be negligible. Detection of elevated levels of parathyroid hormone should lead to the search for an adenoma. Patient management is directed at reducing calcitriol synthesis by treating the granulomatous lesions with steroids. Equally important measures in the management of such patients are restriction of calcium intake, avoidance of dietary supplements that contain vitamin D, shunning exposure to sunlight, and increased fluid intake.

FIGURE 8-9 (see Color Plate) Micrograph of granulomatous lesions of the renal interstitium that are observed in 15% to 40% of patients with sarcoidosis. The highest rate reported in the literature is 40%. This figure is based on autopsy findings, which often reveal occasional granulomas of the kidney without any evidence of functional or clinical abnormality. The lower figure of 15%, or less, more clearly reflects diffuse infiltration of the kidneys with granulomas associated with clinical evidence of abnormal renal function, as shown here. Generally, enlarged kidneys are noted on renal ultrasonography.

8.6

Systemic Diseases and the Kidney

DIFFERENTIAL DIAGNOSIS OF GRANULOMATOUS LESIONS IN RENAL SARCOIDOSIS Lesion Drug-induced Sarcoid Wegener’s granulomatosis Other (less common): Tuberculosis Brucellosis Vasculitis Systemic lupus erythematosus Idiopathic

Patients, %

FIGURE 8-10 Differential diagnosis of granulomatous lesions in renal sarcoidosis. Once considered rare, granulomatous interstitial nephritis is now observed in 10% of kidney biopsy results. Most of these are seen in cases of drug hypersensitivity. The commonly implicated drugs are antibiotics and nonsteroidal anti-inflammatory drugs. Sarcoidosis and Wegener’s granulomatosis each account for 5% to 10% of cases observed on kidney biopsy. Other less common and rather rare causes include tuberculosis, angiitis, and lupus erythematosus. In some 15% to 20% of cases, the cause of the granulomatous lesions is never established.

55–70 5–10 5–10

15–20

Clinical Course FIGURE 8-11 Micrograph of fibrosis. As a rule, abnormal renal function in patients with sarcoidosis is due to tubulointerstitial nephritis rather than granulomatous infiltration, which certainly is true in patients with progressive loss of renal function. Fibrosis may occur in the absence of granulomas but generally reflects the residual fibrosis of granulomatous lesions that have subsided or responded to steroid therapy. It is important to monitor renal function closely in such patients and initiate proper measures to retard the course of progressive renal failure. As with all other forms of tubulointerstitial nephritis, tubular dysfunction is a common finding in such cases. The reduction in the glomerular filtration rate usually is modest but can progress to end-stage renal disease. Progression to end-stage disease tends to occur in older men who have minimal pulmonary involvement.

Renal Involvement in Sarcoidosis

Pre-R

Serum creatinine, mg/100mL

8

R

7 6 5 4

8.7

FIGURE 8-12 Clinical course of granulomatous nephritis. Extensive granulomatous infiltration of the kidneys can result in acute renal failure as a presenting clinical feature of sarcoidosis in the absence of any evidence of other organ involvement. As a rule, improvement in renal function occurs after steroid therapy (R), as shown here, in the clinical course of one such patient. (From Bolton et al. [2]; with permission.)

3 2 1

60

Creatinine clearance, mL/min

50 40 30

20 10

Hematocrit, %

40

30 20

10 Prednisone qod, mg

60 30 September

October

Nov. Dec. Jan. Feb. Mar. April May June July

Time, mo

CASE REPORT OF A PATIENT WITH SARCOIDOSIS HAVING RETROPERITONEAL FIBROSIS Patient profile A man aged 40 years with established diagnosis of pulmonary sarcoidosis that had responded to steroids Presentation: hypertension (200/140 mm Hg) and proteinuria (4 g/d) Intravenous pyelogram: asymmetric kidneys with delayed appearance of contrast on right Surgery: sclerotic matrix affecting aorta and proximal renal artery Kidney biopsy: focal and global glomerulosclerosis, interstitial fibrosis Postoperative course: persistent hypertension

FIGURE 8-13 Obstructive nephropathy due to sarcoidosis. Acute deterioration of renal function in sarcoidosis very rarely results from obstructive nephropathy caused by intrarenal granulomatous infiltrates or from extensive retroperitoneal lymphadenopathy or fibrosis causing obstruction of the renal vasculature or ureteral outflow [3,4]. (From Grodin et al. [3]; with permission.)

8.8

Systemic Diseases and the Kidney

CASE REPORT OF A PATIENT WITH SARCOIDOSIS HAVING GLOMERULOPATHY

CASE REPORT OF A PATIENT WITH RECURRENT GRANULOMATOUS SARCOID NEPHRITIS IN A TRANSPLANTED KIDNEY

Patient profile Aged 13 y

A man aged 57 years with 3 months’ history of progressive edema Past history: pulmonary sarcoidosis, treated with steroids for 10 years, on 5 mg 4 times a day on admission Physical examination: blood pressure, 180/95 mm Hg; peripheral edema Laboratory test results: blood urea nitrogen, 32 mg/dL; creatinine, 4.3 mg/dL; albumin, 2.9 g/dL; cholesterol, 543 mg/dL; urinalysis, 6–8 erythrocyte/high-power field, 3 + protein; 24-h urine protein, 1.5 g Kidney biopsy: membranous glomerulopathy; no granulomas

FIGURE 8-14 Sarcoid-associated glomerulopathy. Whereas renal involvement in sarcoidosis primarily is due to abnormalities of calcium metabolism and tubulointerstitial nephritis, rare cases of glomerulopathy have been associated with sarcoidosis. The detection of an abnormal urine sediment and proteinuria in a patient with sarcoidosis should always lead to consideration of glomerular disease. A variety of glomerular lesions have been reported in patients with sarcoidosis, including membranous glomerulopathy, minimal change disease, membranoproliferative glomerulonephritis, focal glomerulosclerosis, immunoglobulin A nephropathy, and crescentic glomerulonephritis. Of these, membranous glomerulopathy is more common. These rare cases may represent a chance coexistence of two separate diseases; however, their occurrence in a disease of altered immunity may reflect a causative association. Mesangial deposits of C3 have been observed in cases of sarcoid granulomatous nephritis in the absence of any clinical evidence of glomerular disease. Circulating immune complexes are detected in about half of cases of sarcoidosis in the absence of any evidence of renal involvement by granulomatous nephritis or glomerular lesions. As such, the presence of immune-mediated glomerulopathy may well be more than coincidental in occasional cases in which the patient may be predisposed by genetic or other as yet unidentified factors. (From Taylor et al. [5]; with permission.)

Aged 19 y

Aged 26 y

Sarcoidosis with pulmonary, hepatic, and ophthalmic symptoms Responded to steroids Steroids discontinued due to cataract and hypertension Renal involvement progressive to end-stage renal disease Cadaveric transplantation after 3 months of dialysis Medications: azathioprine, 75 mg per day; prednisone tapered to 15 mg 4 times a day Creatinine, 3.1 mg/dL; creatinine clearance, 20 mL/min; blood pressure, 150/84 mm Hg Transplanted kidney biopsy: diffuse granulomatous infiltration Treatment: prednisone increased to 60 mg/d for 6 wk Response: creatine, 2.5 mg/dL; creatinine clearance, 35 mL/min

FIGURE 8-15 Recurrent granulomatous sarcoid nephritis in a transplanted kidney. In patients with sarcoidosis having renal involvement whose renal failure has progressed to end-stage renal disease, kidney transplantation can be successful. However, due consideration should be given to the fact that recurrence of sarcoidosis in renal allografts have been reported. Conversely, documented cases exist in which sarcoidosis was transmitted by cardiac or bone marrow transplantation. This observation has been taken as evidence of an infectious or transmissible cause of sarcoidosis that highlights the problem of transplantation in patients with sarcoidosis. (From Shen et al. [6]; with permission.)

References 1. 2.

3.

Newman LS, Rose CS, Maier LA: Sarcoidosis. N Engl J Med 1997, 336:1224–1234. Bolton WK, Atuk NO, Rametta C, et al.: Reversible renal failure from isolated granulomatous renal sarcoidosis. Clin Nephrol 1976, 5:88–92. Grodin M, Filastre JP, Ducastelle T, et al.: Sarcoidosis retroperitoneal fibrosis, renal arterial involvement and unilateral focal glomerulosclerosis. Arch Intern Med 1980, 140:1240–1242.

4. 5.

6

Cuppage FE, Emmott DF, Duncan KA: Renal failure secondary to sarcoidosis. Am J Kidney Dis 1990, 11:519–521. Taylor RG, Fisher C, Hoffbrand BI: Sarcoidosis and membranous glomerulonephritis: a significant association. Br Med J 1982, 284:1297–1298. Shen SY, Hall-Craggs M, Posner JN, Shalozz B: Recurrent sarcoid granulomatous nephritis and reactive tuberculin test in a renal transplant recipient. Am J Med 1986, 80:699–702.

Selected Bibliography Casella FJ, Allon M: The kidney in sarcoidosis. J Am Soc Nephrol 1993, 3:1555–1562. Romer FK: Renal manifestations and abnormal calcium metabolism in sarcoidosis. Quart J Med 1980, 49:233–247.

Fuss M, Pepersack T, Gillet C, et al.: Calcium and vitamin D metabolism in granulomatous diseases. Clin Rheumatol 1992, 11:28–36. Hanedouche T, Grateau G, Noel LH, et al.: Renal granulomatous sarcoidosis: Report of 6 cases. Nephrol Dial Transplant 1990, 5: 18–24.

Renal Involvement in Essential Mixed Cryoglobulinemia Giuseppe D’Amico Franco Ferrario

U

p to the end of the 1980s, the cause of about 30% of both type II and III mixed cryoglobulinemias (MC) in patients was not known, and this subgroup of patients were referred to as having essential mixed cryoglobulinemia. Essential mixed cryoglobulinemia was characterized clinically by systemic signs, mainly purpura, arthralgias, and fever, together with hepatic, neurologic, and renal symptoms. During this decade, antibodies against hepatitis C virus (HCV) antigens and HCV RNA (which is a marker of active viremia) have been detected in the serum of up to 90% of these patients. Only when a monoclonal rheumatoid factor, usually an immunoglobulin Mk (IgMk), is the anti-IgG component of the mixed cryoglobulinemia (type II MC) does this distinctive glomerular and vascular involvement of the kidney occur. The most frequent histologic picture, especially in the acute stages, is a membranoproliferative glomerulonephritis (MPGN) with subendothelial deposits, with some characterizing features both by light and electron microscopy. However, a less distinctive picture of lobular MPGN is found at biopsy in 20% of patients, and of a mesangioproliferative glomerulonephritis in another 20%. In all cases, the two components of MC, IgG, and IgM, together with complement, are found by immunofluoroscopy. The clinical picture varies during the long-term course of the disease, being characterized by periods of temporary reactivation (nephritic or nephrotic syndrome, sometimes with rapidly occurring renal insufficiency) and long-lasting periods of partial remission. Only infrequently does end-stage renal failure develop; however, mortality as a result of the other complications of the systemic disease (mainly cardiovascular) is rather frequent.

CHAPTER

9

9.2

Systemic Diseases and the Kidney

During acute flare-ups, antiviral treatment (interferon-) is insufficient to control the renal disease, even when it reduces viremia. Steroids, usually associated with immunosuppressive drugs (cyclophosphamide), are then necessary to control renal disease. Hepatitis C virus can infect B lymphocytes and stimulate them to synthesize the cryoprecipitating polyclonal rheumatoid factors responsible for type III MC. In some patients with this polyclonal B-cell activation, additional but as yet uncharacter-

ized events might induce the shift to abnormal proliferation of a clone of B cells, producing a monoclonal IgM rheumatoid factor. Thus, a type II MC is induced that can be considered a lymphoproliferative disorder. It has been suggested that the IgMk produced by this permanent clone of B cells has affinity for the glomerular matrix and can deposit, in the glomerulus together with the IgG to which it binds in the blood, IgG that probably acts as an anti-HCV antigen antibody.

CLASSIFICATION OF CRYOGLOBULINEMIAS AND ASSOCIATED DISEASES Type I: single monoclonal IgA, IgG, or IgM

Type II: polyclonal IgG bound to monoclonal anti-IgG rheumatoid factor*

Multiple myeloma

B-lymphocytic neoplasm

Waldenström’s macroglobulinemia

Diffuse lymphoma

Chronic lymphocytic leukemia

Chronic lymphocytic leukemia

Idiopathic monoclonal gammopathy

Sjögren’s syndrome Essential

Type III: polyclonal IgG bound to polyclonal anti-IgG rheumatoid factor* Autoimmune diseases: SLE, polyarteritis nodosa, rheumatoid arthritis, scleroderma, Sjögren’s syndrome, and Henöch-Schonlein purpura Infections diseases: mononucleosis, cytomegalovirus, hepatitis B, subacute bacterial endocarditis, leprosy, malaria, schistosomiasis, toxoplasmosis, AIDS Miscellaneous diseases: primary proliferative glomerulonephritis, lymphoma, chronic hepatitis, biliary cirrhosis Essential

*Usually IgM. From Brouet and coworkers [1]; with permission.

FIGURE 9-1 Classification of cryoglobulinemias and associated diseases as proposed by Brouet and coworkers in 1974 [1]. Up to the end of the 1980s, the cause of about 30% of both types II and III mixed cryoglobulins was

DETECTION OF CIRCULATING CRYOGLOBULINS AND DETERMINATION OF CRYOPRECIPITATE Prewarm syringe, needle, and tubes at 37°C Take 20 mL of whole blood and put it immediately at 37°C Incubate for 2 h at 37°C to allow clotting Centrifuge twice at 1700 g X 10 at 37°C to discard platelets and erythrocytes Cryoglobulins precipitate reversibly from cooled serum Keep serum at 4°C in a conical graduate tube Look at the serum after 7 d Centrifuge serum at 400 g X 10 at 4°C and calculate the cryocrit as the percentage of packed cryoglobulins and serum ratio

not clear, and this group of mixed cryoglobulinemias was called essential [2,3]. As indicated in Figure 9-4, it now is evident that most essential mixed cryoglobulinemias are associated with hepatitis C virus infection. FIGURE 9-2 Correct methodology for detecting circulating cryoglobulins. Cryoglobulins are immunoglobulins that precipitate reversibly from cooled serum.

9.3

Renal Involvement in Essential Mixed Cryoglobulinemia

A

B

FIGURE 9-3 (see Color Plate) Immunoglobulin composition and clonality of mixed cryoglobulins characterized by immunofixation. The cryoglobulins (isolated, as indicated in Fig. 9-2) are resuspended in three volumes of cold phosphate-buffered saline at 4°C and then washed by centrifuging at 1700 g for 10 minutes at 4°C; the supernatant is discarded. This procedure is repeat-

ed at least four times. Next, the cryoprecipitate is solubilized in three volumes of phospate-buffered saline at 37°C before gel electrophoresis is performed. A, Example of type II mixed cryoglobulin; the immunoglobulin M rheumatoid factor contains  but not  light chains and therefore is monoclonal. B, Example of type III mixed cryoglobulin; the immunoglobulin M rheumatoid factor contains both  and  light chains and therefore is polyclonal. (Beckman Paragon® IFE gel.)

PREVALENCE OF HEPATITIS C VIRUS AND HEPATITIS C VIRUS RNA IN ESSENTIAL AND SECONDARY MIXED CRYOGLOBULINEMIAS* Study

Types of mixed cryoglobulinema

Ferri et al. [5] Galli et al. [6]

II and III EMC II and III EMC

Pechère-Bertschi et al. [7] Agnello et al. [8] Misiani et al. [9] Pasquariello et al. [10] Cacoub et al. [11]

II and III EMC II EMC II EMC II EMC with GN II and III EMC SMC II and III EMC II EMC II EMC wtih GN III EMC

Bichard et al. [12] D’Amico, Unpublished data

Serum HCV antibodies Patients tested, n

Positive patients, %

52 129 63 15 19 75 26 63 52 — 41 28 13

54 80 70 87 42 96 100 52 27 — 95 93 77

Serum HCV RNA Patients tested, n

Positive patients, %

7 19 28 7 16

71 84 93 100 63

15 41 28 13

93 95 93 77

*According to published data [4]. EMC—essential mixed cryoglobulinemia; GN—glomerulonephritis; HCV—hepatitis C virus; SMC—secondary mixed cryoglobulinemia.

FIGURE 9-4 Second-generation enzyme-linked immunosorbent assay has been used by all the authors listed here (with the exception of Agnello and coworkers [9], who used a recombinant immunoblot assay) to measure anti–hepatitic C virus (HCV)

antibodies. The prevalence of positivity of HCV RNA in the 15 patients studied by Bichard and coworkers [12] increased from 60% to 93% when cryoprecipitate from serum was tested.

9.4

Systemic Diseases and the Kidney

FREQUENT EXTRARENAL SIGNS IN PATIENTS WITH TYPES II AND III MIXED CRYOGLOBULINEMIA Signs and symptoms Cutaneous purpura Arthralgias Fever Hepatosplenomegaly Neuropathy Abdominal pain

Prevalence during course of disease, % ≈ 95 ≈ 85 ≈ 60 ≈ 95 ≈ 40 ≈ 30

FIGURE 9-5 Extrarenal signs frequently present in patients with types II and III mixed cryoglobulinemia, either essential or due to hepatitis C virus infection, with or without cryoglobulinemic nephropathy. In patients with cryoglobulinemic nephropathy, the systemic signs usually appear months or years before renal complications develop. The onset of these signs, however, may be concomitant with or even subsequent to the onset of renal signs. Abdominal pain is due to mesenteric vsasculitis [13].

FIGURE 9-6 A purpuric rash of the legs in a patient with mixed cryoglobulinemia associated with hepatitis C virus infection.

DISTINCTIVE FEATURES OF MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS, OR CRYOGLOBULINEMIC GLOMERULONEPHRITIS Exudative component The major constituent of intracapillary proliferation is an infiltration of leukocytes, mainly monocytes, that sometimes is massive. Intraluminal thrombi Huge deposits of cryoglobulins called intraluminal thrombi sometimes fill the capillary lumen. Interposition of monocytes in the double contour of the capillary wall Monocytes, in close contact with the subendothelial deposits of cryoglobulins, are interposed between the glomerular basement membrane and the newly formed membranelike material, to give the double-contoured appearance of the capillary wall, whereas peripheral interposition of mesangial matrix and cells is moderate. Structured crystalloid deposits on electron microscopy Intraluminal and subendothelial deposits of cryoglobulins sometimes show a specific fibrillar structure on electron microscopy. Vasculitis of small and medium-sized arteries Necrotizing arteritis, without concomitant features of segmental necrotizing glomerulonephritis, is found in one third of patients.

FIGURE 9-7 The distinctive features of the membranoproliferative glomerulonephritis. This disorder, called cryoglobulinemic glomerulonephritis, occurs only in patients with type II mixed cryoglobulinemia, especially in the acute stage of the disease [4,14]. In about 20% of patients with type II mixed cryoglobulinemia, a less distinctive picture of lobular membranoproliferation is found, whereas an additional 20% exhibit mild mesangial proliferation. These various types of histologic lesions can be found by repeat biopsies in the same patient during different stages of the disease.

Renal Involvement in Essential Mixed Cryoglobulinemia

FIGURE 9-8 Membranoproliferative exudative glomerulonephritis in patients with type II mixed cryoglobulinemia. The marked endocapillary hypercellularity also is due to massive intraglomerular infiltration of mononuclear leukocytes, mainly monocytes (Fig. 9-9). Mesangial cell proliferation and mesangial matrix expansion are mild. Many loops show a thickened glomerular capillary wall, with frequent double-contoured basement membrane. (Trichrome stain  250.)

9.5

FIGURE 9-9 Immunohistochemical staining with anti–monocyte-macrophage antibody (CD68). This reaction confirms that the intracapillary hypercellularity is due mainly to accumulation of these mononuclear leukocytes. Their average number in acute stages of cryoglobulinemic glomerulonephritis is four times greater than in severe proliferative lupus nephritis [15]. (Immunoperoxidase  250.)

FIGURE 9-10 (see Color Plate) Monocyte in close contact with a massive endocapillary deposit showing phagocytic activity. (Uranyl acetate–lead citrate  8000.) (Courtesy of Department of Pathology, San Carlo Borromeo Hospital, Milan, Italy.)

FIGURE 9-11 (see Color Plate) Presence of huge intracapillary deposits typical of cryoglobulinemic glomerulonephritis. These huge intracapillary deposits are called intraluminal thrombi. The only possible differential diagnosis is with glomerulonephritis secondary to Waldenström macroglobulinemia. The glomerulus shows morphologic lesions similar to those seen in Figure 9-8, characterized by marked endocapillary hypercellularity mainly a result of mononuclear leukocyte accumulation. Two large intraluminal deposits, stained in green and red, are evident in the part of the glomerular tuft opposite the vascular pole. It is now well known that these deposits are expressions of acute and massive intracapillary precipitation of circulating cryoglobulins. (Trichrome stain  250.)

9.6

Systemic Diseases and the Kidney FIGURE 9-12 Electron microscopy of subendothelial and endocapillary deposits showing an amorphous structure. In a minority of cases, as illustrated here, a specific annular and cylindrical structure is shown. This structure is identical to that seen in the in vitro precipitate of the same patients and consists of cylinders 100- to 1000-µm long, with a hollow axis, appearing in cross-sections as annular bodies [16]. (Uranyl acetate–lead citrate  22,000.) (Courtesy of Department of Pathology, San Carlo Borromeo Hospital, Milan, Italy.)

FIGURE 9-13 Silver stain showing the double-contoured appearance of the basement membrane. This morphologic aspect is diffuse and more clearly visible than in idiopathic membranoproliferative glomerulonephritis or lupus nephritis. (Silver stain  250.)

FIGURE 9-14 Interposition of monocytes in cryoglobulinemic glomerulnephritis. Two monocytes containing lysosomes are interposed, together with electron-dense subendothelial deposits, between the glomerular basement membrane and the newly formed basement-membrane–like material of the double-contoured capillary wall. The interposition of monocytes is a distinctive feature of cryoglobulinemic glomerulnephritis [17,18]. Mesangial matrix and mesangial cell interposition, however, usually are less evident than in idiopathic membranoproliferative glomerulonephritis, as is glomerular sclerosis. (Uranyl acetate-lead citrate  8000.) (Courtesy of Department of Pathology, San Carlo Borromeo Hospital, Milan, Italy.) FIGURE 9-15 Morphologic pattern of lobular glomerulonephritis. This pattern is present in 20% of cases, characterized by intense mesangial proliferation and peripheral mesangial matrix expansion associated with centrolobular sclerosis. This histologic picture is indistinguishable from that of idiopathic membranoproliferative glomerulonephritis type I, except for the presence of some degree of monocyte infiltration. (Trichrome  250.)

Renal Involvement in Essential Mixed Cryoglobulinemia

9.7

FIGURE 9-16 The glomerulus showing only mild mesangial proliferation and mesangial matrix expansion. Thickening of the glomerular basement membrane is not evident. This picture frequently is present in cases clinically characterized only by mild urinary abnormalities (inactive phase). Moreover, in many cases in which a biopsy is taken during the acute phase of the disease with typical membranoproliferative patterns with or without thrombi, a second renal biopsy will show clear regression of the morphologically acute lesions with only mild mesangioproliferative alteration. (Trichrome  250.)

A

B FIGURE 9-17 (see Color Plate) The pattern of immunohistologic glomerular staining varies according to the different glomerular patterns seen on light microscopy. A, Diffuse granular subendothelial deposits along the capillary walls, with or without very rare intraluminal thrombi. (Immunoglobulin M  250). B, Intense massive staining of the deposits totally filling the capillary lumina. Faint and irregular parietal deposits also are present. (Immunoglobulin  250.) C, Parietal deposits with more evident peripheral lobular distribution. (Immunoglobulin  250.) The components of mixed cryoglobulinemia immunoglobulin M and G, usually associated with C3, are the most frequently found immunoreactants.

C

9.8

Systemic Diseases and the Kidney

FIGURE 9-18 Interstitial infiltrates having different degrees of intensity and diffusion. When present, these infiltrates are composed not only of T lymphocytes and monocyte macrophages, as in most glomerular diseases, but also of B lymphocytes. (Periodic acid–Schiff reaction  100.)

FIGURE 9-19 (see Color Plate) Arteritis of small and medium-sized arteries. In about one third of cases an arteritis of small and medium-size arteries also is present. The artery shows diffuse fibrinoid necrosis of the vessel wall (in red) and intraparietal and perivascular leukocyte infiltration. It is worth emphasizing that even in the presence of renal arteritis we have never found in patients with cryoglobulinemia a picture of necrotizing crescentic glomerulonephritis, now considered a specific aspect of capillaritis in primary vasculitis (antineutrophil cytoplasm antibody–associated). This finding suggets that the vasculitic damage is limited to arterial vessels of larger size. (Trichrome  100.)

RENAL SYNDROME AT PRESENTATION IN PATIENTS WITH CRYOGLOBULINEMIC GLOMERULONEPHRITIS AND ASSOCIATED HISTOLOGIC LESION Renal syndrome

Patients, %

Isolated proteinuria with microscopic hematuria, sometimes associated with moderate chronic renal insufficiency

≈55

Acute nephritic syndrome, sometimes complicated by acute oliguric renal failure

≈25

Nephrotic syndrome

≈20

Frequent histologic features Membranoproliferative glomerulonephritis (MPGN), with moderate infiltration of monocytes Lobular MPGN Mesangioproliferative glomerulonephritis MPGN with leukocytic infiltration, or intraluminal thrombi owing to abrupt massive precipitation of cryoglobulins, usually associated with renal and systemic vasculitis, or both MPGN, frequently of lobular type, with some infiltration of monocytes

FIGURE 9-20 Renal syndrome at presentation in patients with cryoglobulinemic glomerulonephritis and associated histologic lesion. During the course of this disease, both the systemic and renal signs may vary remarkably, with periods of exacerbation alternating with periods of quiescence. Very often, exacerbation of the extrarenal signs is associated with exacerbation of renal disease (recurrent episodes of nephritic or nephrotic syndrome); however, a flare-up of renal disease may occur even in the absence of exacerbation of the extrarenal signs. Partial or total prolonged remission occurs spontaneously or after treatment in 10% to 15% of patients. Arterial hypertension frequently is severe and is present in most patients with cryoglobulinemic nephropathy.

Renal Involvement in Essential Mixed Cryoglobulinemia

LABORATORY ABNORMALITIES IN ESSENTIAL MIXED CRYOGLOBULINEMIA

CLINICAL OUTCOMES OF 105 PATIENTS STUDIED IN THREE MILAN HOSPITALS FROM 1966 TO 1990

Circulating cryoglobulins Cryocrits ranging from 2% to 70%, with large variations during the course of the disease Hypocomplementemia Very low levels of early C components (C1q and C4) and CH50; slightly low levels of C3; and high levels of late C components, C5 and C9

FIGURE 9-21 Relevant laboratory abnormalities in “essential” mixed cryoglobulinemia. During the course of this disease, cryoglobulins may temporarily become undetectable. Low levels of serum C4 cannot be corrected by treatment. Low levels of C3 frequently are found during clinical flare-ups and can be corrected by treatment.

TREATMENT OF ACUTE RENAL EXACERBATIONS OF CRYOGLOBULINEMIC GLOMERULONEPHRITIS AND VASCULITIS Steriods are used to control inflammatory renal and systemic involvement Cytotoxic drugs are used to block production of new cryoglobulins by the specific lymphocytic clone that produces the monoclonal immunoglobulin Mk RF, and therefore, the precipitating cryoglobulins Plasma exchange is used to remove circulating cryoglobulins from the blood before they deposit in the glomerulus and arterial walls

PROPOSED TREATMENT FOR MIXED CRYOGLOBULINEMIA ASSOCIATED WITH HEPATITIS C VIRUS INFECTION Drug

Dosage

Duration

Interferon- Steriods

3.0–6.0 MU, 3 times weekly Methylprednisolone, 0.75–1.0 g/d, intravenously Prednisone, 0.5 mg/kg of body weight tapered over a few weeks until maintenance dose of 10–15 mg/d is achieved 2 mg/kg of body weight Exchanges of 3 L of plasma, 3 times weekly

6–12 mo 3d 6 mo

Cyclophosphamide Plasmapheresis

9.9

3–4 mo 2–3 wk

49% cumulative 10-year probability of survival, without renal failure 40% of patients died, mostly from cardiovascular diseases, liver failure, or infections 14% of patients progressed to chronic renal failure and required dialysis 14% of patients achieved complete and prolonged remission of renal symptoms

FIGURE 9-22 The clinical outcomes in 105 patients studied in three hospitals in Milan, Italy, between 1966 and 1990. The medial total follow-up time from clinical onset was approximately 11 years [19].

FIGURE 9-23 This approach to treatment of the acute renal exacerbations of cryoglobulinemia and vasculitis used previously when the viral cause of the disease was unknown is still valid now that the viral cause is evident. It is a common experience that the antiviral agent interferon-, when given alone, does not control renal complications in the acute stage of the disease [20].

FIGURE 9-24 The proposed treatment for mixed cryoglobulinemia associated with hepatitis C virus infection in the presence of severe acute signs of renal involvement, ie, glomerulonephritis and vascultits. Plasma exchange is used only when acute renal insufficiency caused by massive precipitation of cryoglobulins is present. Interferon- is given for more than 6 months only when negation of hepatitis C virus RNA is achieved in the first months, suggesting a beneficial effect on the viremia. Only the antiviral treatment with interferon- eventually associated with low doses of steriods to conrol the systemic signs of mixed cryoglobulinemias should be given if renal involvement is mild. The association of interferon- with another antiviral agent ribavirin, 0.6 to 1.0 g/d orally, now is being tested in patients with hepatitis C virus infection, with promising results [20].

9.10

Systemic Diseases and the Kidney

– Infection by HCV – Emergence of a permanent clone producing IgMk RF

B lymphocyte

IgMk RF HCV

IgG Ab Serum HCV-IgG

HCV-IgG-IgMk

Deposition of anti-HCV Precipitation of In situ binding of immune complexes the circulating HCV-IgG Ab to predeposited IgMk Glomerulus type II cryo MPGN without cryoglobulinemia Cryoglobulinemic GN

FIGURE 9-25 The mechanisms of renal complications induced by hepatitis C virus (HCV) infection, with or without associated mixed cryoglobulinemia, according to our hypothesis. As illustrated, the prevalent pathogenetic mechanism is the deposition in the glomerulus of a monoclonal IgM rheumatoid factor (RF) with particular affinity for the glomerular matrix, which is produced by permanent clones of B lymphocytes infected by HCV. It is unknown whether the IgM RF deposits in the glomerulus alone, with subsequent in situ binding of IgG (perhaps bound already to viral antigens, or as a complex composed of HCV antigens, IgG anti-HCV antibodies, and IgMk RF). Only recently have specific HCV-related proteins been detected in glomerular structures using indirect immunochemistry. As depicted on the left, it is possible that in a minority of cases immune complexes composed of HCV antigens and anti-HCV IgG antibodies can deposit directly in the glomerular structures, in the absence of a concomitant type II MC with a monoclonal IgM RF. This deposition induces an immune-complex glomerulonephritis similar to that described in patients infected with the hepatitis B virus. (Adapted from D’Amico [21].)

Acknowledgments We thank Dr. M.P. Rastaldi of the Division of Nephrology and Drs. E. Schiaffino and R. Boeri of the Department of Pathology of the Hospital of San Carlo Borromeo for their help.

References 1. Brouet JC, Clauvel JP, Danon F, et al.: Biological and clinical significance of cryoglobulins: a report of 86 cases. Am J Med 1974, 57:775–778. 2. Meltzer M, Franklin EC, Elias K, et al.: Cryoglobulinemia: a clinical and laboratory study. II. Cryoglobulins with rheumatoid factor activity. Am J Med 1966, 40:837–856. 3. Gorevic PD, Kassab HJ, Levo Y, et al.: Mixed cryoglobulinemia: clinical aspects and long-term follow-up of 40 patients. Am J Med 1980, 69:287–308. 4. D’Amico G: Cryoglobulinemic glomerulonephritis: a membranoproliferative glomerulo-nephritis induced by hepatitis C virus. Am J Kidney Dis 1995, 25:361–369. 5. Ferri C, Greco F, Longobardo G: Antibodies to hepatitis C virus in patients with mixed cryoglobulinemia. Arthritis Rheum 1991, 34:1606–1610. 6. Galli M, Monti G, Munteverde A: Hepatitis C virus and mixed cryoglobulinemias. Lancet 1992, 1:989. 7. Pechère-Bertschi A, Perrin L, De Sassure P, et al.: Hepatitis C: a possible etiology for cryoglobulinemia type II. Clin Exp Immunol 1992, 89:419–422. 8. Agnello V, Chung RT, Kaplan LM: A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 1992, 327:1490–1495. 9. Misiani R, Bellavita P, Fenili D: Hepatitis C virus and cryoglobulinemia [letter]. N Engl J Med 1993, 328:1121. 10. Pasquariello A, Ferri C, Moriconi L, et al.: Cryoglobulinemic membranoproliferative glomerulonephritis associated with hepatis C virus [letter]. Am J Nephrol 1993, 13:300–304. 11. Cacoub P, Lunel Fabiani F, Musset L, et al.: Mixed cryoglobulinemia and hepatitis C virus. Am J Med 1994, 96:124–132. 12. Bichard P, Ounanian A, Girard M, et al.: High prevalence of hepatitis C virus RNA in the supernatant and the cryoprecipitate of patients with essential and secondary type II mixed cryoglobulinemia. J Hepatol 1994, 21:58–63.

13. D’Amico G, Ferrario F, Colasanti G, Bucci A: Glomerulonephritis in essential mixed cryoglobulinemia (EMC). In Proceedings of the XXI Congress of the European Dialysis and Transplant Association. Edited by Davison PJ, Guillou PJ. London: Pitman; 1985:527–547. 14. D’Amico G, Colasanti G, Ferrario F, Sinico RA: Renal involvement in essential mixed cryoglobulinemia. Kidney Int 1989, 35:1004–1014. 15. Castiglione A, Bucci A, Fellin G, et al.: The relationship of infiltrating renal leukocytes to disease activity in lupus and cryoglobulinemic glomerulonephritis. Nephron 1988, 50:14–23. 16. Cordonnier D, Martin H, Groslambert P, et al.: Mixed IgG-IgM cryoglobulinemia with glomerulonephritis. Immunochemical fluorescent and ultrastructural study of kidney and in vitro cryoprecipitate. Am J Med 1975, 59:867–872. 17. Mazzucco G, Monga G, Casanova S, Cagnoli L: Cell interposition in glomerular capillary walls in cryoglobulinemic glomerulonephritis: ultrastructural investigation of 23 cases. Ultrastruct Pathol 1986, 10:355–361. 18. D’Amico G, Colasanti G, Ferrario F et al.: L’atteinte rénale dans la cryoglobulinémie mixte essentielle: un type particulier de néphropathie à médiation immunologique. In Actualités Néphrologiques. Edited by Flammarion Médecine Sciences; 1987:201–219. 19. Tarantino A, Campise M, Banfi G, et al.: Long-term predictors of survival in essential mixed cryoglobulinemic glomerulonephritis. Kidney Int 1995, 47:618–623. 20. D’Amico G, Fornasieri A: Cryoglobulinemia. In Current Therapy in Nephrology and Hypertension: A Companion to Brenner and Rector’s the Kidney. Edited by Brady HR, Wilcox CS. Philadelphia: WB Saunders Company; 1998 (in press). 21. D’Amico G: Is type II mixed cryoglobulinaemia an essential part of hepatitis C virus (HCV)-associated glomerulonephritis? Nephrol Dial Transplant 1995, 1279–1282.

Kidney Disease and Hypertension in Pregnancy Phyllis August

K

idney disease and hypertensive disorders in pregnancy are discussed. Pregnancy in women with kidney disease is associated with significant complications when renal function is impaired and hypertension predates pregnancy. When renal function is well preserved and hypertension absent, the outlook for both mother and fetus is excellent. The basis for the close interrelationship between reproductive function and renal function is intriguing and suggests that intact renal function is necessary for the physiologic adjustments to pregnancy, such as vasodilation, lower blood pressure, increased plasma volume, and increased cardiac output. The renal physiologic adjustments to pregnancy are reviewed, including hemodynamic and metabolic alterations. The common primary and secondary renal diseases that may occur in pregnant women also are discussed. Some considerations for the management of end-stage renal disease in pregnancy are given. Hypertensive disorders in pregnancy are far more common than is renal disease. Almost 10% of all pregnancies are complicated by either preeclampsia, chronic hypertension, or transient hypertension. Preeclampsia is of particular interest because it is associated with life-threatening manifestations, including seizures (eclampsia), renal failure, coagulopathy, and rarely, stroke. Significant progress has been made in our understanding of some of the pathophysiologic manifestations of preeclampsia; however, the cause of this disease remains unknown. The diagnostic categories of hypertension in pregnancy, pathophysiology of preeclampsia, and important principles of prevention and treatment also are reviewed.

CHAPTER

10

10.2

Systemic Diseases and the Kidney

Anatomic Changes in the Kidney During Pregnancy

Increased kidney size

Increased renal blood flow Increased glomerular filtration rate

FIGURE 10-1 Anatomic changes in the kidney during pregnancy. During pregnancy, kidney size increases by about 1 cm. More striking are the changes in the urinary tract. The calyces, renal pelvis, and ureters dilate. The dilation is more marked on the right side than the left and is apparent as early as the first trimester. Hormonal mechanisms and mechanical obstruction are responsible. Intravenous pyelography may demonstrate the iliac sign in which ureteral dilation terminates at the level of the pelvic brim where the ureter crosses the iliac artery. Ureteral dilation and urinary stasis contribute to the increased incidence of asymptomatic bacteriuria and pyelonephritis in pregnancy.

Dilation of urinary tract

Changes in Renal Function During Pregnancy ↓ Uric acid reabsorption

↑ Renin

Renal vasodilation ↑ Glomerular filtration rate ↑ Renal blood flow ↓ Serum creatinine ↑ Urinary protein

↑ Aldosterone ↑ Sodium reabsorption ↑ Water reabsorption ↑ Urinary calcium ↑ Glucosuria ↑ Aminoaciduria

FIGURE 10-2 Changes in renal function during pregnancy. Marked renal hemodynamic changes are apparent by the end of the first trimester. Both the glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) increase by 50%. ERPF probably increases to a greater extent, and thus, the filtration fraction is decreased during early and mid pregnancy. Micropuncture studies performed in animals suggest the basis for the increase in GFR is primarily the increase in glomerular plasma flow [1]. The average creatinine level and urea nitrogen concentration are slightly lower than in pregnant women than in those who are not pregnant (0.5 mg/d and 9 mg/dL, respectively). The increased filtered load also results in increased urinary protein excretion, glucosuria, and aminoaciduria. The uric acid clearance rates increase to a greater extent than does the GFR. Hypercalciuria is a result of increased GFR and of increases in circulating 1,25-dihydroxy-vitamin D3 in pregnancy (absorptive hypercalciuria). The renin-angiotensin system is stimulated during gestation, and cumulative retention of approximately 950 mEq of sodium occurs. This sodium retention results from a complex interplay between natriuretic and antinatriuretic stimuli present during gestation [2].

10.3

Kidney Disease and Hypertension in Pregnancy

Serum Electrolytes in Pregnancy A Altered osmoregulation:

B Serum chloride levels are

↓ Serum sodium and ↓ Posm with ↓ Osmotic Threshold for the argenine vasopressin release and thirst

unchanged compared with women who are not pregnant

Na+ 136 mEq/L

Cl104 mEq/L

3.7 mEq/L K+

20 mEq/L HCO3

C Mild hypokalemia may be

D Mild respiratory alkalosis is

observed due to ↑ glomerular filtration rate, ↑ urine flow, and ↑ aldosterone

FIGURE 10-3 Serum electrolytes in pregnancy. A, During normal gestation, serum osmolality decreases by 10 mosm/L and serum sodium (Na+) decreases by 5 mEq/L. A resetting of the osmoreceptor system occurs, with decreased osmotic thresholds for both thirst and vasopressin release [3]. B, Serum chloride (Cl-) levels essentially are unchanged during pregnancy. C, Despite significant increases in aldosterone levels during pregnancy, in most women serum potassium (K+) levels are either normal or, on average, 0.3 mEq/L lower than are values in women who are not pregnant [4]. The ability to conserve potassium may be a result of the elevated progesterone in pregnancy [5]. D, Arterial pH is slightly increased in pregnancy owing to mild respiratory alkalosis. The hyperventilation is believed to be an effect of progesterone. Plasma bicarbonate (HCO-3) concentrations decrease by about 4 mEq/L [6].

associated with small decreases in plasma bicarbonate

Blood Pressure and the Renin-Aldosterone System in Pregnancy 120

14 12 PRA, ng/mL/h

Blood pressure, mmHg

110 100 90

Sitting Standing

80

*

10 8 6

70

4

**

60

2

*

(N)

50 4

A

PRA Postpartum angiotensinogen values

8

12

16

20

24

28

32

36

40

4

PP

Gestation, wk

FIGURE 10-4 Blood pressure and the renin-aldosterone system in pregnancy. Normal pregnancy is associated with profound alterations in cardiovascular and renal physiology. These alterations are accompanied by striking adjustments of the renin-angiotensinaldosterone system. A, Blood pressure and peripheral vascular resistance decrease during normal gestation. The decrease in blood pressure is apparent by the end of the first trimester of

0

B

* *

** *

(7)

(16)

(18) (18) (18) (19) (18) (18)(15)

(19)

8

12

16

PP

20

24

28

32

36 38

Gestation, wk

pregnancy and often approaches prepregnancy levels at term. B, Despite the decrease in blood pressure, plasma renin activity (PRA) increases during the first few weeks of pregnancy; on average, close to a fourfold increase in PRA occurs by the end of the first trimester, with additional increases until at least 20 weeks. The source of the increased renin is thought to be the maternal renal release of renin. (Continued on next page)

10.4

Systemic Diseases and the Kidney

Urine aldosterone Plasma aldosterone

Urine sodium Urine potassium

200

120

C

100

80

80

60

60

40

40

20

20

0

0

FIGURE 10-4 (Continued) C, Changes in renin are associated with commensurate changes in the secretory rate of aldosterone. Although a correlation exists between the increase in renin and that of aldosterone, the latter increases to a greater degree in late pregnancy. This observation suggests that other factors may regulate secretion to a greater degree than does angiotensin II in late gestation. Urinary aldosterone

24-hr Na+ and K+, mEq

100

Plasma aldosterone, ng/100mL

Urine aldosterone, µg/d

150

100

50

0 8

D

12

16

20

24

28

32

36

38

PP

Gestation, wk

increases in late gestation to a greater degree than does plasma aldosterone, which may reflect an increased production of the 3-oxo conjugate measured in urine. D, Despite the marked increases in aldosterone during pregnancy, 24-hour urinary sodium and potassium excretion remain in the normal range. PP— postpartum. (From Wilson and coworkers [7]; with permission.)

Functional Significance of the Stimulated Renin-Angiotensin System in Pregnancy 85

25

80

20

75 70 P < 0.005 *

65

PRA, mg/mL/h

MAP, mm Hg

Pregnant (n = 9) Nonpregnant (n = 8)

10 5

60

A

* P < .05

15

0 T=0

T = 60

B

T=0

T = 60

FIGURE 10-5 Functional significance of the stimulated renin-angiotensin system (RAS) in pregnancy. We determine whether changes in the RAS in pregnancy are primary, and the cause of the increase in plasma volume, or whether these changes are secondary to the vasodilation and changes in blood pressure. To do so, we administered a single dose of captopril to normotensive pregnant women in their first and second trimesters and age-matched normotensive women who were not pregnant. We then measured mean arterial pressure (MAP) and plasma renin activity (PRA) before and 60 minutes after the dose. A, Despite similar baseline blood pressures, blood pressure decreased more in pregnant women compared with those who were not pregnant in response to captopril. This observation suggests that the RAS plays a greater role in supporting blood pressure in pregnancy. B, Baseline PRA was higher in pregnant women compared with those who were not pregnant, and pregnant women had a greater increase in renin after captopril compared with those who were not pregnant. T—time. (From August and coworkers [8]; with permission.)

Kidney Disease and Hypertension in Pregnancy

10.5

Pregnancy and the Course of Renal Disease INTERRELATIONSHIPS BETWEEN PREGNANCY AND RENAL DISEASE Impact of pregnancy on renal disease

Impact of renal disease on pregnancy

Hemodynamic changes → hyperfiltration Increased proteinuria Intercurrent pregnancy-related illness, eg, preeclampsia Possibility of permanent loss of renal function

Increased risk of preeclampsia Increased incidence of prematurity, intrauterine growth retardation

FIGURE 10-6 Pregnancy may influence the course of renal disease. Some women with intrinsic renal disease, particularly those with baseline azotemia and hypertension, suffer more rapid deterioration in renal function after gestation. In general, as kidney disease progresses and function deteriorates, the ability to sustain a healthy pregnancy decreases. The presence of hypertension greatly increases the likelihood of renal deterioration [2]. Although hyperfiltration (increased glomerular filtration rate) is a feature of normal pregnancy, increased intraglomerular pressure is not a major concern because the filtration fraction decreases. Possible factors related to the pregnancy-related deterioration in renal function include the gestational increase in proteinuria and intercurrent pregnancy-related illnesses, such as preeclampsia, that might cause irreversible loss of renal function. Women with renal disease are at greater risk for complications related to pregnancy such as preeclampsia, premature delivery, and intrauterine growth retardation.

Diabetes Mellitus and Pregnancy RENAL DISEASE CAUSED BY SYSTEMIC ILLNESS Gestation in pregnant women with diabetic nephropathy is complicated by the following: Increased proteinuria, 70% Decreased creatinine clearance, 40% Increased blood pressure, 70% Preeclampsia, 35% Fetal developmental problems, 20% Fetal demise, 6%

FIGURE 10-7 Diabetes mellitus is a common disorder in pregnant women. Patients with overt nephropathy are likely to develop increased proteinuria and mild but usually reversible deteriorations in renal function during pregnancy. Hypertension is common, and preeclampsia occurs in 35% of women. (From Reece and coworkers [9]; with permission.)

10.6

Systemic Diseases and the Kidney

Pregnancy and Systemic Lupus Erythematosus RENAL DISEASE ASSOCIATED WITH SYSTEMIC ILLNESS Pregnancy and SLE*

Antiphospholipid antibody syndrome in pregnancy

Poor outcome is associated with the following: Active disease at conception Disease first appearing during pregnancy Hypertension, azotemia in the first trimester High titers of antiphospholipid antibodies or lupus anticoagulant

Increased fetal loss Arterial and venous thromboses Renal vasculitis, thrombotic microangiopathy Preeclampsia Treatment: heparin and aspirin?

*Systemic lupus erythematosus (SLE) is unpredictable during pregnancy.

FIGURE 10-8 Patients with systemic lupus erythematosus (SLE) often are women in their childbearing years. Pregnancies in women with evidence of nephritis are potentially hazardous, particularly if active disease is present at the time of conception or if the disease first develops during pregnancy. When hypertension and azotemia are present at the time of conception the risk of complications increases, as it does with other nephropathies [10–14]. The presence of high titers of antiphospholipid antibodies also is associated with poor pregnancy outcome [15]. The presence of antiphospholipid antibodies or the lupus anticoagulant is associated with increased fetal loss, particularly in the second trimester; increased risk of arterial and venous thrombosis; manifestations of vasculitis such as thrombotic microangiopathy; and an increased risk of preeclampsia. Treatment consists of anticoagulation with heparin and aspirin.

Lupus Versus Preeclampsia LUPUS FLARE-UP VERSUS PREECLAMPSIA

Proteinuria Hypertension Erythrocyte casts Azotemia Low C3, C4 Abnormal liver function test results Low platelet count Low leukocyte count

SLE

PE

+ + + + + + +

+ + + +/+/-

C—complement; minus sign—absent; plus sign—present; PE—preeclampsia; SLE—systemic lupus erythematosus.

FIGURE 10-9 In the second or third trimester of pregnancy a clinical flare-up of lupus may be difficult to distinguish from preeclampsia. Treatment of a lupus flare-up might involve increased immunosuppression, whereas the appropriate treatment of preeclampsia is delivery. Thus, it is important to accurately distinguish these entities. Preeclampsia is rare before 24 weeks’ gestation. Erythrocyte casts and hypocomplementemia are more likely to be a manifestation of lupus, whereas abnormal liver function test results are seen in preeclampsia and not usually in lupus.

Kidney Disease and Hypertension in Pregnancy

10.7

Chronic Primary Renal Disease in Pregnancy CAUSES OF CHRONIC PRIMARY RENAL DISEASE IN PREGNANCY

FIGURE 10-10 Primary renal disease in pregnancy that is chronic (ie, preceded pregnancy) may result from any of the causes of renal disease in premenopausal women. Overall, the outcome in pregnancy is favorable when the serum creatinine level is less than 1.5 mg/dL and blood pressure levels are normal in early pregnancy.

Anatomic, congenital Glomerulonephritis Interstitial nephritis Polycystic kidney disease

Advanced Renal Disease Caused by Polycystic Kidney Disease POLYCYSTIC KIDNEY DISEASE AND PREGNANCY Increased incidence of urinary tract infection Maternal hypertension associated with poor outcome Extrarenal complications: subarachnoid hemorrhage, liver cysts

FIGURE 10-11 Although advanced renal disease caused by polycystic kidney disease (PKD) usually develops after childbearing, women with this condition may have hypertension or mild azotemia. Certain considerations are relevant to pregnancy. Pregnancy is associated with an increased incidence of asymptomatic bacteriuria and urinary infection that may be more severe in women with PKD. The presence of maternal hypertension has been shown to be associated with adverse pregnancy outcomes [16]. Pregnancy has been reported to be associated with increased size and number of liver cysts owing to estrogen stimulation. Women with intracranial aneurysms may be at increased risk of subarachnoid hemorrhage during labor.

Management of Chronic Renal Disease During Pregnancy MANAGEMENT OF CHRONIC RENAL DISEASE DURING PREGNANCY Preconception counseling Multidisciplinary approach Frequent monitoring of blood pressure (every 1–2 wk) and renal function (every mo) Balanced diet (moderate sodium, protein) Maintain blood pressure at 120–140/80–90 mm Hg Monitor for signs of preeclampsia

FIGURE 10-12 Management of chronic renal disease during pregnancy is best accomplished with a multidisciplinary team of specialists. Preconception counseling permits the explanation of risks involved with pregnancy. Patients should understand the need for frequent monitoring of blood pressure and renal function. Protein restriction is not advisable during gestation. Salt intake should not be severely restricted. When renal function is impaired, modest salt restriction may help control blood pressure. Blood pressure should be maintained at a level at which the risk of maternal complications owing to elevated blood pressure is low. Patients should be monitored closely for signs of preeclampsia, particularly in the third trimester.

10.8

Systemic Diseases and the Kidney

Renal Disease During Pregnancy MOST COMMON CAUSES OF DE NOVO RENAL DISEASE IN PREGNANCY Glomerulonephritis Lupus nephritis Acute renal failure

Interstitial nephritis Obstructive uropathy

FIGURE 10-13 Renal disease may develop de novo during pregnancy. The usual causes are new-onset glomerulonephritis or interstitial nephritis, lupus nephritis, or acute renal failure. Rarely, obstructive uropathy develops as a result of stone disease or large myomas that have increased in size during pregnancy.

Investigation of the Cause of Renal Disease During Pregnancy RENAL EVALUATION DURING PREGNANCY Serology Function Ultrasonography Biopsy: <32 wk Deteriorating function Morbid nephrotic syndrome

FIGURE 10-14 Investigation of the cause of renal disease during pregnancy can be conducted with serologic, functional, and ultrasonographic testing. Renal biopsy is rarely performed during gestation. Renal biopsy usually is reserved for situations in which renal function suddenly deteriorates without apparent cause or when symptomatic nephrotic syndrome occurs, particularly when azotemia is present. Almost no role exists for renal biopsy after gestational week 32 because at this stage the fetus will likely be delivered, independent of biopsy results [17].

New-Onset Azotemia, Proteinuria, and Hypertension Occurring in the Second Half of Pregnancy INTRINSIC RENAL DISEASE VERSUS PREECLAMPSIA

Serum creatinine Urinary protein Uric acid Blood pressure Liver function test results Platelet count Urine analysis

Renal disease

Preeclampsia

>1.0 mg/dL Variable Variable Variable Normal Normal Variable

0.8–1.2 mg/dL >300 mg/d >5.5 mg/dL >140/90 mm Hg May be increased May be decreased Protein, with or without erythrocytes, leukocytes

FIGURE 10-15 New-onset azotemia, proteinuria, and hypertension occurring in the second half of pregnancy should be distinguished from preeclampsia. Most cases of preeclampsia are associated with only mild azotemia; significant azotemia is more suggestive of renal disease. Azotemia in the absence of proteinuria or hypertension would be unusual in preeclampsia, and thus, would be more suggestive of intrinsic renal disease. Thrombocytopenia, elevated liver function test results, and significant anemia are not typical features of renal disease (except for thrombotic microangiopathic syndromes) and are features of the variant of preeclampsia known as the hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome.

Kidney Disease and Hypertension in Pregnancy

10.9

Acute Tubular Necrosis and Pregnancy ACUTE RENAL FAILURE IN PREGNANCY Acute tubular necrosis; hemodynamic factors, toxins, serious infection, and so on Acute interstitial nephritis Acute fatty liver of pregnancy Preeclampsia-HELLP syndrome Microangiopathic syndromes Acute cortical necrosis: obstetric hemorrhage

FIGURE 10-16 Most pregnant women with acute renal failure have acute tubular necrosis secondary to either hemodynamic factors, toxins, or serious infection. Occasionally, glomerulonephritis or obstructive nephropathy may be seen. Acute cortical necrosis may complicate severe obstetric hemorrhage. Acute renal failure may be a complication of the rare syndrome of acute fatty liver of pregnancy, a disorder that occurs late in gestation characterized by jaundice and severe hepatic dysfunction. This syndrome has features that overlap with the hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome variant of preeclampsia as well as microangiopathic syndromes (eg, hemolytic uremic syndrome and thrombotic thrombocytopenic purpura).

HELLP—hemolysis, elevated liver enzymes, and low platelet count.

HELLP Syndrome, AFLP, TTP, and HUS DIFFERENTIAL DIAGNOSIS OF MICROANGIOPATHIC SYNDROMES DURING PREGNANCY

Hypertension Renal insufficiency Fever, neurologic symptoms Onset Platelet count Liver function test results Partial thromboplastin time Antithrombin III

HELLP

AFLP

TTP

HUS

80% Mild to moderate 0

25–50% Moderate 0

Occasional Mild to moderate ++

Present Severe 0

3rd trimester Low to very low High to very high

Any time Low to very low Usually normal

Postpartum Low to very low Usually normal

Normal to high

3rd trimester Low to very low High to extremely high High

Normal

Normal

Low

Low

Normal

Normal

AFLP—acute fatty liver of pregnancy; HELLP—hemolysis, elevated liver enzymes, and low platelet count; HUS–hemolytic uremic syndrome; TTP—thrombotic thrombocytopenic purpura. Adapted from Saltiel et al. [18].

FIGURE 10-17 Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome; acute fatty liver of pregnancy (AFLP); thrombotic thrombocytopenic purpura (TTP); and hemolytic uremic syndrome (HUS) have similar clinical and laboratory features [18,19]. The subtle differences are summarized. (Adapted from Saltiel and coworkers [18].)

10.10

Systemic Diseases and the Kidney

Fertility in Women in End-Stage Renal Disease DIALYSIS AND PREGNANCY Successful outcome, 20–30% High incidence of prematurity Outcome related to residual maternal renal function Management: Increased hours on dialysis Erythropoietin therapy Blood pressure control Therapy with low doses of heparin Continuous ambulatory peritoneal dialysis versus hemodialysis ?

FIGURE 10-18 Because fertility is decreased in end-stage renal disease, pregnancy is uncommon in women on chronic dialysis. When pregnancies occur, however, only about 20% to 30% are successful, with the chances of success increasing when residual renal function exists [20]. The overall strategy should be to maintain blood chemistry levels as close as possible to normal by increasing the number of hours of dialysis to 20 or more. Erythropoietin may be used in pregnancy. Blood pressure control is important, and low doses of heparin should be used to prevent bleeding. There are no apparent advantages of chronic ambulatory peritoneal dialysis compared with hemodialysis. The incidence of worsening maternal hypertension and subsequent premature delivery is high.

Fertility and Renal Transplantation FIGURE 10-19 Fertility is restored after successful renal transplantation. Pregnancy outcome is improved if renal function is normal and hypertension is absent. It is advisable to wait 2 years after transplantation before pregnancy so that renal function is stable and doses of immunosuppressants are lowest [21]. Cyclosporine, prednisone, and azathioprine are safe during pregnancy and are not associated with fetal abnormalities. Limited experience exists with mycophenolate mofetil during pregnancy.

RENAL TRANSPLANTATION AND PREGNANCY Prognosis depends on blood pressure and baseline renal function (<1.5–2 mg/dL; normal blood pressure) Controversy over whether pregnancy accelerates graft loss Patients are advised to wait 2 y after transplantation before pregnancy

Hypertensive Disorders in Pregnancy Developing nations

Developed nations Sepsis 8%

Hemorrhage 20% Sepsis 40%

HTN 15% Other 25%

100–800/100,000 (deaths, births)

Embolism 20% Abortion 17%

Other 25% HTN 17%

Hemorrhage 13% 12/100,000 (deaths, births)

FIGURE 10-20 Mortality and hypertension. Worldwide, hypertensive disorders are a major cause of maternal mortality, accounting for almost 20% of maternal deaths. Most deaths occur in women with eclampsia and severe hypertension (HTN) and are due to intracerebral hemorrhage [22].

Kidney Disease and Hypertension in Pregnancy

FETAL CONSEQUENCES OF MATERNAL HYPERTENSION DURING PREGNANCY

CLASSIFICATION OF HYPERTENSIVE DISORDERS IN PREGNANCY

3- to 6-fold increase in stillbirths 5- to 15-fold increase in intrauterine growth restriction Premature delivery Long-term developmental and neurologic problems

Preeclampsia, eclampsia Chronic hypertension Chronic hypertension with superimposed preeclampsia Transient hypertension

FIGURE 10-21 Hypertensive disorders in pregnancy are associated with increased incidences of stillbirth, fetal growth restriction, premature delivery, and long-term developmental problems secondary to prematurity. These complications are more frequent when hypertension is due to preeclampsia.

FIGURE 10-22 Several classification systems exist for hypertensive disorders of pregnancy. The one used most commonly in the United States is that proposed in 1972 by the American College of Obstetricians and Gynecologists and endorsed by the National High Blood Pressure Education Program. The distinction is made between the pregnancy-specific hypertensive disorder (preeclampsia, and the convulsive form, eclampsia) and chronic hypertension that precedes pregnancy, which usually is due to essential hypertension. Women with chronic hypertension are at greater risk for preeclampsia (20–25%). Transient hypertension refers to late pregnancy elevations in blood pressure, without any of the laboratory or clinical features of preeclampsia. This disorder may recur with each pregnancy (in contrast to preeclampsia, which usually is a disease of first pregnancy) and usually indicates a genetic predisposition to essential hypertension.

CLINICAL FEATURES OF CHRONIC HYPERTENSION IN PREGNANCY Women are older, more likely to be multiparous Hypertension: present before 20 wk, or documented previous pregnancy Blood pressure may be significantly lower or normal in mid pregnancy Risk of superimposed preeclampsia of 15–30%

10.11

CLINICAL FEATURES OF PREECLAMPSIA Historical: Nulliparity Multiple gestations Family history Preexisting renal or vascular decrease Hypertension: 140/90 mm Hg after 20 wk or 30 mm Hg increase in systolic pressure or 15 mm Hg increase in diastolic pressure Sudden appearance of edema, especially in hands and face Rapid weight gain Headache, visual disturbances, abdominal or chest pain

FIGURE 10-23 The diagnosis of preeclampsia is strengthened when one or more of the risk factors are present. Hypertension develops after 20 weeks, with normal blood pressures in the first half of pregnancy. Although edema is a feature of many normal pregnancies, its sudden appearance in the face and hands in association with a rapid weight gain, is suggestive of preeclampsia. Headache, visual disturbances, and abdominal or chest pain are signs of impending eclampsia.

FIGURE 10-24 Women with chronic hypertension are usually older and may be multiparous. Although hypertension often is detectable before 20 weeks, in some women the pregnancy-mediated vasodilation is sufficient to normalize blood pressure so that women with stage 1 or 2 hypertension may have normal blood pressures by the time of their first antepartum visit. The risk of preeclampsia is substantially increased in women with chronic hypertension.

10.12

Systemic Diseases and the Kidney

LABORATORY ABNORMALITIES IN PREECLAMPSIA AND CHRONIC HYPERTENSION

Renal: Creatinine

Uric acid Urinary protein Urinary calcium Heme: Hematocrit Platelets Liver function tests: Aspartate aminotransferase Alanine aminotransferase Albumin

Chronic hypertension

Preeclampsia

Normal

Normal <300 mg/d >200 mg/d

Increased; increased blood urea nitrogen, creatinine Increased (>5.5 mg/dL) >300 mg/d <150 mg/d

Normal Normal

Increased (>38%) Decreased

Normal Normal Normal

Increased Increased Decreased

Pathophysiology of preeclampsia

Fetal syndrome (IUGR, IUD, prematurity)

Maternal syndrome (HTN, renal, CNS)

Maternal disease Vasoplasm Intravascular coagulation Endothelial dysfunction

Placental disease Abdominal implantation Placental vascular lesions

Genetic susceptibility (maternal x fetal)

FIGURE 10-25 Laboratory tests are helpful in making the diagnosis of preeclampsia. In addition to proteinuria, which may occur late in the course of the disease, hyperuricemia, mild azotemia, hemoconcentration, and hypocalciuria are observed commonly. Some women with preeclampsia may develop a microangiopathic syndrome with hemolysis, elevated liver enzymes, and low platelet counts (HELLP). The presence of the HELLP syndrome usually reflects severe disease and is considered an indication for delivery. Women with uncomplicated chronic hypertension have normal laboratory test results unless superimposed preeclampsia or underlying renal disease exists.

FIGURE 10-26 Preeclampsia is a syndrome with both maternal and fetal manifestations. Current evidence suggests that an underlying genetic predisposition leads to abnormalities in placental adaptation to the maternal spiral arteries that supply blood to the developing fetoplacental unit. These abnormalities in the maternal spiral arteries lead to inadequate perfusion of the placenta and may be the earliest changes responsible for the maternal disease. The maternal disease is characterized by widespread vascular endothelial cell dysfunction, resulting in vasospasm and intravascular coagulation and, ultimately, in hypertension (HTN), renal, hepatic, and central nervous system (CNS) abnormalities. The fetal syndrome is a consequence of inadequate placental circulation and is characterized by growth restriction and, rarely, demise. Premature delivery may occur in an attempt to ameliorate the maternal condition. IUD— intrauterine death; IUGR—intrauterine growth retardation.

10.13

Kidney Disease and Hypertension in Pregnancy

FIGURE 10-27 A positive family history is a risk factor for preeclampsia, and the incidence is approximately 4 times greater in first-degree relatives of index cases [23]. Cooper and coworkers [24] also noted an increased incidence in relatives by marriage (eg, daughter-in-laws), and 10 instances in which the disease occurred in one but not the other monozygotic twin. These data raise the possibility of paternal or fetal genetic influence [24]. The mode of inheritance of preeclampsia is not known. Several possibilities have been suggested, including a recessive gene with the possibility of a maternal-fetal genotype-by-genotype interaction or a dominant maternal gene with incomplete penetrance.

GENETICS OF PREECLAMPSIA Increased incidence observed in mothers, daughters, granddaughters of probands Mode of inheritance unknown: Single recessive gene ? Shared maternal-fetal recessive gene ? Dominant gene with incomplete penetrance ?

Normal pregnancy

Preeclampsia

A

Fetus (placenta)

B Myometrium

Spiral arteries

Cytotrophoblast stem cells

Decidua

Mother (uterus)

Cell column of anchoring villus

AV Fetal

Uterine blood vessels

stroma

Basement membrane

Syncytiotrophoblast

FV

Maternal blood space Invasion

Zone I

Zone II and III

Zone IV

Zone V

A Umbilical artery Villus (containing fetal arteriole and venule)

Intervillus space (maternal blood)

Umbilical vein

FIGURE 10-28 Uteroplacental circulation in normal pregnancy and preeclampsia. A, Normal placentation involves the transformation of the branches of the maternal uterine arteries—the spiral arteries—from thickwalled muscular arteries into saclike flaccid vessels that permit delivery of greater volumes of blood to the uteroplacental unit. B, Evidence exits that in women with preeclampsia this process is incomplete, resulting in relatively narrowed spiral arteries and decreased perfusion of the placenta [25].

FIGURE 10-29 Transformation of the spiral arteries. A, The process by which the maternal spiral arteries are transformed into dilated vessels in pregnancy is believed to involve invasion of the spiral arterial walls by endovascular trophoblastic cells. These cells migrate in retrograde fashion, involving first the decidual and then the myometrial segments of the arteries and then causing considerable disruption at all layers of the vessel wall. The mechanisms involved in this complex process are only beginning to be elucidated. These mechanisms involve alterations in the adhesion molecules of the invading trophoblast cells, such that they acquire an invasive phenotype and mimic vascular endothelial cells [26]. (Continued on next page)

10.14

Systemic Diseases and the Kidney

(b) CTBs

(a)

Endothelium Tunica media

Fully modified region

B

Partially modified region Decidua

(c)

Unmodified region Myometrium

Placental ischemia

Lipid peroxides Cytokines

Endothelial cell damage

Platelet aggregation

Thromboxane A2 ↑ Serotonin, PDGF ↑ PGI2 ↓ NO ↓ Endothelin ↑ Mitogenic factors↑ (eg, PDGF)

Systemic vasoplasm ↓ Organ flow Intravascular coagulation

Thrombin ↑

FIGURE 10-29 (Continued) B, In women destined to develop preeclampsia, trophoblastic invasion of the spiral arteries is incomplete; it may occur in the decidual but not the myometrial segments of the artery, and in some vessels the process does not occur at all. The arteries, therefore, remain thick-walled and muscular, the diameters in the myometrial segments being half those measured during normal pregnancy. Recently, it has been reported that in preeclampsia the invading cytotrophoblasts fail to properly express adhesion receptors necessary for normal remodeling of the maternal spiral arteries [27]. This failure of cytotrophoblast invasion of the spiral arteries is considered to be the morphologic basis for decreased placental perfusion in preeclampsia. (a)—fully modified regions. (b)—partially modified vessel segments. (c)—unmodified vessel segments in the myometrium. AV–anchoring villus; CTBs—cytotrophoblast cells; FV—floating villi. (From Zhou and coworkers [27]; with permission.)

FIGURE 10-30 Pathophysiology of preeclampsia. A major unresolved issue in the pathophysiology of preeclampsia is the mechanism whereby abnormalities in placental modulation of the maternal circulation lead to maternal systemic disease. The current schema, which is a hypothesis, depicts a scenario whereby placental ischemia leads to the release of substances that might be toxic to maternal endothelial cells. The resulting endothelial cell dysfunction also results in increased platelet aggregation. These events lead to the widespread systemic vasospasm, intravascular coagulation and decreased organ flow that are characteristic of preeclampsia. NO—nitric oxide; PDGF—platelet-derived growth factor; PGI2—prostacyclin 2.

Kidney Disease and Hypertension in Pregnancy

10.15

Central nervous sytem

Visual disturbances Seizures Hyperemia, focal anemia Thrombosis, hemorrhage

Cardiac ↓ Cardiac output ↓ Plasma volume ↑ Atrial natriuretic factor Pulmonary edema

Hepatic Periportal hemorrhagic necrosis Subcapsular hematoma ↑ Aspartate aminotransferase ↑ Alanine aminotransferase

Vasospasm Reduced flow Intravascular coagulation Vascular ↑ Systemic vascular resistance ↑ Blood pressure ↑ Angiotensin II sensitivity Renal

Endotheliosis Proteinuria ↓ Glomerular filtration rate ↓ Renal blood flow ↓ Urinary sodium, uric acid, and calcium excretion ↓ Plasma renin activity

FIGURE 10-31 Maternal manifestations of preeclampsia. Preeclampsia is a multisystem maternal disorder, with dramatic alterations in heart, kidney, circulation, liver, and brain. Interestingly, all of these abnormalities resolve within a few weeks of delivery.

10.16

Systemic Diseases and the Kidney

↓ Placental hormones (eg, estrogen, progesterone)

The endothelium and platelet-vessel wall interaction Endothelial cells

Thr

Platelets

+

+

PThr cGMP

− TXA2 5-HT

↑ Circulating endothelial toxins

S NO/PGl2 1

Relaxation Antiproliferation

↑ Sympathetic nervous system Vascular smooth muscle cells

cGMP/cAMP

AII

5-HT

Compensatory responses: ↓ Plasma renin ↓ Aldosterone

A

Endothelin Contraction Proliferation S2 TX ET

FIGURE 10-32 Hypertension in preeclampsia. Although the mechanism of the increased blood pressure in preeclampsia is not established, evidence suggests it may involve multiple processes. A possible scenario involves the following: decreased placental production of estrogen and progesterone, both of which have hemodynamic effects; increased circulating endothelial toxins, possibly released from a poorly perfused placenta; and increased activity of the sympathetic nervous system. These processes may then result in alterations in platelet– vascular endothelial cell function, with decrease in vasodilators such as nitric oxide and prostacyclin and increased production

of vasoconstrictors such as endothelin (ET). Compensatory suppression of the reninangiotensin system occurs, suggesting that excess angiotensin II (AII) does not play a major role in preeclamptic hypertension (HT). Finally, sodium retention owing to renal vasoconstriction may further increase blood pressure. cAMP—cyclic adenosine monophosphate; cGMP— cyclic guanosine monophosphate; 5-HT— serotonin; PThr— parathyroid hormone; S2—serotonergic receptors; Thr—thombin TX— thromboxane; TXA2— thromboxane A2. (Adapted from Lüscher and Dubey [28]; with permission.)

↓ Renin

↑ Proteinuria ↓ Renal vasodilation ↓ Glomerular filtration rate ↓ Renal blood flow

FIGURE 10-33 Light microscopy of the renal lesion of preeclampsia: glomerular endotheliosis. On light microscopy, the glomeruli from preeclamptic women are characterized by swelling of the endothelial and mesangial cells. This swelling results in obliteration of the capillary lumina, giving the appearance of a bloodless glomerulus. On occasion, the mesangium, severely affected, may expand. Thrombosis and fibrinlike material and foam cells may be present, and epithelial crescents have been described in rare instances [2].

↓ Urinary calcium Hypocalciuria ↓ Urate excretion

FIGURE 10-34 Functional renal alterations in preeclampsia. The functional consequences of glomerular endotheliosis and of the hormonal alterations in preeclampsia are summarized in this schematic diagram of the nephron in preeclampsia. Suppression of the reninangiotensin system occurs, probably in response to vasoconstriction and elevated blood pressure. The glomerular lesion leads to proteinuria, which may be heavy. Renal hemodynamic changes include modest decreases in the glomerular filtration rate (GFR) and renal blood flow (RBF). Decreased sodium and uric acid excretion may be caused by increased proximal tubular reabsorption. The mechanism for the marked hypocalciuria is not known.

Kidney Disease and Hypertension in Pregnancy

Control Odds ratio and 95% Cl (horizontal line) therapy (antiplatelet: placebo)

Trial

Number of trials

Antiplatelet therapy

Smaller studies (<200 women)

11

10/319 (3.1%)

50/284 (17.6%)

5/156 5/303 12/565 69/1570 9/103) 313/4659

8/74 17/303 9/477 94/1565 11/105) 352/4650

Larger studies: EPHREDA (1990) Hauth (1993) Italian (1993) Sibai (1993) Viinikka (1993) CLASP (1994) All larger trials

6

413/7356

491/7174

All trials

17

423/7675 (5.5%)

541/7458 (7.3%)

Odds ratio Overall results 25% SD 6 odds reduction (2p = 0.00002)

0 0.5 1.0 1.5 Antiplatelet therapy better

Favors calcium

Study Marya et al.,1987 Villar et al.,1987 Lopez-Jaramillo et al.,1989 Lopez-Jaramillo et al.,1990 Montanaro et al.,1990 Villar and Repke,1990 Belizan et al.,1991 Cong et al.,1993 Sanchez-Ramos et al.,1994 Pooled estimate 0.001

Antiplatelet therapy worse

Favors control

0.65 (0.31–1.38) 0.43 (0.06–3.14) 0.03 (0.002–0.49) 0.07 (0.004–1.27) 0.25 (0.06–1.03) 0.13 (0.007–2.65) 0.66 (0.34–1.27) 0.19 (0.009–4.10) 0.22 (0.07–0.74) 0.38 (0.22–0.65) 0.01

0.1 OR

1.0

10.0

10.17

FIGURE 10-35 Prevention of preeclampsia with low-dose aspirin. Investigators have sought methods to prevent preeclampsia (eg, salt restriction, prophylactic diuretics, and high-protein diets). One approach that has been extensively investigated in the last 10 years is therapy with low-dose aspirin. It was hypothesized that such therapy reversed the imbalance between prostacyclin and thromboxane that may be responsible for some of the manifestations of the disease. Several large trials now have been completed, and most have had negative results. Shown here is an overview of the effects of aspirin on proteinuric preeclampsia reported from all trials of antiplatelet therapy (through 1994) as analyzed by the Collaborative Low-dose Aspirin in Pregnancy (CLASP) Collaborative Group [28]. Odds ratios (area proportional to amount of information contributed) and 99% confidence interval (CI) are plotted for various trials. A black square to the left of the solid vertical line suggests a benefit (however, this indication is significant at 2p >0.01 only if the entire CI is to the left of solid vertical line). (From CLASP Collaborative Group [29]; with permission.) FIGURE 10-36 Prevention of preeclampsia using calcium supplementation. Another preventive strategy that has been extensively investigated, with conflicting outcomes, is calcium supplementation. The rationale for this approach is based on the observations that low dietary calcium intake may increase the risk for preeclampsia, and that preeclampsia is characterized by abnormalities in calcium metabolism that suggest a calcium deficit, eg, decreased vitamin D and hypocalciuria [31]. A recent meta-analysis of 14 trials of calcium supplementation in pregnancy concluded that calcium supplementation during pregnancy leads to reductions in blood pressure and a lower incidence of preeclampsia. In contrast, a large randomized trial of calcium supplementation in 4589 low-risk women failed to demonstrate a benefit of calcium therapy [31]. CI—confidence interval; OR—odds ratio. (From Bucher and coworkers [30]; with permission.)

10.18

Systemic Diseases and the Kidney

TREATMENT OF PREECLAMPSIA Close monitoring of maternal and fetal conditions Hospitalization in most cases Lower blood pressure for maternal safety Seizure prophylaxis with magnesium sulfate Timely delivery

ANTIHYPERTENSIVE THERAPY IN PREECLAMPSIA Decreased uteroplacental blood flow and placental ischemia are central to the pathogenesis of preeclampsia. Lowering blood pressure does not prevent or cure preeclampsia and does not benefit the fetus unless delivery can be safely postponed. Lowering blood pressure is appropriate for maternal safety: maintain blood pressure at 130–150/85–100 mm Hg.

FIGURE 10-37 Treatment of preeclampsia requires close monitoring of both the maternal and fetal condition to maximize chances of avoiding catastrophes such as seizures, renal failure, and fetal demise. Close surveillance is best accomplished in the hospital in all but the mildest cases. Maternal hypertension should be treated to avoid cerebrovascular and cardiovascular complications. Magnesium sulfate is the treatment of choice for seizure prophylaxis and usually is instituted immediately after delivery. When the fetus is mature, delivery is indicated in all cases. When the fetus is immature, the decision to deliver is made after carefully assessing both the maternal and fetal condition. When maternal health is in jeopardy, delivery is necessary, even with a premature fetus.

FIGURE 10-38 Some controversy exists regarding when to institute antihypertensive therapy in women with preeclampsia. The basis for this controversy is that decreased uteroplacental perfusion is believed to be important in the pathophysiology of this disorder, and concern exists that lowering maternal blood pressure may compromise uteroplacental blood flow and lead to fetal distress. Furthermore, lowering maternal blood pressure does not cure preeclampsia. Thus, antihypertensive therapy is instituted when the blood pressure reaches a level at which the physician considers the maternal condition to be in danger from hypertension. For most physicians, this treatment threshold is at approximately 150/100 mm Hg. Aggressive lowering of blood pressure is not advisable.

ANTIHYPERTENSIVE THERAPY IN PREECLAMPSIA Imminent delivery

Delivery postponed

Hydralazine (intravenous, intramuscular) Labetalol (intravenous) Calcium channel blockers Diazoxide (intravenous)

Methyldopa Labetalol, other  blockers Calcium channel blockers Hydralazine  blockers Clonidine

FIGURE 10-39 When blood pressure increases acutely and delivery is likely within the next 24 hours, use of a parenteral antihypertensive agent is preferable. Intravenous hydralazine or labetalol are acceptable agents for pregnant women, and both have been used successfully in preeclampsia. Calcium channel blockers should be used with caution because they may act synergistically with magnesium sulfate, resulting in precipitous decreases in blood pressure. Rarely, agents such as diazoxide may be needed; however, when hypertension is severe, maternal safety takes priority over pregnancy status. When delivery can be postponed safely for several days, an oral agent is indicated. Methyldopa is one of the safest drugs in pregnancy and has been used extensively with excellent maternal and fetal outcome. Labetalol and other  blockers have been used successfully in preeclampsia. Calcium channel blockers also may be used as either second- or third-line agents. Oral hydralazine is safe in pregnancy. Limited experience exists with  blockers or clonidine, although anecdotal reports suggest these agents are safe.

10.19

Kidney Disease and Hypertension in Pregnancy Treatment alogrithm for chronic hypertension Systolic

Preconception

140

Screen for secondary hypertension (pheo, renovascular hypertension) Counseling: Increased risk of preeclampsia (25%) Lifestyle adjustments: increase rest, decrease exercise Adjust medications: discontinue ACE inhibitors

130 120 110

Diastolic

Blood pressure, mm Hg

150

100

First trimester

90

Diastolic BP, mm Hg 90–100

<90

80

Consider careful decrease in BP medication

70 60 Prepregnancy

10

20

28

32

38

≥ 100

Adjust medications: Increase medication Stop ACE and angiotensin II β blockers Decrease diuretic dose

Baseline evaluation for secondary hypertension if clinically suspected

Gestation, wk

FIGURE 10-40 Blood pressure changes during pregnancy in women with chronic hypertension. Women with preexisting or chronic hypertension during pregnancy have a favorable prognosis, unless preeclampsia develops. The risk of superimposed preeclampsia is about 25%. Women with this complication are at greater risk for fetal complications during pregnancy, including premature delivery, growth restriction, and perinatal mortality. Women with chronic hypertension experience a decrease in blood pressure during pregnancy that may permit withdrawal of some or all antihypertensive medication. In those women with uncomplicated chronic hypertension (solid line), blood pressure decreases in the first trimester, then may decrease even further in the second trimester. An increase in both systolic and diastolic blood pressure may occur during the third trimester to levels at prepregnancy or early first trimester. In those women who develop superimposed preeclampsia (broken lines), blood pressure often decreases in the first trimester. There is often a failure to decrease further in the second trimester, however, and blood pressures may actually begin to increase slightly. Blood pressure then increases significantly when preeclampsia develops [33].

ANTIHYPERTENSIVE THERAPY FOR CHRONIC HYPERTENSION DURING PREGNANCY Methyldopa  blockers (labetalol) Calcium channel blockers Hydralazine Diuretics

Second trimester Nonpharmacologic treatment ❑ Home BP monitoring ❑ Adequate rest Diastolic BP, mm Hg 90–100

<90 Consider careful decrease in BP medication

Continue treatment

≥ 100 Indicates significant hypertension: consider stopping work; close surveillance for preeclampsia

Third trimester Increased surveillance for preeclampsia Check BP every 2 weeks

FIGURE 10-41 Treatment algorithm for chronic hypertension. Ideally, patients with chronic hypertension should be evaluated before pregnancy so that secondary hypertension can be diagnosed and treated appropriately. Women can be counseled regarding the need for possible life-style adjustments, and medications can be adjusted. Blood pressure (BP) medications may require adjustment, depending on the magnitude of the pregnancy-related changes in blood pressure. In the latter half of pregnancy, close surveillance for early signs of preeclampsia increases the likelihood the condition will be diagnosed before it progresses to a severe stage.

FIGURE 10-42 The overall treatment goals of chronic hypertension in pregnancy are to ensure a successful full-term delivery of a healthy infant without jeopardizing maternal well-being. The level of blood pressure control that is tolerated in pregnancy may be higher, because the risk of exposure of the fetus to additional antihypertensive agents might outweigh the benefits to the mother (for the duration of pregnancy) of having a normal blood pressure. Most antihypertensive agents have been evaluated only sporadically during gestation, and careful follow-up of children exposed in utero to many of the agents is lacking. The only antihypertensive agent for which such follow-up exists is methyldopa. Because no adverse effects have been documented in offspring of exposed mothers, methyldopa is considered to be one of the safest drugs during pregnancy.  blockers and calcium channel blockers are acceptable second- and third-line agents. Diuretics can be used at low doses, particularly in salt-sensitive hypertensive patients on chronic diuretic therapy. Angiotensin-converting enzyme inhibitors are contraindicated in pregnancy because they adversely affect fetal renal function. Angiotensin II receptor antagonists are presumed to have similar effects but have not been evaluated in human pregnancy.

10.20

Systemic Diseases and the Kidney

References 1. Baylis C: Glomerular filtration and volume regulation in gravid animal models. Clin Obstet Gynaecol 1987, 1:789. 2. Lindheimer MD, Katz AI: The kidney and hypertension in pregnancy. In The Kidney, edn 4. Edited by Brenner BM, Rector FC. Philadelphia: WB Saunders Co; 1991:1551–1595. 3. Davison JM, Shiells EA, Philips PR, Lindheimer MD: Serial evaluation of vasopressin release and thirst in human pregnancy: role of chorionic gonadotropin in the osmoregulatory changes of gestation. J Clin Invest 1988, 81:798. 4. Lindheimer MD, Richardson DA, Ehrlich EN, Katz AI: Potassium homeostasis in pregnancy. J Reprod Med 1987, 32:517. 5. Brown MA, Sinosich MJ, Saunders DM, Gallery EDM: Potassium regulation and progesterone-aldosterone interrelationships in human pregnancy. A prospective study. Am J Obstet Gynecol 1986, 155:349. 6. Lim VS, Katz AI, Lindheimer MD: Acid-base regulation in pregnancy. Am J Physiol 1976, 231:1764. 7. Wilson M, Morganti AA, Zervoudakis I, et al.: Blood pressure, the reninaldosterone system and sex steroids throughout normal pregnancy. Am J Med 1980, 68:97. 8. August P, Mueller FB, Sealey JE, Edersheim TG: Role of reninangiotensin system in blood pressure regulation in pregnancy. Lancet 1995, 345:896–897. 9. Diabetic nephropathy. Pregnancy performance and fetal-maternal outcome. Am J Obstet Gynecol 1988, 159:56. 10. Hayslett JP, Lynn RI: Effect of pregnancy in patients with lupus nephropathy. Kidney Int 18:207, 1980. 11. Houser MT, Fish AJ, Tagatz GE, et al.: Pregnancy and systemic lupus erythematosus. Am J Obstet Gynecol 1980, 138:409. 12. Fine LG, Barnett EV, Danovitch GM, et al.: Systemic lupus erythematosus in pregnancy. Ann Intern Med 1981, 94:667. 13. Imbasciati E, Surian M, Bottino S, et al: Lupus nephropathy and pregnancy. A study of 26 pregnancies in patients with systemic lupus erythematosus and nephritis. Nephron 1984, 36:46. 14. Jungers P, Dougodos M, Pelissier C, et al.: Lupus nephropathy and pregnancy. Report of 104 cases in 36 patients. Arch Intern Med 1982, 142:771. 15. Lockshin MD, Druzin MC, Goel S, et al.: Antibody to cardiolipin as a predictor of fetal distress on death in pregnant patients with systemic lupus erythematosus. N Engl J Med 1985, 313:152. 16. Chapman AB, Johnson AM, Gabow PA: Pregnancy outcome and its relationship to progression of renal failure in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1994, 5:1178–1185. 17: Lindheimer MD, Davison JM. Renal biopsy during pregnancy: “To b... or not to b...” Br J Obstet Gynecol 1987, 94:932. 18. Saltiel C, Legendre, Grunfeld JP, et al.: Hemolytic uremic syndrome in association with pregnancy. In Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura. Edited by Kaplan BS, Trompeter RS, Moake JL. New York: Marcel Dekker; 1992:241–254.

19. Sibai BM, Kustermann L, Velasco J: Current understanding of severe preeclampsia, pregnancy-associated hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, hemolysis, elevated liver enzymes, and low platelet syndrome, and postpartum acute renal failure: different clinical syndromes or just different names? Curr Opinion Nephrol Hypertens 1994, 3:436–445. 20. Hou S: Peritoneal dialysis and hemodialysis in pregnancy. Clin Obstet Gynaecol (Balliere) 1994, 8:491–510. 21. Davison JM: Pregnancy in renal allograft recipients: problems, prognosis, and practicalities. Clinc Obstet Gynaecol (Balliere) 1994, 8:511–535. 22. Douglas KA, Redman CW: Eclampsia in the United Kingdom. BMJ 1994, 309:1395–1400. 23. Chesley LC, Annitto JE, Cosgrove RA: Pregnancy in the sisters and daughters of eclamptic women. Pathol Microbiol 1961, 24:662. 24. Cooper DW, Brenneckes SP, Wilton AN: Genetics of pre-eclampsia. Hypertens Preg 1993, 12:1. 25. Khong TY, WF De, Robertson WB, Brosens I: Inadequate maternal vascular response to placentation in pregnancies complicated by preeclampsia and small for gestational age infants. Br J Obstet Gynaecol 1986, 93:1049–1059. 26. Zhou Y, Fisher SJ, Janatpour M: Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion? J Clin Invest 1997, 99:2139–2151. 27. Zhou Y, Damsky CH, Fisher SJ: Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome? J Clin Invest 1997, 99:2152–2164. 28. Lüscher TF, Dubey RK: Endothelium and platelet=derived vasoactive substances: role in the regulation of vascular tone and growth. In Hypertension: Pathophysiology, Diagnosis and Management, edn 2. New York: Raven Press; 1995: 609–630. 29. CLASP Collaborative Group. CLASP: A randomized trial of low-dose aspirin for the prevention and treatment of preeclampsia among 9364 pregnant women. Lancet 1994, 343:619–629. 30. Bucher HC, Guyatt GH, Cook RJ, et al.: Effect of calcium supplementation on pregnancy-induced hypertension and preeclampsia: a metaanalysis of randomized controlled trials. JAMA 1996, 275:1113–1117. 31. Hojo M, August P: Calcium metabolism in normal and hypertensive pregnancy. Semin Nephrol 1995, 15:504–511. 32. Levine RJ, Hauth JC, Curet LB, et al.: Trial of calcium to prevent preeclampsia. N Engl J Med 1997, 337:69–76. 33. August P, Lenz T, Ales KL, et al.: Longitudinal study of the renin angiotensin system in hypertensive women: deviations related to the development of superimposed preeclampsia. Am J Obstet Gynecol 1990, 163:1612–1621.

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias Jo H.M. Berden Karel J.M. Assmann

R

enal involvement in systemic lupus erythematosus (SLE), dysproteinemias, and certain rheumatic diseases, namely rheumatoid arthritis, Sjögren’s syndrome, and scleroderma (systemic sclerosis), is discussed. SLE is a systemic autoimmune disease that can lead to disease manifestations in almost every organ. SLE is characterized by the formation of a wide array of autoantibodies mainly directed against nuclear autoantigens, of which antibodies against double-stranded DNA (dsDNA) are the most prominent. Although the cause is still obscure, considerable progress has been made recently by identification of the nucleosome as the major driving autoantigen in SLE and the possible role of disturbances in apoptosis in disease development. The section on SLE reviews the major clinical and serologic features of the disease, the serologic analysis, new insights into the pathophysiology of lupus nephritis, and the histologic assessment of kidney biopsies. The therapeutic options for treatment of lupus nephritis are discussed as are the results of treatment of endstage renal disease in patients with SLE. The second part of this chapter deals with the renal involvement in dysproteinemias. The renal lesions of these diseases, characterized by an overproduction of abnormal immunoglobulins or their subunits, are quite heterogeneous. Because the kidney often is affected in these disorders, it is not unusual for examination of a kidney biopsy specimen to reveal clues for the diagnosis. On immunofluorescence, the distribution of the light or heavy chain isotype, or both, can be detected in the tissue deposits, whereas electron microscopy can define the ultrastructural organization. Incidence and types of renal involvement, the pathogenesis and risk factors for the various types of renal lesions, the histology of the different renal manifestations, and an

CHAPTER

11

11.2

Systemic Diseases and the Kidney

overview of the therapy are given. The renal manifestations of cryoglobulinemias and fibrillary and immunotactoid glomerulonephritis also are discussed.

The third part of this chapter presents a concise review of renal involvement in rheumatoid arthritis, Sjögren’s syndrome, and scleroderma.

Systemic Lupus Erythematosus CUMULATIVE INCIDENCE OF CLINICAL SYMPTOMS AND AUTOANTIBODY FORMATION IN SYSTEMIC LUPUS ERYTHEMATOSUS Percent Frequency of major clinical symptoms Musculoarticular symptoms Cutaneous manifestations Renal involvement Neuropsychiatric disease Pulmonary and cardiac disease Hematologic abnormalities Occurrence of major autoantibody specificities Antinuclear autoantibody Anti–double-stranded DNA Antihistone Antinucleosome Anti-Sm Anti-ribonucleoprotein (RNP) Anti–Sjögren’s syndrome (SS-A) (Ro) Anti-SS-B (La) Anticardiolipin Antierythrocyte Antilymphocyte Antithrombocyte

60–95 55–80 40–55 30–60 20–40 60–85 95 60–75 50–70 Up to 80 10–30 10–30 20–60 15–40 10–30 50–60 50–70 10–30

FIGURE 11-1 This overview of the major clinical symptoms illustrates the systemic character of lupus erythematosus. Depending on patient selection, renal involvement occurs in up to half of patients. In almost all patients, antibodies are formed against nuclear antigens, as detected by antinuclear antibody (ANA) testing. These ANAs are either directed against nucleic acids (DNA), nuclear proteins (histones, Sm, ribonucleoprotein, Sjögren’s syndrome-A [SS-A], and SS-B) or nucleosomes that consist of DNA and the DNA binding proteins histones. In addition, antibodies can be formed against the anionic phospholipid cardiolipin. This latter antibody specificity is characteristic for the antiphospholipid syndrome either primary or secondary to systemic lupus erythematosus. All these antigens recognized by lupus autoantibodies share the property that they are present in apoptotic blebs at the surface of cells undergoing apoptosis. In addition to these ANAs, autoantibodies against blood cells frequently develop in lupus, giving rise to hemolytic anemia positive on Coombs testing, lymphopenia, or thrombopenia.

EPIDEMIOLOGIC AND GENETIC CHARACTERISTICS OF SYSTEMIC LUPUS ERYTHEMATOSUS Epidemiology

Genetics

Prevalence: between 25 and 250 per 100,000 persons, depending on racial and geographic background Race: more prevalent in Asians and blacks Gender: female preponderance; gender ratio between 20 and 40 years; male:female, 1:9 Age: onset mainly between 20–40 y

Concordancy in twins Monozygotic: 50–60% Dizygotic: 5–10% Familial aggregation in 10% Association with the following: HLA: B7, B8, DR2, DR3, DQW1 Complement: C4A Q0 C1q or C4 deficiency Fc  receptor IIA low-affinity phenotype X chromosome ?

FIGURE 11-2 The major epidemiologic characteristics of systemic lupus erythematosus are listed. The prevalence of the disease depends on ethnic background. The highest prevalence is seen in Asians and Blacks. As in other systemic autoimmune diseases, there is a striking preponderance in women, especially during childbearing age. This preponderance is related to hormonal status. Animal studies have shown that estrogens have a facilitating effect on disease expression, whereas androgens have a suppressive effect. The importance of estrogens is further substantiated by the fact that changes in the hormonal homeostasis (eg, at onset of puberty, during use of oral anticontraceptives, and during pregnancy and puerperium) are associated with an increased frequency of lupus onset and disease flare-up. The genetic susceptibility is illustrated by the concordance of the disease in twins, occurrence of familial aggregation, and association with certain genes, mainly human leukocyte antigens (HLA).

11.3

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias

ANA test

THE 1982 REVISED AMERICAN RHEUMATISM ASSOCIATION CRITERIA FOR CLASSIFICATION OF SYSTEMIC LUPUS ERYTHEMATOSUS Criterion 1. Malar rash 2. Discoid rash 3. Photosensitivity 4. Oral ulcers 5. Arthritis (two or more joints) 6. Serositis: Pleuritis or pericarditis 7. Renal disorder: Proteinuria > 0.5 g/24 h or cellular casts (red, hemoglobin, granular, tubular, or mixed) 8. Neurologic disorder: Seizures or psychosis 9. Hematologic disorder: Hemolytic anemia or leukopenia (<4  109/L) or lymphopenia (<1.5  109/L) or thrombopenia (<100  109/L) 10. Immunologic disorder: Positive LE cell test result or positive anti–double-stranded DNA or positive anti-Sm or false-positive TPI/VDRL test 11. Antinuclear antibody

Sensitivity, %*

Specificity, %*

57 18 43 27 86 56

96 99 96 96 37 86

51

94

20

98

59

89

85

93

99

49

*The sensitivity was calculated as the percentage of patients with SLE who were positive for this criterion over those in whom this criterion was analyzed. The specificity was calculated as the percentage of the number of patients in the control group who were negative or normal for that criterion over those in whom this criterion was analyzed. TPI—treponemal immobilization; VDRL—Venereal Disease Research Laboratory. Data from Tan et al. [1].

FIGURE 11-3 These criteria were selected for their sensitivity and specificity in classifying patients with systemic lupus erythematosus (SLE). In the selection process, these criteria were analyzed in 177 patients with SLE and 162 patients in the control group matched for age, gender, and race. Patients in the control group had a nontraumatic nondegenerative connective tissue disease, mainly rheumatoid arthritis (n = 95). The presence of four of these criteria for the diagnosis of SLE has a sensitivity of 96% and specificity of 96% in patients with SLE. For the purpose of identifying patients in clinical studies, it is determined that a patient has SLE when at least four of these criteria are present, serially or simultaneously, during any interval of observation.

Negative No further evaluation unless strong clinical suspicion

Positive

? Western blot test on nuclear extracts

Negative

Crithidia lucillae

? anti-ENA

Positive

Ouchterlony immunodiffusion using ENAs

Farr assay

FIGURE 11-4 Algorithm for analysis of antinuclear antibodies (ANA) in systemic lupus erythematosus. To demonstrate the presence of antinuclear antibodies the ANA test is used as a screening procedure. Details of this ANA test and the different ANA patterns are given in Figure 11-5. A positive ANA test result indicates the presence of antinuclear antibodies. Although the pattern of ANA can give an indication about the specificity of the antinuclear antibody, additional tests are needed to define this specificity. Antibody specificity to doublestranded DNA (dsDNA) can be identified by the Crithidia assay (Fig. 11-6), in which a single-celled organism is used that has purely dsDNA in the kinetoplast. When this test result is positive, the titer of anti-dsDNA antibodies can be determined using the Farr assay (Fig. 11-7). When these anti-dsDNA test results are negative, ANA positivity is most likely caused by antibodies directed against nuclear proteins. Autoantibodies can be analyzed by the Western blot test on nuclear extracts (Fig. 11-8). The advantage of this technique over the Ouchterlony technique using extractable nuclear antigens (ENA), is that the Western blot test allows identification of a large number of autoantibody specificities in one test, although both tests do not completely overlap.

FIGURE 11-5 Patterns of antinuclear antibody (ANA) staining. The ANA test is carried out by incubation of the serum with either preparations of cultured cells (eg, human cervical carcinoma cells [HeLa cells]) or sections of normal tissue (mostly liver). Antibodies bound to the nucleus are detected by a fluorescinated anti– human immunoglobulin antibody that can reveal four distinctive staining patterns: A, homogeneous; B, rim or peripheral;

A

B

(Continued on next page)

11.4

Systemic Diseases and the Kidney

C

D

Nucleus Mitochondrion

+

Kinetoplast + dsDNA

Anti-dsDNA

Crithidia luciliae

+

Fluorescent labeled antihuman immunoglobulin

FIGURE 11-5 (Continued) C, speckled; and D, nucleolar. Although not conclusive, these patterns can give an indication about the autoantibody specificity causing the nuclear staining. The homogeneous and peripheral patterns mainly are caused by autoantibodies directed against the nucleosome (histone–DNA complex) or doublestranded DNA. The speckled pattern can be observed in antibodies against the nuclear proteins Sm, ribonucleoprotein, Sjögren’s syndrome-A [SS-A] (Ro), SS-B (La), Jo-1, topoisomerase I, and anticentromere antibodies. The nucleolar staining is associated with antibodies against nucleolus-specific RNA, as seen in certain limited forms of scleroderma. (From Maddison [2]; with permission.) FIGURE 11-6 Screening for anti–doubled-stranded DNA (dsDNA) antibodies using the Crithidia assay. The hemoflagellate Crithidia luciliae contains in its kinetoplast pure dsDNA, not complexed to proteins [3]. Serially diluted serum samples are added to the slide carrying Crithidia cells. Binding of antibodies is visualized by fluorescinated anti–immunoglobulin G antibodies. Antibodies to dsDNA are almost pathognomonic for systemic lupus erythematosus and therefore can be regarded as marker antibodies [4]. (From Klippel and Croft [5]; with permission.)

Fluorescence of kinetoplast

Test serum containing anti-dsDNA

Radiolabeled dsDNA added

DNA–anti-DNA complexes precipitated by ammonium sulphate

Radioactivity in precipitate measured

FIGURE 11-7 Farr assay for quantitative measurement of anti-double-e-stranded DNA (dsDNA) antibodies. The serum to be tested is added to a tube containing radiolabeled dsDNA. When antibodies to dsDNA are present, they bind to the dsDNA. Eventually, formed complexes are precipitated in 50% ammonium sulfate. By testing several dilutions of the serum and comparing them with a standard curve the results can be expressed in units per milliliter. Because high salt conditions are used, this assay detects only high avidity anti-dsDNA antibodies [4]. Positivity and titer in this Farr assay are correlated with renal disease in patients with systemic lupus erythematosus. This titer can be used to monitor lupus disease activity together with complement levels and clinical parameters. In 80% to 90% of cases, disease onset or flare-up is associated with increases in anti-dsDNA titers in the Farr assay [6]. (From Maddison [2]; with permission.)

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias

Topo I

Scl-55

RNP

70,000

SS-B

SS-50

A Sm

B B’ C

Centromere

CR-17 D

1

Dysregulation of apoptosis

2

3

4

5

6

Persistence of autoreactive T cells

Decreased phagocytosis Quantitative and qualitative changes in nucleosomes

Antinucleosome Ab, anti-DNA Ab

In situ binding of nucleosomes to GBM (HS?)

Deposition of circulating nucleosome-Ab complex

Nucleosome-mediated Ab-binding to GBM

Activation of complement, glomerulonephritis

FIGURE 11-9 Hypothesis for the pathophysiology of lupus nephritis. In recent years, evidence has emerged that the process of apoptosis is disturbed in systemic lupus erythematosus (SLE). The first indication was found in the MRL/l lupus mouse model, in which a deficiency of the Fas receptor was identified [9]. Activation of this Fas receptor induces apoptosis. Transgenic correction of the Fas-receptor defect prevents development of lupus [10]. In human SLE, Fas receptor expression is normal; however, a number of other observations indicate abnormalities in apoptosis [11,12] (Fig. 11-10). Alterations in apoptosis can lead to the persistence of autoreactive T and B cells, because apoptosis is the major mechanism for the elimination of autoreactive cells. In addition, these alterations can lead to quantitative and qualitative differences in the release of nucleosomes (Fig. 11-10). Nucleosomes are the basic structures of chromatin. They consist of pairs of the core histones H2A, H2B, H3, and H4 around which double-stranded DNA (dsDNA) is wrapped twice. DNA in the circulation

11.5

FIGURE 11-8 Western blot test of autoantibodies on nuclear extracts. Nuclear proteins extracted from human cervical carcinoma cells (HeLa cells) are separated on polyacrylamide gel and transferred to nitrocellulose. Subsequently, identical strips of the blot are incubated with various patient sera. Binding of autoantibodies can be visualized with peroxidase or alkaline phosphatase–labeled antihuman immunoglobulin. Lane 1: anti-ribonucleoprotein (RNP) and centromere (CR-17) activity Lane 2: anti-Sm (B/B-D) Lane 3: anti-RNP and anti-Sm Lane 4: anti–Sjögren’s syndrome (SS-B) (La) Lane 5: anticentromere Lane 6: antitopoisomerase I (Topo I) Antibodies against Sm are rather specific for systemic lupus erythematosus (SLE) and can be used as marker antibody, anti-ribonucleoprotein for mixed connective tissue disease (MCTD), centromere (CR17) for the limited variant of scleroderma, SS-B for Sjögren’s syndrome and SLE, and topoisomerase I for systemic scleroderma. The Western blot test is a simplified version of the currently available technique, which allows identification of autoantibodies to much more autoantigens. Reference 7 provides a full description of the diagnostic possibilities. (From Van Venrooij et al. [8]; with permission.) of patients with SLE is present in the form of oligonucleosomes [13]; the only way to generate these oligonucleosomes is by the process of apoptosis. Presently, ample evidence exists that the autoimmune response in SLE is T-cell–dependent and autoantigen-driven [14]. However, dsDNA is very poorly immunogenic, which is in line with the fact that antigen-presenting cells cannot present DNA-derived oligonucleotides to T cells by way of their major histocompatibility complex class II molecules. However, recently it has become evident that the nucleosome is the driving autoantigen in SLE. In murine lupus, T cells specific for nucleosomes have been identified. These T cells not only drive the formation of nucleosome-specific autoantibodies (ie, antibodies that react with the intact nucleosome but not with its constituent DNA and histones) but also the formation of anti-DNA and antihistone antibodies [15]. The histone-derived epitopes that drive these responses recently have been identified [16]. These nucleosome-specific autoantibodies precede the emergence of anti-dsDNA and antihistone antibodies, suggesting that the loss of tolerance for nucleosomes is an initial key event in SLE [17,18]. Both in human and murine lupus, nucleosome-specific antibodies are detected in up to 80% of cases [18–20]. Figure 11-11 illustrates the central role of the nucleosome in the generation of the antinuclear autoantibody repertoire. These antinucleosome and anti-DNA antibodies, after complex formation with the nucleosome, can localize in the glomerular basement membrane (GBM) by way of binding to heparan sulfate (HS). This binding occurs through binding of the cationic histone part of the nucleosome to the anionic HS, as demonstrated by in vivo perfusion studies [21]. The relevance of this binding mechanism for lupus nephritis was shown by the elution of nucleosome-specific autoantibodies from glomeruli, identification of nucleosome deposits in glomeruli of patients with lupus nephritis, and presence of nucleosome–antinucleosome antibody complexes in the glomerular capillary wall in patients with lupus nephritis [18,22–25]. The pathophysiologic significance of this nucleosome-mediated binding to the GBM was illustrated by the observation that heparin could prevent this binding and inhibit the glomerular inflammation and proteinuria in lupus mice [26]. References 11 and 14 provide a more detailed description of these mechanisms.

11.6

Systemic Diseases and the Kidney

INDICATIONS FOR A DISTURBED APOPTOSIS IN HUMAN SYSTEMIC LUPUS ERYTHEMATOSUS Finding

Study

Increased expression of Fas receptor Circulating levels of soluble Fas Increased Normal Increased in vitro apoptosis of lymphocytes Abnormal anti-CD3–induced apoptosis Apoptosis-induced alterations of autoantigens Proteolysis

Mysler et al. [28], Lorenz et al. [29]

Phosphorylation Reactive oxygen species–mediated damage Apoptosis-induced surface expression of autoantigens Decreased phagocytosis of apoptotic cell

Cheng et al. [30] Goel et al. [31], Knipping et al. [32] Lorenz et al. [29], Emlen et al. [33] Kovacs et al. [34] Casciola-Rosen et al. [35], Casiano et al. [36], Rosen and Casciola-Rosen [37], Casiano [38] Utz et al. [39] Cooke et al. [40] Casciola-Rosen et al. [41], Jordan and Kuebler [42] Herrmann et al. [43]

Chromatin

Anti-HMG B cell

Anti-DNA B cell

MHC II-Peptide

CD40L Anti-Histone B cell

CD40

CD4

Histonepeptide Th cell

FIGURE 11-10 On the one hand, indications exist that apoptosis is increased in human systemic lupus erythematosus (SLE) (eg, increased Fas expression and increased in vitro apoptosis). On the other hand, some findings suggest that apoptosis is decreased (eg, increased levels of soluble Fas, increased bcl-2 expression, and decreased anti-CD3–induced apoptosis). Bcl-2 is a physiologic inhibitor of apoptosis, and transgenic induction of bcl-2 overexpression leads to lupuslike autoimmunity [27]. Although presently it is difficult to reconcile these findings, it is clear that changes in the delicate balances governing apoptosis can lead to apoptosis at the wrong moment (too late) or at the wrong place (systemically instead of locally).

TCR Anti-nucleosome B cell

FIGURE 11-11 Central role of T cells specific for nucleosomal histone peptides in the generation of the antinuclear autoantibody repertoire in systemic lupus erythematosus. The cascade begins with the uptake of nucleosomes by B cells by way of their antigen receptor. After endosomal antigen processing, these B cells present histone peptides to T cells. After activation of the T cell, it provides help to the presenting B cell, leading to the formation of nucleosome-specific autoantibodies. Binding of B cells to other determinants on the nucleosome (B cells specific for DNA, histones, or the nonhistone chromosomal peptides high-mobility group proteins [HMG]) and antigen-processing by these B cells, can generate additional antinuclear autoantibody responses (anti–doubled-stranded DNA, antihistone, and anti-HMG). This intramolecular antigen-spreading owing to different endosomal antigen-processing revealing cryptic neoepitopes, is now known for a number of autoimmune responses [44]. MHC—major histocompatibility complex; TCR—T-cell receptor. (From Datta and Kaliyaperumal [45]; with permission.)

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias

WORLD HEALTH ORGANIZATION MORPHOLOGIC CLASSIFICATION OF LUPUS NEPHRITIS (1995 REVISED VERSION) Class I. Normal glomeruli A. Nil (by all techniques) B. Normal on light microscopy but deposits seen on electron or immunofluorescence microscopy II. Pure mesangial alterations (mesangiopathy) A. Mesangial widening, mild hypercellularity, or both B. Moderate hypercellularity III. Focal segmental glomerulonephritis (associated with mild or moderate mesangial alterations) A. Active necrotizing lesions B. Active and sclerosing lesions C. Sclerosing lesions IV. Diffuse glomerulonephritis (Severe mesangial, endocapillary, or mesangiocapillary proliferation, and/or extensive subendothelial deposits. Mesangial deposits are present invariably and subepithelial deposits often, and may be numerous.) A. Without segmental lesions B. With active necrotizing lesions C. With active and sclerosing lesions D. With sclerosing lesions V. Diffuse membranous glomerulonephritis A. Pure membranous glomerulonephritis B. Associated with lesions of category II (A or B) VI. Advanced sclerosing glomerulonephritis

FIGURE 11-12 The various morphologic manifestations of lupus nephritis are classified in several categories based on criteria formulated in 1974, modified in 1982 and 1995, and designated as the World Health Organization (WHO) classification of lupus nephritis [46,47]. The different forms of glomerulonephritis, as morphologically defined by the WHO classification, also are characterized by typical patterns of deposits of several classes of immunoglobulins and complement factors [48]. Class I lupus nephritis has been defined by normal glomeruli by all techniques, or by normal glomeruli on light microscopy, with minor deposits as seen on immunofluorescence (IF) or electron microscopy (EM). Class I lupus nephritis is believed to be a rare manifestation, and its existence is challenged by many pathologists. The mildest form of lupus nephritis, class II, is characterized by a mild or moderate increase of mesangial cells accompanied by mesangial deposits of immunoglobulins and complement. These mesangial deposits are regarded as the most characteristic immunopathologic feature of lupus nephritis. The more severe forms of lupus nephritis not only show an increase of mesangial deposits but also deposits

11.7

along the capillary loops. Dependent on the severity of the morphologic damage, the extent of immune deposits, and whether less or more than half of glomeruli are affected, this form of proliferative lupus nephritis was divided into focal segmental glomerulonephritis (class III) and diffuse glomerulonephritis (class IV). The distinction between class III and class IV, however, is arbitrary; it also is unreliable in clinical practice. Therefore, the recent modification of the WHO classification (1995) proposes a new definition of classes III and IV lupus nephritis. All more severe forms of proliferative lupus nephritis are included in class IV and specified as mild, moderate, or severe, depending on the severity on the glomerular damage. In active lesions there occurs a large increase in mesangial cells; an influx of monocytes or granulocytes; so-called hyaline thrombi in the capillary lumina; and necrosis of the capillary loops, defined as severe mesangial proliferative or endocapillary proliferative glomerulonephritis, and sometimes with varying degrees of extracapillary proliferation. In chronic disease, mesangiocapillary lesions are present with extensive subendothelial deposits (wire loops), duplication of the glomerular basement membrane (GBM), cellular interposition, and varying increases of mesangial cells and matrix. On electron microscopy, the deposits have a homogeneous or fine granular structure with sometimes organized “fingerprint” patterns. Frequently, tubuloreticular structures are present in the cytoplasm of endothelial cells, inclusions also found in viral infections, such as human immunodeficiency virus, and related to  -interferon. Class III is now restricted to patients with active or sclerosing focal segmental necrotizing lesions accompanied by mild increase of mesangial cells. Membranous lupus nephritis (class V) is hardly distinguishable from the idiopathic form of lupus nephritis. However, membranous lupus nephritis often is accompanied by a mild or moderate increase of mesangial cells or matrix, and the subepithelial deposits contain more classes of immunoglobulins (so-called full-house) than does the idiopathic form. In addition, it is not unusual to find small subendothelial and mesangial deposits. The subepithelial deposits are either globally distributed along the glomerular basement membrane (GBM) or more segmentally localized. The subepithelial deposits also are a frequent occurrence in class IV lupus nephritis. According to the most recent version of the WHO classification [47], class V is now restricted to cases that are predominantly characterized by subepithelial immune complexes. More advanced or end-stage cases of focal and diffuse proliferative lupus nephritis characterized by a pronounced sclerosis and hyalinosis are classified as class VI lupus nephritis. Interstitial fibrosis, accompanied by tubular atrophy and influx of mononuclear cells, is a frequent finding, especially in the chronic forms of classes III, IV, and V. Lesions resembling chronic tubulointerstitial nephritis without glomerular alterations also have been described in some patients with SLE. In these cases, on immunofluorescence, it is not unusual to find granular immune complexes in the tubular basement membranes. Reference 47 provides additional information on the 1995 revised WHO classification. Examples of the different forms of SLE nephritis are presented in Figs. 11-14 to 11-20. (From Churg and coworkers [47]; with permission.)

11.8

Systemic Diseases and the Kidney FIGURE 11-13 The value of the analysis of lupus glomerulonephritis according to the World Health Organization (WHO) classification for prognosis and treatment can be enhanced by including indices of activity and chronicity. These indices were proposed in the National Institutes of Health (NIH) index [49]. The extent of the active and chronic lesions is assessed according to the scoring system here. A chronicity index of 3 or higher and an activity index of 12 or higher are associated with a significantly greater risk for the development of end-stage renal disease [14].

NATIONAL INSTITUTES OF HEALTH HISTOLOGIC SCORING SYSTEM FOR ACTIVITY AND CHRONICITY IN LUPUS NEPHRITIS Activity index

Chronicity index Glomerular sclerosis Fibrous crescents

Tubulointerstitial

Endocapillary hypercellularity Leukocyte infiltration Fibrinoid necrosis, karyorrhexis* Cellular crescents* Hyalin deposits, wire loops Mononuclear cell infiltration

Maximal score

24

Glomerular

Fibrosis Tubular atrophy 12

Scoring per item from 0 to 3; for parameters with asterisks, the score is doubled.

Histology of Lupus Nephritis U

L

A

C FIGURE 11-14 Lupus nephritis class II. A, A moderate increase of mesangial cells is seen on light microscopy. B, Immunofluorescence. Mesangial deposits of immunoglobulin G. C, Electron microscopy shows electron-dense deposits restricted to the mesangial area. L—capillary lumen; U—urinary space. (Panel A, methenamine silver. Original magnification 400, 520, 10,000, respectively.)

B

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias

A

B

FIGURE 11-15 Lupus nephritis class III. A, Segmental necrotizing lesion surrounded by an increased number of epithelial cells. B, Immunofluorescence. Next to mesangial deposits of immuno-globulin G there also are deposits in the periphery of some loops (arrows). C, Immunofluorescence. Fibrin

A

B

C

D

11.9

C deposits in a necrotizing lesion. According to the 1995 modified World Health Organization classification, this is a characteristic immunopathologic lesion of class III lupus nephritis. (Panel A, methenamine silver. Original magnification 400, 400, 520, respectively.) FIGURE 11-16 Lupus nephritis class IV on light microscopy and immunofluorescence. A and B, Diffuse endocapillary proliferative pattern of injury with an increase of mesangial cells and an influx of mononuclear cells and some granulocytes. Panel B shows a necrotizing lesion (arrow). C, A mesangiocapillary pattern of injury with duplication of the glomerular basement membrane (GBM), an increase of mesangial cells and matrix, and massive subendothelial deposits (wire loops). In addition, spikes (membranous component) can be found on the epithelial side of the GBM (arrow). D, Immunofluorescence. The characteristic pattern of the immune deposits (immunoglobulin G) of class IV lupus nephritis, predominantly localized along the capillary wall. (Panels A, B, C, methenamine silver. Original magnification 360, 360, 740, 300, respectively.)

11.10

Systemic Diseases and the Kidney FIGURE 11-17 Lupus nephritis class IV. A representative electron micrograph shows diffuse lupus nephritis with subendothelial and mesangial electron-dense deposits with additional massive subepithelial deposits (asterisk). GBM—glomerular basement membrane; U—urinary space. (Original magnification 12,000.)

GBM

* U

S

A

S

L

C FIGURE 11-18 Lupus nephritis class V. A, Discrete spikes on the epithelial side of the glomerular basement membrane (GBM) (arrows), and a moderate increase of mesangial cells. B, Immunofluorescence. Fine granular deposits of immunoglobulin G along the capillary wall in a characteristic membranous pattern. C, Electron micrograph reveals electron-dense deposits on the epithelial side of the GBM between spikes. Between an increased number of mesangial cells small deposits also are present (arrows). L—capillary lumen; S—spikes; U—urinary space. (Panel A, methenamine silver, original magnification 700, 400, 3100, respectively.)

B

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias

11.11

FIGURE 11-19 Lupus nephritis class VI. Sclerosing glomerulonephritis with extensive sclerosis of most of the capillary tuft. (Methenamine silver, original magnification 700.)

FIGURE 11-20 Chronic tubulointerstitial nephritis. A, Extensive interstitial fibrosis accompanied by tubular atrophy and a mononuclear cell infiltration B, Immunofluorescence. Granular deposits of immunoglobulin G in tubular basement membranes. (Panel A, methenamine silver, original magnification 100, 400, respectively.)

A

B

Incidence of the different forms of lupus nephritis, % Class IV 57

Class III 15 Class II 10 Class I 1 Class VI 2 Class V 15

FIGURE 11-21 Incidence of the different forms of lupus nephritis classified according to the World Health Organization (WHO) classification. The incidence of the different forms categorized according to the WHO classification depends on patient selection and ethnic background. The percentages represent an average of the data reported in the literature. Most patients have a diffuse proliferative form of lupus nephritis (WHO class IV).

11.12

Systemic Diseases and the Kidney

100 Class II Class III Class IV Class V

80

Percentage

60

40

20

FIGURE 11-22 Incidence of renal manifestations and serologic abnormalities in the different forms of lupus nephritis. The clinical manifestations of lupus nephritis are not different from other forms of glomerulonephritis and include a nephritic sediment (dysmorphic erythrocytes and erythrocyte casts), proteinuria or nephrotic syndrome, impaired renal function, and hypertension. Although certain clinical manifestations are more prevalent in certain forms (nephrotic syndrome for World Health Organization (WHO)

wC

3

n sio

/lo

ten

An

ti-d

sDN

A+

per Hy

ctio un al f ren red pai Im

Ne

ph

rot

ic s

Pro

ynd

tein

rom

n

a uri

ent im sed tive Ac

e

0

class V, nephritic sediment for WHO class IV), it is clear that on the basis of clinical symptoms it is not possible to classify the form of nephritis correctly. This inability underlines the necessity for obtaining a renal biopsy specimen. In addition, listed are the occurrence of both a positive result on performing a Farr assay and a low complement 3 level for the different forms of lupus nephritis. Anti-dsDNA— anti–double-stranded DNA. (Adapted from Appel et al. [50]).

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias

TREATMENT OF THE DIFFERENT FORMS OF LUPUS NEPHRITIS World Health Organization classification I II III, IV

Treatment options Treatment guided by extrarenal lesions Corticosteroids: Cyclophosphamide pulses, oral prednisone Methylprednisolone pulses, azathioprine, low doses oral prednisone Corticosteroids (and azathioprine or cyclophosphamide) No further immunosuppression ? Supportive treatment

V VI

FIGURE 11-23 Treatment options for the different forms of lupus nephritis are summarized. Only for World Health Organization (WHO) classes III, IV, and V are a limited number of prospective studies available. For the other forms, a balanced compilation is made from the literature and personal experience. Reference 14 supplies a more detailed analysis of the therapeutic options. For class I lupus nephritis, no specific renal therapy is necessary; treatment is dictated by the presence of extrarenal symptoms. In general, patients with class II lupus nephritis respond satisfactorily to monotherapy with oral corticosteroids. The patient, however,

6

4 ∆ Chronicity index

must be monitored for transition to a more severe form, which is generally heralded by worsening of clinical renal symptoms. For patients with classes III and IV lupus nephritis, corticosteroid monotherapy is not sufficient (Fig. 11-24). Cytotoxic immunosuppressive therapy, either cyclophosphamide or azathioprine, should be added to the treatment. The choice of one of these drugs over the other is discussed in Figures 11-24, 11-25, and 11-26. According to a recent analysis [51], patients with a pure membranous lupus nephritis without a proliferative component (class V, according to the 1995 revised WHO classification) respond satisfactorily to corticosteroid monotherapy. Patients who have a membranous nephropathy with a proliferative component (formerly classified as WHO class VC or VD) have a much worse prognosis and should be treated as are patients with a class IV lupus nephritis. When a patient with class V (A or B) lupus nephritis does not respond to corticosteroids, addition of azathioprine or cyclophosphamide should be considered (as in idiopathic membranous glomerulonephritis, in which oral treatment seems to be superior over monthly intravenous pulses [52–54]). When cyclophosphamide treatment is initiated the therapeutic response should be evaluated after 6 months, and the drug should be discontinued if no improvement has occurred [55]. Treatment of WHO class VI nephritis should be balanced on weighing the risks of intensification of immunosuppressive treatment and the expected benefits. When renal function already is strongly impaired and the renal biopsy specimen shows predominantly chronic irreversible lesions, further deterioration of renal function may be unavoidable. Therefore, an increase in immunosuppressive therapy is questionable. This approach is strengthened by the fact that lupus disease activity mostly subsides during renal replacement therapy. Results of renal transplantation are good, and the disease rarely recurs after transplantation [14]. FIGURE 11-24 Change in chronicity index in repeat biopsies after treatment with prednisone (PRED) alone or prednisone and cytotoxic drugs (CTD). The addition of cytotoxic drugs to the treatment regimen of patients with World Health Organization (WHO) class III or IV nephritis clearly improves renal and patient survival [56,57]. The pathophysiologic basis for this beneficial effect is illustrated, displaying the change in chronicity index between the first and second kidney biopsies over time. As can be seen during prednisone monotherapy, there is a clear increase of the chronicity index (A);

8

2

(Continued on next page)

0 PRED

-2

-4 0

A

11.13

33

66 Time interval, m

99

132

11.14

Systemic Diseases and the Kidney

Azathioprine Oral cyclophosphamide Intravenous cyclophosphamide Combined use of azathioprine and cyclophosphamide

8

6

FIGURE 11-24 (Continued) whereas in patients treated with prednisone and cytotoxic drugs (B) the chronic lesions, on average, do not progress. Various studies have shown that this chronicity index is the strongest predictor of development of end-stage renal disease [14]. (From Balow et al. [58]; with permission.)

∆ Chronicity index

4

2

0

-2 CTD

-4 0

33

66

132

0

100

IVCY AZCY

20

POCY AZ

40 60

PRED

80 100 0

A

99

Time interval, m

Cumulative survival, %

Probability of end-stage renal disease

B

20

40

60

FIGURE 11-25 A, The probability of end-stage renal disease in patients with proliferative lupus nephritis treated with different drug regimens. This update of the prospective trial by the National Institutes of Health (NIH) on the treatment of these patients clearly demonstrates that prednisone monotherapy, in a significantly greater proportion of patients, leads to the development of end-stage renal disease compared with patients on regimens containing cytotoxic drugs. The results between azathioprine and drug regimens containing cyclophosphamide are not significantly different. Note that in up to 7 years the results do not differ between the different treatment groups. From these studies it is clear that although the therapeutic efficacy is equal for the three treatment regimens containing cyclophosphamide, less side effects occurred in patients treated with intravenous pulses of cyclophosphamide. B, Renal survival in patients with World Health Organization (WHO) class IV lupus nephritis treated with either cyclophosphamide (CPM) or azathioprine (AZ). The NIH trial [56,59] did not reveal a significant difference between the therapeutic efficacy of cyclophosphamide and azathioprine (A). However, the side

60 CPM

40

}

20

AZA

0

80 100 120 140 160 180 200 220 Months

80

0

B

24

48

72

96

120

Months

effects of both drugs are not identical. Cyclophosphamide has a greater bone marrow toxicity, leads to amenorrhea in many patients, is teratogenic, and displays an unique urothelial toxicity (hemorrhagic cystitis and bladder carcinoma). Therefore, prospective studies comparing cyclophosphamide with azathioprine are warranted but not available. The results of the NIH trial are compared with those reported for azathioprine [57,60–62]. This analysis, carried out by Cameron [57], does not reveal a significant difference between cyclophosphamide and azathioprine. A recent meta-analysis [63] again showed that monotherapy with prednisone was inferior to treatment with cytotoxic drugs in combination with steroids. However, as in the NIH trial and the analysis by Cameron, no differences were found between cyclophosphamide and azathioprine in preserving renal function. AZ—azathioprine; AZCY— combined therapy with azathioprine and cyclophosphamide; IVCY—intravenous pulses of cyclophosphamide; POCY—oral cyclophosphamide. (Panel A from Steinberg and Steinberg [59]; with permission. Panel B from Cameron [57]; with permission.)

11.15

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias

RISK FACTORS FOR DEVELOPMENT OF END-STAGE RENAL DISEASE IN SYSTEMIC LUPUS ERYTHEMATOSUS Clinical characteristics

Treatment characteristics

Histologic characteristics

Demographic characteristics

Elevated initial serum creatinine Nephrotic range proteinuria Low C3 Hematocrit ≤ 26% Hypertension Persistent disease activity

No normalization of elevated creatinine Treatment with prednisone only

World Health Organization class IV Activity index ≥ 12 Chronicity index ≥ 3

Male gender Black race Age ≤ 24 y Low socioeconomic status

FIGURE 11-26 These risk factors were identified in different analyzes in different patient groups. Not all these parameters were confirmed in all studies, probably because of differences in definitions used, composition of the cohort studied, duration of

follow-up, and so on. The most powerful predictors seem to be an elevated serum creatinine level at entry into the trial, a chronicity index of 3 or higher, and persistent or remitting renal disease activity [14,64].

100

100

Patients, %

Survival, %

Hemodialysis CAPD

80

80 60 40

All patients Hemodialysis CAPD

20

60 40 20

0

0 0

12

24

36

48

60

Months on dialysis

FIGURE 11-27 Survival of patients with systemic lupus erythematosus (SLE) on dialysis. Although initially dialysis treatment was not offered to patients with SLE because of the systemic nature of their illness, it later became clear that patients with SLE tolerate dialysis treatment as well as do patients with non-SLE renal diseases. The overall patient survival is good (90% at 5 years), and no differences exist in patient survival between those treated with continuous ambulatory peritoneal dialysis (CAPD) as compared with hemodialysis. (Data from Nossent et al. [65].)

0

1–10

>10

Maximal Nonrenal SLEDAI

FIGURE 11-28 Severity of systemic lupus erythematosus (SLE) disease activity during hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Lupus disease activity generally decreases during dialysis treatment. As assessed by the SLE Disease Activity Index (SLEDAI) [66], the maximal nonrenal SLEDAI decreased during dialysis in 49% of patients, remained stable in 42%, and showed progression in 9%. Despite the fact that immunosuppression was minimized, in 90% of patients cytotoxic drug therapy was discontinued and in 55% the dose of steroids was considerably reduced [65]. In addition, in this analysis no differences were found in disease activity in patients treated with either hemodialysis or CAPD. The maximal nonrenal SLEDAI scores were divided in three groups: 0, no extrarenal disease activity; 1 to 10, moderate extrarenal disease activity; over 10, high extrarenal disease activity.

11.16

Systemic Diseases and the Kidney 25

100

20 Number of patients

80 Actuarial Survival, %

Before dialysis During dialysis After transplantation

60

40 Patient/SLE Patient/non-SLE Graft/SLE Graft/non-SLE

20

15

10

5

0

0 0

12 24 Months after transplantation

0

36

1–10

>10

Maximal nonrenal SLEDAI score

FIGURE 11-29 Graft and patient survival after renal transplantation in patients with systemic lupus erythematosus (SLE). For this analysis only patients with first transplantations using a cadaveric donor kidney were included. Both graft and patient survival were calculated for 165 patients with SLE who received transplantation between 1984 and 1992. These data are compared with the results in 21,726 patients with non-SLE glomerular diseases who received transplantation in the same time period. Both graft and patient survival were not significantly different between the two groups. (From Berden [14]; with permission. Data from G. Persijn, Eurotransplant, Leiden, the Netherlands.)

FIGURE 11-30 Lupus disease activity after renal transplantation. Disease activity was assessed in 28 patients with systemic lupus erythematosus (SLE) by calculating the maximal nonrenal SLE Disease Activity Index (SLEDAI) in the time periods before dialysis, during dialysis, and after renal transplantation. The maximal nonrenal SLEDAI scores were divided in three groups: 0, no extrarenal disease activity; 1 to 10, moderate extrarenal disease activity; over 10, high extrarenal disease activity. Note that before dialysis all patients had extrarenal lupus disease activity but that after renal transplantation no patient had high disease activity. These data illustrate that the decrease in disease activity that begins during dialysis treatment continues after renal transplantation. In addition, recurrence of lupus nephritis after renal transplantation is rare [67]. (From Berden [14]; with permission. Data from Nossent et al. [68].)

Renal Involvement in Dysproteinemias Heavy chains

Light chains

Only light chains 17% IgD/IgE 1% IgG 59%

IgA 23%

None 10%

κ 60%

λ 30%

FIGURE 11-31 Frequency of isotypes of heavy and light chains produced by non–immunoglobulin (Ig) M myelomas. Most paraproteins produced belong to the IgG class. Note that in approximately 20% of myelomas only light chains are produced, of which two thirds belong to the  isotype and one third to the  isotype [69,70]. These frequency distributions mirror those of Ig classes and light chain isotypes in the serum.

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias

11.17

FIGURE 11-32 Incidence of renal involvement in dysproteinemias. This incidence is not identical for all paraproteinemias. The reason is directly related to the frequency and degree of light chain proteinuria [71]. Ig—immunoglobulin. (From Pruzanski [72]; with permission.)

100

90

80

Cumulative incidence, %

70 60

50 40

30 20

10

0 IgG

IgA

IgD

κ

λ

Paraproteinemia

Types of renal involvement in dysproteinemias Uncontrolled proliferation of single B cell Overproduction, secretion of monoclonal Ig or Ig fragment Monoclonal Ig deposition diseases Renal localization in different forms Fibrils

Crystals

Casts

Granular precipitates

AL (or AH) amyloidosis

Fanconi's syndrome

Myeloma cast nephropathy

LCDD LHCDD HCDD

Organized structures Tubules, fibrils Paraproteins Cryoglobulins Type I TypeII Immunotactoid GN Fibrillary GN

Nonamyloidotic

FIGURE 11-33 Types of renal involvement in dysproteinemias. The uncontrolled proliferation of a B-cell clone leads to overproduction of a monoclonal immunoglobulin (Ig), either an intact molecule or fragments thereof (light or heavy chains). These molecules can

deposit in the kidney and other vital organs, depending on the immunoglobulin class, light or heavy chain isotype, and other only partly understood physiochemical properties. The terminology used in these disorders is sometimes confusing and inconsistent. We use the definitions proposed by Gallo and Kumar [73]. All diseases characterized by deposits of monoclonal immunoglobulin–related material are named monoclonal immunoglobulin deposition diseases (MIDD). These deposits can occur in several forms, as outlined in the figure, and are identified by specific stains (such as congo red) and on immunofluorescence and electron microscopy. The histologic and clinical manifestations are dependent on the type of deposition. Included in this overview are fibrillary and immunotactoid glomerulonephritis, which in certain cases also show deposits containing monoclonal immunoglobulins. AH— heavy chain amyloidosis; AL—light chain amyloidosis; GN—glomerulonephritis; HCDD—heavy chain deposition disease; LCDD—light chain DD; LHCDD—light and heavy chain DD.

11.18

Systemic Diseases and the Kidney

Pathogenesis of renal lesions in dysproteinemias Deposition either as light chain, amyloid, or cryglobulins

Reabsorption of light chains Toxic injury

Glomerulus

Decreased sodium and light chain reabsorption and increased distal delivery Tubular atrophy

PCT

DT

Cortex Light chains filtered

Outer medulla

Plasma cell invasion

CCT

PR Cast injury

Giant cell infiltration interstitial infiltration

TAL LC + THP = cast

Inner medulla

FIGURE 11-34 Pathogenesis of the different types of renal lesions in dysproteinemias. Paraproteins can deposit in the glomerular basement membrane (GBM) (and tubular basement membrane [TBM]) either as light or heavy chains, unmodified immunoglobulins, amyloids, or cryoglobulins. Because of their size of 22 kD, light chains are freely filtered through the GBM. These light chains are then reabsorbed by proximal tubular cells. This process can induce a cascade of

events. Because some of these light chains are relatively resistant to proteolysis, they can induce lysosomal damage. This damage can give rise to functional impairment of the proximal tubular cell, leading to a decreased resorptive capacity (eg, for sodium and light chains) and thereby increasing the distal delivery. When this lysosomal overload leads to intracellular crystal formation, Fanconi’s syndrome may ensue. Increased distal delivery of light chains can then induce precipitation of light chains together with Tamm-Horsfall protein (THP) that is secreted in the loop of Henle. This precipitation is enhanced by an increased tubular fluid sodium chloride concentration. Other factors that enhance cast formation are listed in Figure 11-43. This intratubular cast formation leads to obstruction, tubular damage, and an interstitial inflammatory response with leakage of THP in the interstitium, inducing macrophage influx and giant cell formation. This entity is known as myeloma cast nephropathy. Finally, interstitial plasma cell invasion may occur in patients with myeloma, although this rarely leads to clinical symptoms and most often is only diagnosed by kidney biopsy specimen or is seen at autopsy. CCT—cortical collecting tubule; DT—distal tubule; LC—light chains; PCT—proximal convoluted tubule; PR—pars recta; TAL—thin ascending limb. (Adapted from Winearls [69].)

Histology of Renal Lesions in Dysproteinemias

A

FIGURE 11-35 (see Color Plate) Light chain amyloidosis. Amyloid deposits associated with dysproteinemias are predominantly composed of fragments of the light chain variable region (AL amyloidosis) and very rarely of fragments of heavy chain variable regions (AH amyloidosis) [74]. On light microscopy, this type of amyloid is indistinguishable from amyloid of other origin. The homogeneous and amorphous material, faintly pink-stained with eosin or sometimes brownish-stained with methenamine silver, is deposited in the mesangium and along the capillary loops of the glomeruli, in the vessels, and occasionally in the interstitium. Amyloid frequently is localized in the glomerular basement membrane (GBM) as sheaths of fibrils or spicules that are larger and more irregularly arranged than are the spikes in membranous glomerulopathy. Congo red–stained sections viewed under polarized light reveal the specific apple-green birefringence, the gold standard for the diagnosis. Amyloid deposits are sometimes stained with commercially available antisera against light chains. In addition, these deposits also are positive for amyloid P, heparan sulfate proteoglycan, and apolipoprotein E. On electron microscopy, amyloid is composed of long, randomly distributed, nonbranching fibrils with diameters of 8 to 12 nm. A, Amyloid deposits in mesangium and the capillary wall (arrows: spicules). (Continued on next page)

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias

11.19

FIGURE 11-35 (Continued) B, Amyloid deposits in the renal arteries in a congo red–stained slide and viewed under polarized light. Amyloid has an apple-green color. C, Immunofluorescence. Amyloid deposits in the mesangium stained with anti- antibodies. (Panel A, methenamine silver. Original magnification 550, 350, 400, respectively.)

B

C U

Pod

GBM

A

A

FIGURE 11-36 Light chain amyloidosis on electron microscopy. A, Characteristic fibrillar pattern of amyloid deposits. Long, randomly distributed, nonbranching fibrils with diameters of 8 to 12 nm. B, Amyloid fibrils in the capillary lumen and capillary wall with extension through the glomerular basement membrane (GBM) into the subepithelial space (arrow) fibrils arranged in parallel forming spicules). (Original magnification 48,000, 20,000, respectively.)

B

B

FIGURE 11-37 (see Color Plate) Light chain deposition disease. In about 60% of patients with this renal lesion, nodular expansion of the mesangium is seen that resembles nodular diabetic nephropathy [75,76]. The nodules stained purple with periodic acid–Schiff (PAS) stain have a homogeneous appearance, and those stained with methenamine silver are pink-brownish in color. In a few cases, a more mesangiocapillary pattern of injury is present. The tubular basement membranes (TBMs) are

thickened, as seen in the PAS-stained sections. In the remaining cases, no renal lesions can be seen on light microscopy. On immunofluorescence, linear staining of basement membranes of glomeruli, tubuli, and vessels can be observed for one of the light chains ( > ). In most cases, the TBMs are more heavily stained than are the glomerular basement membranes (GBMs). Congo red staining is negative for amyloid. On electron microscopy, fine granular electron-dense material can be found in most cases along the endothelial side of the GBM, in the mesangium, and along the interstitial side of the TBM. A few cases of heavy chain and of light and heavy chain deposition disease have been described, in most cases with identical morphologic characteristics as described in light chain deposition disease [77,78]. A, Nodular glomerulosclerosis with nodular increase of mesangial matrix. B, Linear staining of the GBM, mesangium, Bowman’s capsule, and TBM for the  light chain. (Continued on next page)

11.20

Systemic Diseases and the Kidney FIGURE 11-37 (Continued) C and D, Electron-dense granular deposits in the GBM (C) and around the TBM (D). L—capillary lumen; Pod— podocyte. (Panel A, methenamine silver. Original magnification 400, 400, 15,000, 6500, respectively.)

Pod

GBM L

TBM

C

D

A

B

D

C

FIGURE 11-38 Cast nephropathy. The casts have a homogeneous, fractured, or crystalline appearance with sharp angular or irregular edges and are present in the distal and collecting tubules [73]. These casts are composed of aggregated  or  light chains mixed with Tamm-Horsfall protein (THP). Sometimes the tubular cells shows necrosis accompanied by disruptions of the tubular basement membrane (TBM). Proximal tubular cells show hyaline droplets or vacuoles with needlelike, tubular, or complex crystalline material. Casts are surrounded by macrophages and multinucleated giant cells. On electron microscopy, the casts have a granular, homogeneous, or fibrillary appearance with occasional needlelike crystals. The fibrils that surround the casts are probably THP. In most cases, a varying degree of interstitial fibrosis exists, accompanied by mononuclear cell infiltration and tubular atrophy. Congo red staining for amyloid is usually negative. The glomeruli are normal. A, Low magnification with casts in the distal tubules, and interstitial fibrosis with atrophic tubules (chronic tubulointerstitial nephritis). B, Brown-colored cast surrounded by macrophages. C, Eosinophilic homogeneous cast. D, Immunofluorescence. Casts are stained for  light chains. (Panels A, B, C, methenamine silver. Original magnification 160, 400, 600, 200, respectively.)

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias

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FIGURE 11-39 Fanconi’s syndrome in a patient with  light chain proteinuria. A, Vacuolization of proximal tubular epithelial cells. Vacuoles contain light-brown-colored material. B, Immunofluorescence. The granular material in tubular cells is stained for  light chains. C, Low-power view of a proximal tubular epithelial cell with vacuoles containing organized or crystalline material. D, High-power view of the vacuoles containing tubular or ladderlike crystalline structures. BB—brush border. (Panel A, methenamine silver. Original magnification 600, 400, 7000, 19,000, respectively.)

A

B BB

C

D

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Systemic Diseases and the Kidney

C A

FIGURE 11-40 Glomerular deposition of immunoglobulin A- paraproteins. No paraproteins or cryoglobulins could be found in the serum of this patient. In addition, the urinary excretion of light chains was not detectable. A, A mesangiocapillary pattern of injury with deposition of eosinophilic material in the capillary wall and mesangium. B, Immunofluorescence. The deposits were positive for  light chains (and immunoglobulin A). C, Ultrastructurally, below the glomerular basement membrane, organized deposits composed of parallel arranged fibrils or gridlike structures can be seen. (Panel A, methenamine silver, original magnification 400, 400, 25,000, respectively.)

B

A FIGURE 11-41 (see Color Plate) Glomerular deposition of immunoglobulin G– in a patient with multiple myeloma. A, Glomerulus with many intracapillary protein thrombi. B, The material was composed of

B closely packed tubules arranged in parallel. (Panel A, toluidine blue. Original magnification 600, 130,000, respectively.)

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias

A

D

A

B

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C

FIGURE 11-42 Mixed cryoglobulinemia. Of the three types of cryoglobulins, types I and II contain monoclonal immunoglobulins (Ig). Type I cryoglobulins occur in monoclonal gammopathies and lymphomas and consist of a single monoclonal immunoglobulin. Type II cryoglobulins (also called mixed cryoglobulinemia) occur in systemic infections, autoimmune diseases, and malignancies. Type II cryoglobulins consist of two components, a monoclonal immunoglobulin, most frequently IgM, with rheumatoid factor activity directed to the polyclonal IgG component. Various patterns of glomerular injury can be found, such as a diffuse endocapillary proliferative glomerulonephritis with a prominent influx of monocytes, or a mesangiocapillary glomerulonephritis. Less frequently, a diffuse mesangial proliferative, sclerosing glomerulonephritis, or both can be seen. Eosinophilic aggregates along the glomerular basement membrane (GBM) or in the lumina designated as thrombi frequently are present. Type II cryoglobulinemia is sometimes accompanied by a vasculitis. The aggregates in the glomeruli of type I, as seen on immunofluorescence, have a composition identical to that of the cryoglobulins in the serum. The deposits in type II contain IgG, IgM, and complement. Ultrastructurally, the deposits usually demonstrate an organized or crystalline appearance. In type I, the deposits frequently are organized in closely packed fibrils, long tubules, or crystals. In type II, short tubulo-annular structures can be found. Sometimes aggregates in the glomeruli composed of a single monoclonal immunoglobulin component can be demonstrated in patients without evidence of a monoclonal immunoglobulin or cryoglobulins in the serum. A, Diffuse endocapillary proliferative glomerulonephritis with prominent influx of mononuclear cells. B, Mixed pattern of injury in a patient with Sjögren’s syndrome. Intracapillary thrombi, increase of mesangial cells and matrix, and occasionally duplication of the GBM. C, Immunofluorescence with staining for IgM. D, Electron microscopy of tubular and annular structures in the glomerular deposits. (Parts A, B, methenamine silver. Original magnification 400, 400, 200, 120,000, respectively.)

B

FIGURE 11-43 Biopsy specimen of immunotactoid glomerulonephritis with immunoglobulin A– deposits. The patient had no signs of a monoclonal gammopathy or lymphoma. A, Mild increase of mesangial matrix with segmental irregularity of the capillary wall. B, Immunofluorescence. The deposits are positive for  (and immunoglobulin A) C, Below the glomerular basement membrane, seen is an accumulation of short microtubules with a diameter of about 30 nm. (Part A, methenamine silver. Original magnification 400, 400, 25,000, respectively.) (Continued on next page)

11.24

Systemic Diseases and the Kidney FIGURE 11-43 (Continued) Immunotactoid and fibrillary glomerulonephritis are comprised of lesions characterized by the deposition of immunoglobulins (and complement) arranged in randomly distributed fibrils or microtubules in the capillary wall and mesangium [89,90]. These lesions are thicker than are amyloid fibrils and are negative on congo-red staining. Although presently it is not clear whether these forms of glomerulonephritis are different disease entities or are different morphologic expressions of one disease, some morphologic and clinical features exist that suggest fibrillary glomerulonephritis must be distinguished from immunotactoid glomerulonephritis [91]. Immunotactoid glomerulonephritis shows deposition of microtubules with diameters of 35 to 50 nm and commonly is associated with a lymphoproliferative disease. The deposited immunoglobulins frequently are of monoclonal composition. In contrast, fibrillary glomerulonephritis is characterized by fibrils with diameters of about 18 to 20 nm. The deposited immunoglobulins usually are polyclonal and very rarely monoclonal. An association with a lymphoproliferative disease is uncommon in contrast to immunotactoid glomerulonephritis.

C

A

C FIGURE 11-44 Fibrillary glomerulonephritis. A, Moderate widening of mesangial areas by increase of matrix. B, Immunofluorescence. Heavy staining for IgG (and complement,  and  light chains). C, Ultrastructurally, randomly distributed long fibrils with diameters of 18 to 22 nm are localized in the capillary wall. (Panel A, methenamine silver. Original magnification 400, 300, 27,000, respectively.)

B

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias

CLINICAL PRESENTATION, FREQUENCY, AND CAUSES OF RENAL INVOLVEMENT IN DYSPROTEINEMIAS Acute deterioration of renal function (5–10%) Dehydration Hypercalcemia Cast nephropathy Crescentic glomerulonephritis Chronic renal insufficiency (45–75%) Myeloma cast nephropathy Light chain (AL) amyloidosis Interstitial plasma cell infiltration (rare) Proteinuria-nephrotic syndrome (50–80%) Light chain (AL) amyloidosis Light chain deposition disease Heavy chain deposition disease Cryoglobulinemic glomerular lesions Fanconi’s syndrome (1%) Secondary lesions (20–30%) Pyelonephritis Nephrocalcinosis Hyperuricemic nephropathy

FIGURE 11-45 Renal involvement in dysproteinemias can lead to different clinical manifestations: acute renal failure; progressive deterioration of renal function; proteinuria, which very often is in the nephrotic range; or, seldom, Fanconi’s syndrome. Furthermore, a number of secondary conditions may occur that can induce additional renal damage. Certain features are associated with particular clinical symptoms. The type of clinical lesion that develops is predominantly determined by the so-called nephrotoxic characteristics of the excreted light chains, as demonstrated by infusion of light chains into mice. These infusions led to the same type of renal lesion as in humans [79,80]. Some of these nephrotoxic factors are listed in Figure 11-43.

11.25

RISK FACTORS FOR RENAL INVOLVEMENT IN DYSPROTEINEMIAS Factors enhancing amyloid formation Unfolding of paraprotein  Light chain Factors enhancing cast nephropathy High urinary excretion of light chains Binding of light chain to Tamm-Horsfall protein (THP) Iso-electric point of light chain ≥5.1 ? (enhances binding to anionic THP (pI:3.2) Tendency to self-aggregation of light chains  Light chain High levels of acute-phase proteins Resistance of light chain to urinary or macrophage-derived proteases Factors enhancing monoclonal immunoglobulin deposition  Light chain Presence of hydrophobic aminoacids in CDR1 or CDR2 of VL-chain Deletion of CH1 domain Fc part immunoglobulin Factors enhancing acute renal failure Hypercalcemia (19–44%)* Dehydration (10–65%) Urinary tract infection (8–44%) Nephrotoxic drugs (aminoglycosides; nonsteroidal anti-inflammatory drugs) (0–26%) Intravenous radio contrast media (0–11%) Loop diuretics *Percentage of patients in which this factor contributed to the development of acute renal failure. From Winearls [69]; with permission.

FIGURE 11-46 Factors reported in the literature to be associated with development of the different renal lesions in patients with myeloma are summarized. The amyloidogenic potential is enhanced by certain amino acids that promote unfolding of the light chain and by the  isotype of the light chain. In amyloidosis, the variable regions of the light chains are deposited predominantly after metabolization by macrophages. A number of factors have been characterized that enhance the binding of light chains to Tamm-Horsfall protein (THP), which is a critical event in the development of cast nephropathy. In monoclonal immunoglobulin deposition diseases, the granular deposits are composed mainly of the constant regions of light (and seldom heavy) chains. Hypercalcemia, which frequently occurs in patients with myeloma and results from increased interleukin-6–mediated bone resorption, can contribute to renal impairment by way of different mechanisms: dehydration (hyperemesis and nephrogenic diabetes insipidus), induction of nephrocalcinosis, and enhancement of light chain aggregation with THP. All other factors either diminish tubular flow or increase distal tubular sodium concentration, thereby again enhancing cast formation.

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TREATMENT OF RENAL LESIONS IN DYSPROTEINEMIAS Renal therapy

Antitumor therapy

Preventive measures: Rehydration, forced diuresis (>3 L/24 h) Correction hypercalcemia Alkalinization of urine (pH ≥7) Cessation of nephrotoxic drugs Treatment of infections Colchicine ? Plasmapheresis in acute renal failure Recovery of renal function increases from 0–18% in the control group to 43–84% with plasmapheresis Dialysis 54% survival after 1 y, and 25% after 2 y Theoretically, PD could result in a better removal of light chains Renal transplantation Light chain amyloidosis: 29 patients; high nonrenal mortality rate, 30% recurrence rate Light chain deposition disease: 12 patients; 50% recurrence rate Cryoglobulinemia: 50% recurrence rate Multiple myeloma: 18 patients with low-grade disease; 8 alive, 5 succumbed to infection, and 5 to recurrence

Melphalan-prednisone First-line therapy: 45% remission rate

Vincristine-adriamycine-dexamethazone (VAD)* Second-line therapy: relapses, 40% remission; refractory cases, 25% remission High-dose chemotherapy and bone marrow transplantation Relatively good results in patients without renal involvement. No data for patients with renal involvement

*VAD protocol has the advantage that drug metabolism is independent of kidney function, whereas the melphalan dose must be adjusted to renal function.

FIGURE 11-47 Treatment should be directed at ameliorating the renal lesion and reduction of the production of paraproteins. In patients with myeloma it is very important to prevent situations that could precipitate acute renal failure. In this respect, dehydration and hypercalcemia are very harmful. Measures should be taken to maintain a high fluid intake. When radiocontrast agents are necessary, hydration before the study decreases the chance of intratubular cast formation between light chains and the contrast agent. Alkalization of the urine can reduce the interaction between light chains and TammHorsfall protein (THP). Nephrotoxic drugs (such as nonsteroidal anti-inflammatory drugs and gentamycin) should not be used because they further enhance tubular dysfunction. Experimental studies suggest that colchicine may be helpful in reducing cast formation either by decreasing THP secretion or modifying the interaction between THP and light chains. Presently, no data exist that document the clinical efficacy of this treatment. Plasmapheresis has the potential to remove the toxic light chains from the circulation, although in certain patients the serum concentration can be rather low. Plasmapheresis alone does not reduce the rate of production of the paraprotein; therefore, this treatment should be combined with chemotherapy. Patients with extensive cast formation and interstitial changes seem to respond less well to

plasmapheresis that do those without cast formation and interstitial changes [81]. Of two controlled studies, only one showed a beneficial effect of addition of plasmapheresis to chemotherapy [82,83]. The major determinant for success seems to be a good response to chemotherapy [83]. Furthermore, patients with extensive cast formation and interstitial changes seem to respond less well to chemotherapy than do those without cast formation and interstitial changes [81,83]. The patient with end-stage renal disease can be treated with dialysis, although survival is poor and dependent on the success of chemotherapy. The experience of renal transplantation in patients with dysproteinemias is, for obvious reasons, rather limited. The results are rather disappointing with a high mortality rate, especially in patients with multiple myeloma and amyloidosis. Patients surviving for more than 1 year show a high recurrence rate [84–87]. Discussion of antitumor therapy is beyond the scope of this review. Briefly, treatment with melphalan and prednisone is considered to be the first choice, whereas more aggressive treatment with vincristine-adriamycin-dexamethasone is given to patients who do not respond to or who relapse after melphalan and prednisone therapy. Recently, more encouraging results have been obtained with ablative chemotherapy and stem-cell reinfusion [88]. PD—peritoneal dialysis.

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias

11.27

Renal Involvement in Rheumatic Diseases Causes of renal involvement in rheumatoid arthritis MGN 14%

MesPGN 23%

AA amyloidosis 18% No lesions 15% TIN 9% Vasculitis, CGN, other 21%

FIGURE 11-48 Causes of renal involvement in rheumatoid arthritis. In rheumatoid arthritis, a variety of renal disorders may occur secondary to either the underlying disease or to drugs used to treat it. The most frequent abnormality is a mesangial proliferative glomerulonephritis (MesPGN) with, in most cases, only mesangial immunoglobulin M (IgM) and sometimes IgA and complement 3 (C3) deposits. IgG and C1q deposits are very rare. A correlation exists with the levels of rheumatoid factor; however, the underlying mechanism is unclear. Clinically, MPGN is characterized by hematuria and proteinuria. Membranous glomerulopathy (MGN) in rheumatoid arthritis is mostly associated with gold or D-penicillamine treatment. MGN is seen more frequently in patients after therapy with D-penicillamine (7–14%) than after gold therapy (3–9%). When a patient

RENAL MANIFESTATIONS IN SJÖGREN’S SYNDROME Manifestation Interstitial nephritis with or without tubular dysfunction Tubular dysfunction (distal > proximal) associated with interstitial infiltrates and granuloma formation Clinical symptoms: Type 1 renal tubular acidosis Fanconi’s syndrome Nephrogenic diabetes insipidus Hypokalemia Glomerulonephritis Mesangiocapillary glomerulonephritis Membranous glomerulonephritis Vasculitis Mostly extrarenal (skin, muscle, nerve); occasionally in the kidney

% 30–60 20–25

3–5

<5

is positive for HLA-DR3 the risk for gold-induced MGN increases 10- to 30-fold and that for D-penicillamine increases 3- to 10-fold. Discontinuation of therapy leads to remission of the proteinurianephrotic syndrome in almost all cases, although it may be a year before complete recovery is achieved. MGN may occur in patients with rheumatoid arthritis not treated with gold or D-penicillamine. The mechanism for this is not clear. Amyloidosis is associated with active joint disease. This type of amyloidosis is secondary to the deposition of the acute-phase reactant serum amyloid A (SAA) protein. This SAA is partly digested by macrophages and deposited in the tissues as AA amyloid. When a patient with active rheumatoid arthritis develops a nephrotic syndrome, AA amyloidosis is the most likely cause. No good treatment options exist for AA amyloidosis, other than treating the underlying disease. Renal transplantation in these patients is associated with a 3-year patient survival rate of 50% [92]. Especially in the early period after transplantation, there were high cardiovascular- and infection-related mortality rates. The rate of recurrence was approximately 20%. The development of tubulointerstitial nephritis (TIN) in patients with rheumatoid arthritis is related to the prolonged use of analgesics, especially multicomponent analgesics and nonsteroidal antiinflammatory drugs. A number of other renal conditions may develop in patients with rheumatoid arthritis. Vasculitis is associated with long-standing and nodular rheumatoid arthritis with high levels of rheumatoid factor. This condition may be associated with a crescentic glomerulonephritis (CGN) that, on immunofluorescence, is negative for immunoglobulin and complement deposits, as in Wegener’s granulomatosis. The best treatment consists of cyclophosphamide and prednisone. References 93 and 94 provide more details on renal involvement in rheumatoid arthritis. Because the histologic abnormalities are not specific for rheumatoid arthritis, no histologic examples are given. They can be found elsewhere in this book. (Data from Emery and Adu [94].) FIGURE 11-49 The clinical manifestations of the tubulointerstitial nephritis in Sjögren’s syndrome can vary and depend on localization of the functional impairment. Occasionally, symptoms of tubular dysfunction precede development of symptoms of Sjögren’s syndrome. It is unclear what causes these tubular dysfunctions. When the degree of tubulointerstitial damage is not chronic, corticosteroids are beneficial. Glomerular involvement is rare in Sjögren’s syndrome. When a glomerulonephritis is present, the patient should be evaluated for the presence of cryoglobulins and existence of systemic lupus erythematosus. Reference 95 provides a more detailed description of this subject.

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RENAL INVOLVEMENT IN SCLERODERMA Incidence of renal involvement

Risk factors for renal crisis

Clinical characteristics of renal crisis

Therapy for renal crisis

Based on autopsy studies, 60–70% Based on clinical symptoms, 30–50% Scleroderma renal crisis, 10–15%

Diffuse form of scleroderma Rapid progression of skin lesions HLA BW35, DR3, DR5 Race (Blacks > whites) Use of corticosteroids or cyclosporine A? Cold exposure ?

Acute onset Marked to severe (malignant) hypertension (10% of patients remain normotensive) Features of malignant hypertension Micro-angiopathic hemolytic anemia and thrombopenia Mostly normal urinary sediment (in cases with malignant hypertension hematuria possible) Progressive decline of renal function

Prevention of reduction of renal perfusion (eg, dehydration, diuretics, cyclosporin A, nonsteroidal anti-inflammatory drugs) Angiotensin-converting enzyme inhibitors (even in patients with normotension) Renal replacement therapy

FIGURE 11-50 The main features of renal involvement in scleroderma are summarized. The major manifestation is the so-called renal crisis. Besides this often life-threatening manifestation, other patients may display milder forms of renal involvement, clinically characterized by mild proteinuria or slight deterioration of kidney function. Renal involvement is more common in patients with the diffuse form of scleroderma that is serologically characterized by antibodies against topoisomerase I or RNA polymerase III. Patients with progressive skin disease should be monitored carefully for hypertension and signs of renal involvement. Early institution of angiotensin-converting enzyme (ACE) inhibition in patients with micro-albuminuria can prevent further deterioration of kidney function [96,97]. ACE inhibition is also

the mainstay of treatment for patients with scleroderma renal crisis, because it will significantly reduce progression to renal failure, increase the chance of recovery if renal failure has already developed, and improve the 1-year patient survival rate. Renal replacement therapy (hemodialysis or continuous ambulatory peritoneal dialysis) should be offered to patients whose renal function does not recover. The patient survival rate, however, is lower than in patients with other collagen-vascular diseases such as lupus nephritis. Limited experience with renal transplantation indicates that successful transplantation is possible, especially in patients with quiescent disease. Recurrence in the transplanted kidney has been reported [84]. References 96 to 98 provide more extensive reviews on the subject. FIGURE 11-51 Scleroderma. In the acute phase, small- and medium-sized renal arteries show mucoid thickening of the intima with severe narrowing of the lumen. Sometimes these lesions are accompanied by thrombosis and fibrinoid necrosis of the arterioles and glomeruli. Morphologically, the vascular alterations resemble malignant nephrosclerosis (malignant hypertension) or hemolytic-uremic syndrome. In the chronic phase, the mucoid intimal material is replaced by fibrous tissue. A, Severe narrowing of a small-sized renal artery owing to extensive endothelial widening with ischemia of glomeruli. B, Accumulation of mucopolysaccharide material in the widened endothelial layer. (Continued on next page)

A

B

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FIGURE 11-51 (Continued) C, Severe intimal fibrosis of a medium-sized artery of a more chronic phase of scleroderma. (Panel A, methenamine silver, original magnification 100. Panel B, alcian blue stain, original magnification 100. Panel C, cellulose acetate butyrate stain, original magnification 150.)

C

References 1. Tan EM, Cohen AS, Fries JF, et al.: The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheumatol 1982, 25:1271–1277. 2. Maddison PJ: Systemic lupus erythematosus variants. In Slide Atlas of Rheumatology. Edited by Dieppe PA, Bacon PA, Bamji AN, Watt I. London: Gower; 1984:9.1–9.14. 3. Aarden LA, De Groot ER, Feltkamp TEW: Immunology of DNA. III. Crithidia luciliae: a simple substrate for the detection of anti-dsDNA with the immunofluorescence technique. Ann NY Acad Sci 1975, 254:505–509. 4. Smeenk RJT, Berden JHM, Swaak AJG: dsDNA autoantibodies. In Autoantibodies. Edited by Peter JB, Shoenfeld Y. Amsterdam: Elsevier; 1996:227–236. 5. Klippel JH, Croft JD: Systemic lupus erythematosus. In Slide Atlas of Rheumatology. Edited by Dieppe PA, Bacon PA, Bamji AN, Watt I. London: Gower; 1984:8.1–8.14. 6. ter Borg EJ, Horst G, Hummel EJ, et al.: Predictive value of rises in anti–double-stranded DNA antibody levels for disease exacerbations in systemic lupus erythematosus: a long term prospective study. Arthritis Rheumatol 1990, 33:634–643. 7. Verheyen R, Salden M, Van Venrooij WJ: Protein blotting. In Manual of Biological Markers of Disease. Edited by van Venrooij WJ, Maini RN. Dordrecht: Kluwer; 1997:A4.1–A4.25. 8. Van Venrooij WJ, De Rooij DJ, van de Putte LBA, Habets WJ: De serologische herkenning van gedefinieerde kernantigenen bij collageenziekten: immunoblotting als nieuw diagnostisch middel. Ned Tijdschr Geneeskd 1985, 129:1124–1129. 9. Watanabe-Fukunaga R, Brannan CI, Copeland NG, et al.: Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 1992, 356:314–317. 10. Singer GG, Carrera AC, Marshak-Rothstein A, et al.: Apoptosis, Fas and systemic autoimmunity: the MRL/lpr model. Curr Opinion Immunol 1994, 6:913–920. 11. Tax WJM, Kramers C, van Bruggen MCJ, Berden JHM: Apoptosis, nucleosomes, and nephritis in systemic lupus erythematosus. Kidney Int 1995, 48:666–673. 1. Berden JHM: Systemic lupus erythematosus: disturbed apoptosis? Ned Tijdschr Geneeskd 1997, 141:1848–1854. 13. Rumore PM, Steinman CR: Endogenous circulating DNA in systemic lupus erythematosus. Occurrence as multimeric complexes bound to histone. J Clin Invest 1990, 86:69–74. 14. Berden JHM: Lupus nephritis. Nephrology Forum. Kidney Int 1997, 52:538–558.

15. Mohan C, Adams S, Stanik V, Datta SK: Nucleosome, a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J Exp Med 1993, 177:1367–1381. 16. Kaliyaperumal A, Mohan C, Wu W, Datta SK: Nucleosomal peptide epitopes for nephritis-inducing T helper cells of murine lupus. J Exp Med 1996, 183:2459–2469. 17. Burlingame RW, Rubin RL, Balderas RS, Theofilopoulos AN: Genesis and evolution of anti-chromatin autoantibodies in murine lupus implicates T-dependent immunization with self antigen. J Clin Invest 1993, 91:1687–1696. 18. Amoura Z, Chabre H, Koutouzov S, et al.: Nucleosome-restricted antibodies are detected before anti-dsDNA and/or antihistone antibodies in serum of MRL-Mp lpr/lpr and +/+ mice, and are present in kidney eluates of lupus mice with proteinuria. Arthritis Rheumatol 1994, 37:1684–1688. 19. Burlingame RW, Boey ML, Starkebaum G, Rubin RL: The central role of chromatin in autoimmune responses to histones and DNA in systemic lupus erythematosus. J Clin Invest 1994, 94:184–192. 20. Chabre H, Amoura Z, Piette JC, et al.: Presence of nucleosomerestricted antibodies in patients with systemic lupus erythematosus. Arthritis Rheumatol 1995, 38:1485–1491. 21. Kramers C, Hylkema MN, van Bruggen MCJ, et al.: Anti-nucleosome antibodies complexed to nucleosomal antigens show anti-DNA reactivity and bind to rat glomerular basement membrane in vivo. J Clin Invest 1994, 94:568–577. 22. van Bruggen MCJ, Kramers C, Hylkema MN, et al.: Significance of antinuclear and anti-extra cellular matrix auto-antibodies for albuminuria in MRL/l mice. A longitudinal study on plasma and glomerular eluates. Clin Exp Immunol 1996, 105:132–139. 23. van Bruggen MCJ, Kramers C, Walgreen B, et al.: Nucleosomes and histones are present in glomerular deposits in human lupus nephritis. Nephrol Dial Transplant 1997, 12:57–66. 24. van den Born J, van den Heuvel LPWJ, Bakker MAH, et al.: Distribution of GBM heparan sulphate proteoglycan core protein and side chains in human glomerular diseases. Kidney Int 1993, 43:454–463. 25. van Bruggen MCJ, Kramers C, Hylkema MN, et al.: Decrease of heparan sulfate staining in the glomerular basement membrane in murine lupus nephritis. Am J Pathol 1995, 146:753–763. 26. van Bruggen MCJ, Walgreen B, Rijke GPM, et al.: Heparin and heparinoids prevent the binding of immune complexes containing nucleosomal antigens to the GBM and delay nephritis in MRL/l mice. Kidney Int 1996, 50:1555–1564.

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27. Strasser A, Whittingham S, Vaux DL, et al.: Enforced bcl-2 expression in B-lymphoid cells prolongs antibody responses and exhibits autoimmune diseases. Proc Natl Acad Sci USA 1991, 88:8661–8665. 28. Mysler E, Bini P, Drappa J, et al.: The apoptosis-1/Fas protein in human systemic lupus erythematosus. J Clin Invest 1994, 93:1029–1034. 29. Lorenz H, Gruenke M, Hieronymus T, et al.: In vitro apoptosis and expression of apoptosis related molecules in lymphocytes from patients with systemic lupus erythematosus and other autoimmune diseases. Arthritis Rheumatol 1997, 40:306–317. 30. Cheng J, Zhou T, Liu C, et al.: Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science 1994, 263:1759–1762. 31. Goel N, Ulrich DT, St.Clair EW, et al.: Lack of correlation between serum soluble Fas/APO-1 levels and autoimmune disease. Arthritis Rheumatol 1995, 38:1738–1743. 32. Knipping E, Krammer PH, Onel KB, et al.: Levels of soluble Fas/APO1/CD95 in systemic lupus erythematosus and juvenile rheumatoid arthritis. Arthritis Rheumatol 1995, 38:1735–1737. 33. Emlen W, Niebur J, Kadera R: Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus. J Immunol 1994, 152:3685–3692. 34. Kovacs B, Vassilopoulos D, Vogelgesang SA, Tsokos GC: Defective CD3mediated cell death in activated T cells from patients with systemic lupus erythematosus: role of decreased intracellular TNF-. Clin Immunol Immunopathol 1996, 81:293–302. 35. Casciola-Rosen LA, Anhalt G, Rosen A: DNA-dependent protein kinase is one of a subset of autoantigens specifically cleaved early during apoptosis. J Exp Med 1995, 182:1625–1634. 36. Casiano CA, Martin SJ, Green DR, Tan EM: Selective cleavage of nuclear autoantigens during CD95(Fas/APO-1)-mediated T cell apoptosis. J Exp Med 1996, 183:765–770. 37. Rosen A, Casciola-Rosen LA: Macromolecular substrates for the ICElike proteases during apoptosis. J Cell Biochem 1997, 64:50–54. 38. Casiano C, Tan EM: Recent developments in the understanding of antinuclear autoantibodies. Int Arch Allergy Immunol 1996, 111:308–313. 39. Utz P, Hottelet M, Schur PH, Anderson P: Proteins phosphorylated during stress-induced apoptosis are common targets for autoantibody production in patients with systemic lupus erythematosus. J Exp Med 1997, 185:843–854. 40. Cooke MS, Mistry N, Wood C, et al.: Immunogenicity of DNA damaged by reactive oxygen species. Implications for anti-DNA antibodies in lupus. Free Rad Bio Med 1997, 22:151–159. 41. Casciola-Rosen LA, Anhalt G, Rosen A: Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med 1994, 179:1317–1330. 42. Jordan P, Kuebler D: Autoimmune diseases: nuclear autoantigens can be found at the cell surface. Mol Biol Rep 1996, 22:63–66. 43. Hermann M, Voll RE, Zoller RM, et al.: Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum 1998, 41:1241–1250. 44. Mamula MJ: Lupus autoimmunity: from peptides to particles. Immunol Rev 1995, 144:301–314. 45. Datta SK, Kaliyaperumal A: Nucleosome-driven autoimmune response in lupus. Pathogenic T helper cell epitopes and co-stimulatory signals. In B Lymphocytes and Autoimmunity. Edited by Chiorazzi N, Lahita RG, Pavelka K, Ferrarini M. New York: New York Academy of Sciences; 1997:155–170. 46. Churg J, Sobin LH: Lupus nephritis. In Renal Diseases. Classification and Atlas of Glomerular Diseases. Edited by Churg J. Tokyo: IgakuShoin; 1982:127–149. 47. Churg J, Bernstein J, Glassock RJ: Lupus nephritis. In Renal Diseases. Classification and Atlas of Glomerular Diseases, edn 2. Edited by Churg J, Bernstein J, Glassock RJ. New York: Igaku-Shoin; 1995:151–180. 48. D’Agati VD: Systemic lupus erythematosus. In Renal Biopsy Interpretation. Edited by Silva FG, D’Agati VD, Nadasdy T. New York: Churchill Livingstone; 1996:181–220.

49. Austin III HA, Muenz LR, Joyce KM, et al.: Diffuse proliferative lupus nephritis: identification of specific pathologic features affecting renal outcome. Kidney Int 1984, 25:689–695. 50. Appel GB, Silva FG, Pirani CL, et al.: Renal involvement in systemic lupus erythematosus. Medicine 1975, 57:371–410. 51. Sloan RP, Schwartz MM, Korbet SM, Borok RZ, and the Lupus Nephritis Collaborative Study Group: Long-term outcome in systemic lupus erythematosus membranous glomerulonephritis. J Am Soc Nephrol 1996, 7:299–305. 52. Bruns FJ, Adler S, Fraley DS, Segel DP: Sustained remission of membranous glomerulonephritis after cyclophosphamide and prednisone. Ann Intern Med 1991, 114:725–730. 53. Reichert LJM, Huysmans FTM, Assmann KJM, et al.: Preserving renal function in patients with membranous nephropathy: daily oral chlorambucil compared with intermittent monthly pulses of cyclophosphamide. Ann Intern Med 1994, 121:328–333. 54. Falk RJ, Hogan SL, Muller KE, Jenette C, and the Glomerular Disease Collaborative Network: Treatment of progressive membranous glomerulopathy. A randomized trial comparing cyclophosphamide and corticosteroids with corticosteroids alone. Ann Intern Med 1992, 116:438–445. 55. Appel GB, Valeri A: The course and treatment of lupus nephritis. Ann Rev Med 1994, 45:525–537. 56. Austin III HA, Klippel JH, Balow JE, et al.: Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med 1986, 314:614–619. 57. Cameron JS: What is the role of long-term cytotoxic agents in the treatment of lupus nephritis? J Nephrol 1993, 6:172–176. 58. Balow JE, Austin III HA, Muenz LR, et al.: Effect of treatment of the evolution of renal abnormalities in lupus nephritis. N Engl J Med 1984, 311:491–495. 59. Steinberg AD, Steinberg SC: Longterm preservation of renal function in patients with lupus nephritis receiving treatment that includes cyclophosphamide versus those treated with prednisone only. Arthritis Rheumatol 1991, 34:945–950. 60. Esdaile JM, Levinton C, Federgreen W, et al.: The clinical and renal biopsy predictors of long term outcome in lupus nephritis. Q J Med 1989, 72:779–833. 61. Ponticelli C, Zucchelli P, Moroni G, et al.: Long-term prognosis of diffuse lupus nephritis. Clin Nephrol 1987, 28:263–271. 62. Cameron JS, Turner BR, Ogg CS, et al.: Systemic lupus with nephritis: a long term study. Q J Med 1979, 48:1–24. 63. Bansal VK, Beto JA: Treatment of lupus nephritis: a meta-analysis of clinical trials. Am J Kidney Dis 1997, 29:193–199. 64. Nossent HC, Henzen-Logmans SC, Vroom TM, et al.: Contribution of renal biopsy data in predicting outcome in lupus nephritis. Arthritis Rheumatol 1990, 33:970–977. 65. Nossent JC, Swaak AJG, Berden JHM: Systemic lupus erythematosus: analysis of disease activity in 55 patients with end stage renal failure treated with hemodialysis or continuous ambulatory peritoneal dialysis. Am J Med 1990, 89:169–174. 66. Bombardier C, Gladman DD, Urowitz MB, et al.: Derivation of the SLEDAI. A disease activity index for lupus patients. Committee on Prognosis Studies in SLE. Arthritis Rheumatol 1992, 35:630–640. 67. Nossent JC: End stage renal disease in patients with systemic lupus erythematosus. In Lupus Nephritis. Edited by Lewis EJ. Oxford: Oxford University Press; 1998: in press. 68. Nossent JC, Swaak AJG, Berden JHM: Systemic lupus erythematosus after renal transplantation: patient and graft survival and disease activity. Ann Intern Med 1991, 114:183–188. 69. Winearls CG: Acute myeloma kidney. Nephrology Forum. Kidney Int 1995, 48:1347–1361. 70. Kyle RA: Multiple myeloma. Review of 869 cases. Mayo Clin Proc 1975, 50:29–40. 71. Alexanian R, Barlogie B, Dixon D: Renal failure in multiple myeloma. Pathogenesis and prognostic implications. Arch Int Med 1990, 150:1693–1695.

Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 72. Pruzanski W: Clinical manifestations of multiple myeloma: relation to class and type of the M component. Can Med Assoc J 1976, 114:896–897. 73. Gallo G, Kumar V: Hematopoietic disorders. In Renal Biopsy Interpretation. Edited by Silva FG, D’Agati VD, Nadasdy T. New York: Churchill Livingstone; 1996:259–282. 74. Enlitz M, Weiss DT, Solomon A: Immunoglobulin heavy-chain-associated amyloidosis. Proc Natl Acad Sci USA 1990, 87:6542–6546. 75. Preudhomme JL, Aucouturier P, Touchard G, et al.: Monoclonal immunoglobulin deposition disease (Randall type). Relationship with structural abnormalities of immunoglobulin chains. Kidney Int 1994, 46:965–972. 76. Sanders PW, Herrera GA: Monoclonal immunoglobulin light chainrelated renal diseases. Semin Nephrol 1993, 13:324–341. 77. Buxbaum JN, Chuba JV, Hellman GC, et al.: Monoclonal immunoglobulin deposition disease: light chain and light and heavy chain deposition diseases and their relation to light chain amyloidosis: clinical features, immunopathology, and molecular analyses. Ann Intern Med 1990, 112:455–464. 78. Autocouterier P, Khamlichi AA, Touchard G, et al.: Brief report: heavychain deposition disease. Nucl Acids Res 1993, 329:1389–1393. 79. Solomon A, Weiss DT, Kattine AA: Nephrotoxic potential of Bence Jones proteins. N Engl J Med 1991, 324:1845–1851. 80. Sanders PW, Booker BB: Pathobiology of cast nephropathy from human Bence Jones proteins. J Clin Invest 1992, 89:630–639. 81. Johnson WJ, Kyle RA, Pineda AA, et al.: Treatment of renal failure associated with multiple myeloma. Plasmapheresis, hemodialysis and chemotherapy. Arch Intern Med 1990, 150:863–869. 82. Zucchelli P, Pasquali S, Cagnoli L, Ferrari G: Controlled plasma exchange trial in acute renal failure due to multiple myeloma. Kidney Int 1988, 33:1175–1180. 83. Misiani R, Tiraboschi G, Mingardi G, Mecca G: Management of myeloma kidney: an anti–light chain approach. Am J Kidney Dis 1987, 10:28–33. 84. Ramos EL, Tisher CC: Recurrent disease in the kidney transplant. Am J Kidney Dis 1994, 24:142–154.

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85. Harrison KL, Alpers CE, Davis CL: De novo amyloidosis in a renal allograft: a case report and review of the literature. Am J Kidney Dis 1993, 22:468–476. 86. Sammett D, Dagher F, Abbi R, et al.: Renal transplantation in multiple myeloma. Transplantation 1996, 62:1577–1580. 87. Gerlag PGG, Koene RAP, Berden JHM: Renal transplantation in light chain nephropathy: case report and review of the literature. Clin Nephrol 1986, 25:101–104. 88. Varet B, Choukroun G, Grunfeld JP: Multiple myeloma. Part II: treatment. Nephron 1995, 70:18–20. 89. Iskander SS, Falk RJ, Jenette JC: Clinical and pathologic features of fibrillary glomerulonephritis. Kidney Int 1992, 42:1401–1407. 90. Fogo A, Qureshi N, Horn RG: Morphologic and clinical features of fibrillary versus immunotactoid glomerulonephritis. Am J Kidney Dis 1993, 22:367–377. 91. Alpers CE: Fibrillary glomerulonephritis and immunotactoid glomerulopathy. Curr Opinion Nephrol Hyperts 1994, 3:349–355. 92. Pasternack A, Ahonen J, Kuhlback B: Renal transplantation in 45 patients with amyloidosis. Transplantation 1986, 42:598–601. 93. Helin H, Korpela M, Mustonen J, Pasternack A: Rheumatoid arthritis and ankylosing spondylitis. In The Kidney in Collagen-Vascular Diseases. Edited by Grishman E, Churg J, Needle MA, Vankataseshan VS. New York: Raven Press; 1993:149–166. 94. Emery P, Adu D: The patient with rheumatoid arthritis, mixed connective tissue disease or polymyositis. In Oxford Textbook of Clinical Nephrology, edn 2. Edited by Davison AM, Cameron JS, Grunfeld JP, et al. Oxford: Oxford University Press; 1998:975–993. 95. Winer RL: Sjögren’s syndrome. In The Kidney in Collagen-Vascular Diseases. Edited by Grishman E, Churg J, Needle MA, Venkataseshan VS. New York: Raven Press; 1993:179–187. 96. Donohue JF: Scleroderma and the kidney. Kidney Int 1992, 41:462–477. 97. Steen VD: Scleroderma renal crisis. Rheumatol Dis Clin North Am 1996, 22:861–878. 98. D’Agati VD, Cannon PJ: Scleroderma (systemic sclerosis). In The Kidney in Collagen-Vascular Diseases. Edited by Grishman E, Churg J, Needle MA, Venkataseshan VS. New York: Raven Press; 1993:121–147.

Principles of Dialysis: Diffusion, Convection, and Dialysis Machines Robert W. Hamilton

C

hronic renal failure is the final common pathway of a number of kidney diseases. The choices for a patient who reaches the point where renal function is insufficient to sustain life are 1) chronic dialysis treatments (either hemodialysis or peritoneal dialysis), 2) renal transplantation, or 3) death. With renal failure of any cause, there are many physiologic derangements. Homeostasis of water and minerals (sodium, potassium, chloride, calcium, phosphorus, magnesium, sulfate), and excretion of the daily metabolic load of fixed hydrogen ions is no longer possible. Toxic end-products of nitrogen metabolism (urea, creatinine, uric acid, among others) accumulate in blood and tissue. Finally, the kidneys are no longer able to function as endocrine organs in the production of erythropoietin and 1,25-dihydroxycholecalciferol (calcitriol). Dialysis procedures remove nitrogenous end-products of catabolism and begin the correction of the salt, water, and acid-base derangements associated with renal failure. Dialysis is an imperfect treatment for the myriad abnormalities that occur in renal failure, as it does not correct the endocrine functions of the kidney. Indications for starting dialysis for chronic renal failure are empiric and vary among physicians. Some begin dialysis when residual glomerular filtration rate (GFR) falls below 10 mL/min /1.73 m2 body surface area (15 mL/min/1.73 m2 in diabetics.) Others institute treatment when the patient loses the stamina to sustain normal daily work and activity. Most agree that, in the face of symptoms (nausea, vomiting, anorexia, fatigability, diminished sensorium) and signs (pericardial friction rub, refractory pulmonary edema, metabolic acidosis, foot or wrist drop, asterixis) of uremia, dialysis treatments are urgently indicated.

CHAPTER

1

1.2

Dialysis as Treatment of End-Stage Renal Disease

FUNCTIONS OF THE KIDNEY AND PATHOPHYSIOLOGY OF RENAL FAILURE Function

Dysfunction

Salt, water, and acid-base balance Water balance Sodium balance Potassium balance Bicarbonate balance Magnesium balance Phosphate balance Excretion of nitrogenous end products Urea Creatinine Uric acid Amines Guanidine derivatives Endocrine-metabolic Conversion of vitamin D to active metabolite Production of erythropoietin Renin

Salt, water, and acid-base balance Fluid retention and hyponatremia Edema, congestive heart failure, hypertension Hyperkalemia Metabolic acidosis, osteodystrophy Hypermagnesemia Hyperphosphatemia, osteodystrophy Excretion of nitrogenous end products ?Anorexia, nausea, pruritus, pericarditis, polyneuropathy, encephalopathy, thrombocytopathy

Endocrine-metabolic Osteomalacia, osteodystrophy Anemia Hypertension

FIGURE 1-1 Functions of the kidney and pathophysiology of renal failure.

Blood

Membrane

Dialysate

Na+

Na+

K+

K+

Ca2+ HCO3–

Ca2+ HCO3–

Creatinine Urea

Creatinine Urea

FIGURE 1-2 Statue of Thomas Graham in George Square, Glasgow, Scotland. The physicochemical basis for dialysis was first described by the Scottish chemist Thomas Graham. In his 1854 paper “On Osmotic Force” he described the movements of various solutes of differing concentrations through a membrane he had fashioned from an ox bladder. (From Graham [1].)

FIGURE 1-3 Membrane fluxes in dialysis. Dialysis is the process of separating elements in a solution by diffusion across a semipermeable membrane (diffusive solute transport) down a concentration gradient. This is the principal process for removing the end-products of nitrogen metabolism (urea, creatinine, uric acid), and for repletion of the bicarbonate deficit of the metabolic acidosis associated with renal failure in humans. The preponderance of diffusion as the result of gradient is shown by the displacement of the arrow.

1.3

Principles of Dialysis: Difusion, Convection, and Dialysis Machines

Bicarbonate concentrate

Acidified concentrate

Air embolus detector

Water Pump

Heater

Membrane unit

Pump

Patient Mix 1

Conductivity monitor

Mix 2 Volume balance system

Deaerator

Spent dialysate pump

Spent dialysate

Drain

Ultrafiltrate pump

Heat exchanger

FIGURE 1-4 Simplified schematic of typical hemodialysis system. In hemodialysis, blood from the patient is circulated through a synthetic extracorporeal membrane and returned to the patient. The opposite side of that membrane is washed with an electrolyte solution (dialysate) containing the normal constituents of plasma water. The apparatus contains a blood pump to circulate the blood through the system, proportioning

Dialysate

Blood

Blood

Dialysate

Blood Dialysate

Blood leak detector

Blood pump

Heparin pump

pumps that mix a concentrated salt solution with water purified by reverse osmosis and/or deionization to produce the dialysate, a means of removing excess fluid from the blood (mismatching dialysate inflow and outflow to the dialysate compartment), and a series of pressure, conductivity, and air embolus monitors to protect the patient. Dialysate is warmed to body temperature by a heater. FIGURE 1-5 The hemodialysis membrane. Most membranes are derived from cellulose. (The earliest clinically useful hemodialyzers were made from cellophane sausage casing.) Other names of these materials include cupraphane, hemophan, cellulose acetate. They are usually sterilized by ethylene oxide or gamma irradiation by the manufacturer. They are relatively porous to fluid and solute but do not allow large molecules (albumin, vitamin B12) to pass freely. There is some suggestion that cupraphane membranes sterilized by ethylene oxide have a high incidence of biosensitization, meaning that the patient may have a form of allergic reaction to the membrane. Polysulfone, polyacrylonitrile, and polymethylmethacrylate membranes are more biocompatible and more porous (high flux membranes). They are most often formed into hollow fibers. Blood travels down the center of these fibers, and dialysate circulates around the outside of the fibers but inside a plastic casing. Water for dialysis must meet critical chemical and bacteriologic standards. These are listed in Figures 1-6 and 1-7.

1.4

Dialysis as Treatment of End-Stage Renal Disease

ASSOCIATION FOR THE ADVANCEMENT OF MEDICAL INSTRUMENTATION CHEMICAL STANDARD FOR WATER FOR HEMODIALYSIS Substance

Concentration (mg/L)

Aluminum Arsenic Barium Cadmium Calcium Chloramine Chlorine Chromium Copper Fluoride Lead Magnesium Mercury Nitrate Potassium Selenium Silver Sodium Sulfate Zinc

FIGURE 1-6 Association for the Advancement of Medical Instrumentation (AAMI) chemical standards for water for hemodialysis. Before hemodialysis can be performed, water analysis is performed. Water for hemodialysis generally requires reverse osmosis treatment and a deionizer for “polishing” the water. Organic materials, chlorine, and chloramine are removed by charcoal filtration. (From Vlchek [2]; with permission.)

0.01 0.005 0.1 0.001 2.0 0.1 0.5 0.014 0.1 0.2 0.005 4.0 0.0002 2.0 8.0 0.009 0.005 70 100 0.1

ASSOCIATION FOR THE ADVANCEMENT OF MEDICAL INSTRUMENTATION BACTERIOLOGIC STANDARDS FOR DIALYSIS WATER AND PREPARED DIALYSATE Colony-forming units/mL Dialysis water Prepared dialysate

<200 <2000

dn dc = –DA dt dx

FIGURE 1-8 Factors that govern diffusion, where dn/dt = the rate of movement of molecules per unit time; D = Fick’s diffusion coefficient;

FIGURE 1-7 Association for the Advancement of Medical Instrumentation (AAMI) bacteriologic standards for dialysis water and prepared dialysate. Excess bacteria in water can lead to pyrogen reactions. Treated water supply systems are designed so that there are no dead-end connections. Because the antiseptic agents (chlorine and chloramine) have been removed in water treatment, the water is prone to develop such problems if stagnation is allowed. (From Bland and Favero [3]; with permission.)

A = area of the boundary through which molecules move; dc = concentration gradient; and dx = distance through which molecules move. Hemodialysis depends on the process of diffusion for removal of solutes. The amount of material removed depends on the magnitude of the concentration gradient, the distance the molecule travels, and the area through which diffusion takes place. For this reason those dialyzers that have a large surface area, thin membranes, and are designed to maximize the effect of concentration gradient (countercurrent design) are most efficient at removing solutes.

Principles of Dialysis: Difusion, Convection, and Dialysis Machines

D=

250

3

FIGURE 1-9 Fick’s diffusion constant, where D = Fick’s diffusion coefficient, k = Boltzman’s constant; T = absolute temperature;  = viscosity; N = Avogadro’s number; M = molecular weight; and  = partial molal volume. The diffusion constant is proportional to the temperature of the solution and inversely proportional to the viscosity and the size of the molecule removed.

4πN 3Μυ

FIGURE 1-10 Effect of blood flow on clearance of various solutes, Fresenius F-5 membrane. The amount of solute cleared by a dialyzer depends on the amount delivered to the membrane. The usual blood flow is 300–400 mL/min, which is adequate to deliver the dialysis prescription. On institution of dialysis to a very uremic patient the blood flow is decreased to 160 to 180 mL/min to avoid disequilibrium syndrome. As time goes on, blood flow can be increased to standard flows as the patient adjusts to dialysis. Most patients require hemodialysis at least thrice weekly. From this graph it is also evident that small molecules such as urea (molecular weight 60 D) are cleared more easily than large molecules such as vitamin B12 (molecular weight 1355 D).

Urea Creatinine Phosphate

200 Clearance, mL/min

kΤ 6πη

Vitamin B12

150

1.5

100 50 0 0

100 200 300 Blood flow, mL/min

400

FIGURE 1-11 Hydrostatic ultrafiltration also takes place during hemodialysis. Because the spent dialysate effluent pump (see Fig. 1-4) creates negative pressure on the dialysate compartment of the membrane unit and the blood pump creates positive pressure in the blood compartment, there is a net hydrostatic pressure gradient between the compartments. This causes a flow of water and dissolved substances from blood to the dialysate compartment. The process of solute transfer associated with this flow of water is called “convective transport.” In hemodialysis, the amount of low–molecular weight solute (eg, urea) removed by convection is negligible. In the continuous renal replacement therapies, this is a major mechanism for solute transport.

200

100

Pressure, mmHg

0

–100

–200

–300

–400 Blood compartment

Dialysate Net transmembrane compartment pressure

1.6

Dialysis as Treatment of End-Stage Renal Disease FIGURE 1-12 Dialysis membranes differ in their ability to remove fluid. Differences in ultrafiltration coefficient (UFR) are shown for two different membranes, F-5 and F-50. The F-50 is considered a high-flux membrane.

35

UFR, mL/h/mmHg

30 25 20 15 10 5 0

F–5

F–50

References 1.

Graham T: The Bakerian lecture—on osmotic force. Philos Trans R Soc Lond 1854, 144:177–228.

2.

Vlchek DL: Monitoring a hemodialysis water treatment system. In AAMI Standards and Recommended Practices, vol. 3. Arlington, VA: Association for the Advancement of Medical Instrumentation; 1993:267–277.

3.

4.

Bland LA, Favero MS: Microbiologic aspects of hemodialysis systems. In AAMI Standards and Recommended Practices, vol. 3. Arlington, VA: Association for the Advancement of Medical Instrumentation; 1993:257–265. Daniels F, Alberty RA: Physical Chemistry. New York : John Wiley & Sons; 1955.

Dialysate Composition in Hemodialysis and Peritoneal Dialysis Biff F. Palmer

T

he goal of dialysis for patients with chronic renal failure is to restore the composition of the body’s fluid environment toward normal. This is accomplished principally by formulating a dialysate whose constituent concentrations are set to approximate normal values in the body. Over time, by diffusional transfer along favorable concentration gradients, the concentrations of solutes that were initially increased or decreased tend to be corrected. When an abnormal electrolyte concentration poses immediate danger, the dialysate concentration of that electrolyte can be set at a nonphysiologic level to achieve a more rapid correction. On a more chronic basis the composition of the dialysate can be individually adjusted in order to meet the specific needs of each patient.

Dialysate Composition for Hemodialysis In the early days of hemodialysis, the dialysate sodium concentration was deliberately set low to avoid problems of chronic volume overload such as hypertension and heart failure. As volume removal became more rapid because of shorter dialysis times, symptomatic hypotension emerged as a common and often disabling problem during dialysis. It soon became apparent that changes in the serum sodium concentration—and more specifically changes in serum osmolality— were contributing to the development of this hemodynamic instability. A decline in plasma osmolality during regular hemodialysis favors a

CHAPTER

2

2.2

Dialysis as Treatment of End-Stage Renal Disease

um from

erbate hemodynamic instability during the dialysis procedure [21]. In this regard, the intradialysis drop in blood pressure noted in patients dialyzed against a low-calcium bath, while statistically significant, is minor in degree [22,23]. Nevertheless, for patients who are prone to intradialysis hypotension avoiding low calcium dialysate concentration may be of benefit. On the other hand, the use of a lower calcium concentration in the dialysate allows the use of increased doses of calcium-containing phosphate binders and lessens dependence on binders containing aluminum. In addition, use of 1,25-dihydroxyvitamin D can be liberalized to reduce circulating levels of parathyroid hormone and, thus, the risk of inducing hypercalcemia. With dialysate calcium concentrations below 1.5 mmol/L, however, patients need close monitoring to ensure that negative calcium balance does not develop and that parathyroid hormone levels remain in an acceptable range [24].

plasma to dialysate. The use of a higher sodium concentration

Dialysate Composition for Peritoneal Dialysis

fluid shift from the extracellular space to the intracellular space, thus exacerbating the volume-depleting effects of dialysis. With the advent of high-clearance dialyzers and more efficient dialysis techniques, this decline in plasma osmolality becomes more apparent, as solute is removed more rapidly. Use of dialysate of low sodium concentration would tend further to enhance the intracellular shift of fluid, as plasma tends to become even more hyposmolar consequent to the movement of sodi-

dialysate (>140 mEq/L) has been among the most efficacious and best tolerated therapies for episodic hypotension [1–3]. The high sodium concentration prevents a marked decline in the plasma osmolality during dialysis, thus protecting the extracellular volume by minimizing osmotic fluid loss into the cells. In the early 1960s acetate became the standard dialysate buffer for correcting uremic acidosis and offsetting the diffusive losses of bicarbonate during hemodialysis. Over the next several years reports began to accumulate that linked routine use of acetate with cardiovascular instability and hypotension during dialysis. As a result, dialysate containing bicarbonate began to re-emerge as the principal dialysate buffer, especially as advances in biotechnology made bicarbonate dialysate less expensive and less cumbersome to use. For the most part, the bicarbonate concentration used consistently in most dialysis centers is 35 mmol/L. Emphasis is now being placed on individually adjusting the dialysate bicarbonate concentration so as to maintain the predialysis tCO2 concentration above 23 mmol/L [12–16]. Increasing evidence suggests that correction of chronic acidosis is of clinical benefit in terms of bone metabolism and nutrition. Dialysis assumes a major role in the maintenance of a normal serum potassium concentration in patients with end-stage renal disease. Excess potassium is removed by using a dialysate with a lower potassium concentration, so that a gradient is achieved that favors movement of potassium. In general, one can expect only up to 70 to 90 mEq of potassium to be removed during a typical dialysis session. As a result, one should not overestimate the effectiveness of dialysis in the treatment of severe hyperkalemia. The total amount removed varies considerably and is affected by changes in acid-base status, in tonicity, in glucose and insulin concentration, and in catecholamine activity [17–20]. The concentration of calcium in the dialysate has implications for metabolic bone disease and hemodynamic stability. Like the other constituents of the dialysate, the calcium concentration should be tailored to the individual patient [21]. Some data suggest that lowering the dialysate calcium concentration would exac-

To meet the ultrafiltration requirements of patients on peritoneal dialysis, the peritoneal dialysate is deliberately rendered hyperosmolar relative to plasma, to create an osmotic gradient that favors net movement of water into the peritoneal cavity. In commercially available peritoneal dialysates, glucose serves as the osmotic agent that enhances ultrafiltration. Available concentrations range from 1.5% to 4.25% dextrose. Over time, the osmolality of the dialysate declines as a result of water moving into the peritoneal cavity and of absorption of dialysate glucose. The absorption of glucose contributes substantially to the calorie intake of patients on continuous peritoneal dialysis. Over time, this carbohydrate load is thought to contribute to progressive obesity, hypertriglyceridemia, and decreased nutrition as a result of loss of appetite and decreased protein intake. In addition, the high glucose concentrations and high osmolality of currently available solutions may have inhibitory effects on the function of leukocytes, peritoneal macrophages, and mesothelial cells [25]. In an attempt to develop a more physiologic solution, various new osmotic agents are now under investigation. Some of these may prove useful as alternatives to the standard glucose solutions. Those that contain amino acids have received the most attention. The sodium concentration in the ultrafiltrate during peritoneal dialysis is usually less than that of extracellular fluid, so there is a tendency toward water loss and development of hypernatremia. Commercially available peritoneal dialysates have a sodium concentration of 132 mEq/L to compensate for this tendency toward dehydration. The effect is more pronounced with increasing frequency of exchanges and with increasing dialysate glucose concentrations. Use of the more hypertonic solutions and frequent cycling can result in significant dehydration and hypernatremia. As a result of stimulated thirst, water intake and weight may increase, resulting in a vicious cycle. Potassium is cleared by peritoneal dialysis at a rate similar to that of urea. With chronic ambulatory peritoneal dialysis and 10 L of drainage per day, approximately 35 to 46 mEq of potassium is removed per day. Daily potassium intake is usually greater than this, yet significant hyperkalemia is uncommon in these patients. Presumably potassium balance is maintained by increased colonic secretion of potassium and by some residual

2.3

Dialysate Composition in Hemodialysis and Peritoneal Dialysis renal excretion. Given these considerations, potassium is not routinely added to the dialysate. The buffer present in most commercially available peritoneal dialysate solutions is lactate. In patients with normal hepatic function, lactate is rapidly converted to bicarbonate, so that each mM of lactate absorbed generates one mM of bicarbonate. Even with the most aggressive peritoneal dialysis there is no appreciable accumulation of circulating lactate. The rapid metabolism of lactate to bicarbonate maintains the high dialysate-plasma lactate gradient necessary for continued

absorption. The pH of commercially available peritoneal dialysis solutions is purposely made acidic by adding hydrochloric acid to prevent dextrose from caramelizing during the sterilization procedure. Once instilled, the pH of the solution rises to values greater than 7.0. There is some evidence that the acidic pH of the dialysate, in addition to the high osmolality, may impair the host’s peritoneal defenses [25,26]. To avoid negative calcium balance—and possibly to suppress circulating parathyroid hormone—commercially available peritoneal dialysis solutions evolved to have a calcium concentration

150 Interstitial space Cell Cell

Low-sodium dialysate

BUN

Intravascular space

H2O Decreased osmolality

BUN

Step Linear Exponential

High-sodium dialysate

BUN

H2O

Stable osmolality

H2O BUN

Na

H2O

• Less vascular refilling •↓Peripheral vasoconstriction •Exacerbated autonomic insufficiency -inhibits afferent sensing -↓ CNS efferent outflow •Venous pooling secondary to ↑ PGE2

Na concentration, mEq/L

Baseline

145

140

Hypotension 1

of 3.5 mEq/L (1.75 mmol/L). This concentration is equal to or slightly greater than the ionized concentration in the serum of most patients. As a result, there is net calcium absorption in most patients treated with a conventional chronic ambulatory peritoneal dialysis regimen. As the use of calcium-containing phosphate binders has increased, hypercalcemia has become a common problem when utilizing the 3.5 mEq/L calcium dialysate. This complication has been particularly common in patients treated with peritoneal dialysis, since they have a much greater incidence of adynamic bone disease than do hemodialysis patients [27]. In fact, the continual positive calcium balance associated with the 3.5-mEq/L solution has been suggested to be a contributing factor in the development of this lesion. The low bone turnover state typical of this disorder impairs accrual

2 Time, h

3

4

of administered calcium, contributing to the development of hypercalcemia. As a result, there has been increased interest in using a strategy similar to that employed in hemodialysis, namely, lowering the calcium content of the dialysate. This strategy can allow increased use of calcium-containing phosphate binders and more liberal use of 1,25-dihydroxyvitamin D to effect decreases in the circulating level of parathyroid hormone. In this way, development of hypercalcemia can be minimized.

Dialysate Na in Hemodialysis

2.4

Dialysis as Treatment of End-Stage Renal Disease

INDICATIONS AND CONTRAINDICATIONS FOR USE OF SODIUM MODELING (HIGH/LOW PROGRAMS) Indications Intradialysis hypotension Cramping Initiation of hemodialysis in setting of severe azotemia Hemodynamic instability (eg, intensive care setting) Contraindications Intradialysis development of hypertension Large interdialysis weight gain induced by high-sodium dialysate Hypernatremia

FIGURE 2-1 Use of a low-sodium dialysate is more often associated with intradialysis hypotension as a result of several mechanisms [4]. The drop in serum osmolality as urea is removed leads to a shift of water into the intracellular compartment that prevents adequate refilling of the intravascular space. This intracellular movement of

Dialysate Buffer in Hemodialysis Acid concentrate NaCl CaCl KCL MgCl Acetic acid Dextrose NaHCO3 concentrate NaHCO3

Pure H2O

Final dialysate Na Cl Ca Acetate K HCO3 Mg Dextrose

137 mEq/L 105 mEq/L 3.0 mEq/L 4.0 mEq/L 2.0 mEq/L 33 mEq/L 0.75 mEq/L 200 mg/dl

water, combined with removal of water by ultrafiltration, leads to contraction of the intravascular space and contributes to the development of hypotension. High-sodium dialysate helps to minimize the development of hypo-osmolality. As a result, fluid can be mobilized from the intracellular and interstitial compartments to refill the intravascular space during volume removal. Other potential mechanisms whereby low-sodium dialysate contributes to hypotension are indicated. Na—sodium; BUN—blood urea nitrogen; PGE2—prostaglandin E2. FIGURE 2-2 There has been interest in varying the concentration of sodium (Na) in the dialysate during the dialysis procedure so as to minimize the potential complications of a high-sodium solution and yet retain the beneficial hemodynamic effects. A high sodium concentration dialysate is used initially and progressively the concentration is reduced toward isotonic or even hypo-

H 2O

MECHANISMS BY WHICH ACETATE BUFFER CONTRIBUTES TO HEMODYNAMIC INSTABILITY Directly decreases peripheral vascular resistance in approximately 10% of patients Stimulates release of the vasodilator compound interleukin 1 Induces metabolic acidosis via bicarbonate loss through the dialyzer Produces arterial hypoxemia and increased oxygen consumption ?Decreased myocardial contractility

tonic levels by the end of the procedure. The concentration of sodium can be reduced in a linear, exponential, or step pattern. This method of sodium control allows for a diffusive sodium influx early in the session to prevent a rapid decline in plasma osmolality secondary to efflux of urea and other small-molecular weight solutes. During the remainder of the procedure, when the reduction in osmolality accompanying urea removal is less abrupt, the dialysate is sodium level is set lower, thus minimizing the development of

2.5

Dialysate Composition in Hemodialysis and Peritoneal Dialysis

hypertonicity and any resultant excessive thirst, fluid gain, and hypertension in the interdialysis period. In some but not all studies, sodium modeling has been shown to be effective in treating intradialysis hypotension

5.0

and cramps [5-11]. FIGURE 2-3 Indications and contraindications for use of sodium modeling (high/low programs). Use of a sodium modeling program is not indicated in all patients. In fact most patients do well with the dialysate sodium set at 140 mEq/L. As a result the physician needs to be aware of the benefits as well as the dangers of sodium remodeling.

Start hemodialysis

Plasma potassium, mM

4.5

4.0

3.5

3.0 End hemodialysis

2.5 0

1

2 Time, h

3

4

5

Dialysis membrane

FACTORS RELATED TO DIALYSIS THAT AFFECT DISTRIBUTION OF POTASSIUM BETWEEN CELLS AND THE EXTRACELLULAR FLUID

K+ Factors that enhance cell potassium uptake Insulin 2-adrenergic receptor agonists Alkalemia Factors that reduce cell potassium uptake or increase potassium efflux 2-adrenergic receptor blockers Acidemia (mineral acidosis) Hypertonicity -adrenergic receptor agonists

FIGURE 2-4 The current utilization of a bicarbonate dialysate requires a specially designed system that mixes a bicarbonate and an acid concentrate with purified water. The acid concentrate contains a small amount of lactic or acetic acid and all the calcium and magnesium. The exclusion of these cations from the bicarbonate concentrate prevents the precipitation of magnesium and calcium carbonate that would otherwise occur in the setting of a high bicarbonate concentration. During the mixing procedure the acid in the acid

A

Dialysis membrane

K+

K+ B

K+

Less K removal

Glucose-containing dialysate Correction of metabolic acidosis during hemodialysis Pre-dialysis treatment with β-stimulants

concentrate reacts with an equimolar amount of bicarbonate to generate carbonic acid and carbon dioxide. The generation of carbon dioxide causes the pH of the final solution to fall to approximately 7.0–7.4. The acidic pH and the lower concentrations in the final mixture allow the calcium and magnesium to remain in solution. The final concentration of bicarbonate in the dialysate is approximately 33–38 mmol/L.

2.6

Dialysis as Treatment of End-Stage Renal Disease

FIGURE 2-5

Step 1: Control serum phosphate Low-phosphate diet (800–1000 mg/d) Phophate binders

Step 2: Normalize serum calcium If calcium is still low after control of phosphate, treat with 1,25-(OH)2 vitamin D Use calcium-containing phosphate binders 1.0–1.5 g dietary calcium

Step 3: Control secondary hyperparathyroidism Treat with 1,25(OH)2 vitamin D

Individualize dialysate calcium

Low-calcium dialysate

Low-calcium dialysate High-calcium dialysate

Helps prevent hypercalcemia secondary to high-dose calcium containing phosphate binders and vitamin D Monitor for negative calcium balance

Promotes positive calcium balance Suppresses parathyroid hormone levels Better hemodynamic stability Risk of hypercalcemia ? Risk of adynamic bone disease

Mechanisms by which acetate buffer contributes to hemodynamic instability. Although bicarbonate is the standard buffer in use today, hemodynamically stable patients can be dialyzed safely using as acetate-containing dialysis solution. Since muscle is the primary site of metabolism of acetate, patients with reduced muscle mass tend to be acetate intolerant. Such patients include malnourished and elderly patients and women.

Dialysate Potassium in Hemodialysis

Dialysate Composition in Hemodialysis and Peritoneal Dialysis

2.7

FIGURE 2-6

ADVANTAGES AND DISADVANTAGES OF INDIVIDUALIZING VARIOUS COMPONENTS OF HEMODIALYSATE Dialysate component and adjustment

Advantages

Disadvantages

Sodium: Increased

More hemodynamic stability, less cramping

Dipsogenic effect, increased interdialytic weight gain, ? chronic hypertension Intradialytic hypotension and cramping more common

Decreased (rarely used) Calcium: Increased Decreased Potassium: Increased Decreased Bicarbonate: Increased Decreased Magnesium: Increased Decreased

Less interdialytic weight gain Suppression of PTH, promotes hemodynamic stability in HD Permits greater use of vitamin D and calcium containing phosphate binders

Hypercalcemia with vitamin D and high-dose calcium-containing phosphate binders, ? contribution to adynamic bone disease in PD Potential for negative calcium balance, stimulation of PTH, slight decrease in hemodynamic stability

Less arrhythmias in setting of digoxin or coronary heart disease ? improved hemodynamic stability Permits greater dietary intake of potassium with less hyperkalemia ? improvement in myocardial contractility

Limited by hyperkalemia

Corrects chronic acidosis thereby benefits nutrition and bone metabolism Less metabolic alkalosis

Post-dialysis metabolic alkalosis Potential for chronic acidosis

? Less arrhythmias, ? hemodynamic benefit Permits greater use of magnesium containing phosphate binders which in tum permits reduced dose of calcium binders and results in less hypercalcemia

Potential for hypermagnesemia Symptomatic hypomagnesemia

Increased arrhythmias, may exacerbate autonomic insufficiency

Plasma potassium concentration can be expected to fall rapidly in the early stages of dialysis, but as it drops, potassium removal becomes less efficient [17,18]. Since potassium is

freely permeable across the dialysis membrane, movement of potassium from the intracellular space to the extracellular space appears to be the limiting factor that accounts for the smaller fractional decline in potassium concentration at lower plasma potassium concentrations.

COMPOSITION OF A COMMERCIALLY AVAILABLE PERITONEAL DIALYSATE Solute Sodium, mEq/L Potassium, mEq/L Chloride , mEq/L Calcium , mEq/L Magnesium, mEq/L D, L-Lactate, mEq/L Glucose, g/dL Osmolality pH

Dianeal PD-2 132 0 96 3.5 0.5 40 1.5, 2.5, 4.25 346, 396, 485 5.2

Presumably, the movement of potassium out of cells and into the extracellular space is slower than the removal of potassium from the extracellular space into the dialysate, so a disequilibrium is created. The rate of potassium removal is largely a function of its predialysis concentration. The higher the initial plasma concentration, the greater is the plasma-dialysate gradient and, thus, the more potassium is removed. After the completion of a standard dialysis treatment there is an increase in the plasma concentration of potassium secondary to continued exit of potassium from the intracellular space to the extracellular space in an attempt to re-establish the intracellular-extracellular potassium gradient. FIGURE 2-7

2.8

Dialysis as Treatment of End-Stage Renal Disease

The total extracellular potassium content is only about 50 to 60 mEq/L. Without mechanisms to shift potassium into the cell, small potassium loads would lead to severe hyperkalemia. These mechanisms are of particular importance in patients with end-stage renal disease since the major route of potassium excretion is eliminated from the body by residual renal clearance and enhanced gastrointestinal excretion.

FIGURE 2-8 During a typical dialysis session approximately 80 to 100 mEq/L of potassium is removed from the body. A, Potassium (K) flux from the extracellular space across the dialysis membrane exceeds the flux of potassium out of the intracellular space. B, The movement of potassium between the intra- and extracellular spaces is controlled by a number of factors that can be modified during the dialysis procedure [17,18]. As compared with a glucose-free dialysate, a bath that contains glucose is associated with less potassium removal [19]. The presence of glucose in the dialysate stimulates insulin release, which in turn has the effect of shifting potassium into the intracellular space, where it becomes less available for removal by dialysis. Dialysis in patients who are acidotic is also associated with less potassium removal since potassium is shifted into cells as the serum bicarbonate concentration rises. Finally, patients treated with inhaled  stimulants, as for treatment of hyperkalemia, will have less potassium removed during dialysis since  stimulation causes a shift of potassium into the cell [20].

High-Efficiency and High-Flux Hemodialysis Sivasankaran Ambalavanan Gary Rabetoy Alfred K. Cheung

H

emodialysis remains the major modality of renal replacement therapy in the United States. Since the 1970s the drive for shorter dialysis time with high urea clearance rates has led to the development of high-efficiency hemodialysis. In the 1990s, certain biocompatible features and the desire to remove amyloidogenic 2microglobulin has led to the popularity of high-flux dialysis. During the 1990s, the use of high-efficiency and high-flux membranes has steadily increased and use of conventional membrane has declined [1]. In 1994, a survey by the Centers for Disease Control showed that high-flux dialysis was used in 45% and high-efficiency dialysis in 51% of dialysis centers (Fig. 3-1) [1]. Despite the increasing use of these new hemodialysis modalities the clinical risks and benefits of high-performance therapies are not welldefined. In the literature published over the past 10 years the definitions of high-efficiency and high-flux dialysis have been confusing. Currently, treatment quantity is not only defined by time but also by dialyzer characteristics, ie, blood and dialysate flow rates. In the past, when the efficiency of dialysis and blood flow rates tended to be low, treatment quantity was satisfactorily defined by time. Today, however, treatment time is not a useful expression of treatment quantity because efficiency per unit time is highly variable.

CHAPTER

3

3.2

Dialysis as Treatment of End-Stage Renal Disease

Dialyzers 50

HIGH-PERFORMANCE EXTRACORPOREAL THERAPIES FOR END-STAGE RENAL DISEASE

Centers, %

40

FIGURE 3-2 The four highperformance extracorporeal therapies for end-stage renal disease are listed [2].

High-efficiency hemodialysis High-flux hemodialysis Hemofiltration, intermittent Hemodiafiltration, intermittent

30

20

10

0 1986

1988

1990

1992

1994

1996

Year

FIGURE 3-1 Centers using high-flux dialyzers have increased threefold from 1986 to 1996 because of their ability to remove middle molecules. (From Tokars and coworkers [1]; with permission.)

DEFINITIONS OF FLUX, PERMEABILITY, AND EFFICIENCY Flux Measure of ultrafiltration capacity Low and high flux are based on the ultrafiltration coefficient (Kuf) Low flux: Kuf <10 mL/h/mm Hg High flux: Kuf >20 mL/h/mm Hg Permeability Measure of the clearance of the middle molecular weight molecule (eg, 2-microglobulin) General correlation between flux and permeability Low permeability: 2-microglobulin clearance <10 mL/min High permeability: 2-microglobulin clearance >20 mL/min Efficiency Measure of urea clearance Low and high efficiency are based on the urea KoA value Low efficiency: KoA <500 mL/min High efficiency: KoA >600 mL/min Ko—mass transfer coefficient; A—surface area.

FIGURE 3-3 Definitions of flux, permeability, and efficiency. The urea value KoA, as conventionally defined in hemodialysis, is an estimate of the clearance of urea (a surrogate marker of low molecular weight uremic toxins) under conditions of infinite blood and dialysate flow rates. The following equation is used to calculate this value: 1-Kd/Qb QbQd KoA= ln Qb-Qd 1-Kd/Qd where Ko = mass transfer coefficient A = surface area Qb = blood flow rate Qd = dialysate flow rate ln = natural log Kd = mean of blood and dialysate side urea clearance As conventionally defined in hemodialysis, flux is the rate of water transfer across the hemodialysis membrane. Dissolved solutes are removed by convection (solvent drag effect). Permeability is a measure of the clearance rate of molecules of middle molecular weight, sometimes defined using 2-microglobulin (molecular weight, 11,800 D) as the surrogate [3,4]. Dialyzers that permit 2-microglobulin clearance of over 20 mL/min under usual clinical flow and ultrafiltration conditions have been defined as highpermeability membrane dialyzers. Because of the general correlation between water flux and the clearance rate of molecules of middle molecular weight, the term high-flux membrane has been used commonly to denote high-permeability membrane.

High-Efficiency and High-Flux Hemodialysis

FIGURE 3-4 Theoretic KoA profile of high- and low-flux dialyzers and highand low-efficiency dialyzers. Note that here the definition of KoA applies to the product of the mass transfer coefficient and surface area for solutes having a wide range of molecular weights, and is not limited to urea. Note also the logarithmic scales on both axes [3]. Ko—mass transfer coefficient; A—surface area. (From Cheung and Leypoldt [3]; with permission.)

1000 High flux

100

KOA, mL/min

3.3

10 Low flux

1 High efficiency Low efficiency

0.1

0.01 10

100

1000

100,000

10,000

Solute molecular weight, D

FIGURE 3-5 Classification of high-performance dialysis. Some authors have defined high-efficiency hemodialysis as treatment in which the urea clearance rate exceeds 210 mL/min. High-flux dialysis, arbitrarily defined as a 2-microglobulin clearance of over 20 mL/min, is achieved using high-flux membranes [3,4].

CLASSIFICATION OF HIGHPERFORMANCE DIALYSIS High-efficiency low-flux hemodialysis High-efficiency high-flux hemodialysis Low-efficiency high-flux hemodialysis

400

CHARACTERISTICS OF HIGH-EFFICIENCY DIALYSIS

Urea clearance rate, mL/min

350

KOA=1000

300 250 KOA=500

200 150

Urea clearance rate is usually >210 mL/min Urea KoA of the dialyzer is usually >600 mL/min Ultrafiltration coefficient of the dialyzer (Kuf) may be high or low Clearance of middle molecular weight molecules may be high or low Dialysis can be performed using either cellulosic or synthetic membrane dialyzers

100 Ko—mass transfer coefficient; A—surface area.

50 0 0

50

150

250

350

450

500

Blood flow rate, mL/min

FIGURE 3-6 Comparison of urea clearance rates between low- and high-efficiency hemodialyzers (urea KoA = 500 and 1000 mL/min, respectively). The urea clearance rate increases with the blood flow rate and gradually reaches a plateau for both types of dialyzers. The plateau value of KoA is higher for the high-efficiency dialyzer. At low blood flow rates (<200 mL/min), however, the capacity of the high-efficiency dialyzer cannot be exploited and the clearance rate is similar to that of the low-flux dialyzer [3,6]. Ko—mass transfer coefficient; A—surface area. (From Collins [6]; with permission.)

FIGURE 3-7 Characteristics of high-efficiency dialysis. High-efficiency dialysis is arbitrarily defined by a high clearance rate of urea (>210 mL/min). High-efficiency membranes can be made from either cellulosic or synthetic materials. Depending on the membrane material and surface area, the removal of water (as measured by the ultrafiltration coefficient or Kuf) and molecules of middle molecular weight (as measured by 2-microglobulin clearance) may be high or low [3,4,6,7].

3.4

Dialysis as Treatment of End-Stage Renal Disease FIGURE 3-8 Differences between high- and low-efficiency hemodialysis. Conventional hemodialysis refers to low-efficiency low-flux hemodialysis that was the popular modality before the 1980s [3,6].

DIFFERENCES BETWEEN HIGH- AND LOW-EFFICIENCY HEMODIALYSIS

Dialyzer KoA Blood flow Dialysate flow Bicarbonate dialysate

High efficiency, mL/min

Low efficiency, mL/min

≥600 ≥350 ≥500 Necessary

<500 <350 <500 Optimal

Ko—mass transfer coefficient; A—surface area.

TECHNICAL REQUIREMENTS FOR HIGH-EFFICIENCY DIALYSIS High-efficiency dialyzer Large surface area (A) High mass transfer coefficient (Ko) Both (high KoA) High blood flow (≥350 mL/min) High dialysate flow (≥500 mL/min) Bicarbonate dialysate

FIGURE 3-9 Technical requirements for high-efficiency dialysis. The KoA is the theoretic value of the urea clearance rate under conditions of infinite blood and dialysate flow. High blood and dialysate flow rates are necessary to achieve optimal performance of high-efficiency dialyzers. Bicarbonate-containing dialysate is necessary to prevent symptoms associated with acetate intolerance (ie, nausea, vomiting, headache, and hypotension), worsening of metabolic acidosis, and cardiac arrhythmia [6,8,9]. Ko—mass transfer coefficient; A—surface area.

CONCENTRATION OF DIALYSATE IN HIGH-EFFICIENCY DIALYSIS Dialysate

Concentration

Sodium Potassium Acetate Bicarbonate Magnesium Calcium Glucose

139–145 mEq/L 0–4 mEq/L 2.5–4.5 mEq/L 35–40 mEq/L 1 mEq/L 2.5–3.5 mEq/L 0–200 mg/dL

FIGURE 3-10 Concentration of dialysate in high-efficiency dialysis. Although the concentration of other ions is variable, high bicarbonate concentration, relative to that of acetate, is essential for high-efficiency dialysis in order to minimize the transfer of acetate into the patient.

FACTORS INFLUENCING BLOOD FLOW IN HIGH-EFFICIENCY HEMODIALYSIS Type of access Native arteriovenous fistulae, polytetrafluoroethylene grafts, twin catheter systems: high blood flow rate, >350 mL/min Permanent catheters, temporary intravenous catheters: low blood flow rate, <350 mL/min Needle design: size, thickness, and length Blood tubing Pump design

FIGURE 3-11 Factors influencing blood flow in high-efficiency hemodialysis. Arteriovenous fistulae often have blood flow rates of over 1000 mL/min, as measured by current noninvasive devices. Polytetrafluoroethylene grafts and the newly introduced twin catheter systems also are capable of providing the blood flow rates necessary for high-efficiency hemodialysis. In contrast, most other temporary or semipermanent catheters cannot provide sufficient blood flow reliably enough for adequate dialysis delivery in a short time period. Needles, blood tubing diameter, and blood pumps may also contribute to this problem [8,9].

High-Efficiency and High-Flux Hemodialysis

CAUSES OF HIGH-EFFICIENCY DIALYSIS FAILURE Access-related Low blood flow rate High recirculation rate Time-related Patient not adherent to prescribed time Staff not adherent to prescribed time Failure to adjust time for conditions such as alarm, dialysate bypass, and hypotension

FIGURE 3-12 Causes of high-efficiency dialysis failure. The maintenance of a high blood flow rate (>350 mL/min) is essential for high-efficiency hemodialysis. Fistula recirculation, regardless of the blood flow rate, compromises achievement of the urea Kt/V goal. Interruptions during the prescribed short treatment time further compromise the overall delivery of the prescribed Kt/V [6,7]. K—urea clearance; t—time of therapy; V—volume of distribution.

BENEFITS OF HIGHEFFICIENCY DIALYSIS Higher clearance of small solutes, such as urea, compared with conventional dialysis without increase in treatment time Better control of chemistry Potentially reduced morbidity Potentially higher patient survival rates

FIGURE 3-13 Benefits of high-efficiency dialysis. With improved control of biochemical parameters (such as potassium, hydrogen ions, phosphate, urea, and other nitrogenous compounds) the potential exists for reduced morbidity and mortality without increasing dialysis treatment time [5,7].

CHARACTERISTICS OF HIGH-FLUX DIALYSIS Dialyzer membranes are characterized by a high ultrafiltration coefficient (Kuf > 20 mL/h/mm Hg) High clearance of middle molecular weight molecules occurs (eg, 2-microglobulin) Urea clearance can be high or low, depending on the urea KoA of the dialyzer Dialyzers are made of either synthetic or cellulosic membranes High-flux dialysis requires an automated ultrafiltration control system

3.5

LIMITATIONS OF HIGHEFFICIENCY DIALYSIS Hemodynamic instability Low margin of safety if short treatment time is prescribed Potential vascular access damage Dialysis disequilibrium syndrome

FIGURE 3-14 Limitations of high-efficiency dialysis. Removal of a large volume of fluid over a short time period (2–2.5 h) increases the likelihood of hypotension, especially in patients with poor cardiac function or autonomic neuropathy. The loss of a fixed amount of treatment time has a proportionally greater impact during a short treatment time than during a long treatment time. Thus, the margin of safety is narrower if a short treatment time is used in conjunction with high-efficiency dialysis compared with conventional hemodialysis with a longer treatment time. Although unproved, high blood flow rates may predispose patients to vascular access damage. Rapid solute shifts potentially precipitate the dialysis disequilibrium syndrome in those patients with a very high blood urea nitrogen concentration, especially during the first treatment [3,7,9].

FIGURE 3-15 Characteristics of high-flux dialysis. Because of the high ultrafiltration coefficients of high-flux membranes, high-flux dialysis requires an automated ultrafiltration control system to avoid accidental profound intravascular volume depletion. Because high-flux membranes tend to have larger pores, clearance of middle molecular weight molecules is usually high. Urea clearance rates for high-flux dialyzers are still dependent on urea KoA values, which can be either high (ie, high-flux high-efficiency) or low (ie, high-flux lowefficiency) [3,4,10]. Ko—mass transfer coefficient; A—surface area.

3.6

Dialysis as Treatment of End-Stage Renal Disease

TECHNICAL REQUIREMENTS FOR HIGH-FLUX DIALYSIS

POTENTIAL BENEFITS OF HIGH-FLUX DIALYSIS

High-flux dialyzer Automated ultrafiltration control system

FIGURE 3-16 Technical requirements for high-flux dialysis. Because of the potential for reverse filtration (movement of fluid from dialysate to the blood compartment) to occur, use of a pyrogen-free dialysate is preferred but not mandatory. Bicarbonate concentrate used to prepare dialysate is particularly prone to bacterial overgrowth when stored for more than 2 days [5,8].

Delayed onset and risk of dialysis-related amyloidosis because of enhanced 2-microglobulin clearance [11,12] Increased patient survival resulting from higher clearance of middle molecular weight molecules [12,13,15,16] Reduced morbidity and hospital admissions [14,16] Improved lipid profile [16,17] Higher clearance of aluminum [18] Improved nutritional status [19,20] Reduced risk of infection [16,21] Preserved residual renal function [22]

Low-flux low-efficiency CA90 CF12 Low-flux high-efficiency CA150 T150 High-flux low-efficiency F50 PAN 150P High-flux high-efficiency CT190 F80

Enhanced drug clearance, requiring supplemental dose after dialysis High cost of dialyzers

FIGURE 3-18 Limitations of high-flux dialysis. The enhanced clearance of drugs depends on the physicochemical characteristics of the specific drug and dialysis membrane. Because of their relative high costs, highflux dialyzers are usually reused.

FIGURE 3-17 Potential benefits of high-flux dialysis. Data are accumulating that support many potential benefits of high-flux dialysis. Large-scale randomized prospective trials, however, are unavailable.

EXAMPLES OF COMMONLY USED DIALYZERS Dialyzer type

LIMITATIONS OF HIGH-FLUX DIALYSIS

Material

Surface area, m2

KoA (in vitro), mL/min

Cellulose acetate Cuprammonium

0.9 0.7

410 418

Cellulose acetate Cuprammonium

1.5 1.5

660 730

Polysulfone Polyacrylonitrile

0.9 1.0

520 420

Cellulose triacetate Polysulfone

1.9 1.8

920 945

Ko—mass transfer coefficient; A—surface area. Adapted from Leypoldt and coworkers [4] and Van Stone [22].

FIGURE 3-19 Examples of commonly used dialyzers. “Efficiency” refers to the capacity to remove urea; “flux” refers to the capacity to remove water, and indirectly, the capacity to remove molecules of middle molecular weight. Cellulosic membranes can be either low flux or high flux. Similarly, synthetic membranes can be either low flux or high flux. Highefficiency membranes usually have large surface areas.

High-Efficiency and High-Flux Hemodialysis

3.7

Solutes Cb

Cb

Cb

Postdilution

Ultrafiltrate Solute flux Fluid flux Cd

Solute flux Predilution

Blood

Membrane

Ultrafiltrate

FIGURE 3-20 Solute transport in hemodialysis. The primary mechanism of solute transport in hemodialysis is diffusion, although convective transport is also contributory. Solutes small enough to pass through the dialysis membrane diffuse down a concentration gradient from a higher plasma concentration (Cb) to a lower dialysate concentration (Cd). The arrow represents the direction of solute transport.

Postdilution

Ultrafiltrate

Dialysate

Predilution Blood

Blood

Membrane

Ultrafiltrate

FIGURE 3-21 Solute clearance in hemofiltration. Hemofiltration achieves solute clearance by convection (or the solvent drag effect) through the membrane. In contrast to diffusive hemodialysis, fluid flux is a prerequisite for the removal of solutes during hemofiltration, whereas the concentration gradient is not. For small solutes (eg, urea) that traverse the membrane unimpeded, concentrations in the blood compartment (Cb) and ultrafiltrate compartment (Cuf) are equivalent. For some molecules of middle molecular weight whose movement across the membrane is partially restricted, Cuf is lower than is Cb (ie, the sieving coefficient, defined as Cuf/Cb, is less than 1.0).

Blood

FIGURE 3-22 Fluid replacement in hemofiltration. Because hemofiltration achieves substantial solute clearance by removing large volumes of plasma water (which contains the dissolved solutes), the removed fluid must be replaced. The replacement fluid can be infused into the extracorporeal circuit before the blood enters the filter (predilution, or replacement before expenditure) or after the blood leaves the filter (postdilution). More replacement fluid is required when it is given before filtration rather than after to provide equivalent solute clearance because the plasma in the filter (and therefore the ultrafiltrate) is diluted in the predilution mode.

FIGURE 3-23 Addition of diffusive transport in hemodiafiltration. In hemodiafiltration, diffusive transport is added to hemofiltration to augment the clearance of solutes (usually small solutes such as urea and potassium). Solute clearance is accomplished by circulating dialysate in the dialysate-ultrafiltrate compartment. Hemodiafiltration is particularly useful in patients who have hypercatabolism with large urea generation.

3.8

Dialysis as Treatment of End-Stage Renal Disease

Membranes Bacteria

Macrophage ET

FIGURE 3-24 Backfiltration, or reverse filtration, of endotoxins (ET) from dialysate to blood. Reverse filtration of ET is particularly prone to occur when high-flux membranes are used and the dialysate is heavily contaminated with bacteria (>2000 CFU/mL) and may result in pyrogenic reactions. The dialysis membranes are impermeable to intact ET; however, their fragments (some of which still are pyrogenic) may be small enough to traverse the membrane. Although the membrane is impermeable to bacteria and blood cells, a mechanical break in the membrane could result in bacteremia.

ET fragments

Dialysate

Membrane

Blood

H 2O H 2O H 2O H 2O H 2O

FIGURE 3-25 Dialysis membranes with small and large pores. Although a general correlation exists between the (water) flux and the (middle molecular weight molecule) permeability of dialysis membranes, they are not synonymous. A, Membrane with numerous small pores that allow high water flux but no 2-microglobulin transport. B, Membrane with a smaller surface area and fewer pores, with the pore size sufficiently large to allow 2-microglobulin transport. The ultrafiltration coefficient and hence the water flux of the two membranes are equivalent.

A H 2O H 2O

H 2O H 2O

B

A FIGURE 3-26 Scanning electron microscopy of a conventional low-flux-membrane hollow fiber (panel A) and a synthetic high-flux-membrane hollow fiber (panel B). The low-flux membrane consists of a single layer of relatively homogenous material. The high-flux membrane has a three-layer structure, ie, finger, sponge, and skin. The skin is a thin semipermeable layer that functions as the selective barrier; it is mechanically supported by the sponge and finger layers. (Magnification: finger,  14,000; sponge  17,000; skin  85,000.) (Courtesy of Goehl H, Gambrogroup).

B

High-Efficiency and High-Flux Hemodialysis

3.9

Dialysate flow rate FIGURE 3-27 Effect of the dialysate flow rate (Qd) on the urea clearance rate by a high-efficiency dialyzer with a urea KoA value of 800 mL/min. At low blood flow rates (<200 mL/min), no difference exists in urea clearance rates between the two different Qd conditions, because equilibrium in urea concentrations between blood and dialysate is readily achieved. When the blood flow rate is high (>300 mL/min), the higher Qd maintains a higher concentration gradient for diffusion of urea, and therefore, the urea clearance rate is higher. Recent studies have shown that the KoA value of dialyzers also increases with higher dialysate flow rates [4], presumably because of more uniform distribution of dialysate flow. Therefore, the actual urea clearance rate may increase further (red line). Ko—mass transfer coefficient; A—surface area.

300

Urea clearance rate, mL/min

280 260 240 220 200 180 160 Qd=800 Qd=500

140 120 100 200

250

300 350 400 Blood flow rate, mL/min

450

500

Backfiltration Blood flow

Pressure, mm Hg

150

Dialysate flow

Blood /Dialysate inlet outlet Pbi

Blood /Dialysate outlet inlet

140

Pdi

130

Ultrafiltrate

x Back filtrate

120 Pdo

110 100

Pbo

FIGURE 3-28 Pressure inside the blood compartment (dark colored arrow) and the dialysate compartment (light colored arrow) with a fixed net zero ultrafiltration rate. The pressure gradually decreases in the blood compartment as blood travels from the inlet toward the outlet. Beyond a certain point along the dialyzer length (x, where the two pressure lines intersect), the pressure in the dialysate compartment exceeds that in the blood compartment, forcing fluid to move from the dialysate to the blood compartment. This movement of fluid in the direction opposite to that of the designed ultrafiltration is called backfiltration. Backfiltration may carry with it contaminants (eg, endotoxins) from the dialysate. Increasing the net ultrafiltration rate shifts the pressure intersection point to the right and diminishes backfiltration.

3.10

Dialysis as Treatment of End-Stage Renal Disease

References 1. Tokars JI, Alter MJ, Miller E, et al.: National surveillance of dialysis associated disease in the United States: 1994. ASAIO J 1997, 43:108–119.

13. Chandran PKG, Liggett R, Kirkpatrick B: Patient survival on PAN/AN 69 membrane hemodialysis: a ten year analysis. J Am Soc Nephrol 1993, 4:1199–1204.

2. United States Renal Data System, 97: Treatment modalities for ESRD patients. Am J Kidney Dis 1997, 30:S54–S66.

14. Hornberger JC, Chernew M, Petersen J, Garber AM: A multivariate analysis of mortality and hospital admissions with high-flux dialysis. J Am Soc Nephrol 1992, 3:1227–1236.

3. Cheung AK, Leypoldt JK: The hemodialysis membranes: a historical perspective, current state and future prospect. Sem Nephrol 1997, 17:196–213. 4. Leypoldt JK, Cheung AK, Agodoa LY, et al.: Hemodialyzer mass transfer–area coefficients for urea increase at high dialysate flow rates. Kidney Int 1997, 51:2013–2017. 5. Collins AJ, Keshaviah P: High-efficiency, high flux therapies in clinical dialysis. In Clinical Dialysis, edn 3. Edited by Nissenson AR. 1995:848–863. 6. Collins AJ: High-flux, high-efficiency procedures. In Principles and Practice of Hemodialysis. Edited by Henrich W. Norwalk, CT: Appleton & Large; 1996:76–88. 7. von Albertini B, Bosch JP: Short hemodialysis. Am J Nephrol 1991, 11:169–173. 8. Keshaviah P, Luehmann D, Ilstrup K, Collins A: Technical requirements for rapid high-efficiency therapies. Artificial Organs 1986, 10:189–194. 9. Shinaberger JH, Miller JH, Gardner PW: Short treatment. In Replacement of Renal Function by Dialysis, edn 3. Edited by Maher JF. Norwell, MA: Kluwer Academic Publishers; 1989:360–381. 10. Barth RH: High flux hemodialysis: overcoming the tyranny of time. Contrib Nephrol 1993, 102:73–97. 11. Van Ypersele, De Strihou C, Jadoul M, et al.: The working party on dialysis amyloidosis: effect of dialysis membrane and patient’s age on signs of dialysis-related amyloidosis. Kidney Int 1991, 39:1012–1019. 12. Koda Y, Nishi S, Miyazaki S, et al.: Switch from conventional to highflux membrane reduces the risk of carpal tunnel syndrome and mortality of hemodialysis patients. Kidney Int 1997, 52:1096–1101.

15. Hakim RM, Held PJ, Stannard DC, et al.: Effect of the dialysis membrane on mortality of chronic hemodialysis patients. Kidney Int 1996, 50:566–570. 16. Churchill DN: Clinical impact of biocompatible dialysis membranes on patient morbidity and mortality: an appraisal of evidence. Nephrol Dial Trans 1995, 10(suppl):52–56. 17. Seres DS, Srain GW, Hashim SA, et al.: Improvement of plasma lipoprotein profiles during high flux dialysis. J Am Soc Nephrol 1993, 3:1409–1415. 18. Mailloux LU: Dialysis modality and patient outcome. UpToDate Med 1995. 19. Parker TF III, Wingard RL, Husni L, et al.: Effect of the membrane biocompatibility on nutritional parameters in chronic hemodialysis patients. Kidney Int 1996, 49:551–556. 20. Ikizler TA, Hakim RM: Nutrition in end-stage renal disease. Kidney Int 1996, 50:343–357. 21. Hakim RM, Wingard RL, Parker RA, et al.: Effects of biocompatibility on hospitalizations and infectious morbidity in chronic hemodialysis patients. J Am Soc Nephrol 1994, 5:450. 22. Van Stone JC: Hemodialysis apparatus. In Handbook of Dialysis, edn 2. Edited by Daugirdas JT, Ing TS. Boston/New York: Little, Brown & Co.; 1994:31–52.

Principles of Peritoneal Dialysis Ramesh Khanna Karl D. Nolph

P

eritoneal dialysis is a technique whereby infusion of dialysis solution into the peritoneal cavity is followed by a variable dwell time and subsequent drainage. Continuous ambulatory peritoneal dialysis (CAPD) is a continuous treatment consisting of four to five 2-L dialysis exchanges per day (Fig. 4-1A). Diurnal exchanges last 4 to 6 hours, and the nocturnal exchange remains in the peritoneal cavity for 6 to 8 hours. Continuous cyclic peritoneal dialysis, in reality, is a continuous treatment carried out with an automated cycler machine (Fig. 4-1B). Multiple short-dwell exchanges are performed at night with the aid of an automated cycler machine. Other peritoneal dialysis treatments consist of intermittent regimens (Fig. 4-2A-C). During peritoneal dialysis, solutes and fluids are exchanged between the capillary blood and the intraperitoneal fluid through a biologic membrane, the peritoneum. The three-layered peritoneal membrane consists of 1) the mesothelium, a continuous monolayer of flat cells, and their basement membranes; 2) a very compliant interstitium; and 3) the capillary wall, consisting of a continuous layer of mainly nonfenestrated endothelial cells, supported by a basement membrane. The mesothelial layer is considered to be less of a transport barrier to fluid and solutes, including macromolecules, than is the endothelial layer [1]. The capillary endothelial cell membrane is permeable to water through aquaporins (radius of approximately 0.2 to 0.4 nm) [2]. In addition, small solutes and water are transported through ubiquitous small pores (radius of approximately 0.4 to 0.55 nm). Sparsely populated large pores (radius of approximately 0.25 nm, perhaps mainly venular) transport macromolecules passively. Diffusion and convection move small molecules through the interstitium with its gel and sol phases, which are restrictive owing to the phenomenon of exclusion [3,4]. The splanchnic blood flow in the normal adult ranges from 1.0 to 2.4 L/min, arising from celiac and mesenteric arteries [5]. The lymphatic vessels located primarily in the subdiaphragmatic region drain fluid and solutes from the peritoneal cavity through bulk transport.

CHAPTER

4

4.2

Dialysis as Treatment of End-Stage Renal Disease

The extent of lymph drainage from the peritoneal cavity is a subject of controversy owing to the lack of a direct method to measure lymph flow. Dialysis solution contains electrolytes in physiologic concentrations to facilitate correction of acid-base and electrolyte abnormalities. High concentrations of glucose in the dialysis solution generate ultrafiltration in proportion to the overall osmotic gradient, the reflection coefficients of small solutes relative to the peritoneum, and the peritoneal membrane hydraulic permeability. Removal of solutes such as urea, creatinine, phosphate, and other metabolic end products from the body depends on the development of concentration gradients between blood and intraperitoneal fluid, and the transport is driven by the process of diffusion. The amount of solute removal is a function of the degree of its concentration gradient, the molecular size, membrane permeability and surface area, duration of dialysis, and charge. Ultrafiltration adds a convective component proportionately more important as the molecular size of the solute increases. The peritoneal equilibration test is a clinical tool used to characterize the peritoneal membrane transport properties [6]. Solute transport rates are assessed by the rates of their equilibration between the peritoneal capillary blood and dialysate (see Fig. 4-8). The ratio of solute concentrations in dialysate and plasma at specific times during the dwell signifies the extent of solute transport. The

fraction of glucose absorbed from the dialysate at specific times can be determined by the ratio of dialysate glucose concentrations at specific times to the initial level in the dialysis solution. Tests are standardized for the following: duration of the preceding exchange before the test; inflow volume; positions during inflow, drain, and dwell; durations of inflow and drain; sampling methods and processing; and laboratory assays [7]. Creatinine and urea clearance rates are the most commonly used indices of dialysis adequacy in clinical settings. Contributions of residual renal clearances are significant in determining the adequacy of dialysis. The mass-transfer area coefficient (MTAC) represents the clearance rate by diffusion in the absence of ultrafiltration and when the rate of solute accumulation in the dialysis solution is zero. Peritoneal clearance is influenced by both blood and dialysate flow rates and by the MTAC [8]. Therefore, the maximum clearance rate can never be higher than any of these parameters. At infinite blood and dialysate flow rates, the clearance rate is equal to the MTAC and is mass-transfer–limited. Large molecular weight solutes are mass-transfer–limited; therefore, their clearance rates do not increase significantly with high dialysate flow rates [9]. In CAPD, blood flow and MTAC rates are higher than is the maximum achievable urea clearance rate. However, the urea clearance rate approximately matches the dialysate flow rate, suggesting that the dialysate flow rate limits CAPD clearances.

Peritoneal Dialysis Regimens Day

Night

Day

Night

Day

Night

Day

Night

Left 2.0 1.0 0.0

A

Right 2.0 1.0 0.0

B

Exchanges, n

FIGURE 4-1 Continuous peritoneal dialysis regimens. A, Continuous ambulatory peritoneal dialysis (CAPD); B, continuous cyclic peritoneal dialysis (CCPD) is shown. Multiple sequential exchanges are performed during the day and night so that dialysis occurs 24 hours a day, 7 days a week.

4.3

Principles of Peritoneal Dialysis

Day

Night

Day

Day

Night

Day

FIGURE 4-2 Intermittent peritoneal dialysis regimens. Peritoneal dialysis is performed every day but only during certain hours. A, In daytime ambulatory peritoneal dialysis (DAPD), multiple manual exchanges are performed during the waking hours. B, Nightly peritoneal dialysis (NPD) is also performed while patients are asleep using an automated cycler machine. One or two additional daytime manual exchanges are added to enhance solute clearances.

Night

Left 2.0 1.0 0.0

A

Left

Night

2.0 1.0 0.0

B

Solute Removal Blood urea nitrogen, mg/dL

24 100

60 40 20 0

Dialysate Blood

–20 0

A

80

160

240

320

400

480

Creatinine, mg/dL

20

80

FIGURE 4-3 Solute removal. Solute concentration gradients are at maximum at the beginning of dialysis and diminish gradually as dialysis progresses. As the gradients diminish, the solute removal rates decrease. Solute removal can be enhanced by increasing the dialysate flow

12 8 4

Dialysate Blood

0

560

Time, min

16

B

0

40

80

120

160 200 Time, min

240

280

320

360

rate by either increasing the intraperitoneal dialysate volume per exchange or increasing the frequency of exchange. By convection or enhanced diffusion, solutes are able to accompany the bulk flow of water. (From Nolph and coworkers [10]; with permission.)

Dialysis as Treatment of End-Stage Renal Disease 1.0

1.0

0.9

0.9 Dialysate to plasma ratio

0.8 0.7 0.6 0.5 0.4

Urea Creatinine Uric acid Phosphorus Inulin Calcium

0.3 0.2 0.1 0

100

200

A

0

1

2

3

4

5

Dwell time, h

6

7

0.5 0.4

Urea Creatinine Uric acid Phosphorus Inulin Calcium

0.3

0

100

200

B

Total dialysate volume (V)

Creatnine dialysate to plasma ratio (D/P)

A

Low transport

0.5

0.6

0.1

FIGURE 4-4 Solute removal. The rates of change of solute concentrations are similar for 1.5% dextrose dialysis solutions (panel A) and 4.25% dextrose dialysis solutions (panel B). Hypertonic exchanges enhance solute removal owing to larger drain volumes. Net solute diffusion ceases at equilibration when the dialysate to plasma solute ratio (D/P)

High transport

0.7

0.2

300 500 400 Dwell time, min

1.0

0.8

2600 2300 2000 1700 0

NIPD DAPD NTPD CCPD (NE)

1

2

B

FIGURE 4-5 Solute removal. In a highly permeable membrane, smaller molecules (ie, urea and creatinine) are transported at a faster rate from the blood to dialysate than are larger molecules, enhancing solute removal. Similarly, glucose (a small solute used in the peritoneal dialysis solution to generate osmotic force for ultrafiltration across the peritoneal membrane) is also transported faster, but in the opposite direction. This high transporter dissipates the osmotic force more rapidly than does the low transporter. Both osmotic and glucose equilibriums are attained eventually in both groups, but sooner in the high transporter group. Intraperitoneal volume peaks and begins to diminish earlier in the high transporter group. When the membrane is less permeable, solute removal is lower, ultrafiltration volume is larger at 2 hours or more, and glucose equilibriums are attained later.

300 500 400 Dwell time, min

is near 1.0. Smaller size solutes (ie, urea and creatinine) diffuse across the membrane faster, equilibrate sooner, and are influenced more by exchange frequency as compared with larger size solutes (ie, uric acid, phosphates, inulin, and proteins). (From Nolph and coworkers [10]; with permission.)

CAPD

3 4 5 Dwell time, h

CCPD (DE)

6

7

Creatinine clearance per exchange (Ccr)

Dialysate to plasma ratio

4.4

C

D/P=1 Ccr=V

2 1

Ccr=V × D/P

0

1

2

3 4 5 Dwell time, h

6

7

Consequently, intraperitoneal volume peaks later. Ultrafiltration in a low transporter peaks late during dwell time. Therefore, a low transporter continues to generate ultrafiltration even after 8 to 10 hours of dwell. The solute creatinine dialysate to plasma ratio (D/P) increases linearly during the dwell time. Patients with average solute transfer rates have ultrafiltration and mass transfer patterns between those of high and low transporters. NIPD—nightly intermittent peritoneal dialysis; NTPD—nighttime tidal peritoneal dialysis; DAPD—daytime ambulatory peritoneal dialysis; CAPD—continuous ambulatory peritoneal dialysis; CCPD (NE)—continuous cyclic peritoneal dialysis (night exchange); CCPD (DE)—continuous cyclic peritoneal dialysis (day exchange). (From Twardowski [11]; with permission.)

Principles of Peritoneal Dialysis

150 140 130 120 110 100 90 Inflow

Sodium, mLq/L

1.5% dextrose dialysis solutions

100 200 300 400 500 Dwell time, min

150 140 130 120 110 100 90 Inflow

Sodium, mLq/L

Serum and dialysate 4.25% dextrose dialysis solutions

0

B

FIGURE 4-6 Solute sieving. A, Dialysate sodium concentration is initially reduced and tends to return to baseline later during a long dwell exchange of 6 to 8 hours. B, Dialysate sodium concentration decreases, particularly when using 4.25% dextrose dialysis solution, because of the sieving phenomenon. Removal of water during ultrafiltration unaccompanied by sodium, in proportion to its extracellular concentration, is called sodium sieving [7,12]. The peritoneum offers greater resistance to the movement of solutes than does water. This probably relates to approximately half the ultrafiltrate being generated by solute-free water movement through aquaporins channels. Therefore, ultrafiltrate is hypotonic compared with plasma. Dialysate chloride is also reduced below simple Gibbs-Donnan equilibrium, particularly during hypertonic exchanges. Patients with a low peritoneal membrane transport type tend to reduce dialysate sodium concentration more than do other patients. Therefore, during a short dwell exchange of 2 to 4 hours, net electrolyte removal per liter of ultrafiltrate is well below the extracelluar fluid concentration. As a result, severe hypernatremia, excessive thirst, and hypertension may develop. This hindrance can be overcome by lowering the dialysate sodium concentration to 132 mEq/L. In patients who use cyclers with short dwell exchanges and who generate large ultrafiltration volumes, lower sodium concentrations may need to be used (such as 118 mEq/L for 2.5% glucose solutions or 109 mEq/L for 4.25% solutions). In continuous ambulatory peritoneal dialysis with long dwell exchanges of 6 to 8 hours, significant sieving usually does not occur, whereas in automated peritoneal dialysis with short dwell exchanges, sieving may occur. Sieving predisposes patients to thirst and less than optimum blood pressure control, especially in those who have low-normal serum sodium levels, those with low peritoneal membrane transporter rates, or both. (From Nolph and coworkers [10]; with permission.)

Serum and dialysate

0

A

100 200 300 400 Dwell time, min

500

FIGURE 4-7 Fluid removal by ultrafiltration. During peritoneal dialysis, hyperosmolar glucose solution generates ultrafiltration by the process of osmosis. Water movement across the peritoneal membrane is proportional to the transmembrane pressure, membrane area, and membrane hydraulic permeability. The transmembrane pressure is the sum of hydrostatic and osmotic pressure differences between the blood in the peritoneal capillary and dialysis solution in the peritoneal cavity. Net transcapillary ultrafiltration defines net fluid movement from the peritoneal microcirculation into the peritoneal cavity primarily in response to osmotic pressure. Net ultrafiltration would equal the resulting increment in intraperitoneal fluid volume if it were not for peritoneal reabsorption, mostly through the peritoneal lymphatics. Peritoneal reabsorption is continuous and reduces the intraperitoneal volume throughout the dwell. A, The net transcapillary ultrafiltration rate decreases exponentially during the dwell time, owing to dissipation of the glucose osmotic gradient secondary to peritoneal glucose absorption and dilution of the solution glucose by the ultrafiltration. Later in the exchange net, ultrafiltration ceases when the transcapillary ultrafiltration is reduced to a rate equal to the peritoneal reabsorption. B, When the transcapillary ultrafiltration rate decreases below that of the peritoneal reabsorption rate, the net ultrafiltration rate becomes negative. Consequently, the intraperitoneal volume begins to diminish. Thus, peak ultrafiltration and intraperitoneal volumes are observed before osmotic equilibrium during an exchange.

Transcapillary ultrafiltration Lymphatic absorption 600

500

mL/h

400

300 Peak ultrafiltration volume

200

4.5

100

(Continued on next page) 0

A

1

3

Peak intraperitoneal volume

2800 Intraperitoneal

2 Dwell time, h

Dialysate

2600

2400 0

B

1

2 Dwell time, h

3

4

4.6

Dialysis as Treatment of End-Stage Renal Disease

Dialysate Serum

Osmolality, mOsm/L

360 340

300

0

C

Glucose, mOsm/L

Osmotic equilibrium

320

2 3 Dwell time, h

4

Dialysate Serum

2000

Hypothetical glucose equilibrium

1000

0

D

1

FIGURE 4-7 (Continued) C, Osmotic equilibrium most likely precedes glucose equilibrium because of both solute sieving and the higher peritoneal reflection coefficient of glucose compared with other dialysate solutes, allowing net transcapillary ultrafiltration to continue at a low rate even after osmotic equilibrium. D, Ultrafiltration can be maximized by measures that delay osmotic equilibrium, which can be accomplished by using hypertonic glucose solutions, larger volumes, or both, during an exchange. More frequent exchanges shorten dwell times and increase the dialysate flow rate and thus avert attaining osmotic equilibrium. Additionally, potential exists for enhancing ultrafiltration by measures that reduce the peritoneal reabsorption rate. (From Mactier and coworkers [13]; with permission.)

1

2 3 Dwell time, h

4

STANDARDIZED 4-HOUR PERITONEAL EQUILIBRATION TEST

FIGURE 4-8 Standardized 4-hour peritoneal equilibration test. Dt/D0 glucose—final to initial dialysate glucose ratio.

1. Perform an overnight 8- to 12-h preexchange. 2. Drain the overnight exchange (drain time not to exceed 25 min) with patient in the upright position. 3. Infuse 2 L of dialysis solution over 10 min with patient in the supine position. Roll the patient from side to side after every 400-mL infusion. 4. After the completion of infusion (0 time) and at 120 min, drain 200 mL of dialysate. Take a 10-mL sample, and reinfuse the remaining 190 mL into the peritoneal cavity. 5. Position the patient upright, and allow patient ambulation if able. 6. Obtain a serum sample at 120 min. 7. At the end of study (240 min), drain the dialysate with the patient in the upright position (drain time not to exceed 20 min). 8. Measure the drained volume, and take a 10-mL sample from the drained volume after a good mixing. 9. Analyze the blood and dialysate samples for creatinine and glucose concentrations. 10. Correct the serum and dialysate creatinine concentrations for high glucose level (correction factor 0.000531415). 11. Calculate the dialysate to plasma ratios for creatinine, and so on, and calculate the Dt/D0 glucose.

Correction of creatinine levels Corrected creatinine (mg/dL) = Observed creatinine (mg/dL) – (glucose [mg/dL] x 0.000531415)

FIGURE 4-9 Equation to correct the creatinine levels in dialysate and serum. The creatinine levels in dialysate and serum need to be corrected for high glucose levels, which contribute to formation of noncreatinine chromogens during the creatinine assay. The correction factor may vary from one laboratory to another. In our laboratory at the University of Missouri–Columbia, the correction factor is 0.000531415. Accordingly, the corrected creatinine is calculated as in the equation. The correction in the serum is minimal due to low blood sugar levels; however, it is significant in dialysate, especially during the early phase of dwell (0- and 2-hour dialysate samples).

Principles of Peritoneal Dialysis

FIGURE 4-10 Equation to calculate the intraperitoneal residual volume. Residual volume is the volume of dialysate remaining in the peritoneal cavity after drainage over 20 minutes. The residual volume can be determined by knowing the dilution factor for solutes such as potassium, urea, and creatinine during the next instillation. The calculation of residual volumes is based on the assumption that the mixing of fluid in the peritoneal cavity is instantaneous and complete. This equation is used for the calculation, where Vin is instillation volume; S1 is solute concentration in pretest exchange dialysate; S2 is solute concentration in instilled dialysis solution; and S3 is solute concentration immediately after instillation (0 dwell time). The residual volumes by urea, creatinine, glucose, potassium, and protein are calculated and averaged for accuracy. The measurement of residual volumes is of limited clinical usefulness; however, it is of great value in a research setting in which accurate determination of intraperitoneal volume is required.

Intraperitoneal residual volume R=

Vin(S3 – S2) (S1 – S3)

1.1

1.1

0.9 Dialysis to plasma ratio

Dialysis to plasma ratio

0.9 0.7 0.5

0.7 0.5

0.3

0.3

0.1

0.1 1/ 2

1

2

3

1.1

0

4

1/ 2

1

35 Dialysate to plasma ratio × 1000

Glucose

0.9 0.7 0.5 0.3

2

3

4

Hours

B

Hours

A

Final to initial dialysate glucose ratio

Creatinine

Urea

0

Protein

30 25 20 15 10

0

C

1/ 2

1

2 Hours

3

0

4

D

1/ 2

1

2 Hours

FIGURE 4-11 Classification of peritoneal transport function. Based on the peritoneal equilibrium test results, peritoneal transport function may be classified into average, high (H), and low (L) transport types. The average transport group is further subdivided into high-average (HA) and low-average (LA) types. For the population studied by Twardowski and coworkers [6], the transport classification is based on means; standard deviations (SDs); and minimum and maximum dialysate to plasma ratio (D/P) values over 4 hours for urea, creatinine, glucose, protein, potassium, sodium, and corrected creatinine (panels A–G). (Continued on next page)

5

0.1 0

4.7

3

4

4.8

Dialysis as Treatment of End-Stage Renal Disease

Potassium

1.1

FIGURE 4-11 (Continued) The volume of drainage correlates positively with dialysate glucose and negatively with D/P creatinine values at 4-hour dwell times (panel H). (From Twardowski and coworkers [6]; with permission.)

Sodium

1.00

Dialysate to plasma ratio

Dialysate to plasma ratio

0.9

0.7

0.5

0.3

0.70

0

0

E

1/ 2

1

2 Hours

3

0.80 H HA LA L

Max +SD –SD Min

0.1

0.90

4

0

F

1/ 2

1

2 Hours

3

4

ADK vol05 ch p04 fig11F 3500

1.1

Max +SD x –SD Min

Corrected creatinine 3000 0.9

0.7

2000 mL

Dialysate to plasma ratio

2500

1500

0.5

1000 0.3 H HA LA L

0.1 0

G

0

1/ 2

1

2 Hours

3

500 0

4

H

CLINICAL APPLICATIONS OF THE PERITONEAL EQUILIBRATION TEST Peritoneal membrane transport classification 1. Choose peritoneal dialysis regimen. 2. Monitor peritoneal membrane function. 3. Diagnose acute membrane injury. 4. Diagnose causes of inadequate ultrafiltration. 5. Diagnose causes of inadequate solute clearance. 6. Estimate dialysate to plasma ratio of a solute at time t. 7. Diagnose early ultrafiltration failure. 8. Predict dialysis dose. 9. Assess influence of systemic disease on peritoneal membrane function.

Drain volume

Residual pre-eq

Volume post-eq

FIGURE 4-12 In clinical practice it is customary to perform the baseline standardized peritoneal equilibrium test (PET) approximately 3 to 4 weeks after catheter insertion. The PET is repeated when complications occur. The standardized test for clinical use measures dialysate creatinine and glucose levels at 0, 2, and 4 hours of dwell time and serum levels of creatinine and glucose at any time during the test. The extensive unabridged test, as originally proposed by Twardowski and coworkers [6], has become a very important research tool.

Principles of Peritoneal Dialysis

Baseline peritoneal equilibrium test High transporter D/P creatinine

Low average transporter D/P creatinine

High average transporter D/P creatinine

16%

68%

Low transporter D/P creatinine 16%

Baseline peritoneal equilibrium test High

High average

Low average

Low

NIPD DAPD

NIPD CAPD

High-dose CAPD High-dose CCPD

High-dose CCPD only when significant residual renal function is present

1.0

Dialysate to plasma ratio

0.97

0.92 0.9 0.88 0.85 0.80

0.8

0.7 0.0

High High average Low average Low

1.0

2.0

3.0

4.0

4.9

FIGURE 4-13 Population distribution of peritoneal membrane transport types. Baseline peritoneal equilibrium test results of patients on long-term peritoneal dialysis in the United States suggest that approximately 68% have average transport rates, 16% have high transport rates, and another 16% have low transport rates [6]. Similar distributions of transport types have been documented worldwide [14–16]. D/P—dialysate to plasma ratio.

FIGURE 4-14 Using transport type to select a peritoneal dialysis regimen. Because clearance rates continue to increase with time, patients with low transport rates are treated with long dwell exchanges, ie, continuous cyclic peritoneal dialysis (CCPD). Owing to the low rate of increase in the dialysate to plasma ratio (D/P), the clearance rate per unit of time is augmented relatively little by rapid exchange techniques such as nightly intermittent peritoneal dialysis (NIPD). On the contrary, the clearance per exchange rate over long dwell exchanges would be less in patients with high transport rates. During the short dwell time, patients with high transport rates capture maximum ultrafiltration and small solutes are completely equilibrated. Therefore, these patients are best treated with techniques using short dwell exchanges, ie, NIPD or daytime ambulatory peritoneal dialysis (DAPD). Patients with average transport rates can be effectively treated with either short or long dwell exchange techniques. CAPD—continuous ambulatory peritoneal dialysis.

FIGURE 4-15 Diagnosis of early ultrafiltration failure. The dialysate to plasma ratio (D/P) curve of sodium, during the unabridged peritoneal equilibrium test (2.5% dextrose dialysis solution), typically shows an initial decrease owing to the high ultrafiltration rate. Because of sodium sieving, the ultrafiltrate is low in sodium. Consequently, the dialysate sodium is lowered, resulting in a lower D/P ratio of sodium. Later, during the dwell when ultrafiltration ceases, dialysate sodium tends to equilibrate with that of capillary blood, returning the D/P ratio of sodium to baseline. Absence of the initial decrease of the D/P of sodium is an indication of ultrafiltration failure and is typically seen in the early phase of sclerosing encapsulating peritonitis. (From Dobbie and coworkers [17]; with permission.)

4.10

Dialysis as Treatment of End-Stage Renal Disease

(DxV) P where C = clearance in mL/min: DxV = dialysate solute removed per minute; D = dialysate solute concentration; V = volume of dialysate in mL/min; and P = plasma solute concentration C=

or C=(D/P) x V where C = clearance in mL/exchange at time t; D/P = solute equilibrium rate at time t; and V = volume of dialysate at time t

A

Kt/V

B

where K = urea clearance in mL/min; t = minutes of therapy; and V = volume of urea distribution or total body water

Mass-transfer area coefficient The diffusive mass transfer is estimated by M=I

A (C – C ) R P D

where M = diffusive mass transfer: A = effective membrane surface area; I = coefficient of proportionality; R = sum of all resistances; Cp = solute concentration in the potential capillary blood; and CD = solute concentration in the dialysate

A

Dividing both sides of the equation by solute concentration in peripheral blood (CB) will yield instantaneous clearance or the MTAC; M A CP CD =K=I – CB R CB CB

(

B

(

If the peritoneal capillary blood flow is infinite, Cp will equal Cb and A C Ki=I 1– D R CB

( (

If the dialysate flow is also infinite, then Co will equal 0, and A Ki=Kmax=I R

C

FIGURE 4-16 Creatinine and urea clearances rates. These rates are estimated by dividing the amount of solute removed per unit of time by the plasma solute concentration. Alternatively, clearance also can be estimated by multiplying the solute equilibration rate per unit of time by the volume of dialysate into which equilibration occurred over the same unit of time. By convention, the creatinine clearance rate is normalized to body surface area. The urea clearance is normalized to total body water (volume of urea distribution in the body) and is expressed as Kt/V. The Kt/Vvalue is a number without a unit ([mL/min  min]/ mL). During intermittent dialysis, with a dialysate flow rate of 30 mL/min, the typical urea clearance is about 18 to 20 mL/min [18]. Increasing the dialysate flow rates to 3.5 to 12 L/h by rapid exchanges increases the urea clearance rate to a maximum of 30 to 40 mL/min. Beyond this maximum rate, the clearance rate begins to decrease owing to the loss of membrane-fluid contact time with infusion and drainage; inadequate mixing may also occur [19–22]. Clearance could be enhanced by increasing the membrane-solution contact [23]. Continuous dialysate flow techniques using either two catheters or double-lumen catheters also have enhanced the urea clearance rate to a maximum of 40 mL/min. At these high flow rates, poor mixing, channeling, abdominal pain, and poor drainage limit successful application. Maintaining a fluid reservoir in the peritoneal cavity (called tidal peritoneal dialysis) and then replacing only a fraction of the intraperitoneal volume rapidly, increases clearance rates by about 30% compared with the standard technique using the same doses owing to maintaining fluid-membrane contact at higher dialysis-solution flow rates [24–29]. During continuous ambulatory peritoneal dialysis (CAPD) in adults, the optimum volume that ensures complete membrane-solution contact is about 2 L [30,32]. Successful use of 2.5and 3.0-L volumes has been reported in adult patients undergoing CAPD; however, hernial complications are increased [32,33]. FIGURE 4-17 The mass-transfer area coefficient (MTAC). The MTAC represents the clearance rate by diffusion in the absence of ultrafiltration and when the solute accumulation in the dialysis solution is zero [34–39]. MTAC is equal to the product of peritoneal membrane permeability (P) and effective peritoneal membrane surface area (S). Thus, when both capillary blood and dialysate flows are infinite, the clearance rate is directly proportional to the effective peritoneal surface area and inversely proportional to the overall membrane resistance. However, infinite blood and dialysate flows cannot be achieved, and the maximum clearance rate is unattainable. The closest measurable value, the MTAC, was introduced. The MTAC represents an instantaneous clearance without being influenced by ultrafiltration and solute accumulation in the dialysate. The MTAC is measured over a test exchange during which at least two blood and dialysate samples are obtained at different dwell times. The precision of the measurement is enhanced with more data points. The MTAC is seldom used clinically; however, it is a very useful research tool.

Principles of Peritoneal Dialysis

4.11

References 1. Clough G, Michel CC: Quantitative comparisons of hydraulic permeability and endothelial intercellular cleft dimensions in single form capillaries. J Physiol 1988, 405:563–576.

22. Tenckhoff H, Ward G, Boen ST: The influence of dialysate volume and flow rate on peritoneal clearance. Proc Eur Dial Transplant Assoc 1965, 2:113–117.

2. Pannekeet MM, Mulder JB, Weening JJ, et al.: Demonstration of aquaporin-CHIP in peritoneal tissue of uremic and CAPD patients. Peritoneal Dial Int 1996, 16(suppl 1):S54.

23. Trivedi HS, Twardowski ZJ: Long-term successful nocturnal intermittent peritoneal dialysis: a ten-year case study. In Advances in Peritoneal Dialysis. Edited by Khanna R. Toronto, Canada: Peritoneal Dialysis Publications; 1994:81–84.

3. Flessner MF, Dedrick RL, Schultz JS: Exchange of macromolecules between peritoneal cavity and plasma. Am J Physiol 1985, 248:H15. 4. Flessner MF, Fenstermacher JD, Blasberg RG, Dedrick RL: Peritoneal absorption of macromolecules studied by quantitative autoradiography. Am J Physiol 1985, 248:H26.

24. Di Paolo N: Semicontinuous peritoneal dialysis. Dial Transplant 1978, 7:839–842. 25. Finkelstein FO, Kliger AS: Enhanced efficiency of peritoneal dialysis using rapid, small-volume exchanges. ASAIO J 1979, 2:103–106.

6. Twardowski ZJ, Nolph KD, Khanna R, et al.: Peritoneal equilibration test. Peritoneal Dial Bull 1987, 7:138–147.

26. Twardowski ZJ, Nolph KD, Khanna R, et al.: Tidal peritoneal dialysis. In Ambulatory Peritoneal Dialysis: Proceedings of the IVth Congress of the International Society for Peritoneal Dialysis, Venice, Italy, June 1987. Edited by Avram MM, Giordano C. New York: Plenum; 1990:145–149.

7. Ahearn DJ, Nolph KD: Controlled sodium removal with peritoneal dialysis. Trans Am Soc Artif Intern Organs 1972, 28:423.

27. Twardowski ZJ, Prowant BF, Nolph KD, et al.: Chronic nightly tidal peritoneal dialysis (NTPD). ASAIO Trans 1990, 36:M584–M588.

8. Popovich RP, Moncrief JW: Kinetic modeling of peritoneal transport: In Today’s Art of Peritoneal Dialysis. Edited by Trevino-Bacerra A, Boen FST. Basel, Switzerland: Karger; 1979:59–72. [Contributions to Nephrology, 1.]

28. Twardowski ZJ: Tidal peritoneal dialysis: acute and chronic studies. Eur Dial Transplant Nurses Assoc Eur Renal Care Assoc September 1990, 15:4–9. 29. Twardowski ZJ: Tidal peritoneal dialysis. In Dialysis Therapy. Edited by Nissenson AR, Fine RN. Philadelphia: Hanley & Belfus; 1993:153–156. 30. Twardowski ZJ, Nolph KD, Prowant BF, et al.: Efficiency of high volume low frequency continuous ambulatory peritoneal dialysis (CAPD). ASAIO Trans 1983, 29:53–57. 31. Krediet RT, Boeschoten EW, Zuyderhoudt FMJ, et al.: Differences in the peritoneal transport of water, solutes and proteins between dialysis with two- and with three-litre exchanges [thesis]. In Peritoneal Permeability in Continuous Ambulatory Peritoneal Dialysis Patients. Edited by Krediet RT. Amsterdam, Holland: University of Amsterdam; 1986:129–146.

5. Wade OL, Combes B, Childs AW, et al.: The effect of exercise on the splanchnic blood flood and splanchnic blood volume in normal man. Clin Sci 1956, 15:457.

9. Twardowski ZJ: Physiology of peritoneal dialysis. In Clinical Dialysis. Edited by Nissenson AR, Fine RN, Gentile DE, edn 3. Norwalk, CT: Appleton & Lange; 1995:322. 10. Nolph KD, Twardowski ZJ, Popovich RP, et al.: Equilibration of peritoneal dialysis solutions during long dwell exchanges. J Lab Clin Med 1979, 93:246–256. 11. Twardowski ZJ: Nightly peritoneal dialysis (why? who? how? and when?). Trans Am Soc Artif Intern Organs 1990, 36:8–16. 12. Nolph KD, Hano JE, Teschan PE: Peritoneal sodium transport during hypertonic peritoneal dialysis: physiologic mechanisms and clinical implications. Ann Intern Med 1969; 70:931. 13. Mactier RA, Khanna R, Twardowski ZJ, et al.: Contribution of lymphatic absorption to loss of ultrafiltration and solute clearances in continuous ambulatory peritoneal dialysis. J Clin Invest 1987, 80:1311–1316. 14. Zabetakis PM, Krapf R, DeVita MV, et al.: Determining peritoneal dialysis prescriptions by employing a patient-specific protocol. Peritoneal Dial Int 1993, 13:189–193. 15. Wolf CJ, Polsky J, Ntoso KA, et al.: Adequacy of dialysis in CAPD and cycler PD; the PET is enough. Peritoneal Dial Bull 1992, 8:208–211. 16. Struijk DG, Krediet RT, Koomen GCM, et al.: A prospective study of peritoneal transport in CAPD. Kidney Int 1994, 1739–1744. 17. Dobbie JW, Krediet RT, Twardowski ZJ, et al.: A 39-year-old man with loss of ultrafiltration. Peritoneal Dial Int 1994, 14:384–394. 18. Nolph KD, Popovich RP, Ghods AJ, et al.: Determinants of low clearances of small solutes during peritoneal dialysis. Kidney Int 1978, 13:117–123. 19. Boen ST: Kinetics of Peritoneal Dialysis. Baltimore, MD: Medicine; 1961:243–287. 20. Penzotti SC, Mattocks AM: Effects of dwell time, volume of dialysis fluid, and added accelerators on peritoneal dialysis of urea. J Pharm Sci 1971, 60:1520–1522. 21. Pirpasopoulos M, Lindsay RM, Rahman M, et al.: A cost-effectiveness study of dwell time in peritoneal dialysis. Lancet 1972, 2:1135–1136.

32. Twardowski Z, Janicka L: Three exchanges with a 2.5 liter volume for continuous ambulatory peritoneal dialysis. Kidney Int 1981, 20:281–284. 33. Twardowski ZJ, Prowant BF, Nolph KD, et al.: High volume, low frequency continuous ambulatory peritoneal dialysis. Kidney Int 1983, 23:64–70. 34. Randerson DH: Continuous ambulatory peritoneal dialysis-a critical appraisal [thesis]. Sydney, Australia: University of New South Wales; 1980. 35. Pyle WK: Mass transfer in peritoneal dialysis [thesis]. Austin: University of Texas; 1981. 36. Farrell PC, Randerson DH: Mass transfer kinetics in continuous ambulatory peritoneal dialysis. In Proceedings of the First International Symposium on Continuous Ambulatory Peritoneal Dialysis. Edited by Legrain M. Amsterdam, Holland: Excerpta Medica; 1980:34–41. 37. Pyle WK, Moncrief JW, Popovich RP: Peritoneal transport evaluation in CAPD. In CAPD Update. Edited by Moncrief JW, Popovich RP. New York: Masson; 1981:35–52. 38. Pyle WK, Popovich RP, Moncrief JW: Mass transfer in peritoneal dialysis. In Advances in Peritoneal Dialysis. Edited by Gahl GM, Kessel M, Nolph KD. Amsterdam, Holland: Excerpta Medica; 1981:41–46. 39. Garred LF, Canaud B, Farrell PC: A simple kinetic model for assessing peritoneal mass transfer in continuous ambulatory peritoneal dialysis. ASAIO J 1983, 6:131–137.

Dialysis Access and Recirculation Toros Kapoian Jeffrey L. Kaufman John Nosher Richard A. Sherman

S

ince its inception, hemodialysis has been bedeviled by problems of vascular access. Access, from the time of creation and throughout a patient’s dialysis life, consumes significant time, effort, and expense and creates much anxiety and risk for patient and family. Vascular access complications remain the single leading cause of hospitalization and expense for dialysis patients. Some, such as infected access sites, are potentially life threatening. It is common for an access problem to precipitate a crisis related to the end of a patient’s dialysis life. Despite the advances made in hemodialysis technology, the same vascular access problems that plagued dialysis pioneers continue today to confound patient care teams.

CHAPTER

5

5.2

Dialysis as Treatment of End-Stage Renal Disease

Arteriovenous Dialysis Access: Evaluation and Placement EVALUATION FOR HEMODIALYSIS VASCULAR ACCESS History

Physical examination

Surgical cutdown Multiple peripheral catheters

Asymmetry of pulse Asymmetry of blood pressure

Peripherally inserted central catheter line placement

Abnormal capillary refill

Transvenous pacemaker Axillary dissection

Presence of surgical or other scars

Intravenous drug use Obesity Peripheral vascular disease Atherosclerotic disease

Abnormal Allen test

FIGURE 5-1 Evaluation for hemodialysis access. The creation of optimal vascular access requires an integrated approach among patient, nephrologist, and surgeon. The preoperative evaluation includes a thorough history and physical examination. A history of arterial and venous line placements should be sought. The upper extremities are examined for edema and asymmetry of pulse and blood pressure. Access should be placed at the wrist only after it is verified that the radial artery is not the dominant arterial conduit to the hand. The classic study is the Allen test, in which an observer compresses both the radial and ulnar arteries, has the patient exercise the hand by opening and closing to cause blanching, then releases one vessel to be certain that the fingers become perfused. An alternative, and perhaps more precise, test is to verify by Doppler imaging that flow to all digits is maintained despite occlusion of the radial artery. If indicated, vascular imaging studies should be used to delineate the vascular anatomy and rule out arterial or venous disease. Clinically silent stenosis involving the central veins is becoming increasingly common with the improved survival of critically ill patients for whom central vein catheters are commonplace. FIGURE 5-2 Creation of a Brescia-Cimino (radial-cephalic) fistula. The native vein arteriovenous fistula is the preferred choice for hemodialysis access. This simple and effective procedure, in which an artery is connected to an adjacent vein to provide a large volume of blood flow into the superficial venous system, has become less common in recent years. The ideal artery has minimal wall calcification, so that dilation can occur with time and allow unimpeded flow. In addition, the artery should not be affected by proximal stenosis, the most common site being an ostial lesion in the subclavian artery. Ideally, the outflow vein is subjected to minimal dissection or manipulation during the surgical procedure. Forcible distension of veins and rough handling of arteries leads to formation of neointimal fibrous hyperplasia and localized stenosis. The first autogenous access site described was radial-cephalic at the level of the radial styloid process. These can be constructed endvein to side-artery, A and B, or side-to-side, C, between the two vessels. The exposure is conveniently obtained using a transverse incision at the wrist, just proximal to the radial styloid process, where the artery and cephalic vein lie close to one another. In general, the two vessels are just far enough apart so that an end-to-side technique is best. When the vessels overlie each other, some surgeons prefer the side-to-side technique, which allows reversal of blood flow into the dorsum of the hand and then via collaterals into the forearm, theoretically leading to better flow volume over time.

Dialysis Access and Recirculation

FIGURE 5-3 The Brescia-Cimino (radial-cephalic) fistula. The radial-cephalic fistula offers many advantages. It is simple to create and preserves more proximal vessels for future access construction. The lower

5.3

incidence of steal is likely the result of the lower flow rate associated with these accesses. Additionally, such accesses have low rates of thrombosis and infection. The photograph shows a mature Brescia-Cimino fistula in a patient with longstanding diabetes. The fistula outflow vein has numerous aneurysmal segments, and, although they are associated with some tendency toward flow stagnation, they are of no harm to the patient’s dialysis life. They do, however, become obvious targets for the dialysis technical staff, who have a tendency to puncture them repeatedly rather than to utilize new needle insertion sites. The patients arm also demonstrates marked muscle atrophy secondary to advanced diabetic neuropathy, which particularly involves the thenar eminence and the interosseus muscle groups. Complaints of weakness and loss of grip strength in the arm are common and may represent symptoms of steal. In this case, however, the symptoms are due to the intrinsic loss of muscle mass, rather than to steal.

A FIGURE 5-4 The brachial-cephalic vein fistula. If a radial-cephalic vein fistula cannot be constructed, the next best choice for vascular access is the brachial-cephalic vein fistula. Accesses that utilize the brachial artery have the advantage of higher blood flow rates than those that use the radial artery. Although this may improve the efficiency of hemodialysis, it is also associated with increased risk of arm edema and steal. A, The native anatomy of the antecubital veins somewhat resembles the letter M. A more complete depiction is seen in B. The medial volar venous flow enters the basilic system; lateral volar flow enters the cephalic system; and the central connector, which includes a deep tributary, connects the brachial (venae comitantes) system at the brachial artery bifurcation. To create an antecubital autogenous site, there are two general approaches; the surgeon either mobilizes the cephalic vein directly into the brachial artery (C) or “anastomoses” the deep connector between the median antecubital vein and the brachial veins directly to the adjacent artery. It is also possible to prepare a native vein arteriovenous fistula in the antecubital fossa by transposing brachial or basilic veins from the deeper compartment of the brachium to the subcutaneous tissue.

C

5.4

Dialysis as Treatment of End-Stage Renal Disease

FIGURE 5-5 Polytetrafluoroethylene (PTFE) vein graft. The most common synthetic material used for dialysis access construction is the PTFE conduit. This material replaced bovine heterografts; alternative materials such as the umbilical vein graft have not yet made much headway. Because of the infection risk, Dacron bypass grafts have never functioned well for dialysis. PTFE is an inert material that is formed into a pliable conduit. Its ultramicroscopic structure is a series of nodes connected by tiny filaments, leaving pores whose size can be varied

during manufacture. The process of healing after implantation involves ingrowth of fibroblasts into the pore structure, giving a final graft-tissue amalgam that is “incorporated” when encountered by the surgeon for revision. There is virtually no neovascularization through the pores, which are too small for capillary ingrowth. In humans, neointima grow along the graft for no more than 3 cm from the anastomosis. In animal models, neointima can be much more robust, growing along most of the length of the graft and providing it with greater resistance to thrombosis. Typical layouts for the construction of a PTFE access site are A, the forearm loop, and B, linear forearm graft, respectively. Alternative sites include upper arm loop grafts, groin grafts, axillary arteryto-vein grafts, and a variety of other constructions. The sites of choice are limited by the requirements of hemodialysis: delivery of a high rate of blood flow and accessibility to the dialysis staff for cannulation with an adequate length of graft to keep the needles sufficiently separated and allow rotation of cannulation sites.

FIGURE 5-6 Trends in dialysis access sites. Despite our understanding of hemodialysis access and the advantages and disadvantages of the various options available, there is an alarming trend away from the use of native vein fistulas. Of even more concern is the increasing number of patients who begin dialysis without a permanent vascular access in place and the increasing prevalence of central vein catheters. It is not clear whether these trends are the result of age, comorbid conditions such as diabetes and peripheral vascular disease, or simply the untoward effect of late nephrology referral. Although central vein catheters were initially designed for temporary use while an arteriovenous vascular access was being constructed, improvements in design have led to their being used for permanent dialysis access. Nevertheless, central vein catheters, while popular with patients because they obviate “being stuck,” are the source of a variety of access complications, including infection, central vein stenosis, and thrombosis.

Dialysis Access and Recirculation

5.5

Complications of Arteriovenous Dialysis Access Placement

A FIGURE 5-7 Arteriovenous fistula anastomotic stenosis. Arteriovenous fistulas exhibit better long-term patency compared with polytetrafluoroethylene (PTFE) grafts. A, This arteriogram, performed by injecting the brachial artery, demonstrates an end-to-side arteriovenous fistula involving the brachial artery and the cephalic vein. The arrow indicates an area of narrowing adjacent to the anastomosis, the

B most common site for a stenotic lesion in native vein fistulas. B, Angioplasty successfully eliminated the anastomotic stenosis. Limitations on balloon size are often encountered when treating lesions in arteriovenous fistulas because a portion of the balloon must often extend into the donor artery, which typically is of smaller diameter than the outflow vein. FIGURE 5-8 Exposed polytetrafluoroethylene (PTFE) graft. Proper placement of a PTFE graft is crucial for its long-term survival. The graft cannot be too short, as it will deteriorate quickly from puncture limited to only a few sites; if it is too long, however, it will have a greater impedance to flow and a tendency toward thrombosis. The graft should be neither too deep to the skin nor too shallow. When the graft is too shallow, puncture by the dialysis staff is easier, but the skin may be eroded with scarring from repeated use. This photograph shows a linear forearm graft with a segment of exposed PTFE. An exposed graft is a serious problem for several reasons. First, exposure of actual puncture holes eventually leads to hemorrhage. Second, an exposed graft is, by definition, infected. Although some cases have been treated successfully with rotational skin flaps and a long course of antibiotics, the majority do not heal. The ideal treatment is removal of the segment of exposed graft, splicing a segment of new PTFE away from the site of exposure, and allowing secondary wound healing.

5.6

Dialysis as Treatment of End-Stage Renal Disease

A

B

FIGURE 5-9 Extravasation injury to the access site. A, A relatively fresh segment of polytetrafluoroethylene graft was removed during a revision procedure. There is virtually no fibrosis or calcification (associated with repeated puncture). The luminal surface displays the results of multiple sites of puncture and healing. Among the most dramatic and troublesome complications of dialysis is access infiltration. In most cases the infiltration is minor and usually results from either inadequate hemostasis at the end of dialysis or needle perforation through the access site. Extravasation injury to the access is more likely when a needle errantly transfixes a graft or vein or when it accidentally becomes dislodged into the subcutaneous tissue. The venous return needle presents the biggest problem. In the face of typical pump speeds of 400 to 500 mL/min a

potentially huge volume of fluid can enter the soft tissue before the pump stops in response to the alarm for elevated venous pressure. In many cases, the graft is unusable for weeks after such an episode. Continued use of the access in this setting may result in loss of the access site. B, In this example, the infiltration was composed of approximately 400 mL of priming crystalloid and blood, located both deep and superficial to the investing fascia of the arm. The access remained patent and was eventually restored to function; however, a series of percutaneous drainage procedures and open drainage were necessary. Compartment syndrome, with loss of distal motor function or sensation in the arm, is another concern in this setting, and drainage must be performed to treat this surgical emergency. FIGURE 5-10 Outflow vein stenosis. Stenotic lesions are most often found at a polytetrafluoroethylene (PTFE) graft’s venous anastomotic site or within its outflow vein. A, Radiograph depicting an angioplasty balloon inflated across an outflow vein with a stenotic lesion. The “waist” in the balloon (arrow) indicates the location of the stenosis. With increasing inflation pressure the waist disappears, an indication of successful angioplasty. Failure to eliminate the waist in the balloon indicates incomplete dilatation of the lesion. Occasionally, outflow vein stenoses are very resistant to dilatation and require high inflation pressures. This is not surprising given the amount of scarring and intimal hyperplasia that can develop in a dialysis access site. B, Resected graft-venous anastomosis from a one-year-old PTFE graft. The vein wall seen here is enormously thickened. Angioplasty of lesions such as these is often unsuccessful, as this rigid material is likely to rebound to its stenotic state with any manipulation.

A

B

Dialysis Access and Recirculation

A

B

C

D

E FIGURE 5-11 Graft thrombosis due to outflow vein stenosis requiring use of an atherectomy catheter. Thrombectomy of a dialysis access site involves removal of three types of clot. A, The body of a thrombosed access contains a red or purplish thrombus that is often gelatinous. It is easily removed with a balloon-tipped thrombectomy/embolectomy catheter. This photograph also demonstrates the small meniscus of firm, laminar, platelet-rich clot that usually obstructs arterial inflow. On occasion, it is also found at the venous end. This type of clot can be tenacious and may not be removed with thrombolytic therapy or the balloon catheter. A cutdown at the arterial end of the graft may

5.7

be necessary to permit removal of this material under direct visualization. Failure to remove this meniscus invariably leads to rethrombosis. B, This type of clot is demonstrated in an arteriogram performed through the brachial artery following thrombolytic therapy. The arterial end of this polytetrafluoroethylene (PTFE) graft demonstrates a residual intraluminal thrombus (arrow), which is typical of the platelet-rich plug or arterial type thrombus. A third type of clot (not shown) consists of a white laminar material that lines the graft over time, especially in sites of repeated puncture. This material can create a stenosis along the body of the graft and may be removed by curettage at the time of thrombectomy using an atherectomy catheter. Failure to remove this material decreases blood flow through the graft and may lead to rethrombosis. According to Poiseuille’s law, if blood pressure remains constant, a 6-mm graft with 1 mm of circumferential laminar clot accommodates only 20% of the flow originally present, since flow is inversely related to the fourth power of the radius. Eighty percent of thrombosed accesses have an associated stenotic lesion. C, An eccentric focal stenosis is demonstrated at the anastomosis of a PTFE forearm graft and its outflow vein (arrow), which did not respond to percutaneous transluminal angioplasty. The lesion was subsequently resected using a Simpson atherectomy catheter, which consists of a concealed cutting chamber that is deflected into contact with the stenotic lesion of the vessel wall by inflating the associated balloon. With the lesion projecting into the cutting chamber, a high-speed cylindrical cutting blade resects tissue into a collecting chamber. This chamber is rotated sequentially until the circumference of the lesion has been treated. D, The Simpson atherectomy catheter is placed across the stenotic lesion. E, The postprocedure venogram shows that the lesion was successfully resected.

5.8

Dialysis as Treatment of End-Stage Renal Disease FIGURE 5-12 Pulse spray catheter. To increase the efficiency of drug thrombolysis, pulse spray catheters are often used. The technique involves embedding the catheter within the clot and intentionally obstructing the catheter end hole with a guidewire. When the fibrinolytic agent is injected, it is forced out through the catheter sideholes in jets and permeates the clot. With this method, a larger surface area of clot is exposed to the fibrinolytic agent.

FIGURE 5-13 Thrombectomy brush. Several types of mechanical thrombectomy devices have been developed as alternatives to pharmaceutical fibrinolysis. All mechanically macerate or disrupt clot into small fragments that embolize into the central veins and, eventually, the pulmonary vascular bed. This photograph demonstrates a brush attached to a motor drive that imparts high-speed rotary motion to disrupt the thrombus. The danger of most mechanical devices is the risk of vascular injury.

A

B

C

D

FIGURE 5-14 Outflow vein stenosis with stenting. A, Arteriography in this patient with a Brescia-Cimino fistula demonstrates stenosis of the outflow vein approximately 15 cm central to the fistula (arrow). B, Percutaneous transluminal angioplasty was performed in this patient; however, because of immediate elastic recoil, the lesion looks no different after angioplasty. C, Following stent placement (arrow), there is no residual stenosis, and good flow through the stent is apparent. Stents have proven controversial in access sites. Although they may improve patency in central vein stenoses (vide infra), in the periphery they may be a hindrance. Some patients

develop vigorous fibrosis at the venous site of a stent. D, This photograph demonstrates what had occurred only 1 month after stent placement. Stents can be a problem when dealing with subsequent vascular access dysfunction. During thrombectomy, the tiny wires of a stent can puncture balloon catheters. When stented segments restenose, it is impossible to perform open patch angioplasty over such segments, and it becomes necessary to jump to a different venous outflow site. It is not clear whether stents in or adjacent to dialysis grafts are cost effective in maintaining graft patency.

Dialysis Access and Recirculation

A

B

FIGURE 5-15 Intragraft stenosis. A, This arteriogram demonstrates a forearm loop polytetrafluoroethylene (PTFE) graft with an intragraft stenosis (arrow). Stenotic lesions in this site are less common than those involving either the venous anastomosis or the outflow vein. B, These lesions can be treated successfully with percutaneous transluminal angioplasty (arrow). In cases where angioplasty is unsuccessful, intragraft stenoses can also be treated using percutaneous

A

C

5.9

atherectomy or surgical revision. Since this region of the access is subject to needle cannulation, the placement of a stent would be inadvisable. Intragraft stenoses may be located between the sites of the arterial and venous needle placements during dialysis. If so, the most common screening studies, namely venous pressure measurements and recirculation, do not have abnormal findings and the lesion may remain undetected until access thrombosis develops.

B FIGURE 5-16 Aneurysmal degeneration. Severe aneurysmal degeneration poses a significant surgical problem for both patient and surgeon. A, Photograph demonstrating an anastomotic aneurysm in a loop forearm polytetrafluoroethylene (PTFE) graft. This aneurysm is an example of the type of degenerative changes that occasionally occur in both arteries and veins subjected to turbulence and high tangential wall stress. This is common in the native circulation in areas of poststenotic dilatation. The PTFE graft with high flow volumes manifested the enlargement of the venous outflow. This bulge, which constitutes a segment of flow stagnation, is associated with increased risk of thrombosis over time. Since this would jeopardize the long-term function of the access, the area was revised by interposing a short segment of PTFE to a new venous outflow adjacent to the aneurysmal segment. B, Radiograph demonstrating a pseudoaneurysm in the midportion of a forearm loop PTFE graft (arrow). This lesion represents a communication between the graft and a confined space in the tissue surrounding the graft and is a common finding in dialysis patients. C, A pseudoaneurysm in a patient with a 3-year-old left groin PTFE graft. Because of the patient’s severe phobia of central vein catheters, this access was revised in two separate procedures to maintain dialysis continuity. The lateral area of the loop was initially replaced, and when this was healed and functioning well the medial segment was replaced.

5.10

Dialysis as Treatment of End-Stage Renal Disease FIGURE 5-17 Vascular steal. Vascular steal is a common problem of dialysis access sites. The principle of steal is related to two phenomena: 1) calcification or stenosis in the inflow arterial segment proximal to an access site (so that the native artery cannot dilate to meet the increasing demands for flow volume); 2) and an outflow arterial bed in parallel to the fistula origin with higher net vascular resistance than the fistula conduit. If both of these are present, blood flow is diverted to the access site in association with a drop in perfusion pressure to the most acral tissues, the fingers. When steal is severe, trauma to the digits leads to gangrene. Several treatment strategies are available to the surgeon. The access can be “banded,” or purposefully stenosed at its origin to divert flow to the ischemic site. The access can be revised using a tapered graft or the point of origin of the access can be moved more proximally in the arterial tree, in the hope of allowing full flow without diverting distal perfusion pressure. Additionally, one can perform a variety of bypass procedures to divert higher-pressure proximal blood to increase distal perfusion pressure. In severe cases, either the access or the distal digits may be sacrificed to preserve the other.

FIGURE 5-18 Vascular access screening methods. Dialysis grafts have a high incidence of thrombosis, the risk of which increases when graft flow rates (A) fall below 600 to 700 mL/min, particularly with stenotic lesions in or near the graft. Most often, stenoses occur just distal to the graft-vein anastomosis (B) but they can occur proximal to the graft-artery anastomosis (C) or within the graft itself (D). Various

screening methods may help detect grafts at high risk for thrombosis at a point where graft revision (surgical or radiologic) may increase its longevity. Measurement of graft blood flow (using Doppler imaging, ultrasound dilution, or another method) is increasingly available and may be the best screening method. When graft flow declines below dialyzer blood flow (E), blood flows between the needles (F) in a retrograde direction. This development is called recirculation, since it results in repeated uptake and dialysis of blood that has just been dialyzed. Recirculation can be detected by finding evidence that blood from the venous cannula is being taken up by the arterial cannula. This is most often recognized by the finding of an arterial blood urea nitrogen value below that in blood entering the graft. A stenotic lesion in an outflow vein tends to increase the pressure in the vein and graft (G) between the stenosis and the venous needle. This pressure usually ranges from 25 to 50 mm Hg but may increase to more than 70 mm Hg in the presence of stenosis. This pressure can be measured directly or can be estimated from the venous pressure monitor on the dialysis machine at zero blood flow (adjusting for the difference in height between the graft and the transducer). To increase accuracy, this pressure can be normalized by dividing it by the mean arterial pressure. More commonly, this intragraft pressure is determined indirectly by using the dialysis machine’s pressure transducer and a pump speed of 200 mL/min. In this case the measured pressure often exceeds 100 mm Hg in a normal graft, owing to the resistance in the venous needle.

Dialysis Access and Recirculation

5.11

Central Venous Dialysis Access FIGURE 5-19 Right internal jugular vein catheters. The use of central vein catheters has grown significantly over the past several years. These catheters were at one time used only on a temporary basis and served as a “bridge” to permanent vascular access. Improvements in catheter design and function combined with ease of insertion have increased use of central vein catheters in dialysis units. To minimize the risk of central vein stenosis and subsequent thrombosis, central vein catheters should be inserted preferentially into the right internal jugular vein, regardless of whether they are being used for temporary or more permanent purposes. The typical positioning of a double-lumen catheter, A, is with its tip at the junction of the right atrium and the superior vena cava. The catheter has been “tunneled” underneath the skin so that the exit site (large arrow) is located just beneath the right clavicle and distant from the insertion site (small arrow). This catheter also has a cuff into which endothelial cells will grow and produce a biologic barrier to bacterial migration. B, Chest radiograph showing a dialysis central vein catheter that is composed of two separate single-lumen catheters that have been inserted into the right internal jugular vein. The distal tip of the venous catheter is positioned just above the right atrium. Care must be taken, however, to ensure proper placement of catheters with this type of design, because the two single lumens are radiographically indistinguishable.

B FIGURE 5-20 Central vein stenosis. A, Venogram of the central outflow veins performed in a patient with a left upper extremity polytetrafluoroethylene graft and arm edema, B. (Continued on next page)

A

B

5.12

Dialysis as Treatment of End-Stage Renal Disease FIGURE 5-20 (Continued) The angiogram (Panel A) demonstrates complete occlusion of the innominate vein (arrow) with collateral filling in the neck and the chest. The most common cause for stenosis or thrombosis of the central venous system is previous injury from indwelling central vein catheters. Central vein stenosis may not become apparent until an arteriovenous anastomosis is created. This increases blood flow in the outflow veins and may overwhelm a compromised central vein, resulting in the appearance of superficial collateral veins on the neck and chest wall in addition to ipsilateral arm edema. In this example, the occlusion was crossed using an angiographic catheter, and thrombolytic therapy was administered. C, Venography performed after thrombolysis demonstrates severe stenosis of the innominate vein and the superior vena cava (arrow).

C

A

B FIGURE 5-21 Stent deployment. When angioplasty fails, metal stents are introduced to treat outflow vein occlusion. These stents are either balloon expandable or self-expanding. The stages of deployment of the selfexpanding Wallstent (Schneider, Inc, Division of Pfizer Hospital Products, Minneapolis, MN) are seen in these radiographs. A, The radiopaque stent is positioned across the lesion to be treated. B, As the deployment envelope is gradually withdrawn, the stent begins to expand (arrow). These stents shorten during deployment, and this factor must be taken into consideration for proper placement. C, An angioplasty balloon (arrow) is placed in the proximal portion of this completely deployed stent to achieve further expansion. (Continued on next page)

C

Dialysis Access and Recirculation

5.13

FIGURE 5-21 (Continued) D, To improve central vein patency following angioplasty, metal stents have been placed in the innominate vein and the superior vena cava. E, A postprocedure venogram demonstrates no residual stenosis.

D

E FIGURE 5-22 Central vein catheter complications. A, This radiograph demonstrates the tip of this dialysis catheter abutting the wall of the left innominate vein at its junction with the superior vena cava. To maintain adequate dialysis flow rates and minimize fibrin sheath formation, it is important for the catheter tip to be in the superior vena cava, near or in the right atrium. B and C, Injection of contrast through these dialysis catheters demonstrates the contrast outlining the outside of the distal portion of the catheter (arrows). This finding is characteristic of a fibrin sheath with contrast medium trapped between the fibrin sheath and the outer wall of the catheter. Fibrin sheaths are associated with a reduction (often severe) in the achievable blood flow rate and, as a result, inadequate dialysis delivery. They can be lysed by instilling large doses of urokinase (typically 250,000 units) through the catheter ports. If thrombolytic therapy is unsuccessful, the fibrin sheath can be stripped using a snare loop. Although these catheters can function remarkably well, they are prone to thrombosis.

A

(Continued on next page)

B

C

5.14

Dialysis as Treatment of End-Stage Renal Disease FIGURE 5-22 (Continued) D, The clot is typical of one that is remarkably tenacious. Before replacement of this catheter, a variety of manipulations were performed, including attempted thrombolysis with localized infusion of urokinase. A new catheter was placed in the same site in a same-day procedure using local anesthesia.

D FIGURE 5-23 Translumbar catheter placement. Patients receiving chronic hemodialysis may exhaust potential sites for permanent vascular access. Additionally, after long-term use of central vein catheters, these sites also develop irreversible occlusion. In most cases, these patients are trained for peritoneal dialysis; however, some patients cannot tolerate this modality. This patient failed all attempts at arteriovenous and central vein access placement, including those involving the vessels of the lower extremity. Peritoneal dialysis was not possible owing to recurrent disabling pleural effusions. Translumbar placement of tunneled catheters (arrow) into the inferior vena cava can provide a long-term solution for the patient with no apparent remaining access sites.

The Dialysis Prescription and Urea Modeling Biff F. Palmer

H

emodialysis is a life-sustaining procedure for the treatment of patients with end-stage renal disease. In acute renal failure the procedure provides for rapid correction of fluid and electrolyte abnormalities that pose an immediate threat to the patient’s well-being. In chronic renal failure, hemodialysis results in a dramatic reversal of uremic symptoms and helps improve the patient’s functional status and increase patient survival. To achieve these goals the dialysis prescription must ensure that an adequate amount of dialysis is delivered to the patient. Numerous studies have shown a correlation between the delivered dose of hemodialysis and patient morbidity and mortality [1–4]. Therefore, the delivered dose should be measured and monitored routinely to ensure that the patient receives an adequate amount of dialysis. One method of assessing the amount of dialysis delivered is to calculate the Kt/V. The Kt/V is a unitless value that is indicative of the dose of hemodialysis. The Kt/V is best described as the fractional clearance of urea as a function of its distributional volume. The fractional clearance is operationally defined as the product of dialyzer clearance (K) and the treatment time (t). Recent guidelines suggest that the Kt/V be determined by either formal urea kinetic modeling using computational software or by use of the Kt/V natural logarithm formula [5]. The delivered dose also may be assessed using the urea reduction ratio (URR). A number of factors contribute to the amount of dialysis delivered as measured by either the Kt/V or URR. Increasing blood flow rates to 400 mL/min or higher and increasing dialysate flow rates to 800 mL/min are effective ways to increase the amount of delivered dialysis. When increases in blood and dialysate flow rates are no longer effective, use of a high-efficiency membrane can further increase the dose of dialysis (KoA >600 mL/min, where KoA is the constant indicating the efficiency of dialyzers in removing urea). Eventually, increases in blood and dialysate flow rates, even when combined with a high-efficiency membrane, result in no further increase in the urea clearance rate. At this point the most important determinant affecting the dose of dialysis is the amount of time the patient is dialyzed.

CHAPTER

6

6.2

Dialysis as Treatment of End-Stage Renal Disease

Ultrafiltration during dialysis is performed to remove volume that has accumulated during the interdialytic period so that patients can be returned to their dry weight. Dry weight is determined somewhat crudely, being based on clinical findings. The patient’s dry weight is the weight just preceding the development of hypotension. The patient should be normotensive and show no evidence of pulmonary or peripheral edema. A patient’s dry weight frequently changes over time and therefore must be assessed regularly to avoid hypotension or progressive volume overload. During ultrafiltration the driving force for fluid removal is the establishment of a pressure gradient across the dialysis membrane. The water permeability of a dialysis membrane is a function of membrane thickness and pore size and is indicated by its ultrafiltration coefficient (KUf). During ultrafiltration additional solute removal occurs by solvent drag or convection. Because of increased pore size, high-flux membranes (KUf >20 mL/h/mm Hg) are associated with much higher clearances of average to high molecular weight solutes such as 2 microglobulin. Because blood flow rates over 50 to 100 mL/min result in little or no further increase in the clearance of these molecules, clearance is primarily membrane-limited. In contrast, clearance values for urea are not significantly greater with a high-flux membrane compared with a high-efficiency membrane because the blood flow rate, and not the membrane, is the principal determinant of small solute clearance. The biocompatibility of the dialysis membrane is another consideration in the dialysis prescription. A biocompatible dialysis membrane is one in which minimal reaction occurs between the humoral and cellular components of blood as they come into contact with the surface of the dialyzer [6]. One such reaction

that has been used as a marker of biocompatibility is evidence of complement activation. Cellulosic membranes generally tend to be bioincompatible, whereas noncellulosic or synthetic membranes have more biocompatible characteristics. Whether any clinical difference exists in acute or chronic outcomes between biocompatible and bioincompatible membranes is still a matter of debate. Trials designed to address this issue have been mostly uncontrolled, limited in sample size, and often retrospective in nature. Nevertheless, some evidence exists to suggest that bioincompatible membranes may have a greater association with 2 microglobulin-induced amyloidosis, susceptibility to infection, enhanced protein catabolism, and increased patient mortality [5–9]. Another aspect of the dialysis prescription is the composition of the dialysate. The concentrations of sodium, potassium, calcium, and bicarbonate in the dialysate can be individualized such that ionic composition of the body is restored toward normal during the dialytic procedure. This topic is discussed in detail in chapter 2. Although hemodialysis is effective in removing uremic toxins and provides adequate control of fluid and electrolyte abnormalities, the procedure does not provide for the endocrine or metabolic functions of the normal kidney. Therefore, the dialysis prescription often includes medications such as erythropoietin and 1,25(OH)2 vitamin D. The dose of erythropoietin should be adjusted to maintain the hematocrit between 33% and 36% (hemoglobin of 11 g/dL and 12 g/dL, respectively) [10]. Vitamin D therapy is often used in patients undergoing dialysis to help limit the severity of secondary hyperparathyroidism. Dosages usually range from 1 to 2 µg given intravenously with each treatment.

Treatment Diffusion Blood

Dialysate

Urea, 100 mg/dL

Urea, 0 mg/dL

Potassium, 5.0 mEq/L

Potassium, 2.0 mEq/L

Bicarbonate, 20 mEq/L

Bicarbonate, 35 mEq/L

A

Dialysis membrane

FIGURE 6-1 Diffusional and convective flux in hemodialysis. Dialysis is a process whereby the composition of blood is altered by exposing it to dialysate through a semipermeable membrane. Solutes are transported across this membrane by either diffusional or convective flux. A, In diffusive solute transport, solutes cross the dialysis membrane in a direction dictated by the concentration gradient established across the membrane of the hemodialyzer. For example, urea and potassium diffuse from blood to dialysate, whereas bicarbonate diffuses from dialysate to blood. At a given temperature, diffusive transport is directly proportional to both the solute concentration gradient across the membrane and the membrane surface area and inversely proportional to membrane thickness. (Continued on next page)

The Dialysis Prescription and Urea Modeling Ultrafiltration Blood

Dialysate

90 mm Hg

TREATMENT OF HEMODYNAMIC INSTABILITY

–150 mm Hg H 2O H 2O H 2O

B

6.3

Dialysis membrane

FIGURE 6-1 (Continued) B, During hemodialysis water moves from blood to dialysate driven by a hydrostatic pressure gradient between the blood and dialysate compartments, a process referred to as ultrafiltration. The rate of ultrafiltration is determined by the magnitude of this pressure gradient. Movement of water tends to drag solute across the membrane, a process referred to as convective transport or solvent drag. The contribution of convective transport to total solute transport is only significant for average-to-high molecular weight solutes because they tend to have a smaller diffusive flux.

ACCEPTABLE METHODS TO MEASURE HEMODIALYSIS ADEQUACY* • Formal urea kinetic modeling (Kt/V) using computational software • Kt/V = -LN (R0.008  t) + (4-3.5  R)  Uf/wt • Urea reduction ratio

*Recommended by the National Kidney Foundation Dialysis Outcomes Quality

Initiative Clinical Practice Guidelines, which suggest a prescribed minimum Kt/V of 1.3 and a minimum urea reduction ratio of 70%. tLN is the natural logarithm; R is postdialysis blood urea nitrogen (BUN)/predialysis BUN; t is time in hours, Uf is ultrafiltration volume in liters; w is postdialysis weight in kilograms.

Exclude nondialysis-related causes (eg, cardiac ischemia, pericardial effusion, infection) Set the dry weight accurately Optimize the dialysate composition Use a sodium concentration of ≥140 mEq/L Use sodium modeling Use a bicarbonate buffer Avoid low magnesium dialysate Avoid low calcium dialysate Optimize the method of ultrafiltration Use volume-controlled ultrafiltration Use ultrafiltration modeling Use sequential ultrafiltration and isovolemic dialysis Use cool temperature dialysate Maximize cardiac performance Have patients avoid food on day of dialysis Have patients avoid antihypertensive medicines on day of dialysis Pharmacologic prevention Erythropoietin therapy to keep hematocrit >30% Experimental (eg,caffeine, midodrine, ephedrine, phenylephrine, carnitine)

FIGURE 6-2 The common treatments for hemodynamic instability of patients undergoing dialysis. It is important to begin by excluding reversible causes associated with hypotension because failure to recognize these abnormalities can be lethal. Perhaps the most common reason for hemodynamic instability is an inaccurate setting of the dry weight. Once these conditions have been dealt with, the use of a high sodium dialysate, sodium modeling, cool temperature dialysis, and perhaps the administration of midodrine may be attempted. All of these maneuvers are effective in stabilizing blood pressure in dialysis patients. FIGURE 6-3 Acceptable methods to measure hemodialysis adequacy as recommended in the Dialysis Outcomes Quality Initiative (DOQI) Clinical Practice Guidelines. These guidelines may change as new information on the benefit of increasing the dialysis prescription becomes available. For the present, however, they should be considered the minimum targets.

6.4

Dialysis as Treatment of End-Stage Renal Disease

Considerations in Choice of Membranes

KoA 900 High-efficiency dialyzer KoA 650

300

200 e-lim Membran

ited

KoA 300 Conventional dialyzer

Flo wlim ite d

Urea clearance, mL/min

400

100

0 0

100 200 300 Blood flow rate, mL/min

400

2000 1800 1600 KUf=60 mL/h/mm Hg

Ultrafiltration, mL/h

1400

KUf=4 mL/h/mm Hg

1200 KUf=3 mL/h/mm Hg

1000 800 600 400 200 0 0

100

500 200 300 400 Transmembrane pressure, mm Hg

600

FIGURE 6-4 Relationships between membrane efficiency and clearance and blood flow rates in hemodialysis. When prescribing the blood flow rate for a hemodialysis procedure the following must be considered: the relationship between the type of dialysis membrane used, blood flow rate, and clearance rate of a given solute. For a small solute such as urea (molecular weight, 60) initially a linear relationship exists between clearance and blood flow rates. Small solutes are therefore said to be flow-limited because their clearance is highly flow-dependent. At higher blood flow rates, increases in clearance rates progressively decrease as the characteristics of the dialysis membrane become the limiting factor. The efficiency of a dialyzer in removing urea can be described by a constant referred to as KoA, which is determined by factors such as surface area, pore size, and membrane thickness. Use of a high-efficiency membrane (KoA >600 mL/min) can result in further increases in urea clearance rates at high blood flow rates. In contrast, at low blood flow rates no significant difference exists in urea clearance between a conventional and a high-efficiency membrane because blood flow, and not the membrane, is the primary determinant of clearance. FIGURE 6-5 Water permeability of a membrane and control of volumetric ultrafiltration in hemodialysis. The water permeability of a dialysis membrane can vary considerably and is a function of membrane thickness and pore size. The water permeability is indicated by its ultrafiltration coefficient (KUf). The KUf is defined as the number of milliliters of fluid per hour that will be transferred across the membrane per mm Hg pressure gradient across the membrane. A high-flux membrane is characterized by an ultrafiltration coefficient of over 20 mL/h /mm Hg. With such a high water permeability value a small error in setting the transmembrane pressure can result in excessively large amounts of fluid to be removed. As a result, use of these membranes should be restricted to dialysis machines that have volumetric ultrafiltration controls so that the amount of ultrafiltration can be precisely controlled.

The Dialysis Prescription and Urea Modeling

High-efficiency dialyzer High-flux dialyzer Normal kidney

Clearance, mL/min

150

100

6.5

FIGURE 6-6 High-efficiency and high-flux membranes in hemodialysis. These membranes have similar clearance values for low molecular weight solutes such as urea (molecular weight, 60). In this respect both types of membranes have similar KoA values (over 600 mL/min), where KoA is the constant indicating the efficiency of the dialyzer in removing urea. As a result of increased pore size, use of highflux membranes can lead to significantly greater clearance rates of high molecular weight solutes. For example, 2-microglobulin is not removed during dialysis using low-flux membranes (KUf <10 mL/h/mm Hg, where KUf is the ultrafiltration coefficient). With some high-flux membranes, 400 to 600 mg/wk of 2-microglobulin can be removed. The clinical significance of enhanced clearance of 2-microglobulin and other middle molecules using a high-flux dialyzer is currently being studied in a national multicenter hemodialysis trial.

50

0 100

1000

10,000

100,000

Vit (m amin β - w=1 B1 2 m 35 2 (m icrog 5) w= lob 11, ulin 800 )

10 (m Urea w= 60)

0

Solute molecular weight, Daltons

Patients recovering renal function, %

80

60

Polymethyl methacrylate

40 Cuprophane

20

0 0

5

10 15 20 25 Number of hemodialysis treatments

30

FIGURE 6-7 Effects of membrane biocompatibility in hemodialysis. Another consideration in the choice of a dialysis membrane is whether it is biocompatible. In chronic renal failure some evidence exists to suggest that long-term use of biocompatible membranes may be associated with favorable effects on nutrition, infectious risk, and possibly mortality when compared with bioincompatible membranes [5–9]. In the study results shown here, the effect of biocompatibility on renal outcome in a group of patients with acute renal failure who required hemodialysis was examined. Patients received dialysis with a cuprophane membrane (a bioincompatible membrane known to activate complement and neutrophils) or a synthetic membrane made of polymethyl methacrylate (a biocompatible membrane associated with more limited complement and neutrophil activation). The two groups of patients were similar in age, degree of renal failure, and severity of the underlying disease as defined by the Acute Physiology and Chronic Health Evaluation (APACHE) II score. As compared with the bioincompatible membrane, those patients treated with the synthetic biocompatible membrane had a significantly shorter duration of renal failure in terms of number of treatments and duration of dialysis. In the setting of acute renal failure, particularly in patients after transplantation, a biocompatible membrane may be the preferred dialyzer. (From Hakim and coworkers [11]; with permission.)

6.6

Dialysis as Treatment of End-Stage Renal Disease 300 280 QD=800

260

Clearance, mL/min

240

Dialyzer KoA=800

QD=500

220 200

QD=800

180

Dialyzer KoA=400

FIGURE 6-8 Dialysate flow rate in hemodialysis. The clearance of urea also is influenced by the dialysate flow rate. Increased flow rates help maximize the urea concentration gradient along the entire length of the dialysis membrane. Increasing the dialysate flow rate from 500 to 800 mL/min can be expected to increase the urea clearance rate on the order of 10% to 15%. This effect is most pronounced at high blood flow rates and with use of high KoA dialyzers. KoA— constant indicating the efficiency of the dialyzer in removing urea; QD—dialysate flow rate.

QD=500

160 140 120 100 200

250

300

350 400 450 Blood flow rate, mL/min

500

Prescription for Dose Delivery

Urea concentration

1. Dialyzer urea clearance rate KoA of membrane Blood flow Dialysate flow Convective urea flux 2. Treatment time 3. Volume of distribution

1. Urea generation rate Protein catabolic rate 2. Volume of distribution 3. Residual renal function

Dialysis time

Time on

Time off

Interdialytic time

Time on (next dialysis)

FIGURE 6-9 Delivering an adequate dose of dialysis in hemodialysis. Providing an adequate amount of dialysis is an important part of the dialysis prescription. During the dialytic procedure a sharp decrease in the concentration of urea occurs followed by a gradual increase during the interdialytic period. The decrease in urea during dialysis is determined by three main parameters: dialyzer urea clearance rate (K), dialysis treatment time (t), and the volume of urea distribution (V). The dialyzer urea clearance rate (K) is influenced by the characteristics of the dialysis membrane (KoA), blood flow rate, dialysate flow rate, and convective urea flux that occurs with ultrafiltration. The gradual increase in urea during the interdialytic period depends on the rate of urea generation that, in an otherwise stable patient, reflects the dietary protein intake, distribution volume of urea, and presence or absence of residual renal function.

The Dialysis Prescription and Urea Modeling

FACTORS RESULTING IN A REDUCTION OF THE PRESCRIBED DOSE OF HEMODIALYSIS DELIVERED Compromised urea clearance Access recirculation Inadequate blood flow from the vascular access Dialyzer clotting during dialysis (reduction of effective surface area) Blood pump or dialysate flow calibration error Reduction in treatment time Premature discontinuation of dialysis for staff or unit convenience Premature discontinuation of dialysis per patient request Delay in starting treatment owing to patient or staff tardiness Time on dialysis calculated incorrectly Laboratory or blood sampling errors Dilution of predialysis BUN blood sample with saline Drawing of predialysis BUN blood sample after start of the procedure Drawing postdialysis BUN >5 minutes after the procedure

6.7

FIGURE 6-10 Each of the factors listed may play a major role in the reduction of delivered dialysis dose. Particular attention should be paid to the vascular access and to a reduction in the effective surface area of the dialyzer. Perhaps the most important cause for reduction in dialysis time has to do with premature discontinuation of dialysis for the convenience of the patient or staff. Delays in starting dialysis treatment are frequent and may result in a significant loss of dialysis prescription. Finally, particular attention should be paid to the correct sampling of the blood urea nitrogen level and the site from which the sample is drawn.

BUN—blood urea nitrogen.

0.1 0.0 0 0.0 8 0.0 6 4

Increasing ultrafiltation

1.80

0.02 0.00

Kt/v by formal urea kinetic modeling

1.60

1.40

1.20

1.00

0.80

0.60 0.40

0.50

0.60 0.70 Urea reduction ratio, %

0.80

FIGURE 6-11 Monitoring the delivered dose in hemodialysis. Use of the urea reduction ratio (URR) is the simplest way to monitor the delivered dose of hemodialysis. However, a shortcoming of this method compared with formal urea kinetic modeling is that the URR does not account for the contribution of ultrafiltration to the final delivered dose of dialysis. During ultrafiltration, convective transfer of urea from blood to dialysate occurs without a decrease in urea concentration. As a result, with increasing ultrafiltration volumes the Kt/V, as determined by formal urea kinetic modeling, progressively increases at any given URR. For example, a URR of 65% may correspond to a Kt/V as low as 1.1 in the absence of ultrafiltration or as high as 1.35 when ultrafiltration of 10% of body weight occurs.

6.8

Dialysis as Treatment of End-Stage Renal Disease

45

MAJOR COMPONENTS OF DIALYSIS PRESCRIPTION 500 U/kg

40

150 U/kg

Hematocrit, %

35

30 50 U/kg

25

15 U/kg

20

15 0

2

4

12 6 8 10 Weeks of rHuEpo therapy

14

16

FIGURE 6-12 Correction of anemia in chronic renal failure. Anemia is a predictable complication of chronic renal failure that is due partly to reduction in erythropoietin production. Use of recombinant erythropoietin to correct the anemia in patients with chronic renal failure has become standard therapy. The rate of increase in hematocrit is dose-dependent. The indicated doses were given intravenously three times per week. Current guidelines for the initiation of intravenous therapy suggest a starting dosage of 120 to 180 U/kg/wk (typically 9000 U/wk) administered in three divided doses. Administration of erythropoietin subcutaneously has been shown to be more efficient than is intravenous administration. That is, on average, any given increment in hematocrit can be achieved with less erythropoietin when it is given subcutaneously as compared with intravenously. In adults, the subcutaneous dosage of erythropoietin is 80 to 120 U/kg/wk (typically 6000 U/wk) in two to three divided doses. rHuEpo—recombinant human erythropoietin. Data from Eschbach and coworkers [12]; with permission.

Choose a biocompatible membrane Prescribe a Kt/V ≥1.3 or a URR ≥70% Rigorously ensure that the delivered dose equals the amount prescribed When the delivered dose is less than that prescribed do the following: Exclude factors listed in Figure 6-10 Increase blood flow rate ≥400 mL/min Increase dialysate flow rate to ≥800 mL/min Use a high-efficiency dialyzer Increase treatment time Choose dialysate composition: sodium, potassium, bicarbonate, and calcium Adjust ultrafiltration rate to achieve patients’ dry weight (assess dry weight regularly) Adjust recombinant erythropoietin to maintain hematocrit between 33% and 36% When indicated, use 1,25(OH)2 vitamin D for treatment of secondary hyperparathyroidism Use normal saline, hypertonic saline, or mannitol for treatment of intradialytic hypotension URR–urea reduction ratio.

FIGURE 6-13 All these components are important as contributors to a successful dialysis prescription. The Dialysis Outcomes Quality Initiative (DOQI) recommendations should be followed to achieve an adequate dialysis prescription, and the time on dialysis should be monitored carefully. When the delivered dialysis dose is less that prescribed, the reversible factors listed in Figure 6-10 should be addressed first. Subsequently, an increase in blood flow to 400 mL/min should be attempted. Increases in dialyzer surface area and treatment time also may be attempted. In addition, attention should be paid to the correct dialysis composition and to the ultrafiltration rate to make certain that patients achieve a weight as close as possible to their dry weight. Hematocrit should be sustained at 33% to 36%. Finally, vitamin D supplementation to prevent secondary hyperparathyroidism and use of normal saline or other volume expanders are encouraged to treat hypotension during dialysis. KoA—constant indicating the efficiency of the dialyzer in removing urea.

References 1.

2. 3. 4.

5. 6.

Owen WF, Lew NL, Liu Y, Lowrie EG: The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis. N Engl J Med 1993, 329:1001–1006. Hakim RM, Breyer J, Ismail N, Schulman G: Effects of dose of dialysis on morbidity and mortality. Am J Kidney Dis 1994, 23:661–669. Held PJ, Port FK, Wolfe RA, et al.: The dose of hemodialysis and patient mortality. Kidney Int 1996, 50:550–556. Parker TF III, Husni L, Huang W, et al.: Survival of hemodialysis patients in the United States is improved with a greater quantity of dialysis. Am J Kidney Dis 1994, 23:670–680. Hemodialysis Adequacy Work Group: Dialysis Outcomes Quality Initiative (DOQI). Am J Kidney Dis 1997, 30(suppl 2:S22–S31. Hakim, RM: Clinical implications of hemodialysis membrane biocompatibility. Kidney Int 1993, 44:484–494.

7. Vanholder R, Ringoir S, Dhondt A, et al.: Phagocytosis in uremic and hemodialysis patients: a prospective and cross sectional study. Kidney Int 1991, 39:320–327. 8. Gutierrez A, Alvestrand A, Bergstrom J: Membrane selection and muscle protein catabolism. Kidney Int 1992, 42:S86–S90. 9. Hornberger JC, Chernew M, Petersen J, Garber AM: A multivariate analysis of mortality and hospital admissions with high-flux dialysis. J Am Soc Nephrol 1992, 3:1227–1237. 10. Hemodialysis Adequacy Work Group: Dialysis Outcomes Quality Initiative (DOQI). Am J Kidney Dis 1997, 30(suppl 3:S199–S201. 11. Hakim RM, Wingard RL, Parker RA: Effect of the dialysis membrane in the treatment of patients with acute renal failure. N Engl J Med 1994, 331:1338–1342. 12. Eschbach JW, Egrie JC, Downing MR, et al.: Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. N Engl J Med 1987, 316:73–78.

Complications of Dialysis: Selected Topics Robert W. Hamilton

C

omplications observed in end-stage renal disease may be due to the side effects of treatment or to the alterations of pathophysiology that go with kidney failure.

CHAPTER

7

7.2

Dialysis as Treatment of End-Stage Renal Disease

Complications of Hemodialysis COMPLICATIONS OF HEMODIALYSIS Complication

Differential diagnosis

Fever Hypotension

Bacteremia, water-borne pyrogens, overheated dialysate Excessive ultrafiltration, cardiac arrhythmia, air embolus, pericardial tamponade; hemorrhage (gastrointestinal, intracranial, retroperitoneal); anaphylactoid reaction Inadequate removal of chloramine from dialysate, failure of dialysis concentrate delivery system Incomplete removal of aluminum from dialysate water, prescription of aluminum antacids Excessive urea clearance (first treatment), failure of dialysis concentrate delivery system Excessive heparin or other anticoagulant Excessive ultrafiltration

Hemolysis Dementia Seizure Bleeding Muscle cramps

FIGURE 7-1 Complications associated with hemodialysis.

FIGURE 7-3 Thrombosis of the left innominate vein. Thrombosis can be a complication of reliance on subclavian catheters for vascular access for hemodialysis. This was discovered during investigation of edema of the left arm.

FIGURE 7-2 (see Color Plate) Dialyzer hypersensitivity. This patient was switched from a cellulose acetate dialysis membrane to a cuprammonium cellulose one. Within 8 minutes of starting hemodialysis he developed apprehension, diaphoresis, pruritus, palpitations, and wheezing. This eruption was seen over the arm used for arteriovenous access for dialysis. (From Caruana and coworkers [1]; with permission.)

FIGURE 7-4 Dilation of a stricture of the left innominate vein using balloon angioplasty in the patient shown in Figure 7-3.

Complications of Dialysis: Selected Topics

7.3

FIGURE 7-5 (see Color Plate) Ischemia of the index finger. Occasionally the arteriovenous fistula results in radial-tobrachiocephalic steal, leaving inadequate blood supply to the fingers. This risk is especially common in diabetic patients.

FIGURE 7-6 Dialysis-associated amyloidosis. Multiple carpal bone cysts without joint space narrowing in a patient treated with dialysis for 11 years. This phenomenon has been attributed to inadequate clearance of b-2microglobulin using low-permeability, cellulose dialysis membranes. (From van Ypersele de Strihou and coworkers [2]; with permission.)

Complications of Peritoneal Dialysis FIGURE 7-7 Perforation of the bladder on insertion of peritoneal catheter. Bladder perforation can be a complication of blind insertion of a peritoneal catheter. It is recognized by the sudden appearance of glucose-positive “urine” on instillation of the first bag of dialysate. Instillation of radiographic contrast medium confirms the diagnosis.

7.4

Dialysis as Treatment of End-Stage Renal Disease

FIGURE 7-8 (see Color Plate) Peritonitis. In continuous ambulatory peritoneal dialysis (CAPD) peritonitis can easily be recognized by the fact that drained peritoneal fluid becomes opacified. The inability to read the writing on the opposite side of the drained bag (or a newspaper through the bag) correlates with a peritoneal leukocyte count of more than 100 cells per microliter.

FIGURE 7-9 (see Color Plate) Tunnel abscess in patient undergoing continuous ambulatory peritoneal dialysis. Pericatheter infections are a common source of peritonitis. Sometimes, the findings are more subtle than in this case. Prompt treatment with antibiotics is indicated. If the infection fails to respond, removal of the catheter is indicated. FIGURE 7-10 Sclerosing encapsulating peritonitis. This patient had several bouts of peritonitis during the course of her treatment on peritoneal dialysis. She developed partial small bowel obstruction. Abdominal computed tomography revealed a homogeneous mass filling the anterior peritoneum. At laparotomy the mesentery was encased in a “marblelike” fibrotic mass. The patient required long-term home parenteral hyperalimentation for recovery. (From Pusateri and coworkers [3]; with permission.)

7.5

Complications of Dialysis: Selected Topics

Complications of Renal Failure

Pericardial effusion Ventricular septum Right ventricle Left ventricle

FIGURE 7-11 Pericardial tamponade. Narrow pulse pressure and a pericardial friction rub suggest pericarditis (a frequent complication of uremia) especially in patients with chest

FIGURE 7-12 (see Color Plate) Perforating folliculitis. The skin of uremic patients can be intensely pruritic. Earlier, it was attributed to deposition of calcium and phosphorus in the skin. Today, we know that is the result of repeated trauma to the skin associated with scratching.

pain. Pericardial tamponade may present as dialysis-induced hypotension. (Courtesy of T. Pappas, MD, Medical College of Ohio.)

FIGURE 7-13 Acquired cystic disease of the kidney. Abdominal computed tomography demonstrates cystic disease in this patient, who had focal segmental glomerulosclerosis complicated by protein C deficiency and renal vein thrombosis. Eleven years after the initial diagnosis, he developed renal failure requiring hemodialysis. Two years after starting dialysis, he developed hematuria, and these cysts were found. The appearance and clinical course are consistent with acquired cystic disease of the kidney. These cysts carry some risk of malignant transformation.

7.6

Dialysis as Treatment of End-Stage Renal Disease FIGURE 7-14 Malnutrition. Malnutrition is an important risk factor for dialysis patients, as reflected in this graph depicting the relation of death to serum albumin values. Albumin may have antioxidant properties. Low concentrations of serum albumin may favor oxidation of lipids, which renders them more atherogenic. (Data from Owens and coworkers [4].

Risk of death

15

10

5

0 >4.5 4.0–4.4 3.5–3.9 3.0–3.4 2.5–2.9 <2.5 Serum albumin, g/dL

Radiologic Manifestations of Renal Osteodystrophy

FIGURE 7-15 Radiograph of a shoulder involved by osteoporosis. The shoulder joint demonstrates diffuse osteoporosis. There is distal resorption of the clavicle. A small amount of calcification can be seen on the clavicular side of the coracoclavicular ligament. These findings are suggestive of osteitis fibrosa cystica.

FIGURE 7-16 Diffuse bone demineralization as demonstrated in skull radiograph. This radiograph demonstrates the generalized granular appearance that is characteristic of the diffuse demineralization seen in renal osteodystrophy.

7.7

Complications of Dialysis: Selected Topics

FIGURE 7-17 Radiograph of the hands of a patient who has renal osteodystrophy. The hands demonstrate diffuse bilateral osteoporosis. The resorption of the distal phalanges is best seen in the first and second digits of the right hand. The radial side of the middle phalanges of the second and third digits bilaterally demonstrates subperiosteal bone resorption. Soft tissue calcification is present on the radial side of the proximal interphalangeal joint of the second digit of the left hand.

10 min

30

30

50

1 hr

2 hr

FIGURE 7-18 Parathyroid scan. The patient was injected with 24.6 mCi of 99m Tc Cardiolite. Hyperfunction of four parathyroid glands is seen. This technique is often useful to determine the location and number of parathyroid glands before performing subtotal parathyroidectomy. At operation, diffuse hyperplasia of four parathyroid glands was found. (From Ishibashi and coworkers [5].)

References 1.

2.

3.

Caruana RJ, Hamilton RW, Pearson FC: Dialyzer hypersensitivity syndrome: possible role of allergy to ethylene oxide. Am J Nephrol 1985, 5:271–274. van Ypersele de Strihou C, Jadoul M, Malghem J, et al.: Effect of dialysis membrane and patient’s age on signs of dialysis-related amyloidosis. The working party on dialysis amyloidosis. Kidney Int 1991, 39:1012–1019. Pusateri R, Ross R , Marshall R, et al.: Sclerosing encapsulating peritonitis: report of a case with small bowel obstruction managed by long-term home parenteral hyperalimentation and a review of the literature. Am J Kidney Dis 1986, 8:56–60.

4.

5.

Owens WF, Lew NL, Liu L, et al.: The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis. N Engl J Med 1993, 329:1001–1006. Ishibashi M, Nishida H, Hiromatsu Y, et al.: Localization of ectopic parathyroid glands using technetium-99m sestamibi imaging: comparison with magnetic resonance and computed tomographic imaging. Eur J Nuclear Med 1997, 24:197–201.

Histocompatibility Testing and Organ Sharing Lauralynn K. Lebeck Marvin R. Garovoy

H

istocompatibility and its current application in kidney transplantation are discussed. Both theoretic and clinical aspects of human leukocyte antigen testing are described, including antigen typing, antibody detection, and lymphocyte crossmatching. Living related, living unrelated, and cadaveric donor-recipient matching algorithms are discussed with regard to mandatory organ sharing and graft outcomes.

CHAPTER

8

8.2

Transplantation as Treatment of End-Stage Renal Disease

Chromosome 6 (short arm)

Class II

Glyoxylase DP

HLA complex

Class III Class I

DQ DR

DZ DO

B

C

A

Cyp21 TNF

A

F

H G

TNF α TNF β

HSP 70

BF C2

3000

CYP 21-B C4B CYP 21-A C4A

500

4000

J A

3000

B

DRB

DRA

DQB2 DQA2 DQB1 DQA1

LMP 2 TAP 1 LMP 7 TAP 2

DMB DMA

DNA

DPA1 DPA2 DPB1 DPB2

Class I 2000

X E

Class III 1000

C

Class II 0

1500

B

FIGURE 8-1 The major histocompatibility complex (MHC) is a group of closely linked genes that was first appreciated because it was found to contain the structural genes for transplantation antigens. A, The MHC, located on the short arm of chromosome 6, is now recognized to include many other genes important in the regulation of immune responses. B, Regions of the MHC classes I, II, and III. The MHC can be divided into three regions, of which the class I and II regions contain the loci for the human histocompatibility antigen or human leukocyte antigen (HLA). Genes in the class I

Specific locus

HLA

C

The major histocompatibility complex in humans

8

Provisional specificity

Locus HLA

w

Specific antigen

Allele designation DRB1

*

Corresponding antigen

04

03

Specific allele

region encode the a or heavy chain of the class I antigens, HLA-A, B, and C. The class I region is composed of other genes, most of which are pseudogenes and are not expressed. The MHC class II region is more complex, with structural genes for both the a and b chains of the class II molecules. The class II region includes four DP genes, one DN gene, one DO gene, five DQ genes, and a varying number of DR genes (two to 10), depending on the halotype. Many other immune response genes are coded within the class III region. TNF—tumor necrosis factor. FIGURE 8-2 Nomenclature of human leukocyte antigen (HLA) specificities. HLA nomenclature may be confusing to the newcomer, but the format is logical. The prefix HLA precedes all antigens or alleles to define the major histocompatibility complex (MHC) of the species. The designation, A, B, C, DR, and so on, is next and defines the locus. The locus is followed by a number that denotes the serologically defined antigen or a number with an asterisk that denotes the molecularly defined allele. In some cases the letter w is placed before the serologic antigen, indicating it is a workshop designation and the specific assignment is provisional.

Histocompatibility Testing and Organ Sharing

PRETRANSPLANTATION TESTING FOR RENAL PATIENTS HLA phenotype Patient cells tested with known antisera HLA antibody screen Known cells tested with patient sera HLA crossmatch Donor cells tested with patient sera

8.3

FIGURE 8-3 In an immunogenetics and transplantation laboratory, three major types of renal pretransplantation testing are performed routinely. The human leukocyte antigen (HLA) assignments are assigned by serologic methods (ie, complement-dependent cytotoxicity); however, molecular-based methodologies are becoming widely accepted. Most laboratories now have the capability of reporting at least low-resolution molecular class II types. The sera of patients awaiting cadaveric donor kidney transplantation are tested for the degree of alloimmunization by determining the percentage of panel reactive antibodies (PRAs). Current federal regulations require that the serum screening test use lymphocytes as targets; however, because these same regulations no longer mandate monthly screening, assays using soluble antigens may be used as adjuncts to the classic lymphocytotoxic assays. The purpose of cross-match testing is to detect the presence of antibodies in the patients’ serum that are directed against the HLA antigens of the potential donor. When present, the antibodies indicate that the immune system of the recipient has been sensitized to the donor antigens. The various test methods differ in sensitivity, including the multiple variations of the lymphocytotoxicity text, flow cytometry, and enzyme-linked immunosorbent assay (ELISA). The degree of acceptable risk is one factor to be considered in selecting a method of appropriate sensitivity. For example, when the only risk considered unacceptable is that of hyperacute rejection, a technique having lower sensitivity is adequate. A second approach may be to consider the degree to which an individual patient or type of patient is at risk for graft rejection. The patient having a repeat graft is at higher risk for graft rejection than is the patient receiving a primary graft. Because patients differ in their degree of risk, it is appropriate to use different techniques to offset that risk.

MHC I AND II CHARACTERISTICS Class I

Class II

Composed of HLA-A, -B, and -C Ubiquitous distribution Autosomal codominant Target for immune effector mechanism Serologic and molecular detection Heterodimer noncovalently linked Heavy chain (a): Contains variable regions Confers human leukocyte antigen specificity Light chain (b2-microglobulin): Invariant

Composed of HLA-DR, -DQ, and -DP Restricted distribution Autosomal codominant Major role in immune response induction Serologic, molecular, and cellular detection Heterodimer noncovalently linked a Chain: Nonvariable in HLA-DR Contains variable regions in HLA-DQ and -DP b Chain: Contains variable regions Confers most of HLA-DR specificity

FIGURE 8-4 Human leukocyte antigens (HLAs) are heterodimeric cell-surface glycoproteins. HLAs are divided into two classes, according to their biochemical structure and respective functions. Class I antigens (A, B, and C) have a molecular weight of approximately 56,000 D and consist of two chains: a glycoprotein heavy chain (a) and a light chain (b2-microglobulin). The a chain is attached to the cell membrane, whereas b2-microglobulin is associated with the a chain but is not covalently bonded. The HLA class I molecules are found on almost all cells; however, only vestigial amounts remain on mature erythrocytes. Class II antigens (HLA-DR, DQ, and DP) have a molecular weight of approximately 63,000 D and consist of two dissimilar glycoprotein chains, designated a and b, both of which are attached to the membrane. Each chain consists of two extramembranous amino acid domains, and the outer domains of each molecule contain the variable regions corresponding to class II alleles. Although class I antigens are expressed on all nucleated cells of the body, the expression of class II antigens is more restricted. Class II antigens are found on B lymphocytes, activated T lymphocytes, monocyte-macrophages, dendritic cells, and early hematopoietic cells, and of importance in transplantation, endothelial cells.

8.4

Transplantation as Treatment of End-Stage Renal Disease MHC protein

FIGURE 8-5 Biology of the major histocompatibility complex (MHC). A, The biologic function of MHC antigens is to present antigenic peptides to T lymphocytes. In fact, it is an absolute requirement of T-lymphocyte activation for the T cells to “see” the antigenic peptide bound to an MHC molecule. This MHC restriction has been defined on a molecular basis with the elucidation of the crystalline structures of classes I and II MHC molecules. B, The N-terminal domains of the MHC molecules are formed by the folding of portions of their component chains in b-pleated sheets and a helices. C, The sheet portions form a floor, and the helices form the sides of a peptide-binding groove.

T-cell receptor α chain

Processed antigen

β chain

A

B

α1

α2

β2m

α3

C

Peptide

Heavy subunit

A

Peptide

α subunit

β2m subunit

B

β subunit

FIGURE 8-6 The structure of class I and II molecules. Comparison of the crystalline structures of classes I and II molecules has revealed overall structural similarity, with a few significant differences. A, Class I molecules have a groove with deep anchor pockets at each end (a “pita pocket”). These pockets restrict the binding of peptides to those of eight to nine amino acid residues in length. B, The peptide-binding groove of class II molecules is more flexible and relatively open at one end, more like a “hotdog bun,” permitting larger peptides from 13 to 25 amino acid residues in length to bind.

Histocompatibility Testing and Organ Sharing

HLA SPECIFICITIES A

B

B

C

DR

DQ

DP

A1 A2 A203 A210 A3 A9 A10 A11 A19 A23(9) A24(9) A2403 A25(10) A26(10) A28 A29(19) A30(19) A31(19) A32(19) A33(19) A34(10) A36 A43 A66(10) A68(28) A69(28) A74(19) A80

B5 B7 B703 B8 B12 B13 B14 B15 B16 B17 B18 B21 B22 B27 B2708 B35 B37 B38(16) B39(16) B3901 B3902 B40 B4005 B41 B42 B44(12) B45(12) B46 B47 B48 B49(21) B50(21)

B51(5) B5102 B5103 B52(5) B53 B54(22) B55(22) B56(22) B57(17) B58(17) B59 B60(40) B61(40) B62(15) B63(15) B64(14) B65(14) B67 B70 B71(70) B72(70) B73 B75(15) B76(15) B77(15) B7801 B81 Bw4 Bw6

Cw1 Cw2 Cw3 Cw4 Cw5 Cw6 Cw7 Cw8 Cw9(w3) Cw10(w3)

DR1 DR103 DR2 DR3 DR4 DR5 DR6 DR7 DR8 DR9 DR10 DR11(5) DR12(5) DR13(6) DR14(6) DR1403 DR1404 DR15(2) DR16(2) DR17(3) DR18(3) DR51 DR52 DR53

DQ1 DQ2 DQ3 DQ4 DQ5(1) DQ6(1) DQ7(3) DQ8(3) DQ9(3)

DPw1 DPw2 DPw3 DPw4 DPw5 DPw6

Antigens listed in parentheses are the broad antigens, antigens followed by broad antigens in parentheses are the antigen splits.

8.5

FIGURE 8-7 Allelic polymorphism. Allelic polymorphism is a hallmark of the human leukocyte antigen (HLA) system. The extreme polymorphism of the HLA system is seen in the large numbers of different alleles that exist for the multiple major histocompatibility complex (MHC) loci. At any given locus, one of several alternative forms or alleles of a gene can exist. Because so many alleles are possible for each HLA locus, the system is extremely polymorphic. The currently accepted World Health Organization serologically defined alleles are shown here. Established HLA antigens are designated by a number following the letter that denotes the HLA locus (eg, HLA-A1 and HLA-B8). For example, by serologic techniques, 28 distinct antigens are recognized at the HLA-A locus, and 59 defined antigens at the HLA-B locus. Sequencing studies of the HLA-DRB1 gene have identified over 100 distinct alleles, and preliminary analysis indicates that this level of polymorphism will be as high for other loci such as HLA-B. MHC polymorphism ensures effective antigen presentation of most pathogens; however, clinically, MHC polymorphism complicates attempts to find histocompatible donors for solid organ transplantation.

8.6

Transplantation as Treatment of End-Stage Renal Disease Father a b A1

A3

Mother c d A2 A9

Cw7 B8

Cw7 B7

Cw7 B12

Cw4 B35

DR3

DR2

DR5

DR3

Stage 1

Incubate cells and serum

30 min RT

Wash × 3

Add AHG 2 min Stage 2

Add rabbit serum (complement)

Children a

c

A1

a A2

A1

d

b A9

A3

c

b A2

A3

d

Cw7 B8

Cw7 B12

Cw7 B8

Cw4 B35

Cw7 B7

Cw7 B12

Cw7 B7

Cw4 B35

DR3

DR5

DR3

DR3

DR2

DR5

DR2

DR3

FIGURE 8-8 Genetic principles of the major histocompatibility complex (MHC). The MHC demonstrates a number of genetic principles. Each person has two chromosomes and thus two MHC haplotypes, each inherited from one parent. Because the human leukocyte antigen (HLA) genes are autosomal and codominant, the phenotype represents the combined expression of both haplotypes. Each child receives one chromosome and hence one haplotype from each parent. Because each parent has two different number 6 chromosomes, four different combinations of haplotypes are possible in the offspring. This inheritance pattern is an important factor in finding compatible related donors for transplantation. Thus, an individual has a 25% chance of having an HLA-identical or a completely dissimilar sibling and a 50% chance of having a sibling matched for one haplotype. The genes of the HLA region occasionally (≈ 1%) demonstrate chromosomal crossover. These recombinations are then transmitted as new haplotypes to the offspring.

SCORING OF COMPLEMENT-DEPENDENT CYTOTOXICITY REACTIONS Dead cells, % 0–10 11–20 21–50 51–80 80–100 Unreadable

Assigned value 1 2 4 6 8 0

60 min RT

A9

Interpretation Negative Borderline negative Weak positive Positive Strong positive No cells, contamination, bubble

Stage 3

Visualize membrane injury (Eosin-y, AO/EB, etc.)

FIGURE 8-9 Complement-dependent technique. The standard technique used to detect human leukocyte antigen (HLA)-A, -B, -C, -DR, and -DQ antigens has been the microlymphocytotoxicity test. This assay is a complement-dependent cytotoxicity (CDC) in which lymphocytes are used as targets because the HLA antigens are expressed to varying degrees on lymphocytes and a relatively pure suspension of cells can be obtained from anticoagulated peripheral blood. Lymphocytes obtained from lymph nodes or the spleen also may be used. HLA antisera of known specificity are placed in wells on a “Terasaki microdroplet tray.” A concentrated suspension of lymphocytes is added to each well. If the target lymphocytes possess the antigen corresponding to the antibody present in the antiserum, the antibody will affix to the cells. Rabbit complement is then added to the wells and, when sufficient antibody is bound to the lymphocyte membranes, complement is activated. Complement activation injures the cell membranes (lymphocytotoxicity) and increases their permeability. Cell injury is detected by dye exclusion: cells with intact membranes (negative reactions) exclude vital dyes; cells with permeable membranes (positive reactions) take up the dye. Sensitivity of the CDC assay is increased by wash techniques or the use of AHG reagents prior to the addition of complement. Because HLA-DR and -DQ antigens are expressed on B cells and not on resting T cells, typing for these antigens usually requires that the initial lymphocyte preparation be manipulated before testing to yield an enriched B-cell preparation. AHG—antiglobulinaugmented lymphocytotoxicity; RT—room temperature. FIGURE 8-10 Scoring of complement-dependent cytotoxicity. In an effort to standardize interpretation of complement-dependent cytotoxicity (CDC) reactions, a uniform set of scoring criteria have been established. When most of the cells are alive, visually refractile on microscopic examination, a score of 1 is assigned. Conversely, when most of the cells are dead, a score of 8 is assigned. This method of interpretation for CDC reactions is universally used in cross-match testing, antibody screening, and antigen phenotyping for serologically defined HLA-A, -B, -C, -DR, and -DQ. (Adapted from Gebel and Lebeck [1]; with permission.)

Histocompatibility Testing and Organ Sharing

6

7

9

1

2

10 8 5

11 4

3

8.7

FIGURE 8-11 The United Network for Organ Sharing (UNOS) regions. UNOS is a not-for-profit corporation within the United States organized exclusively for charitable, educational, and scientific purposes related to organ procurement and transplantation. Its formation established a national Organ Procurement and Transplantation Network with the mandate to improve the effectiveness of the nation’s renal and extrarenal organ procurement, distribution, and transplantation systems by increasing the availability of and access to donor organs for patients with end-stage organ failure. Additionally, the UNOS maintains quality assurance activities and systematically gathers and analyzes data and regularly publishes the results of the national experience in organ procurement and preservation, tissue typing, and clinical organ transplantation. Functionally, the United States is divided into UNOS regions as detailed on this map. Additional geographic divisions (ie, local designation) defined by the individual organ procurement organizations and the transplantation centers they service comprise the working system for cadaveric renal allocation.

UNITED NETWORK FOR ORGAN SHARING: NUMBER OF PATIENT REGISTRATIONS ON THE NATIONAL TRANSPLANT WAITING LIST AS OF OCTOBER 31, 1997 Kidney number by blood type (%)

Kidney number by race (%)

Kidney number by gender (%)

Type O: 19,654(52.04) Type A: 10,612(28.10) Type B: 6579(17.42) Type AB: 923(2.44) Total: 37,768

White: 18,353(48.59) Black: 13,290(35.19) Hispanic: 3441(9.11) Asian: 2200(5.83) Other: 484(1.28) Total: 37,768

Female: 16,269(43.08) Male: 21,499(56.92) Total: 37,768

FIGURE 8-12 The United Network for Organ Sharing (UNOS) patient waiting list. The UNOS patient waiting list is a computerized list of patients waiting to be matched with specific donor organs in the hope of receiving a transplantation. Patients on the waiting list are registered on the UNOS computer by UNOS member transplantation centers, programs, or organ procurement organizations. The UNOS Match System is an algorithm used to prioritize

Kidney number by transplantation center region (%) Region 1: 1738(4.60) Region 2: 6060(16.05) Region 3: 3844(10.18) Region 4: 2191(5.80) Region 5: 7361(19.49) Region 6: 855(2.26) Region 7: 3826(10.13) Region 8: 1559(4.13) Region 9: 3936(10.42) Region 10: 3121(8.26) Region 11: 3277(8.68) Total: 37,768

Kidney number by age (%) 0–5: 76(0.20) 6–10: 119(0.32) 11–17: 429(1.14) 18–49: 21,102(55.87) 50–64: 12,942(34.27) 65+: 3100(8.21) Tota: 37,768

patients waiting for organs. The system eliminates potential recipients whose size or ABO type is incompatible with that of a donor and then ranks those remaining potential recipients according to a UNOS board-approved system. As indicated here, nearly 40,000 patients are awaiting kidney transplantation in the United States. (Adapted from the United Network for Organ Sharing [2]).

8.8

Transplantation as Treatment of End-Stage Renal Disease

POINT SYSTEM FOR KIDNEY ALLOCATION Time of waiting The “time of waiting” begins when a patient is listed and meets the minimum established criteria on the United Network for Organ Sharing Patient Waiting List. One point will be assigned to the patient waiting for the longest period, with fractions of points being assigned proportionately to all other patients according to their relative time of waiting. Quality of HLA mismatch 10 points if there are no A, B, or DR mismatches. 7 points if there are no B or DR mismatches. 5 points if there is one B or DR mismatch. 2 points if there is a total of two mismatches at the B and DR loci. Panel reactive antibody Patients will be assigned 4 points if they have a panel reactive antibody level of 80% or more. Medical urgency No points will be assigned to patients based on medical urgency for regional or national allocation of kidneys. Locally, the patient’s physician has the authority to use medical judgment in assignment of points for medical urgency. When there is more than one local renal transplantation center, a cooperative medical decision is required before assignment of points for medical urgency. Pediatric kidney transplantation candidates 4 points if the patient is under 11 years of age. 3 points if the patient is over 11 and under 18 years of age.

CROSSMATCH METHODS Lymphocytotoxicity: Auto–crossmatch vs allo–crossmatch T or B cell Short/long/wash/AHG methods IgG vs IgM Flow cytometry Enzyme-linked immunosorbent assay

FIGURE 8-13 Point system for kidney allocation. Kidneys that cannot be allocated to a human leukocyte antigen (HLA)–matched patient are distributed locally to candidates who are ranked according to waiting time, with additional points for degrees of HLA mismatch and antibody sensitization. Pediatric patients, medically urgent cases, and previous donors (living related donors, and so on) also are given a point advantage.

FIGURE 8-14 Crossmatch methods. Early reports correlating a positive crossmatch between recipient serum and donor lymphocytes with hyperacute rejection of transplanted kidneys led to establishing tests of recipient sera as the standard of practice in transplantation. However, controversy remains regarding 1) the level of sensitivity needed for crossmatch testing; 2) the relevance of B-cell crossmatches, a surrogate for class II incompatibilities; 3) the relevance of immunoglobulin class and subclass of donor-reactive antibodies; 4) the significance of historical antibodies, ie, antibodies present previously but not at the time of transplantation; 5) the techniques and type of analyses to be performed for serum screening; and 6) the appropriate frequency and timing of serum screening. Despite a number of variables, when the data from reported studies are considered collectively, several observations can be made. Human leukocyte antigen–donor-specific antibodies present in the recipient at the time of transplantation are a serious risk factor that significantly diminishes graft function and graft survival. Antibodies specific for human leukocyte antigen class II antigens (HLA-DR and -DQ) are as detrimental as are those specific for class I antigens (HLA-A, -B, and -C). The degree of risk resulting from HLA-specific antibodies varies among immunoglobulin classes, with immunoglobulin G antibodies representing the most serious risk. AHG—antiglobulinaugmented lymphocytotoxicity.

250

250

200

200 CD3 PE

SSC

Histocompatibility Testing and Organ Sharing

150 100

150 100

R1

50

50 0

0 0

50

100

A

150 FSC

200

0

250

100

150 FSC

200

250

100 T cell

90

160 Counts

50

B

200

Neg (n = 508)

80

120

70

80

60 M1

Neg (n = 75) Pos (n = 106) Pos (n = 43)

50

40

40

0 0

C

R2

50 100 150 200 ∝ Human IgG-Fc-FITC

First

30

250

0

D

Regraft

6 12 0 6 12 Months after transplantation

FIGURE 8-15 Techniques of crossmatch testing. Early crossmatch testing provided a means to prevent most but not all hyperacute rejections. These early tests were performed with a technique of rather low sensitivity. Subsequently, more sensitive techniques were employed in an attempt to not only prevent all hyperacute rejections but also improve graft survival rates. Techniques that have been used include variations of the lymphocytotoxicity test that incorporate wash steps, change in incubation times or temperatures, or both, or add an antiglobulin reagent. Flow cytometry and an array of other methods such as antibody-

ALTERNATIVE APPROACHES TO HLA MATCHING

CREG*

Associated human leukocyte antigen gene products

1C 2C 5C 7C 8C 12C 4C 6C

A1,3,9,10,11,28,29,30,31,32,33 A2,9,28, B17 B5,15,17,18,35,53,70,49 B7,13,22,2740,41,47,48 B8,14,16,18 B12,13,21,40,41 A24,25,32,34, Bw4 Bw6, Cw1,3,7

Approximate “epitope” frequency, %

C refers to major public epitope or cross-reactive groups (CREG).

80 66 59 64 37 44 85 87

8.9

dependent cellular cytotoxicity also have been tried. Two of the most sensitive techniques are the antiglobulin-augmented lymphocytotoxicity (AHG) and flow cytometric crossmatching. A, The use of flow cytometry to define the lymphocyte population by light scatter parameters, followed by a specific marker for T lymphocytes, ie, CD3 (B) allows this technique to be highly specific for human leukocyte antigen (HLA) class I–positive cells. The donor lymphocytes have been preincubated with recipient serum, washed, and subsequently stained with AHG-Fluorescsin isothiocyanate (FITC), a fluorochrome-labeled antihuman globulin. C, Results of flow cytometric cross-matching are evaluated as shifts in the fluorescence from negative sera and are interpreted as positive or negative based on independently defined cutoffs above the negative. D, Multiple studies in renal transplantation have shown correlations between positive AHG or flow cytometric cross-matches and decreased graft survival at 1 year or more. The largest differences are seen when patients are grouped as primary grafts versus repeat grafts. In some instances the effect of using a more sensitive cross-match technique only can be seen in patients having repeat grafts or those with a higher immunologic risk. CD3 PE—monoclonal antibody to CD3 fluorescent labelled with phycoerythrin; FC—constant fragment of IgG molecule; FITC—fluorescent labelled with fluorescein isothiocynate; FSC—forward scatter; R1—region 1; R2—region 2; SSC—side scatter. (Panel D adapted from Cook [3]; with permission.)

FIGURE 8-16 Alternative approaches to human leukocyte antigen (HLA) matching. Because completely mismatched kidney transplantations function well over long periods, an alternative approach might begin with the hypothesis that six-antigen “mismatched” transplantations were not completely mismatched. Interest in reevaluating the potential roles of cross-reactive groups (CREGs) in transplantation is one such approach. In the early days of serologic HLA testing, a high panel reactive antibody sera was considered to be composed of many antiHLA antibodies. It was later noted, however, that sera of highly sensitized patients awaiting solid organ transplantation were generally composed of a small number of antibodies directed at public antigens, also called CREGs, rather than multiple antibodies, each reacting with a specific conventional HLA antigen. Furthermore, the frequency of the CREGs was much higher, eg, 35% to 88%, than that of even the most common HLA-A and -B antigens. By inference, therefore, matching for donor and recipient antigens included in the same CREG, ie, CREG matching, could result in a higher number of matched transplantations and a lower level of sensitization in patients having repeat grafts. In addition, because of the inclusion of several private HLA-A and -B antigens within a single CREG, a number of relatively rare antigens can be matched more easily, offering the possibility of improved graft survival for a greater number of both white and nonwhite patients. (Adapted from Thelan and Rodey [4]; with permission.)

Transplantation as Treatment of End-Stage Renal Disease

100

100

80

80

60 ABDR MM n 0 3023 1 1305

40 30 20

T 1⁄2 14 12

2

3736

12

3

6312

12

4 5

6414

11

3641 1209

11 10

6

Graft survival (log), %

Graft survival (log), %

8.10

White 1st cadaver UNOS (1991–1996)

10

60 ABDR MM 0

40 30

n

T 1⁄2

301

7

255

7

3

970 2459

6 6

4

3251

6

5

2078

6

6

739

6

1 2

20

Black 1st cadaver UNOS (1991–1996)

10 0

1

A

2

3 4 5 6 7 Years after transplantation

8

9

FIGURE 8-17 The role of human leukocyte antigen (HLA) matching in the United States in whites (A) and blacks (B). Recent large registry analyses of the role for HLA matching in renal transplantation consistently have shown a stepwise decrease in long-term graft survival rates with increasing antigen mismatches. Based on these results the United Network of Organ Sharing (UNOS) incorporated the level of HLA match into its algorithm used nationally for kidney allocation. The UNOS initially determined that transplantations for which all six HLA-A, -B, and -DR antigens matched in the donor and recipient should be performed. Each cadaveric donor type was compared by a computer search with the HLA types of all patients awaiting kidney transplantation. When a patient with six antigen matches was

Serology (antibody defined)

versus

(Low

Molecular Intermediate High resolution)

HLA-DR13

*1301–*1312 *1314–*1330

HLA-DR14

*1401, *1402, *1405–*1429

HLA-DR6

DR1403 DR1404

0

10

B

1

2

3 4 5 6 7 Years after transplantation

8

9

10

identified in an ABO-compatible recipient, the kidney was offered for that patient, and if accepted by the transplantation center, was shipped for transplantation. (Normally, kidneys from a patient with blood type O are allocated only to patients with type O blood, except in the case of patients with six antigen matches.) The UNOS policy regarding mandatory sharing of HLA-matched kidneys has been liberalized twice. The first time was in 1990 to include phenotypically matched pairs with fewer than six antigens. The policy was changed for a second time in 1995 to include zero-mismatched pairs in which the donor could have fewer antigens than the recipient, provided none were mismatched. (Adapted from Cecka [5]; with permission.) FIGURE 8-18 Serologic testing and antigen assignment. Most of the published transplantation outcome data is based on serologic testing and assignment of antigens. These data include algorithm matching based on “broad” human leukocyte antigen (HLA) specificities such as HLA-DR6 that includes HLA-DR13 and HLA-DR14 and their many alleles. The question has now become one of what level of HLA testing is useful clinically for matching purposes in renal transplantation. Although this issue has not been resolved, recent data published from the European Registry upholds the positive effect that “correct” HLA matching has had on renal graft outcome.

Histocompatibility Testing and Organ Sharing

FIGURE 8-19 Classes II and I mismatches in supposed 0 mm shared renal transplantations. The effect on graft survival of shared human leukocyte antigen (HLA) 0mm organs when defined by serologic typing and then confirmed by molecular typing. A strong effect of HLA matching is seen at even 1 year on the graft survival. A, Eighty-six first cadaveric kidney transplantations that were reported by serologic typing as HLA-A, -B, -DR “identical-compatible” were tested by molecular methods. Sixty-four transplantations were confirmed to be HLA-DR compatible; however, mismatches were found in the remaining 22 transplantations. Transplantations in which HLA compatibility was confirmed had a functional success rate of 90% at 1 year compared with 68% for transplantations in which the DNA typing revealed HLA-DR mismatches (P < 0.02). B, An analysis of the influence of HLA-class I DNA typing on kidney graft survival is shown. A total of 183 cadaveric transplantations were confirmed to be HLA-A and B compatible after DNA typing, whereas mismatches were found in the remaining 32 cases. Transplantations in which compatibility was confirmed had a functional success rate of 86.9% at 1 year compared with a 71.9% rate for those in which DNA typing revealed HLA-A or -B mismatches (P = 0.033.) (Panel A adapted from Opelz and coworkers [6]; panel B adapted from Mytilineous and coworkers [7]; with permission.)

100

Graft survival, %

90 DNA: DR 0 mm (n = 64)

80 70

DNA: DR >0 mm (n = 22)

60 50 40 0

3

A

6 Time, mo

100

12

DNA: A+B 0 mm (n = 183)

90 Graft survival, %

9

8.11

80 70

DNA: A+B >0 mm (n = 32)

60 50 0 0

3

B

6 Time, mo

9

12

100

60

90

Living donor

1988

50

70 50 40

88 89 90 91

30 20 10

n 1809 1895 2086 2385

t 1⁄2 12.5 14.3 14.9 14.6

92 93 94 95

n 2527 2828 2914 3117

t 1⁄2 17.0 16.3 17.5 8.8

30 20 10 0

0 0

A

1996

40

60 %

Graft survival, %

80

1

2

3 4 5 Years after transplantation

6

7

8

FIGURE 8-20 Living donor kidney transplantation graft survival rates (A) and donor sources (B). The high graft survival rates reported for recipients of living donor kidneys improved from 89% in 1988 to 93% in 1991 (P < 0.001), even though a substantial increase has occurred in both the number of living donors and centers performing these transplantations. Some of the increase in living donations has been due to a growing acceptance of so-called

Parent

B

Offspring

Sibling

Other relative

Spouse/other unrelated

unconventional donors, ie, spouses and other genetically unrelated donors, as well as distant relatives and half-siblings. In 1988–1989, unrelated donors accounted for 4% of living donor transplantations and distant relatives for 2%. These numbers have tripled and are now at 12% and 6%, respectively. (Panel A from Cecka [8]; panel B adapted from the United Network for Organ Sharing [9]; with permission.)

8.12

Transplantation as Treatment of End-Stage Renal Disease

References 1. 2. 3. 4. 5.

Gebel HM, Lebeck LK: Crossmatch procedures used in organ transplantation. Clin Lab Med 1991, 11:609. United Network for Organ Sharing: UNOS Bulletin 1997, 2. Cook DJ, et al.: An approach to reducing early kidney transplant failure by flow cytometry crossmatching. Clin Transpl 1987, 1:25. Thelan D, Rodey G: American Society of Histocompatibility and Immunogenetics Laboratory Manual, edn 3. Lenexa, KS: ASHI. Cecka JM: The role of HLA in renal transplantation. Human Immunology 1997, 56:6–16.

6. 7. 8.

9.

Opelz et al.: Transplantation 1998, 55:782–785. Mytilenous et al.: Tissue Antigens 1997, 50:355–358. Cecka JM: UNOS Scientific Renal Transplant Registry. In Clinical Transplant Registry. Edited by Cecka JM, Terasaki P. Los Angeles: UCLA; 1996:1–14. United Network for Organ Sharing: UNOS Bulletin 1997, 2.

Transplant Rejection and Its Treatment Laurence Chan

R

ejection is the major cause of graft failure, and if the injury to the tubules and glomeruli is severe, the kidney may not recover. It is therefore important to diagnose acute rejection as soon as possible to institute prompt antirejection therapy. Generally, the success with which rejection can be reversed by immunosuppressive agents determines the chance of long-term success of the transplant [1,2].

CHAPTER

9

9.2

Transplantation as Treatment of End-Stage Renal Disease

Mechanisms of Renal Allograft Rejection Immune response cascade

Allograft

CD2 TCR CD4

HLAclass II

HLAclass I

HLAclass II

APC

HLAclass I CD58

CD4

IL-1

CD4 T cells

Cytokines IL-2R

IL-2

IFN-γ etc.

CD8 T cells

TCR CD8 CD3

CD3

CD2 TCR

CD58

CD8 TCR CD2 CD3

CD3

T cells

B cells NK cells

IL-2R

CD8 T cells

CD4

Clonal expansion HLAclass I

CD2

A

HLAclass II

Graft destruction

B. OVERVIEW OF REJECTION EVENTS Antigen-presenting cells trigger CD4 and CD8 T cells Both a local and systemic immune response develop Cytokines recruit and activate nonspecific cells and accumulate in graft, which facilitates the following events: Development of specific T cells, natural killer cells, or macrophage-mediated cytotoxicity Allograft destruction

Indirect allorecognition CD8+ cytotoxic cell

I

FIGURE 9-1 Aspects of the rejection response. A, The immune response cascade. Rejection is a complex and redundant response to grafted tissue. The major targets of this response are the major histocompatibility complex (MHC) antigens, which are designated as human leukocyte antigens (HLAs) in humans. The HLA region on the short arm of chromosome 6 encompasses more than 3 million nucleotide base pairs. It encodes two structurally distinct classes of cell-surface molecules, termed class I (HLA-A, -B, and -C) and class II (-DR, -DQ, -DP). B, Overview of rejection events. T cells recognize foreign antigens only when the antigen or an immunogenic peptide is associated with a self-HLA molecule on the surface of an accessory cell called the antigen-presenting cell (APC). Helper T cells (CD4) are activated to proliferate, differentiate, and secrete a variety of cytokines. These cytokines increase expression of HLA class II antigens on engrafted tissues, stimulate B lymphocytes to produce antibodies against the allograft, and help cytotoxic T cells, macrophages, and natural killer cells develop cytotoxicity against the graft. C, Possible mechanisms for allorecognition by host T cells. In the direct pathway, T cells recognize intact allo-MHC on the surface of donor cells. The T-cell response that results in early acute cellular rejection is caused mainly by direct allorecognition. In the indirect pathway, T cells recognize processed alloantigens in the context of self-APCs. Indirect presentation may be important in maintaining and amplifying the rejection response, especially in chronic rejection. IFN-g—interferon gamma; IL-1—interleukin-1; IL-2R—interleukin-2 receptor; NK—natural killer. (Panel A adapted from [3]; with permission; panel C adapted from [4]; with permission.)

Direct allorecognition CD8+ cytoxic cell

Th cell

Th cell

Allogeneic cell Shed allogeneic MHC

IL-2

IL-2

II

(Class I–derived peptide presented by responder class II molecule)

Allogeneic (stimulator) antigen presenting cell

Taken up and processed by host antigen-presenting cell

Peptide derived from allogeneic MHC presented on host MHC

C

I

Responder antigen-presenting cell

Class I stimulator Class II haplotype Class III responder haplotype β2 microglobulin

II

9.3

Transplant Rejection and its Treatment

Classification of Rejection A. VARIETIES OF REJECTION Types of rejection Time taken

Cause

Hyperacute

Minutes to hours

Preformed antidonor antibodies and complement

Accelerated

Days

Reactivation of sensitized T cells

Acute

Days to weeks

Primary activation of T cells

Chronic

Months to years

Both immunologic and nonimmunologic factors

FIGURE 9-2 Varieties of rejection (panel A) and immune mechanisms (panel B). On the basis of the pathologic process and the kinetics of the rejection

A FIGURE 9-3 (See Color Plate) Histologic features of hyperacute rejection. Hyperacute rejection is very rare and is caused by antibody-mediated damage to the graft. The clinical manifestation of hyperacute rejection is a failure of the kidney to perfuse properly on release of the vascular clamps just after vascular anastomosis is completed. The kidney initially becomes firm and then rapidly turns blue, spotted, and flabby. The presence

B. IMMUNE MECHANISMS OF RENAL ALLOGRAFT REJECTION Type Hyperacute Accelerated Acute Cellular Vascular Chronic

Humoral

Cellular

+++ ++

+

+ +++ ++

+++ + +?

response, rejection of renal allografts can be commonly divided into hyperacute, accelerated, acute, and chronic types.

B of neutrophils in the glomeruli and peritubular capillaries in the kidney biopsy confirms the diagnosis. A, Hematoxylin and eosin stain of biopsy showing interstitial hemorrhage and extensive coagulative necrosis of tubules and glomeruli, with scattered interstitial inflammatory cells and neutrophils. B, Immunofluorescence stain of kidney with hyperacute rejection showing positive staining of fibrins.

9.4

Transplantation as Treatment of End-Stage Renal Disease

A FIGURE 9-4 Histologic features of acute accelerated rejection. A and B, Photomicrographs showing histologic features of acute accelerated vascular rejection. Glomerular and vascular endothelial infiltrates and swelling are visible. An accelerated rejection, which may start on the second or third day, tends to occur in the previously sensitized patient in

A FIGURE 9-5 Histologic features of acute cellular rejection. A, Mild tubulitis. B, Moderate to severe tubulitis. Acute rejection episodes may occur as early as 5 to 7 days, but are generally seen between 1 and 4 weeks after transplantation. The classic acute rejection episode of the earlier era (ie, azathioprine-prednisolone) was accompanied by swelling and tenderness of the kidney and the onset of oliguria with an associated rise in serum creatinine; these symptoms were usually accompanied by a significant fever. However, in patients who have been treated with cyclosporine, the clinical features of an acute rejection are really quite minimal in that there is perhaps some swelling of the kidney, usually no tenderness, and there may be a minimal to moderate degree of fever. Because such an acute rejection may occur at a time when there is a distinct possibility of

B whom preformed anti-HLA antibodies are present. This type of rejection occurs in patients who have had a previous graft and presents with a decrease in renal function; the clinical picture is similar to that for hyperacute rejection.

B acute cyclosporine toxicity, the differentiation between the two entities may be extremely difficult. The differential diagnosis of acute rejection, acute tubular necrosis, and cyclosporine nephrotoxicity may be difficult, especially in the early posttransplant period when more than one cause of dysfunction can occur together [2]. Knowledge of the natural history of several clinical entities is extremely helpful in limiting the differential diagnosis. Reversible medical and mechanical causes should be excluded first. Percutaneous biopsy of the renal allograft using real-time ultrasound guide is a safe procedure. It provides histologic confirmation of the diagnosis of rejection, aids in the differential diagnosis of graft dysfunction, and allows for assessment of the likelihood of a response to antirejection treatment.

Transplant Rejection and its Treatment

A

9.5

B Hypothetical schema for chronic rejection

C. CHRONIC ALLOGRAFT REJECTION

Acute rejection Antibody deposition Oxidized LDL Infection

Typical clinical presentation Gradual increase in creatinine (months) Non-nephrotic–range proteinuria No recent nephrotoxic events Key pathologic features Interstitial fibrosis Arterial fibrosis and intimal thickening

T cells Macrophages Platelet aggregates

Cytokines/ growth factors

Cell proliferation Fibrosis

Vascular injury Arteriosclerosis

Tubulointerstitial injury Glomerular sclerosis

Reduced nephron mass

D

Graft loss

FIGURE 9-6 Features of chronic rejection. A, Arterial fibrosis and intimal thickening. B. Interstitial fibrosis and tubular atrophy. C, Typical presentation and pathologic features. Chronic rejection occurs during a span of months to years. It appears to be unresponsive to current treatment and has emerged as the major problem facing transplantation [5]. Because chronic rejection is thought to be the end result of uncontrolled repetitive acute rejection episodes or a slowly progressive inflammatory process, its onset may be as early as the first few weeks after transplantation or any time thereafter. D, The likely sequence of events in chronic rejection and potential mediating factors for key steps. Progressive azotemia, proteinuria, and hypertension are the clinical hallmarks of chronic rejection. Immunologic and nonimmunologic mechanisms are thought to play a role in the pathogenesis of this entity. Immunologic mechanisms include antibody-mediated tissue destruction that occurs possibly secondary to antibodydependent cellular cytotoxicity leading to obliterative arteritis, growth factors derived from macrophages and platelets leading to fibrotic degeneration, and glomerular hypertension with hyperfiltration injury due to reduced nephron mass leading to progressive glomerular sclerosis. Nonimmunologic causes can also contribute to the decline in renal function. Atheromatous renovascular disease of the transplant kidney may also be responsible for a significant number of cases of progressive graft failure. (Continued on next page)

9.6

Transplantation as Treatment of End-Stage Renal Disease

Diagnostic and therapeutic approach to chronic rejection Slowly rising creatinine

FIGURE 9-6 (Continued) E, Diagnostic and therapeutic approach to chronic rejection. ATG—antithymocyte globulin; ATN—acute tubular necrosis; BP— blood pressure; CsA—cyclosporine; LDL—low-density lipoprotein.

Check CsA level High

Low

Lower CsA dose and repeat creatinine Improved

No improvement Ultrasound Obstruction

No obstruction Biopsy ATN Glomerulonephritis Recurrent GN de novo GN

Rejection

Acute

Acute on chronic

Adjust immunosuppressant Steroid bolus OKT3 or ATG

Chronic

Temporizing measures Control BP Avoid nephrotoxins

E

BANFF CLASSIFICATION OF RENAL ALLOGRAFT REJECTION Normal Patchy mononuclear cell infiltrates without tubulitis is not uncommon Borderline changes No intimal arteritis; mild tubulitis and endocapillary glomerulitis Acute rejection Grade I: tubulitis ++ Grade II: tubulitis with glomerulitis Grade III: intimal arteritis, interstitial hemorrhage, fibrinoid, thrombosis

FIGURE 9-7 The Banff classification of renal allograft rejection. This schema is an internationally agreed on standardized classification of renal allograft pathology that regards intimal arteritis and tubulitis as the main lesions indicative of acute rejection [6].

Transplant Rejection and its Treatment

9.7

New techniques

Constant (but not excessive) suction

25-G needle Transplanted kidney Wound Inguinal ligament

FIGURE 9-8 Fine-needle aspiration cytology technique for the transplanted kidney. A 23- or 25-gauge spinal needle is used under aseptic conditions. A 20-mL syringe containing 5 mL of RPMI-1640 tissue culture medium is connected to the needle. Ultrasound guidance may be used on the rare occasions when the graft is not easily palpable [8]. Monitoring of other products of inflammation such as neopterin and lymphokines continues to be explored. It has been shown that acute rejection is associated with elevated plasma interleukin (IL)-1 in azathioprine-treated patients and IL-2 in cyclosporine-treated patients. IL-6 is also increased in the serum and urine immediately after transplantation and during acute rejection episodes. The major problem, however, is that infection, particularly viral, can also elevate cytokine levels. Recently, polymerase chain reaction (PCR) has also been used to detect mRNA for IL-2 in fine-needle aspirate of human transplant kidney [7,8]. Using the PCR approach, IL-2 could be detected 2 days before rejection was apparent by histologic or clinical criteria. Reverse transcriptase–PCR has also been used to identify intrarenal expression of cytotoxic molecules (granzyme B and perforin) and immunoregulatory cytokines (IL-2, -4, -10, interferon gamma, and transforming growth factor-b1) in human renal allograft biopsy specimens [9]. Molecular analyses revealed that intragraft display of mRNA encoding granzyme B, IL-10, or IL-2 correlates with acute rejection, and intrarenal expression of transforming growth factor (TGF)-b1 mRNA is associated with chronic rejection. These data suggest that therapeutic strategies directed at the molecular correlates of rejection might refine existing antirejection regimens.

Treatment IMMUNOSUPPRESSION PROTOCOLS Induction protocols Maintenance protocols Early posttransplantation Late posttransplantation Antirejection therapy

FIGURE 9-9 Immunosuppressive therapy protocols. Standard immunosuppressive therapy in renal transplant recipient consists of 1) baseline therapy to prevent rejection, and 2) short courses of antirejection therapy using high-dose methylprednisolone, monoclonal antibodies or polyclonal antisera such as antilymphocyte globulin (ALG) and antithymocyte globulin (ATG). Antilymphocyte globulin is prepared by immunizing rabbits or horses with human lymphoid cells derived from the thymus or cultured B-cell lines. Disadvantages of using polyclonal ALS include lot-to-lot variability, cumbersome production and purification, nonselective targeting of all lymphocytes, and the need to administer the medication via central venous access. Despite these limitations, ALG has been used both for prophylaxis against and for the primary treatment of acute rejection. A typical recommended dose for acute rejection is 10 to 15 mg/kg daily for 7 to 10 days. The reversal rate has been between 75% and 100% in different series. In contrast to murine monoclonal antibodies (eg, OKT3), ALS does not generally induce a host antibody response to the rabbit or horse serum. As a result, there is a greater opportunity for successful readministration.

9.8

Transplantation as Treatment of End-Stage Renal Disease FIGURE 9-10 Induction (panel A) and maintenance (panel B) immunosuppression protocols. These immunosuppressive protocols differ from center to center. There are numerous variations, but the essential features are 1) the prednisone dosage is high initially and then reduced to a maintenance dose of 10 to 15 mg/d over 6 to 9 months, and 2) the cyclosporine dosage is 8 to 12 mg/kg/d given as a single or twice daily dose, and dosage is adjusted according to trough plasma and serum blood levels. To maintain immunosuppression provided by cyclosporine and to reduce the incidence of cyclosporine side effects, azathioprine or mycophenolate has also been used with lower dosages of cyclosporine. The results of this triple therapy are excellent, with first-year graft survival greater than 85% reported in most instances and with a substantial number of patients having no rejection at all. Although this type of regimen was the most common, there have been a number of exceptions [2,10]. Recently, mycophenolate mofetil has been approved by the US Food and Drug Administration for prophylaxis of renal transplant rejection [11]. This agent was developed as a replacement to azathioprine for maintenance immunosuppression. FK506 is a new immunosuppressive agent that has been approved by the FDA. FK506 is similar to cyclosporine in its mode of action, efficacy, and toxicity profile. The drug has been used in kidney transplantation. FK506 may be beneficial in renal transplantation as rescue therapy in patients taking cyclosporine who have recurrent or resistant rejection episodes [12–14].

A. INDUCTION PROTOCOLS Standard induction Corticosteroids Azathioprine or mycophenolate Cyclosporine or FK506 Antibody induction OKT3 or antithymocyte gamma globulin

B. MAINTENANCE IMMUNOSUPPRESSION Cyclosporine or FK506 Mycophenolate Prednisolone

ATG OKT3

ATG OKT3

Postantigenic differentiation

MPA AZA CD4

CD4 ATG OKT3

Class II HLA antigen

ATG OKT3

Prolife ration

IL-1

TNF-α

Steroids CD4

CsA FK506 RPM

MPA Ant ibod y

IL-2

Steroids

CD8

Cy

to k

CD8

B lymphocyte

Stimulated macrophage

s

Macrophage

IL-2

ine

Allogeneic cell

CD4

ATG OKT3

Class I HLA antigen

IL-1 CD8

ration Prolife

CD8

ATG OKT3

AZA MPA ATG OKT3

A FIGURE 9-11 Mechanism of action of immunusuppressive drugs. A, The sites of action of the commonly used immunosuppressive drugs. Immunosuppressive drugs interfere with allograft rejection at various sites in the rejection pathways. Glucocorticoids block the release of

ATG OKT3

γ-Interferon

interleukin (IL)-1 by macrophages, cyclosporine (CsA) and FK506 interfere with IL-2 production from activated helper T cells, and azathioprine (AZA) and mycophenolate mofetil (MPA) prevent proliferation of cytotoxic and helper T cells. (Continued on next page)

9.9

Transplant Rejection and its Treatment

TCR signal

IL-2R

Nucleus

TCR signal

TCR Cyclosporin A FK506

Nucleus

TCR signal

TCR

T lymphocyte LKR signal

IL-2R LKR signal TCR Nucleus

Il-2

IL-2R LKR signal

Rapamycin

TCR

Nucleus

Cell differentiation Cell proliferation

B

FIGURE 9-11 (Continued) B, Mechanism of action of CsA, FK506, and rapamycin (RPM). CsA and FK506 block the transduction of the signal from the Tcell receptor (TCR) after it has recognized antigen, which leads to the production of lymphokines such as IL-2, whereas RPM blocks the lymphokine receptor signal, eg, IL-2 plus IL-2 receptor (IL-2R), which leads to cell proliferation. The addition of a prophylactic course of antithymocyte globulin (ATG) or OKT3 with delay of the administration of CsA or FK506 during the initial postoperative periods has been advocated by some groups. OKT3 prophylaxis was associated with a lower rate of early acute rejection and fewer rejection episodes per patient. Prophylactic use of these agents appears to be most effective in high-risk cadaver transplant recipients, including those who are sensitized or who have two HLA-DR mismatches or a prolonged cold ischemia time [2,10]. IFN-g—interferon gamma; TNF-a—tumor necrosis factor-a.

Treatment algorithm for acute rejection

A. ANTIREJECTION THERAPY REGIMENS

Acute rejection Intravenous methylprednisolone, 0.5 or 1 g x 3 d OKT3 Antithymocyte gamma globulin Rabbit antithymocyte globulin Humanized anti-CD25 (IL-2 receptor) intravenously every 2 wk Anti–ICAM-1 and anti–LFA-1 antibodies

FIGURE 9-12 Treatment of acute rejection. A, Typical antirejection therapy regimens. B, Treatment algorithm. A biopsy should be performed whenever possible. The first-line treatment for acute rejection in most centers is pulse methylprednisolone, 500 to 1000 mg, given intravenously daily for 3 to 5 days. The expected reversal rate for the first episode of acute cellular rejection is 60% to 70% with this regimen [15–17]. Steroid-resistant rejection is defined as a lack of improvement in urine output or the plasma creatinine concentration within 3 to 4 days. In this setting, OKT3 or polyclonal anti–T-cell antibodies should be considered [18]. The use of these potent therapies should be confined to acute rejections with acute components that are potentially reversible, eg, mononuclear interstitial cell infiltrate with tubulitis or endovasculitis with acute inflammatory endothelial infiltrate [19,21]. ATG—antithymocyte globulin; ICAM-1—intercellular adhesion molecule-1; LFA-1—leukocyte function-associated antigen-1.

Mild

Severe

Steroid bolus Resolves

Rising creatinine OKT3 or polyplonal antibodies x 10 d Resolves

Persistent acute rejection on repeat biopsy Evaluate OKT3 antibody titer

B

Low

High

ATG or OKT3

ATG

9.10

Transplantation as Treatment of End-Stage Renal Disease

A. MAJOR SIDE EFFECTS OF IMMUNOSUPPRESSIVE AGENTS

Nephrotoxicity Neurotoxicity Hirsutism Gingival hypertrophy ????? Hypertension

Cyclosporine

FK506

+++ + +++ ++ 0 +++

++ ++ 0 0 + +

Azathioprine

Mycophenolate mofetil

++ ++ + ++ + +?

Infection Marrow suppression Hepatic dysfunction Megaloblastic anemia Hair loss ? Neoplastic

+ + 0 0 ?

FIGURE 9-13 Side effects of immunosuppressive agents. A, The major side effects of several immunosuppressive agents. The major complication of pulse steroids is increased susceptibility to infection. Other potential problems include acute hyperglycemia, hypertension, peptic ulcer disease, and psychiatric disturbances including euphoria and depression. B, Vasoconstriction of the afferent arteriole (AA) caused by cyclosporine. (From English et al. [22]; with permission.)

B

Spleen

Lymph nodes Washed white cells Thymus Subcutaneous injection

Globulin extracted

Intravenous infusion

Vial FIGURE 9-14 The making of a polyclonal antilymphocyte preparation. Antilymphocyte globulin (ALG) or antithymocyte globulin (ATG) are polyclonal antisera derived from immunization of lymphocytes, lymphoblasts, or thymocytes into rabbits, goats, or horses. These agents have been used prophylactically as induction therapy during the early posttransplantation period and for treatment of acute rejection. Most centers reduce concomitant immunosuppression (eg, stop cyclosporine and lower azathioprine dose) to decrease infectious complications. Antithymocyte gamma globulin (ATGAM) is the only FDA-approved

Horse serum

polyclonal preparation. Two rabbit immunoglobulin preparations, raised by immunization with thymocytes or with a human lymphoblastoid line, are scheduled for phase III multicenter testing versus ATGAM or OKT3, respectively. Potential side effects include fever, chills, erythema, thrombocytopenia, local phlebitis, serum sickness, and anaphylaxis. The potential for development of host anti-ALG antibodies has not been a significant problem because of the use of less immunogenic preparations and probably because ALG suppresses the immune response to the foreign protein itself [2,10].

Transplant Rejection and its Treatment Fuse with polyethylene glycol

Spleen cells

Myeloma cells

Assay hybrid cells

Select desired hybrids

Propagate desired clones Grow in mass culture

Freeze Thaw

Produce in animals Antibody

A. RECOMMENDED PROTOCOL FOR OKT3 TREATMENT Evaluation and treatment before administration Physical examination Laboratory tests including complete blood count Monitor intake and output; record weight changes Chest radiograph Hemodialysis or ultrafiltration for volume overload Premedication on day 0 and 1 Methylprednisolone, 250–500 mg IV given 1 h prior to dose Methylprednisolone or hydrocortisone sodium succinate, 250–500 mg IV given 30 min after the dose Diphenhydramine, 50 mg IV 30 min prior to dose daily Acetaminophen, 650 mg PO 30 min prior to dose Discontinue cyclosporine, maintain azathioprine at 25 mg/d Administer OKT3, 5 mg/d IV, days 0–13 Monitor clinical course Check CD3 level on day 3 Increase OKT3 dosage to 10 mg/d if either: Anti-OKT3 antibody is high OKT3 level is low CD3 level is not low

Antibody

9.11

FIGURE 9-15 The making of a monoclonal antibody. OKT3 is a mouse monoclonal antibody directed against the CD3 molecule of the T lymphocyte. OKT3 has been used either from the time of transplantation to prevent rejection or to treat an acute rejection episode. It has been shown in a randomized clinical trial to reverse 95% of primary rejection episodes compared with 75% with high-dose steroids in patients who received azathioprineprednisone immunosuppression. In patients receiving triple therapy (cyclosporineazathioprine-prednisone), 82% of primary rejection episodes were successfully reversed by OKT3 versus 63% with high-dose steroids. Like antilymphocyte globulin (ALG), reduction of concomitant immunosuppression (discontinuation of cyclosporine and reduction of azathioprine or mycophenolate mofetil dose) decreases the incidence of infectious complications. Side effects include fever, rigors, diarrhea, myalgia, arthralgia, aseptic meningitis, dyspnea, and wheezing, but these rarely persist beyond the second day of therapy. Release of tumor necrosis factor (TNF), interleukin-2, and interferon gamma in serum are found after OKT3 injection. The acute pulmonary compromise due to a capillary leak syndrome rarely has been seen because patients are brought to within 3% of dry weight before initiation of OKT3 treatment. Infectious complications, particularly infection with cytomegalovirus, are increased after multiple courses of OKT3.

FIGURE 9-16 Treatment with OKT3. A, Recommended protocol for OKT3 treatment. The development of host anti-OKT3 antibodies is a potential problem for the reuse of this drug in previously treated patients. About 33% to 100% of patients develop antimouse antibodies after the first exposure to OKT3, depending on concomitant immunosuppression. Anti-OKT3 titers of 1:10,000 or more usually correlate with lack of clinical response. If anti-OKT3 antibodies are of low titer, retreatment with OKT3 is almost always successful. If retreatment is attempted with antimouse titers of 1:100 or more, then certain laboratory parameters, including the peripheral lymphocyte count, CD3 T cells, and trough free circulating OKT3 should be monitored. If the absolute CD3 T-lymphocyte count is greater than 10 per microliter or free circulating trough OKT3 level is not detected, it may be indicative of an inadequate dose of OKT3. The dose of OKT3 can be increased from 5 to 10 mg/d [21]. (Continued on next page)

9.12

Transplantation as Treatment of End-Stage Renal Disease

Anti–OKT3 antibodies

80 70

%CD+cells

60

CD3

50 OKT3 treatment

40 30

CD4

20

CD8

10

FIGURE 9-16 (Continued) B, Monitoring of peripheral blood T cells in a patient receiving OKT3 treatment. The absence of CD3+ cells from the circulation is the best parameter for monitoring the effectiveness of OKT3. Failure of the CD-positive percentage to fall or a fall followed by a rapid rise indicates the appearance of blocking antibodies. Approximately 50% to 60% of patients who receive OKT3 will produce human antimouse antibodies (HAMA), generally in low titers (< 1:100). Low antibody titers do not affect the response to retreatment (reversal rate almost 100%) if the rejection episode occurs within 90 days after transplantation. Conversely, titers above 1:100 or recurrent rejection beyond 90 days is associated with a reversal rate of less than 25%. The reversal rate is essentially zero when both high HAMA titers and late rejection are present. PO—orally; IV—intravenous.

0 0

1

2

5

9

13

Hours

B

16

22 Days

Chimeric antibody Mouse antibody

Reshaped antibody

Mouse determinants

} Human determinants A

IgG1 depleting

IgG4 nondepleting

TCR/CD3 MHC/Ag APC

Signal 1

B7-1

T-cell

CD28 X

B7-2 CTLA4 Signal 2

B

CTLA41g

Signal 1 without signal 2 results in: T-cell anergy Th2>Th1 Apoptosis

FIGURE 9-17 New immunosuppressive agents. New agents such as mycophenolate mofetil, FK506, and rapamycin are currently under evaluation for refractory acute rejection. In addition, both mycophenolate and rapamycin prevent chronic allograft rejection in experimental animals. Whether this important observation is reproducible in humans remains to be determined by long-term study. A, Humanized monoclonal antibodies. The development of genetically engineered humanized monoclonal antibodies will largely eliminate the anti-antibody response, thereby increasing the utility of anti–T-cell antibodies in the treatment of recurrent rejection. Experimental antibody therapies are now being designed to directly target the CD4 molecule, the interleukin-2 receptor, the CD3 molecule by a humanized form of monoclonal anti-CD3, and adhesion molecules such as intercellular adhesion molecule-1 or leukocyte functionassociated antigen-1 [23]. Humanized monoclonal antibodies are essentially human immunoglobulin G (IgG), nonimmunologic with a long half-life, and potentially can be administered intravenously about every 2 weeks. Humanized anti-CD25 (IL-2 receptora chain) monoclonal antibodies has been shown to be effective in lowering the incidence of acute renal allograft rejection. Its role in the treatment of rejection, however, has not been explored. With increasing specificity for lymphocytes, these new agents are likely to have fewer toxicities and better efficacy. B, Therapeutic application of CTLA41g to transplant rejection. APC—antigen-presenting cell; MHC—major histocompatibility complex; TCR—T-cell receptor.

Transplant Rejection and its Treatment

9.13

References 1. Terasaki PI, Cecka JM, Gjertson DW, et al.: Risk rate and long-term kidney transplant survival. Clin Transpl 1996, 443. 2. Chan L, Kam I: Outcome and complications of renal transplantation. In Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW: 1997. 3. J Clin Immunol 1995, 15:184. 4. Nephrol Dial Transpl 1997, 12 [editorial comments]. 5. Shaikewitz ST, Chan L: Chronic renal transplant rejection. Am J Kidney Dis 1994, 23:884. 6. Solez K, Axelsen RA, Benediktsson H, et al.: International standardization of criteria for the histologic diagnosis of renal allograft rejection: the Banff working classification on renal transplant pathology. Kidney Int 1993, 44:411. 7. Helderman JH, Hernandez J, Sagalowsky A, et al.: Confirmation of the utility of fine needle aspiration biopsy of the renal allograft. Kidney Int 1988, 34:376. 8. Von Willebrand E, Hughes D: Fine-needle aspiration cytology of the transplanted kidney. In Kidney Transplantation, edn 4. Edited by Morris PJ. 1994:301. 9. Suthanthiran M: Clinical application of molecular biology: a study of allograft rejection with polymerase chain reaction. Am J Med Sci 1997, 313:264. 10. Halloren PF, Lui SL, Miller L: Review of transplantation 1996. Clin Transpl 1996. 11. Sollinger HW for the US Renal Transplant Mycophenolate Mofetil Study Group: Mycophenolate mofetil for prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation 1995, 60:225. 12. Jordan ML, Shapiro R, Vivas SA, et al.: FK506 “rescue” for resistant rejection of renal allografts under primary cyclosporine immunosuppression. Transplantation 1994, 57:860.

13. Woodle ES, Thistlethwaite JR, Gordon JH, et al.: A multicenter trial of FK506 (tacrolimus) therapy in refractory acute renal allograft rejection. Transplantation 1996, 62:594. 14. Jordan ML, Naraghi R, Shapiro R, et al.: Tacrolimus rescue therapy for renal allograft rejection: five year experience. Transplantation 1997, 63:223. 15. Gray D, Shepherd H, Daar A, et al.: Oral versus intravenous high dose steroid treatment of renal allograft rejection. Lancet 1978, 1:117. 16. Chan L, French ME, Beare J, et al.: Prospective trial of high dose versus low dose prednisone in renal transplantation. Transpl Proc 1980, 12:323. 17. Auphan N, DiDonato JA, Rosette C, et al.: Immunosuppression by glucocorticoids: inhibition of NF-kB activation through induction of IkBa. Science 1995, 270:286. 18. Ortho Multicenter Study Group: A randomized trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. N Engl J Med 1985, 313:337. 19. Norman DJ, Shield CF, Henell KR, et al.: Effectiveness of a second course of OKT3 monoclonal anti-T cell antibody for treatment of renal allograft rejection. Transplantation 1988, 46:523. 20. Schroeder TJ, Weiss MA, Smith RD, et al.: The efficacy of OKT3 in vascular rejection. Transplantation 1991, 51:312. 21. Schroeder TJ, First MR: Monoclonal antibodies in organ transplantation. Am J Kidney Dis 1994, 23:138. 22. English J, et al.: Transplantation 1987, 44:135. 23. Strom TB, Ettenger RB: Investigational immunosuppressants: biologics. In Primer on Transplantation. Edited by Norman D, Suki W.

Post-transplant Infections Connie L. Davis

A

lthough the rates are markedly decreased from previous decades, infection is the most important cause of early morbidity and mortality following transplantation. Infection is closely linked to the degree of immunosuppression and thus to the frequency and intensity of rejection and its therapy. The potential sources of infection in the transplant patient are multiple, including organisms from the allograft itself and from the environment. Patients should be advised to be sensible to possible exposures and to wash their hands thoroughly when exposed to infected individuals or human excrement, specifically, exposures in daycare and occupational settings as well as during gardening and pet care. In those taking immunosuppressive agents, signs and symptoms of infections are frequently blunted until disease is far advanced. Therefore, due to the unusual nature of the infections and the lack of timely symptom development, the key to patient survival is the prevention of infection. Infections may be prevented by pretransplant vaccinations, along with prophylactic medications, preemptive monitoring and behavior modification. Currently, the most common infectious problems within the first month following transplantation are bacterial infections of the wound, lines, and lungs. Additionally, herpetic stomatitis is common. Beyond 1 month following transplantation, infections are related to more intense immunosuppression and include viral, fungal, protozoal, and unusual bacterial infections. Although hepatitis may occasionally cause fulminate and fatal disease if acquired peritransplantation, the manifestations of hepatitis B or hepatitis C infections occur years following transplantation.

CHAPTER

10

10.2

Transplantation as Treatment of End-Stage Renal Disease

Conventional

CLASSIFICATION OF INFECTIONS OCCURRING IN TRANSPLANT PATIENTS

Unconventional Viral

CMV onset EBV VZV papova adenovirus

HSV

CMV chorioretinitis

Fungal TB Pneumocystis CNS

Listeria Aspergillus, nocardia, toxoplasma

Bacterial

Cryptococcus

Wound Pneumonia line-related

Hepatitis Hepatitis B

Onset of non-A, non-B hepatitis

UTI: Relatively benign

UTI: bacteremia, pyelitis, relapse

0

1

2

3 4 Time, mo

5

6

Transplant

FIGURE 10-1 Timetable for the occurrence of infection in the renal transplant patient. Exceptions to this chronology are frequent. CMV— cytomegalovirus; CNS—central nervous system; EBV—EpsteinBarr virus; HSV—herpes simplex virus; UTI—urinary tract infection; VZV—varicella-zoster virus. (Adapted from Rubin and coworkers. [1]; with permission.)

Infections related to technical complications* Transplantation of a contaminated allograft, anastomotic leak or stenosis, wound hematoma, intravenous line contamination, iatrogenic damage to the skin, mismanagement of endotracheal tube leading to aspiration, infection related to biliary, urinary, and drainage catheters Infections related to excessive nosocomial hazard Aspergillus species, Legionella species, Pseudomonas aeruginosa, and other gramnegative bacilli, Nocardia asteroides Infections related to particular exposures within the community Systemic mycotic infections in certain geographic areas Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Strongyloides stercoralis Community-acquired opportunistic infection resulting from ubiquitous saphrophytes in the environment† Cryptococcus neoformans, Aspergillus species, Nocardia asteroides, Pneumocystis carinii Respiratory infections circulating in the community Mycobacterium tuberculosis, influenza, adenoviruses, parainfluenza, respiratory syncytial virus Infections acquired by the ingestion of contaminated food/water Salmonella species, Listeria monocytogenes Viral infections of particular importance in transplant patients Herpes group viruses, hepatitis viruses, papillomavirus, HIV *All lead to infection with gram-negative bacilli, Staphylococcus species, and/or Candida species. †The incidence and severity of these infections and, to a lesser extent, the other infections listed, are related to the net state of immunosuppression present in a particular patient.

FIGURE 10-2 Classifications of infections occurring in transplant patients. (Adapted from Rubin [2]; with permission.)

50

Patients, n

40

Timing of infection

Period of prophylaxis

Bacterial (mean 60 days) CMV (mean 70 days) Non-CMV viral (mean 145 days) Fungal (mean 163 days)

30 20 10 0

1

2

3 Months after transplant

4–6

7–12

FIGURE 10-3 Timing of infections following kidney/pancreas transplantation at a single transplantation center using antiviral (ganciclovir IV followed by acyclovir) and antibacterial (trimethoprim-sulfamethoxazole) prophylaxis. CMV—cytomegalovirus. (From Stratta [3]; with permission.)

Post-transplant Infections

10.3

Preventive Strategies INFECTIOUS DISEASE HISTORY TO BE TAKEN PRIOR TO TRANSPLANTATION

FIGURE 10-4 Infectious disease history to be taken prior to transplantation.

1. Past immunizations. 2. Past infections or exposures to infections. A. Bacterial Rheumatic fever, sinusitis, ear infections, urinary tract infections, pyelonephritis, pneumonia, diverticulitis, tuberculosis B. Viral Measles, mumps, varicella, rubella, hepatitis 3. Chronic or recurrent infections, such as pneumonia, sinusitis, urinary tract infection, or diverticulitis 4. Surgical history, such as splenectomy 5. Transfusion or previous transplant history and dates 6. Past travel history, including military service 7. Past immunosuppressive drug treatment (eg, for asthma, renal disease, or rheumatologic disease) 8. Lifestyle A. Smoking, drinking, illicit drug use, marijuana smoking B. Sexual partners, orientation, unprotected contact and date, safety practices used, sexually transmitted diseases, genital warts C. Food, consumption of raw fish or meat, consumption of unpasteurized products, such as milk, cheese, fruit juices, or tofu D. Avocation—gardening and the use of gloves, cleaning sheds, hiking, camping, water sources, bathing pets, cleaning pet litter and cages, hunting practices E. Vocation—jobs that require exposure to possible infectious agents, such as daycare, ministry, small closed offices, garbage collections or dump workers, construction workers, forestry workers, health care, veterinarians, farmers

PRETRANSPLANT VACCINATIONS OR BOOSTERS TO BE GIVEN TO ALL TRANSPLANT RECIPIENTS UNLESS RECENT ADMINISTRATION CAN BE DOCUMENTED

FIGURE 10-5 Pretransplant vaccinations or boosters to be given to all transplant recipients unless recent administration can be documented.

1. Td (Tetanus toxoid, diphtheria) 2. Pneumococcal vaccine 3. Hepatitis B 4. Influenza

PRETRANSPLANT VACCINATIONS TO BE GIVEN IF SERONEGATIVE OR PAST INFECTION BY HISTORY CANNOT BE DOCUMENTED 1. Measles-mumps-rubella vaccine 2. Polio 3. Varicella (0.5 mL subcutaneously followed by booster of 0.5 mL in 4–8 weeks) 4. Haemophilus influenza type B

FIGURE 10-6 Pretransplant vaccinations to be given if seronegative or past infection by history cannot be documented.

10.4

Transplantation as Treatment of End-Stage Renal Disease

INACTIVATED VACCINES THAT ARE CONSIDERED SAFE AND MAY BE GIVEN AS NEEDED POST-TRANSPLANT FOR ANTICIPATED EXPOSURE

VACCINES THAT MAY NOT BE GIVEN (LIVE ATTENUATED VACCINES) 1. Bacille Calmette-Guérin (BCG) 2. Measles 3. Mumps 4. Rubella 5. Oral polio 6. Oral typhoid 7. Yellow fever

1. Anthrax 2. Cholera 3. Rabies vaccine absorbed 4. Human diploid cell rabies vaccine 5. Inactivated typhoid vaccine, capsular polysaccharide parenteral vaccine, or heat phenol-treated parenteral vaccine 6. Japanese encephalitis virus vaccine 7. Meningococcal vaccine 8. Plague vaccine

FIGURE 10-8 Vaccines that may not be given include live attenuated vaccines. FIGURE 10-7 Inactivated vaccines that are considered safe and may be given as needed post-transplant for anticipated exposure.

A. DOSAGE AND ADMINISTRATION GUIDELINES FOR VACCINES AVAILABLE IN THE UNITED STATES Vaccine

Dosage

Route of administration

Type

DT Td DTP DTaP (Acel-Imune) DTP-HbOC (Tetramune)

0.5 mL 0.5 mL 0.5 mL 0.5 mL 0.5 mL

IM IM IM IM IM

Toxoids Toxoids Diphtheria and tetanus toxoids with killed B. pertussis organisms Diphtheria and tetanus toxoids with acellular pertussis Diphtheria and tetanus toxoids with killed B. pertussis organisms and Haemophilus b conjugate (diphtheria CRM197 protein conjugate)

Haemophilus B, conjugate vaccine ProHIBit (PRP-D), manufactured by Connaught Laboratories HibTITER (HbOC), manufactured by Praxis Biologicals PedvaxHib (PRP-OMP), manufactured by MSD Hepatitis B

0.5 mL 0.5 mL

IM IM

Polysaccharide (diphtheria toxoid conjugate)

0.5 mL

IM

Oligosaccharide (diphtheria CRM protein conjugate)

0.5 mL

IM

Polysaccharide (meningococcal protein conjugate)

IM in the anterolateral thigh or in the upper arm; SC in individuals at risk of hemorrhage

Yeast recombinant–derived inactivated viral antigen

Infants born to HBsAg-negative mothers and children < y[ ] Recombivax HB (MSD) Engerix-B (SKF)

2.5 µg (0.25 mL) 10 µg (0.5 mL)

FIGURE 10-9 A–D, General immunization guidelines. HBOC—haemophilus B influenzae–diphtheria protein conjugate vaccine, oligosaccharide; ID—intradermal; IM—intramuscularly; DT—diphtheria tetanus; DTP—diphtheria tetanus pertussis; MMR—measles mumps rubella; MR—measles rubella; MSD—Merck Sharpe & Dohme;

PRP-D—haemophilus B–diphtheria toxoid conjugate vaccine, polysaccharide; PRP-OMP—haemophilus influenzae type b–meningococcal protein conjugate vaccine; SC—subcutaneous; SKF—SmithKline and French; Td—tetanus, diphtheria. (From Isada and coworkers [4]; with permission.) (Continued on next page)

Post-transplant Infections

10.5

B. DOSAGE AND ADMINISTRATION GUIDELINES FOR VACCINES AVAILABLE IN THE UNITED STATES Infants born to HBsAg-positive mothers (immunization and administration of 0.5 mL hepatitis B immune globulin is recommended for infants born to HBsAg mothers using different administration sites) within 12 hours of birth; administer vaccine at birth; repeat vaccine dose at 1 and 6 months following the initial dose

Vaccine

Dosage

Recombivax HB (MSD) Engerix-B (SKF) Children 11–19 y Recombivax HB (MSD) Engerix-B (SKF) Adults > 19 y Recombivax HB (MSD) Engerix-B (SKF) Dialysis patients and immunosuppressed patients Recombivax HB (MSD) Engerix-B (SKF)

5 µg (0.5 mL) 10 µg (0.5 mL) 5 µg (0.5 mL) 20 µg (1 mL) 10 µg (1 mL) 20 µg (1 mL) <11 y, 20 µg (0.5 mL); ≥11 y, 40 µg, (1 mL) using special dialysis formulation <11 y, 20 µg (1 mL); ≥11 y, 40 µg (2 mL), give as two 1 mL doses at different sites

C. DOSAGE AND ADMINISTRATION GUIDELINES FOR VACCINES AVAILABLE IN THE UNITED STATES Vaccine

Dosage

Influenza Split virus only in pediatric patients 6–35 mo 3–8 y ≥9 y Measles

0.25 mL (1 or 2 doses) 0.5 mL (1 or 2 doses) 0.5 mL (1 dose) 0.5 mL

Route of administration

Type

IM (2 doses 4+ weeks apart in children <9 years of age not previously immunized; only 1 dose needed for annual updates)

Inactivated virus subvirion (split) (contraindicated in patients allergic to chicken eggs)

SC

Live virus (contraindicated in patients with anaphylactic allergy to neomycin)

Most areas: Two doses (1st dose at 12 months with MMR; 2nd dose at 4–6 years or 11–12 years, depending on local school entry requirements). High-risk area: Two doses (1st dose at 12 months with MMR; 2nd dose as above). Children 6–15 months in epidemic situations: Dose is given at the time of first contact with a health care provider; children<1 year of age should receive single antigen measles vaccine. If vaccinated before 1 year, revaccinate at 15 months with MMR. A 3rd dose is administered at 4–6 years or 11–12 years, depending on local school entry requirements.

FIGURE 10-9 (Continued)

(Continued on next page)

10.6

Transplantation as Treatment of End-Stage Renal Disease

D. DOSAGE AND ADMINISTRATION GUIDELINES FOR VACCINES AVAILABLE IN THE UNITED STATES Children 6–15 months in epidemic situations: Dose is given at the time of first contact with a health care provider; children<1 year of age should receive single antigen measles vaccine. If vaccinated before 1 year, revaccinate at 15 months with MMR. A 3rd dose is administered at 4–6 years or 11–12 years, depending on local school entry requirements.

Vaccine

Dosage, mL

Route of administration

Type

Meningococcal MMR MR Mumps Pneumococcal polyvalent Poliovirus (OPV) trivalent Poliovirus (IPV) trivalent Rabies Rubella Tetanus (adsorbed) Tetanus (fluid) Yellow fever

0.5 0.5 0.5 0.5 0.5 (≥2 y)

SC SC SC SC IM or SC (IM preferred)

Polysaccharide Live virus Live virus Live virus Polysaccharide

0.5

Oral

Live virus

0.5

SC

Inactivated virus

1 0.5 (≥12mo) 0.5 0.5 0.5

IM ‡‡, ID§§ SC IM IM, SC SC

Inactivated virus Live virus Toxoid Toxoid Live attenuated virus

FIGURE 10-9 (Continued)

PRETRANSPLANT VIRAL SEROLOGIES TO CHECK AT THE PRETRANSPLANT VISIT Viral serology

Treatment, work-up modification or change in post-transplant treatment

Herpes simplex virus 1, 2 Epstein-Barr virus

If positive, treat early post-transplant with acyclovir, famciclovir, or ganciclovir If negative, consider post-transplant ganciclovir. Test donor due to risk of post-transplant lymphoma with primary infection Consider vaccination with Oka strain live attenuated virus if negative or treatment with acyclovir following clinical exposure If the recipient is positive or donor positive, consider prophylactic or preemptive antiviral treatment If positive, check HBeAg and HBDNA and biopsy. If HBDNA positive, consider pretransplant antiviral treatment with interferon if biopsy allows. Consult hepatologist regarding other treatment options If positive, check HCV RNA status by polymerase chain reaction. If positive biopsy even with normal transaminase values and consider pretransplant treatment with interferon Consider safety of transplantation if true positive. More data are required to make an informed decision

Varicella-zoster virus Cytomegalovirus HBsAg

Hepatitis C virus HIV

FIGURE 10-10 Pretransplant viral serologies to check at the pretransplant visit.

Post-transplant Infections FIGURE 10-11 Pretransplant bacterial serologies.

PRETRANSPLANT BACTERIAL SEROLOGIES Serology

Modification

RPR (Rapid plasma reagin)

If positive, check with a treponemal specific test–Fluorescent treponemal antibody absorbed test (FTA-ABS) or microhemagglutination assay for treponema pallidum (MHA-TP) If positive the general recommendation without documented previous treatment after first evaluating a chest radiograph is isoniazid 300 mg/d to continue for 6 months or 9 to 12 months post-transplant

PPD

10.7

EFFECT AND POSSIBLE EFFECTS OF PROPHYLACTIC ANTIVIRAL STRATEGIES No treatment

Acyclovir orally 3 3M

Ganciclovir IV acyclovir PO 3 3M

CMVIgG 3 5 doses

Ganciclovir 3 3M PO

Risk: ↑ HSV ↑ CMV ↑ VZV ↑ EBV ↑ Adenovirus ↑ HHV6 ↑ HHV8

↓ HSV Slight ↓ CMV ↓ VZV Slight ↓ EBV No change in adenovirus Slight ↓ HHV6 Slight ↓ HHV8

↓ HSV Slight ↓ CMV ↓ VZV ↓ EBV ? Adenovirus Slight ↓ HHV6 Slight ↓ HHV8

? Effect Slight ↓ CMV ? Effect ? Effect ? Effect ? Effect ? Effect

↓ HSV ↓ CMV ↓ VZV ↓ EBV ? Slight ↓ in adenovirus ? ↓ HHV6 ? ↓ HHV8

FIGURE 10-12 Effect and possible effects of prophylactic antiviral strategies. CMV— cytomegalovirus; EBV—Epstein-Barr virus; HHV6—human herpes

virus 6; HHV8—human herpes virus 8; HSV—herpes simplex; VZV— varicella zoster. Question mark indicates question as to the effect.

PROPHYLACTIC ANTIBACTERIAL AND ANTIPROTOZOAL STRATEGIES Type of infection

Treatment perioperatively or postoperatively

Wound

Against uropathogens and staphylococci, eg, ampicillin-sulbactam, cefazolin plus aztreonam 3 24 to 48 hours adjusted for renal function Risk ↑ urinary leak, hematoma, lymphocele Common choices Trimethoprim sulfamethoxazole Ciprofloxacin Cephazolin Ampicillin Duration of treatment varies An important factor is the presence of the urinary catheter Trimethoprim sulfamethoxazole Trimethoprim sulfamethoxazole Trimethoprim sulfamethoxazole Trimethoprim sulfamethoxazole Trimethoprim sulfamethoxazole

Urinary tract

Legionella Pneumocystis Toxoplasmosis Nocardia Listeria monocytogenes

FIGURE 10-13 Prophylactic antibacterial/ antiprotozoal strategies.

10.8

Transplantation as Treatment of End-Stage Renal Disease

Prevention Strategies PREVENTION OF RESPIRATORY INFECTIONS IN THE IMMUNOSUPPRESSED PATIENT Infection

Options for prevention

Pneumococcal pneumonia Influenza illness Haemophilus influenzae Tuberculosis Mycobacterium avium complex illness Pneumocystis carinii pneumonia CMV pneumonia

Pneumococcal vaccination; oral penicillin prophylaxis; passive prophylaxis with immune globulin Annual influenza vaccination; amantadine or rimantadine prophylaxis (for influenza A virus only) H. influenza type B vaccination Case finding and early treatment; infection control procedures; preventive therapy with isoniazid Rifabutin prophylaxis Prophylaxis with oral trimethoprim-sulfamethoxazole or aerosolized pentamidine Use of CMV-seronegative organs and blood products for CMV-seronegative recipients; passive prophylaxis with CMV immune globulin; prophylaxis with antiviral agents (acyclovir, ganciclovir) Identification of source; institution of control measures associated with potable water, such as hyperchlorination, maintenance of hot water temperature above 50°C (122°F) Use of HEPA filter to minimize airborne spores; avoidance of decaying leaves and vegetation Prophylaxis with antifungal agents Avoidance of pigeons and pigeon droppings; prophylaxis with antifungal agents Complete travel history to identify patients at risk; avoidance of areas of high exposure to Histoplasma; formalin treatment of infected soil Complete travel history to identify patients at risk; avoidance of areas of high exposure to Coccidioides immitis Complete travel history to identify patients at risk; ova and parasite analysis of stool specimen in patients at risk; thiabendazole prophylaxis

Legionella pneumonia Aspergillosis Candida illness Cryptococcosis Histoplasmosis Coccidioidomycosis Strongyloidiasis

FIGURE 10-14 Prevention strategies for the prevention of pulmonary infection. CMV—cytomegalovirus; HEPA—high-efficiency particulate air. (Adapted from Maguire and Wormser [5]; with permission.)

10.9

Post-transplant Infections

PASSIVE IMMUNIZATION AGENTS—IMMUNE GLOBULINS Immune globulin Hepatitis B (H-BIG*) Percutaneous inoculation Perinatal Sexual exposure Immune globulin (IG) Hepatitis A prophylaxis

Hepatitis B Hepatitis C Measles† Rabies‡ Tetanus (serious, contaminated, wounds; <3 previous tetanus vaccine doses) Varicella-zoster §(VZIG)

Dosage

Route IM

0.06 mL/kg/dose (within 24 h) (5 mL max) 0.5 mL/dose (within 12 h of birth) 0.06 mL/kg/dose (within 14 d of contact) (5 mL max) IM* 0.02 mL/kg/dose (as soon as possible or within 2 wk after exposure) (single exposure) 0.06 mL/kg/dose (>3 mo or continuous exposure) repeat every 4–6 mo 0.06 mL/kg/dose (H-BIG should be used) 0.06 mL/kg/dose (percutaneous exposure) 0.25 mL/kg/dose (max 15 mL/dose) (within 6 d of exposure) 0.5 mL/kg/dose (max 15 mL/dose) (immunocompromised children) 20 IU/kg/dose (within 3 d) 250–500 units/dose Within 48 hours but not later than 96 hours after exposure 0–10 kg 125 units = 1 vial 10.1–20 kg 250 units = 2 vials 20.1–30 kg 375 units = 3 vials 30.1–40 kg 500 units = 4 vials >40 kg 625 units = 5 vials

IM IM ¶

*Deep IM in the gluteal region for large doses only. Deltoid muscle or the anterolateral aspect of the thigh are preferred sites for injection. No greater than 5 mL/site in adults or large children; 1–3 mL/site in small children and infants. Maximum dose: 20 mL at one time. †IG prophylaxis may not be indicated in a patient who has received IGIV within 3 weeks of exposure. ‡1/2 of dose used to infiltrate the wound with the remaining 1/2 of dose given IM Rabies immune globulin is not recommended in previously HDCV immunized patients. †No greater than 2.5 mL of VZIG/one injection site. Doses >2.5 mL should be divided and administered at different sites.

FIGURE 10-15 Passive immunization agents for prevention postexposure. HBIG—hepatitis B immune globulin; HDCV—human diploid cell rabies vaccine; IG—immune globulin; IGIV—intravenous

immune globulin; IM—intramuscularly; VZIG—varicella zoster immune globulin. (From Isada and coworkers [4]; with permission.)

10.10

Transplantation as Treatment of End-Stage Renal Disease FIGURE 10-16 Live virus vaccinations generally not given to transplant patients. IG—immune globulin; OPV—poliovirus vaccine live oral. (From Isada and coworkers [4]; with permission.)

GUIDELINES FOR SPACING THE ADMINISTRATION OF IMMUNE GLOBULIN (IG) PREPARATIONS AND VACCINES Immunobiologic combinations

Recommended minimum interval between doses

Simultaneous administration None. May be given simultaneously at different sites or at any time between doses. Should generally not be given simultaneously. If unavoidable to do so, give at different sites and revaccinate or test for seroconversion in 3 months. Example: MMR should not be given to patients who have received immune globulin within the previous 3 months.

IG and killed antigen IG and live antigen

Nonsimultaneous administration First IG Killed antigen IG Live antigen

Second Killed antigen IG Live antigen IG

None None 6 wk, and preferably 3 mo 2 wk

*The live virus vaccines, OPV, and yellow fever are exceptions to these recommendations. Either vaccine may be administered simultaneously or any time before or after IG without significantly decreasing antibody response.

O N

N H2N

HN

N

N

CH3COO

CH3COO

H 2N

O

N

N

HN

O

HO

Valacyclovir Acyclovir

N

HN N HO

Acyclovir

OH

Ganciclovir

77%

54%

15%

2%–7%

100% liver/GI

100%* R

91% unchanged urine

Plasma t1/2:

2–3 h

2–3 h

2–3 h

2–3 h

Intracellular t1/2:

7–20 h

0.7–1 h

0.7–1 h

6 h–3 wk

HSV/V2V/EBV

HSV/V2V/EBV

HSV/V2V/EBV

HHV8, CMV, adeno, HBV

Antiviral spectrum:

NH2 3Na

+

O –O

O

P C • 6H2O O – O–

N

N O

Phosphonoformicacid Foscarnet

O O

O

N

OCH2P(OH)2•2H2O OH

HOCH2

N

S

Cidofuvir

Lamivudine 86% oral bioavailability

IV

IV

2–6 h

3–4 h

5–7 h

Tissue t1/2:

87.5±41.8 h

17–65 h

10–15 h

Metabolism:

100% renal excretion

85% renal excretion

70%–90% renal excretion

Administration: t1/2:

B

N O

100%* R

Oral bioavailability:

A

O N

HN

N

H 2N

N H O (CH3)CH C C O NH+3Cl–

Famciclovir Penciclovir Excretion:

O N

FIGURE 10-17 Antiviral agents. Asterisk indicates excreted unchanged in the urine; all antivirals are subject to changes in t1/2 with changing renal function. Adeno—adenovirus;

CMV—cytomegalovirus; EBV—Epstein-Barr virus; HHV8–human herpesvirus 8; HSV—herpes simplex virus; VZV—varicella-zoster virus.

Post-transplant Infections

Acyclovir Valacyclovir Famciclovir

R1

viral thymidine kinase

Drug-P1

cell kinase

Drug P2

cell kinase

cell kinase

GP3

R2

R1

Ganciclovir

Cidofovir

cell car v UL97 GP1 kinase gene product autophosphorylating protein kinase cellular enzymes

GP2

viral DNA Polymerase

Drug P3

cell kinase

R2

viral DNA Polymerase

CP2 (no viral enzymes needed)

DRUG INTERACTIONS BETWEEN ANTIVIRALS, ANTIFUNGALS, ANTIBACTERIALS, ANTIMYCOBACTERIALS, AND ANTIPROTOZOALS WITH CYCLOSPORINE AND FK506 Drug

Effect on CSA/FK506

Antifungals Amphotericin B Clotrimazole troches (more in FK506) Ketoconazole (keto>itra>fluconazole) Griseofulvin Antibacterial Clarithromycin Doxycycline Erythromycin Gentamicin Nafcillin Rifampin Rifabutin Sulfamethoxazole/trimethoprim Ticarcillin Antimycobacterial Isoniazid Pyrazinamide Antiparasitic Chloroquine

FIGURE 10-18 Antiviral activation and action (acyclovir, valacyclovir, famciclovir, ganciclovir). Resistance (R) to antivirals has been found at the level of viral thymidine kinase (R1) and DNA polymerase (R2). Ganciclovir is monophosphorylated in cytomegalovirus (CMV)-infected cells by the CMV UL97 gene product. Acyclovir, valacyclovir, and famciclovir are not easily phosphorylated in CMV-infected cells. Cidofovir does not require viral enzymes to be phosphorylated to the active diphosphonate. FIGURE 10-19 Drug interactions between antivirals, antifungals, antibacterials, antimycobacterials, and antiprotozoals with cyclosporine and FK506. (From Lake [6] and Yee [7]; with permission.)

Nephrotoxicity of combination ↑↑ ↑

↑ ↑↑ ↓

↑

↑ ↑ ↑↑

↑ ↓ ↓↓ ↓↓ ↓ ↑

↑

↓ ↓ ↑

FIGURE 10-20 Infections transmitted to transplant recipients via the donor organ.

INFECTIONS TRANSMITTED TO TRANSPLANT RECIPIENTS VIA THE DONOR ORGAN Virus

10.11

Bacteria

HIV, cytomegalovirus, Aerobe (gram positive), herpes simplex virus, aerobe (gram negative), Epstein-Barr virus, anaerobes, Mycobacterium hepatitis B virus, tuberculosis, atypical hepatitis C virus, mycobacteria hepatitis D virus, ? hepatitis G virus, adenovirus (?), parvovirus (?), papillomavirus, rabies, Creutzfeldt-Jakob

Fungi

Parasitic

Candida albicans, Malaria toxoplasmosis, Histoplasma capsulatum, trypanosomiasis, Cryptococcus neoformans, strongyloidiasis Marosporium apiospermum

10.12

Transplantation as Treatment of End-Stage Renal Disease

Cytomegalovirus Envelope Tegument Attachment and penetration Capsid

Egress Cytoplasm

Nucleus

IE E L

Uncoating

Release of viral DNA

Transcription Protein synthesis Replication DNA

Scaffold

Assembly

Packaging

FIGURE 10-21 The lifecycle of cytomegalovirus (CMV). The envelope binds with the cell membrane, and the DNA is uncoated and transferred into the nucleus, where cell protein synthesis machinery is used to manufacture new DNA and capsid. The DNA is packaged into the capsid and returns to the cytoplasm, where the tegument and envelope are assembled around the capsid and the whole virus transported to the cellular surface and released.

CMV is a double-stranded DNA virus that causes disease following transplantation after primary infection, reinfection, or reactivation of latent infections. CMV disease is seen most frequently within the first 4 to 6 months of transplantation if no antiviral prophylaxis is used; however, in the presence of antiviral prophylaxis and new immunosuppressive agents, the onset of CMV disease may be shifted to longer intervals from transplantation. There also may be a slight increase in the occurrence of CMV enteritis with the use of some of the newer combinations of immunosuppressive agents. When the recipient is CMV positive and receives an organ from a CMV-positive donor, reactivation of the latent infection in the recipient is responsible for 15% to 30% of the infections seen, and reinfection with the virus from the donor is responsible for 70%. CMV disease prevention may be accomplished by administering prophylactic antiviral agents or by the use of routine surveillance testing. Variables to be considered in an individual’s risk of CMV disease development are the use of antilymphocyte medications, and the donor and recipient, CMV serostatus. The highest risk group for CMV disease is the group at risk for primary CMV exposure and those given antilymphocyte preparations. Specifically, increased CMV disease is seen during situations that trigger viral replication. High levels of tumor necrosis factor alpha, such as levels occurring during infections or after OKT3 administration, activate the CMV promoter, thus stimulating the conversion from the latent to the reactivated state. All of the prophylactic strategies for the prevention of CMV disease have shown some benefit in different studies; currently, however, the most effective approach is oral ganciclovir. A more bioavailable oral ganciclovir may even increase the effectiveness and is now under investigation. Oral ganciclovir is started when the patient is able to take oral medications within the first week following transplantation and is administered at a dose of 1 g 3 times a day for 3 months following transplantation adjusted for renal function. The protective effect is also seen in those who have received antilymphocyte preparations. The most desirable solution would be a vaccine that induced natural immunity mechanisms. Vaccines targeted against the structural glycoproteins of CMV are currently continuing under development but are not yet available; their ultimate effectiveness is not known at this time. As patients who already have had natural infections are not immune to reinfection or reactivation, a vaccine solution may not be possible.

Post-transplant Infections

MANIFESTATIONS OF CMV DISEASE IN RENAL TRANSPLANT RECIPIENTS

10.13

FIGURE 10-22 Manifestations of cytomegalovirus (CMV) disease in renal transplant recipients.

CMV disease A. Syndrome: fever, leukopenia, malaise, lack of another cause B. Organ specific: hepatitis, enteritis—duodenum, colon; pancreatitis; pneumonitis; interstitial nephritis, retinitis C. Risk of CMV disease by donor Recipient serostatus without antiviral prophylaxis D/R D+RD+R+ D-R+ D-R-

Infection* 70%–100% 50%–80%

Disease 56%–80% 27%–39% 0%–27% <5%

*Infection determined by new anti-CMV antibody development or a greater than fourfold rise in anti-CMV titers.

FIGURE 10-23 (see Color Plates) Endoscopic aspects of cytomegalovirus (CMV) infection. A, CMV esophageal ulcers. B, CMV duodenal ulcers.

A

B FIGURE 10-24 (see Color Plate) Histologic lesion in cytomegalovirus infection.

10.14

Transplantation as Treatment of End-Stage Renal Disease

RANDOMIZED TRIALS EVALUATING CMV PROPHYLACTIC STRATEGIES ADMINISTERED DURING THE TIME OF GREATEST RISK FOR CMV DISEASE Control

Treated

Drug

Author

Induction or Rejection Antilymphocyte

Serostatus

n

CMV Disease

n

CMV Disease

IgG

Metsellar Steinmuller Teuschert Snydman* Boland

ATG-rej ALG/OKT3 None “Some” None

All patients R+ D+RD+RD+R-

20 18 18 35 11

30% 39% 100% 60% 18%

19 16 18 24 11

37% 13% 20% 21% 27%

Acyclovir—PO

Balfour

ALG

All patients

51

29%

53

8%

7 8

100% 38%

6 9

17% 11%

Subgroups D+RD+R+ Ganciclovir

Valacyclovir

Rondeau

ATG/OKT3

D+R-

15

73%

17

47%

Conti

Antilymphocyte

R+

18

56%

22

9%

Hibberd

OKT3

R+

49

33%

64

14%

Brennan

ATG

D+or R+

23

61%

19

21%

Squillet

NA

R+

204

10.8%

204

0%

Dosing Cytotec, 6 doses Sandoglobulin, 5 doses Cytotec, 11 doses Cytotec Cytotec, 5 doses Acyclovir 800 mg po qid x 3 months

Ganciclovir 5 mg/kg bid IV d14–28 Ganciclovir with antilymphocyte drug 2.5 mg/kg/IV bid Ganciclovir 2.5 mg/kg/d during ALG Oral ganciclovir 1 g tid 2 g qid

*Antilymphocyte serum was given to two globulin and eight control patients as induction therapy and four globulin and seven control patients as antirejection therapy.

FIGURE 10-25 Randomized trials evaluating cytomegalovirus (CMV) prophylactic strategies administered during the time of greatest risk for CMV disease.

Post-transplant Infections

FIGURE 10-26 The “prevention” of cytomegalovirus (CMV) disease. This figure shows the different strategies for the management of CMV-positive transplant recipients or recipients of CMVpositive organs.

The "prevention" of CMV disease CMV D+ CMV R+

Preemptive treatment CMV antigenemia testing or PCR testing weekly starting the third or fourth postoperative week

(–)* or low titer positive-depending on the laboratory threshold

(+) Treat with IV ganciclovir 5 mg/kg bid adjusted for renal function × 10–14 d

Antiviral prophylaxis For all CMV D+ R–, D+ R+, D– R+ the following have been employed ‡a. po ganciclovir 1 g tid × 3 months b. IV ganciclovir post transplant only or followed by oral acyclovir for 3 months c. Oral high dose acyclovir 800 mg po qid × 3 months d. Pooled IV IgG or CMV hyperimmune globulin

10.15

†No testing or antiviral therapy Wait for infection

* Different laboratories have different thresholds for clinically significant positive tests.

Continue surveillance

† The most costly approach. ‡ The most convenient and effective. Both ganciclovir and acyclovir are adjusted for

renal function.

DETECTION OF CMV DISEASE AND INFECTION Antibodies: the development of IGM anti-CMV antibodies, a four fold or greater increase in IgG titers Culture: A. Standard culture in a fibroblast monolayer Results may require up to 6 wk B. Shell vial cultures—the buffy coat is centrifuged onto fibroblasts increasing fibroblast infection. Viral infection is detected by applying a monoclonal antibody directed against the 72-Kd major immediate early protein of CMV. RBCs in the buffy coat may be toxic to the monolayer resulting in a false-negative test. Urine and BAL specimens may be positive without predicting disease. Results are available in 16 to 36 h. Other: A. Antigenemia—Granulocytes and monocytes are isolated and stained with a monoclonal antibody against a matrix, tegument protein pp65 (structural late protein). Culture is not required, granulocytes and monocytes from the buffy coat are stained, testing results are available in 4 to 6 h. It may be argued that the positivity may not be due to replicating virus in the WBCs but due to exogenous acquisition from infected endothelial cells. The number of antigen positive cells per unit number of WBC counted that determines the onset of symptomatic diseases depends upon the individual laboratory; however, usually over 10 positive cells per 105 WBC precede the onset of symptoms by approximately 1 week. B. Polymerase chain reaction—For the detection of CMV DNA in whole blood or serum. CMV DNA is amplified from whole blood or serum. The sensitivity and predictive value depend on the laboratory.

FIGURE 10-27 Detection of cytomegalovirus (CMV) disease and infection. BAL—bronchoalveolar lavage; RBC—red blood cell; WBC—white blood cell.

10.16

Transplantation as Treatment of End-Stage Renal Disease

Tuberculosis SOME ANTITUBERCULOSIS DRUGS Drug Primary antituberculous therapy Isoniazid*† (I.N.H., and others) Rifampin*‡(Rifadin, Rimactane) Pyrazinamide§ Ethambutol¶(Myambutol) Other Drugs Capreomycin (Capastat) Kanamycin (Kantrex, and others) Streptomycin** Cycloserine (Seromycin, and others) Ethionamide (Trecator-SC) Ciprofloxacin (Cipro) Ofloxacin (Floxin)

Adult dosage (daily)

Pediatric dosage (daily)

Main adverse effects

300 mg 600 mg 15–30 mg/kg 15 mg/kg (about 1 g)

10–20 mg/kg (max. 300 mg) 10–20 mg/kg (max. 600 mg) same as adult same as adult

Hepatic toxicity Hepatic toxicity, flu-like syndrome Hepatic toxicity, hyperuricemia Optic neuritis

15 mg/kg IM or IV 15 mg/kg IM†† 250–500 mg bid‡‡ 250–500 mg bid 500–750 mg bid 200–400 mg q12h or 400–800 mg/day

15–30 mg/kg 15–30 mg/kg 20–40 mg/kg IM 15–20 mg/kg 15–20 mg/kg Not recommended Not recommended

Auditory and vestibular toxicity, renal damage Auditory toxicity, renal damage Vestibular toxicity, renal damage Psychiatric symptoms, seizures Gastrointestinal and hepatic toxicity Nausea Nausea

*Rifamate (containing rifampin 300 mg plus isoniazid 150 mg) is also available †Can be given orally or parenterally. Pyridoxine should be given to prevent neuropathy in malnourished or pregnant patients and those with alcoholism or diabetes. For intermittent use after a few weeks to months of daily dosage, the dosage is 15 mg/kg twice/wk (max. 900 mg). ‡Available orally or intravenously. For intermittent use after a few weeks to months of daily dosage, the dosage is 600 mg twice/wk. §For intermittent use after a few weeks to months of daily dosage, the dosage is 40–50 mg/kg twice/wk (max. 3 g). ¶Daily dosage should be 25 mg/kg/d if organism isoniazid-resistant or during first 1 to 2 months; decrease dosage if renal function diminished. For intermittent use after a few weeks to months of daily dosage, the dosage is 50 mg/kg twice/wk. **Temporarily not available in the United States. ††For patients > 40 years old, 500 to 750 mg/d or 20 mg/kg twice/wk; decrease dosage if renal function is diminished. Some clinicians change to lower dosage at 60 rather than 40 years of age. ‡‡Some authorities recommend pyridoxine 50 mg for every 250 mg of cycloserine to decrease the incidence of adverse psychiatric effects.

FIGURE 10-28 The treatment of tuberculosis (TB) depends on the clinical presentation. Pretransplant prophylaxis for a positive purified protein derivative, if given, is with isoniazid 300 mg/d up to, or following, transplantation. Post-transplant treatment is more accepted, but due to the possible high rate of hepatotoxicity, many centers have chosen not to administer prophylaxis. Treatment of pulmonary disease should include at least two to three drugs (depending on resistance patterns in the area) for 6 to 9 months. Treatment of

disseminated disease or extrapulmonary disease should include three or four drugs for 12 to 18 months. When starting treatment with isoniazid and rifampicin, care should be taken to increase the glucocorticoid dose twofold and the cyclosporine by threefold to fivefold. This is because rifampicin (and somewhat isoniazid) induces the metabolism of steroids and cyclosporine and FK506 through the P450 cytochrome system. (Adapted from Med Lett Drugs Ther [8]; with permission.)

Post-transplant Infections

10.17

Protozoal/Parasitic Infections DIAGNOSTIC TECHNIQUES FOR PNEUMOCYSTIS CARINII INFECTION Technique

Yield

Complications

Comments*

Routine sputum Induced sputum Transtracheal aspiration Gallium scan Bronchoalveolar lavage (BAL) BAL/brushing BAL/transbronchial biopsy Open lung biopsy

Poor 30%–75% Fair (with experience) Nonspecific >50% (>95% in AIDS) As for BAL alone Over 90% (all patients) Over 95% (all patients)

Needle aspirate

Up to 60%

Rare Rare Common: bleeding; subcutaneous air Injection site Bleeding, aspiration fever, bronchospasm As for BAL See BAL; pneumothorax Anesthesia, air leakage, altered respiration, wound infection Pneumothorax, bleeding

Cultures needed First choice; excellent in AIDS Rarely worthwhile Positive in >95% of infected patients Wedged terminal BAL with immunofluorescence Not useful for P. carinii Impression smears; cultures/pathology “Gold standard” noninfectious/infectious processes; large sample Best in localized disease

*All samples should be cultured and stained for bacteria (including mycobacteria), fungi, viruses, and examined for protozoa. Optimal procedures depend on the locally available expertise.

FIGURE 10-29 Diagnostic techniques for Pneumocystis carinii infection. (Adapted from Fishman [9]; with permission.) FIGURE 10-30 The treatment of Pneumocystis carinii infection. (Adapted from Fishman [9]; with permission.)

THE TREATMENT OF PNEUMOCYSTIS CARINII

Agent(s) (route)

Dose

Options†

Trimethoprim and sulfamethoxazole (TMP-SMZ) (IV/po) Pentamidine isethionate (IV) Dapsone (po) with TMP (po/IV) Clindamycin (IV/po) and primaquine Trimetrexate (IV) with folinic acid (po) (leucovorin) Pyrimethamine (po)

15 mg/kg/d TMP (to 20) 75 mg/kg/d SMZ (to 100)

Treat through rash: reduce TMP or SMZ by one half; desensitize

4 mg/kg/d 300 mg/d maximum 100 mg/d 15–20 mg/kg/d (900 mg) 600–900 mg q 6 h 15–30 mg base po qd 30–45 mg/m2/d 80–100 mg/m2/d

Lower dose (2–3 mg/kg); IM not advised

Load 50 mg bid x 2 d, then 25–50 mg qd Load 75 mg/kg, then 100 mg/kg/qd 750 mg po tid

Not studied fully

with sulfadiazine Atovaquone (po)

Methemoglobinemia; G6PD; may be tolerated in sulfadiazine allergy Methemoglobinemia; diarrhea (pyrimethamine for primaquine) Leukopenia, anemia; thrombocytopenia; relapse common

Maximum 4 g in two doses; up to 8 g Variable absorbance, improved with fatty food; rash

*Adjunctive therapies (see text); corticosteroids (high dose with rapid taper); possibly interferon gamma; granulocyte-macrophage colony-stimulating factor. †Based on clinical judgment of physicians; some agents are not approved by the Food and Drug Administration for this indication.

10.18

Transplantation as Treatment of End-Stage Renal Disease

ANTIBIOTIC THERAPY FOR TOXOPLASMA GONDII INFECTION Drug†

Dose

Duration

Comments

Pyrimethamine

100 mg po x 2 (then) 25 mg–50 mg po, qd, or qod Sulfadiazine 4 g po (then 1–1.5 g po qid or tri-sulfapyridine; (75–100 mg/kg/d) 600–1200 mg IV or 600 mg po q6h 1 g po tid or qid

Load 3–6 wk

Bone marrow suppression; may give folinic acid 5 mg po/im qod except leukemia

3–6 wk

Decrease dose for neutropenia; sulfa allergy common

3–6 wk

Slower resolution than with sulfa; C. difficile colitis In pregnancy or sulfa allergy with pyrimethamine; CNS data limited

Sulfonamide

Clindamycin Spiramycin

3–6 wk

FIGURE 10-31 Antibiotic therapy for Toxoplasma gondii infection. (Adapted from Fishman [9]; with permission.)

*Active infection: twice weekly blood counts are necessary to detect bone marrow suppression resulting from therapy. Lifelong prophylaxis after acute infection is recommended in transplant and AIDS patients. †Investigational: trimetrexate, atovaquone, macrolides, gamma interferon.

Yeast and Fungal Infections FIGURE 10-32 (see Color Plate) Candida esophagitis seen on esophagogastroduodenoscopy.

FIGURE 10-33 (see Color Plate) Endoscopic view of severe esophagitis.

Post-transplant Infections

10.19

FIGURE 10-34 (see Color Plate) Displayed are Aspergillus as fungus balls, which are proliferating masses of fungal hyphae. The hyphae are septute, 5 to 10 µm thick, and branch at acute 40º angles. Aspergillus frequently invades blood vessels, causing hemorrhage and necrotizing inflammation with downstream infarction. This image shows three fungus balls in the lung (Gomori-Ammon stain for fungi).

TREATMENT OF FUNGAL INFECTIONS IN THE SOLID-ORGAN TRANSPLANT RECIPIENT BY CATEGORY OF INFECTION Category of infection

Prophylactic

Mucocutaneous candidiasis Candiduria

Nystatin (oral)

Preemptive

Definitive

Fluconazole*

Fluconazole Amphotericin B bladder irrigation; Fluconazole†

Invasive candidiasis Life-threatening Catheter-associated‡ Less-ill, sensitive organism Aspergillosis Mucormycosis, Phaeohyphomycosis, Hyalohyphomycosis Cryptococcosis

Histoplasmosis, Coccidioidomycosis, Blastomycosis Pneumocystis carinii

Itraconazole¶

Fluconazole††

?Itraconazole‡‡

TMP/SMX

Itraconazole††

Amphotericin B (0.5–1.0 mg/kg) +/– flucytosine Amphotericin B Fluconazole in selected cases§ Fluconazole Amphotericin B (1.0–1.5 mg/kg)** Amphotericin B (1.0-1.5 mg/kg)**

Amphotericin B + flucytosine x 2 wk, then Fluconazole x 4–10 wk if clinical and microbiologic response Amphotericin B; itraconazole may be useful as primary therapy TMP/SMX

*Asymptomatic candiduria in renal transplant recipients †Not T. glabrata or other resistant species ‡Removal of catheter §Less ill, sensitive organism, nephrotoxicity owing to amphotericin B and proven microbiologic and clinical response ¶Pulmonary colonization immediately before or after transplantation **Surgical débridement where possible ††Excision of focal pulmonary nodule due to C. neoformans or H. capsulatum ‡‡For coccidioidomycosis in endemic areas

FIGURE 10-35 Treatment of fungal infections in the solidorgan transplant recipient by category of infection. TMP/SMX—trimethoprimsulfamethoxazole. (Adapted from Hadley and Karchmer [10]; with permission.)

10.20

Transplantation as Treatment of End-Stage Renal Disease

Hepatitis B 31

100

24

22

12

19

9

7

18

80 Cumulative survival, %

20 17

90

6

70

5

15

60

Dialysis 13

13

Transplant

50 40

1 11 9

9 6

30 20 10 0 0

2

4 6 8 Years following detection of HBsAg

10

FIGURE 10-36 Survival of hepatitis B virus (HBV)–infected patients with end-stage renal disease treated with either dialysis or transplantation. Patients infected with HBV (hepatitis B surface antigen [HBsAg] positive) on hemodialysis were matched for age with 22 previously transplanted HBsAg-positive patients. This study shows the reason for concern and investigation as to the safety of transplantation in HBV-infected patients. Although there are other studies showing a significantly decreased survival in patients transplanted with HBV infection, most currently show equivalent survival of over 10 years. The cause of death in the HBV-infected group, however, may more often be from infection and liver failure than from cardiac disease.

The safety of transplantation in HBsAg-positive patients has been debated for over 25 years. Increased mortality, if seen, is usually seen beyond 10 years following transplantation and is often secondary to liver failure or sepsis. The acquisition of hepatitis B infections post-transplant, however, does carry a worse prognosis. Virtually all patients with severe chronic active hepatitis, and 50% to 60% of those with mild chronic active hepatitis on liver biopsy prior to transplantation, will progress to cirrhosis. Patients with chronic persistent hepatitis usually do not show histologic progression over 4 to 5 years of follow-up, although mild lesions do not guarantee preservation of hepatic function over longer periods. The complete natural history of hepatitis B following transplantation is not known, as biopsies have been performed largely in those who have abnormal liver function tests; however, one recent study, that included analyses of all individuals who were HBsAg positive around the time of transplantation, has shown histologic progression in 85.3% of those who were rebiopsied with the development of hepatocellular carcinoma in eight of 35 patients who developed cirrhosis. A key to management of patients who were HBsAg positive following transplantation is to periodically monitor the liver by ultrasound and to perform a serum alpha-fetoprotein level to detect hepatocellular carcinoma at the earliest possible stage. The key to minimizing the effects of hepatitis B infections following transplantation, however, is to administer the hepatitis B vaccine as early as possible in the treatment for end-stage renal disease. It is noted that 60% will develop antihepatitis B titers when vaccinated while on dialysis compared with only 40% of those who have already been transplanted. Co-infection with hepatitis C may result in more aggressive liver disease but so far has not led to a marked decrease in patient survival. Because of the high risk of acute renal failure or rejection with the use of interferon post-transplant, treatment of hepatitis B with interferon following renal transplantation is not advised. Lamivudine or other experimental antihepatitis agents may be used pretransplant for patients with hepatitis B infection. (Figure adapted from Harnett and coworkers. [11]; with permission.)

10.21

Post-transplant Infections

POST-TRANSPLANT SURVIVAL IN HEPATITIS B–INFECTED PATIENTS Patients evaluated, n

1 y, %

3 y, %

Author

Year

HBsAg +

HBsAg –

HBsAg +

HBsAg –

Pirson Hillis Touraine Dhar Roy Pfaff

1977 1979 1989 1991 1994 1997

61 16 140 51 85 781

60 149 869 541 172 13,287

94 55 94 92 100 88.8

95 90 93 98 100 91.8

5 y, %

HBsAg + HBsAg – 28

HBsAg +

10 y, %

HBsAg –

60

80

91 88 75 77.6

88 93 75 80.6

HBsAg +

HBsAg –

80 87

82

66 61.6

68 (8 y) 65.8

+—HBsAg positive; –—HBsAg negative. Later studies have usually shown comparable patient and graft survival in HBsAg-positive patients compared with HBsAg-negative patients. There may only be a slight 3% to 4% difference overall in long-term graft and patient survival in favor of HBsAg-negative patients.

FIGURE 10-37 Post-transplant survival in hepatitis B–infected patients. Later studies have shown comparable patient and graft survival in hepatitis B surface antigen (HBsAg)–positive patients compared with HBsAgnegative patients. There may only be a slight 3% to 4% difference

overall (in favor of HBsAg-negative patients) in long-term graft and patient survival. (Data from Pirson and coworkers [12], Hillis and coworkers [13], Touraine and coworkers [14], Dhar and coworkers [15], Roy and coworkers [16], and Pfaff and Blanton [17].)

CHRONIC HEPATITIS B INFECTION IN HBsAg-POSITIVE RENAL TRANSPLANT RECIPIENTS: RESULTS OF LIVER BIOPSIES PERFORMED PERITRANSPLANT AND A MEDIAN OF 66 MONTHS LATER First Biopsy n = 131 Histology Normal Chronic persistent Chronic active Cirrhosis Miscellaneous

% 39% 25% 25% 0% 11%

Second biopsy n = 101 66 months →

% 6% 18% 42% 28% 6%

Histologic deterioration was seen in 85.3% of those rebiopsied with hepatocellular carcinoma seen in 8/35 with cirrhosis. Patients had not been treated with anti-HBV agents. 151 patients were HBsAg positive, median age 46, 35 females, 116 males. Immunosuppression in 124 was prednisone and azathioprine and in 27 cyclosporine, azathioprine, and prednisone. The median follow-up was 125 months (range 1 to 320). Median time of HBsAg positively was 176 months with 20% acquiring HBV infection post-transplant.

FIGURE 10-38 Chronic hepatitis B infection in hepatitis B surface antigen (HBsAg)–positive renal transplant recipients. Results of liver biopsies performed peritransplant and a median of 66 months later in 131 of 151 HBsAg+ patients. Histologic determination was seen in 85.3% of patients rebiopsied, with hepatocellular carcinoma seen in eight of 35 patients with cirrhosis. Patients had not been treated with anti-hepatitis B virus agents. With a median age of 46, 151 patients were HBsAg positive (35 female, 116 male). Immunosuppression in 124 patients was with prednisone and azathioprine, and in 27 patients was with cyclosporine, azathioprine, and prednisone. (From Fornairon and coworkers [18]; with permission.)

10.22

Transplantation as Treatment of End-Stage Renal Disease

CHRONIC HEPATITIS B INFECTION: CAUSES OF DEATH IN 151 HBSAG-POSITIVE PATIENTS OVER 125 MONTHS Liver related (n = 15) Spontaneous bacterial peritonitis Hepatocellular carcinoma Liver failure Fibrosing cholestatic hepatitis

Not liver related (n = 26) 6 4 5 2

Cancer Sepsis Cardiovascular Stroke Other

FIGURE 10-39 Chronic hepatitis B infection. Causes of death in 151 hepatitis B surface antigen (HBsAg)–positive patients over 125 months. Death following transplantation is more frequently due to sepsis and liver failure in patients with hepatitis than in patients without chronic hepatitis. (From Fornairon and coworkers [18]; with permission.)

6 8 5 3 4

Death following transplantation in patients with hepatitis is more frequently caused by sepsis and liver failure than in patients with chronic hepatitis.

Hepatitis B virus screening in renal transplant candidates

(–)No further testing

(+) eAg HBV DNA

(–) DNA indicates lack of viral replication

? Biopsy ? Use antiviral Consult hepatology

except by routine dialysis schedule

(+) DNA/eAg (+)

Cumulative survival, %

Hepatitis B virus Screen by HBsAg

1.0 0.9 0.8 0.7 HCV+HBV– (n=189) HCV+HBV+ (n=46)

0.6 0.5 0

Biopsy

Cirrhosis

Mild to severe hepatitis (CPH, CAH)

No renal transplant alone Referral to Liver transplant center (if appropriate) that transplants HBV DNA(+) candidates

Consider treatment

FDA approved interferon

Lamividine Famacyclovir Labucovir Adefovir

In trials

FIGURE 10-40 Hepatitis screening in renal transplant candidates. CAH— chronic active hepatitis; CPH—chronic persistent hepatitis; HBsAg—hepatitis B surface antigen; HBV—hepatitis B virus.

12

24

36

48

60 72 Months

84

96

108

120

FIGURE 10-41 Patient survival in 235 hepatitis C virus (HCV)-positive patients. Patients coinfected with HCV and hepatitis B virus (HBV) had comparable survival 12 years after transplant as those infected with HCV alone although fibrosis was more common in dually infected patients. Results were based on 27 biopsies in patients who were both HCV positive and HBV positive and 81 biopsies in patients who were both HCV positive and HBV negative. Over time, liver failure occurred more frequently in patients who were both HCV and HBV positive (17%) than in patients who were both HCV positive and HBV negative (7%). (From Pouteil-Noble and coworkers [19]; with permission.)

10.23

Post-transplant Infections

Hepatitis C Other high risk 30% 16% Drug-related 4% STD history 1% Prison 9% Low SES

Injection drug use 43%

Sexual 15%

Transfusions 4% Occupation/hemodialysis 4%

Unknown 1% Household 3%

FIGURE 10-42 Risk factors associated with reported cases of acute hepatitis C in the United States (1991 to 1995). Hepatitis C transplant infection prior to transplantation has not been definitively shown in most studies to markedly affect survival for at least 5 years following renal transplantation. Furthermore, hepatitis C–positive individuals who are otherwise good transplant candidates appear to have increased survival when transplanted, compared with staying on dialysis. Liver biopsies performed prior to transplantation have usually shown mild histological changes or chronic persistent hepatitis, but sequential biopsies have not been performed for a long enough period of time and compared with survival to outline the natural history. Transaminase levels do not help to predict histology or outcome. Death in hepatitis C–positive individuals is more often related to infection than in hepatitis C–negative transplant recipients. Post-transplant treatment with interferon alpha has led to an unacceptably high rate of both rejection and acute renal failure secondary to severe interstitial edema without tubulitis. Additionally, except for a few individuals, interferon has not resulted in long-term viral clearance. Most studies show the return of hepatitis C viremia within 1 month following cessation of interferon. At this point it appears that hepatitis G infections (also caused by an RNA virus) in renal transplant recipients, although occasionally associated with slight increases in chronic hepatitis, are not associated with decreased survival.

E2/NS1 glycoprotein

Hepatitis C virus screening in renal transplant candidates Hepatitis C virus Screen for HCV by EIA-2 or 3

HCV (Ab) (+) 55 nm

RNA

33 nm core

+

PCR

Liver biopsy

E1 glycoprotein

FIGURE 10-43 Proposed structure of the hepatitis C virus.

Referral for liver and kidney transplant

–

Cleared infection Repeat PCR in high-risk group in 6 months

Lipoprotein envelope Cirrhosis

HCV Ab (–) no further testing unless high-risk behavior

Mild changes CPH (mild hepatitis) CAH (moderate to severe hepatitis)

Transplant Monitor clinically for the onset of cirrhosis Monitor carefully for infection

Referral for Interferon treatment Currently unknown sustained response

Transplant

FIGURE 10-44 Hepatitis screening in renal transplant candidates. CAH—chronic active hepatitis; CPH—chronic persistent hepatitis; HCV(ab)— hepatitis C virus antibody; PCR—polymerase chain reaction.

10.24

Transplantation as Treatment of End-Stage Renal Disease FIGURE 10-45 The survival of hepatitis C virus (HCV)–infected patients after transplant group 1 or while awaiting transplantation group 2. Patients who are transplanted have an increased survival. A small biopsy study of dialysis (n = 14) and transplant (n = 14) patients showed no difference in histologic progression in transplant recipients. The amount of fibrosis, however, was slightly increased. (Adapted from Knoll and coworkers. [20]; with permission.)

Fraction of patients surviving

1.0 0.9

Group I

0.8 Group II

0.7 0.6 0.5 0

12

100

24 Time, mo

36

48

FIGURE 10-46 Five-year patient (panel A) and graft (panel B) survival in hepatitis C virus (HCV)–positive and HCV-negative patients from recent reports from United States centers. There is no significant difference over 5 years in patient or kidney graft survival. MCW—Medical College of Wisconsin; Miami—University of Miami; NEOB—New England Organ Bank; UCSF CAD— University of California, San Francisco with cadaveric donors; UCSF LRD—University of California, San Francisco, with living related donors; UW—University of Washington.

HCV + HCV –

Survival, %

80 60 40 20 0

100

MCW

Miami

UCSF LRD

UCSF CAD

NEOB

UW 3 yr

Miami

UCSF LRD

UCSF CAD

NEOB

UW 3 yr

HCV + HCV –

Survival, %

80 60 40 20 0

MCW

Post-transplant Infections

RENAL AND HEPATIC OUTCOME IN PATIENTS TREATED WITH INTERFERON ALPHA FOLLOWING RENAL TRANSPLANT FOR HCV INFECTION Author Year Number treated HCV + HBV + Dose mU, SC, TIW Normalization of ALT Discontinued treatment Number with cirrhosis PCR +→PCR – Relapse→PCR + Acute renal failure Rejection Lost transplant New proteinuria

Thervet 1994 13 4 3–5 1 7 8 NA NA 2 0 0 NA

Magnone 1995 11 1 1.5–5 NA 7 NA NA NA 0 7 6 NA

Rostaing 1995 14 0 3 10 7 1 4 4 5 0 1 2

Rostaing* 1996 16 NA 3 NA 9 NA NA NA 6 0 3 NA

Yasumura 1997 6 0 6 6 0 0 2 0 0 1 0 1

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FIGURE 10-47 Renal and hepatic outcome in patients treated with interferon alpha post-renal transplant for hepatitis C virus (HCV) infection. Interferon treatment results in a high rate of transplant acute renal failure or rejection. Transplant biopsies in those with acute renal failure show severe diffuse edema. Acute renal failure is not very responsive to steroids. Virologic clearing is rare, as HCV-RNA is detectable, on average, 1 month after discontinuing interferon if the polymerase chain reaction (PCR) became negative during treatment. ALT— alanine aminotransferase; SC—subcutaneously; TIW—three times a week. (Data from Thervet and coworkers [21], Magnone and coworkers [22], Rostaing and coworkers [23,24], and Yasumura and coworkers [25].)

*Most are overlapping patients with the 1995 study.

Hepatitis G HEPATITIS G VIRUS IN RENAL TRANSPLANTATION: PREVALENCE OF INFECTION AND ASSOCIATED FINDINGS Author Year Location % infection % with HCV infection % with chronic ALT elevation Rejection rate % with HBsAg Survival versus HGV negative

Dussol 1997 Marseille 28% 12.5% 12.5% Unchanged 8% NA

Murthy* 1997 NEOB 18% 28% 35% Unchanged NA Unchanged

Fabrizi 1997 Milan 36% 91% 18% NA 18% NA

*One patient may have acquired HGV through the donor organ. Five of 10 pretransplant positive patients became HGV RNA negative post-transplant.

FIGURE 10-48 Hepatitis G virus (HGV) in renal transplantation: prevalence of infection and associated findings. Hepatitis G virus is an RNA virus of the flaviviridae family. Hepatitis G virus was isolated independently by two different groups of investigators and called hepatitis GB viruses by Simmons and colleagues, and hepatitis G virus by Lenin and colleagues. It now appears that GB virus-A and GB virus-B are tamarin viruses and GBV-C is a human virus with

sequence homology of more than 95% with the hepatitis GV sequence. The virus has been shown to be transmitted by transfusions, including plasma products, by frequent parenteral exposure, including intravenous (IV) drug abuse, by sexual exposure, and by mother to child transmission. In the United States, the prevalence of hepatitis G virus is 1.7% among healthy volunteer blood donors, 8.3% among cadaveric organ donors, and 33% among IV drug abusers. Among chronic hemodialysis patients, the prevalence of hepatitis G virus RNA has been variable, ranging from 3.1% in Japan to 55% in Indonesia and some areas in France. Likewise, the reported incidence of co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) is extremely variable. Hepatitis G virus RNA is detected by reverse transcriptase polymerase chain reaction (PCR). The development of reliable serologic assays for hepatitis G has been difficult due to the lack of linear epitopes expressed by hepatitis G virus. The risk for pretransplant hepatitis G infection is associated with increasing numbers of blood transfusions and with longer duration of dialysis. Post-transplantation, most patients with hepatitis G virus remain viremic; however, patients have been shown to clear the virus post-transplant. At this time, hepatitis G virus does not appear to invoke a poor outcome after transplantation, either in the form of severe liver disease or increased mortality; however, the long-term studies needed to provide a firm conclusion about this have not been performed. The question of transmission of hepatitis G virus via transplantation is still under investigation. NA—not available; NEOB— New England Organ Bank. (Data from Dussol and coworkers [26], Murthy and coworkers [27], and Fabrizi and coworkers [28].)

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Transplantation as Treatment of End-Stage Renal Disease FIGURE 10-49 Kaplan-Meier estimate of graft survival among recipients with GBV-C RNA and without GBV-C RNA before transplantation. Death with a functioning graft is included as a cause of graft loss. The relative risk of graft loss among recipients with pretransplantation GBV-C RNA (and 95% CI of the risk) was calculated using a proportional hazards model. The number of patients at risk at the beginning of each 12-month interval is provided. (Adapted from Murthy and coworkers [27]; with permission.)

Probability of graft survival

1.0 0.8 0.6 0.4 Relative risk: 0.88 (0.37, 2.09) GBV-C negative GBV-C positive

0.2 0.0 0

12

24

36

48 60 Time, mo

72

84

96

108

GBV-C neg. 79 GBV-C pos. 16

63 12

58 10

54 10

50 10

35 9

26 9

14 4

0 0

46 10

Value of Pretransplant Liver Biopsy HEPATITIS MARKERS AND HISTOPATHOLOGIC DIAGNOSIS FROM LIVER BIOPSIES PRIOR TO TRANSPLANT

HbsAg (+) Anti-HCV (+) HBsAg and anti-HCV (+) Anti-HBs and anti-HCV (+) Anti-HBs (+) Total

CAH

CPH

CIRH

Normal

HSTAS

Other

Total

2 11 1 8 – 22

2 4 – 2 – 8

1 – – 1 – 2

1 10 1 9 13 34

– 2 – 1 – 3

1 3 – 1 – 5

7 30 2 22 13 74

FIGURE 10-50 Liver biopsy in the evaluation of hemodialysis patients who are renal transplant candidates. Seventy-four patients were biopsied. Forty-six percent of patients had normal or nonspecific changes in their liver biopsies, 30% CAH, 11% CPH, and 3% cirrhosis. Liver enzymes are poor predictors of histology in ESRD. Although with current management HBV-positive and HCV-positive recipients can enjoy comparable 10-year survival to noninfected patients, those with moderate to severe hepatitis more frequently progress histologically and may develop sepsis or liver failure. Liver biopsy aids in the long-term plan for the individual patients’ immunosuppression and hepatic and infection monitoring. Furthermore, pretransplant antiviral medications may be beneficial, especially interferon, where post-transplant administration is not advisable because of markedly increased rates of acute renal failure and rejection.(Adapted from Özdogan and coworkers. [29]; with permission.)

Hepatitis A infections are associated with acute hepatitis and, on occasion, with acute renal failure. Hepatitis A infections can be prevented by either using immunoglobulin injections or, more currently, a hepatitis A vaccine that is given as a two-dose series. This is an inactivated virus that is produced in human fibroblast cell culture and is given to adults as an initial and second dose 6 to 12 months later. The effectiveness of this vaccination has not yet been tested in renal transplant recipients, nor are there specific guidelines on the administration prior to transplantation, but given the lack of toxicity, it may very well be advised in the future to give this to patients with end-stage renal disease and, specifically, to patients who are considering transplantation. CAH—chronic active hepatitis; CPH—chronic persistent hepatitis; CIRH—cirrhosis; HSTAS— hepatic steatosis.

Post-transplant Infections

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Viral Interstitial Nephritis FIGURE 10-51 Viruses that cause interstitial nephritis in renal transplant recipients. Consider this condition when nonspecific inflammation is seen on biopsy or unexplained rejection occurs. Viruses may cause renal disease by direct infection of the glomerular and/or tubular cells or by the immune response directed against virally infected cells. Most commonly nonspecific interstitial inflammation is seen but severe tubular injury by mononuclear cells, peritubular inflammation, and interstitial fibrosis may also be seen. The presentation of virally mediated interstitial nephritis may be acute or subacute. In addition to routine light microscopy, occasionally evaluation by immunofluorescence, electron microscopy, or special stains for light microscopy are necessary to make the diagnosis.

VIRAL INTERSTITIAL NEPHRITIS Adenovirus BK virus Cytomegalovirus Epstein-Barr virus Herpes simplex virus 1, 2, 6 Varicella-zoster virus Hantavirus Hepatitis C virus–possible HIV

Proportion of patients with AIDS

HIV 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

No cyclosporine treatment (n=13) Cyclosporine treatment (n=40)

P=0.001

0

6 12 18 24 30 36 42 48 54 60 Months since transplantation-related HIV-1 infection

66

FIGURE 10-52 The occurrence of AIDS in HIV-infected transplant recipients according to immunosuppressive treatment. Immunosuppression included cyclosporine in 40 individuals and no cyclosporine in 13 individuals. The precise natural history of HIV infection following renal transplantation is still not well delineated. The largest single series from Pittsburgh analyzed 11 patients who were HIV positive prior to transplantation and 14 patients who developed HIV infections following transplantation. Of the 11 patients infected before transplantation, six were alive an average of 3.3 years following transplantation. Five patients had died, however; three of AIDS-related complications. Of the 14 patients infected peritransplantation, seven patients were alive at follow-up an average of 4.8 years later. There had been seven deaths, three due to AIDS. Complications seemed to correlate with increased immunosuppression for rejec-

tion. Another report evaluating 53 patients infected with HIV around the time of transplantation found that patients treated with cyclosporine appeared to have a better long-term prognosis than those who were treated with prednisone and azathioprine. In summary, although there are no firm conclusions, it appears that there is not much difference between pre- or post-transplant acquisition of HIV infection, although some authors, based on small numbers of patients, have concluded that the age of the patient and the duration of the infection are both prognostic factors. It also appears that approximately 25% of HIV-infected individuals do poorly within the first 6 months of transplantation, especially following antirejection treatment (Rubin, unpublished data). Another 25% of individuals appear to do very well 6 years and beyond following transplantation. The remainder of the individuals seem to develop AIDS within 3 to 3.5 years after transplantation, with an average survival of about 3 months after the onset of AIDS. It has also been noted that cytomegalovirus or other infections that may increase HIV proliferation may influence this outcome, and that prophylactic antimicrobial strategies may alter the “natural history.” Currently, it is advised that all transplant candidates be screened for the presence of HIV antibody and counseled about the possible consequences of further immunosuppression, but not be categorically denied transplantation if they are otherwise asymptomatic. Patient management following transplantation should be focused on the avoidance of large increases in immunosuppression and opportunistic infections, with special attention to the viral, pneumocystic, and mycobacterial infections that these individuals may develop. Antiretroviral strategies in transplantation require study. (Adapted from Schwarz and coworkers [30]; with permission.)

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Transplantation as Treatment of End-Stage Renal Disease

Herpes Simplex Virus FIGURE 10-53 (see Color Plate) Linear esophageal ulcers caused by herpes simplex virus (HSV) and Candida. Infection with HSV-1 and -2 leads to stomatitis and esophagitis post-transplantation without acyclovir prophylaxis. Additionally, paronychia, corneal ulcers, encephalitis, genital lesions, disseminated involvement of the gastrointestinal tract, pancreas, and liver, and interstitial nephritis has been seen. HSV-6 causes exanthem subitum in children, mononucleosis, and hepatitis. There has been some evidence that reactivation infections may be associated with rejection in transplant recipients. Both reactivation and reinfection may occur. HSV-8 is associated with Kaposi’s sarcoma. Prevention of these infections has been achieved using prophylactic acyclovir following transplantation. If clinical symptoms occur from HSV, they usually are treated with acyclovir adjusted for renal function.

FIGURE 10-54 (see Color Plate) Varicella-zoster virus (VZV) infection. Primary VZV infections usually result in typical vesicular eruptions of generalized onset without dermatomal localization. Reactivation infection of the virus from the dorsal root ganglion usually causes a dermatomally localized vesicular eruption. By the time of renal transplantation, over

94% of adults have evidence of a prior VZV infection. In those patients previously infected, antibody titers increase following transplantation. Pretransplant screening is recommended to advise the patient on treatment of post-transplant exposures. Post-transplant exposures to zoster or chickenpox in the nonimmune individual should be treated with acyclovir, famcyclovir, or varicella-zoster immune globulin. Immune globulin is rarely required at this time. Patients with the new onset of varicella infection following transplantation or with diffuse zoster should be treated with intravenous acyclovir, 10 mg/kg, three times per day, or famcyclorir depending on renal function. Infection in the transplant recipient, particularly in those who are primarily infected, can result in encephalitis, disseminated intravascular coagulation, pneumonia, bowel involvement, pancreatitis, dermatitis, and hepatitis. The attack rate in nonimmune individuals of household contacts with varicella infections is 80% to 90%. Therefore, if individuals have not previously had varicella infections at the time of transplant evaluation, vaccination with a live attenuated strain could be considered. Recently this strategy has been used in children prior to renal transplantation. Attack rates in vaccinated individuals may be up to 31%, but the disease that develops is much milder compared with those susceptible individuals not previously vaccinated. Should resistant strains of varicella develop, foscarnet has been effective. Foscarnet is associated with a renal decline in renal function. (Adapted from Friedman-Kien [31]; with permission.)

Post-transplant Infections

FIGURE 10-55 Adenovirus infection of the colon. Adenovirus infections normally cause asymptomatic infections, coryza, or pharyngitis. Infection in the first decade of life usually protects individuals from future infection as long as the immune system is intact; however, in transplant recipients, adenovirus types 11, 34, and 35 have been shown to cause interstitial pneumonia, conjunctivitis, hemorrhagic cystitis, hepatitic necrosis, interstitial nephritis and gastroenteritis, and disseminated disease. Adenovirus infection may be latent prior to transplant and reactivate post-transplant, or a primary infection may be acquired.

Adenovirus has been shown to infect the bladder, uroepithelial cells, renal tubular cells (distal greater than proximal), the endothelium of the glomeruli and peritubular capillaries, and, occasionally, mesangial cells. The outcome of adenovirus infection is related to the type of immunosuppression and the recipient age. The death rate during active infection in renal transplantation may be as high as 18% but may be even higher in younger patients. The onset of disease after transplantation is usually within 6 months of the transplant. Clinically, the most frequent symptoms of an adenovirus infection involve difficult micturition, including gross hematuria, fever, and, occasionally, renal dysfunction. The diagnosis is suspected when bacterial cultures are negative but there is gross hematuria. The urinary symptoms usually last 2 to 4 weeks. The diagnosis is made by urine culture or by electron microscopy or light microscopy, where adenoviruses are seen as intranuclear basophilic viral inclusions with a narrow halo between the inclusions and the nuclear membrane. Treatment has been somewhat successful using ganciclovir. Interferon therapy is difficult because of the risk of acute renal failure or rejection in transplant recipients. Furthermore, efficacy is questionable because of the virus’ ability to inhibit the mode of action of interferon. Ribavirin has successfully cleared the virus in several immunosuppressed patients. The use of IVIG has not been associated with reliable results. In the future, cidofovir may also be used for the treatment of adenovirus infections, but renal insufficiency and proteinuria may limit use.

CENTRAL NERVOUS SYSTEM INFECTION IN THE TRANSPLANT RECIPIENT Incidence 5%; mortality up to 85% for CNS infections Acute to subacute L. monocytogenes Subacute to chronic Cryptococcus neoformans Mycobacterium tuberculosis Coccidiodes immitis Focal brain infection Aspergillus L. monocytogenes T. gondii N. asteroides Candida albicans Cryptococcus Progressive dementia Polyomavirus, HSV, CMV, HIV Symptoms Headache—may be mild, may have little meningismus Fever—may be mild ± altered consciousness Cerebrospinal fluid Lymphocytic pleocytosis (viral/fungal/MTB) Hypoglycorrhaia Neutrophilic pleocytosis (bacterial)

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Over three-fourths of central nervous system infection is accounted for by L. monocytogenes C. neoformans A. fumigatus Timing Early Listeria Nocardia Toxoplasma Aspergillus Late—as above and due to chronic enhanced immunosuppression plus Cryptococcus and tuberculosis Diagnosis Physical examination CT scan identifies hypodense ring-enhancing lesions CSF examination Directed lesional aspirates

FIGURE 10-56 Central nervous system infection in the transplant recipient. CNS—central nervous system; CSF—cerebrospinal fluid; MTB— mycobacterium tuberculosis.

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Transplantation as Treatment of End-Stage Renal Disease

CAUSES OF HEADACHE IN THE TRANSPLANT RECIPIENT Medications OKT3 (aseptic meningitis) ATG IVIgG Cyclosporine Tacrolimus Antihypertensives Calcium channel blockers ACE inhibitors Nitrates Hydralozine Minoxidil Hypertension Neck “tension,” muscle pulls, ligamental irritation Sinusitis Ocular abnormalities Excessive vomiting Migraine headaches exacerbated by cyclosporine, tacrolimus, and calcium channel blockers Stroke Infection of the central nervous system

FIGURE 10-57 Causes of headache in the transplant recipient. ACE—angiotensinconverting enzyme; CNS—central nervous system; ATG—antithymocyte globulin.

WORK-UP OF AN UNEXPLAINED HEADACHE History Character, pattern, positional relationships Fever, duration of headache and fever Location of headache Visual, movement, sensory impairment Bowel or bladder incontinence Trauma Medications old and new Time of medications and relationships to headache Physical examination Eye Neurological Complete the rest of the examination If no papilledema or focal neurological deficit→lumbar puncture If papilledema or focal deficit→CT first if no mass lesion→lumbar puncture Cerebrospinal fluid is sent for Cell count and differential Protein Glucose Gram’s stain Fungal stains Acid fast stain Fungal culture Mycobacterial cultures Bacterial cultures Cryptococcal antigen Save cerebrospinal fluid in addition for other tests including Histoplasma capsulatum or Coccidiodes immitis antibody titers

FIGURE 10-58 Work-up of an unexplained headache.

FIGURE 10-59 Epstein-Barr virus (EBV). EBV is associated with asymptomatic infection, mononucleosis, hepatitis, and, rarely, interstitial nephritis. In transplant recipients, posttransplant lymphoproliferative disorder (PTLD) is also associated with EBV. EBV promotes B-cell proliferation, if left unchecked by immunosuppressive agents targeting the T-cell system. This chest radiograph shows multiple pulmonary nodules of PTLD. Symptoms vary from no symptoms to diffuse organ involvement causing dysfunction. Any area of the body may be involved, with frequent sites being the gums, chest, abdomen, and central nervous system. PTLD occurs during the first posttransplant year in approximately 50% of those developing PTLD. It is seen in 1% to 2% of renal transplant recipients. Primary EBV infection following transplantation and antilymphocyte agent use is associated with an increased risk. Increasing quantitative blood EBV DNA levels may predict the onset of PTLD.

Post-transplant Infections

10.31

Viral Meningitis VIRAL MENINGITIS Causal agents Enterovirus Coxsackie* ECHO* Poliovirus Adenovirus Mumps Arbovirus Herpes group† Cytomegalovirus* Herpes simplex virus 1 and 2* HHV-6* HHV-8* Varicella-zoster virus* Epstein-Barr virus*

Coronavirus HIV Influenza A, B Lymphocytic choriomeningitis virus Parainfluenza virus Rabies virus Rhinoviruses Rotavirus Japanese encephalitis virus* Tick borne encephalitis virus PML (JC) virus (in development)* BK virus (in development)*

FIGURE 10-60 Viruses causing meningitis in transplant recipients. The presentation is usually with fever and headache alone or in conjunction with headache may be the initial symptom. Nuchal rigidity is rare in the transplant patient. Cerebrospinal fluid samples should be saved for viral analysis and analysis should be requested if the diagnosis is not rapidly available from standard studies.

* Cerebrospinal fluid polymerase chain reaction available to make the diagnosis but locations vary † Increased in transplant patients

Black Hairy Tongue FIGURE 10-61 (see Color Plate) Black hairy tongue is the result of hypertrophy of filiform papillae of the tongue, often seen in transplant patients after antibiotic treatment. The origin is unknown but is associated with topical or systemic antibiotics, poor oral hygiene, smoking, alcohol, and the use of mouthwashes. Most often there are no symptoms; however, nausea, gagging, taste alteration, or halitosis are reported by some patients. Treatment includes brushing with a soft brush and, occasionally, topical vitamin B, salicylic acid, gentian violet, or surgical removal. This entity is not to be confused with hairy leukoplakia, which is composed of white corrugated plaques on the lateral surface of the tongue. These lesions may be small and flat or extensive and hairy. Microscopic evaluation shows epithelial cells with herpetic viral inclusions, specifically Epstein-Barr virus. Treatment is oral acyclovir.

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Transplantation as Treatment of End-Stage Renal Disease

Tinea Versicolor FIGURE 10-62 (see Color Plate) Tinea versicolor (pityriasis versicolor) is a chronic superficial fungal disease caused by Malassezia furfur, a yeast normally found on the skin. It is in yeast form in the unaffected skin areas and in the mycelial phase on affected skin. The disease usually is located on the upper trunk, neck, or upper arms. Symptoms may include scaling, erythema, and pruritis. It may appear as slightly scaly brown macules or whitish macules. Treatment options include oral or topical terbinafine (1% cream or gel), oral or topical ketoconazole, oral fluconazole, or topical treatments, such as ciclopiroxolamine, piroctoneolamine, zinc pyrithione, or sulfur-containing substances, such as selenium sulfide; the most common treatment is selenium. Patients are asked to wet themselves in the shower, turn off the water, apply the selenium and let it sit for 10 minutes, and then rinse. Also, oral fluconazole, 200 mg, once or repeated once a week later is a simple and effective treatment. Of note, oral terbinafine, 250 mg, daily for 12 weeks is associated with slightly decreased cyclosporine levels. Terbinafine is an allylamine that binds to a small subfraction of hepatic cytochrome P450 in a type I fashion. Side effects seen during terbinafine use include gastrointestinal distress in up to 5% of patients and skin rashes in 2% of patients.

Kaposi’s Sarcoma FIGURE 10-63 (see Color Plate) Kaposi’s sarcoma of the lower leg in a male transplant recipient. Kaposi’s sarcoma is a tumor, perhaps of lymphatic endothelial origin, that presents as purple papules or plaques that advance to nodules of the extremities, oral mucosa, or viscera. In transplant recipients it presents on average by 21 months post-transplant, with the largest number (46%) within the first post-transplant year. It is seen most often in men (3:1) and in those of Arabic, black, Italian, Jewish, and Greek ancestry. It accounts for 5.7% of the malignancies reported to the Cincinnati Transplant Tumor Registry (nonmelanoma skin cancers and in situ carcinomas of the uterine cervix excluded). Transplant programs in Italy and Saudi Arabia have reported higher rates of post-transplant Kaposi’s sarcoma. Visceral involvement is less common in the transplant recipient than in the AIDS patient, but it must be remembered that it may be seen in the liver, lungs, gastrointestinal tract, and nodes. Mortality is increased with visceral involvement (57% versus 23%). HHV-8 has been proposed as the causal agent of this tumor; however, not all investigators feel the evidence is conclusive. Of note, the occurrence in AIDS patients is decreased in those who receive foscarnet, cidofovir, and ganciclovir, but not acyclovir. Treatment includes decreasing immunosuppression, local radiation, excision, interferon, or chemotherapy.

Post-transplant Infections

10.33

Mucormycosis

FIGURE 10-64 Mucormycosis is caused by fungi of the order Mucorales, including Rhizopus, Absidia, and Mucor. Mucorales are ubiquitous saprophytes found in the soil and on decaying organic material, including bread and fruit. Human infection is believed to be caused by the inhalation of spores that initially land on the oral and nasal mucosa. Direct inoculation into tissues, however, has been reported.

Most of the spores, once in the tissue, are contained by the phagocytic response. If this fails, as it often does in patients with diabetes mellitus and those otherwise immunosuppressed, germination begins and hyphae develop. The hyphae, as shown in the micrograph, are large, nonseptate, rectangular, and branch at right angles. Infection begins with the invasion of blood vessels, which causes necrosis and dissemination of the infection. The most common site of involvement is the rhino-orbital-cerebral area, accounting for approximately 70% of cases; however, pulmonary, cutaneous, gastrointestinal, and disseminated infection may be seen. The chest radiograph during pulmonary infections may show an infiltrate, nodule, cavitary lesion, or pleural effusion. Gastric involvement may range from colonization of peptic ulcers to infiltrative disease with vascular invasion causing perforation. Although classic for mucormycosis, a black eschar of the skin, nasal mucosa, or palate is present in only about 20% of patients early in the course of the disease and cannot be relied on for assistance in early diagnosis. Survival is dependent on early diagnosis. Diagnosis is by biopsy with classic histologic findings and by culture of tissue. Treatment includes amphotericin B, surgical removal of the lesion, packing of the sinus areas with amphotericin B–soaked packs, and perhaps hyperbaric oxygen. Liposomal amphotericin B has also been effective. Treatment must include both surgery and amphotericin B.

Condyloma Acuminata

A FIGURE 10-65 Condyloma acuminata (anogenital/venereal warts) are caused by infection with human papillomavirus 6 or 11. In transplant recipients they may become extremely extensive. Treatment has included fluorouracil, podophyllin, podophyllotoxin, intralesional interferon, topical interferon, systemic interferon, and, more recently, imiquimod, which causes the induction of cytokines, especially

B interferon alpha. Lesions have responded in 50% of nontransplant patients receiving the 5% cream. Invasive treatments have included surgical excision, cryotherapy, electrocautery, and carbon dioxide laser. Recurrences are common. A, Condyloma acuminata in a male transplant recipient. B, Condyloma acuminata in a female transplant recipient.

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Transplantation as Treatment of End-Stage Renal Disease

Verruca Vulgaris

A

C

B FIGURE 10-66 Verruca vulgaris (common warts) are caused by human papillomaviruses 1, 2, 3, 4, 5, 8, 11, 16, and 18, as well as others, with the highest percentage by type 4. Warts are found most often on the fingers, arms, elbows, and knees and are much more numerous in the immunosuppressed patient. Treatment modalities have been the same as for condyloma acuminata, with the addition of topical cidofovir and hyperthermia. Therapy should be planned based on the location, extent, and size of the lesions. Not all lesions need treatment. Early dermatologic referral is needed for those lesions that appear to be advancing rapidly as certain papilloma viruses (16, 18, 31, 51, 52, 56) have been associated with squamous cell carcinomas of the skin and cervix. A and B, Verruca vulgaris of the finger and knee. Note the large size and multiple warts. C, Verruca planae, flat warts at multiple locations of the hand, also often seen on the face.

Post-transplant Infections

10.35

Molluscum Contagiosum

A

C

B

FIGURE 10-67 Molluscum contagiosum is an infection of the skin caused by the molluscum contagiosum virus, a member of the pox virus family. Molluscum does not grow in culture or infected laboratory animals. Manifestations are pearly, pink, dome-shaped, glistening, firm lesions; in immunosuppressed patients, however, they may be over 1 cm in diameter and multiple lesions may occur together. The infection usually lasts up to 2 months in immunocompetent patients, but a chronic, recalcitrant, and disfiguring infection may occur in immunosuppressed patients. The virus is contracted and spreads via close contact with an infected person, fomites, or via autoinoculation. The incubation period is 2 weeks to 6 months. The diagnosis is made visually or by direct examination of curettings from the center of the lesion showing molluscum intracytoplasmic inclusion bodies. Treatment is started for the prevention of spreading, to relieve symptoms, and for cosmetic reasons. Treatment includes cryotherapy, curettage, podophyllin, cantharidin, trichloroacetic acid, phenol, salicylic acid, strong iodine solutions, lactic acid, tretinoin, silver nitrate, and interferon alpha topical or intralesional, and possibly oral cimetidine, with adhesive tape occlusion. None of the available treatments result in a rapid or definite clearance in the immunosuppressed patient. Treatment of the underlying retrovirus infection has been shown to help in AIDS patients, and perhaps reviewing the degree of immunosuppression in the transplant patient will help. A, Molluscum contagiosum papule. Note pearly umbilicaled appearance. B, Histologic slide of molluscum showing a cross section of the papule. C, Close-up view of the molluscum bodies.

10.36

Transplantation as Treatment of End-Stage Renal Disease

Intestinal Protozoa SIMILARITIES AMONG THE INTESTINAL SPORE-FORMING PROTOZOA History Identified as human pathogens in recent decades Once considered rare pathogens; now known to commonly cause infections The AIDS epidemic increased awareness and recognition Biology Protozoa Intracellular location in epithelial cells of the intestine Spore or oocyst form is shed in stool Pathogenesis of diarrhea Unknown; possible abnormalities of absorption, secretion, and motility Intense infection of small bowel associated with dense inflammatory infiltrate May be associated with villus blunting and crypt hyperplasia Nonulcerative and noninvasive* Gut function and morphology related to number of organisms† Epidemiology Common in tropical regions and places with poor sanitation Transmission is through fecal-oral route, person-to-person contact, and water or food† Endemic disease of children‡ Common source of epidemics in institutions and communities‡ May cause traveler’s diarrhea

Clinical manifestations Asymptomatic infection Self-limited diarrhea, nausea, and abdominal discomfort in healthy children and adults Prolonged (subacute) diarrhea in some immunocompetent patients‡ Chronic diarrhea in immunodeficient patients Diagnosis Microscopic stool examination should be initial approach Detection of cysts or spores in stool requires expertise and proper stains Antibiotic treatment Not usually indicated in healthy persons with acute infection Indicated for chronic infection in immunodeficient patients‡

*Septata intestinalis may invade the mucosa. †Probably true for all; conclusively shown only for cryptosporidia. ‡Not proven for microsporidia.

FIGURE 10-68 Cryptosporidia, Isospora, cyclospora, and microsporidia are intestinal spore-forming protozoa that infect enterocytes predominately of the small intestine. Infection occurs by ingesting the spores (oocytes) by person-to-person contact or ingesting contaminated food or water, including city or swimming pool water [32]. Infections in immunocompetent individuals may be asymptomatic or self-limited and associated with mild to moderate diarrhea and, less frequently, nausea, abdominal cramping, vomiting, and fever.

In immunodeficient patients, especially those with T-cell impairment, the infections may cause severe persistent diarrhea. The most common infection among the intestinal protozoas is cryptosporidium. The general prevalence of cryptosporidia in stool specimens in Europe and North America is 1% to 3%, and in Asia and Africa is 5% to 10%. Antibodies to cryptosporidia, however, have been found in 32% to 58% of adults. (Adapted from Goodgame [33]; with permission.)

Post-transplant Infections

10.37

Histoplasmosis

FIGURE 10-69 Histoplasmosis is caused by the thermal dimorphic fungus Histoplasma capsulatum that exists in its mycelial phase in nature and in the yeast form in the human body. It is found in the soil enriched with bird or bat droppings in the Ohio and Mississippi River Valleys and in Texas, Virginia, Delaware, and Maryland. Disease is caused by primary infection or by reactivation of latent infection. Primary infection is acquired by inhalation of infectious microconidia, by direct inoculation into the skin, or via an infected allograft. Once the microconidia is lodged in the alveolar and

interstitial spaces, it becomes a yeast, multiplies intracellularly, and disseminates until cell-mediated immunity develops (2 to 10 weeks). Organisms that disseminate concentrate in the reticuloendothelial system. Disseminated disease is marked by fever, weight loss, weakness, fatigue, and mild respiratory symptoms. There may also be organ-specific symptoms, including those of urinary tract obstruction. Histoplasma may be found in the glomerular capillary macrophages or macrophages within the interstitium and be associated with focal medullary necrosis or papillary necrosis. The most common symptom of infection is fever, and often there are skin lesions, as shown in this figure, but central nervous system involvement is rare in transplant patients, as are abnormal chest radiographs. When present, chest radiographic findings include diffuse, nodular, patchy, or miliary infiltrates; hilar adenopathy is uncommon. Diagnosis is made by identification of the yeast on a smear, histopathologic detection of intracellular organisms in viable pulmonary tissue, a fourfold rise in antibody titers (only seen in about 50% of immunosuppressed patients), culture of the blood or tissue, or a urine antigen assay. Identification of the organism causing culture growth of a white, fuzzy mold (Histoplasma, Blastomyces, Coccidioides) is now performed by DNA hybridization. The bone marrow may be the most reliable source for sampling and staining for organisms. Treatment is amphotericin B occasionally, with long-term oral intraconazole after completing amphotericin. Resolution of infection may be monitored by following the Histoplasma urinary antigen.

Cryptococcosis

FIGURE 10-70 Cutaneous cryptococcosis, multiple lesions on the arm. Cryptococcus neoformans is an encapsulated yeast that exists worldwide, predominately in the soil contaminated by bird and other animal droppings. Infection is through inhalation with dissemination to the central nervous system (CNS), skin, mucous membranes, bone, bone marrow, and genitourinary tract. Infection has also occurred through the renal allograft. The most common disease site is the

CNS, where patients present with headache, fever, mental confusion, seizures, papilledema, long tract signs, or, uncommonly, meningismus. The onset of infection is anywhere from 6 months to years following transplantation. The onset may be very insidious, with nausea and headache occurring for weeks to months before the fever develops. Pulmonary involvement presents asymptomatically or with dyspnea and cough. The chest radiograph shows wide variability in that circumscribed pulmonary nodules, alveolar infiltrates, interstitial infiltrates with or without effusions, and cavitation may be seen. Cutaneous disease may be the first sign of dissemination in up to 30% of cases. Diagnosis is made by the identification of the yeast in the cerebrospinal fluid (CSF) or pulmonary secretions, the detection of cryptococcal antigen in the CSF or blood, or culture. Amphotericin B is the most common agent used for treatment, with some also favoring the use of flucytosine and perhaps azole therapy for maintenance to prevent relapse. Specific patients may be treated with fluconazole alone. Serial determinations of the serum cryptococcal antigen, which is positive in over 95% of patients with cryptococcal meningitis, may help to follow and modify the course of therapy. Patients should be treated until the cryptococcal antigen is negative, and then for another 2 to 4 weeks for added safety.

10.38

Transplantation as Treatment of End-Stage Renal Disease

Herpes Simplex FIGURE 10-71 (see Color Plate) Primary oral herpes simplex, mucosal membrane showing vesicles and ulceration.

FIGURE 10-72 (see Color Plate) Primary herpes simplex stomatitis.

FIGURE 10-73 Cutaneous herpes simplex–herpetic whitlow. This condition may be confused with a bacterial infection.

Post-transplant Infections

10.39

Central Nervous System Infections CEREBROSPINAL FLUID FINDINGS BY TYPE OF MENINGITIS Type Viral Fungal Tuberculous Bacterial

WBC Count (per mm)

Differential, %

Protein Level, mg/dL

Glucose level, mg/dL

Stain used

5.–500 40–400 100–1000 400–100,000

>50 lymphocytes >50 lymphocytes >80 lymphocytes >90 PMNs

30–150 40–150 40–150 (may exceed 400) 80–500

Normal to low Normal Normal to low <35

Gram’s India ink and cryptococcal antigen Acid-fast Gram’s

FIGURE 10-74 Cerebrospinal fluid findings in patients with bacterial meningitis. (Adapted from Maxon and Jacobs [34]; with permission.)

References 1. Rubin RH, Wolfson JS, Cosimi AB, et al.: Infection in the renal transplant recipient. Am J Med 1981, 70:405–411. 2. Rubin RH: Infectious disease complications of renal transplantation. Kidney Int 1993, 44:221–236. 3. Stratta R: International Congress on Immunosuppression, Orlando, FL, 1998. 4. Isada CM, Kastan BL, Goldman MD, et al.: Infectious Disease Handbook, edn. 2. Lexi Comp, Inc., 1997–1998. 5. Maguire GP, Wormser GP: Preventing infections in the immunocompromised: Part 2. Journal of Respiratory Diseases 1994, 15:408. 6. Lake KD: Management of drug interactions with cyclosporine. Pharmacotherapy 1991, 11:110S–118S. 7. Yee GC: Pharmacokinetic interactions between cyclosporine and other drugs. Transplant Proc 1990, 22:1203–1207. 8. Drugs for tuberculosis [letter]. Med Lett Drugs Ther 1992, 24:10–12. 9. Fishman JA: Pneumocystis carinii and parasitic infections in transplantation. Infect Dis Clin North Am 1995, 9:1005–1044. 10. Hadley S, Karchmer AW: Fungal infections in solid organ transplant recipients. Infect Dis Clin 1995, 19:1045–1074. 11. Harnett JD, Zeldis JB, Parfrey PS, et al.: Hepatitis B disease in dialysis and transplant patients: further epidemiologic and serologic studies. Transplantation 1987, 44:369. 12. Pirson Y, Alexandre GPJ, van Ypersele de Strihou C: Long-term effect of HBs antigenemia on patient survival after renal transplantation. N Engl J Med 1977, 296:194–196. 13. Hillis WD, Hillis A, Walker WG: Hepatitis B surface antigenemia in renal transplant recipients: increased mortality risk. JAMA 1979, 242:329. 14. Touraine JL, Traeger J: Renal TX at the University of Lyon. Clin Transpl 1989, 5:229–238. 15. Dhar JM, Al-Khader AA, Al-Sulaiman MH, Al-Hasani MK: The significance and implications of hepatitis B infection in renal transplant recipients. Transplant Proc 1991, 23:1785-1786. 16. Roy DM, Thomas PP, Dakshinamurthy KV, et al.: Long-term survival in living related donor renal allograft recipients with hepatitis B infection. Transplantation 1994, 58:118–119.

17. Pfaff WW, Blanton JW: Hepatitis antigenemia and survival after renal transplantation. Clin Transplant 1997, 11:476–479. 18. Fornairon S, Pol S, Legendre C, et al.: The longterm virologic and pathologic impact of renal transplantation on chronic hepatitis B virus infection. Transplantation 1996, 62:297–299. 19. Pouteil-Noble C, Tardy JC, Chossegros P, et al.: Co-infection by hepatitis B virus and hepatitis C virus in renal transplantation: morbidity and mortality in 1098 patients. Nephrol Dial Transplant 1995, 10 (suppl 6):122–124. 20. Knoll GA, Tankersley MR, Lee JY, et al.: The impact of renal transplantation on survival in hepatitis C–positive end-stage renal disease patients. Am J Kidney Dis 1997, 29:608–614. 21. Thervet E, Pol S, Legendre C, et al.: Low-dose recombinant leukocyte interferon-a treatment of hepatitis C–positive end-stage renal disease patients: a pilot study. Transplantation 1994, 58:625–627. 22. Magnone M, Holley JL, Shapiro R, et al.: Interferon-a-induced acute renal allograft rejection. Transplantation 1995, 59:1068–1070. 23. Rostaing L, Izopet J, Baron E, et al.: Treatment of chronic hepatitis C with recombinant interferon alpha in kidney transplant recipients. Transplantation 1995, 59:1426–1431. 24. Rostaing L, Modesto A, Baron E, et al.: Acute renal failure in kidney transplant patients treated with interferon alpha 2b for chronic hepatitis C. Nephron 1996, 74:512–516. 25. Yasumura T, Nakajima H, Hamashima T, et al.: Long-term outcome of recombinant INF-a treatment of chronic hepatitis C in kidney transplant recipients. Transplant Proc 1997, 29:784–786. 26. Dussol B, Charrel R, De Lamballerie X, et al.: Prevalence of hepatitis G virus infection in Kidney transplant recipients. Transplantation 1997, 64:537–539. 27. Murthy BVR, Muerhoff AS, Desai SM, et al: Impact of pretransplantation GB virus C infection on the outcome of renal transplantation. J Am Soc Nephrol 1997, 8:1164–1173. 28. Fabrizi F, Lunghi G, Bacchini G, et al.: Hepatitis G virus infection in chronic dialysis patients and kidney transplant recipients. Nephrol Dial Transplant 1997, 12:1645–1651.

10.40

Transplantation as Treatment of End-Stage Renal Disease

29. Histopathological impacts of hepatitis virus infection in hemodialysis patients: Should liver biopsy be performed before renal transplantation? Artif Organs 1997, 21:355–358. 30. Schwartz A, Offermann G, Keller F, et al.: The effect of cyclosporine on the progression of human immunodeficiency virus type 1 infection transmitted by transplantation: data on four cases and review of the literature. Transplantation 1993, 55:99-103. 31. Friedman-Kien AE: Cutaneous manifestations. In Atlas of Infectious Diseases, vol 1 (edn 2): AIDS. Philadelphia: Current Medicine; 1997:5.1–5.18.32.

32. Lemon JM, McAnulty JM, Bawden-Smith J: Outbreak of cryptosporidiosis linked to an indoor swimming pool. Med J Aust 1996, 165:613–616. 33. Goodgame RW: Understanding intestinal spore-forming protozoa: cryptosporidia, microsporidia, isosporidia, and cyclospora. Ann Intern Med 1996, 124:429–441. 34. Maxson S, Jacobs: Viral meningitis: tips to rapidly diagnose treatable causes. Postgrad Med 1993, 93:153–166.

Immunosuppressive Therapy and Protocols Angelo M. de Mattos

T

he 1990s have seen major steps in the dissection of basic mechanisms of allorecognition, and renal graft survival has achieved unprecedented clinical results. Transplantation has turned into a widespread modality of therapy for patients with chronic renal failure that benefits thousands worldwide. Combinations of immunosuppressive agents have proved to be an effective strategy to inhibit diverse pathways of the multifaceted immune system, allowing the reduction of both dosage and adverse effects of each individual drug. As understanding of the molecular basis of the immune response has expanded rapidly, so have the possibilities for designing therapeutic interventions that are more effective, more specific, and safer than are current treatment options. As we reach the end of the century, several different and innovative approaches will add to this fascinating and complex therapy.

CHAPTER

11

11.2

Transplantation as Treatment of End-Stage Renal Disease

Ca

Tac/FK-BP

Csa/Cyp Calcineurin

IL-2

X P NF-ATc

RNA

NF-AT box DNA

FIGURE 11-1 Mechanism of action for cyclosporine (Csa) and tacrolimus (Tac). The common cytoplasmic target for cyclosporine and tacrolimus is calcineurin. After binding to cyclophillin (Cyp), cyclosporine interacts with calcineurin, inhibiting its catalytic domain. Thus dephosphorylation of transcription factors is prevented, as exemplified by the nuclear factor of activated T lymphocyte (NF-AT). Despite having a different ligand called FK-binding protein (FK-BP), tacrolimus inhibits calcineurin in a similar way. Because phosphorylated transcription factors cannot cross the nuclear membrane, the production of key factors for lymphocyte activation and proliferation (ie, interleukin-2, tumor necrosis factor-,  interferon, c-myc, and others) is inhibited [1]. NF-ATc—nuclear factor of activated T-lymphocytecytoplasmic form; P—phosphorus; Ca—calcium.

DNA

IL-2 IL-2 receptor p

p

m-TOR

PHAS-1 PHAS-1 eIF-4F

Rapa/FKBP

G1 S G0 M

G2

FIGURE 11-2 Proposed mechanism of action for rapamycin (rapa). Rapamycin binds to FK-binding protein (FK-BP). However, the immunosuppressive properties of rapamycin are not due to inhibition of calcineurin. Rapamycin blocks the activating signal delivered by growth factors (exemplified by the interleukin-2 [IL-2] receptor) by blocking the translation of the coding of messenger RNA (mRNA) for key proteins required for progression through the G1 phase of the cell cycle. In this model the mammalian target of rapamycin (m-TOR, also called FRAP or RAFT1), phosphorylates the translational repressor PHAS-I. Arrest of the cell cycle results, and the proliferation of lymphocytes is thereby inhibited. The full understanding of the mechanism(s) of action of rapamycin is the focus of intense research at this time [2]. elF-4—translation initiation factor belonging to the Ets family; G(0,1, and 2)—quiescent; M—mitosis; S—synthesis.

Immunosuppressive Therapy and Protocols

Azathioprine PRPP HGPRT

TIMP

6-MP

6-m-MP Allopurinol

Thiouric acid HGPRT

IMP

Mycophenolate, mizoribine

D IMP

PRPP + Adenine

AMP

GMP

ATP

GTP

Energy

Hypoxanthine + PRPP

RNA, DNA

Csa or FK-506

HGPRT

Guanine + PRPP

Energy, signaling

Glycoproteins

}

Monotherapy

}

Dual therapy

}

Triple therapy

Csa or FK-506 Steroid Csa or FK-506 Aza or MMF Csa or FK-506 Steroid Aza or MMF Antilymphocytic Csa or FK-506 Steroid Aza or MMF

}

Antilymphocytic

Quadruple therapy (induction versus sequential)

Csa or FK-506 Steroid Aza or MMF

1 week

1 month

11.3

FIGURE 11-3 Mechanism of immunosuppression of azathioprine and mycophenolate mofetil (MMF). Azathioprine and MMF prevent lymphocyte proliferation by way of inhibition of purine base synthesis, thus resulting in decreased production of the building blocks of nucleic acids (ie, DNA and RNA). Azathioprine is metabolized to 6-mercaptopurine (6-MP), which is further converted to 6-ionosine monophosphate. This molecule inhibits key enzymes in the de novo pathway of purine synthesis (adenosine monophosphate [AMP] and guanosine monophosphate [GMP]). MMF is metabolized to mycophenolic acid, which is a noncompetitive inhibitor of the enzyme that converts inosine monophosphate (IMP) to GMP. The depletion of GMP may have effects other than inhibition of nucleic acid production. Some events of T-lymphocyte activation are independent of guanosine triphosphate (GTP), as is the assembling of certain adhesion molecules. ATP—adenosine triphosphate; HGPRT—hypoxanthine-guanine phosphoribosyl transferase; IMPD— inosine-monophosphate dehydrogenase; PRPP—phosphoribosyl pyrophosphate; 6-m-MP—6-methyl-mercaptopurine; TIMP— thioinosine monophosphate. (Adapted from de Mattos and coworkers [3,4].)

FIGURE 11-4 Summary of strategies for combining immunosuppressive agents. Currently, monotherapy (usually cyclosporine [Csa]) is not used in the United States. Dual therapy (involving cyclosporine or tacrolimus) is used commonly in Europe. Most centers in the United States use triple or quadruple therapy (induction or sequential). Some centers continue the induction with the antilymphocytic biologic agent for a predetermined period (usually 10–14 days), overlapping with the initiation of cyclosporine (or tacrolimus). Alternatively, the biologic agent is discontinued and cyclosporine (or tacrolimus) begun as soon as the graft function reaches a determined threshold, resulting in no overlap of these two agents. In living donor transplants, azathioprine (Aza) is commonly begun a few days before surgery. [5]. FK-506— tacrolimus; MMF—mycophenolate mofetil.

11.4

A

Transplantation as Treatment of End-Stage Renal Disease

Murine Monoclonal antibody

B

Muromonab OKT3 Anti-Tac SDZ-CHIB T10B9 BMA 031 WT 32 Anti-ICAM 1 33B3-1

Humanized-chimeric

Humanized-grafted

Type

Target

Murine Murine Murine/Human Murine Murine Murine Murine Rat

FIGURE 11-5 Evolution of monoclonal antilymphocytic antibodies. Monoclonal antibodies are the result of complex genetic engineering techniques. A, Differences among murine, chimeric, and “humanized” antibodies. Attempts to reduce side effects, improve efficacy, and decrease xenosensitization are the main reasons for development of these modifications on the murine molecule. B, The different monoclonal antibodies, their classification regarding the molecular structure, and their targets. Muromonab OKT3 (Ortho Pharmaceutical, Raritan, NJ) is the only monoclonal antibody commercially available at this time [6]. CD3— monomorphic membrane co-receptor present in T-lymphocytes; IL-2R—interleukin-2R; TCR—T-cell receptor.

CD3 IL-2R (CD25) IL-2R (CD25) TCR TCR CD3 CD54 IL-2R (CD25)

FIGURE 11-6 Experimental model of the vasoconstrictive effect of cyclosporine. Some of the acute nephrotoxicity of cyclosporine is due to the significant yet reversible vasoconstrictive effect of the drug. A, Scanning electron micrograph of glomerulus of a rat not exposed to cyclosporine. Arrow indicates glomerular capillary loop. AA—afferent artery. B, After 14 days of cyclosporine treatment, the entire length of an afferent arteriole shows narrowing (magnification  500). Arrow indicates afferent artery. (From English and coworkers [7]; with permission.)

A

B

Immunosuppressive Therapy and Protocols

11.5

AGENTS USED IN RENAL TRANSPLANTATION Drug

Dosage

Adverse reactions

Cost

Cyclosporine Sandimmune (Sandoz Pharmaceuticals, East Hanover, NJ) Neoral (Sandoz Pharmaceuticals, East Hanover, NJ)

Starting dose: 7–10 mg/kg/d in 2 divided doses Maintenance: based on blood levels Starting dose: 7–10 mg/kg/d in 2 divided doses Maintenance: based on blood levels IV Csa equals one third of oral Csa; IV cyclosporine is given by continuous infusion over 24 h Starting and maintenance dose: 1–3 mg/kg/d; IV dose equals half of oral dose Decrease dose by half for 50% decrease in leukocyte count Hold dose for leukocyte count of <3000

Nephrotoxicity, hypertension, gingival overgrowth, hirsutism, hepatotoxicity, neurotoxicity, hypomagnesia, hyperkalemia Same

Gelcaps: $1.61/25 mg; $6.42/100 mg Liquid: $6.41/100 mg, orally Gelcaps: $1.44/25 mg; $5.77/100 mg Liquid: $6.38/100 mg, orally $113.32/100 mg, IV

Leukopenia, anemia, thrombocytopenia, hepatitis, pancreatitis, alopecia, skin cancer, aplastic anemia (rare)

$1.29/50-mg tablet $101.18/100-mg vial, IV

Azathioprine Imuran (Glaxo Wellcome, Research Triangle Park, NC) Azathioprine (Roxane Laboratories, Columbus, OH) Azathioprine sodium (injectable) (Bedford Laboratories, Bedford, OH) OKT3 (Ortho Pharmaceutical, Raritan, NJ) Muromonab-cd3

Antithymocyte globulin Atgam (Upjohn Co, Kalamazoo, MI) Prednisone (various manufacturers) Deltasone (Upjohn Co, Kalamazoo, MI) FK-506, tacrolimus Prograf (Fujisawa USA, Inc, Deerfield, IL)

Mycophenolate mofetil CellCept (Roche Laboratories, Nutley, NJ) Daclizumab (Roche Laboratories, Nutley, NJ) Simulect (Novartis Pharmaceuticals Inc., East Hanover, NJ)

$1.16/50-mg tablet $81.60/100-mg vial, IV

Induction: 2 mg/d (low-dose) 5 mg/d (standard) Rejection treatment: 5 mg/d Hold (delay) dose for weight gain >3% or temperature >39°C Increase dose based on CD3+ cell count and CD3 density (suggested) Discontinue if anti-OKT3 antibody titer >1:1000 Starting dose: 15–30 mg/kg/d Decrease (or hold) dose for leukocytes <3000 or platelets <100,000 Starting dose: 500 to 1000-mg infusion for 3–5 d Maintenance: taper schedule (variable)

Starting dose: 0.15–0.3 mg/kg/d in 2 divided doses Avoid IV (0.05–0.1 mg/kg/d as a continuous infusion over 24 h) Maintenance: based on blood levels Starting dose: 2–3 g/d orally in 2 divided doses (IV preparation in clinical trials) Maintenance: based on GI and bone marrow toxicities 1 mg/kg/d every 2 wk for a total of 5 doses 20 mg/d, given on days 0 and 4 post transplant

Cytokine release syndrome: fever, chills, chest pain, dyspnea, wheezing, noncardiogenic pulmonary edema, nausea, vomiting, diarrhea, headache, aseptic meningitis, seizures, skin rash

$672.00/5-mg vial

Leukopenia, thrombocytopenia, fever, chills, skin rash, back pain, headache, nausea, vomiting, diarrhea, horse serum sickness Fat redistribution, increased appetite, weight gain, hyperlipidemia, hypertension, peripheral edema, hyperglycemia, skin atrophy, poor healing, acne, night sweats, insomnia, mood changes, blurred vision, cataracts glaucoma, osteoporosis Nephrotoxicity, hypertension, hepatotoxicity, pancreatitis, diabetes, seizures, headache, insomnia, tremor, paresthesia

$262.24/250-mg vial

$0.02–$0.05/5-mg tablet Methylprednisolone, IV $17.88–$35.50/500-mg vial

$2.39/1-mg caplet $11.97/5-mg caplet $222.00/5-mg ampule, IV

Nausea, vomiting, diarrhea, leukopenia, anemia, thrombocytopenia

$2.04/250-mg caplet $4.08/500-mg tablet $102.00/500-mg, IV

Reported same as placebo

$418.20/25 mg, IV

Reported same as placebo

$1224.00/20mg, IV

Cost to the pharmacist based on the average wholesale price listing in Red Book, 1997 [8]. CD3—monomorphic membrane co-receptor present in T-lymphocytes; Csa—cyclosporine; GI—gastrointestinal. Adapted from de Mattos and coworkers [3,4].

FIGURE 11-7 A summary of the immunosuppressive agents currently used in human renal transplantation is given. Dosages and costs are subject to local variation.

11.6

Transplantation as Treatment of End-Stage Renal Disease

CLINICALLY RELEVANT DRUG INTERACTIONS WITH IMMUNOSUPPRESSIVE DRUGS Drug Cyclosporin A and tacrolimus Diltiazem Nicardipine Verapamil Erythromycin Clarithromycin Ketoconazole Fluconazole Itraconazole Methylprednisolone (high dose only) Carbamazepine Phenobarbital Phenytoin Rifampin Aminoglycosides Amphotericin B Cimetidine Lovastatin Azathioprine Allopurinol Warfarin ACE inhibitors Mycophenolate mofetil Acyclovir-ganciclovir (high doses only) Antiacids Cholestyramine

Effect

Mechanism

Increased blood levels

Decreased metabolism (inhibition of cytochrome P-450-IIIA 4)

Increased blood levels

Decreased metabolism (inhibition of cytochrome P-450-IIIA 4)

Increased blood levels

Decreased metabolism (inhibition of cytochrome P-450-IIIA 4)

Increased blood levels Decreased blood levels

Unknown Increased metabolism (inhibition of cytochrome P-450-IIIA 4)

Increased renal dysfunction

Additive nephrotoxicity

Increased serum creatinine Decreased metabolism

Competition for tubular secretion Myositis, increased creatine phosphokinase, rhabdomyolysis

Increased bone marrow toxicity Decreased anticoagulation effect Increased bone marrow toxicity

Inhibiting xantine oxidase Increased prothrombin synthesis or activity Not established

Increased levels of acyclovir-ganciclovir and mycophenolate mofetil Decreased absorption Decreased absorption

Competition for tubular secretion Binding to mycophenolate mofetil Interferes with enterohepatic circulation

ACE—angiotensin-converting enzyme. Adapted from de Mattos and coworkers [3,4].

FIGURE 11-8 Clinical relevant drug interactions with immunosuppressive agents. Close monitoring of drug levels is required periodically with concomitant use of drugs with potential interaction. Drug level monitoring is

clinically available for cyclosporin A and tacrolimus. Monitoring of non-immunosuppressive drug level is also important when used with potential interacting immunosuppressive agents.

Immunosuppressive Therapy and Protocols

NEW IMMUNOSUPPRESSIVE AGENTS UNDERGOING CLINICAL TRIALS Agent

Mechanism of action

Rapamycin Leflunomide

Inhibition of cytokine action (downstream of interleukin-2 receptor and other growth factors) Inhibition of cytokine action (expression of or signaling by way of interleukin-2 receptor) Inhibition of DNA and RNA synthesis (pyrimidine pathway) Inhibition of DNA and RNA synthesis (pyrimidine pathway) Unknown (related to heat-shock proteins?) Unknown (stimulation of suppressor cells?) Inhibition of DNA and RNA synthesis (de novo purine pathway) Blockage of T-cell co-stimulatory pathway

Brequinar Deoxyspergualin SKF-105685 Mizoribine CTLA-4Ig

11.7

FIGURE 11-9 Proposed mechanisms of action of new immunosuppressive drugs currently undergoing clinical or preclinical trials in organ transplantation [9].

Acknowledgments The author would like to thank Ali Olyaei, Pharm D., for his assistance with the preparation of this manuscript.

References 1.

Clipstone NA, Crabtree GR: Calcineurin is the key signaling enzyme in T lymphocyte activation and the target of the immunosuppressive drug.Ann NY Acad Sci USA 1993, 696:20–30.

6.

2.

Brunn GJ, Hudson CC, Sekulic A, et al.: Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin.Science 1997, 277:99–101.

7.

3.

de Mattos AM, Olyaei AJ, Bennet WM: Pharmacology of immunosuppressive medications used in renal diseases and transplantation.Am J Kid Dis 1996, 28:631–637.

8.

4.

de Mattos AM, Olyaei AJ, Bennet WM: Mechanism and risks of immunosuppressive therapy. In Immunologic Renal Disease. Edited by Neilson EG, Couser WG. Philadelphia: Lippincott-Raven; 1996:861–885.

5.

9.

Barry JM: Immunosuppressive drugs in renal transplantation: a review of the regimens. Drug 1992, 44:554–566. Powelson JA, Cosimi AB: Antilymphocyte globulin and monoclonal antibodies. In Kidney Transplantation: Principles and Practice, edn 4. Edited by Morris PJ. Philadelphia: WB Saunders Co; 1994. English J, Evan A, Houghton DC, Bennett WM: Cyclosporineinduced acute renal dysfunction in the rat.Transplantation 1987, 44:135–141. Red Book: Drug Topics®. Montvale, NJ: Medical Economics Company, Inc., 1998. First MR: An update on new immunosuppressive drugs undergoing preclinical and clinical trials: potential applications in organ transplantation.Am J Kid Dis1997, 29:303–317.

Evaluation of Prospective Donors and Recipients Bertram L. Kasiske

A

ll patients should be considered for transplantation when it is determined that renal replacement therapy will someday be required. In some cases, the evaluation can be completed and the patient can receive transplantation before initiating chronic maintenance dialysis. Prospective candidates for transplantation must be carefully screened for potentially fatal cancers and infections that are made worse by immunosuppression. Hepatic, pulmonary, cardiovascular, and gastrointestinal disorders all may increase the risks of surgery and chronic immunosuppression. Patients must be carefully screened for these disorders. In many cases, intervention before transplantation may help reduce the recipient’s risks of transplantation. Detailed guidelines have been established to evaluate prospective candidates for transplantation [1]. Living donors offer the recipient optimal graft survival, reduced waiting time, and an opportunity for preemptive transplantation (ie, before initiating dialysis). The evaluation of prospective living donors must ensure that the donation is safe for both donor and recipient. However, the primary focus of this evaluation must always be on protecting the well-being of the prospective donor. Both the short-term surgical risks and the long-term risks of having a single kidney must be carefully defined. The evaluation also must ensure the donor has no disease that could be transmitted with the kidney. Guidelines have been developed for the evaluation of living prospective donors [2]. When no suitable living donors are available, the prospective recipient can be placed on the waiting list for a cadaveric kidney. Unfortunately, because the number of patients needing cadaveric kidneys has grown much faster than has the number of available kidneys, the median waiting time is now over 2 years. This shortage has led many transplantation centers to use cadaveric kidneys, which are associated with reduced graft survival. In particular, graft survival is affected by the age of the kidney donor. Many centers are expanding the age limits of acceptability to reduce waiting times. A detailed discussion of the selection, retrieval, preservation, and allocation of cadaveric kidneys is beyond the scope of this review.

CHAPTER

12

12.2

Transplantation as Treatment of End-Stage Renal Disease

Evaluation of Prospective Transplantation Recipients Initial evaluation of recipients Irreversible renal failure

Currently on dialysis?

Monitor rate GFR decline

No

Yes Dialysis likely in 6 months?

No

Yes Prospective living donor?

FIGURE 12-1 Initiating the evaluation. Before transplantation it must be clearly established that renal failure in the patient is irreversible. When the prospective recipient is not already on chronic maintenance dialysis, however, preemptive transplantation (ie, transplantation before initiating dialysis) should be considered. Because the waiting time for a cadaveric kidney is generally long, preemptive transplantation usually is possible only when a prospective living donor is available. In any case, the rate of decline in the glomerular filtration rate (GFR) must be monitored closely in patients with progressive renal disease. The evaluation process should begin when it is anticipated that transplantation may be required within 6 months. (From Kasiske and coworkers. [1]; with permission.)

Yes

No Evaluate prospective living donor

Evaluate potential recipient

Cancer screening in recipients Screen for cancer

Current or past evidence of cancer?

Yes

No Appropriate disease-free interval?

Proceed with evaluation

FIGURE 12-2 Screening for cancer. An active malignancy is an absolute contraindication to transplantation. Effective screening measures for patients at risk include chest radiograph, mammogram, PAP test, stool Hemoccult, digital rectal examination, and flexible sigmoidoscopy examination. Patients who have had a life-threatening malignancy but are potentially cured may be candidates for transplantation when there has been an appropriate disease-free interval. This interval generally is at least 2 years, and longer in the case of some malignancies. (From Kasiske and coworkers [1].)

12.3

Evaluation of Prospective Donors and Recipients

Screening for infection in recipients Yes

Active infection?

100 90

Appropriate treatment and disease-free interval

80

No HIV positive?

Discourage transplantation

No History of TB or positive PPD without adequate therapy?

Yes

Consider prophylactic treatment

Graft survival, %

70 Yes

60 50 40 CMV r/d n/n n/p p/n p/p

30

No

20 Assess risk for other infections

n 4670 5970 7299 11,257

10 0

FIGURE 12-3 Screening for infection. An active potentially life-threatening infection is a contraindication to transplantation. Patients with human immunodeficiency virus (HIV) are usually not candidates for transplantation. Patients with a history of tuberculosis (TB) or a positive purified protein derivative (PPD) skin test who have not been adequately treated should generally receive prophylactic therapy. (From Kasiske and coworkers [1].)

Assessment for recurrent renal disease in recipients Renal disease with potential to recur? No

Yes

Wait until quiescent Yes

Risk acceptable? No

Proceed with evaluation

Avoid transplantation

0

1

2

3

4

5

Years after transplantation

FIGURE 12-4 Assessing the risks of cytomegalovirus (CMV) infection after transplantation. CMV is a major cause of morbidity and mortality after transplantation. The incidence and severity of CMV are associated with the serologic status of the donor (d) and recipient (r), the risks generally being the following: recipient negative–donor negative less than recipient positive–donor negative less than recipient negative– donor positive less than recipient positive–donor positive. As shown in these data from the United Network for Organ Sharing Scientific Registry, the rate of graft survival tends to be less in recipients of kidneys from donors who test positive for CMV infection. The serologic status of both the donor and recipient is often used to determine which patients are candidates for prophylactic or preemptive anti-CMV therapy after transplantation. (From Cecka [3]; with permission.)

FIGURE 12-5 Assessing the risk of renal disease recurrence. Although the risk for recurrence of the underlying renal disease is rarely great enough to preclude transplantation, patients and physicians must be aware of this risk. In some cases it may be prudent to delay transplantation until the underlying disease is quiescent. (From Kasiske and coworkers [1].)

12.4

Transplantation as Treatment of End-Stage Renal Disease

100 90

Cannot recur 411

Can recur in transplant organ 685

3072

31

80 1058

3-year graft survival, %

70

39 134

41

5421

HSP

Diabetes type II

101

60 50 40 30 20 10 0

Alport's syndrome

PKD

FSGS

MPGN

HUS

IgA

Scleroderma Oxalosis

Evaluation for liver disease in recipients Symptoms or enzymes suggesting liver disease?

Evaluation for viral hepatitis in recipients Consider cholecystectomy for gallstones

Yes

No

Yes

Discontinue

Toxic drug or alcohol No

Consider biopsy and treatment Measure HBsAg and HCV antibody

Yes

FIGURE 12-6 The influence of underlying renal disease on graft survival. As shown in these data from the United Network for Organ Sharing Scientific Registry, 3-year graft survival rates in groups of patients with different underlying causes of renal failure vary substantially. The 3-year graft survival rates for recipients with renal diseases that do not recur (eg, Alport’s syndrome and polycystic kidney disease [PKD] were about 80%. Graft survival rates for patients with diseases that may recur in the transplanted kidney varied from 60% to 83%. Of course, most of these differences in graft survival may be due to factors associated with the underlying cause of renal failure (eg, cardiovascular disease) and not disease recurrence itself. Focal segmental glomerulosclerosis (FSGS), hemolytic uremic syndrome (HUS), Henoch-Schönlein purpura (HSP), and hereditary oxalosis can cause graft failure relatively soon after transplantation. Membranoproliferative glomerulonephritis (MPGN), scleroderma, IgA nephropathy, and diabetes generally cause graft failure only after several years. Numbers above bars indicate number of patients who had that disease. (From Cecka [3]; with permission.)

Elevated TIBC or ferritin No

Positive HBeAg or HCV?

∆ Antibody or HBeAg?

Yes

Yes

No

No Yes

Elevated enzymes? No Elect Yes biopsy?

Severe disease on biopsy?

Yes

Consider avoiding transplantation

Yes

Acceptable risk?

No

No

No

FIGURE 12-7 Evaluation of patients with signs and symptoms of liver disease. Patients with cholecystitis should be considered for cholecystectomy. For other patients with signs and symptoms of liver disease, potential hepatic toxins should be considered. The incidence of liver disease from iron deposition has declined with the diminishing use of blood transfusions in dialysis patients, but may be seen occasionally in patients with a high total iron binding capacity (TIBC) or ferritin. All prospective candidates for transplantation must be screened for hepatitis B and C by testing for the presence of hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV) antibodies. Both viruses can cause potentially fatal liver disease after transplantation. Fortunately, the incidence of hepatitis B is declining among patients with renal disease, largely as a result of the use of effective vaccination programs. (From Kasiske and coworkers [1]; with permission.)

Proceed with evaluation

No

Moderate disease on biopsy?

FIGURE 12-8 Viral hepatitis. Patients whose test results are positive for  antibodies or hepatitis e-antigen (HBeAg) are at high risk for succumbing to liver disease and most likely are not candidates for transplantation. A liver biopsy should be considered for all patients with hepatitis C virus (HCV) antibodies or hepatitis B surface antigen. Patients with severe chronic active hepatitis or cirrhosis on biopsy generally are not candidates for renal transplantation unless simultaneous liver transplantation is being considered. Whether antiviral therapy before transplantation can increase the number of patients who are candidates for transplantation is unclear. (From Kasiske and coworkers [1]; with permission.)

12.5

Evaluation of Prospective Donors and Recipients 1.0

78

59

52

47

45

34

20

2

1.0

69

67

62

57

45

29

5

22

17

15

12

11

8

6

1

0.8 Patient survival, %

Graft survival, %

0.8

79

0.6 0.4

21

16

13

10

9

7

6

1

Relative risk: 1.27 (0.62, 2.60)

0.2

0.6 0.4

Relative risk: 3.33 (1.40, 7.93)

Anti–HCV positive Anti–HCV negative

0.2

Anti–HCV positive Anti–HCV negative

0

0 0

2

4

6

Years after transplantation

A

0

8

2

FIGURE 12-9 Effects of pretransplantation hepatitis C virus (HCV) serology results on survival of the graft (A) and patient (B). Numbers above (anti–HCV negative) and below (anti–HCV positive) survival curves indicate the number of patients at risk during that time interval. The relative risk after transplantation associated with the patient testing positive for HCV antibodies before

Past history of IHD?

Yes

Active angina?

Smoking cessation program

No

High risk for IHD?

Yes

Stress test positive? No

No Severe lung disease on function tests?

Yes

Risk factor intervention

Wait until adequate resolution with therapy

FIGURE 12-10 Lung disease. Few studies exist that address the effects of cigarette smoking on outcome after renal transplantation. Because the risks of transplantation surgery no doubt are increased by cigarette smoking, candidates for transplantation should be referred to smoking cessation programs. (From Kasiske and coworkers [1]; with permission.)

Yes

No Yes

Imaged coronary lesions severe? Yes Revascularization successful? No

No

Proceed with evaluation

Yes

No

No

No Yes

8

Evaluation of IHD in recipients

Yes

Currently smoking?

6

transplantation also is shown, along with 95% confidence intervals. Although no statistically significant effect of HCV on graft survival was seen, patient survival was significantly diminished among those who tested positive for HCV after transplantation. Not all investigators have confirmed these findings. (From Periera and coworkers [4]; with permission.)

Evaluation of effects of smoking in recipients Dyspnea on exertion or smoking history?

4 Years after transplantation

B

Evaluate for CHF

Reconsider transplantation candidacy

FIGURE 12-11 Ischemic heart disease (IHD). The incidence of IHD is several fold higher in renal transplantation recipients compared with the general population. Patients with IHD before transplantation are at high risk to develop IHD events after transplantation. Therefore, angiography should be considered in candidates for transplantation who have angina pectoris. Candidates with currently asymptomatic IHD and those at high risk for IHD should undergo a stress test. Patients with severe coronary artery disease on angiography must be considered for a revascularization procedure before transplantation. Aggressive management of risk factors is appropriate for all patients, with or without IHD. (From Kasiske and coworkers [1]; with permission.)

12.6

Transplantation as Treatment of End-Stage Renal Disease 100

(13)

Free of cardiac events, %

90

(9)

Revascularized

80

(7) (10)

70 60 50 40

(4)

30

Medically treated

20

(2)

10 0 0

3

6

9

12

15

18

21

24

Follow-up, mo

Evaluation of CHF in recipients Signs and symptoms of CHF?

Yes

Exclude secondary causes

Yes

Adequate response to medical management?

No Proceed with evaluation

No

Reconsider transplant candidacy

Evaluation of CVD in recipients History of stroke or TIA?

Yes

Recent symptoms? No

Yes

Consider carotid ultrasonography

No Carotid bruit?

Yes

Refer to neurologist

No High-risk ADPKD patient? No Yes Large intracranial aneurysm on imaging? No

Risk factor intervention

Yes

Consider prophylactic surgery

Proceed with evaluation

FIGURE 12-12 Effects of surgical versus medical management of coronary disease before renal transplantation in candidates who have insulin-dependent diabetes. In this study, 26 patients with insulin-dependent diabetes who were found to have over 75% stenoses in one or more coronary arteries were randomly allocated to either medical management or a revascularization procedure before transplantation. Ten of the 13 patients who were managed medically and 2 of the 13 who had revascularization performed had a cardiovascular disease end point within a median of 8.4 months after transplantation (P < 0.01). These findings suggest that transplantation candidates who have diabetes should be screened for silent coronary artery disease because revascularization decreases morbidity and mortality after transplantation. The numbers in parentheses indicate the number of patients being followed at that time. (From Manske and coworkers [5]; with permission.)

FIGURE 12-13 Congestive heart failure (CHF). Myocardial performance has been shown to improve in some patients after renal transplantation. Thus, a low ejection fraction alone does not automatically exclude patients from transplantation. In contrast, patients with severe irreversible myocardial disease may not be good candidates for transplantation. Occasionally, patients may be candidates for simultaneous heart and kidney transplantation. (From Kasiske and coworkers [1]; with permission.)

FIGURE 12-14 Cerebral vascular disease (CVD). Patients must not undergo surgery within 6 months of a stroke or transient ischemic attack (TIA). Asymptomatic patients with a carotid bruit should be considered for carotid ultrasonography because patients with severe carotid disease may be candidates for prophylactic surgery. Patients with autosomal dominant polycystic kidney disease (ADPKD) and either a previous episode or a positive family history of a ruptured intracranial aneurysm must be screened with computed tomography or magnetic resonance imaging. Patients found to have an aneurysm over 7 mm in diameter may benefit from prophylactic surgery. (From Kasiske and coworkers [1]; with permission.)

Evaluation of Prospective Donors and Recipients

Evaluation of PVP in recipients PVD unresponsive to conservative management?

Yes

Consider invasive intervention

No

Aortoiliac vascular disease?

Yes

12.7

FIGURE 12-15 Peripheral vascular disease (PVD). Peripheral vascular disease is commonly associated with coronary artery disease, cerebral vascular disease, or both. However, PVD itself may require intervention before transplantation to prevent infection and sepsis after transplantation. In addition, some patients may have aortoiliac disease severe enough to require intervention before transplantation. Rarely, vascular disease is severe enough to make it difficult to find an artery suitable for the anastomosis of the allograft renal artery. (From Kasiske and coworkers [1]; with permission.)

Consider repair before or at transplantation

No Proceed with evaluation

Psychosocial evaluation of recipients Psychosocial evaluation

Free of limiting cognitive impairment?

No

Yes Recent alcohol or drug abuse? No

Yes

Yes

Free of limiting No psychiatric illness?

Supervised abstinence? No

Yes History of limiting medication noncompliance?

Yes

Refer until resolved

No Proceed with evaluation

FIGURE 12-16 Psychosocial evaluation. Patients must be free of cognitive impairments and able to give informed consent. Most transplantation centers require patients with a history of alcohol or drug abuse to demonstrate a period of supervised abstinence, generally 6 months or more [6]. Similarly, patients with a past history of medication adherence poor enough to suspect that the immunosuppressive regimen will be compromised may need to delay transplantation until reasonable adherence can be demonstrated [6]. (From Kasiske and coworkers [1]; with permission.)

12.8

Transplantation as Treatment of End-Stage Renal Disease FIGURE 12-17 Assessing the medical risks of transplantation surgery. Obesity increases the risks of surgery, and a weight reduction program before transplantation must be considered for very obese patients. Older age is a relative contraindication to transplantation; however, it is difficult to precisely define an upper age limit for all patients. Rather, age and overall medical condition must be considered together. Hypertension should be controlled before transplantation. When control of hypertension is difficult, bilateral nephrectomy should be considered before transplantation. BMI—body mass index. (From Kasiske and coworkers [1]; with permission.)

Assessment of the medical risks to recipients Yes

BMI >35 kg/m2 No

Consider weight reduction program Yes

Age >65? No

Yes

No

Additional risk acceptable?

Hypertension unresponsive to medical management?

No further evaluation

Native kidney nephrectomy

Yes

No Proceed with evaluation

*

90 80 70 60 50 40 30 20 10 0

100

*

*

*

*

*

*

90

*

80 70

* 0

Obese patients Nonobese patients Obese patient grafts Nonobese patient grafts

3

6

9

12

15

18

21

24

Time, mo

Graft survival, %

Survival, %

100

60 50 40 Age 0–5 6–18 19–45 46–60 >60

30 20

FIGURE 12-18 Effects of obesity on patient and graft survival. In this case-control study, 46 obese (body mass index > 30 kg/m2) recipients of cadaveric renal transplantation were compared with nonobese controls matched for the following after transplantation: age, gender, diabetes, panel reactive antibody status, graft number, cardiovascular disease, date of transplantation, and immunosuppression. Survival of patients and grafts was significantly less among obese patients compared with controls (P < 0.01 and P < 0.05, respectively). The following occurred more often in obese versus nonobese patients: delayed graft function, postoperative complications, wound complications, and new-onset diabetes. (From Holley and coworkers [7]; with permission.)

10

n 198 1144 14994 10933 3908

t1/2 15.1 8.7 9.4 9.9 8.0

0 0

1

2

3

4

5

Years after transplantation

FIGURE 12-19 Effects of the recipient’s age on renal allograft survival. Data from the United Network for Organ Sharing Scientific Registry indicate that recipients over the age of 60 have slightly less allograft survival compared with younger recipients. t1/2—graft survival half-life (in years) the first year after transplantation. (From Cecka [3]; with permission.)

12.9

Evaluation of Prospective Donors and Recipients Evaluation of diabetes and hyperparathyroidism in recipients

84.7

Consider simultaneous kidney-pancreas transplantation

Yes

Pancreas graft survival, %

Difficult to control diabetes?

100

No

Symptomatic hyperparathyroidism or uncontrolled hypercalcemia?

Yes

Consider parathyroidectomy

80

73.5

77.4

73.2 69.0

71.4

52.5

46.0 39.4

40

27.7 27.7

20

22.6 Previous kidney transplantation (n=273)

0.25

Proceed with evaluation

Yes

History of recurrent UTIs?

No

No

Yes

Yes

Proceed with evaluation

No Indications for native kidney nephrectomy?

No

No

Consider ureteral diversion or intermittent self-catheterization

Yes Yes Consider native kidney nephrectomy

3.0

4.0

5.0

FIGURE 12-22 Urologic evaluation of transplantation recipients. Patients without signs and symptoms of bladder dysfunction generally do not need additional urologic testing. However, patients with bladder dysfunction must be evaluated to ensure that the bladder is functional after transplantation and that potential sources of urinary tract infection (UTI) are eliminated. Such patients can be screened initially with voiding cystourethrography (VCUG). (From Kasiske and coworkers [1]; with permission.)

No Ultrasonography, cystoscopy, and/or retrograde pyelogram normal?

2.0

FIGURE 12-21 Pancreas graft survival in recipients of pancreatic transplantation with simultaneous, no previous, and previous kidney transplantation. Survival rates of pancreatic grafts are best when pancreatic and kidney transplantations are performed at the same time. (Data from the United Network for Organ Sharing Scientific Registry [8].)

Urologic evaluation in recipients Signs or symptoms of bladder dysfunction?

1.0

Years after transplantation

FIGURE 12-20 Diabetes and hyperparathyroidism. Patients with difficult to control diabetes may be candidates for simultaneous kidney-pancreas transplantation. However, patients with diabetes who have a living donor are generally better off undergoing transplantation with the living donor kidney alone. Patients with symptomatic hyperparathyroidism or uncontrolled hypercalcemia should be considered for parathyroidectomy before transplantation. Medications that interfere with the metabolism of immunosuppressive agents such as cyclosporine should be substituted with appropriate alternatives, if possible, before transplantation. (From Kasiske and coworkers [1]; with permission.)

VCUG normal?

No previous kidney transplantation

39.2

0

Discontinue or reduce risk

Yes

No

Yes

61.8

54.4

60

No

Need for medication that may jeopardize recipient or graft?

Simultaneous kidney transplantation (n=3336)

Bladder insufficiency?

12.10

Transplantation as Treatment of End-Stage Renal Disease PUD and pancreatitis

Evaluation of active colonic disease in recipients Signs or symptoms of active PUD?

Yes

History of diverticulitis?

Yes

No Severe diverticular disease on barium enema?

No

Yes

Consider partial colectomy

Endoscopic or radiographic confirmation? No

No Yes

Other active colonic disease?

Yes

Adequate response to medical management?

Defer transplantation until quiescent

FIGURE 12-23 Diverticulitis and inflammatory bowel disease. Patients with a history of symptomatic diverticulitis must be evaluated for partial colectomy before transplantation. Inflammatory bowel disease generally should be quiescent at the time of transplantation. (From Kasiske and coworkers [1]; with permission.)

No

Consider cadaveric donor

Yes Blood and tissue typing

ABO compatible?

No

Yes T-cell CDC X-match negative?

No

Assess likelihood of false-positive results

Yes Yes

HLA identical?

Presence of autoantibodies?

No

Yes No

Proceed with evaluation

Transplantation

History of pancreatitis?

Yes

Delay transplantation until evaluation and treatment

No Proceed with evaluation

FIGURE 12-24 Peptic ulcer disease (PUD) and pancreatitis. Patients with PUD or pancreatitis must undergo evaluation and treatment before transplantation. Both conditions may be exacerbated by corticosteroids used after transplantation. (From Kasiske and coworkers [1]; with permission.) FIGURE 12-25 Immunologic evaluation for living donor transplantation. Generally, transplantation donors and recipients must have compatible blood groups. Tissue typing is also carried out, and the degree of human leukocyte antigen (HLA) matching may be taken into account in selecting the best living donor when more than one donor is available. Just before transplantation, the recipient’s serum is tested against donor cells to be certain no preformed antibodies are present in the recipient that may cause a hyperacute rejection. A positive crossmatch (X-match) generally precludes transplantation from that donor. CDC—cell-dependent cytotoxicity. (From Kasiske and coworkers [1]; with permission.)

Evaluation of transplantation from a living donor Potential living donor?

Consider pretransplantation surgical treatment

Yes

No Proceed with evaluation

No

Consider other donor

12.11

Evaluation of Prospective Donors and Recipients Donor-specific transfusions in recipients

100 1y

P= 0.02

2444

40

3303

Transplantation

No

P= 0.04

50 15,087

X-match negative?

Yes

60

20,461

Yes

3164

Negative X-match, flow cytometry, or antiglobulin?

Consider DST

76.4%

70

4172

No

19,187

Yes

84%

80

26,585

No

5 y>1 y

90 Adjusted graft survival, %

First transplantation?

Consider other donor

0

1-5

6-10

>10

0

1-5

6-10

>10

0

FIGURE 12-26 Donor-specific transfusion (DST). When the living donor is non– human leukocyte antigen identical and it is the recipient’s first transplantation, some centers use donor-specific blood transfusions before transplantation to enhance graft survival. Unfortunately, donor-specific transfusions may induce the formation of antibodies against the donor that will preclude the transplantation. Most centers have abandoned the use of random blood transfusions as part of the preparation of recipients for cadaveric transplantation. X-match— cross-match. (From Kasiske and coworkers [1]; with permission.)

Immunologic evaluation for cadaveric transplantation No living donor

No First transplantation?

Review typing from previous grafts

Yes PRA ≥11%

No

Autologous X-match positive?

Yes

No

Yes

PRA after DTT or analogous cell adsorption

Identify HLA specificities

Waiting list

Periodic antibody screening

Yes Increasing PRA? No

No

Final CDC X-match negative?

Yes

Transplantation

Number of pretransplantation transfusions

FIGURE 12-27 Effects of random blood transfusions on first cadaveric renal allograft survival. Blood transfusions before transplantation had a small but statistically significant beneficial effect on 1-year graft survival. However, a small reduction occurred in 5-year graft survival (among patients who survived at least 1 year with a functioning kidney) that was attributable to random donor blood transfusions before transplantation (From Gjertson [9]; with permission.) FIGURE 12-28 Immunologic evaluation for cadaveric transplantation. Donors and recipients must have compatible blood groups. Tissue typing is carried out, and the degree of matching is used in the allocation of cadaveric organs. Some data suggest that the presence of human leukocyte antigen (HLA) mismatches that were also mismatched in a previous graft (especially at the DR locus) may lead to early graft loss. Thus, it may be wise to avoid these mismatches. When the percentage of panel reactive antibodies (PRA) is over 10%, tests may be carried out to determine whether some of the antibodies are autoreactive rather than alloreactive. Autoreactive antibodies may not increase the risk for graft loss as do alloreactive antibodies. The presence of high titers of alloreactive antibodies usually is due to previous pregnancies, transplantations, and blood transfusions. Determining antibody specificities may be useful in avoiding certain HLA antigens. In the highly sensitized patient (PRA > 50%) it may be difficult to find a complement-dependent cytotoxicity (CDC) cross-matched (X-match) negative donor. Avoiding blood transfusions may help the titer decrease over time. DTT—1, 4-dithiothreitol (DTT). (From Kasiske and coworkers [1]; with permission.)

12.12

Transplantation as Treatment of End-Stage Renal Disease

100

100

90 80

90

70

80

60

HLA-identical sibling donor (n= 1984) Spousal donor (n= 368) Parental donor (n= 3368) Living unrelated donor (n=129) Cadaveric graft (n= 43,341) Cadaveric graft, urine flow 1st day, no dialysis (n=32,281) Cadaveric graft, no urine 1st day, dialysis required in 1st week (n= 11,060)

50 40 30 20 10 0 0

70 Graft survival, %

Graft survival, %

Evaluation of Prospective Living Donors

3

1 2 Years after transplantation

P< 0.025

60 50 40 30 Graft: HLA-identical 1-haplotype Zero-haplotype

20

FIGURE 12-29 Effects of donor source on renal allograft survival. Data from the United Network for Organ Sharing Scientific Registry were used to compare 3-year graft survival rates between recipients of kidneys from different donor sources. The best graft survival was seen in recipients of human leukocyte antigen (HLA)–identical sibling donors. Grafts from spouses and other living unrelated donors, however, survived just as well as did grafts from parental donors and better than grafts from cadaveric donors. These data have encouraged centers to use emotionally related donors to avoid the long waiting times for cadaveric kidneys. (From Terasaki and coworkers [10]; with permission.)

Candidate for renal transplantation

Yes

Willing and available ABO-compatible living related donor?

No

Yes

No Evaluate for cadaveric transplantation

No

No

Willing and available ABO-compatible emotionally related donor?

Cross-match negative?

t1/2 25.5 16.0 11.9

0 0

1

2

3

4

5

Years after transplantation

FIGURE 12-30 Effects of human leukocyte antigen (HLA) matching on living related graft survival. Graft survival is best for HLA-identical grafts from siblings and next best for one-haplotype mismatched grafts. Importantly, the half-life (t1/2) of grafts that survived at least 1 year is proportional to the degree of matching. This information can be used along with other factors to select the most suitable among two or more living prospective donors. (From Cecka [3]; with permission.) FIGURE 12-31 Use of living donors. A suitable living donor is better than a cadaveric donor because graft survival is better and preemptive transplantation is possible. The best donor usually is a family member. Psychosocial and biological factors must be taken into account when choosing among two or more living prospective donors. Every effort must be made to ensure that the donation is truly voluntary. Caregivers should tell prospective donors that if they do not wish to donate, then friends and relatives will be told “the donor was not medically suitable.” (From Kasiske and coworkers [2]; with permission.)

Choice of living donor versus cadaveric transplantation

Willing to accept living donor?

10

n 2288 3082 808

Yes

Yes Proceed with evaluation

12.13

Evaluation of Prospective Donors and Recipients Preliminary evaluation for a living donor Yes

Economic risk acceptable?

Risk assessment for living donor

Psychosocial evaluation

No

No

Age and renal function acceptable? Yes

No

Voluntarism reasonably certain?

No

Yes

Yes Yes

Surgical risk acceptable?

Financial incentive?

Preliminary medical evaluation

No

No

Long-term risk acceptable?

Yes

Yes Yes

Consider alternative donor

Consider alternative donor

No No Risk acceptable?

Risk of recurrent disease?

HIV, hepatitis, or pregnancy test positive? No

Risk acceptable?

Yes

CMV titer positive or history of tuberculosis?

Yes

Yes

Proceed with evaluation

FIGURE 12-32 Preliminary evaluation of a living prospective donor. The prospective donor must be made aware of the possible costs associated with donation, including travel to and from the transplantation center and time away from work. The prospective donor must undergo a psychological evaluation to ensure the donation is voluntary. A preliminary medical evaluation should assess the risks of transmitting infectious diseases with the kidney, eg, infection with human immunodeficiency virus (HIV) and cytomegalovirus (CMV). (From Kasiske and coworkers [2]; with permission.)

27

Transplantation centers, %

22

20 15 13

13

10 6 3

No age exclusion

55

60

65

70

No

Screening for diabetes negative?

Yes

Proceed with evaluation

FIGURE 12-33 Assessing risks. Older age may place the living prospective donor at greater surgical risk and may be associated with reduced graft survival for the recipient. The prospective donor must be informed of both the short-term surgical risks (very low in the absence of cardiovascular disease and other risk factors) and the long-term consequences of having only one kidney. With regard to long-term risks, it should be considered whether there is a familial disease that the living donor may be at risk to acquire and whether having only one kidney would alter the natural history of renal disease progression. These questions are often most pertinent for relatives of patients with diabetes. (From Kasiske and coworkers [2]; with permission.) FIGURE 12-34 Donor age restrictions used by transplantation centers. Results of an American Society of Transplantation survey of the United Network for Organ Sharing centers showed that many centers either use no specific age exclusion criteria or have no policy. Among those that use an upper age limit, there appears to be a bell-shaped curve, with 65 years of age at the median. (From Bia and coworkers [11]; with permission.)

30

0

Risk of diabetes? No

Yes No

No

75–80

Exclude if age in years is greater than:

No policy or do not know

12.14

Transplantation as Treatment of End-Stage Renal Disease 100 90

90

Progressive effect (each 10 y) (0.3) (1.4) (2.5)

Static effect (–20.2) (–17.1) (–14.0)

88

80 Transplantation centers, %

-20

-15

70

0

5

61

60 (52)

50

Progressive effect (each 10 y) (76) (101)

46

40

0

25

30

50 Proteinuria, mg/d

75

Static effect (2.4)

(–0.3)

20

100

(5.1)

Progressive effect (each 10 y) (0) (1.1) (2.2)

10 0 Mildly elevated FBS

Normal FBS but abnormal GTT

Mild type II diabetes < 50y

0

Mild type II diabetes < 30y

FIGURE 12-35 Screening living prospective donors for diabetes. Results of the survey of the United Network for Organ Sharing centers showed that most centers exclude patients with a mildly elevated fasting blood sugar (FBS) and patients with normal FBS but an abnormal glucose tolerance test (GTT). Most centers exclude donors with mild type II diabetes. (From Bia and coworkers [11]; with permission.)

64 54

50

40

30 20

20 12

10

9

0 Persistently 130/90 mm Hg

2.0 3.0 4.0 Systolic blood pressure, mm Hg

5.0

FIGURE 12-37 Blood pressure (BP) criteria for excluding living prospective donors. Results of the survey of the United Network for Organ Sharing centers showed that most exclude prospective donors who require antihypertensive medication or whose BP is persistently elevated over 130/80 mm Hg. However, most centers do not exclude living prospective donors who occasionally have BP readings over 130/80 mm Hg or patients with so-called white coat hypertension. (From Bia and coworkers [11]; with permission.)

60

Controlled on one BP medication

1.0

FIGURE 12-36 Long-term risks of kidney donation. In a meta-analysis combining 48 studies of the long-term effects of reduced renal mass in humans, no evidence was found of a progressive decline in renal function after a 50% reduction in renal mass. Indeed, a small but statistically significant increase occurred over time in the glomerular filtration rate. A small increase in urine protein excretion occurred; however, the rate of increase per decade was less than that generally considered an abnormal amount of protein excretion, eg, 150 mg/d. A small increase in systolic blood pressure was noted; however, it was not enough to lead to an increase in the incidence of hypertension. Thus, it appears that the long-term risks of kidney donation are very small. Shown are multiple linear regression coefficients and 95% confidence intervals. Failure of the confidence interval to include zero indicates P < 0.05. (From Kasiske and coworkers [12]; with permission.)

70

Transplantation centers, %

-10 -5 Glomerular filtration rate, mL/min

Occasionally 130/90 mm Hg

130/90 mm Hg in doctor's office only

No policy or do not know

12.15

Evaluation of Prospective Donors and Recipients Evaluation of prospective donors with proteinuria, hypertension, or kidney stones

Evaluation of donor risks in recipients with familial renal diseases

No

Proteinuria or pyuria?

Relative with ADPKD? Yes

Yes Evaluation indicates low risk?

Yes Yes

No

Normal renal imaging and low risk for ADPKD?

Hypertension?

Blood pressure high normal? Yes No

Yes

Female with acceptable low risk?

Yes Proceed with evaluation

Evaluate

Yes

Risk acceptable?

FIGURE 12-38 Proteinuria, hypertension, or kidney stones in living prospective donors. Prospective donors with pyuria must be evaluated for possible infection and other reversible abnormalities. Proteinuria is generally a contraindication to donation. Hypertension also must be considered at least a relative contraindication to donation. Patients with a history of nephrolithiasis but no current or recent stones may be considered for donation after first undergoing urologic and metabolic evaluations for stones. (From Kasiske and coworkers [2]; with permission.)

Final evaluation of prospective living donors No

Yes Angiography results acceptable?

Yes

No

Yes Schedule transplantation surgery

Consider alternative donor

No

Yes

Proceed with evaluation

Yes

No

Yes

Cross-match negative?

Male with no hematuria? No

No

History of kidney stones

No

Male with No hematuria?

No

Donor-specific transfusion?

No

Yes

Risk acceptable?

No

Relative with hereditary nephritis?

Yes

No

No

Consider alternative donor

Consider alternative donor

No

Evaluation indicates low risk?

No Yes

Isolated hematuria

FIGURE 12-39 Risks to the related donor when the recipient has familial renal disease. Donors for relatives with autosomal dominant polycystic kidney disease (ADPKD) may be permitted to donate if over 25 years old and results on renal imaging are negative for cysts. Some younger persons may be permitted to donate if genetic studies indicate that the risk for subsequent ADPKD is very low. Male relatives of individuals with hereditary nephritis can be donors if they do not have hematuria. Male relatives with hematuria cannot be donors. Female relatives without hematuria may donate; however, women of child-bearing age who might be carriers must consider the possibility of someday donating a kidney to a child of their own with the disease. Female relatives with hematuria should not donate when other evidence of renal disease exists; however, in the absence of such evidence the exact risk of donation is unknown. Occasionally, donors with isolated microhematuria (not hereditary) and a negative evaluation may be suitable donors. (From Kasiske and coworkers [2]; with permission.) FIGURE 12-40 Final steps in evaluating a living prospective donor. Renal artery angiography is performed to define the anatomy of the renal artery system and exclude other previously undetected abnormalities. Recent studies have shown that spiral computerized tomography can replace angiography without loss of sensitivity or specificity and with less risk and inconvenience to the prospective donor. (From Kasiske and coworkers [2]; with permission.)

12.16

Transplantation as Treatment of End-Stage Renal Disease

Use of Marginal Cadaveric Donor Kidneys FIGURE 12-41 Donor age. When there are no suitable living donors, recipients are placed on the cadaveric waiting list. The transplantation center must always decide whether a particular cadaveric kidney being offered for transplantation is suitable for the individual recipient. The shortage of organs and long waiting times have caused many centers to accept kidneys from older donors and kidneys that may be damaged. Data from the United Network for Organ Sharing clearly demonstrate the decreased graft survival rates of kidneys from older donors. As a compromise, some advocate using kidneys from older donors for older recipients. In any case, so-called marginal kidneys should be offered to recipients with appropriate informed consent. (From Cecka [3]; with permission.)

100 90 80

Graft survival, %

70 60 50 40 Age 6–18 19–30 31–45 46–60 >60

30 20 10

n 6652 7354 7532 6476 1928

t1/2 10.9 11.7 9.8 6.9 5.2

0 0

1

2

3

4

5

Years after transplantation

References 1.

2.

3.

4.

5.

6.

7.

Kasiske BL, Ramos EL, Gaston RS, et al.: The evaluation of renal transplant candidates: clinical practice guidelines. J Am Soc Nephrol 1995, 6:1–34. Kasiske BL, Ravenscraft M, Ramos EL, et al.: The evaluation of living renal transplant donors: clinical practice guidelines. J Am Soc Nephrol 1996, 7:2288–2313. Cecka JM: The UNOS Scientific Renal Transplant Registry. In Clinical Transplants 1996. Edited by Cecka JM, Terasaki PI. Los Angeles: UCLA Tissue Typing Laboratory, 1997:1–14. Periera BJG, Wright TL, Schmid CH, Levey AS: The impact of pretransplantation hepatitis C infection on the outcome of renal transplantation. Transplantation 1995, 60:799–805. Manske CL, Wang Y, Rector T, et al.: Coronary revascularisation in insulin-dependent diabetic patients with chronic renal failure. Lancet 1992, 340:998–1002. Ramos EL, Kasiske BL, Alexander SR, et al.: The evaluation of candidates for renal transplantation: the current practice of U.S. transplant centers. Transplantation 1994, 57:490–497. Holley JL, Shapiro R, Lopatin WB, et al.: Obesity as a risk factor following cadaveric renal transplantation. Transplantation 1990, 49:387–389.

8. 1996 Annual Report of the U.S. Scientific Registry for Transplant Recipients and the Organ Procurement and Transplantation Network– Transplant Data: 1988–1995. UNOS, Richmond, VA, and the Division of Transplantation, Bureau of Health Resources Development, Health Resources and Services Administration, U.S. Department of Health and Human Services; 1996. 9. Gjertson DW: A multi-factor analysis of kidney graft outcomes at one and five years posttransplantation: 1996 UNOS Update. In Clinical Transplants 1996. Edited by Cecka JM, Terasaki PI. Los Angeles: UCLA Tissue Typing Laboratory. 1997: 343–360. 10. Terasaki PI, Checka M, Gjertson DW, Takemoto S: High survival rates of kidney transplants from spousal and living unrelated donors. N Engl J Med 1995, 333:333–336. 11. Bia MJ, Ramos EL, Danovitch GM, et al.: Evaluation of living renal donors. the current practice of US transplant centers. Transplantation 1995, 60:322–327. 12. Kasiske BL, Ma JZ, Louis TA, Swan SK: Long-term effects of reduced renal mass in humans. Kidney Int 1995, 48:814–819.

Medical Complications of Renal Transplantation Robert S. Gaston

W

ith long-term function of allografts increasingly the norm, detection and management of medical complications assume greater importance in the care of renal transplantation recipients. At least two trends in transplantation seem likely to make medical surveillance even more crucial. First, better control of adverse immunologic events early after transplantation has significantly reduced graft loss caused by rejection; the impact of later events (especially death with a functioning organ and chronic rejection) on graft and patient survival is proportionately larger. Second, with successful transplantation now fairly routine, it is being offered to a broader spectrum of candidates, including increasingly older patients with multiple coexisting medical problems. Because more patients with immunosuppression are now being cared for over increasingly longer periods of time, the impact of comorbid events on outcomes must be reduced. Medical complications in the renal allograft recipient represent the often overlapping impact of several variables. At the time of transplantation, significant comorbidity may already be present and can be of immediate concern. Other problems may have originated in the milieu of chronic renal failure, such as hyperparathyroid bone disease or hypertension, but may evolve differently after transplantation. Finally, new complications may result from specific toxicities of pharmaceutical agents, reflecting the overall impact of immunosuppression. In many cases, all of these elements contribute to overt clinical illness. For instance, cardiovascular disease is now the most common cause of death in renal allograft recipients [1]. Coronary disease may have predated transplantation (indeed, coronary disease is a common cause of death among all patients with end-stage renal disease). After transplantation, hypertension and hyperlipidemia, perhaps exacerbated by administration of cyclosporine and corticosteroids, result in accelerated atherosclerosis, further potentiating preexisting cardiac problems. To intervene appropriately requires a comprehensive understanding of all the variables involved: any decision to lessen the impact of one risk factor (eg, withdrawing steroids) may result in unintended consequences (eg, acute rejection).

CHAPTER

13

13.2

Transplantation as Treatment of End-Stage Renal Disease

An obvious prerequisite to caring for transplant recipients is a thorough understanding of immunosuppressive therapies [2]. Although acute rejection can occur at any time, the greatest risk is during the first 90 days after transplantation. Accordingly, immunosuppression is most intense during this time, and the chances of suffering its consequences are great (eg, drug toxicities, infection, and some malignancies [lymphoma]). In general, tapering to a less arduous regimen over time is done, with resulting reduction in the risks of toxicity and infection. With long-term survival, however, the duration rather than the intensity of immunosuppression becomes more critical and strongly influences the risks of other complications, including malignancies (skin), bone disease, and atherosclerosis. Current maintenance immunosuppressive therapy involves multidrug regimens (including azathioprine or mycophenolate mofetil [MMF] and corticosteroids) built around a cornerstone,

the calcineurin-inhibitor (either cyclosporine or tacrolimus) [2]. Therapeutic considerations in treating patients on either of the calcineurin inhibitors are remarkably similar in terms of both adverse effects and drug interactions (Figs. 13-1 and 13-2) [3–5]. Common azathioprine toxicities include bone marrow suppression and alopecia. Because azathioprine is metabolized by xanthine oxidase, concomitant use with allopurinol is problematic. MMF causes less bone marrow suppression than does azathioprine and does not interact with allopurinol, facilitating therapy of gout. However, gastrointestinal complaints (usually dose-related nausea, bloating, or diarrhea) are common. In addition, MMF may exacerbate the gastrointestinal toxicity of tacrolimus. Corticosteroid toxicities are well described; protocols designed to minimize corticosteroid exposure of transplantation recipients remain the ideal pursued by many physicians who treat these patients.

ADVERSE EFFECTS OF CYCLOSPORINE AND TACROLIMUS Renal

Gastrointestinal

Hypertension

Hepatotoxicity (abnormal transaminase levels) Nephrotoxicity (azotemia) Nausea, vomiting, diarrhea (FK > CyA)

Metabolic

Cosmetic

Glucose intolerance (FK > CyA)

Gingival hypertrophy Headache (CyA only, especially Paresthesias in combination with Seizures calcium antagonists) Tremor Hirsutism (CyA > FK)

Hyperkalemia Hyperlipidemia (CyA > FK) Hyperuricemia Hypomagnesemia

COMMON DRUG INTERACTIONS WITH CYTOKINE INHIBITORS Drugs that commonly increase blood levels of cyclosporine and tacrolimus Bromocryptine Cimetidine Clarithromycin Clotrimazole Diltiazem Erythromycin Fluconazole Itraconazole Ketoconazole Mefredil Methylprednisolone Nicardipine Verapamil Drugs that commonly decrease blood levels of cyclosporine and tacrolimus Carbamazepine Phenobarbital Phenytoin Rifampin

Neurologic

FIGURE 13-1 Despite differing structures, both cyclosporine and tacrolimus bind to intracellular receptors in T cells, forming a combination that then inhibits calcineurindependent pathways of cell activation. Although slight differences exist in sideeffect profiles between the two drugs, their overall impact is remarkably similar. In many cases, dose reduction may ameliorate the toxic effect; however, the benefit of dose reduction must be weighed against increasing the risk of acute rejection in each patient. CyA–cyclosporine; FK–tacrolimus.

FIGURE 13-2 Cyclosporine and tacrolimus are subject to remarkably similar interactions, owing in part to a common pathway of metabolic degradation, the cytochrome P-450 enzyme system. Although the drugs listed here predictably alter blood levels of the calcineurin inhibitors, other interactions may also occur.

Medical Complications of Renal Transplantation

FIGURE 13-3 Risk of acute rejection in cadaver kidney transplantation. This graph, derived from the parametric analysis techniques of Blackstone and coworkers [6], depicts the risk of acute rejection over time. Using an immunosuppressive protocol including cyclosporine, mycophenolate mofetil, and prednisone, the risk of acute rejection is greatest during the first 2 months after transplantation, diminishing significantly afterward. Because the risk of rejection is greatest, immunosuppressive therapy is most intense during this period. Correspondingly, complications related to immunosuppressive therapy (including infections and specific drug toxicities) also are most likely during this time.

1.0 0.8 Risk month

13.3

0.6 0.4 0.2 0.0 0

2 4 6 8 10 Months posttransplant

12

Incidence rate

1.0 Rejection Toxicity

0.8 0.6 0.4 0.2 0 5

7.5

10 12.5 15 17.5 20 Tacrolimus level (whole blood), ng/mL

22.5

25

FIGURE 13-4 Relationship between blood levels of tacrolimus, immunosuppressive efficacy, and toxicity [7]. As tacrolimus levels diminish, particularly during the early period after transplantation, the risk of toxicity is reduced accordingly. However, the risk of acute rejection increases. Toxicity still can occur at very low drug levels, as can rejection at high levels. The relationship between these variables beyond the first 6 to 12 months after transplantation is not well established. A similar plot could be constructed for cyclosporine. (Adapted from Kershner and Fitzsimmons [7].)

Complications of Immunosuppression Malignancy Kaposi's (6%)

Other (36%)

Lymphomas (24%)

Skin and lip (34%)

FIGURE 13-5 Types and distribution of malignancies among renal transplant recipients in the current era of cyclosporine use. In these patients the risk of malignancy is increased approximately fourfold when compared with the general population [8]. Malignancies likely to be encountered in the transplantation recipient differ from those most common in the general population [9,10]. Lymphomas and Kaposi’s sarcoma may evolve as a consequence of viral infections. Women are at an increased risk for cervical carcinoma, again related to infection (human papilloma virus). Surprisingly, the solid tumors most commonly seen in the general population (eg, of the breast, lung, colon, and prostate) do not occur with significantly greater frequency among transplant recipients. Nonetheless, long-term care of these patients should involve standard screening for these malignancies at appropriate intervals. (From Penn [9]; with permission.)

13.4

Transplantation as Treatment of End-Stage Renal Disease

FIGURE 13-6 Primary basal cell carcinoma. Cutaneous carcinomas (primarily basal cell and squamous cell) comprise the greatest percentage of tumors in transplant recipients. They tend to be most problematic in fair-skinned persons whose lifestyle includes significant sun exposure; the risk increases with duration of immunosuppression. In immunocompetent patients the risks of these lesions usually are limited; however, in transplant recipients these lesions can be very aggressive and metastasize locally or even systemically. The best management is aggressive prevention: exposure to ultraviolet radiation from the sun should be minimized through diligent use of protective clothing, hats, and sunscreen. When suspicious lesions develop, early recognition and removal are of utmost importance.

FIGURE 13-7 Posttransplantation lymphoproliferative disease (PTLD): histologic appearance of a renal allograft infiltrated by a monoclonal proliferation of B lymphocytes. Non-Hodgkin’s lymphomas, of which PTLD is a variant, occur in 1% to 3% of transplant recipients and in many cases are linked to an infectious cause. PTLD can be of either polyclonal or monoclonal B-cell composition, with lymphocytes driven to proliferate by infection with the Epstein-Barr virus [11–13]. Development of PTLD is strongly linked to the intensity of immunosuppression and may regress with its reduction. However, most often in the setting of splanchnic involvement and monoclonal proliferation, as depicted, PTLD can follow a more aggressive unrelenting course despite withdrawal of immunosuppressive therapy.

Hematologic Complications Serum erythropoietin level, U/L

200 1st peak

2nd peak

150 100 50 25 0

0

10

20

30 40 50 60 Days after transplantation

70

80

FIGURE 13-8 The course of normal erythropoiesis after renal transplantation showing mean serum erythropoietin levels of 31 recipients [14]. An initial burst of erythropoietin (EPO) secretion at the time of engraftment does not result in erythropoiesis. As excellent graft function is achieved, a second burst of EPO secretion is normally followed by effective production of erythrocytes. The hatched area

is the range of serum erythropoietin levels in normal persons without anemia. Anemia is a common complication. Many patients leave the dialysis population with diminished iron stores and are unable to respond to erythropoietin produced by the successful allograft. Iron replacement therapy successfully restores erythropoiesis in these patients. Another common cause of anemia after transplantation is bone marrow suppression owing to drug therapy with azathioprine or mycophenolate mofetil (MMF), an effect that is usually dose-related [15,16]. Other drugs, notably angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists, may also inhibit erythropoiesis [17]. Neutropenia also is a common complication after transplantation. It can reflect dose-related bone marrow suppression owing to drug therapy with azathioprine or MMF or an idiosyncratic response to a number of drugs commonly used in this population (acyclovir, ganciclovir, sulfa-trimethoprim, H2 blockers). Alternatively, neutropenia can be a manifestation of systemic viral, fungal, or tubercular infections. The approach to the patient with neutropenia usually involves reducing the dose or discontinuing the potential offending agents, along with a careful search for infections. In some settings of refractory neutropenia, administration of filgrastim (granulocyte colonystimulating factor, Neupogen®) reduces the duration and severity of neutropenia. (From Sun and coworkers [14]; with permission.)

Hematocrit, %

Medical Complications of Renal Transplantation 62 60 58 56 54 52 50 48 46 44 42 40 PRE

1

2 3 4 5 6 9 Months on enalapril (mean 7±4.5 mo)

12

15

13.5

FIGURE 13-9 Posttransplant erythrocytosis (PTE). PTE (a hematocrit of >0.52) affects 5% to 10% of renal transplantrecipients, most commonly male recipients with excellent allograft function [17]. PTE usually occurs during the first year after transplantation. Although it may resolve spontaneously in some patients, PTE persists in many. It has been linked to an increased risk of thromboembolic events; however, our own experience is that such events are uncommon. Previous management involved serial phlebotomy to maintain the hematocrit at 0.55 or less (dashed line). More recently, hematocrit levels have been found to normalize in almost all affected patients with a small daily dose of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor antagonist. The pathogenetic mechanisms underlying PTE and its response to these therapies remain poorly understood; although elevated serum erythropoietin levels decrease with ACEI use, other pathways also appear to be involved.

Death rate per 1000 patient years

Cardiovascular Complications 8 Diabetic Nondiabetic

7 6 5 4 3 2 1 0

FIGURE 13-10 Causes of death in renal allograft recipients. Cardiovascular diseases are the most common cause of death, largely reflecting the high prevalence of coronary artery disease in this population [1]. The risks are particularly high among recipients who have diabetes, as many as 50% of whom, even if asymptomatic, may have significant coronary disease at the time of transplantation evaluation [18]. Effective management of cardiac disease after transplantation mandates documentation of preexisting disease in patients at greatest risk [19].

Malignancy Cardiac Infectious Stroke Cause of death in patients with functioning transplants

DEMOGRAPHIC VARIABLES HIGHLY PREDICTIVE OF CORONARY DISEASE IN RENAL TRANSPLANTATION CANDIDATES WITH INSULIN-DEPENDENT DIABETES MELLITUS Age > 45 y Electrocardiographic abnormality: nonspecific ST-T wave changes History of cigarette smoking Duration of diabetes > 25 y

FIGURE 13-11 Demographic variables highly predictive of coronary disease in renal transplantation candidates with insulin-dependent diabetes mellitus. Most transplant centers screen potential candi-

dates, particularly persons with diabetes, for coronary disease before transplantation. In patients with diabetes who have end-stage renal disease with none of the demographic characteristics listed, the risk for coronary disease is low. Conversely, in patients who are insulin-dependent and have any of these risk factors, the prevalence of coronary disease is sufficiently high to justify angiography. A randomized study of medical therapy versus revascularization in transplantation candidates who have insulin-dependent diabetes and coronary disease showed superior outcomes with prophylactic revascularization, even in the absence of overt symptomatology [20]. (Adapted from Manske and coworkers [18].)

13.6

Transplantation as Treatment of End-Stage Renal Disease

75

50

,

n=591

n=429

60

40

45

30

30

20 74%

15

63%

10

0

0 100

200

300

400

70

Cholesterol, mg/dL

130

190

310

LDL, mg/dL

75

40 n=588

,

250

n=430

60

32

45

24

30

16

15

FIGURE 13-12 Hypercholesterolemia and hypertriglyceridemia. Hypercholesterolemia and hypertriglyceridemia are common after kidney transplantation. Approximately two thirds of transplant recipients have low density lipoprotein (LDL) or total cholesterol levels signifying increased cardiac risk; 29% have elevated triglyceride levels 2 years after transplantation (Kasiske, Unpublished data). Not only is hyperlipidemia a clear risk factor for coronary disease (see Figs. 13-13 and 13-14), but it may also contribute to the progressive graft dysfunction associated with chronic rejection [21,22]. HDL—high density lipoprotein. (From Bristol-Myers Squibb [23]; with permission.)

10%

8

29%

0

0 100

200

300

400

0

Triglycerides, mg/dL

35

50

65

80

95

HDL, mg/dL

RISK FACTORS FOR CORONARY MORBIDITY IN RENAL ALLOGRAFT RECIPIENTS

GUIDELINES FOR LIPID-LOWERING THERAPY Diet therapy

Positive

Negative

Age: Male ≥ 45 y Female ≥ 55 y or premature menopause Family history of premature coronary heart disease Smoking Hypertension HDL cholesterol < 35 mg/dL Diabetes mellitus

HDL cholesterol ≥ 60 mg/dL

FIGURE 13-13 Risk factors for coronary morbidity in renal allograft recipients. In addition to elevated low density lipoprotein (LDL) cholesterol levels, risk factors known to contribute to coronary morbidity often are present in renal allograft recipients. About 40% of recipients are over 45 years old, and 23% have diabetes. Smoking, hypertension, and hyperlipidemia are among the risk factors most amenable to long-term modification. (For guidelines in instituting lipid-lowering therapy see Figure 13-14 [24].)

LDL cholesterol, mg/dL

Initiation

Goal

No CHD and <2 risk factors No CHD and ≥2 risk factors CHD

≥160 ≥130 ≥100

<160 <130 ≤100

Diet plus drug therapy LDL cholesterol, mg/dL

Initiation

Goal

No CHD and <2 risk factors No CHD and ≥2 risk factors CHD

≥190 ≥160 ≥130

<160 <130 ≤100

FIGURE 13-14 The indications for lipid-lowering therapy and its goals are based on the clinical history, risk factor profile (see Fig. 13-13), and low density lipoprotein (LDL) cholesterol level in individual patients. CHD—coronary heat disease. (From Grundy [24]; with permission.)

Medical Complications of Renal Transplantation

Lipid level, mg/dL

Prograf CyA p<0.001 229.8

250

P<0.05 198.6

193.9

13.7

FIGURE 13-15 Cyclosporine (CyA) and corticosteroid therapies clearly contribute to hyperlipidemia in renal allograft recipients. Although dose reduction can reduce lipid levels, it may also increase the risk of acute rejection. As depicted, early experience in a large multicenter trial indicates that tacrolimus may have a less adverse impact on lipid metabolism than does cyclosporine [25]. (From Fujisawa USA [26]; with permission.)

165.4

125

0

Cholesterol

Triglycerides

THERAPEUTIC OPTIONS IN LIPID-LOWERING THERAPY HDL cholesterol Cholesterol LDL cholesterol Triglycerides Control groups Diet HMG CoA inhibitors Fibrates Fish oil Probucol Niacin

CAUSES OF HYPERTENSION AFTER TRANSPLANTATION Intrinsic

Extrinsic

1±11 -28±14 -56±9

1±6 -21±15 -51±6

-15±22 -59±25 -49±18

2±4 5±8 3.5±4.5

Delayed graft function

Native kidneys

Acute rejection

-38±12 23±43 -66±21 -48±28

-36±9

-69±24 -86±80

3±6

Cyclosporine nephropathy, chronic

Immunosuppression: Cyclosporine Tacrolimus Corticosteroids

-49

-13.5±12 10±10

Chronic rejection Recurrent primary renal disease (glomerulonephritis, hemolytic uremic syndrome, and so on)

Transplantation renal artery stenosis Hypercalcemia

mg/dL changes ±95% CI.

FIGURE 13-16 A recent meta-analysis of published trials in renal transplant recipients demonstrated these benefits of the various treatments. Pharmacologic therapy should be instituted at low doses with cautious surveillance for potential adverse effects, especially liver dysfunction or rhabdomyolysis. These adverse events may occur more frequently in transplant recipients owing to the effect of cyclosporine on drug disposition. Levels of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors are substantially higher in patients receiving both drugs [27]. HDL—high density lipoprotein; LDL—low density lipoprotein. (Adapted from Massy and coworkers [27]; with permission.)

FIGURE 13-17 In the current era of immunosuppressive therapy, hypertension affects roughly two thirds of transplant recipients. Unlike hypertension in the general population, posttransplant hypertension often reflects the impact of readily definable (and potentially treatable) factors on systemic blood pressure [28–30]. These may be grouped conveniently into those originating within the allograft (intrinsic) and those originating elsewhere (extrinsic).

13.8

Transplantation as Treatment of End-Stage Renal Disease Diagnosis and treatment of hypertension in the renal transplant recipient

Blood pressure ≥140/90 Stable GFR? Yes

Evaluate allograft function No

Optimal blood levels of cyclosporine or tacrolimus? Yes

No

Reduce dose of cyclosporine or tacrolimus

ECF volume status acceptable? Yes

No

Consider salt restriction and/or diuretic

Administer antihypertensive agent (CA, ACEI, or other)

Intervention fails to normalize BP

Adequate response to therapy?

Multidrug regimen: add agents of different classes as necessary

No

Yes Acceptable side effect profile? Yes Continue antihypertensive therapy Reassess periodically

Yes

Adequate response to therapy? No Re-evaluate allograft function and drug therapy Consider TRAS

FIGURE 13-18 Hypertension in the renal transplant recipient. In these patients it may be possible to approach diagnosis and therapy in a fairly standardized fashion. In transplant recipients with blood pressure readings consistently over 140/90 mm Hg, intervention is warranted. The initial approach includes assessment of allograft function, extracellular fluid volume (ECF) status, and immunosuppressive dosing. If these variables are stable, it is reasonable to proceed with antihypertensive therapy. Calcium antagonists (CA) are effective agents and may offer the added benefit of attenuating cyclosporineinduced changes in renal hemodynamics. Verapamil, diltiazem, nicardipine, and mibefradil increase blood levels of cyclosporine and tacrolimus and should be used with caution. Common problems with CAs that may limit their use include cost, refractory edema, and gingival hyperplasia. Angiotensin antagonists (ACEIs and receptor antagonists) are also effective; their use requires close monitoring of renal function, serum potassium levels, and hematocrit levels. Diuretics frequently are useful adjuncts to therapy in recipients owing to the salt retention that often accompanies cyclosporine use. Other antihypertensive medications offer no particular benefits or drawbacks and can be employed as needed. The rationale of multidrug therapy is to employ agents that block hypertensive responses via interruption of differing pathogenetic pathways. As antihypertensive drugs are added, this consideration should remain paramount [31,32]. GFR—glomerular filtration rate; TRAS—transplanted renal artery stenosis.

FIGURE 13-19 Transplant renal artery stenosis (TRAS). TRAS accounts for less than 5% of cases of hypertension after transplantation. Nonetheless, TRAS should always be considered in patients with refractory hypertension who develop renal insufficiency after addition of an ACEI to the therapeutic regimen. Although noninvasive studies (such as a renal scan with captopril) may be helpful in diagnosing TRAS, angiography remains the gold standard for diagnosis. Revascularization of the allograft by either surgical or angioplastic techniques may improve renal function and ameliorate hypertension [33,34].

Medical Complications of Renal Transplantation

13.9

Gastrointestinal Complications GASTROINTESTINAL TRACT COMPLICATIONS IN RENAL TRANSPLANTATION RECIPIENTS

Drug Cyclosporine Tacrolimus MMF Azathioprine

A

Nausea and vomiting

Diarrhea

4 30 20 12

3 32 31 Rare

Other complications Hepatotoxicity, constipation Hepatotoxicity, constipation Constipation, dyspepsia Hepatotoxicity, pancreatitis

B

FIGURE 13-20 Complications affecting the gastrointestinal (GI) tract remain relatively common in transplant recipients. Both tacrolimus and mycophenolate mofetil (MMF) cause bloating, nausea, vomiting, and diarrhea in a dose-dependent manner, particularly when used in combination [15,16,25]. Some authors have noted that this rather nonspecific GI toxicity occurs more commonly with Neoral® than with Sandimmune® (both from Sandoz Pharmaceuticals, East Hanover, NJ).

FIGURE 13-21 (See Color Plate) Endoscopic image of candida esophagitis with diffuse white exudate (panel A) and colitis induced by cytomegalovirus infection with submucosal hemorrhage, ulcers, and diffuse mucosal edema (panel B). The availability and common use of effective prophylaxis against acid-peptic disease (eg, H2 blockers, omeprazole, and antacids) have significantly reduced the frequency of upper gastrointestinal bleeding. However, infectious agents such as cytomegalovirus and candida continue to be problematic, particularly in the setting of the more intense immunosuppression afforded by drugs such as mycophenolate mofetil (MMF) and tacrolimus.

FIGURE 13-22 Histologic image of chronic active hepatitis secondary to infection with the hepatitis C virus (HCV). Note the periportal distribution of the lymphocytic infiltrate. Recent identification of HCV has caused intense reevaluation of the causes, frequency, and natural history of liver disease in renal allograft recipients. As the percentage of patients with end-stage renal disease who are infected with the hepatitis B virus has diminished, HCV has become the most problematic cause of liver disease. In recipients with HCV antibodies, immunosuppressive therapy may potentiate liver injury from the virus and accelerate the course of time over which cirrhosis develops. Nonetheless, in patients who desire transplantation and have wellpreserved liver function, little evidence exists of better longevity on dialysis. HCV can be transmitted easily from donor to recipient in solid organ transplantation. Because kidney transplantation is not a life-saving procedure, most transplant centers choose not to use kidneys from donors who are infected with HCV. Previously, liver disease was thought to be a common cause of death in renal allograft recipients. As blood transfusions have become less common in the dialysis population and hepatitis B virus less prevalent, the risk of death owing to hepatic disease seems to have diminished. Unfortunately, therapies for HCV-related hepatitis (interferon-) have proved to be of questionable efficacy and may stimulate rejection of the renal allograft [35–37].

13.10

Transplantation as Treatment of End-Stage Renal Disease

Musculoskeletal and Metabolic Complications

Change in density, %

0

Males Females Both genders

–3 *

–6

* *

–9

* * *

–12 18 0 6 Months after transplantation

FIGURE 13-23 Mean percentage changes in bone mineral density of the lumbar spine after transplantation. Substantial bone loss can occur quite early after transplantation. Metabolic bone disease in this setting is usually multifactorial. Most often, patients who had end-stage renal disease before transplantation already have some degree of renal osteodystrophy, exacerbated in some cases by the impact of aluminum toxicity or 2-microglobulin amyloidosis. Patients with diabetes are particularly at risk for low-turnover bone disease. Administration of corticosteroids and cyclosporine also contributes to bone loss. Although biochemical evidence of secondary hyperparathyroidism usually resolves during the first year after transplantation, some patients may have persistent parathyroid-driven bone resorption, with or without hypercalcemia, and may require surgical parathyroidectomy. Asterisk— values significantly different from those at the time of transplantation. (From Julian and coworkers [38]; with permission.)

FIGURE 13-24 Bone densitometry. Bone densitometry offers a noninvasive method to quantitate bone mass. Here, a renal transplant recipient demonstrates marked osteoporosis, with bone density greater than 2 standard deviations below age- and gender-matched controls. In recent years, new therapeutic options (including bisphosphonates, estrogens, and thiazides) have offered hope of preserving or even increasing bone mass [38,39]. BMD—bone mass density.

FIGURE 13-25 Magnetic resonance imaging of osteonecrosis. Osteonecrosis most commonly affects the femoral head but can affect any weightbearing bone. The most debilitating complication of renal transplantation, its incidence seems to be decreasing (<10% of transplant recipients). This decrease reflects better management of calcium and bone homeostasis during long-term dialysis and less intense steroid use after transplantation. The pathogenesis of osteonecrosis remains poorly understood, and therapeutic options are limited (pain management while awaiting progression to the need for joint replacement). Magnetic resonance imaging is a sensitive diagnostic method, allowing detection of osteonecrosis at a very early stage [39].

FIGURE 13-26 Photograph of gouty inflammation of joints (tophus). Gout is the clinical manifestation of hyperuricemia. After transplantation, cyclosporine can exacerbate hyperuricemia, and severe gout can be problematic even in the presence of chronic immunosuppression. Management of gouty arthritis usually involves some combination of colchicine and judicious use of short courses of nonsteroidal anti-inflammatory drugs. Concomitant administration of allopurinol and azathioprine can cause profound bone marrow suppression and is avoided by most physicians who treat transplant recipients. Because the metabolism of mycophenolate mofetil (MMF) is not dependent on xanthine oxidase, use of allopurinol in patients treated with MMF is relatively safe [39,40].

13.11

Medical Complications of Renal Transplantation

INCIDENCE OF POST-TRANSPLANT DIABETES MELLITUS PTDM (defined as requiring insulin ≥ 30 d)

Initial At 1 year At 18 mo

Prograf * (n=151) % n

CyA (n=151) % n

30 25 18

8 5 0

15.9 18.5 12.0

4.0 3.3 3.3

P value >0.001 >0.001

*Patients without history of diabetes.

FIGURE 13-27 Photograph of gingival hyperplasia. Gingival hyperplasia occurs in approximately 10% of transplant recipients treated with cyclosporine. Its severity reflects the interaction of effective dental hygiene, cyclosporine dose, and concomitant administration of calcium antagonists (particularly dihydropyridines). This complication does not seem to occur with use of tacrolimus, and complete resolution of gingival hyperplasia has been noted with conversion from cyclosporine-based therapy [25,41].

FIGURE 13-28 Post-transplantation diabetes mellitus (PTDM). PTDM complicates the course of treatment in 5% to 10% of patients on cyclosporinebased immunosuppressive therapy. It is more common in blacks and in patients with a family history of glucose intolerance. PTDM often reflects the substantial steroid-related weight gain that sometimes occurs after transplantation. The severity of PTDM can be attenuated by weight loss and corticosteroid withdrawal, although the latter may not be advisable owing to the risk of rejection. In a multicenter trial, PTDM occurred with greater frequency among patients treated with tacrolimus, particularly blacks. Although PTDM resolved over time in almost half of affected patients (as doses of tacrolimus and corticosteroids were gradually reduced), PTDM remained more common in patients receiving tacrolimus [25,42,43]. CyA—cyclosporine. (From Fujisawa USA [26]; with permission.)

Acknowledgments The author thanks his colleagues at the University of Alabama at Birmingham for contributing many of the illustrations used in this

chapter: Drs. Ralph Crowe, Bruce Julian, Catherine Listinsky, Brendan McGuire, Klaus Monckemuller and Colleen Shimazu.

References 1. 2.

3. 4.

5.

United States Renal Data System: 1996 Annual Data Report. Bethesda, MD: The National Institutes of Health; 1996. Suthanthiran M, Morris RE, Strom TB: Immunosuppressants: cellular and molecular mechanisms of action. Am J Kidney Dis 1996, 28:159–172. Venkataramanan R, Swaminathan A, Prasad T, et al.: Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet 1995, 29:404–430. Borel JF, Baumann G, Chapman I, et al.: In vivo pharmacological effects of cyclosporin and some analogues. Adv Pharmacol 1996, 35:115–246. Campana C, Regazzi MB, Buggia I, Molinaro M: Clinically significant drug interactions with cyclosporin. An update. Clin Pharmacokinet 1996, 30:141–179.

6. Blackstone EH, Naftel DC, Turner ME: The decompensation of time varying hazard into phases, each incorporating a separate stream of concomitant information. J Am Stat Assoc 1986, 81:615. 7. Kershner RP, Fitzsimmons WE: Relationship of FK506 whole blood concentrations and efficacy and toxicity after liver and kidney transplantation. Transplantation 1996, 62:920–926. 8. Gaya SBM, Rees AJ, Lechler RI, et al.: Malignant disease in patients with long-term renal transplantations. Transplantation 1995, 59:1705–1709. 9. Penn I: Cancers in cyclosporine-treated versus azathioprine-treated patients. Transplantation Proc 1996, 28:876–878. 10. Penn I: Occurrence of cancers in immunosuppressed organ transplantation recipients. In Clinical Transplantations 1994. Edited by Terasaki PI, Cecka JM, Los Angeles: UCLA Tissue Typing Laboratory; 1995, 99–109.

13.12

Transplantation as Treatment of End-Stage Renal Disease

11. Randhawa PS, Jaffe R, Demetris AJ, et al.: Expression of Epstein-Barr virus–encoded small RNA (by the EBER-1 gene) in liver specimens from transplantation recipients with post-transplantation lymphoproliferative disease. N Engl J Med 1992, 327:1710–1714.

27. Massy ZA, Ma JZ, Louis TA, Kasiske BL: Lipid-lowering therapy in patients with renal disease. Kidney Int 1995, 48:188–198. 28. Luke RG. Hypertension in renal transplantation recipients. Kidney Int 1987, 31:1024–1037.

12. Cockfield SM, Preiksaitis JK, Jewell LD, Parfrey NA: Post-transplantation lymphoproliferative disorder in renal allograft recipients. Transplantation 1993, 56:88–96.

29. Chapman JR, Marcen R, Arias M, et al.: Hypertension after renal transplantation. A comparison of cyclosporine and conventional immunosuppression. Transplantation 1987, 43:860–864. 30. Curtis JJ: Hypertension following kidney transplantation. Am J Kidney Dis 1994, 23:471–475.

13. Young L, Alfieri C, Hennessy K, et al.: Expression of Epstein-Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease. N Engl J Med 1989, 321:1080–1085. 14. Sun CH, Ward HJ, Wellington LP, et al.: Serum erythropoietin levels after renal transplantation. N Engl J Med 1989, 321:151–157. 15. Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group: A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation 1996, 61:1029–1037. 16. Sollinger HW, US Renal Transplantation Mycophenolate Mofetil Study Group: Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation 1995, 60:225–232. 17. Gaston RS, Julian BA, Curtis JJ: Posttransplantation erythrocytosis: an enigma revisited. Am J Kidney Dis 1994, 24:1–11. 18. Manske CL, Wilson RF, Wang Y, Thomas W: Atherosclerotic vascular complications in diabetic transplantation candidates. Am J Kidney Dis 1997, 29:601–607. 19. Manske CL, Thomas W, Wang Y, Wilson RF: Screening diabetic transplantation candidates for coronary artery disease: identification of a low risk subgroup. Kidney Int 1993, 44:617–621. 20. Manske C, Wang Y, Wilson RF, et al.: Coronary revascularization in insulin dependent diabetic patients with chronic renal failure. Lancet 1992, 340:998–1002. 21. Kasiske BL: Risk factors for accelerated atherosclerosis in renal transplantation recipients. Am J Med 1988, 84:987–992. 22. Massy ZA, Guijarro C, Wiederkehr MR, et al.: Chronic renal allograft rejection: immunologic and nonimmunologic risk factors. Kidney Int 1996, 49:518–524. 23. Bristol-Myers Squibb: Hyperlipidemia and atherosclerosis in organ transplantation: can we alter the natural history? Princeton: BristolMyers Squibb. 24. Grundy SM for the National Cholesterol Education Program: Second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Circulation 1994, 89:1329–1445. 25. Pirsch JD, Miller J, Deierhoi MH, et al.: A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. Transplantation 1997, 63:977–983. 26. Fujisawa USA, Inc.: Comparative trial of Prograf®-based therapy vs. cyclosporine-based therapy after cadaveric renal transplantation. Deerfield, IL: Fujisawa USA, Inc.

31. Gaston RS, Curtis JJ: Hypertension in renal transplant recipients. In Therapy in Nephrology and Hypertension. Edited by Brady HR, Wilcox CS. Philadelphia: W.B. Saunders Co; 1999:440–443. 32. Curtis JJ, Luke RG, Jones P: Hypertension in cyclosporine-treated renal transplantation recipients is sodium-dependent. Am J Med 1988, 85:134–138. 33. Curtis JJ, Luke RG, Whelchel JD, et al.: Inhibition of angiotensinconverting enzyme in renal transplantation recipients with hypertension. N Engl J Med 1983, 308:377–381. 34. Hricik DE, Browning PJ, Kopelman R, et al.: Captopril-induced functional renal insufficiency in patients with bilateral renal-artery stenoses or renal-artery stenosis in a solitary kidney. N Engl J Med 1983, 308:373–376. 35. Vosnides GG: Hepatitis C in renal transplantation. Kidney Int 1997, 52:843–861. 36. Pereira BJG, Levey AS: Hepatitis C virus infection in dialysis and renal transplantation. Kidney Int 1997, 51:981–999. 37. Knoll GA, Tankersley MR, Lee J, et al.: The impact of renal transplantation on survival in hepatitis C-positive ESRD patients. Am J Kidney Dis 1997, 29:608–614. 38. Julian BA, Laskow DA, Dubovsky J, et al.: Rapid loss of vertebral mineral density after renal transplantation. N Engl J Med 1991, 325:544–550. 39. Julian BA, Quarles LD, Niemann KMW: Musculoskeletal complications after renal transplantation: pathogenesis and treatment. Am J Kidney Dis 1992, 19:99–120. 40. Lin HY, Rocher LL, McQuillan MA, et al.: Cyclosporine-induced hyperuricemia and gout. N Engl J Med 1989, 321:287–292. 41. Noble S, Markham A: Cyclosporin: a review of the pharmacokinetic properties, clinical efficacy and tolerability of a microlesion-based formulation (Neoral). Drugs 1995, 50:924–941. 42. Jindal RM: Posttransplantation diabetes mellitus: a review. Transplantation 1994, 58:1289–1298. 43. Hricik DE, Mayes JT, Schulak JA: Independent effects of cyclosporine and prednisone on posttransplantation hypercholesterolemia. Am J Kidney Dis 1991, 18:353–358.

Technical Aspects of Renal Transplantation John M. Barry

R

enal transplantation is the preferred treatment method of endstage renal disease (ESRD). It is more cost-effective than is maintenance dialysis [1] and usually provides the patient with a better quality of life [2]. Adjusted mortality risk ratios indicate a significant reduction in mortality for kidney transplantation recipients when compared with that for patients receiving dialysis and patients receiving dialysis who are on a waiting list for renal transplantation (Fig. 14-1) [3]. The indication for renal transplantation is irreversible renal failure that requires or will soon require long-term dialytic therapy. The evaluation of candidates for renal transplantation is discussed in Chapter 12. Generally accepted contraindications are noncompliance, active malignancy, active infection, high probability of operative mortality, and unsuitable anatomy for technical success [4]. The technical aspects of kidney transplantation are discussed, primarily through the illustrations of kidney preparation and of a living donor renal transplantation. Kidneys from living donors require little preparation by the transplantation team because most of the dissection has already been done during the nephrectomy. Further separation of the renal artery or arteries from the renal vein(s) will allow separation of the arterial and venous suture lines in the recipient and will prevent the technical inconvenience of side-by-side anastomoses. The right kidney from a living donor usually has a cuff of the inferior vena cava attached to the renal vein. This provides the recipient team with maximum renal vein length and a wide lumen for anastomosis. The renal arteries in a kidney graft from a living donor are not attached to aortic patches as they usually are in the cadaveric kidney. The technical aspects of livingdonor harvesting are not illustrated here.

CHAPTER

14

14.2

Transplantation as Treatment of End-Stage Renal Disease

ADJUSTED MORTALITY RISK RATIOS FOR END-STAGE RENAL DISEASE BY TREATMENT MODALITY Treatment modality

Risk ratio

All patients on dialysis

1.0

Patients on dialysis who are on a waiting list

0.48

Cadaveric kidney transplantation recipients

0.32

Living-donor related kidney transplantation recipients

0.21

TECHNICAL CONSIDERATIONS FOR RECIPIENTS OF KIDNEY TRANSPLANTATION Kidney graft

Recipient

Right or left Gross appearance and size Arterial anatomy Venous anatomy Ureteral anatomy

Abdominal wall anatomy Size Arterial anatomy Venous anatomy Urinary tract anatomy and function Gender

Data from US Renal Data System [3].

FIGURE 14-1 The adjusted mortality risk ratio for patients on dialysis placed on the renal transplantation waiting list is greater than that for kidney transplantation recipients, suggesting transplantation itself results in a reduced mortality risk for patients with end-stage renal disease who are treated [3].

FIGURE 14-2 A number of factors concerning the kidney graft and recipient determine the technique of renal transplantation in each recipient. Placement of the kidney graft in the contralateral iliac fossa is preferable because the renal pelvis becomes the most medial of the vital renal structures and thus readily available for future reconstruction if ureteral stenosis occurs. Areas of previous abdominal surgery such as ileostomy, colostomy, renal transplantation, or a peritoneal dialysis exit site are avoided, if possible. A kidney too large for the recipient’s iliac fossa is usually placed in the right retroperitoneal space and revascularized with the aorta or common iliac artery and interior vena cava or common iliac vein. Pelvic vascular disease and previous renal transplantation determine whether the aorta or internal iliac, external iliac, common iliac, native renal or splenic artery will be selected for renal artery anastomosis. The use of both internal iliac arteries in serial renal transplantations in men is avoided to prevent impotence [5]. The method of urinary tract reconstruction depends primarily on the status of the recipient’s bladder, continent reservoir, or incontinent intestinal conduit.

Cadaveric Kidney Graft FIGURE 14-3 Instrument setup for cadaveric kidney graft preparation. The towel prevents renal movement during dissection.

Technical Aspects of Renal Transplantation FIGURE 14-4 Preparation of a left cadaveric kidney graft. The kidney and its vital structures are surrounded by other tissues. The cadaveric kidney graft can require an hour of preparation time because the specimen usually includes a portion of the inferior vena cava, an aortic cuff, the adrenal gland, variable amounts of perinephric tissue, sometimes pieces of muscle, and occasionally damaged renal vessels.

FIGURE 14-6 Renal artery dissection. In this posterior view, the aortic patch and main renal artery have been separated from the surrounding tissues.

14.3

FIGURE 14-5 Renal vein dissection. The adrenal and gonadal veins have been isolated. They will be divided between ligatures.

FIGURE 14-7 Left cadaver kidney graft after preparation. The adrenal gland and excess perinephric tissue have been removed. Fibrofatty tissue is left around the renal pelvis and ureter to ensure blood supply to the ureter. The aortic patch, renal vein, and ureter will be further modified to provide a “best fit” in the recipient.

14.4

Transplantation as Treatment of End-Stage Renal Disease

Preparation of Kidney Graft Vessels FIGURE 14-8 Venoplasties for right renal vein extension of a cadaveric kidney graft [6–8]. A–C, Use being made of the inferior vena cava. D,Use being made of the external iliac vein of the cadaveric donor.

A

A

B

C

B

D

C E

or

FIGURE 14-9 Preparation of the renal allograft with multiple renal arteries [9]. A and B, The use of aortic patches when the kidney is from a cadaveric donor is demonstrated. C and D, The possibilities that exist when an aortic patch is not part of the specimen, such as when the kidney is from a living donor. E, The segmental renal artery also can be anastomosed to the inferior epigastric artery using an endto-end technique.

D

The Kidney Transplantation Operation DIVISION OF OPERATING ROOM RESPONSIBILITIES FOR RECIPIENTS OF KIDNEY TRANSPLANTATION Anesthesiologist

Surgeon

Anesthetic induction Placement of central venous access line Administration of antibiotics Administration of immunosuppressants Administration of heparin Assurance of conditions for diuresis

Patient position Bladder catheterization Initial skin preparation Incision and exposure of operative site Renal revascularization Urinary tract reconstruction Wound closure

FIGURE 14-10 After the induction of anesthesia, the anesthesia team places a double- or triple-lumen central venous access catheter, usually via the internal jugular vein. While that is taking place, the surgical team places a retention catheter (usually 20F with a 5-mL balloon), fills the bladder to 30 cm H2 pressure or 250 mL (whichever occurs first), connects the catheter to a three-way system or clamped urinary drainage system, and places the clamp(s) within reach of the anesthesiologist for control during the operation. The preoperative antibiotic is administered by the anesthesia team. The surgical team shaves both sides of the patient’s abdomen from just above the umbilicus to the distal edge of the mons pubis. The skin is wiped with alcohol, and the nursing team completes the skin preparation. The skin over both iliac fossae is prepared in the event an unexpected vascular contraindication is detected on the chosen side. If immunosuppressant therapy has not been administered, the anesthesia team begins that protocol.

Technical Aspects of Renal Transplantation

14.5

Adult Recipient

FIGURE 14-11 Surgeon’s view of the right iliac fossa operative site. In this procedure, a 40-year-old man will be receiving his brother’s left kidney, which has a single artery, single vein, and single ureter. The renal vessels will be anastomosed to his right external iliac artery and vein, and urinary tract reconstruction will be by extravesical ureteroneocystostomy [10,11]. The patient is positioned with the head slightly down, supine, and rotated toward the surgeon, who is standing on the patient’s left side.

FIGURE 14-12 (see Color Plate) Exposure of the right iliac fossa. The contents of the iliac fossa are exposed by incising the skin, subcutaneous tissues, anterior rectus sheath, external and internal oblique muscles, and the transversalis muscle and fascia. The inferior epigastric artery is divided between ligatures, the spermatic cord is preserved (in women, the round ligament is divided between ligatures), and the rectus muscle and peritoneum are retracted medially. This exposes the genitofemoral nerve (white umbilical tape), the external iliac vein (blue tape), and the external and internal iliac arteries (red tapes).

FIGURE 14-13 Determining “best fit.” The kidney graft is placed in the wound and the renal vessels stretched to the recipient vessels to determine the best sites for the arterial and venous anastomoses.

FIGURE 14-14 Isolation of the arteriotomy site. Heparin (30–50 U/kg) is administered intravenously, and vascular clamps are placed on the external iliac artery. The distal clamp is applied first so that the arterial pressure will distend the targeted artery. The external iliac artery is incised longitudinally, the lumen is irrigated with heparinized saline, and fine monofilament vascular sutures are placed in four quadrants to receive the spatulated renal artery. When the recipient artery has significant arteriosclerosis, an endarterectomy can be done or a 5- or 6-mm aortic punch can be used to create a smooth round arteriotomy.

14.6

Transplantation as Treatment of End-Stage Renal Disease

FIGURE 14-15 Completed end-to-side renal artery–to–external iliac artery anastomosis. Many surgeons perform the arterial anastomosis first because it is smaller than is the venous anastomosis. Thus, the kidney can be moved about more easily to expose the arterial anastomosis when it is not tethered by a previously completed venous anastomosis. An ice-cold electrolyte solution is periodically dripped onto the kidney graft to keep it cold during vascular reconstruction.

FIGURE 14-16 Isolation of the right external iliac vein. The kidney is retracted medially, and a segment of the external iliac vein is isolated between Rumel tourniquets. The cephalad tourniquet is applied first so that increased venous pressure will dilate the vein.

FIGURE 14-17 Renal vein anastomotic setup. The renal vein is anastomosed to the side of the external iliac vein with the same suture technique that was used for the arterial anastomosis.

FIGURE 14-18 Completed venous and arterial anastomoses.

Technical Aspects of Renal Transplantation

14.7

FIGURE 14-19 Revascularized kidney transplantation. The usual clamp release sequence is as follows: proximal vein, distal artery, proximal artery, and distal vein. Arterial spasm is treated by subadventitial injection of papaverine.

FIGURE 14-20 Urinary tract reconstruction [10–11]. Unstented parallel incision extravesical ureteroneocystostomy requires a bladder full of antibiotic solution, clearance of fat from the superolateral surface of the bladder, and placement of the ureter under the spermatic cord to prevent ureteral obstruction. Parallel incisions are made 2 cm apart in the seromuscular layer of the bladder to expose the bladder mucosa.

FIGURE 14-21 Submucosal tunnel creation. A right-angle clamp is used to develop the tunnel and to pull the transplantation ureter through it.

FIGURE 14-22 Bladder mucosa incision. After the ureter is spatulated on its ventral surface, single-armed 5-0 absorbable sutures are placed in the “heel” and in each of the “dog-ears” of the ureter. A double-armed horizontal mattress suture of the same material is placed in the “toe” of the ureter so that the needles exit on the mucosal side. The bladder is drained by unclamping the catheter tubing, and the bladder mucosa is incised.

14.8

Transplantation as Treatment of End-Stage Renal Disease

FIGURE 14-23 Partially completed ureteral anastomosis. The “heel” and “dog-ears” of the spatulated ureter have been sutured to the bladder mucosa. The horizontal mattress suture will be passed through the full thickness of the bladder wall and tied distal to the seromuscular incision. This will close the “toe” and anchor the ureter to the bladder.

FIGURE 14-24 Completed ureteroneocystostomy. The distal seromuscular incision has been closed over the ureter, which now lies in a submucosal tunnel.

FIGURE 14-25 Deep wound closure. A suction drain has been placed around the kidney graft deep in the wound, and the musculofascial interrupted sutures are ready to be tied.

FIGURE 14-26 Completed wound closure. Scarpa’s fascia has been closed over the musculofascial sutures, and the skin has been closed with a 4-0 absorbable subcuticular suture. This procedure accurately approximates the skin and eliminates subsequent staple or skin suture removal.

Technical Aspects of Renal Transplantation

14.9

DIURESIS ENHANCEMENT IN KIDNEY TRANSPLANTATION Living-donor kidney transplantation

Cadaveric kidney transplantation

Maintain CVP 5–10 cm H2O Maintain MAP ≥ 60 mm Hg Maintain SBP ≥ 90 mm Hg Mannitol, 0.20 g/kg, IV over 1 h, start with first vascular anastomosis Furosemide, 0.20 mg/kg, IV during second half of second vascular anastomosis

Same Same Same Increase mannitol dose to 1 g/kg (maximum 50 g) IV Increase furosemide dose to 1 mg/kg IV Albumin, 1 g/kg (to 50 g), IV over 2–3 h Verapamil, 0–10 mg, into renal artery based on blood pressure and weight

FIGURE 14-27 Artist’s depiction of the completed kidney transplantation.

CVP—central venous pressure; IV—intravenous; MAP—mean arterial pressure; SBP—systemic blood pressure. Modified from Dawidson and Ar’Rajab [12].

FIGURE 14-28 Maneuvers for diuresis enhancement [12]. Several intraoperative maneuvers can be used to promote diuresis.

Child Recipient FIGURE 14-29 Transplantation of a kidney from an adult into a small child. The technique is modified for transplantation of a large kidney into a small recipient. The renal artery is anastomosed to the distal aorta or common iliac artery, and the shortened renal vein is anastomosed to the interior vena cava or common iliac vein.

14.10

Transplantation as Treatment of End-Stage Renal Disease

Postoperative Care FIGURE 14-30 Postoperative clinical pathway.

POSTOPERATIVE CARE DURING HOSPITALIZATION AFTER KIDNEY TRANSPLANTATION Remove on 5th postoperative day, administer dose of antibiotic Remove 6–12 wk postoperatively in clinic Remove when ≤ 30 mL/24 h or in 3 wk if volume > 30 mL/24 h Discontinue in 24–48 h (check intraoperative culture results first) Patient-controlled analgesia Living donor: fixed rate of 125–200 mL/h of D5W in 0.45% normal saline Cadaveric donor: replace insensible loss with D5W, replace urine output mL for mL with 0.45% normal saline Immunosuppressants Protocol (covered in Chapter 11) Protocol (covered in Chapter 10) Infection prevention Peptic ulcer prevention Protocol (covered in Chapter 12) Foley catheter Ureteral stent, if used Suction drain(s) Antibiotics Pain control Intravenous fluids

IV—intravenous.

Urologic Complications Evaluation of kidney transplantation hydronephrosis Hydronephrosis

Radioisotope venogram + furosemide wash-out

T1/2 < 10–20 min

T1/2 10–20 min

T1/2 > 10–20 min

Percutaneous nephrostomy

Percutaneous nephrostomy

Nephrostogram

Nephrostogram

Nephrostomy drainage plus serial serum creatinine levels No

No repair

or

Obstruction ?

Whitaker test

Yes

Repair

FIGURE 14-31 Algorithm for evaluation of kidney transplantation hydronephrosis [9]. The generally accepted criterion for exclusion of upper urinary tract obstruction is a washing out of half of the radioisotope from the renal pelvis in less than 10 minutes. Obstruction is considered to be present when this value is over 20 minutes. Percutaneous nephrostomy allows anatomic definition of the obstruction and temporary drainage of the hydronephrotic kidney. A generally accepted criterion for the diagnosis of obstruction with the percutaneous pressure-flow Whitaker test is fluid infusion into the pelvis at the rate of 10 mL/min, resulting in a renal pelvic pressure over 20 cm H2O.

Technical Aspects of Renal Transplantation

FIGURE 14-32 Causes of renal transplantation ureteral obstruction. Hydronephrosis owing to ureteral obstruction is one of the two most common urologic complications for which invasive therapy is required, the other being perigraft fluid collection. Early causes of ureteral obstruction are usually apparent within the first few days after renal transplantation. Late causes become apparent weeks to years later.

CAUSES OF KIDNEY TRANSPLANTATION URETERAL OBSTRUCTION Cause

Early

Blood clot Edema Technical error Lymphocele Ischemia Periureteral fibrosis Stone Tumor

X X X X

Late

X X X X X

Evaluation of treatment of perigraft fluid collection Perigraft fluid collection > 50 mL ? Hydronephrosis ? Decreased renal function ? Ipsilateral leg swelling ? Fever ? Pain ?

"No" to all

"Yes" to any Aspirate

Serum

Lymph

Urine

Blood

Pus

Repeat ultrasound No

Significant recurrence ? Yes

Restudy as necessary

14.11

Serum

Lymph

Repair

Urine

Blood

Explore

Drain

FIGURE 14-33 Algorithm for evaluation and treatment of perigraft fluid collection [9]. Perigraft fluid collection is one of the two most common urologic complications for which invasive therapy is required, the other being hydronephrosis owing to ureteral obstruction. Serum, urine, lymphatic fluid, blood, and pus can be differentiated by creatinine and hematocrit determinations and by microscopic examination of the fluid. Urine has a high creatinine level, serum and lymphatic fluid have low creatinine levels, and blood has a relatively high hematocrit level. Lymphocytes are present in lymphatic fluid, and polymorphonuclear leukocytes with or without organisms are present in pus. Open surgical drainage is usually necessary for fluid collections showing infection. Significant lymphoceles have been successfully treated with percutaneous sclerosis or by marsupialization into the peritoneal cavity by either a laparoscopic or open surgical technique. Persistent urinary extravasation often requires open surgical repair. Significant bleeding requires exploration and control of bleeding.

14.12

Transplantation as Treatment of End-Stage Renal Disease

Results of Renal Transplantation US KIDNEY GRAFT SURVIVAL RATES FOR TRANSPLANTATIONS DONE FROM 1991 TO 1995 Donor

Number

1 y, %

5 y, %

10 y (projected), %

Cadaver Living

36,417 13,771

84 92

60 75

43 62

Data from Cecka [13].

FIGURE14-34 The 5-year patient survival rates for recipients of cadaveric and livingdonor kidney transplantations were 81% and 90%, respectively [13]. Kidney transplantation survival rates have steadily improved since the 1970s because of the following: careful recipient selection and preparation, improvement in histocompatibility techniques and organ sharing, contributions from our colleagues in government and the judiciary, improvements in immunosuppressive therapy and infection control, careful monitoring of recipients, and refinement of surgical techniques. What we accomplish today as a matter of routine was only imagined by a few just decades ago.

References 1.

2.

United Network for Organ Sharing: The UNOS Statement of Principles and Objectives of Equitable Organ Allocation. UNOS Update 1994, 10:20. Evans RW, Manninea DL, Garrison LP, et al.: The quality of life of patients with end-stage renal disease. N Engl J Med 1985, 312:553.

3.

US Renal Data System, USRDS 1997 Annual Data Report, National Institutes of Health, Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases, 1997:72–73.

4.

Nohr C: Non-AIDS immunosuppression. In Care of the Surgical Patient, Vol. 2. Edited by Wilmore DW, Brennan MF, Harken AH, et al. New York: Scientific American; 1989:1–18.

5.

Gittes RF, Waters WB: Sexual impotence: the overlooked complication of a second renal transplant. J Urol 1979, 121:719. Barry JM, Fuchs EF: Right renal vein extension in cadaver kidney transplantation. Arch Surg 1978, 113:300.

6. 7.

Corry RJ, Kelly SE: Technique for lengthening the right renal vein of cadaver donor kidneys. Am J Surg 1978, 135:867.

8. Barry JM, Hefty TR, Sasaki T: Clam-shell technique for right renal vein extension in cadaver kidney transplantation. J Urol 1988, 140:1479. 9. Barry JM: Renal transplantation. In Campbell’s Urology. Edited by Walsh PC, Retik AB, Vaughan ED, Wein AJ. Philadelphia: WB Saunders Co, 1997:505–530. 10. Barry JM: Unstented extravesical ureteroneocystostomy in kidney transplantation. J Urol 1983, 129:918. 11. Gibbons WS, Barry JM, Hefty TR: Complications following unstented parallel incision extravesical ureteroneocystostomy in 1000 kidney transplants. J Urol 1992, 148:38. 12. Dawidson IJA, Ar’Rajab A: Perioperative fluid and drug therapy during cadaver kidney transplantation. In Clinical Transplants 1992. Edited by Terasaki PI, Secka JM. Los Angeles: UCLA Tissue Typing Laboratory; 1993:267–284. 13. Cecka JM: The UNOS Scientific Renal Transplant Registry. In Clinical Transplants 1996. Edited by Terasaki PI, Cecka JM. Los Angeles: UCLA Tissue Typing Laboratory; 1997:114.

Kidney-Pancreas Transplantation John D. Pirsch Jon S. Odorico Hans W. Sollinger

I

n the United States, diabetes mellitus is the third most common disease and fourth leading cause of death from disease. Diabetes is the leading cause of blindness, the number one cause of amputations and impotence, and one of the most frequently occurring chronic childhood diseases. Diabetes is also the leading cause of end-stage renal disease in the United States, with a prevalence rate of 31% compared with other renal diseases. Diabetes is also the most frequent indication for kidney transplantation, accounting for 22% of all transplantation operations. Increasingly, pancreas transplantation is being offered to patients who would benefit from kidney transplantation (called simultaneous pancreas-kidney transplantation) or who have had a previously successful kidney transplantation (called sequential pancreas after kidney transplantation). Relatively few transplantation centers are performing pancreas transplantation alone in patients with severe life-threatening complications of diabetes. Pancreas transplantation has been criticized because of the increased morbidity associated with the procedure and lack of controlled trials demonstrating significant benefit to the secondary complications of diabetes. However, many of these criticisms have been overcome with improvement in surgical techniques and pancreas transplantation preservation and with more potent immunosuppressive regimens. The relative frequency of pancreas transplantation, common surgical procedures, and outcomes of patients undergoing pancreas transplantation are discussed.

CHAPTER

15

15.2

Transplantation as Treatment of End-Stage Renal Disease Urologic 2%

Unknown 6%

Unknown 6% Other 11%

PCKD 5%

Other 18%

Nephritis 8% GN 19%

PCKD 8%

DM 31%

GN 26%

HTN 12%

HTN 26%

Diabetes 22%

FIGURE 15-1 Disease prevalence resulting in end-stage renal disease (ESRD) from the United States Renal Data Service (1993 to 1995). In the continental United States at the end of 1995, 257,266 patients had ESRD. Diabetes mellitus (DM) accounts for nearly one third of all patients newly diagnosed with ESRD who require kidney transplantation. GN—glomerulonephritis; HTN—hypertensive nephropathy; PCKD—polycystic kidney disease.

1200

Total US NonUS

FIGURE 15-2 Kidney transplantations by diagnosis (October 1987 through December 1994). Approximately 10,000 patients receive kidney transplantations in a given year. Of the primary renal diseases requiring transplantation, diabetes accounted for 22% of all kidney transplantations performed in the United States. GN—glomerulonephritis; HTN—hypertensive nephropathy; PCKD—polycystic kidney disease.

n=9012 n=6640 n=2372 157 774

1000

800

201 528

181 530

90

91

201 417 600

400

200

32 66

6 9

11 8

78

79

19 20

30 24

36 38

80

81

82

85 50

112 51

111 112

147 170

218 146

130 1027

115 1022

95

96

167 842

200 557

213 249

0 Pre78

83

84

85

86

87

88

89

Year

FIGURE 15-3 Pancreas transplantations per year. The number of pancreas transplantations performed per year in the United States has been increasing. In 1995 and 1996, over 1000 pancreas transplantations were performed in the United States. A smaller number were performed outside of the United States.

92

93

94

15.3

Kidney-Pancreas Transplantation

8000

INCLUSION CRITERIA FOR PANCREAS TRANSPLANTATION

7000

Recipient number

6000

Type I diabetes mellitus Ability to undergo the procedure Emotional and psychological stability Age less than 60 y Secondary complications of diabetes Financial resources

5000 4000 3000 2000 1000 0 1988

1989

1990

1991

1992

1993

1994

1995

Year

FIGURE 15-4 Relative proportion of simultaneous pancreas-kidney (SPK) transplantations versus cadaveric kidney transplantations in the United States. Despite an increasing number of SPK transplantations over the past 7 years, pancreas transplantation is a less common procedure than is cadaveric kidney transplantation alone.

1000

EXCLUSION CRITERIA FOR PANCREAS TRANSPLANTATION

Number of transplants

800 Significant cardiac disease Substance abuse Psychiatric illness History of noncompliance Extreme obesity Active infection or malignancy No secondary complications of diabetes

FIGURE 15-5 The inclusion criteria for pancreas transplantation are relatively few. Patients usually have type I diabetes mellitus and must have the physical stamina to undergo a major abdominal operation. The patient’s age is important, with 60 years of age usually being the cutoff. In some transplantation centers, the cutoff age is 50 years. The patient should demonstrate emotional and psychological stability, and significant secondary complications of diabetes must be present. Because Medicare does not pay for pancreas transplantations, recipients must use either private insurance or personal funds.

SPK PTA PAK

600

400

200

FIGURE 15-6 The exclusion criteria for pancreas transplantation include significant cardiac disease, substance abuse, psychiatric illness, and a history of noncompliance. Extreme obesity, active infection, and malignancy are relative contraindications to transplantation. Patients with few or very mild secondary complications of diabetes may be candidates for kidney transplantation alone.

0 1988

1989

1990

1991

1992

1993

1994

1995

1996

Year

FIGURE 15-7 Types of pancreas transplantation procedures and relative frequency per year (January 1988 through December 1996). Three different indications for pancreas transplantation exist. Patients with type I insulin-dependent diabetes who require kidney transplantation may undergo a simultaneous pancreas-kidney (SPK) transplantation or receive a kidney transplantation followed by a pancreas transplantation during a separate operation (called pancreas after kidney [PAK] transplantation). Patients without significant renal disease may undergo pancreas transplantation alone (PTA). The relative proportion of the types of transplantations is shown. Most pancreas transplantations performed in the United States are of the SPK type, followed by PAK transplantations. Presently, few PTA transplantations are performed.

15.4

Transplantation as Treatment of End-Stage Renal Disease

Transplantation Operation

FIGURE 15-8 Simultaneous pancreas-kidney allograft procedure. Most pancreas transplantations performed in the United States are whole organ pancreaticoduodenal allografts from cadaveric donors transplanted simultaneously with the kidney from the same donor [1]. Because the pancreas from a patient with diabetes still subserves digestive function, it is not removed. Therefore, the pancreaticoduodenal allograft is transplanted to an ectopic location, usually the right iliac fossa. Similarly, the kidney allograft is transplanted ectopically to the contralateral iliac fossa. The reconstructed arterial supply to the pancreas, as shown in Figure 15-9, is anastomosed to the common

or external iliac artery. The portal vein of the allograft is anastomosed to the common iliac vein or distal inferior vena cava. Likewise, on the left side the renal artery and vein are anastomosed to the common iliac artery and vein, respectively. To restore the continuity of the urinary tract, a standard ureteroneocystostomy is constructed to the dome of the bladder. Because the pancreas has dual endocrine and exocrine functions, it is necessary to perform another anastomosis to handle exocrine secretions. A variety of techniques to manage pancreatic exocrine secretions have been proffered over the years with less than satisfactory results. These include duct occlusion, open drainage into the peritoneal cavity, and creation of a button of duodenum and anastomosing this or the pancreatic duct directly to the bladder. Currently, the most commonly performed technique in the United States is drainage of pancreatic exocrine secretions into the bladder (bladder drainage, BD), as depicted [1]. The BD technique involves fashioning a short segment of donor duodenum, which is transplanted along with the pancreas. Then the donor duodenum is anastomosed to the dome of the recipient bladder in a side-to-side manner. In this way exocrine secretions, including enzymes, proenzymes, water, and sodium bicarbonate, are diverted into the urinary tract. This technique is safe, reliable, and well tolerated; however, it is associated with a number of specific urinary tract complications. As a consequence of implantation into the iliac fossa, the pancreatic allograft is drained into the systemic venous circulation, as depicted. This results in systemic venous, rather than portal venous, insulin release and peripheral hyperinsulinemia. An alternative approach practiced by some surgeons is portal venous drainage. In this approach the portal vein of the allograft is anastomosed to the superior mesenteric vein of the recipient in an end-to-side fashion. This technique establishes drainage of insulin into the portal venous blood flow, perhaps a more physiologic situation (procedure not shown). The results of the two techniques are largely comparable. Fortunately, patients have suffered no adverse effects of systemic venous drainage and hyperinsulinemia. Solitary pancreaticoduodenal allografts are implanted into either iliac fossa, at whichever point the iliac vessels permit vascular anastomoses. This procedure is done, usually and preferentially, on the right side. Otherwise, the operative sequence duplicates that of the combined procedure.

Kidney-Pancreas Transplantation

Ligated splenic A and V

Splenic A

15.5

Iliac “Y” graft Ligated CBD

SMA Ligated SMA and SMV

FIGURE 15-9 Preparation of the pancreaticoduodenal allograft and arterial reconstruction. The donor pancreas, duodenum, and spleen are perfused in situ with cold University of Wisconsin solution and harvested en bloc with the liver. The pancreaticoduodenal graft is separated from the liver graft and prepared on the surgical back table at 4oC. The spleen is first removed by ligating the splenic artery and vein. The duodenal segment is shortened to approximately 10 cm, and the suture lines are reinforced. The common bile duct (CBD) and the superior mesenteric artery and vein (SMA and SMV) have been ligated previously in the donor. A variety of techniques exist to reconstruct the dual arterial blood supply to the pancreas. In our experience, the most favorable approach entails using an iliac artery bifurcation graft harvested from the same donor. As shown, the external iliac arterial limb of the graft is anastomosed to the SMA, and the hypogastric arterial limb is anastomosed to the splenic artery. This technique is reliable and associated with a very low thrombosis rate. The venous anastomosis (portal vein to iliac vein or inferior vena cava) can be performed without tension by complete mobilization of both the donor portal vein and the recipient iliac vein. A venous extension graft is rarely necessary and probably increases the risk of thrombosis.

FIGURE 15-10 Enteric drainage (ED) technique. An alternative approach to bladder drainage, ED is, perhaps, a more physiologic method of handling pancreatic exocrine secretions. ED is the preferred method in Europe and is rapidly gaining popularity in the United States [1]. Most commonly, it is performed as depicted without a Roux-en-Y anastomosis. The donor duodenal segment is anastomosed in a side-to-side fashion to the ileum or distal jejunum. Long-term graft survival, thrombosis rates, and primary nonfunction rates are no different when comparing the two techniques [1–3]. Performed with expertise, both techniques should yield excellent results. Several significant advantages of the ED technique over bladder drainage make ED our technique of choice.

15.6

Transplantation as Treatment of End-Stage Renal Disease

COMPARISON OF BLADDER DRAINAGE VERSUS ENTERIC DRAINAGE TECHNIQUES Bladder drainage (BD)

Enteric drainage (ED)

Advantages Ability to monitor urinary amylase levels as an indicator of rejection [6] ?Decreased risk of perioperative intra-abdominal infections

Advantages No need for enteric conversion in up to 25% of patients who have urologic complications Less metabolic acidosis and chronic dehydration [3] Shorter length of hospital stay secondary to less dehydration Early removal of urinary catheter and fewer UTIs Ability to perform portal venous drainage, if desired Disadvantages ?Increased risks of perioperative peripancreatic infections Difficult to diagnose pancreatic enzyme leaks

Disadvantages Risks of developing urologic complications in up to 25% of patients, including urethritis, urethral disruption, and hematuria Risk of recurrent UTIs greater for BD than for ED [3] Prolonged urinary catheter drainage needed to decompress bladder anastomosis for healing Frequent postoperative admissions for dehydration and metabolic acidosis and need for bicarbonate replacement UTIs—urinary tract infections.

FIGURE 15-11 Early attempts using enteric drainage (ED) techniques resulted in prohibitively high rates of intra-abdominal abscesses, wound infections, and mycotic aneurysms threatening both graft and patient. Thereafter, bladder drainage (BD) via a duodenocystostomy evolved in the United States as the safest and most frequently performed exocrine drainage procedure. It has been suggested that BD affords the ability to monitor urinary amylase levels as an indicator of rejection, which may be useful in the setting of a solitary pancreas transplant. However, in recipients of simultaneous pancreas-kidney (SPK) transplant in whom kidney function serves as a marker of rejection monitoring of urinary amylase levels is not necessary to achieve excellent long-term graft survival. As experience grew with BD, however, it was found that up to 25% of patients with BD developed a significant urologic or metabolic complication requiring surgical conversion of exocrine secretions to ED [4,5]. Renewed interest in primary ED has resulted. Several

recent retrospective studies have compared BD pancreas transplants to ED transplants. These studies have demonstrated equivalent short-term graft survival rates without increased risks of infectious complications and pancreatic enzyme leaks [1–3]. ED is associated with fewer urinary tract infections (UTIs) and no hematuria. Patients who have ED experience less dehydration and metabolic acidosis and, as a result, a reduced need for fluid resuscitation and bicarbonate supplementation [3]. Finally, in patients who have ED the Foley catheter can be removed within several days, whereas patients who have BD require prolonged drainage (up to 14 days) to permit healing of the duodenocystostomy. Consequently, with ED, patients are able to leave the hospital sooner. ED has proved to be more physiologic and results in less morbidity compared with BD. Therefore, ED is rapidly gaining popularity as the method of choice for handling graft exocrine secretions in pancreas transplantation.

Kidney-Pancreas Transplantation

15.7

Immunosuppression and Monitoring IMMUNOSUPPRESSIVE PROTOCOLS SPK

PAK and PTA

ATGAM (20 mg/kg/d for 10 d) MMF (3 g/d) Neoral® (8 mg/kg/d) Prednisone (500 mg intraoperatively; 250 mg on postoperative days 1 and 2; 30 mg/d thereafter)

ATGAM (20 mg/kg/d for 10 d) or OKT3 (5–10 mg/d for 10 d) MMF (2 g/d) FK506 (8 mg/d) Prednisone (500 mg intraoperatively; 250 mg on postoperative days 1 and 2; 30 mg/d thereafter)

ATGAM—antithymocyte globulin, polyclonal serum; FK506— tacrolimus, Prograf (Fujisawa USA, Inc., Deerfield, IL); MMF—mycophenolate mofetil, RS-61443, CellCept (Roche Laboratories, Nutley, NJ); OKT3—muromonab, murine antihuman CD3 monoclonal antibody; PAK—pancreas after kidney transplantation; PTA—pancreas transplantation alone; SPK—simultaneous pancreas-kidney transplantation.

FIGURE 15-12 Because the best treatment of rejection is prevention, the most efficacious regimen of immunosuppressive drugs should be used first. Quadruple-drug immunosuppressive regimens, including the use of antithymocyte globulin (ATGAM) or OKT3, have been accepted as standard at most pancreas transplant centers. Recent data from the United Network for Organ Sharing and several smaller retrospective comparative trials provide evidence that anti–T-cell antibody induction therapy may lessen the severity and delay the onset of rejection and may improve short-term graft survival in recipients of simultaneous pancreas-kidney (SPK) transplants [1,7,8]. This is the current practice. The development of newer more specific immunosuppressive agents, however, recently has changed the face of modern immunosuppression in solid organ transplantation and raises the possibility of successful pancreas transplantation without induction therapy. Mycophenolate mofetil (MMF) has recently replaced azathioprine (AZA) as maintenance immunosuppressive therapy in kidney transplantation alone, SPK, and pancreas transplantation alone. MMF is a potent noncompetitive reversible

inhibitor of inosine monophosphate dehydrogenase (IMPDH). IMPDH is an essential enzyme in the de novo purine synthetic pathway upon which lymphocyte DNA synthesis and proliferation are strictly dependent. Compared with AZA, MMF has no association with pancreatitis and has less association with leukopenia. Moreover, whereas AZA is not useful in treating ongoing rejection, MMF can salvage refractory acute renal allograft rejection in up to half of patients. By virtue of this mechanism of action, MMF provides more effective and specific immunosuppression with less risk compared with AZA. Similarly, Neoral, a microemulsified formulation of cyclosporine (CsA) has replaced standard CsA therapy with Sandimmune (both drugs from Sandoz Pharmaceuticals, East Hanover, NJ). Because of gastroparesis and autonomic dysfunction, patients with diabetes exhibit unpredictable absorption of CsA. The new formulation of CsA has an increased rate and extent of drug absorption with lower inter- and intra-individual pharmacokinetic variability than does Sandimmune, particularly in patients with diabetes. Improved bioavailability and more reliable pharmacokinetics may translate into fewer rejection episodes and improved graft survival. Experience with tacrolimus (FK506) in pancreas transplantation for induction, maintenance, and rescue therapy has demonstrated that it is safe, well tolerated, and has a low risk of glucose intolerance. Moreover, particularly for solitary pancreas transplants, strikingly improved short-term graft survival results have been reported [9,10]. The mechanism of action of FK506 as a calcineurin inhibitor is similar to that of CsA. FK506 has a better side-effect profile compared with CsA, causing less hirsutism, less hyperlipidemia, but somewhat more neurotoxicity. Unlike CsA, FK506 can rescue patients with refractory rejection and treat ongoing rejection. One caveat when using FK506 in combination with MMF is the risk of overimmunosuppression. Several studies have highlighted the fact that FK506 may increase blood levels of the active metabolite of MMF, mycophenolic acid, in a clinically relevant manner [11]. By reducing the incidence of rejection, these modern immunosuppressants have resulted in improved short- and long-term graft survival. Fewer rejection episodes will likely translate into an overall reduction in the glucocorticoid dosage being given in the perioperative period. This reduction may favorably impact short-term infectious complications and long-term steroid-related adverse side effects.

15.8

A

B

C

Transplantation as Treatment of End-Stage Renal Disease FIGURE 15-13 (see Color Plate) Pancreas transplantation biopsy. Pancreas allograft biopsy is the gold standard for evaluating pancreas allograft dysfunction and for diagnosing acute rejection. In a pancreas transplantation recipient, indications for the need of a biopsy to rule out rejection include elevated amylase or lipase levels, unexplained fever, and glucose intolerance. In patients with simultaneous pancreas-kidney (SPK) transplantation, pancreas rejection most commonly (about 90%) occurs simultaneously with kidney rejection. As a result, a diagnosis of rejection relies almost entirely on serum creatinine, b2-microglobulin, and renal allograft biopsy. However, in the setting of sequential pancreas after kidney transplantation or pancreas transplantation alone (PTA) in which isolated pancreas rejection occurs, predicting rejection with a serologic or urinary marker is more difficult. To date, no marker has been identified that can predict rejection accurately enough to warrant treatment without first performing a biopsy. Thus, the ability to perform pancreas allograft biopsy is essential in the postoperative care of recipients of PTA. In addition to a biopsy, radiologic evaluation of the allograft with ultrasonography (to evaluate vascular flow) and computed tomography (CT) scan (to rule out pancreatic enzyme leaks and fluid collections) are complementary studies that deserve consideration for all episodes of allograft dysfunction. Percutaneous core biopsies of the pancreas allograft with realtime ultrasonography or CT guidance have been shown to be safe and reliable [12–14]. A and B, After the gland is assessed for vascular patency an appropriate portion of the pancreas is identified that is free of major vessels and overlying viscera (usually the body or tail). C, A 20-gauge automated biopsy needle is advanced into the pancreas graft under real-time ultrasonography, and a biopsy is obtained. In pancreaticoduodenal grafts with bladder drainage (BD) a cytoscopic transduodenal biopsy offers the opportunity to obtain biopsy specimens from both the pancreas and duodenum. Success rates for obtaining tissue for pathologic review in both techniques are 85% to 95%. Firm adherence of the pancreas to surrounding structures and use of real-time ultrasonography reduce the risks of complications related to biopsy. Overall, complications occur in 5% to 10% of patients, which can include bleeding, pancreatic duct leak, hematuria (in BD pancreas transplants), and asymptomatic transient hyperamylasemia. Rarely does a complication require a repeat operation or result in graft loss.

Kidney-Pancreas Transplantation

15.9

Management of Complications

A

B

C FIGURE 15-14 Pancreas allograft rejection. Rejection occurs with greater frequency after pancreas and simultaneous pancreas-kidney (SPK) transplantation than after kidney transplantation alone, predictably in 75% to 85% of patients. This difference requires a strategically different

approach that balances aggressive immunosuppression against risks of infection. A diagnosis of rejection is dependent on biopsy of either the kidney or pancreas allograft in recipients of SPK transplantation or of the pancreas allograft in pancreas transplantation alone. Because of the double-edged sword of aggressive antirejection treatment, an episode of graft dysfunction should not be treated without biopsy-proven histopathologic evidence of immunologic graft injury. Ruling out infectious and anatomic causes of graft dysfunction with appropriate radiologic studies is equally important. Drachenberg and coworkers [15] and Nakhleh and Sutherland [16] have defined histologic criteria for grading pancreas allograft rejection that are practical from the standpoint of being able to prognosticate outcome and response to therapy. Serial histologic studies of pancreas rejection (as in this case) have shown that lymphocytic infiltrates initially involve the exocrine portion of the gland and that islet cell tissue becomes involved later [12]. As a result, exocrine dysfunction is frequently the first clinical sign of rejection (manifested by either elevated serum amylase or decreased urinary amylase levels). Consequently, early rejections without evidence of islet cell involvement usually can be treated successfully. On the contrary, the success of antirejection treatment is far less successful when initiated after the development of hyperglycemia [17]. A, Normal pancreas allograft core biopsy demonstrating an acinar lobule and preserved individual islet of Langerhans without inflammatory infiltrate (magnification 3 200). B, Needle core biopsy demonstrating glandular architecture with fibrous septae interdigitating between acinar lobules. An infiltrate is present that can be described as mononuclear, predominantly lymphocytic, perivascular, and septal. Endothelialitis is seen in a medium-sized vein at the upper central edge of the biopsy specimen. These features are consistent with mild acute cellular rejection (magnification 3 200). C, Needle core biopsy demonstrating intense septal inflammation with activated lymphocytes. Early acinar inflammation is present in the right upper lobule. Eosinophils also are present in the dense septal infiltrate. These findings also are consistent with mild acute cellular rejection (magnification 3 200). Moderate rejection is characterized by significant acinar inflammation and arteritis. Severe rejection is suggested when, in addition to the features listed above, confluent acinar necrosis with extensive acinar inflammation and ductal epithelial necrosis are present. Features indicating a poor prognosis include arteritis, confluent acinar necrosis, islet inflammation and necrosis, ductal epithelial necrosis, and fibrosis. Mild acute rejection usually is reversible with bolus corticosteroid therapy. In contrast to renal allograft rejections, however, most mild pancreas allograft rejections are somewhat recalcitrant to bolus steroid immunotherapy. Steroids may worsen potentially compromised glycemic control, thus complicating treatment. Therefore, significant rejection of the pancreas allograft may be best treated with antibody therapy, although a randomized control trial comparing the two treatment options has not been carried out. FK506 is commonly employed as rescue therapy in pancreas transplant episode recipients who are experiencing a significant acute rejection episode while on cyclosporine or Neoral (Sandoz Pharmaceuticals, East Hanover, NJ). Irreversible allograft rejection was a frequent occurrence several years ago. Today, it is unusual, occurring in less than 5% of patients.

15.10

Transplantation as Treatment of End-Stage Renal Disease

Indications for enteric conversion Metabolic acidosis 2% Reflux pancreatitis Recurrent 3% urinary Hematuria 19%

Urethritis 23%

tract infections 11%

Leak 42%

FIGURE 15-15 Indications for enteric conversion (EC). A set of complications unique to pancreas transplantation arise as a consequence of urinary diversion of graft exocrine secretions. The development of one of these complications is the most frequent cause for re-admission to the hospital after pancreas transplantation with BD. These include the following: persistent gross hematuria, recurrent or chronic urinary tract infections (UTIs), urethritis, urethral stricture or disruption, urinary or pancreatic enzyme leak, graft (reflux) pancreatitis, and excessive bicarbonate loss and acidosis [18]. Surgical conversion to ED is indicated when these complications are incapacitating or refractory to conservative therapy. Except for leaks and pancreatitis, these complications are largely avoided in ED pancreas grafts. Hematuria in the immediate postoperative period is usually mild and self-limited, occasionally requiring irrigation, cytoscopic fulguration, or both. Hematuria occurring late after transplantation (ie, months to years) may be caused by UTIs, suture granulomas, bladder stones, or ulceration of the duodenal segment. In total, hematuria occurs in 17% of patients. Conversion to ED is indicated when hematuria persists despite appropriate therapy and is required in up to a third of patients who present with late or chronic hematuria. Pancreatic enzyme or urinary leaks also can occur in the early postoperative period or as late as several years after transplantation. Early leaks usually occur at the bladder-duodenum suture line, whereas late leaks occur most commonly at the lateral duodenal staple line or at the location of a duodenal ulcer. The cause is unclear. Whereas some early leaks may be technically related, late leaks are more likely a result of rejection, cytomegalovirus infection, ischemia, or a combination of all these. Patients usually present with sudden-onset lower abdominal pain, fever, leukocytosis, increased serum amylase and slightly increased creatinine. Diagnosis is confirmed by cystogram (see Fig. 15-17). Fortunately this complication is unusual, occurring in 10% to 15% of patients. The most common infectious complication after pancreas transplantation is UTI, occurring in 63% of pancreas transplant recipients with BD. These recipients may be more predisposed to UTIs than are kidney transplant recipients because of the additive effect of several factors. These factors include alkalinization of the urine secondary to bicarbonate exocrine secretion, presence of a diabetic neurogenic bladder with incomplete emptying, mucosal injury at the bladder anastomosis, and prolonged catheter drainage. Occasionally, a cause for therapyresistant or recurrent infections is found on cystoscopy and study of the upper tracts also is indicated. When no source is found, EC is indicated. If persistent, urethritis may result in urethral stricture, disruption, or both. Although its exact cause is unclear, urethritis is most likely caused by the digestive action of pancreatic enzymes on the urothelium. Urethritis usually is manifested as perineal pain and discomfort during urination and seems to occur almost exclusively in males. Initially, conservative treatment with Foley catheter drainage for several weeks is recommended. When perforation occurs, it usually is in the membranous portion of the urethra and presents with perineal and testicular swelling. To avoid complications of urethral stricture and disruption, early enteric conversion is recommended when urethritis fails to respond to an initial short course of conservative treatment. Fortunately, these complications are unusual, occurring in only 5% of simultaneous pancreas-kidney (SPK) transplantation recipients. Early postoperative hyperamylasemia, thought to be caused by preservation injury, is not uncommon and, fortunately, usually is asymptomatic and improves rapidly. Persistent or marked elevations of amylase indicate possible technical errors, including ductal ligation or leak. Graft pancreatitis (sometimes referred to as reflux pancreatitis) presents in a manner similar to that of a leak. Graft pancreatitis is further defined by absence of a leak on radiologic study; evidence of gland edema on CT scan, without evidence of abscess or fluid collections; and; most important, resolution of symptoms within 48 hours of Foley catheter drainage. Treatment with Foley catheter drainage for several days is usually successful. When an infection is found in the patient’s urine at this time, appropriate parenteral antibiotics may be beneficial. Metabolic acidosis is present postoperatively in about 80% of patients after pancreas transplantation with BD and usually is due to excessive urinary loss of bicarbonate-containing exocrine fluids. Because urinary bicarbonate loss is accompanied by an obligate loss of fluid, low serum levels are associated with dehydration. Oral fluid replacement should be instituted to maintain a serum bicarbonate level of at least 20 to 25 mg/dL, and dehydration is treated appropriately. Fortunately, this problem usually stabilizes over time and infrequently requires conversion from bladder to enteric drainage.

Kidney-Pancreas Transplantation 1.0 0.9

Percent

Fraction of patients converted

0.8 0.7 0.6 0.5

Time to EC

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

0.4

15.11

0

1

2

3

4 5 Years

6

7

8

0.3 0.2

Duodenum Side to side duodenoenterostomy

0.1 Kaplan-Meier rate = 28%

0.0 0

A

1

2

3

4

5

6

7 8 Years

9

10 11 12 13 14 15

B

FIGURE 15-16 Incidence and procedure in enteric conversion (EC). A, Surgical conversion of pancreatic exocrine secretions from bladder drainage to enteric drainage is necessary in many patients. Whereas half of patients receive EC within the first postoperative year, a significant percentage must undergo EC up to 5 years after transplantation. B, EC involves taking down the duodenocystostomy, repairing the bladder, and performing a simple side-to-side duodenoenterostomy. In our experience of performing 95 ECs over a 14-year period in

Bladder

480 simultaneous pancreas-kidney (SPK) transplant recipients, only one graft was lost within 3 months of EC [5]. No differences were found in patient, kidney, or pancreas graft survival when comparing SPK transplant recipients who underwent EC with those who did not. The frequency of urologic complications and need for EC have prompted a changing trend toward performing primary enteric drainage; however, neither of these problems appears to impact negatively on graft survival.

FIGURE 15-17 Pancreatic enzyme and urinary leaks. A leak of urine, activated pancreatic enzymes, or both, is one of the most devastating and life-threatening infectious complications after pancreas transplantation. Patients exhibit sudden-onset lower abdominal pain, fever, leukocytosis, increased serum amylase levels, and increased serum creatinine levels. Diagnosis is confirmed by cystogram. When no leak is identified, voiding cystourethrography (VCUG) with gastrograffin (panel A) or a VCUG using technetium (Tc99m) in normal saline is performed (panels B–E). (Continued on next page)

A

15.12

Transplantation as Treatment of End-Stage Renal Disease

B

C

D

E

FIGURE 15-17 (Continued) In our opinion, a Tc99m-VCUG is the most sensitive test, because extravasation may occur only during the high-pressure phase of voiding [19]. B, This gastrograffin-VCUG demonstrates duodenal segment and anastomosis in the region of the dome of the bladder in an oblique anteroposterior projection. A leak of contrast is identified at the lateral duodenal segment staple line. B and C, Normal Tc99mVCUG scintigraphy is shown. Radioactive tracer is seen within the confines of the intact urinary tract, refluxing into the duodenal segment (large black arrow) and renal transplantation collecting system (small black arrow). D and E, Tc99m-VCUG demonstrates spill of radioactive tracer outside of the bladder and duodenal segment (large white arrowhead). Later, radioactive tracer is also present in the pelvis and between loops of bowel throughout the peritoneal cavity (small white arrowheads). For small leaks that are contained early, treatment consists of bladder decompression with a urinary catheter for 2 to 3 weeks. Large leaks and those that recur after conservative therapy require exploration, repair of the involved suture line, and enteric conversion.

Careful inspection of the duodenal segment is essential, and biopsy of the duodenal mucosa to search for rejection or cytomegalovirus pathology may be revealing in determining the cause. In most cases, however, the exact cause remains enigmatic despite careful investigation. In some cases, simultaneous diversion of the fecal stream with a Roux-en-Y anastomosis or proximal ileotransverse colostomy is advocated. Rarely is a urinary leak secondary to disruption of the ureteroneocystostomy. Enzyme leaks are more difficult to diagnose in enterically drained pancreata. A diagnosis in this setting relies on contrast-enhanced computed tomography (CT) scan, which usually demonstrates peripancreatic fluid collections. When drained percutaneously, these fluid collections reveal infection with enteric organisms and an elevated fluid amylase level. Surgical treatment of leaks in ED pancreata requires an individualized approach that usually involves repair, drainage, and diversion of the fecal stream. An expeditious diagnosis, depending on a high index of suspicion, and aggressive surgical intervention are essential to manage these life-threatening complications.

Kidney-Pancreas Transplantation

15.13

FIGURE 15-18 Urethral disruption. When left untreated, urethritis usually progresses to urethral disruption. Retrograde urethrography in a recipient of a simultaneous pancreas-kidney transplant with bladder drainage demonstrates perforation of the membranous urethra with extensive extravasation of contrast. Immediate treatment is placement of a suprapubic cystostomy or, if possible, a Foley catheter. Enteric conversion follows, which is 100% successful. Sequelae of this process include stricture and bladder outlet obstruction.

FIGURE 15-19 Patient and graft survival rates for simultaneous pancreas-kidney (SPK) transplantations in the United States. The survival rates have improved over the past 10 years. The current 1-year patient survival rate for SPK is 94% (panel A), with an 89% kidney graft survival rate (panel B) and 82% pancreas graft survival rate (panel C). The differences over time are highly significant between all eras.

SPK patient survival by era US cadaveric pancreas transplantations 10/1/1987–7/31/1997

100 90

%

80 70

Years 87–89 90–91 92–93 94–97

60 50

n Txs 532 908 1125 2387

1 Yr surv. 90% 91% 92% 94%

P = 0.002

40 0

6

12

A

18 24 30 36 42 Months posttransplantation

48

54

60

SPK pancreas graft function by era US cadaveric pancreas transplantations 10/1/1987–7/31/1997

100 80

%

60 Years 87–89 90–91 92–93 94–97

40 20

n Txs 532 908 1125 2387

1 Yr surv. 74% 75% 79% 82%

P = 0.0001

0 0

6

12

B

18 24 30 36 42 Months posttransplantation

48

54

60

SPK kidney graft function by era US cadaveric pancreas transplantations 10/1/1987–7/31/1997

100 90

%

80 70

Years 87–89 90–91 92–93 94–97

60 50

n Txs 532 908 1125 2387

1 Yr surv. 86% 84% 86% 89%

P = 0.004

40 0

C

6

12

18 24 30 36 42 Months posttransplantation

48

54

60

15.14

Transplantation as Treatment of End-Stage Renal Disease

100

PAK patient survival by era

PTA graft function by era

US cadaveric pancreas transplantations 10/1/87–7/31/97

US cadaveric pancreas transplantations 10/1/87–7/31/97

100

90 80

60

70

Years 87–89 90–91 92–93 94–97

60 50

n Txs 77 76 84 209

1 Yr surv. 90% 96% 90% 95%

0

6

12

20 P = NS

18 24 30 36 42 Months posttransplantation

48

54

P ≤ 0.0001

0 0

60

6

12

A

Years 87–89 90–91 92–93 94–97

80

n Txs 1 Yr surv. 77 56% 76 51% 84 52% 209 70%

% 20

70

Years 87–89 90–91 92–93 94–97

50 P ≤ 0.008

0 6

12

18 24 30 36 42 Months posttransplantation

48

54

EFFECTS OF PANCREAS TRANSPLANTATION ALONE ON SECONDARY COMPLICATIONS OF DIABETES Beneficial Stabilization and improvement Beneficial Major None Minimal

n Txs 46 49 72 92

1 Yr surv. 93% 90% 90% 93%

P = NS

40 0

60

FIGURE 15-20 Patient (panel A) and graft (panel B) survival rates for sequential pancreas after kidney (PAK) transplantations. For patients with PAK, the survival rate is similar to simultaneous pancreas-kidney transplantations but graft survival has been poorer until very recently. The 1-year PAK graft survival rate has improved from 52% to nearly 70%. NS—not significant.

Maintenance of normoglycemia Neuropathy Prevention of recurrent nephropathy Quality of life Retinopathy Vascular disease

60

80

60

0

54

90

40

B

48

US cadaveric pancreas transplantations 10/1/87–7/31/97

100

%

60

18 24 30 36 42 Months posttransplantation

PTA patient survival by era

PAK graft function by era US cadaveric pancreas transplantations 10/1/87–7/31/97

100

1 Yr surv. 46% 51% 56% 74%

40

40

A

n Txs 46 49 72 92

%

%

Years 87–89 90–91 92–93 94–97

80

B

6

12

18 24 30 36 42 Months posttransplantation

48

54

60

FIGURE 15-21 Graft (panel A) and patient (panel B) survival rates for pancreas transplantation alone (PTA). A much smaller number of PTAs have been performed in the United States compared with sequential pancreas after kidney (PAK) transplantations and simultaneous pancreas-kidney (SPK) transplantations. The patient survival rate for PTA is similar to those of SPK and PAK transplantation; however, the PTA graft survival rate has been closer to that of the PAK rate until the most recent transplantation era. Advancements in immunosuppressive therapy have improved the 1-year graft survival rate of PTA transplantations from 56% to 74%. NS—not significant. FIGURE 15-22 Multiple studies have been performed on the effects of pancreas transplantation on the secondary complications of diabetes. Unfortunately, most of these studies were performed with small numbers of patients and were not randomized controlled studies. There are four major benefits of pancreas transplantation for the secondary complications of diabetes: 1) Normoglycemia has been demonstrated for an extended period of time as long as the pancreas is functioning; 2) nephropathy has been shown to improve; 3) pancreas transplantation appears to prevent recurrent diabetic nephropathy in the transplanted kidney; and 4) quality of life. Complete freedom from insulin injections, appears to be the major benefit of pancreas transplantation. Unfortunately, pancreas transplantation does not appear to reverse established diabetic nephropathy in patients with their own kidneys, and established retinopathy and vascular disease do not appear to improve.

Hemoglobin A1, % of total hemoglobin

Kidney-Pancreas Transplantation

FIGURE 15-23 Glycosylated hemoglobin before and after pancreas transplantation. All patients have an abnormal hemoglobin A1 value before pancreas transplantation. Most patients, however, maintain a normal hemoglobin A1C after successful pancreas transplantation. (From Morel and coworkers [20]; with permission).

16 14 12 10 8 6 4 Before transplantation

12±4 mo 26±6 mo After transplantation

100

Motor index

–1.0

*

–1.5 –2.0 –2.5 –0.5

Percent eyes with stable retinopathy grade

–0.5

A

15.15

75 50 25

Pancreas transplant Control

0 0

12

24

42

0

12 24 36 48 60 Time following pancreas transplantation, mo

72

Sensory index

–1.0 –1.5

*

–2.0 –2.5

Autonomic index

B

–0.5

0

12

24

42 Kidney pancreas Control

–1.0 –1.5 –2.0 –2.5 0

C

12

24 Months

42

FIGURE 15-24 Effects of pancreas transplantation on diabetic neuropathy. Careful studies of motor index (panel A), sensory index (panel B), and autonomic index (panel C) show a general trend of improvement over 42 months in patients who received pancreas transplantation compared with patients in the control group. In patients with pancreas transplantation, 70% had improved results on motor nerve tests, nearly 60% on sensory tests, and 45% on autonomic tests. In patients in the control group, only 30% had improved results on motor and sensory tests, 12% had improved autonomic tests, and nearly 50% had deterioration of neurologic function. (From Kennedy and coworkers [21]; with permission).

FIGURE 15-25 Effects of pancreas transplantation on diabetic retinopathy. Retinopathy does not appear to improve after pancreas transplantation. A similar rate of deterioration was observed in both patients who had successful pancreas transplantation compared with patients with diabetes who had kidney transplantation alone. (From Ramsay and coworkers [22]; with permission).

15.16

0.5

2p = 0.02

4 3 2 1 0

0.2

0.0 Kidney alone

B

Kidney/ pancreas

0.7

Kidney alone

FIGURE 15-26 Effects of pancreas transplantation on recurrent diabetic nephropathy. Pancreas transplantation appears to prevent the subsequent development of diabetic nephropathy in renal allografts [23]. Both mean glomerular volume (panel A) and mesangial volume (panel B) were significantly lower in patients with successful pancreas transplantation compared with recipients with diabetes who had unsuccessful pancreas transplantation.

Kidney/ pancreas

0.5 0.4 0.3 0.2 0

1.8 Total mesangium per glomerulus, × 106 µm3

Mean glomerular volume, × 106 µm3

3.5

0.6 Mesangial fractional volume

0.3

0.1

A

A

2p = 0.004

0.4 Mesangium volume

Glomerular volume

5

Transplantation as Treatment of End-Stage Renal Disease

3.0 2.5 2.0 1.5 1.0

Baseline 5 y Comparison group

B

1.2 0.9 0.6 0.3 0

0 Baseline 5 y Pancreas transplant recipients

1.5

Baseline 5 y Pancreas transplant recipients

FIGURE 15-27 Effects of pancreas transplantation on established diabetic nephropathy. Although there appears to be a benefit in the prevention of diabetic nephropathy, there does not appear to be a benefit in patients who undergo pancreas transplantation in reversing established diabetic glomerular lesions. In this study,

Baseline 5 y Comparison group

C

Baseline 5 y Pancreas transplant recipients

Baseline 5 y Comparison group

mesangial fractional volume increased (panel A) and mean glomerular volume decreased (panel B) in pancreas transplantation recipients but no significant change in total mesangial volume (panel C) occurred over a 5-year follow-up. (From Fioretto and coworkers [24]; with permission). FIGURE 15-28 (see Color Plates) Effects of pancreas transplantation on microvascular disease. The benefits of pancreas transplantation on vascular disease have been variable. A, In this study, thermography demonstrated a clear-cut improvement in diabetic microvascular disease after successful pancreas transplantation [25]. B, However, no evidence exists that successful pancreas transplantation results in the regression of established macrovascular disease.

A

B

Kidney-Pancreas Transplantation

15.17

References 1. Gruessner A, Sutherland DER: Pancreas transplantation in the United States (US) and Non-US as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR). In Clinical Transplants 1996. Edited by Cecka JM, Terasaki PI. Los Angeles: UCLA Tissue Typing Laboratory; 1996:47–67. 2. Kuo PC, Johnson LB, Schweitzer EJ, Bartlett ST: Simultaneous pancreas/ kidney transplantation: a comparison of enteric and bladder drainage of exocrine pancreatic secretions. Transplantation 1997, 63:238–243. 3. Odorico JS, Becker YI, Van der Werf WJ, et al.: Advances in pancreas transplantation: the University of Wisconsin experience. In Clinical Transplants 1997. Edited by Terasaki PI, Cecka JM. Los Angeles: UCLA Tissue Typing Laboratory; 1998:157–166. 4. Sollinger HW, Messing EM, Eckhoff DE, et al.: Urological complications in 210 consecutive simultaneous pancreas-kidney transplants with bladder drainage. Ann Surg 1993, 218:561–570. 5. Van der Werf WJ, Odorico JS, D’Alessandro AM, et al.: Enteric conversion of bladder drained pancreas allografts: experience in 95 patients. Transplantation Proc 1998, 30:441–442. 6. Prieto M, Sutherland DER, Fernandez-Cruz L, et al.: Experimental and clinical experience with urine amylase monitoring for early diagnosis of rejection in pancreas transplantation. Transplantation 1987, 43:73–79. 7. Brayman KL, Egidi MF, Naji A, et al.: Is induction therapy necessary for successful simultaneous pancreas and kidney transplantation in the cyclosporine era? Transplantation Proc 1994, 26:2525–2527. 8. Wadstrom J, Brekke B, Wramner L, et al.: Triple versus quadruple induction immunosuppression in pancreas transplantation. Transplantation Proc 1995, 27:1317–1318. 9. Bartlett ST, Schweitzer EJ, Johnson LB, et al.: Equivalent success of simultaneous pancreas kidney and solitary pancreas transplantation. A prospective trial of tacrolimus immunosuppression with percutaneous biopsy. Ann Surg 1996, 224:440–449. 10. Gruessner RW, Burke GW, Stratta R, et al.: A multicenter analysis of the first experience with FK506 for induction and rescue therapy after pancreas transplantation. Transplantation 1996, 61:261–273. 11. Zucker K, Rosen A, Tsaroucha A, et al.: Augmentation of mycophenolate mofetil pharmacokinetics in renal transplant patients receiving Prograf® and CellCept®in combination therapy. Transplantation Proc 1997, 29:334–336. 12. Allen RDM, Wilson TG, Grierson JM, et al.: Percutaneous biopsy of bladder-drained pancreas transplants. Transplantation 1991, 51:1213–1216.

13. Gaber AO, Gaber LW, Shokouh-Amiri MH, Hathaway D: Percutaneous biopsy of pancreas transplants. Transplantation 1992, 54:548–550. 14. Bernardino M, Fernandez M, Neylan J, et al.: Pancreatic transplants: CT-guided biopsy. Radiology 1990, 177:709–711. 15. Drachenberg CB, Papadimitriou JC, Klassen DK, et al.: Evaluation of pancreas transplant needle biopsy. Transplantation 1997, 63:1579–1586. 16. Nakhleh RE, Sutherland DER: Pancreas rejection: significance of histopathologic findings with implication for classification of rejection. Am J Surg Pathol 1992, 16:1098–1107. 17. Stratta RJ, Taylor RJ, Weide LG, et al.: A prospective randomized trial of OKT3 vs. ATGAM induction therapy in pancreas transplant recipients. Transplantation Proc 1996, 28:927–928. 18. Sollinger HW, Odorico JS, Knechtle SJ, et al.: Experience with 500 simultaneous pancreas-kidney transplants. Ann Surg 1998, 228: 284–296. 19. Rayhill SC, Odorico JS, Heisey DM, et al.: A comparison of the sensitivities of contrast and isotope voiding cystourethrograms for the detection of pancreas transplant bladder leaks. Transplantation Proc 1995, 27:3143–3144. 20. Morel P, Goetz FC, Moudry-Munns K, et al.: Long-term glucose control in patients with pancreatic transplants. Ann Intern Med 1991, 115:694–699. 21. Kennedy WR, Navarro X, Goetz FC, et al.: Effects of pancreatic transplantation on diabetic neuropathy. N Engl J Med 1990, 322:1031–1037. 22. Ramsay RC, Goetz FC, Sutherland DER, et al.: Progression of diabetic retinopathy after pancreas transplantation for insulin-dependent diabetes mellitus. N Engl J Med 1988, 318:208–214. 23. Bilous RW, Mauer SM, Sutherland DER, et al.: The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes. N Engl J Med 1989, 321:80–85. 24. Fioretto P, Mauer SM, Bilous RW, et al.: Effects of pancreas transplantation on glomerular structure in insulin-dependent diabetic patients with their own kidneys. Lancet 1993, 342:1193–1196. 25. Abendroth D, Landgraf R, Illner W-D, Land W: Evidence for reversibility of diabetic microangiopathy following pancreas transplantation. Transplantation Proc 1989, 21:2850–2851.

Transplantation in Children Jeanne A. Mowry

R

enal transplantation in children has been considered the treatment of choice for end-stage renal disease for many years [1]. Successful transplantation allows for improved physical, social, and psychological rehabilitation, enabling a child to have a quality of life that usually is not attainable with dialysis. Improvements in technology in pediatric transplantation have been significant in the 1990s; however, owing to the inherent potential risks and benefits, the optimal timing for transplantation needs to be individualized to the child. Currently, dialysis and transplantation need to be viewed as complementary parts of each child’s lifelong treatment plan. Renal transplantation in children carries with it special issues and problems that vary somewhat from those in adult transplantation. Because children are constantly growing and developing, technical, metabolic, immunologic, and psychological factors exist that are unique to children and must be considered. The current status of pediatric renal transplantation is reviewed, summarizing immunosuppressive regimens, outcomes, and complications. Because of the low incidence of end-stage renal disease in children, much of the information available about current practices and trends regarding pediatric renal transplantation has been collected by national registries. To supplement the United States Renal Data Source, the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) was initiated in 1987 in an effort to capture information to improve the care of pediatric renal allograft recipients. Current NAPRTCS data include information collected voluntarily from 123 centers on 3066 children who received renal transplantation on or after January 1, 1987 [2]. This registry has been helpful in providing a mechanism through which the clinical course of a large number of children can be evaluated.

CHAPTER

16

16.2

Transplantation as Treatment of End-Stage Renal Disease

End-Stage Renal Disease Frequency FIGURE 16-1 The incidence of pediatric end-stage renal disease per million population by age and gender and adjusted for race is depicted, as reported by the United States Renal Data Source. This graph shows the average rate per year, 1993 to 1995. (From United States Renal Data System [3]; with permission.)

Rate per million population per year

30 Male Female

25

24 21

20 15

12

10 11

10

7 4

5

10

6 4

0 0–4

5–9

10–14 15–19 Age, y

Total 0–19

Etiology DISEASES CAUSING END-STAGE RENAL DISEASE Disease category

Children <18 years, %*

Urologic malformations Renal dysplasia Other congenital causes Focal segmental glomerulosclerosis Other glomerulonephritides and immunologic diseases Hypertensive nephropathy Diabetic nephropathy All other causes

Adults 20–64 years, % †,

26 17 15 11 14

4 0.3 5 2 17

0 0.1 17

22 40 10

FIGURE 16-2 Different diseases causing end-stage renal disease in children and adults. The leading causes of chronic renal failure in young children are inherited disorders or congenital abnormalities of the urinary tract, especially obstructive uropathy and reflux nephropathy. Focal segmental glomerulosclerosis and other glomerular disorders are seen more often in older children. Almost no children develop end-stage renal disease as a result of diabetic nephropathy and hypertension, the leading causes of end-stage renal disease in adults. (From Harmon [4]; with permission.)

*Data from North American Pediatric Renal Transplant Cooperative Study. †Data fromUnited States Renal Data Source.

Each age group, %

50

Age group 0–4 (n = 715) Age group 5–19 (n = 4052)

44

40

37

30 20 10

17

21 15

13 13

11 5

6

13

5

0 GlomeruloCystic, Interstitial Hypertension Collagen Other and nephritis hereditary, nephritis and and vascular unknown and pyelonephritis disease diseases congenital diseases

FIGURE 16-3 Data from the United States Renal Data Source of the incident pediatric cases by disease group and age group (0–4 vs 5–19 years), as a percentage of total pediatric end-stage renal disease within each age group. The numbers on top of the bars indicate the percentage within each age group over 5 years, 1991 to 1995. (From Harmon [4]; with permission.)

Transplantation in Children

FIGURE 16-4 Voiding cystourethrogram in a child with posterior urethral valves showing gross dilation of the posterior urethra with an abrupt change in caliber at the level of the external sphincter. Obstructive uropathy is reported to be the cause of end-stage renal disease in 16.5% of pediatric transplantation recipients (the primary cause along with aplastic, hypoplastic, and dysplastic kidneys) in the North American Pediatric Renal Transplant Cooperative Study 1995 Annual Report. (Courtesy of Philip Silberberg, MD.)

FIGURE 16-5 Voiding cystourethrogram in grade 5 reflux nephropathy showing gross dilation of the collecting system and blunting of the fornices. Renal parenchymal scarring and destruction usually occur before the age of 5 years but may occur in older age groups. Intrarenal reflux extends the vesicoureteric reflux into the collecting tubules and nephrons, allowing urinary access to the renal parenchyma that can lead to renal scarring. (Courtesy of Philip Silberberg, MD.)

16.3

FIGURE 16-6 Plain radiograph of a child with prune-belly syndrome showing a markedly protuberant abdomen. This syndrome, also referred to as Eagle-Barrett syndrome or triad syndrome, occurs almost exclusively in males. The three classic physical findings are the deficiency of the abdominal wall musculature, urinary tract anomalies characterized by an extremely dilated urinary tract, and bilateral intraabdominal testes. A wide spectrum in the severity of abnormalities is seen, with most children having some degree of renal dysplasia, along with bladder and ureteric dysplasias (partial or complex lack of smooth muscle). (Courtesy of Philip Silberberg, MD.)

Rate of pediatric renal transplantations per 100 dialysis patient-years

Transplantation Rates FIGURE 16-7 Data from the United States Renal Data Source showing the 1995 rates of pediatric renal transplantations per 100 dialysis patientyears by recipient age. The rate of kidney transplantation varies inversely with recipient age group. Emphasis is placed on living related donors in the pediatric group with end-stage renal disease. (From United States Renal Data System [3]; with permission.)

50 43

40 30

28

28

Living related donor Cadaveric donor 33 31 22

20

24

27 26

16 11

10

5

0 0–4

5–9

10–14

15–19

Recipient age

Total 0–19

20–44 (adult)

16.4

Transplantation as Treatment of End-Stage Renal Disease FIGURE 16-8 The national renal transplantation waiting list as of September 30, 1997. (From United Network for Organ Sharing Bulletin [6]; with permission.)

NUMBER OF PATIENTS ON TRANSPLANTATION WAITING LIST Age groups, y

Number, %

0–5

78 0.21 124 0.33 421 1.13 20,971 56.07 12,784 34.18 3026 8.09 37,404

6–10 11–17 18–49 50–64 65+ Total

Renal Allograft Outcome 100

60 40

80 60 40 Primary First repeat

20

Living donor Cadaveric donor

20

100

Living donors

Graft survival, %

80

Graft survival, %

Graft survival, %

100

0

10

20

30 40 Follow-up, mo

50

60

FIGURE 16-9 The estimated graft survival probabilities by allograft source from the 1995 North American Pediatric Renal Transplant Cooperative Study Annual Report. The overall median follow-up for patients with functioning grafts is 29 months. The estimated graft survival probabilities have improved by approximately 1 percentage point for cadaveric donor grafts compared with the data in the 1994 report. For living related donor grafts the estimated graft survival probabilities are similar to those in the previous report at 1 and 2 years, and 1 percentage point higher at 4 years. (From Warady and coworkers [5]; with permission.)

0

A

12 24 36 48 Time posttransplantation, mo

80 60 40 Primary First repeat

20

0

0

Cadaveric donors

0

60

0

B

12 24 36 48 60 Time posttransplantation, mo

FIGURE 16-10 Graft loss in young infants and children often caused by irreversible acute rejection episodes. Rejection is, perhaps, a result of heightened immune response in this age group [7]. Despite an improvement in graft survival in children over the past 5 years, the half-life of renal grafts in pediatric patients remains around 10 years [8]. This half-life means that many of these children will need a second transplantation in their lifetime. Depicted are the North American Pediatric Renal Transplant Cooperative Study data stratifying the analysis of the percentage of graft survival by donor source. A, Graft survival rates for living donor transplantations, primary and first repeat. B, Survival rates for cadaveric donor source transplantations. Graft survival rates for repeat transplantations did not correlate with early or late failure of the primary graft. (From Tejani and Sullivan [9]; with permission.)

16.5

Transplantation in Children

Factors Affecting Outcome Donor Age and Source Living donors 0 –1 years 2–5 years 6–12 years >12 years

110 100 Calculated clearance, mL/min per 1.73m2

90 80

FIGURE 16-11 Data from the North American Pediatric Renal Transplant Cooperative Study for pediatric kidney allograft function, measured as calculated creatinine clearance values for both cadaveric and living donors. Regardless of the donor source, younger recipients begin with higher calculated creatinine clearance values with a more rapid decline in function. Older recipients have more stable calculated creatinine clearance values with less of a decline in function.

70 60 50 Cadaveric donors

110

100 90 80 70 60 50 6 12 18 24 30 36 42 48 54 60 Follow-up, mo

0.0

RISK FACTORS ASSOCIATED WITH GRAFT FAILURE In (relative risk)

–0.2

Cadaveric donor

–0.4 –0.6 –0.8 –1.0 0

10

20 30 40 Cadaveric donor age, y

50

FIGURE 16-12 The relationship between cadaveric donor age and the logarithm of the relative risk of graft loss from all causes for pediatric recipients of cadaver-donor renal transplantations. The “perfect” donor is 21 years of age. The risk of graft loss is higher when the grafts used are from either younger or older donors. An equivalent risk of graft loss exists from donors who are 6 and 55 years of age. (From Harmon [10]; with permission.)

Recipient age (<2 y) Donor age (<6 y) Previous transplantation ATG, ALG, OKT3 early administration (none) More than 5 lifetime transfusions No DR matches Annual cohort (1992 vs 1987)

Relative risk increase

P

2.03 1.47 1.36 1.36 1.37 1.23 1.29

0.001 0.001 0.004 0.001 0.001 0.01 0.04

1.4 1.9 1.7

0.08 <0.001 <0.001

Living related donor Recipient age <2 y Black race More than 5 previous transfusions

FIGURE 16-13 Risk factors associated with graft failure in a proportional hazards model for recipients of donor grafts. ATG—antithrombocytic globulin; ALG—antilymphocytic globulin. (From Warady and coworkers [5]; with permission.)

16.6

Transplantation as Treatment of End-Stage Renal Disease

Recipient Age FIGURE 16-14 Relationship between recipient age and the relative risk of graft loss for children who receive cadaveric donor transplantation. A strong inverse relationship exists between the risk of graft loss and recipient age, particularly in the group under 2 years of age. (From Harmon [10]; with permission.)

1.0 0.9 Relative risk

0.8 0.7 0.6 0.5 0.4 0

4

2

6 8 10 12 14 16 18 Recipient age, y

Human Leukocyte Antigen Matching No A, no B, no DR No A, no B, DR match A and B match, no DR A and B and DR match

100

Graft survival, %

90 80 70 60 50 0

0.5

1

1.5 Time, y

2

2.5

FIGURE 16-15 Results of 4 years of experience monitoring outcomes by the North American Pediatric Renal Transplant Cooperative Study. These results suggest a statistically significant beneficial effect of donor-related matching (P ≤ 0.05) when analyzing this allele with other effects unique to pediatric patients with regard to age. This figure displays the subgroup with a match at both the A and the B locus, or at neither, and compares that with the effect of adding a donor-related (DR) antigen on the percentage of renal allografts surviving after transplantation. Owing to the relatively short follow-up, small sample size (1558 patients), and nonimmunologic factors pertinent to pediatric transplantation, it is difficult to determine separate time-varying effects of class I versus class II matching. However, it does seem clear that no antigen matching has a worse prognosis at 1 year (72% graft survival) versus 1 or more antigen matching at each locus (1-year 81% survival, 2-year 69% survival). (From McEnery and Stablein [11]; with permission.)

Preparation for Transplantation Preemptive versus Previous Dialysis 100

Living donor

90

90

80

80

Graft survival, %

Graft survival, %

100

70 60 50

70 60 50

Preemptive Prior dialysis

40

Preemptive Prior dialysis

40

30

30 0

A

Cadaveric donor

10 20 30 40 50 Time posttransplantation, mo

0

B

10 20 30 40 50 Time posttransplantation, mo

FIGURE 16-16 Percentage of graft survival of initial living (panel A) and cadaveric donor (panel B) grafts in recipients with and without (preemptive) dialysis, indicating better survival rates in those who did not receive dialysis previously. The survival probabilities in the preemptive group are significantly better until adjustments are made for recipient age (0–1 years vs others) and number of previous transplantations (>5 vs 0–5) in a proportional hazards model. (From Fine and coworkers [12]; with permission.)

16.7

Transplantation in Children

Vaccinations Hepatitis B (Hep B)

Hep B-1 Hep B-3

Hep B-2 Diptheria tetanus pertussis (DPT) H. influenzae type b (Hib) Polio

DTaP or DTP

DTaP or DTP

DTaP or DTP

Hib

Hib

Hib

Polio

Polio

Hep B DTaP or DTP

DTaP or DTP

Hib Polio

Polio

Measles-mumpsrubella (M-M-R)

M-M-R or

M-M-R Var

Varicella (Var) Birth

1

2

4

6 Age, mo

FIGURE 16-17 Infection remains a major cause of morbidity and mortality in pediatric transplantation recipients. Many infections can be successfully prevented by immunization. The recommended US immunization schedule for children (January–December 1997) before transplantation is outlined. Diphtheria-tetanus-pertussis vaccine, Haemophilus influenza type b vaccine, inactivated poliovirus vaccine, and hepatitis B immunizations can be given after transplantation but their efficacy may be suboptimal. The live attenuated vaccines, oral polio vaccine (OPV), measles-mumps-rubella (M-M-R) vaccine, and varicella virus vaccine, usually are recommended to be given only after immunosuppressive therapy has been discontinued for 3 months. Influenza A vaccines also should be administered yearly in the fall to pediatric transplantation recipients. The advent of the varicella virus vaccine may decrease the chances of pediatric transplantation recipients developing severe chickenpox and the incidence of zoster [13]. A recent survey by the North American Pediatric Renal Transplant Cooperative Study found that almost 90% of centers recommend the use of influenza vaccine, whereas only 60% of centers recommend pneumococcal

Td

12

15

M-M-R Var

18

4-6

11-12

14-16

Age, y

vaccine for children with renal disease. Between 5% and 12% of centers recommend live viral vaccines, including OPV, M-M-R vaccine, and varicella virus vaccine, for immunosuppressed patients after renal transplantation. (From Furth and coworkers [14]; with permission.) Vaccines are listed under the routinely recommended ages. Bars indicate the range of acceptable ages for vaccination. Shaded bars indicate catch-up vaccination: at 11 to 12 years of age, hepatitis B vaccine should be administered to children not previously vaccinated, and varicella virus vaccine should be administered to children not previously vaccinated who lack a reliable history of having had chickenpox. This schedule indicates the recommended age for routine administration of currently licensed childhood vaccines. Some combination vaccines are available and may be used whenever administration of all components of the vaccine is indicated. Providers should consult the manufacturers’ package inserts for detailed recommendations. Approved by the Advisory Committee on Immunization Practices (ACIP), American Academy of Pediatrics (AAP), and American Academy of Family Physicians (AAFP). (See Red Book [13] for more information.)

16.8

Transplantation as Treatment of End-Stage Renal Disease

Immunosuppression IMMUNOSUPPRESSIVE THERAPY AND FUNCTIONING GRAFTS Month 6 (n = 2999)

Month 12 (n = 2606)

Month 24 (n = 1915)

Month 36 (n = 1358)

Month 48 (n = 890)

Month 60 (n = 543)

Treated, % MMD*

Treated, % MMD*

Treated, % MMD*

Treated, % MMD*

Treated, % MMD*

Treated, % MMD*

Prednisone Living donor Cadaveric donor Cyclosporine Living donor Cadaveric donor Azathioprine Living donor Cadaveric donor

96 96 97 93 90 95 88 87 89

0.28 0.27 0.29 6.81 6.94 6.73 1.69 1.69 1.69

95 94 97 92 90 94 88 86 90

0.22 0.21 0.22 6.15 6.26 6.06 1.67 1.67 1.66

95 94 96 90 87 93 88 87 90

0.19 0.18 0.19 5.49 5.37 5.58 1.66 1.69 1.62

95 95 95 89 86 92 88 87 89

0.17 0.17 0.17 4.99 4.88 5.08 1.64 1.67 1.58

95 96 94 88 85 90 89 89 87

0.16 0.16 0.16 4.69 4.28 4.89 1.68 1.73 1.64

96 97 95 87 81 92 88 86 90

0.15 0.15 0.16 4.52 4.29 4.65 1.64 1.76 1.57

*MMD—median daily doses, in mg/kg.

FIGURE 16-18 Data from the North American Pediatric Renal Transplant Cooperative Study on immunosuppressive therapy and functioning grafts at selected times. The median daily dose of prednisone decreased from 0.28 mg/kg at 6 months to 0.17 mg/kg at 36 months, and then to 0.15 mg/kg at 5 years after transplantation. Alternate-day prednisone was prescribed to 9% of recipients at 6 months, 17% at 12 months, 24% at 24 months, and

27% at 48 months after transplantation. The daily dose of azathioprine did not change over time. The mean dose of cyclosporine has increased over the years in the most recent reported study: the mean 1-year dosages after transplantation were 6.5, 7.0, 7.7, and 8.0 mg/kg/d for transplantations occurring in 1987, 1989, 1991, and 1993, respectively. (From Warady and coworkers [5]; with permission.)

Cyclosporine 20

Mean (± upper 95% CI)

Recipient age, y

Cadaveric donor

18

0–1 2–5 6–12 >12

16 14 12 10 8 6 4 2 0 1

A

6

12

18 24 30 Time posttransplantation, mo

FIGURE 16-19 Data from the North American Pediatric Renal Transplant Cooperative Study of the maintenance dose of cyclosporine by donor source, recipient age, and time after transplantation. The dosage for the first month

36

42

48

for 0- to 1-year-old cadaveric donor graft recipients (panel A) is 15.0 mg/kg/d, which is similar to the 14.4 mg/kg/d the living related donor graft recipients (panel B) receive. (Continued on next page)

16.9

Transplantation in Children 20 Living related donor

18

Recipient age, y 0–1 2–5 6–12 >12

Mean (+upper 95% CI)

16 14 12 10 8 6 4 2 0 1

6

12

18 24 30 Time posttransplantation, mo

B

36

42

48

FIGURE 16-19 (Continued) By 4 years after transplantation the mean doses of all age groups are similar (mean and upper 95% CIs). (From Tejani and Sullivan [15]; with permission.)

LATE FIRST REJECTION RATES Mean year-1 CsA dosage, mg/kg/d CsA dosage, mg/kg/d*

N

0 >0 and ≤4.0 >4.0 and ≤5.9 >5.9 and ≤8.6 >8.6

80 185 186 188 184

Number of rejections Rejecting, % 9 41 44 46 29

11.3 22.2 23.7 24.5 15.8

Rejection (±SD)

Nonrejection (±SD)

0.0 2.9(±0.8) 4.9(±0.6) 6.9(±0.8) 11.7(±2.7)

0.0 3.1(±0.7) 5.0(±0.6) 7.3 (±0.8) 12.6(±4.1)

*Chi-squared test of percentage rejecting among four nonzero dose groups (P = 0.163).

FIGURE 16-20 Data from the North American Pediatric Renal Transplant Cooperative Study on late first rejection rates by quartiles of maintenance cyclosporine dose at 1 year. The first acute rejection occurred over 1 year after transplantation. Patients not receiving cyclosporine (human leukocyte antigen–identical or those receiving tacrolimus [FK-506]) form a small group. The difference between the rejection rates for the other four groups are not statistically significant. The lowest rate of late first rejection, however, is observed in those patients receiving dosages of cyclosporine over 8.6 mg/kg/d. CsA— cyclosporine; SD—standard deviation. (From Tejani and Sullivan [15]; with permission.)

16.10

Transplantation as Treatment of End-Stage Renal Disease

Tacrolimus COMPARISON OF TACROLIMUS AND CYCLOSPORINE Major advantages of tacrolimus Steroid sparing Less hypertension Rescue of cyclosporine-resistant rejections Minor advantages of tacrolimus Better graft survival Less hirsutism Less gingival hypertrophy Less neurologic dysfunction Less metabolic acidosis Less hyperlipidemia

Major disadvantages of tacrolimus Increased viral infections Cytomegalovirus Epstein-Barr virus Increased lymphoproliferative disease Minor disadvantages of tacrolimus Increased acute rejection? More diabetogenic? Hyperkalemia? Hypomagnesemia? Similarities of tacrolimus and cyclosporine Nephrotoxicity

FIGURE 16-21 The experience at Children’s Hospital of Pittsburgh using tacrolimus has been that 14% of 43 pediatric patients managed with tacrolimus for a mean period of 25 months developed posttransplantation lymphoproliferative disease (PTLD). This occurrence is very high compared with PTLD reported by the North American Pediatric Renal Transplant Cooperative Study in only six of 1550 (0.39% or 0.10%/y) children managed with various cyclosporine regimens [16]. Epstein-Barr virus (EBV) has a primary role in the development of PTLD, and an even higher rate of EBVrelated PTLD has been reported in children receiving tacrolimus for liver transplantation or rescue [17,18]. Children seem to have a greater predisposition to PTLD than do adults. Therefore, children need closer monitoring for this disorder when being managed with tacrolimus. The major advantages of tacrolimus over cyclosporine are a reduced severity of hypertension and an improved cosmetic appearance that, in turn, may improve patient compliance with medications. (From Ellis [19]; with permission.)

Mycophenolate Mofetil

Acute rejection episode, %

50

48%

40 30

26% 19%

20 10 0 Living donor

Cadaveric Mycophenolate donor mofetil

Azathioprine

FIGURE 16-22 Initial studies at the University of California, Los Angeles Medical Center (UCLA), using mycophenolate mofetil along with cyclosporine and prednisone, instead of azathioprine. In 37 pediatric renal transplantation recipients, an overall incidence of first acute rejection of just 19% was found (only 13% were clinically significant). This is a decrease compared with the historical incidence at UCLA (1987–1994) of acute rejection episodes in living related and cadaveric donor transplantations, which is 26% and 48%, respectively. The researchers saw a moderate increase in the incidence of infection after transplantation (mostly caused by cyclomegalovirus) and gastrointestinal side effects. (From Ettenger and coworkers [20]; with permission.)

Transplantation in Children

16.11

Growth in End-Stage Renal Disease

Growth rate, cm/y

Transplantation versus Dialysis 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

Kidney transplantation (n = 724)

US general population

Dialysis (n = 578)

0

2

4

6

P< 0.01

8

10 Age, y

1.0 Height ∆ Z

Average follow-up for calculating ESRD growth rate = 10.4 mo

0.5 0 0 12 18 24 30 36 42 48 54 60 Follow-up, mo Sample sizes for height ∆ Z at follow-up months: Age group, y 6 24 48 0 –1 years 155 99 48 2–5 years 441 312 160 6–12 years 1023 716 374 13–17 years 1112 625 235

12 14 16 Average age, 12.7 y

18

FIGURE 16-23 Chronic renal insufficiency and end-stage renal disease (ESRD) resulting in physical growth and sexual development well below the potential for age and gender [21]. One of the benefits of transplantation in children has been to improve the growth rate; however, this may not occur in all patients [16,22,23]. Depicted is the overall comparison between adjusted annualized growth rates by age for prevalent pediatric transplantation and dialysis patients (1990 USRDS data) [24] and the US general population (1976–1980 data from the National Center for Health Statistics) [25]. Shown are the results of a linear regression analysis of growth rates for 578 patients on dialysis and 724 transplantation recipients. Growth rates were adjusted to reflect the average characteristics of patients with ESRD at each age with regard to gender, race, ethnicity, baseline height, and duration of ESRD. At almost all ages, growth rates were higher for transplantation recipients compared with patients on dialysis; however, the degree of advantage declined with age. No pubertal growth spurt was seen in either treatment group. Although growth rates in adolescents between 15 and 18 years of age were higher than expected for both the dialysis and transplantation groups, the average height achieved at the end of the study was still lower than expected. (From Turenne and coworkers [26]; with permission.)

FIGURE 16-24 Data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) on the mean change from baseline in standardized height scores in patients with graft function. The height standard deviation score (SDS), or Z score, is the current accepted measurement used to evaluate accelerated growth. The Z score is an attempt to standardize the height deficit of children with renal failure to the height of healthy children. A positive change in Z score (+ Z), for example, indicates a reduction in height deficit (ie, an acceleration of growth). At transplantation the mean height deficit (Z score or SDS) for all patients was -2.16 standard deviations (SD) below the appropriate age- and gender-adjusted levels. Recipients under 6 years of age at the time of transplantation showed acceleration in linear growth after transplantation at 4 years’ follow-up. Children 6 years of age or older at time of transplantation showed no improvement in height deficit at 4 years’ follow-up. Z score— patient’s height - height at 50% for age and standard deviation of height for age. (From Warady and coworkers [5]; with permission.)

16.12

Transplantation as Treatment of End-Stage Renal Disease

Alternate-Day Corticosteroids

Change in height SDS

0.8

Daily Alternate day * Significant difference between daily and alternate day group

0.6

* *

*

0.4

FIGURE 16-25 Corticosteroids are an integral part of pediatric renal transplantation immunosuppressive protocols. In addition to hypertension and hyperlipidemia, one of the main adverse effects of daily steroid dosing in children is growth retardation. A review of North American Pediatric Renal Transplant Cooperative Study data, looking at the change in the height standard deviation score (SDS) from 30 days after transplantation to 12 to 60 months after transplantation analyzed the difference between the 1477 children treated continuously on a daily or alternate-day steroid regimen. The mean change in SDS was significantly greater for the alternate-day group at each 12-month interval (P < 0.05). Of note is the fact that at 12 months, those children on alternate-day steroids had a mean serum creatinine of 1.06 ± 0.04 mg/dL as compared with 1.28 ± 0.02 mg/dL for those on daily steroids (P < 0.001). Alternate-day therapy also was more common in children without a rejection episode in the first 12 months after transplantation, recipients of living donor grafts, white recipients, and children 2 to 12 years of age at the time of transplantation. (From Jabs and coworkers [27]; with permission.)

*

*

0.2 0 –0.2 12

100

24 36 48 Time posttransplantation, mo

100

Living donor

Graft survival, %

80 70

80 70 Daily Alternate day

60

Daily Alternate day

60

50

50 10

A

Cadaveric donor

90

90 Graft survival, %

60

20

30

40 50 Time, mo

60

10

B

20

30

40 50 Time, mo

60

FIGURE 16-26 Data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) evaluating the effects of alternate-day steroids on graft survival. Patients receiving alternate-day steroids at 12 months were compared with those receiving daily steroids. The NAPRTCS found that the survival of living donor (panel A) and cadaveric (panel B) grafts subsequent to 12 months did not differ between the steroid treatment groups. Because a number of factors contribute to graft survival and the patients were not randomly delegated to steroid treatment groups, a proportional hazards regression model for graft survival after 12 months also was developed. Again, the use of alternate-day steroids had no adverse effect on graft survival for recipients of either living or cadaveric donor grafts. (From Jabs and coworkers [27]; with permission.)

Transplantation in Children

16.13

Recombinant Human Growth Hormone After Transplantation HEIGHT VELOCITY AND HEIGHT STANDARD DEVIATION SCORES Change in  height SDS

Change in height velocity, cm/y Pubertal status

Control

Treated

Control

Treated

Prepubertal

0.3 ± 1.6 (n = 30) 0.6 ± 1.8 (n = 11) 0.7 ± 2.1 (n = 18)

3.7 ± 1.6* (n = 28) 4.9 ± 3* (n = 9) 4.3 ± 2.2* (n = 29)

+0.1 ± 0.3 (n = 30) 0.1 ± 0.4 (n = 11) +0.1 ± 0.5 (n = 18)

+0.6 ± 0.3* (n = 28) +0.6 ± 0.6* (n = 9) +0.7 ± 0.5* (n = 29)

Entering puberty Pubertal

*P < 0.0001 compared with control groups.

FIGURE 16-27 Because growth often remains poor despite a functioning renal graft, a large multicenter controlled study was initiated to evaluate the effectiveness of recombinant human growth hormone in stimulating growth in children with a kidney allograft. In all three groups a

Mean semiquantitative score (0–6) 0 Interstitium Focal inflammation (lymphocytes) Diffuse inflammation Focal fibrosis Diffuse fibrosis

1

2

3

4

5

6

Growth hormone– treated recipients Nontreated recipients

Mean score Growth hormone– Nontreated treated (SD) (SD) 1.6(1.7) 1.1(1.9) 2.6(1.8) 1.7(1.7)

1.4(0.8) 0.9(0.9) 2.1(0.4) 0.7(1.0)

Glomeruli Mesangial cell proliferation Mesangial matrix increase

1.3(1.5) 1.7(1.4)

1.4(0.8) 2.7(1.0)

Arterioles Endothelial swelling Endothelial proliferation Intimal proliferation

0.3(0.8) 0.6(1.0) 1.6(1.6)

0.6(1.1) 0.3(0.8) 0.9(1.1)

1.0(0.8) 2.1(0.7) 1.1(1.2)

1.1(1.2) 0.7(0.8) 0.4(0.5)

Proximal tubules Dilation Atrophy Casts

P < 0.05 between groups

significantly different growth velocity and change in height SDS occurred during the first year of treatment with growth hormone (P < 0.0001) compared with a control group. Preliminary data from the second year of treatment also show a continued improvement in growth velocity compared with baseline; however, not of the magnitude seen during the first year. The mean glomerular filtration rate did not change significantly in the group receiving growth hormone. Acute rejection episodes were noted more frequently during treatment with growth hormone, especially for patients with a history of more than one episode. However, other factors, such as noncompliance with immunosuppressive medications, were not analyzed and cannot be excluded. Values are expressed as mean ± standard deviation. SDS—standard deviation score. (From Broyer [28]; with permission.) FIGURE 16-28 A Finnish study investigating the possible association between growth hormone treatment and acceleration of chronic rejection and late allograft dysfunction in prepubertal children. The most common histologic findings between the eight growth hormone– treated and eight nontreated renal transplantation recipients are scored and compared (matched for age, donor age, human leukocyte antigen, immunosuppression, and renal function) 36 months after transplantation. Improvement in growth was clear during administration of growth hormone, without a negative influence on allograft survival. No significant difference in the amount of lymphocyte infiltration of the allografts between patients and the control group was seen. No acute rejection episodes occurred in the recipients treated with growth hormone but one occurred in the control group. SD—standard deviation. (From Laine and coworkers [29]; with permission.)

16.14

Transplantation as Treatment of End-Stage Renal Disease

SAFETY AND EFFICACY OF GROWTH HORMONE TREATMENT Glomerular filtration rate, mL/min/1.73 m2* Reference

Patients, n

Bartosh et al. Benfield et al. Fine et al. Ingulli and Tejani Tonshoff et al.

5 11 13 17 10

Van Dop et al. Van Es et al.

9 17

Prepubertal Pubertal

19

Serum creatinine, mg/dL

Before

After

Before

After

51 + 6.8 75 + 20 67 + 27

58 + 29 60 + 18 63 + 25

1.4 + 0.1

1.6 + 0.6

1.5

1.6*

59† (23 - 118)

49† (19 - 102)* 1.6 + 0.6

2.1 + 0.9*

71† (25 - 150)

72† (4.4 - 172)

67† (29 - 152)

83† (24 - 121)

*P value significant. †Median values.

FIGURE 16-29 Analysis of the safety and efficacy of growth hormone in pediatric renal transplantation recipients. Overall, a catch-up in growth was reported in each study, with changes in height standard deviation score from 0.2 to 1.0. These results were not as favorable as those reported when growth hormone was used in patients with chronic renal failure, perhaps owing to the use of corticosteroids after transplantation. In three studies, renal function was significantly decreased after administration of growth hormone. Twelve acute rejection episodes and four graft losses occurred; however, a causal relationship is unclear [30]. A controlled trial using growth hormone after transplantation is currently underway by the North American Pediatric Renal Transplant Cooperative Study to help establish the efficacy and safety of growth hormone in pediatric transplantation recipients. Calculated clearance according to the Schwartz formula, except for Tonshoff (inulin clearance) [31]. (From Tonshoff [31]; with permission.)

Complications after Transplantation Acute Rejection DIAGNOSIS OF ACUTE REJECTION Clinical picture Fever, weight gain, enlargement and tenderness of graft, hypertension, reduced urinary output, decreased renal function, reduced urinary sodium excretion, and increased proteinuria Cyclosporine trough blood level When these levels are higher than expected, cyclosporine nephrotoxicity is suspected; however, this does not rule out rejection—very low levels, in the presence of elevated serum creatinine, suggest acute rejection, perhaps as a result of noncompliance Radionuclide renal studies Provide information about blood flow and the excretion index, and aid in excluding extravasation and obstruction Renal sonography with Doppler ultrasonography Provides information about kidney size, renal blood flow, corticomedullary differentiation, pyramid shape, and the collecting system; establishes the diagnosis of obstruction, extravasation, and renal artery stenosis Renal arteriogram Establishes the diagnosis of major renal vessel stenosis or occlusion Magnetic resonance imaging Establishes the diagnosis of obstruction, renal vessel stenosis, or occlusion; aids in evaluating the corticomedullary junction and pyramid shape Fine-needle aspiration biopsy Identifies inflammatory cells in the graft, tubular damage, cyclosporine toxicity, and cytomegalovirus infection; aids in differentiating rejection, acute tubular necrosis, cytomegalovirus infection, and cyclosporine nephrotoxicity Renal biopsy Remains the gold standard for determining rejection and cyclosporine nephrotoxicity

FIGURE 16-30 When impaired graft function occurs in pediatric renal transplantation recipients, rejection is the most common cause. A number of other conditions exist that also can result in an increase in serum creatinine and blood urea nitrogen, a decrease in urine output, or both, which must be differentiated from rejection. In small children with large allografts, the most sensitive indication of rejection is hypertension. It is important to remember that in small children, a small increase in serum creatinine can reflect a significant decrease in the glomerular filtration rate. Several methods to establish the cause of renal allograft dysfunction are described; however, the diagnostic gold standard is the allograft core biopsy. Biopsy can easily be performed percutaneously in most children and should not be postponed once other variables have been eliminated and rejection is likely. (From Yadin and coworkers [32]; with permission.)

Transplantation in Children

FIGURE 16-31 Data from the 1995 North American Pediatric Renal Transplant Cooperative Study showing that the cumulative risk for first rejection is similar for living donor (LD) and cadaveric donor (CD) recipients in the first few weeks after transplantation. After the first month, however, the cumulative risk for a first rejection is higher for recipients of a CD graft. By the end of the 48th month, 56% of LD recipients and 71% of CD recipients have had at least one rejection episode. Rejections were completely reversed (return to baseline creatinine) in 53% of LD graft recipients, partially reversed (improved graft function but no return to baseline creatinine) in 40%, and resulted in graft failure or death in 4% of cases. In CD, rejection episodes were completely reversed in 49%, partially reversed in 45%, and resulted in graft failure or death in 6%. (From Warady and coworkers [5]; with permission.)

100

Rejection, %

80 60 40 20

Living donor Cadaveric donor

0 0

12

16.15

24 36 Follow-up, mo

48

60

Chronic Rejection PREDICTORS OF GRAFT FAILURE FROM CHRONIC REJECTION Relative risk increase

P value

3.1 4.3 2.3 1.6 1.6

<0.001 <0.001 <0.001 0.001 0.003

Acute rejection ≥2 acute rejections Late (>365 d) initial acute rejection Cadaveric donor source Black recipient

FIGURE 16-32 Multivariate analysis of data from the North American Pediatric Renal Transplant Cooperative Study evaluating predictors of graft failure from chronic rejection. A proportional hazards analysis of time to chronic rejection failure, eliminating other failures, is used to evaluate predictors of graft failure from chronic rejection. A 3.1fold increased risk of failure from chronic rejection was seen after a single rejection episode. A second rejection increased the risk to over 13 times that of children who did not experience rejection. (From Tejani and coworkers [33]; with permission.)

CAUSES OF GRAFT FAILURE Index graft failures

Second graft failures*

Total graft failures

n = 881 (%)

n = 104 (%)

n = 985 (%)

28(3.2) 107(12.2) 16(1.8) 9(1.0) 26(3.0) 167(19.0) 239(27.1) 10(1.1) 17(1.9) 9(1.0) 4(0.5) 18(2.0) 9(1.0) 56(6.5) 98(9.0) 67(7.6)

2(1.9) 20(19.2) 2(1.9) 2(1.9) 5(4.8) 16(15.4) 28(26.9) 0(0.0) 2(1.9) 0(0.0) 2(1.9) 1(1.0) 1(1.0) 10(9.6) 9(8.7) 4(3.8)

30(3.0) 127(12.9) 18(1.8) 11(1.1) 31(3.1) 183(18.6) 267(27.1) 10(1.0) 19(1.9) 9(0.9) 6(0.6) 19(1.9) 10(1.0) 67(6.8) 107(10.9) 71(7.2)

Cause Primary nonfunction Vascular thrombosis Miscellaneous technical Hyperacute rejection, <24 h Accelerated rejection, 2–7 d Acute rejection Chronic rejection Renal artery stenosis Infection/discontinued medication Cyclosporine toxicity De novo kidney disease Patient discontinued medication Malignancy Recurrence of original disease Death Other *Four patients have had three graft failures.

FIGURE 16-33 Data from the North American Pediatric Renal Transplant Cooperative Study showing causes of graft failure. Chronic rejection has become the most common cause of graft failure (27.1%). Acute rejection causes up to 18.6% of graft failures. Recurrence of primary disease (focal segmental glomerulosclerosis) accounts for 6.8% of all failures. Vascular thrombosis continues to cause a significant number of graft failures (12.9%). (From Warady and coworkers [5]; with permission.)

16.16

Transplantation as Treatment of End-Stage Renal Disease

Vascular Thrombosis Day after transplantation

All thrombosis, %

100

Day > 15 Day 6–14 Day 3–5 Day 2 Day 1 Day 0

80 60 40

FIGURE 16-34 Data from the North American Pediatric Renal Transplant Cooperative Study showing vascular thrombosis is the third most common cause of graft failure in pediatric transplantation recipients. The incidence varies between centers and has been reported to be as high as 20% in children under 2 years of age [34]. This figure depicts the timing of thrombotic graft failure by donor source. Most of the thromboses occurred soon after transplantation. (From Singh and coworkers [35]; with permission.)

20 0 Living donor Cadaveric donor n = 38 n = 100

UNIVARIATE ANALYSIS OF RISK FACTORS

All Recipient age 0–1 y 2–5 y 6–12 y >12 y Donor age 0–5 y 5–10 y >10 y Cold ischemia time <24 h >24 h Day 0/1 Antilymphocyte therapy No Yes Day 0/1 cyclosporine therapy No Yes Previous transplantation No Yes Native nephrectomy No Yes Previous dialysis No Yes Persistent ATN with >7 d of function No Yes *P < 0.01, test for trend. †P = 0.01, test for trend.

Living donor, n

%

Cadaveric donor, n

%

38/2060

1.8

100/2334

4.3

6/172 12/341 5/732 15/783

3.5* 3.4 0.7 1.9

7/78 19/343 36/827 38/1086

9.0† 5.5 4.4 3.5

32/386 11/245 54/1667

8.3* 4.5 3.2

44/1363 51/909

3.2* 5.6

28/1187 10/873

2.4 1.2

61/990 39/1344

6.2* 2.9

29/1115 9/945

2.6* 1.0

66/1682 34/652

3.9 5.2

30/1886 8/174

1.6* 4.6

66/1723 34/611

3.8 5.6

26/1440 12/617

1.8 1.9

82/1790 18/540

4.6 3.3

11/680 27/1380

1.6 2.0

13/319 87/2015

4.1 4.3

10/1929 3/79

0.5* 3.8

22/1844 13/365

1.2* 3.6

FIGURE 16-35 Recent univariate analysis of risk factors by the North American Pediatric Renal Transplant Cooperative Study. Although the mechanisms that lead to thrombosis are unclear, numerous factors have been implicated, whether they be by direct or indirect means. In cadaveric donor kidney recipients, children less than 2 years of age had a significantly higher rate of thrombosis, as did children who received kidneys from donors who were under 5 years of age. Recipients of cadaveric donor kidneys with prolonged cold ischemia time had a higher rate of thrombosis than did those with a cold ischemia time under 24 hours. ATN—acute tubular necrosis. (From Singh and coworkers [35]; with permission.)

Transplantation in Children

16.17

Hypertension EVALUATING HYPERTENSION Months after transplantation Pretransplantation Patients, n Significant hypertension, % Severe hypertension, %

230 11 23

1

6

12

24

264 14 26

262 16 13

261 16 10

257 9 9

FIGURE 16-36 Data from the North American Pediatric Renal Transplant Cooperative Study evaluating hypertension. Hypertension is common in children after renal transplantation. The definition of hypertension used was taken from the Report of the Second Task Force on Blood Pressure Control in Children [15]. The percentage of children exceeding age-adjusted blood pressure standards decreased considerably over the 2-year period. (From Baluarte and coworkers [36]; with permission.)

CYCLOSPORINE DOSAGES IN RECIPIENTS WITH AND WITHOUT HYPERTENSION 1 mo Degree of hypertension Normotensive Significant Severe

n

2y

CsA dosage, mg/kg

161 36 69

8.2 9.4 10.0 P = 0.11

n

FIGURE 16-37 North American Pediatric Renal Transplant Cooperative Study evaluating cyclosporine dosages in recipients with and without hypertension. CsA—cyclosporine. (From Baluarte and coworkers [36]; with permission.)

CsA dosage, mg/kg

213 22 22

3.9 4.8 4.7 P = 0.23

Recurrent Disease GRAFT FAILURE FROM RECURRENT DISEASE Disease FSGS MPGN type I MPGN type II SLE HSP HUS Classical Atypical

Recurrence rate, %

Clinical severity

Those with recurrence whose graft failed, %

25–30 70 100 5–40 55–85

High Mild Low Low Low to mild

40–50 12–30 10–20 5 5–20

12–20 ±25

Moderate High

0–10 40–50

FIGURE 16-38 Recurrence rates and graft failure from recurrent disease. Some primary renal diseases may recur in the allograft, making the underlying disease an important consideration when evaluating a child for renal transplantation. Focal segmental glomerular sclerosis and atypical hemolytic uremic syndrome recur in roughly 25% of cases. These diseases are severe clinically and lead to the highest percentage of graft failures, ie, 40% to 50%. In contrast, membranoproliferative glomerulonephritis type II recurs in all cases; however, it is not very severe clinically and leads to graft failure in only 10% to 20% of patients. FSGS—focal segmental glomerulosclerosis; HSP— Henoch-Schönlein purpura; HUS—hemolytic-uremic syndrome; MPGN—membranoproliferative glomerulonephritis; SLE— systemic lupus erythematosus. (From Fine and Ettenger [37]; with permission.)

16.18

Transplantation as Treatment of End-Stage Renal Disease

Other Causes of Renal Allograft Loss 100 100

90

90 Graft survival, %

Graft survival, %

80 70 60 Congenital and structural Glomerulonephritis Focal segmental glomerulosclerosis Congenital nephrotic syndrome

50 40 0

10

20 30 Months

40

70 60

40 30

50

0

B

90

90

80

80

Graft survival, %

100

Graft survival, %

100

70 60 50

30

20 30 Months

40

50

60 Hemolytic uremic syndrome Renal infarction Cystinosis Familial nephritis

40 30

0

A

10

70

50

Congenital and structural Glomerulonephritis Focal segmental glomerulosclerosis Congenital nephrotic syndrome

40

Hemolytic uremic syndrome Renal infarction Cystinosis Familial nephritis

50

30

A

80

10

20 30 Months

40

50

B

0

10

20 30 Months

40

50

FIGURE 16-39 Data from the North American Pediatric Renal Transplant Cooperative Study showing that those patients receiving living donor kidneys who have congenital nephrotic syndrome (CNS), focal segmental glomerulosclerosis (FSG) (panel A) or hemolytic uremic syndrome (HUS) (panel B) had the lowest 2-year graft survival rates. These rates range from 74.3% to 80.6%. In patients with focal segmental glomerular sclerosis, graft failure was attributed to disease recurrence in 13 of 39 (33%) patients who received kidneys from living related donors. B, The patients with familial nephritis or cystinosis had the highest graft survival rates (88.9% and 92.9%, respectively). (From Kashton and coworkers [38]; with permission.) FIGURE 16-40 Data from the North American Pediatric Renal Transplant Cooperative Study for cadaveric donor renal allografts showing that the lowest graft survival rates occurred in children with focal segmental glomerular sclerosis or congenital nephrotic syndrome (panel A), or hemolytic uremic syndrome (panel B). These rates range from 40% to 58.9%. In patients with focal segmental glomerular sclerosis, graft failure was attributed to disease recurrence in 14 of 81 (17%) patients who received cadaveric donor kidneys. A, The highest graft survival rate correlated with the diagnosis of congenital and structural disease and glomerulonephritis (72.2% and 73.5%, respectively). (From Kashton and coworkers [38]; with permission.)

Mortality in Recipients FIGURE 16-41 Data from the United States Renal Data Source on pediatric patient 1-year death rates by age group and treatment mortality. Survival follow-up began on day 91 after onset of endstage renal disease for patients on dialysis incident in 1994, and from the date of transplantation for patients receiving transplantations in 1994 [3]. CD Tx—cadaveric donor transplant; LRD Tx—living related donor transplant. (From United States Renal Data System [3]; with permission.)

1-year Kaplan-Meier death rates, %

15

Dialysis

10

5 CD Tx LRD Tx

0 0–4

5–9

10–14 Age groups

15–19

Transplantation in Children

FIGURE 16-42 Data from the United States Renal Data Source regarding distribution of causes of death in children aged 0 to 19, 1993 to 1995. (From United States Renal Data System [3]; with permission.)

30

Deaths, %

Total deaths = 290 Percentages add to 100

25

24

20 13

12

10

7

6

16.19

6

4

4

0 Cardiac Acute arrest myocardial infarction

Other cardiac causes

Cardiovascular disease

Infection Malignancy Hemorrhage Other known causes

CAUSES OF DEATH BY AGE GROUP Recipient age 0–1 Cause of death All causes Viral infection Bacterial infection Other infections Malignancy Cardiopulmonary Hemorrhage Recurrence of original disease Dialysis-related complications Other Unknown

2–5

13–17

n (%)

n (%)

n (%)

n (%)

27(100.0) 5(18.5) 3(11.1) 4(14.8) 1(3.7) 5(18.5) 3(11.1) 1(3.7) 1(3.7) 4(14.8) 0(0.0)

33(100.0) 1(3.0) 6(18.1) 5(15.2) 2(6.1) 7(21.2) 4(12.1) 1(3.0) 0(0.0) 5(15.2) 2(6.1)

33(100.0) 6(18.2) 5(15.2) 3(9.1) 2(6.1) 10(30.3) 3(9.1) 0(0.0) 0(0.0) 3(9.1) 1(3.0)

43(100.0) 8(18.6) 6(14.0) 3(7.0) 4(9.3) 6(14.0) 6(14.0) 1(2.3) 3(7.0) 5(11.6) 1(2.3)

FIGURE 16-43 Data from the North American Pediatric Renal Transplant Cooperative Study on causes of death by age group. This study revealed a high rate of attrition among pediatric transplantation recipients under the age of 5 years. It is unclear whether this high rate is due to a higher rate of infection. (From Tejani and coworkers [39]; with permission.)

FIGURE 16-44 Data from the 1995 North American Pediatric Renal Transplant Cooperative Study showing a total of 214 deaths. Infection was the leading cause of death, occurring in 74 patients. This graph depicts the survival distribution estimates by donor source. Infants aged under 2 years at the time of transplantation have a mortality rate of 14%. This rate is significantly higher (P < 0.001) than in other age groups, with a mortality rate between 4.7% and 8.0%. (From Warady and coworkers [5]; with permission.)

100 95 Patient survival, %

6–12

Unknown causes

90 85 80 75

Living donor Cadaveric donor

70 0

12

24 36 48 Follow-up, mo

60

Numbers at risk at: Baseline 12 24 36 48 Living donor 1800 1393 1033 815 535 Cadaveric donor 1873 1362 1080 774 536

16.20

Transplantation as Treatment of End-Stage Renal Disease

Recipient age 0–1 (n = 154) 2–5 (n = 413) 6–12 (n = 926) 13–17 (n = 964)

Cumulative mortality, %

30 25 20 15 10

FIGURE 16-45 Data from the North American Pediatric Renal Transplant Cooperative Study of patient mortality by recipient age. A significant difference (P < 0.001) in 1-year mortality rates by age groups occurred: 13.6% (21 of 154) for 0- to 1-year-old recipients; 8.0% (33 of 413) for 2- to 5-year-old recipients; 3.6% (33 of 926) for 6- to 12-year-old recipients; and 4.5% (43 of 964) for 13- to 17-year-old recipients. Mortality also is increased for recipients of kidneys from young cadaveric donors. A dramatic increase in cumulative mortality is seen, with increasing concordance between young donor and recipient ages. (From Tejani and coworkers [39]; with permission.)

5 0 0

Cumulative mortality, %

30

10 20 30 40 Time posttransplantation, mo

Acute tubular necrosis No (n = 2140) Yes (n = 310)

25 20

FIGURE 16-46 The effect of acute tubular necrosis (ATN) on patient survival. The development of ATN leads to a significantly higher (P = 0.0001) mortality rate of 13.2% (risk ratio of 3.1) for the 310 patients reported on in the registry. A 25% mortality rate and 6.4 risk ratio were noted for the 188 patients who developed graft failure within 30 days after transplantation (P < 0.001). (From Tejani and coworkers [39]; with permission.)

15 10 5 0 0

10 20 30 40 Time posttransplantation, mo

References 1. Ettenger RB: Renal transplantation. In Renal Disease in Children. Edited by Barakat AY. New York: Springer-Verlag; 1990:371–384. 2. Warady BA, Hebert D, Sullivan EK, et al.: Renal transplantation, chronic dialysis and chronic renal insufficiency in children and adolescents: 1995 Annual Report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol 1997, 11:49–64. 3. United States Renal Data System: USRDS 1997 Annual Data Report. Am J Kidney Dis 30:S128–144. 4. Harmon WE: Treatment of children with chronic renal failure. Kidney Int 1995, 47:951–961. 5. Warady BA, Hebert D, Sullivan EK, et al.: Renal transplantation, chronic dialysis and chronic renal insufficiency in children and adolescents: 1995 Annual Report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol 1997, 11:49–64. 6. UNOS Bull 1997, 2(10), October. 7. Tejani A, Stablein D, Alexander S, et al.: Analysis of rejection outcomes and implications. Transplantation 1995, 59:502. 8. Stablein DM, Tejani A: Five-year patient and graft survival in North American children. Kidney Int 1995, 44:516. 9. Tejani A, Sullivan EK: Factors that impact on the outcome of second renal transplants in children. Transplantation 1996, 62:606–611. 10. Harmon WE: Treatment of children with chronic renal failure. Kidney Int 1995, 47:951–961.

11. McEnery P, Stablein DM: Does human lymphocyte antigen matching improve the outcome in pediatric renal transplants? J Am Soc Nephrol 1992, 2:S234–S237. 12. Fine RN, Tejani A, Sullivan EK: Pre-emptive renal transplantation in children: report of the North American Pediatric Renal Transplant Cooperative Study. Clin Transplantation 1994, 8:474–478. 13. Red Book: Report of the Committee on Infectious Diseases, edn 24. Edited by Georges Peter. Elk Grove: American Academy of Pediatrics; 1997:18–19. 14. Furth SL, Neu AM, Sullivan EK, et al.: Immunization practices in children with renal disease: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol 1997, 11:443–446. 15. Tejani A, Sullivan EK: Higher maintenance cyclosporine dose decreased the risk of graft failure in North American children: a report of the North American Pediatric Renal Transplant Study. J Am Soc Nephrol 1996, 7:550–555. 16. McEnery PT, Stablein DM, Arbus G, Tejani A: Renal transplantation in children: a report of the North American Pediatric Renal Transplant Cooperative Study. N Engl J Med 1992, 326:1727–1732. 17. Tzakis AG, Reyes J, Todo S, et al.: Two-year experience with FK-506 in pediatric patients. Transplant Proc 1993, 25:619–621. 18. Reding R, Wallemacq PE, Lamy ME, et al. Conversion from cyclosporine to FK-506 for salvage of immunocompromised pediatric liver allografts. Transplant 1994, 57:93–100.

Transplantation in Children 19. Ellis D. Clinical use of tacrolimus (FK-506) in infants and children with renal transplants. Pediatr Nephrol 1995, 9:487–494. 20. Ettenger R, Cohen A, Nast C, et al.: Mycophenolate mofetil as maintenance immunosuppression in pediatric renal transplantation. Transplant Proc 1997, 29:340–341. 21. Rees L, Rigden SPA, Ward GM: Chronic renal failure and growth. Arch Dis Child 1989, 64:573–577. 22. Tejani A, Fine R, Alexander S, et al.: Factors predictive of sustained growth in children after renal transplantation: The North American Pediatric Renal Transplant Cooperative Study. J Pediatr 1993, 122:397–402. 23. Harmon WE, Jabs K: Factors affecting growth after renal transplantation. J Am Soc Nephrol 1992, 2:S295–S303.

16.21

30. Ingulli E, Tejani A: An analytical review of growth hormone studies in children after renal transplantation. Pediatr Nephrol 1995, 9:S61–S65. 31. Tonshoff B: Efficacy and safety of growth hormone treatment in short children with renal allografts: 3-year experience. Kidney Int 44:199–207. 32. Yadin O, Grimm PC, Ettenger RB: Renal transplantation in children. Pediatr Ann 1991, 20:662–667. 33. Tejani A, Cortes C, Stablein D: Clinical correlates of chronic rejection in pediatric renal Transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study. Transplantation 1996, 61:1054–1058.

24. United States Renal Data System: USRDS 1995 Annual Data Report. Bethesda, MD, The National Institutes of Health, The National Institute of Diabetes and Digestive and Kidney Diseases, 1995. Am J Kidney Dis 1995, 26:S1–S186.

34. Palleschi J, Novick AC, Braun WE: Vascular complications of renal transplantation. Urology 1990, 16:61.

25. Najjar MF, Rowland M: Anthropometric reference data and the prevalence of overweight. Vital Health Stat 1987, 11:1073.

36. Baluarte HJ, Gruskin AB, Ingelfinger JR, et al.: Analysis of hypertension in children post-renal transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPTRCS). Pediatr Nephrol 1994, 8:570–573.

26. Turenne MN, Port FK, Strawderman RL, et al.: Growth rates in pediatric dialysis patients and renal transplant recipients. Am J Kidney Dis 1997, 30:193–203. 27. Jabs K, Sullivan EK, Avner ED, Harmon WE: Alternate day steroid dosing improves growth without adversely affecting graft survival or long-term graft function. Transplantation 1996, 61:31–36. 28. Broyer M: Results and side-effects of treating children with growth hormone after kidney transplantation: a preliminary report. Acta Paediatr Suppl 1996, 417:76–79. 29. Laine J, Krogerus L, Sarna S, et al.: Recombinant human growth hormone treatment: its effect on renal allograft function and histology. Transplantation 1996, 61:898–903.

35. Singh A, Stablein D, Tejani A: Risk factors for vascular thrombosis in pediatric renal transplantation. Transplantation 1997, 63:1263–1267.

37. Fine RN, Ettenger R: Renal transplantation in children. Kidney Transplantation: Principles and Practice, edn 4. Edited by Morris PJ. Philadelphia: WB Saunders Company; 1994:418. 38. Kashton CE, McEnery PT, Tejani A, Stablein DM: Renal allograft survival according to primary diagnosis: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol 1995, 9:679–684. 39. Tejani A, Sullivan EK, Alexander S, et al.: Post-transplant deaths and factors that influence the mortality rate in North American children. Transplantation 1994, 57:547–553.

Recurrent Disease in the Transplanted Kidney Jeremy B. Levy

M

any patients receiving renal allografts become identified simply as recipients of kidney transplantation. All subsequent events involving changes in renal function are attributed to the process and natural history of transplantation itself: acute and chronic rejection, immunosuppressive drug nephrotoxicity, graft vasculature thrombosis or stenosis, ischemia, infection, and lymphoproliferative disorders. However, it is important to remember the nature of the underlying disease that caused the initial renal failure, even if the disease occurred many years previously. Recurrence of the primary disease often causes pathologic changes within the allograft; clinical manifestations such as proteinuria and hematuria; and less commonly, renal failure. Thus, focal segmental glomerulosclerosis (FSGS) frequently causes recurrent proteinuria after transplantation, which may begin as early as minutes after the graft is vascularized [1]. All patients with diabetes develop recurrent basement membrane and mesangial pathology within their allografts [2], and recurrent oxalate deposition can cause rapid renal allograft failure in patients with oxalosis [3]. Identifying patients at particular risk of primary disease recurrence allows consideration of therapeutic maneuvers that may minimize the incidence of recurrence. Living-related transplantation poses additional dilemmas. For many nephritides good evidence exists for an increased incidence of recurrent primary disease in related as opposed to cadaveric grafts. Data from the Eurotransplant Registry suggests a fourfold increased incidence of recurrence of glomerulonephritis, causing graft loss in grafts from living related donors (16.7% vs 4%) [4]. Finally, the recurrence of glomerulonephritis after transplantation, in particular, can cause specific diagnostic problems. It may be caused by recurrent disease, development of de novo glomerulonephritis in the transplanted organ, or transplanted glomerulonephritis from a donor with unrecognized disease. Glomerulonephritis after transplantation must be distinguished from chronic rejection causing glomerulopathy and cyclosporine-induced glomerulotoxicity. Each of the following diseases can present diagnostic dilemmas and cause graft failure:

CHAPTER

17

17.2

Transplantation as Treatment of End-Stage Renal Disease

recurrence of FSGS, mesangial immunoglobulin A disease, hemolytic uremic syndrome, mesangiocapillary glomerulonephritis, and anti–glomerular basement membrane disease. Overall, three groups of diseases recur in patients with transplantations: metabolic disorders, especially primary hyperoxaluria and diabetes; systemic diseases, including systemic lupus erythematosus, sickle cell disease, systemic sclerosis, hepatitis C virus–associated nephropathies and systemic vasculitis; and a variety of glomerulonephritides. For immunemediated systemic diseases the standard transplantation immunosuppressive regimens often prevent recurrence of primary

DISEASES THAT RECUR AFTER KIDNEY TRANSPLANTATION Metabolic

Systemic

Glomerulonephritis

Diabetes mellitus Oxalosis Amyloidosis Fabry’s disease

Systemic lupus erythematosus Systemic vasculitis Sickle cell disease Hepatitis C virus– associated nephropathy Systemic sclerosis

Immunoglobulin A nephropathy Focal segmental glomerulosclerosis Henoch-Schonlein purpura Membranous nephropathy MCGN Hemolytic uremic syndrome Anti–glomerular basement membrane disease

DIFFERENTIAL DIAGNOSIS OF RECURRENT DISEASE AFTER KIDNEY TRANSPLANTATION De novo glomerulonephritis Transplanted glomerulonephritis Chronic rejection Acute allograft glomerulopathy Chronic allograft glomerulopathy Cyclosporine toxicity Acute rejection Allograft ischemia Cytomegalovirus infection

disease, which also may be true for the glomerulonephritides. Some evidence exists that in the glomerulonephritides there is a reduced incidence of recurrence with the use of cyclosporine. Confirmed recurrence of all the glomerulonephritides causes graft loss in 4% of adults and 7% of children receiving allografts [4,5]. Although few data exist on the treatment of most forms of recurrent nephritis, plasma exchange or immunoadsorption are proving beneficial at reducing nephrotic range proteinuria in recurrent FSGS [6,7], and recurrent renal oxalate deposition often can be abrogated after transplantation in patients with primary hyperoxaluria [8,9]. FIGURE 17-1 Many diseases can recur in transplanted kidneys, although fewer cause graft failure. Those disorders that can cause loss of allografts include oxalosis (primary hyperoxaluria) and some glomerulonephritides, particularly mesangiocapillary glomerulonephritis (MCGN), focal segmental glomerulosclerosis, and sometimes hemolytic uremic syndrome. Diabetes recurs almost universally in isolated renal grafts but rarely causes graft failure. Histologic recurrence of diabetic vascular pathology and glomerular pathology is much more infrequent in patients receiving combined pancreas and kidney transplantations [10,11]. Hepatitis C virus is now recognized as a cause of a number of problems after transplantation, including an increased risk of recurrent and de novo glomerulonephritis (MCGN and membranous) and allograft glomerulopathy [12].

FIGURE 17-2 Acute cellular rejection and cyclosporine toxicity usually can be distinguished easily from recurrent glomerular disease. Recurrent hemolytic uremic syndrome, however, can cause a microangiopathy similar to cyclosporine toxicity, with erythrocyte fragments visible both in blood films and within glomerular capillary loops. The major diagnostic difficulty lies with chronic rejection, especially in the form of transplantation glomerulopathy, and de novo or transplanted glomerulonephritis. Chronic transplantation glomerulopathy occurs in 4% of renal allografts and usually is associated with proteinuria of more than 1 g/d, beginning a few months after transplantation. Chronic glomerulopathy shares some features with both recurrent mesangiocapillary glomerulonephritis type I and hemolytic uremic syndrome: glomerular capillary wall thickening, mesangial expansion, and double contour patterns of the capillary walls with mesangial cell interposition [13]. Thus, a definitive diagnosis of recurrent nephritis may require histologic characterization of the underlying primary renal disease and a graft biopsy before transplantation.

Recurrent Disease in the Transplanted Kidney

17.3

FIGURE 17-3 Biopsy showing rejection (panel A) and membranous changes (panel B) in a woman 8 months after transplantation. The patient initially had idiopathic membranous nephropathy that progressed to end-stage renal failure over 5 years. She subsequently received a cadaveric allograft but developed proteinuria and renal dysfunction after 8 months. The biopsy shows recurrent membranous disease, with thickened glomerular capillary loops (and spikes on a silver stain), and features of acute interstitial rejection, with a pronounced cellular infiltrate and tubulitis. Additional sections also showed evidence of chronic cyclosporine toxicity. In many patients, transplantation biopsies have features of several pathologic processes. Recurrent nephritis can be overlooked in a biopsy showing evidence of chronic rejection, cyclosporine toxicity, or both.

A

B

INVESTIGATING RECURRENT DISEASE AFTER KIDNEY TRANSPLANTATION Renal biopsy with immunofluorescence and electron microscopy Cyclosporin A level Urine microscopy and culture 24-h urine protein Renal ultrasonography Anti–glomerular basement membrane autoantibody and antineutrophil cytoplasm antibody Cytomegalovirus serology and viral antigen detection Hepatitis C virus serology and RNA detection

FIGURE 17-4 Confirming a diagnosis of recurrent disease requires a renal biopsy. Features that favor recurrence include an active urine sediment with erythrocytes and erythrocyte casts, heavy proteinuria, and normal cyclosporine levels. Serologic testing for anti–glomerular basement membrane antibody is important in patients with Alport’s or Goodpasture’s syndrome, and blood film examination for patients with previous hemolytic uremic syndrome. Immunofluorescence and electron microscopic studies are rarely performed routinely on transplantation biopsies but can be vital in making a diagnosis of recurrent nephritis.

17.4

Transplantation as Treatment of End-Stage Renal Disease

RECURRENT DISEASES AFTER KIDNEY TRANSPLANTATION Recurrent diseases that commonly cause graft failure

Histologic recurrence only, graft failure uncommon

Histologic recurrence rare

Primary hyperoxaluria type I Focal segmental glomerulosclerosis Hemolytic uremic syndrome Henoch-Schonlein purpura Mesangiocapillary GN type I (and less commonly, type II) Immunoglobulin A disease?

Diabetes mellitus Immunoglobulin A disease Henoch-Schonlein purpura Membranous GN Mesangiocapillary GN type II Anti–glomerular basement membrane disease Systemic vasculitis (antineutrophil cytoplasm antibody–associated) Fabry’s disease

Systemic lupus erythematosus Systemic vasculitis Idiopathic rapidly progressive GN Membranous GN

FIGURE 17-5 The prevalence and incidence of recurrent disease after transplantation is difficult to ascertain. Certainly, system lupus erythematosus and idiopathic rapidly progressive glomerulonephritis rarely recur in grafts, whereas in some groups of patients recurrence of focal segmental glomerulosclerosis is universal [4]. There is much debate as to the frequency of recurrence of immunoglobulin A disease and whether there is any association of recurrence with graft dysfunction

[14,15]. Recurrence of an underlying primary renal disease may cause changes within the allograft and predispose patients to acute rejection and graft failure, eg, upregulation of human leukocyte antigens in parenchymal tissue. Proteinuria and dyslipidemia also can lead to changes in the expression of cell surface proteins critical for antigen presentation and immune regulation.

HISTOLOGIC AND CLINICAL RECURRENCE OF RENAL DISEASE AFTER KIDNEY TRANSPLANTATION Disease Diabetes mellitus Primary hyperoxaluria Focal segmental glomerulosclerosis Immunoglobulin A nephropathy Henoch-Schonlein purpura Mesangiocapillary glomerulonephritis type I Mesangiocapillary glomerulonephritis type II Membranous nephropathy Anti–glomerular basement membrane disease Systemic lupus erythematosus Hemolytic uremic syndrome Vasculitis Amyloidosis

Histologic recurrence rate, % 50–100 40–100 10–15 without risk factors 50–100 with risk factors 25–75 30–75 9–70 30–40 3–57 5–10 <1 0–45 1–16 20–33

Clinical recurrence rate, % 10, after 10 years 32–100 50 1–40 1–45 50–100 10–20 50 25 Rare 10–50 0–40 20–60

FIGURE 17-6 Accurate data for recurrence rates are difficult to obtain, especially because transplantation biopsies often are not performed routinely after transplantation without a specific indication. Thus, some recurrence rates may be overrepresented in failing grafts, with asymptomatic recurrence being undetected. Many recurrent diseases do not cause urinary abnormalities or symptoms. Diseases that are slowly progressive also may be underrepresented in studies with only a short follow-up time (eg, immunoglobulin A disease).

17.5

Recurrent Disease in the Transplanted Kidney 100 Patients with glomerulonephritis Patients without glomerulonephritis

80

Graft survival, %

Graft survival, %

100

60 40 20

80 60 40 Patients with glomerulonephritis Patients without glomerulonephritis

20

0

0 0

5

A

10

15

20

25

0

Grafted before 1983, y

5

B

FIGURE 17-7 Actuarial cadaveric survival curves in patients with or without glomerulonephritis (GN) as the primary disease. A Significantly worse renal graft survival in patients receiving grafts before 1983 if their underlying disease was GN, rather than any other disease (P < 0.015; diabetes excluded). B, Since the introduction of

10

Grafted since 1983, y

cyclosporine (in transplantations after 1983), graft survival curves are the same for patients with or without GN. For patients receiving a living related graft, however, GN still carries an excess risk of recurrent disease causing graft failure [4]. (Adapted from from Michielsen [16].)

RECURRENCE OF ORIGINAL GLOMERULONEPHRITIS CAUSING GRAFT FAILURE Living related donor (LRD) kidney transplantations Years after transplantation 0–1 1–2 2–3 3–4 4–5 Total

Cadaveric kidney transplantations

All LRD transplantation failures from recurrent GN, %

LRD graft failures from recurrent GN, %

All cadaveric transplantation failures from recurrent GN, %

Cadaveric graft failures from recurrent GN, %

1.9 0.7 1.5 0 0.8 4.4

25 9 33 0 14 16.7

0.2 0.5 0.3 0.25 0.3 1.3

1.5 8.7 5.8 4.8 6.6 4

FIGURE 17-8 Several studies have reported an increased incidence of recurrent glomerulonephritis (GN) after renal transplantation in grafts from living related donors. In one study with histologic data available on both donors and recipients, GN recurred in 8.7% of 149 cadaveric grafts compared with 25.8% of 124 living donor grafts [16,17]. The data shown here are from the Eurotransplant Registry. These data demonstrate a substantial excess of recurrent GN causing graft failure

in living donor grafts compared with cadaveric grafts from the same centers over the same time period [4]. Up to one third of all the graft failures in grafts from living related donors were due to recurrent disease compared with less than 1 in 10 graft failures in cadaveric transplantations. No difference in recurrence rates was seen in any of the first 5 years after transplantation. GN—glomerulonephritis. (Adapted from Kotanko and coworkers [4].)

17.6

Transplantation as Treatment of End-Stage Renal Disease 40

40

35 Graft loss from recurrence, %

45

Recurrence, %

35 30 25 20 15 P<0.02

10

Nephx No Nephx

5

30 25 20 15

5

A

10 Time of follow-up, y

CAUSE OF GRAFT LOSS IN RENAL GRAFT RECIPIENTS WITH DIABETES DURING THE FIRST AND SECOND DECADES

Deaths with functioning grafts: Cardiovascular disease Sepsis Malignancy Other Rejection Recurrent diabetic nephropathy Technical Other

0

5

10

First decade, % (No. of patients)

Second decade, % (No. of patients)

56 (104) 16 14 2 24 31 (62) 0 (0) 8 (14) 5 (9)

76 (19) 40 4 16 16 16(4) 8 (2) 0 (0) 0 (0)

FIGURE 17-10 Recurrence of diabetes in renal allografts is a common histologic finding but a rare cause of graft loss. The most frequent cause of death in the second decade after transplantation was cardiovascular disease, and the most common cause of graft loss was the death of a patient with a functioning graft. Only 2 of 100 patients surviving more than 10 years suffered graft loss from recurrent diabetic nephropathy, occurring at 12.6 and 13.6 years after transplantation [2]. The incidence of vascular complications and the need for amputations, however, are substantially increased in patients with diabetes receiving transplantations. In most centers, overall graft survival rates are lower for recipients with diabetes than for those without diabetes. (Adapted from Najarian and coworkers [2].)

15

20

Time of follow-up, y

B

FIGURE 17-9 Bilateral pretransplantation native nephrectomy has been advocated to reduce the likelihood of recurrence of nephritis in renal transplantations. The data shown here indicate that of 364 transplantations in patients with a diagnosis of primary glomerulonephritis, an increased recurrence rate exists in those 61 patients with bilateral pretransplantation nephrectomies compared with the 303 patients

Cause

0

20

15

Nephx No Nephx

5

0 0

P<0.01

10

without nephrectomy (24.6% vs 12.2%; P < 0.02) [18]. Overall, 14% of patients having transplantation developed recurrent glomerulonephritis (panel A), and 52% of grafts in these patients failed (panel B). Thus, pretransplantation nephrectomy has no place in preventing recurrent nephritis. (From Odorico and coworkers [18].)

Hyaline vasculopathy almost universal Glomerular capillary basement membrane thickening Mesangial Transplant expansion, microalbuminuria

0

2

3

4

18% of patients have severe mesangial expansion (Kimmelsteil-Wilson nodules)

13

Years

FIGURE 17-11 Diabetic changes in renal allografts transplanted into patients with diabetes. Diabetic changes (especially glomerular capillary wall thickening and hyaline vasculopathy) probably occur in all these recipients [2,10]. Diabetic changes occur slowly, however, and rarely are severe enough to cause graft dysfunction. The serum creatinine at 10 years in 95 patients from Minnesota with renal allografts functioning for more than 10 years was 1.5 ´0.1 mg/dL (mean ´ standard error of the mean) and in 10 patients with allograft function for 15 or more years was 1.6 ´0.3 mg/dL [2]. Classic nodular glomerulosclerosis is much rarer. Recurrence of diabetic nephropathy can be prevented by simultaneous pancreatic and renal transplantation. At 2 years, most patients receiving a combined pancreatic and kidney graft have no histologic changes on renal biopsy and normal basement membrane thickness on electron microscopy of glomerular tissue [10,11]. Intensive insulin treatment with good glycemic control after transplantation also prevents the development of recurrent glomerular and arteriolar lesions.

Recurrent Disease in the Transplanted Kidney

17.7

Alanine: glyoxylate aminotransferase (AGT) Glycine

Glyoxylate Cofactor: pyridoxine Lactate dehydrogenase L-α-hydroxy acid oxidase Glycolate oxidase

Glyoxylate reductase

Oxalate

Glycolate

FIGURE 17-12 Primary hyperoxaluria type I in renal failure. Primary hyperoxaluria type I is an autosomal recessive inborn error of metabolism resulting from a deficiency (or occasionally incorrect subcellular localization) of hepatic peroxisomal alanine–glyoxylate aminotransferase [8]. Patients excrete excess oxalate as a result of the increased glyoxylate pool. In many patients, renal disease is manifested by chronic renal failure. Once the glomerular filtration rate has decreased below 25 mL/min the combination of oxalate overproduction and reduced urinary excretion leads to systemic oxalosis, with calcium oxalate deposition in many tissues. Renal transplantation alone has yielded poor results in the past, with 1-year graft survival rates of only 26% [3]. Combined hepatorenal transplantation simultaneously replaces renal function and corrects the underlying metabolic defect. The 1-year liver graft survival rate is 88%, with patient survival of 80% at 5 years. Of 24 renal grafts from the European experience of hepatorenal transplantation, 17 were still functioning at 3 months to 2 years after transplantation [19].

PATIENT MANAGEMENT IN RENAL OR HEPATORENAL TRANSPLANTATIONS FOR PRIMARY HYPEROXALURIA Aggressive preoperative dialysis (and possibly continued postoperatively) Maintenance of high urine output Low oxalate, low ascorbic acid, diet low in vitamin D Phosphate supplements Magnesium glycerophosphate High-dose pyridoxine (500 mg/d) Thiazide diuretics

FIGURE 17-13 Histologic slide of a patient who received an isolated renal allograft for primary hyperoxaluria type I in which oxylate crystals are seen clearly within the tubules and interstitium. The major hazards for the renal graft after transplantation include early acute nephrocalcinosis caused by rapid mobilization of the systemic oxalate deposits. Acute tubular obstruction by calcium oxalate crystals also can occur. Late nephrocalcinosis leads to progressive loss of renal function over several years. Rejection episodes are less common in patients receiving combined liver and kidney grafts than in those receiving kidney transplantation alone [3,19]. Acute rejection with renal dysfunction, however, causes additional episodes of acute calcium oxalate deposition in the kidney. Recurrent oxalosis can be seen as early as 3 months after transplantation.

FIGURE 17-14 Daily hemodialysis for at least 1 week before transplantation depletes the systemic oxalate pool to some extent. Some centers continue aggressive hemodialysis after transplantation, regardless of the renal function of the transplanted organ. In patients receiving combined hepatorenal grafts, dietary measures to reduce oxalate production are not as important as they are in patients receiving isolated kidney grafts. In these patients, excess production of oxalate from glyoxylate still occurs. Magnesium and phosphate supplements are powerful inhibitors of calcium oxalate crystallization and should be used in all recipients, whereas thiazide diuretics may reduce urinary calcium excretion. Pyridoxine is a cofactor for alanine– glyoxylate aminotransferase and can increase the activity of the enzyme in some patients. Pyridoxine has no role in combined hepatorenal transplantation. For most patients the ideal option is probably a combined transplantation when their glomerular filtration rate decreases below 25 mL/min [8,9].

17.8

Transplantation as Treatment of End-Stage Renal Disease

AMYLOIDOGENIC AND RELATED DISEASES CAUSING RENAL FAILURE Disease Nonhereditary Systemic amyloidosis associated with chronic inflammatory disorders (especially rheumatoid arthritis) Systemic amyloidosis associated with immune dyscrasia: multiple myeloma, monoclonal gammopathy, occult immune dyscrasia, lymphoma Hereditary Familial Mediterranean fever Ostertag-type (autosomal dominant, early hypertension, and renal impairment) Muckle-Wells syndrome (deafness, nephropathy, urticaria, and limb pain) Hereditary renal amyloidosis Familial nephropathic systemic amyloidosis Light chain deposition disease

FIGURE 17-15 The most common cause of amyloidosis leading to renal failure is rheumatoid arthritis [20]. However, increasing numbers of patients with myeloma and AL amyloid, or primary amyloidosis, are now receiving peripheral blood stem cell transplantations or bone marrow allografts. Thus, these patients are surviving long enough to consider renal transplantation. Over 60 patients with renal failure resulting from systemic amyloid A (AA) amyloidosis have been reported to have received renal allografts. Graft survival in these patients is the same as that of a matched population. Histologic

A

B

Fibril protein

Precursor protein

Amyloid A AL

Serum amyloid A Monoclonal immunoglobulin light chain

Amyloid A Not known Not known Fibrinogen Apolipoprotein A AL or immunoglobulin light chains

Serum amyloid A Not known Not known Fibrinogen Apolipoprotein A Immunoglobulin light chains

recurrence of renal amyloid has been reported in 20% to 33% of these grafts within 2 years of transplantation [20,21]. Patient survival is reduced, owing to infections and vascular complications, to 68% at 1 year and 51% at 2 years. Recurrence is characterized by proteinuria 11 months to 3 years after transplantation. Recurrent light chain deposition disease is found in half of patients receiving allografts, with graft loss in one third despite plasmapheresis and chemotherapy [4]. Heavy proteinuria is seen at the onset of recurrence. AL—primary amyloidosis. FIGURE 17-16 Microradioangiography comparing the vasculature of the kidney in a patient with no disease (panel A) and a patient with homozygous sickle cell disease (panel B) [22]. Despite the frequency of renal damage in sickle cell disease, only 4% of patients progress to end-stage renal disease, and little experience exists with renal transplantation. Three patients have been reported with recurrent sickle cell nephropathy. In one case, a patient developed renal dysfunction 3.5 years after transplantation; a biopsy showed glomerular sclerosis, tubular atrophy, and interstitial fibrosis, without features of rejection. A second study reported recurrent sickle cell nephropathy leading to graft failure in two of eight patients receiving transplantation [23]. Concentration defects were observed within 12 months of grafting. Patients also suffered an increased incidence of sickle cell crises after renal transplantation, possibly associated with the increase in hematocrit.

Recurrent Disease in the Transplanted Kidney

FEATURES OF RECURRENT SYSTEMIC LUPUS ERYTHEMATOSUS Rash Arthralgia Proteinuria (usually nonnephrotic) Increasing anti-DNA antibody titers Increasing antinuclear antibody titers Decreasing complement levels (C3 and C4)

FIGURE 17-17 Nephritis caused by systemic lupus erythematosus (SLE) rarely recurs in transplantations. SLE accounts for approximately 1% of all patients receiving allografts, and less than 1% of these will develop recurrent renal disease. Time to recurrence has been reported as 1.5 to 9 years after transplantation [24,25]. Cyclosporine therapy does not prevent recurrence. It is reasonable to ensure that serologic test results for SLE are minimally abnormal before transplantation and certainly that patients have no evidence of active extrarenal disease. Patients with lupus anticoagulant and anticardiolipin antibodies are at risk of thromboembolic events, including renal graft vein or artery thrombosis. These patients may require anticoagulation therapy, or platelet inhibition with aspirin.

17.9

RELAPSE RATE IN ANTINEUTROPHIL CYTOPLASM ANTIBODY–ASSOCIATED SYSTEMIC VASCULITIS

Series Hammersmith Hospital 1974–1997 [26] Habitz and coworkers 1980–1995 [26] Schmitt and coworkers 1982–1993 [26]

Patients, n

Relapse rate on dialysis, relapses/patient/y

Relapse rate after transplantation, relapses/patient/y

59

0.088

0.018

18

0.24

0.06

18

0.3

0.1

FIGURE 17-18 Recurrence of Wegener’s granulomatosis or microscopic polyangiitis has been reported after transplantation, with overall renal and extrarenal recurrence rates of up to 29% and renal recurrences alone of up to 16% [27]. Graft loss has been reported in up to 40% of patients with renal recurrence. In the most recent data from the Hammersmith Hospital, however, renal recurrences were rare, with only 0.018 relapses per patient per year after transplantation [26]. These patients have often been on long courses of immunosuppressive therapy before receiving a graft. Extrarenal recurrence of Wegener’s granulomatosis can involve the ureter, causing stenosis and obstructive nephropathy. Serial monitoring of antineutrophil cytoplasmic antibodies after transplantation is important in all patients with vasculitis because changes in titer may predict disease relapse [28,29]. (Adapted from Allen and coworkers [26].)

RENAL COMPLICATIONS OF HEPATITIS C VIRUS AFTER KIDNEY TRANSPLANTATION Clinical: Proteinuria Nephrotic syndrome Microscopic hematuria Histologic and laboratory findings Mesangiocapillary glomerulonephritis with or without cryoglobulinemia, hypocomplementemia, rheumatoid factors Membranous nephropathy: normal complement, no cryoglobulinemia or rheumatoid factor Acute and chronic transplantation glomerulopathy

FIGURE 17-19 Recurrence of both mesangiocapillary glomerulonephritis (MCGN) and, less frequently, membranous nephropathy is well described after transplantation. Nineteen cases of de novo or recurrent MCGN after transplantation have been described in patients with hepatitis C virus (HCV) [12]. Almost all had nephrosis and exhibited symptoms 2 to 120 months after transplantation. Eight patients had demonstrable cryoglobulin, nine had hypocomplementemia, and most had normal liver function test results. Membranous GN is the most common de novo GN reported in allografts, and it is possible that HCV infection may be associated with its development [12]. Twenty patients with recurrent or de novo membranous GN and HCV viremia have been reported. In one study, 8% of patients with membranous GN had HCV antibodies and RNA compared with less than 1% of patients with other forms of GN (excluding MCGN) [30]. Prognosis in these patients was poor, with persistent heavy proteinuria and declining renal function.

17.10

Transplantation as Treatment of End-Stage Renal Disease FIGURE 17-20 Focal segmental glomerulosclerosis accounts for 7% to 10% of patients requiring renal replacement therapy. The overall recurrence rate is approximately 20% to 30% [1,4,31]. These numbers, however, may be an underestimate because of biopsy sampling errors. Patients at high risk for recurrence can be identified, particularly children with rapid evolution of their original disease and mesangial expansion on biopsy [1,32]. Recurrence manifests with proteinuria (often 10–40 g/d), developing hours to weeks after transplantation. In children the mean time to recurrence is 14 days. Recurrence is not benign and leads to graft loss in up to half of patients. Patients at highest risk for recurrence should not receive grafts from living related donors.

RISK FACTORS FOR RECURRENT FOCAL SEGMENTAL GLOMERULOSCLEROSIS AFTER TRANSPLANTATION Risk factor

Recurrence rate, %

Age <5 y Age < 15 y with progression to end-stage renal disease within 3 y First graft lost from focal segmental glomerulosclerosis Adults without risk factors

50 80–100 75–85 10–15

Graft loss occurs in half of all patients with recurrent focal segmental glomerulosclerosis and nephrotic syndrome.

A. RECURRENT FOCAL SEGMENTAL GLOMERULOSCLEROSIS AND ACUTE RENAL FAILURE AFTER TRANSPLANTATION Patients with recurrence, n

Patients with no recurrence, n

16 10

7 40

Acute renal failure (23) No acute renal failure (50)

B. ACUTE REJECTION EPISODES AMONG ACUTE RENAL FAILURE CASES Patients with recurrence

>1 acute rejection episode No rejection

Acute renal failure

No acute renal failure

Patients with no recurrence, no acute renal failure

16 0

7 3

11 29

FIGURE 17-21 Patients with recurrent focal segmental glomerulosclerosis are at substantially increased risk of developing both acute renal failure (panel A) after transplantation and acute rejection episodes (panel B). In one study, 23 of 26 patients with recurrence developed one or more episodes of rejection, compared with only 11 of 40 patients without recurrence [31]. Although the mechanism for the increased rate of acute dysfunction and rejection is unclear, proteinuria and dyslipidemia may alter the expression of cell surface immunoregulatory molecules and major histocompatibility complex antigens. (Adapted from Kim and coworkers [31].)

17.11

Recurrent Disease in the Transplanted Kidney

3

8 6

2

4 1

2 0

B

Serum creatinine, mg/dL

5 10

4

8 3

6

2

4

1

2 0

D

500

600

Day after transplantation

Urinary protein excretion, g/d

3

400

8 6

6

4

4 2

2 60

Day after transplantation

A

8

0

155

55

10

110

160

12

210 260

Day after transplantation

Diagnosis

Features

Recurrent FSGS

Recurrent heavy proteinuria within 3 mo Original disease caused renal failure in <3 y Insidious onset of proteinuria Features of chronic rejection on biopsy, especially vascular sclerosis and glomerulopathy Previous thrombotic microangiopathy affecting glomeruli Original disease not FSGS Chronic rejection excluded Characteristic immunohistology and electron microscopy, especially in immunoglobulin A disease

Cyclosporine-related De novo FSGS Other glomerulonephritides

FSGS—focal segmental glomerulosclerosis.

10

8

8

6

6

4

4

2

2

0 500

C

520

540

560

580

Day after transplantation

FIGURE 17-22 Serum creatinine concentrations and urinary protein excretion in four patients (A–D) with recurrent nephrotic syndrome after transplantation treated by protein adsorption. Each bar indicates one cycle of treatment and the numbers above the bars indicate the sessions of treatment in that cycle. A number of studies have demonstrated that both plasma exchange and protein adsorption (using protein A sepharose), can decrease urinary protein excretion in recurrent focal segmental glomerulosclerosis [6,7,33]. Four examples are shown here. In this study, protein excretion decreased by 82% but returned to pretreatment levels within 2 months in seven of eight patients. More intensive treatment regimens have led to longer remissions [7]. The nature of the circulating factor responsible for protein leakage is unknown. There are case reports of children with recurrent focal segmental glomerulosclerosis responding to high-dose intravenous cyclosporine with remission of nephrotic syndrome. However, cyclosporine does not prevent recurrence when used as part of the initial immunosuppressive regimen. (Adapted from Dantal and coworkers [6].)

DIFFERENTIAL DIAGNOSIS OF SEGMENTAL GLOMERULAR SCARS ON TRANSPLANTATION BIOPSY

Rejection

10

Urinary protein excretion, g/d

10

10 Serum creatinine, mg/dL

Serum creatinine, mg/dL

4

4

2 Serum creatinine, mg/dL

5 5

Urinary protein excretion, g/d

3 Urinary protein excretion, g/d

6

FIGURE 17-23 Segmental glomerular scars in a functioning graft is a common finding. The interpretation of the biopsy requires knowledge of the previous histology in the native kidneys and the clinical course after transplantation. Immunohistology and electron microscopy can be particularly helpful in this setting. Recurrent focal segmental glomerulosclerosis is the most common cause of early massive proteinuria. Both rejection and cyclosporine therapy, however, can cause segmental scars indistinguishable from those of focal segmental glomerulosclerosis. Recurrent or de novo immunoglobulin A disease in an allograft also can cause segmental glomerular scarring, but with mesangial hypercellularity, immunoglobulin A detectable by immunostaining, and paramesangial deposits on electron microscopy.

17.12

Transplantation as Treatment of End-Stage Renal Disease

RECURRENT IMMUNOGLOBULIN A DISEASE Features Histologic recurrence, 25%–75% Clinical recurrence, 1%–40% Time to recurrence, 2 mo to 4 y Clinical presentation: asymptomatic, low-grade proteinuria, microscopic hematuria Susceptibility: human leukocyte antigen B35, DR4; immunoglobulin A rheumatoid factors Graft loss, <10%

FIGURE 17-24 Up to 75% of patients with immunoglobulin A (IgA) disease develop histologic recurrence within their grafts, which usually presents with microscopic hematuria and proteinuria [4,14,15]. Many patients, however, only will have recurrence noted on a routine biopsy after transplantation. Most studies suggest that the risk of graft loss resulting from recurrent disease is low (<10%) [4]. However, longterm follow-up in some studies has suggested an increasing rate of graft loss with time, approaching 20% at 46 months [14,15]. Conversely, one study has documented 100% graft survival at 2 years in patients with IgA disease who had IgA anti–human leukocyte antigen (HLA) antibodies [34]. The mechanism is unclear. The association of IgA disease and the HLA alleles B35 and DR4 may explain the increased risk of recurrence in grafts from living related donors because family members are more likely to share HLA genes.

RECURRENT HENOCH-SCHONLEIN PURPURA Features Risk of recurrence, 30%–75% Clinical recurrence, up to 45% Time to recurrence, immediately to 20 mo Clinical presentation: often asymptomatic; hematuria, proteinuria, arthralgia, purpuric rash, melena Susceptibility: rapid development of renal failure in native kidneys, age >14 y Graft loss: up to 20%, increased in grafts from living related donors

FIGURE 17-25 Histologic slide of a biopsy from a patient with recurrent immunoglobulin A (IgA) nephropathy. This patient developed proteinuria 9 months after receiving a cadaveric allograft. The biopsy shows features of recurrent IgA disease with mesangial expansion and a glomerular tuft adhesion to Bowman’s capsule. Immunohistology confirmed deposition of IgA in the mesangium. At the earliest stages of recurrence, mesangial IgA and complement C3 are detectable by 3 months after transplantation, with electron-dense deposits in the paramesangium but normal appearance on light microscopy. In patients with progressive renal dysfunction, crescents often are found in the glomerulus.

FIGURE 17-26 Most studies have shown that histologic recurrence of HenochSchonlein purpura (HSP) is common but rarely causes graft loss. Grafts from living related donors have a substantially increased risk of failure as a result of recurrent HSP. Patients can develop both renal and extrarenal manifestations of HSP, especially arthralgia. Rapid evolution of the original disease and older age at presentation (>14 y) seem to be risk factors for clinical recurrence. Cyclosporine does not prevent recurrence. It has been arbitrarily suggested that transplantation should be avoided for 12 months after resolution of the purpura; however, individual cases of recurrent disease have been reported despite delays of over 3 years between resolution of purpura and grafting.

Recurrent Disease in the Transplanted Kidney

MESANGIOCAPILLARY GLOMERULONEPHRITIS Feature

Type I

Type II

Histologic recurrence Clinical recurrence Time to recurrence Clinical presentation

9%–70% 30%–40% 2 wk to 7 y (median, 1.5 y) Rarely asymptomatic; proteinuria, nephrotic syndrome, microscopic hematuria Grafts from living related donor

50%–100% 10%–20% 1 mo to 7 y (usually <1 y) Frequently asymptomatic nonnephrotic proteinuria, microscopic hematuria

Risk factors

Mononuclear cell nucleus

A

Endothelial cell

Endothelial cell

Capillary lumen

Interpositioned mesangial cell Podocytes

Subendothelial deposits

Basement membrane

Cell nucleus

Capillary lumen

B

Basement membrane

Continuous band of electron-dense material in basement membrane

Podocyte foot processes

Male, rapidly progressive course of initial disease, nephrotic syndrome after transplantation

17.13

FIGURE 17-27 Both mesangiocapillary glomerulonephritis (MCGN) type I (mesangial and subendothelial deposits) and type II (dense deposit disease) commonly recur after transplantation. Silent recurrence is found more often in type II disease, whereas recurrence of type I MCGN frequently causes nephrotic syndrome and graft failure [35]. An increased risk of recurrence of type I MCGN occurs in grafts from living related donors. Type II disease recurs more often in male patients who progressed rapidly to end-stage renal failure before transplantation. The onset of nephrotic syndrome in type II disease usually heralds graft failure. No established treatment for recurrent disease exists, although anecdotally aspirin plus dipyridamole and cyclophosphamide have been used with some success in recurrent type I MCGN. Plasma exchange has been reported to improve the histologic changes and induce a clinical remission in one patient with recurrence of type II MCGN [36].

FIGURE 17-28 Electron micrographs of mesangiocapillary glomerulonephritis (MCGN) type I (A) and type II (B). The histologic features of recurrence are the same as for the primary disease. In type II MCGN the ribbonlike band of electron-dense material within the glomerular basement membrane has been observed as early as 3 weeks after transplantation. Initially, the recurrence is focal but subsequently progresses to involve most of the capillary walls. Failing grafts frequently have segmental glomerular necrosis and extracapillary crescents. Making the diagnosis is not difficult when electron microscopy has been performed on the transplantation biopsy. In MCGN type I, electron-dense deposits first appear in the mesangium and subsequently in a subendothelial position. Mesangial cell interposition frequently is visible on electron microscopy, and on light microscopy the capillary walls appear thickened and show a double contour. The differential diagnosis is MCGN caused by acute or chronic transplantation glomerulopathy. Global changes, immune deposits, and increased mesangial cells, however, are rare in chronic transplantation glomerulopathy. Endocapillary proliferation and macrophages within capillary loops are important features of acute transplantation glomerulopathy, which usually are absent in recurrent MCGN [13].

17.14

Transplantation as Treatment of End-Stage Renal Disease

FEATURES OF RECURRENT AND DE NOVO MEMBRANOUS NEPHROPATHY AFTER TRANSPLANTATION Features

De novo membranous

Recurrent membranous

Incidence Clinical presentation Time of onset Histology

2%–5% Often asymptomatic; proteinuria, nephrotic syndrome develops slowly 4 mo to 6 y (mean 22 mo) Identical to native membranous nephropathy, often shows features of chronic rejection None specific Increased over controls; may be as high as 50% but most patients also have chronic rejection

3%–57% Proteinuria, nephrotic syndrome develops rapidly 1 wk to 2 y (mean 10 mo) Identical to native membranous nephropathy, often shows features of chronic rejection Male gender, aggressive clinical course 50%–60%, but some studies have shown no increased graft failure rate compared with other nephritides

Risk factors for graft failure Incidence of graft failure

FIGURE 17-29 Recurrence of membranous nephropathy in transplantations is variable, with studies reporting incidences from 3% to 57% [4,37]. The major differential diagnosis is de novo membranous nephropathy in patients with a different underlying renal pathology. De novo allograft membranous glomerulonephritis reported in 2% to 5% of transplantations is often asymptomatic and usually associated with chronic rejection

FIGURE 17-30 Histologic slide of a biopsy showing extensive spike formation along the glomerular basement membrane. This woman had recurrent membranous disease 8 months after transplantation. She developed nephrotic range proteinuria and subsequent renal dysfunction. Both recurrent and de novo membranous glomerulonephritis are indistinguishable from idiopathic membranous nephropathy. The initial lesions are generally stage I or II, although the deposits subsequently become diffuse and intramembranous.

[38]. In contrast, recurrent disease frequently causes nephrotic syndrome, developing within the first 2 years after transplantation. Data on the incidence of graft failure attributable to membranous disease are confusing. Cyclosporine therapy has made no difference in the incidence of the two entities, and hepatitis C virus infection may be associated with membranous disease after transplantation.

FIGURE 17-31 (see Color Plate) Histologic slide showing deposition of anti–glomerular basement membrane (GBM) antibody along the GBM, which is seen in over half of patients with Goodpasture’s syndrome who receive an allograft while circulating antibodies are still detectable [39]. In most of these cases no histologic abnormalities are seen within the glomerulus, however, and patients remain asymptomatic with normal renal function. Approximately 25% of patients with antibody deposition will develop features of crescentic and rapidly progressive glomerulonephritis and subsequently suffer graft loss. Delaying transplantation for at least 6 months after antibodies have become undetectable reduces the recurrence rate to only 5% to 15%.

Recurrent Disease in the Transplanted Kidney

Antibody titer, %

100

17.15

DIFFERENTIAL DIAGNOSIS OF LINEAR DEPOSITION OF IMMUNOGLOBULIN ALONG THE GLOMERULAR BASEMENT MEMBRANE IN TRANSPLANTATION BIOPSY Immunosuppression alone

Recurrent anti–glomerular basement membrane disease Anti–glomerular basement membrane disease in patients with Alport’s syndrome Chronic transplant glomerulopathy Diabetes mellitus Myeloma Recurrent mesangiocapillary glomerulonephritis type I (rarely fibrillary nephritis, and normal cadaveric grafts after initial perfusion)

No treatment

50 With plasma exchange + immunosuppression

0 0

3

6

9 Time, mo

12

15

FIGURE 17-32 Without treatment, circulating anti–glomerular basement membrane autoantibodies become undetectable within 6 to 18 months of disease onset [40,41]. Treatment of the primary disease with plasma exchange, cyclophosphamide, and steroids leads to rapid loss of circulating antibodies. Patients who need transplantation while circulating antibodies are still detectable should be treated with plasma exchange before and after transplantation to minimize circulating antibody levels and with cyclophosphamide therapy for 2 months. A similar approach should be used in patients with clinical recurrence. Patients who have linear immunoglobulin deposition in the absence of focal necrosis, crescents, or renal dysfunction do not require treatment.

MUTATIONS IN GLOMERULAR BASEMENT MEMBRANE COLLAGEN GENES Chromosome Collagen 13 2

1 and 2 chains of type IV 3 and 4 chains of type IV

X X

5 chain of type IV 6 chain of type IV

Diseases caused by mutations Autosomal recessive or dominant Alport’s syndrome Classic X-linked Alport’s syndrome Diffuse leiomyomatosis

FIGURE 17-33 Linear immunoglobulin G (IgG) is found in 1% to 4% of routine renal allograft biopsies from patients with neither anti–glomerular basement membrane (GBM) disease nor Alport’s syndrome. Linear antibody deposition in anti-GBM disease is diffuse and global and, in practice, is rarely confused with the nonspecific antibody deposition seen in other conditions. In chronic transplantation glomerulopathy the antibody deposition is focal and segmental, and focal necrosis and cellular crescents are extremely rare. The finding of linear antibody deposits on a transplantation biopsy should lead to testing for circulating anti-GBM antibodies. Early graft loss or dysfunction, along with linear IgG staining, may be the first indication that a patient with an unidentified cause for end-stage renal disease has Alport’s syndrome. FIGURE 17-34 Mutations have been identified in about half of patients with Alport’s syndrome and are found in the genes for the 3, 4, or 5 chains of type IV collagen, which are the major constituents of the glomerular basement membrane. After transplantation, approximately 15% of patients develop linear deposition of immunoglobulin G (IgG) along the glomerular basement membrane (GBM), and circulating anti-GBM antibodies specific for the 3 or 5 chains of type IV collagen [42–44]. It is unclear why only some patients develop antibodies. Clinical disease, however, is rare. Only 20% of patients with antibody deposition develop urinary abnormalities from 1 month to 2 years after grafting. Those patients who do develop proteinuria or hematuria usually lose their grafts. In some cases, treatment with cyclophosphamide did not prevent graft loss.

17.16

Transplantation as Treatment of End-Stage Renal Disease FIGURE 17-35 The microangiopathic hemolysis of recurrent hemolytic uremic syndrome (HUS) is identical to the original disease, with extensive erythrocyte fragmentation and thrombocytopenia. The incidence of HUS recurrence is difficult to assess. At one extreme, five of 11 children suffered graft loss because of recurrent disease. However, most series have reported substantially lower recurrence rates: no recurrences in 16 adults and children, one of 34 grafts in 28 children, and two probable recurrences of 24 grafts in 20 children [4,45,46]. Graft loss occurs in 10% to 50% of patients with recurrence. HUS has been diagnosed 1 day to 15 months after transplantation (usually in less than 2 months), and the incidence of recurrence is increased in patients receiving grafts less than 3 months after their initial disease. Treatment of recurrent disease is plasma exchange for plasma or cryosupernatant, or plasma infusions, and dose reduction of cyclosporine. Recurrence may be prevented by aspirin and dipyridamole. FIGURE 17-36 Blood film abnormalities, microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure occur in accelerated hypertension and acute vascular rejection. A renal biopsy usually distinguishes acute vascular rejection, and malignant hypertension should be obvious clinically. The microangiopathy of cyclosporine can be difficult to differentiate from hemolytic uremic syndrome; however, glomerular pathology usually is less marked and vascular changes more obvious with cyclosporine toxicity. De novo hemolytic uremic syndrome also has been reported in patients treated with tacrolimus (FK-506) [27].

DIFFERENTIAL DIAGNOSIS OF RECURRENT HEMOLYTIC UREMIC SYNDROME Thrombotic microangiopathy associated with cyclosporine Acute vascular rejection Accelerated phase hypertension Tacrolimus- (FK-506) associated thrombotic microangiopathy

OTHER CONDITIONS THAT RECUR IN RENAL ALLOGRAFTS Disease

Recurrence rate

Outcome

Comments

Systemic sclerosis Fabry’s disease

20% Rare recurrence of ceramide in the graft 50% 50% 0%

Usually graft failure Poor

Differentiation from acute and chronic vascular rejection can be difficult Renal transplantation does not halt the progress of Fabry’s disease because the new kidney is not an adequate source of -galactosidase; patients have frequent systemic complications Nephrosis reported between 21 and 60 mo Recurrence associated with extrarenal features including arthralgias and purpura Cystinosis does not recur; however, the allograft can become infiltrated by macrophages containing cysteine, with no pathologic or clinical effect

Immunotactoid glomerulopathy Mixed essential cryoglobulinemia Cystinosis

Nephrotic syndrome Poor Good

FIGURE 17-37 A number of other conditions have been reported to recur in allografts. Very few patients with systemic sclerosis have received transplantation, and the incidence of acute renal failure caused by systemic sclerosis has declined with the widespread use of angiotensinconverting enzyme (ACE) inhibitors. About 20% of patients with a malignant course of scleroderma receiving a transplantation develop

recurrence, which usually causes graft loss. The value of ACE inhibitors after transplantation is unknown. Two of four patients with immunotactoid glomerulopathy developed recurrent disease heralded by massive proteinuria. Transplantation in Fabry’s disease rarely leads to graft-related problems; however, patients die from systemic complications of ceramide deposition.

Recurrent Disease in the Transplanted Kidney

MANAGEMENT OF RECURRENT DISEASE AFTER KIDNEY TRANSPLANTATION Disease

Treatment of recurrence

Focal segmental glomerulosclerosis

Plasma exchange, immunoadsorption, steroids, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs With crescents: plasma exchange, cytotoxics ?Steroids Aspirin, dipyridamole ?Plasma exchange ?Cytotoxics and steroids Plasma exchange, cyclophosphamide Plasma exchange, plasma infusion Cyclophosphamide and steroids Glycemic control Aggressive perioperative dialysis, hydration, low oxalate diet, low ascorbic acid diet, phosphate supplements, magnesium glycerophosphate, pyridoxine

Immunoglobulin A nephropathy Henoch-Schonlein purpura Mesangiocapillary glomerulonephritis type I Mesangiocapillary glomerulonephritis type II Membranous nephropathy Anti–glomerular basement membrane disease Hemolytic uremic syndrome Antineutrophil cytoplasm antibody–associated vasculitis Diabetes Oxalosis

WHEN TO AVOID USING LIVING RELATED DONORS IN KIDNEY TRANSPLANTATION Focal segmental glomerulosclerosis with risk factors for early recurrence Henoch-Schonlein purpura Mesangiocapillary glomerulonephritis type I Mesangiocapillary glomerulonephritis type II with risk factors (familial immunoglobulin A nephropathy and hemolytic uremic syndrome)

17.17

FIGURE 17-38 No controlled data exist on the management of recurrent disease after transplantation. For patients with primary hyperoxaluria, measures to prevent further deposition of oxalate have proved successful in controlling recurrent renal oxalosis [9]. In diabetes mellitus, the pathophysiology of recurrent nephropathy undoubtedly reflects the same insults as those causing the initial renal failure, and good evidence exists that glycemic control can slow the development of end-organ damage. Plasma exchange and immunoadsorption are promising therapies for patients with nephrosis who have recurrent focal segmental glomerulosclerosis; however, these therapies do not provide sustained remission [6,7]. In all these cases, establishing a diagnosis of recurrent disease is critical in identifying a possible treatment modality.

FIGURE 17-39 In these diseases, rapid recurrence leading to graft failure is frequent enough to warrant extreme caution in using living related donors. Even excluding these conditions, the overall rate of recurrence of glomerulonephritis is substantially increased in living related donors, and patients should be made aware of this risk [4]. For familial diseases, the risk of recurrence is even higher (eg, some families with immunoglobulin A disease and hemolytic uremic syndrome). Finally, recurrent glomerulonephritis has been reported in up to 30% of renal isografts, with disease onset between 2 weeks and 16 years after grafting.

References 1. Tejani A, Stablein DH: Recurrence of focal segmental glomerulonephritis posttransplantation: a special report of the North American Pediatric Renal Transplant Cooperative Study. J Am Soc Nephrol 1992, 2(suppl):258–263. 2. Najarian JS, Kaufman DB, Fryd DS, et al.: Long term survival following kidney transplantation in 100 type I diabetic patients. Transplantation 1989, 47:106–113. 3. Broyer M, Brunner FP, Brynger H, et al.: Kidney transplantation in primary oxalosis: data from the EDTA registry. Nephrol Dial Transplant 1990, 5:332–336. 4. Kotanko P, Pusey CD, Levy JB: Recurrent glomerulonephritis following renal transplantation. Transplantation 1997, 63:1045–1052. 5. Cameron JS: Recurrent primary disease following renal transplantation. In Advanced Renal Medicine. Edited by Raine AEG. Oxford: Oxford University Press; 1992:435–448. 6. Dantal J, Bigot E, Bogers W, et al.: Effect of plasma protein adsorption on protein excretion in kidney-transplant recipients with recurrent nephrotic syndrome. N Engl J Med 1994, 330:7–14.

7. Artero ML, Sharma R, Savin VJ, et al.: Plasmapheresis reduces proteinuria and serum capacity to injure glomeruli in patients with recurrent focal glomerulosclerosis. Am J Kidney Dis 1994, 23:574–581. 8. Watts RWE: Primary hyperoxaluria type 1. Q J Med 1994, 87:593–599. 9. Allen AR, Thompson EM, Williams G, et al.: Selective renal transplantation in primary hyperoxaluria type 1. Am J Kidney Dis 1996, 27:891–895. 10. Bilous RW, Mauer SM, Sutherland DE, et al.: The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes. N Engl J Med 1989, 321:80–85. 11. Remuzzi G, Ruggenenti P, Mauer SM: Pancreas and kidney/pancreas transplants: experimental medicine or real improvement? Lancet 1994, 343:27–31. 12. Morales JM, Campistol JM, Andres A, et al.: Glomerular diseases in patients with hepatitis C virus infection after renal transplantation. Curr Opinion Nephrol Hypertens 1997, 6:511–515. 13. Porter KA: Renal transplantation. In Pathology of the Kidney. Edited by Heptinstall RH. Boston: Little, Brown; 1992:1799–1934.

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Transplantation as Treatment of End-Stage Renal Disease

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31. Kim EM, Striegel J, Kim Y, et al.: Recurrence of steroid resistant nephrotic syndrome in kidney transplants is associated with increased acute renal failure and acute rejection. Kidney Int 1994, 45:1440–1445. 32. Senggutuvan P, Cameron JS, Hartley RB, et al.: Recurrence of focal segmental glomerulosclerosis in transplanted kidneys: analysis of incidence and risk factors in 59 allografts. Pediatr Nephrol 1990, 4:21–8. 33. Savin VJ, Sharma R, Sharma M, et al.: Circulating factor associated with increased glomerular permeability to albumin in recurrent focal glomerulosclerosis. N Engl J Med 1996, 334:878–883. 34. Mathew TH: Recurrence of disease following renal transplantation. Am J Kidney Dis 1988, 12:85–96. 35. Glicklich D, Matas AJ, Sablay LB, et al.: Recurrent membranoproliferative glomerulonephritis type I in successive renal transplants. Am J Nephrol 1987, 7:143–149. 36. Oberkircher OR, Enama M, West JC, et al.: Regression of recurrent membranoproliferative glomerulonephritis type II in a transplanted kidney after plasmapheresis. Transplant Proc 1988, 20:418–423. 37. Couchoud C, Pouteil-Noble C, Colon S, et al.: Recurrence of membranous nephropathy after renal transplantation. Transplantation 1995, 59:1275–1279. 38. Schwarz A, Krause PH, Offermann G, et al.: Impact of de novo membranous glomerulonephritis on the clinical course after kidney transplantation. Transplantation 1994, 58:650–654. 39. Levy JB, Pusey CD: Anti-GBM antibody mediated disease. In Nephrology. Edited by Wilkinson R, Jamison R. London: Chapman & Hall; 1997:599–615. 40. Peters DK, Rees AJ, Lockwood CM, et al.: Treatment and prognosis in antibasement membrane antibody mediated nephritis. Transplant Proc 1982, 14:513–21. 41. Simpson IJ, Doak PB, Williams LC, et al.: Plasma exchange in Goodpasture’s syndrome. Am J Nephrol 1982, 2:301–311. 42. Turner AN, Rees AJ: Goodpasture’s disease and Alport’s syndromes. Ann Rev Med 1996, 47:377–386. 43. Kalluri R, van den Heuvel LP, Smeets HJ, et al.: A COL4A3 gene mutation and post-transplant anti- 3(IV) collagen alloantibodies in Alport syndrome. Kidney Int 1995, 47:1199–1204. 44. Ding J, Zhou J, Tryggvason K, et al.: COL4A5 deletions in three patients with Alport syndrome and posttransplant antiglomerular basement membrane nephritis. J Am Soc Nephrol 1994, 5:161–168. 45. Gagnadoux MF, Habib R, Broyer M: Outcome of renal transplantation in 34 cases of childhood hemolytic uremic syndrome and the role of cyclosporine. Transplant Proc 1994, 26:269–270. 46. Agarwal A, Mauer SM, Matas AJ, et al.: Recurrent hemolytic uremic syndrome in an adult renal allograft recipient: current concepts and management. J Am Soc Nephrol 1995, 6:1160–1169.