Chronic Kidney Disease

CHRONIC KIDNEY DISEASE: Causes and Manifestations Vimar A. Luz, MD, FPCP, DPSN

DEFINITIONS Chronic renal disease (CRD) is a pathophysiologic process (last more than 3 months) with multiple etiologies, resulting in the inexorable attrition of nephron number and function, and frequently leading to endstage renal disease (ESRD). ESRD represents a clinical state or condition in which there has been an irreversible loss of endogenous renal function, of a degree sufficient to render the patient permanently dependent upon renal replacement therapy (dialysis or transplantation) in order to avoid lifethreatening uremia.

DEFINITIONS Azotemia- refers to the retention of nitrogenous waste products as renal insufficiency develops

Uremia- is the clinical and laboratory syndrome, reflecting dysfunction of all organ systems as a result of untreated or undertreated acute or chronic renal failure.

Definition Of Chronic Kidney Disease (CKD) GFR <60 mL/min/1.73m2 for ≥3 months, and/or Kidney damage for ≥3 months Identifying kidney damage Proteinuria Urine sediment abnormalities Imaging tests Abnormalities in blood or urine composition Biopsy

NKF. Am J Kidney Dis 2004; 43(5 Suppl 1):S65

ESTIMATION OF GFR Cockcroft-Gault formula MEN

Ccr=(140-age) (weight in kg) or 1.23 (140-age)(wt) 72 x Pcr (mg/dl) Pcr (umol/L)

WOMEN

Ccr= (140-age) (wt) 85 x Pcr(mg/dl)

or 1.04 (140-age)(wt) Pcr (umol/L)

*overestimates Ccr in obese pts and those on low protein diet

Determine chronicity of the disease – History – Renal biopsy- predominance of glomerulosclerosis or interstitial fibrosis – Renal ultrasound to measure kidney size Small kidneys (<9cm) Chronic disease with normal size kidneys – – –

Diabetic nephropathy HIV-assd nephropathy Infiltrative diseases ( myeloma kidney)

Prevalence Of CKD In US Population (Age > 20 Years)

Stage

Description

GFR (mL/min/1.73m )

Number of People

% of Relevant Population

1

Kidney damage with normal or ↑ GFR

≥ 90

5,900,000

3.3

2

Kidney damage with mild ↓ GFR

60-89

5,300,000

3.0

3

Moderate ↓ GFR

30-59

7,600,000

4.3

4

Severe ↓ GFR

15-29

400,000

0.2

5

Kidney failure

< 15 (or dialysis)

300,000

0.1

2

19,500,000 NKF-K/DOQI. Am J Kidney Dis. Dis. 2001;37(suppl 1):S1-S238.

10.9%

NNHeS 2003-2004 Renal Report Prevalence of CKD in Filipino adults using predicted GFR from MDRD equation Stages of GFR

1 2 3 4 5

> =90 60-89 30-59 15-29 <15

72.8% 24.6% 2.2% 0.2% 0.2%

The prevalence of CKD Stage 3 - 5 is 2.6% Approximately 1,212,306 adult Filipinos

National Statistics Office Kidney disease is now # 10 cause of mortality in the Philippines

Stages in Progression of Chronic Kidney Disease and Therapeutic Strategies Complications

Normal

Increased risk

Damage

↓ GFR

Kidney failure

Screening CKD risk Diagnosis Estimate Replacement for CKD reduction; & treatment;progression; by dialysis risk Screening for Treat Treat & transplant factors: CKD co-morbid complications; diabetes conditions; Prepare for hypertensi Slow replacement on progression age >60 family history US ethnic minorities

CKD death

6 Mechanisms of Renal Disease Progression

6 Mechanisms of Renal Disease Progression Persistent glomerular injury leading to HTN then ↑ single nephron GFR

6 Mechanisms of Renal Disease Progression Persistent glomerular injury leading to HTN then ↑ single nephron GFR Protein leak increasing Angiotension II

6 Mechanisms of Renal Disease Progression Persistent glomerular injury leading to HTN then ↑ single nephron GFR Protein leak increasing Angiotension II Downstream cytokine bath

6 Mechanisms of Renal Disease Progression Persistent glomerular injury leading to HTN then ↑ single nephron GFR Protein leak increasing Angiotension II Downstream cytokine bath Neutrophils then macrophages, T lymphocytes leading to interstitial nephritis

6 Mechanisms of Renal Disease Progression Persistent glomerular injury leading to HTN then ↑ single nephron GFR Protein leak increasing Angiotension II Downstream cytokine bath Neutrophils then macrophages, T lymphocytes leading to interstitial nephritis Tubular epithelium responds by detaching from their basement membrane forming new interstitial fibroblasts

6 Mechanisms of Renal Disease Progression Persistent glomerular injury leading to HTN then ↑ single nephron GFR Protein leak increasing Angiotension II Downstream cytokine bath Neutrophils then macrophages, T lymphocytes leading to interstitial nephritis Tubular epithelium responds by detaching from their basement membrane forming new interstitial fibroblasts Surviving fibroblasts lay down collagenous matrix disrupting adjacent tubules and surrounding vessels leaving an acellular scar

RISK FACTORS FOR CRD family hx of heritable renal disease, HPN, DM, autoimmune disease older age past episode of acute renal failure current evidence of kidney damage even with normal or increased GFR – – –

proteinuria abnormal urinary sediment urinary tract structural abnormalities ( VUR)

Normal annual mean decline in GFR- begins at age 20 to 30 years= 1ml/min per 1.73m2 - mean GFR at age 70 is 70ml/min

CAUSES OF CKD COMMON – Diabetic nephropathy – Glomerulonephritis – Interstitial nephritis (including pyelopnephritis) – Hypertension/vascular – Hereditary/congenital disease – Neoplasms

CAUSES OF CKD LESS COMMON – Metabolic Cystinosis Oxalosis Nephrocalcinosis Cystinuria hyperuricemia

– Vascular Ischemic renal disease Scleroderma Hemolytic uremic syndrome Postpartum renal failure

– Dysproteinemias Amyloid Myeloma Cryoglobulinemia Light chain deposition disease

CAUSES OF CKD LESS COMMON – Hereditary Alport syndrome Fabry disease Tuberous sclerosis Sickle cell disease

– Vasculitis Wegener’s granulomatosis Microscopic polyangitis Polyarteritis nodosa lupus

– Malignancy Renal cell carcinoma lymphoma

– Structural Cystic kidney disease other than adult-onset cystic Congenital and acquired abn of the urinary tract e.g spina bifida,spinal cord injury

Stage 1 and 2- usually asymptomatic Stage 3 and 4Anemia Loss of energy Anorexia Malnutrition Abn in Ca and Ph metabolism Abn in Na, water, K acid-base homeostasis Stage 5Severe disturbances in activities of daily living, sense of well being, nutrition,water and electrolyte homeostasis-----UREMIA

MANIFESTATIONS Neurologic – Central

Daytime drowsiness and a tendency to sleep, which progresses to increasing obtundation and, eventually, coma Decreased attentiveness and performance of cognitive tasks Imprecise memory Slurred speech Asterixis and myoclonus Seizures Disorientation and confusion

– Peripheral

Sensorimotor peripheral neuropathy, often with burning dysesthesia Singultus (hiccup) Restless leg syndrome Increased muscle fatigability and muscle cramps

MANIFESTATIONS Cardiovascular Accelerated atherosclerosis Cardiomyopathy Pericarditis

Pulmonary Atypical pulmonary edema Pneumonitis Fibrinous pleuritis

Gastrointestinal Anorexia progressing to nausea and vomiting Stomatitis and gingivitis Parotitis Peptic ulcer diathesis Gastritis and duodenitis Enterocolitis Pancreatitis Ascites Dermatologic Pruritus Dystrophic calcification Changes in skin pigmentation

Hematologic Anemia Altered neutrophilic chemotaxis Depressed lymphocyte function Bleeding diathesis with platelet dysfunction

Endocrinologic Secondary hyperparathyrodism Carbohydrate intolerance due to insulin resistance Type IV hyperlipidemia Altered peripheral thyroxine metabolism Testicular atrophy Ovarian dysfunction with amenorrhea, dysmenorrhea, dysfunctional uterine bleeding, cystic ovarian disease

Ophthalmic Conjunctival or cornel calcifications

PHYSICAL EXAMINATION Abdominal masses (PKD) Diminished pulses (atherosclerotic peripheral vascular diseases) Abnormal bruit ( renovascular disease) Pallor Excoriations (uremic pruritus) Muscle wasting Uremic breath hypertension

LABORATORY FINDINGS Elevated BUN, creatinine Anemia Hyperphosphatemia Proteinuria Hypoalbuminemia Hypercholesterolemia hyperuricemia Hyperkalemia Hyponatremia Metabolic acidosis

FLUIDS, ELECTROLYTES AND ACID-BASE DISORDERS ECF VOLUME EXPANSION HYPONATREMIA HYPERKALEMIA METABOLIC ACIDOSIS

LIFE THREATHENING EMERGENCIES IN CKD Fluid overload/Pulmonary Edema Hyperkalemia Pericardial Effusion with tamponade Metabolic acidosis

FEATURES OF HYPERKALEMIA Muscle weakness lower extremities and ascends, respiratory muscles and those supplied by cranial nerves are spared abnormal cardiac conduction which can lead to fatal arrhythmia

PERICARDIAL EFFUSION WITH TAMPONADE Subacute tamponade less dramatic; chest discomfort or easy fatigue hypotension with narrow pulse pressure elevated jugular venous pressure Acute tamponade sudden onset associated with chest pain and dyspnea markedly elevated CVP hypotension common heart sounds muted pulsus paradoxus

Manifestations of Metabolic acidosis Involve the respiratory, cardiovascular, neurologic and skeletal systems Kussmaul’s respiration increased susceptibility to cardiac arrhythmia (hyperkalemia) decreased level of consciousness due to a 2’ decrease in intracerebral pH

Phosphorus – A major component of bone, along with calcium – One of the first substances to be deranged in CKD Triggers a sequence of events that may ultimately lead to renal bone disease

Phosphate Binders Further limits the absorption of phosphate by binding it in the gut Administered with meals Conventional binders – Aluminum hydroxide – Calcium salts

Recent developments – Sevelamer hydrochloride – Lanthanum carbonate

CARDIOVASCULAR DISEASE Leading cause of morbidity and mortality in pts with CRD at all stages 30-45% of pts reaching ESRD already have advanced cardiovascular complications Hypertension is the most common complication of CRD and ESRD Volume overload is the major cause of HPN in uremia

Anemia-normochromic, normocytic Declining renal function –beginning at stage 3 – reduced erythropoietin production – decreased red blood cell half-life – tendency toward gastrointestinal bleeding.

ABNORMAL HEMOSTASIS Associated with prolongation of bleeding time Decreased activity of platelet factor III Abnormal platelet aggregation and adhesiveness Impaired prothrombin consumption Manifestations: increased tendency to abnormal bleeding and bruising, occult GI bleeding Greater susceptibility to thromboembolic complications esp nephrotic pts

NEUROMUSCULAR ABNORMALITIES Central, peripheral and autonomic neuropathy Abnormalities in muscle composition and function Due to retained nitrogenous metabolites and middle molecules and PTH Become clinically evident at stage 3 Mild manifestations- disturbances in memory,sleep and concentration Hiccups,cramps, fasciculations, twitching, asterixis, chorea seen in uremia Seizure and coma

GASTROINTESTINAL AND NUTRITIONAL ABNORMALITIES Uremic fetor-breakdown of urea in saliva Gastritis, peptic disease, mucosal ulceration Increased incidence of diverticulitis, pancreatitis Anorexia, hiccups, nausea, vomiting Protein-calorie malnutrition as a consequence of low protein and caloric intake

ENDOCRINE AND METABOLIC DISTURBANCES Impaired glucose metabolism- slowing of the rate of blood glucose level after a glucose load FBS usually normal or slightly elevated Plasma level of insulin slightly elevated Impaired response to insulin and glucose utilization Drug dosing needed, some drugs cant be used, metformin contraindicated when GFR is about 25-50% Low estrogen level Impotence, oligospermia, germinal cell dysplasia common

DERMATOLOGIC ABNORMALITIES Pallor, defective hemostasis (ecchymoses, hematomas) Pruritus, excoriations Deposition of pigmented metabolites or urochromes (uremic frost)

Thank you and good day

GFR differentiation Stage 0 >90 (+) risk factors for CKD Stage 1 ≥90 (+) evidence of kidney damage (proteinuria, abnormal urine sediment and imaging studies) Stage 2 60 to 89 Stage 3 30 to 59 Stage 4 15 to 29 Stage 5 < 15