Pathophysiology Of Clinical Disorders Of Urine Concentration And (1).pdf

CHAPTER 26 -------~------------

PATHOPHYSIOLOGY OF CLINICAL DISORDERS

OF URINE CONCENTRATION AND DILUTION

_ _ _ _ _ _ _ _ _ _ _ _ _ MANUJ£L MARTINEZ-MALDONADO AND SUSAN OPAVA-STITZER

INTRODUCTION

Clinical Diagnosis of Disorders in Concentration and Dilution to concentrate or dilute the urine can be easily rec­ ognized by the maximum or minimum urine concentration the patient is able to achieve. Maximum concentrating ability (Umax) is determined by the urine osmolality reached after a fixed period of dehydration and maximal diluting ability (Umin) by the minimum osmolality of the urine after the oral inges tion of a fixed water-load. These indices, however, do not allow an understanding of the pathophy­ siological alterations leading to the pres­ ence of the defect. Inability to maximally concentrate the urine can be attributed to one or both of two basic tubular defects: first, a failure of maximal free-water generation by the diluting segment in the ascending limb of Henle's loop and second, a failure of the distal tubular epithelium to achieve maxi­ mum permeability to water during water deprivation. These changes singly or com­ bined are capable of reducing maximum concentrating ability. The first brings about the reduction in Umax by diminish­ ing the cortico-papillary solute gradient and thus reducing the gradient for free­ water reabsorption from collecting duct lumen to interstitium. The second re­

A

DEFECT IN THE ABILITY

duces Umax by preventing osmotic equi­ libration of collecting duct Huid with the medullary interstitium (1-3). Inability to produce a maximally dilute urine may likewise be attributed to one or both of two basic tubular defects: first, the failure of maximal free-water generation by the diluting segment, and second, an in­ appropriately high permeability to water of the distal tubular epithelium during water diuresis. The former, while reducing maxi­ mal concentrating ability, also diminishes maximal diluting' ability by resulting in a less than normal dilution of tubular fluid. The second results in the inappropriate re­ absorption of water from the collecting duct in response to the interstitial solute gradient generated by solute reabsorption in the ascending limb. It is readily apparent that a failure of the ascending limb and other diluting seg­ ments to generate normal amounts of free water can result, at low tubular flow rates, in a diminution of both maximal concen· trating and maximal diluting ability. Nevertheless, a comparison of Umax and Umin may be utilized to distinguish be­ tween a permeability defect and a defect in free-water generation. If both concentrat­ ing and diluting ability are reduced, a de­ fect in free-water generation is suggested. Such a defect must involve the active solute reabsorption process in the medullary por­

992

PathojJh)'siolofo,'Y of Clinical Disorders of Urine

tion of the ascending limb of Henle's loop, since involvement of cortical segments alone would affect only diluting ability. In addition, it could represent a reduction in the relative water impermeabili ty of the ascending limb which is essential for freewater generation. If concentrating ability alone is reduced, a defect in appropriate free-wa ter reabsorption in the collecting duct is suggested. On the other hand, if diluting ability is compromised in the presence' of a normal Umax, either abnormal sodium reabsorption in the cortical diluting segment or inappropriately high H 2 0 permeability in the collecting duct is indica teel. These two defects can be distinguished from each other by the effect on sodium excretion (Table 26-1) .

993

nature in the distal convolution or collecting duct would be expected to alter only diluting ability, as illustrated in Table 26-I. The assessment of maximal concentrating and diluting ability by measurement of the urine osmolality alone may be subject to misinterpretation. Tubular defects other than those already mentioned, or conditions which alter solute delivery to the si tes of free-water generation, can also alter the maximum urine concentration achieved during dehydration or the minimum urine concentration attained during water diuresis. Thus, a more precise index of urine concentration and dilution is needed. Such all index is provided by the measurement of free-water reabsorption

Table 26-1 Clinical Use of Ulilin and Umax for Characterization of Defects in COllcelllration and Dilution Fmclio?/aZ

Normal Ascend; I1g lim b defect in NaCI transport 3. Cortical diluting ~egment defect in NaCI transport 4. Collecting duct defect in NaCl transport 5. Loss of ascending limb impermcability to water 6. Loss of collecting duct water permeability in response to ADH 7. Ehanced collecting Cltlct water permeability (in wa tel' diuresis) 1. 2.

In addition, a comparison of concentrating and diluting ability can yield information on the particular nephron segment in which a defect in free-water generation lies. A defect in free-water generation in the ascending limb of Henle's loop would be expected to alter both concentrating and diluting ability, while a defect of the same

Umas

Ulllin

UNaV

N .j.

N

t

<1% >2%

N

t

>2%

N

t

<2%

.j.

t

<1%

.j.

N

<1%

N

t

<1%

(TOH 2 0) and free-water generation (OH 2 0) over a range of distal solute delivery (Figure 26-1). During measurement of TOH 20, circulating levels of antidiuretic hormone must be maximal. To insure this, hypertonic solutions are administered at increasing rates, allowing the calculation of free-water reabsorption from the equation:

Pathophysiology of the Kidney

994

GENERAL FEATURES OF FREE WATER REABSORPTION AND FREE WAfER CLEARANCE

­ Casm

V

CH20 + eN. CH20 + CCI

Figure 26-1. Idealized curves for free water reabsorption and free water clearance. In the case of free water clearance, the similarity of the relationship regardless of the delivery form will only be the case eluring hypotonic NaGI infusion.

=

TCBoO cos m - V where V = urine n;w in ml/min

cosm

=the osmolar clearance =:

UosmV Po

-----coc--­ Sill

Uosm =: the urine osmolality Posm = the plasma osmolality. In this way the capacity to reabsorb free water under conditions of maximal water permeability can be studied at varying rates of solute delivery to the sites of solute re­ absorption. A normal relationship between TCH 20 and osmolar clearance can thus be established (Figure 26-la) and deviations

from this normal curve can be identified. This method is invaluable for determining defects in concentrating ability in situations where solute delivery to the distal nephron may also be altered. In addition, subtle defects in the concen tra ting mechanism, which may not be readily apparent at the low rates of solute excretion which prevail during the measurement of Umax, may be revealed at higher rates of solute excretion. As will be discussed, however, even this measure of urine concentration fails to distinguish the nature of the defect. In a similar manner, free-water genera­ tion or clearance (CH 2 0) can be expressed as a function of solute delivery to the diluting segmen ts of the nephron. In this case, varying amounts of solute are ad­ ministered as hypotonic solution in order to suppress endogenous ADH release so that a condition of minimal water permea­ bility of the distal nephron prevails. Free­ water clearance is calculated from the egua­ tion, cH 2 0 = V - cosmo The correct index of solute delivery in this circumstance has been hotly debated. It is generally agreed that cosm is not an accurate reflection of distal solute delivery during infusion oE hy­ potonic solution. More acceptable indices are V, cH 2 0 + eNa, and cH 2 0 + eCl (4­ 9). The relative merits of these three are currently under scrutiny. In any case, a normal relationship between cH 20 and one of these indices can be established, as shown in Figure 26-2b, and deviations from the normal curve can be identified. A more precise measure of diluting ability is thus obtained, since variations in solute de· livery are accounted for, and defects not apparent at low osmolar clearances may be unmasked. Even this measure of diluting ability, however, fails to characterize the defect, and, as in the case of maximal and minimal urine concentrations, more in­ formation can be gleaned from a compari­

•

Pathophysiology of Clinical Disorders of Urine RELATIONSHIP BETWEEN T'H2 0 AND COSM DURING MANNITOL AND HYPERTONIC SALINE DIURESIS A. Mannitol

-

COSM

­

COSM

Figure 26-2. Idealized curves (with approxi­ mate ranges) for free water reabsorption.

son of TCH 2 0 and cH 20 curves as sum­ marized in Table 26-II. A defect in free­ water generation might be expressed in an alteration of both curves, but a less than maximal water permeability of the collect­ ing duct during antidiuresis would aIlect

the TCH 2 0 curve alone. A greater than normal water permeability during water diuresis would allect only the 01-1 2 0 curve. In the event that a defect in free-water generation is indicated by an effect on both curves, the defect can be localized in the ascending limb of the loop of Henle. A defect in free-water generation which docs not reside in the loop but in the distal con­ volution would be expected to alter only the cH 2 0 curve. As in the case of altera­ tion in Umin alone, this can be distin­ guished from a higher than normal water permeability during water diuresis by the effect on sodium excretion. The tubular defects listed in Tables 26­

I and 26-II, which result in alterations in

Umax, Umin, TCH 2 0 and cH 2 0, may oc­

cur alone or in combination as will be ap­ parent in the following discussion. These may be intrinsic defects or may result from a variety of factors including drug therapy and various types of renal disease. Even in the absence of the tubular de­ fects described above, reductions in the ability to concentrate or dilute the urine may occur. Such could be the case if de-

Table 26-II

Use of T"H 2 0 and cH 2 0 in the Characterization of Clinical Disorders of

Urine Concentration and Dilu tion

1. Normal Ascending limb defect in NaCl transport 3. Cortical diluting segment defect in NaCl transport 4. Collecting duct defect in NaC! transport 5. Loss of ascending limb im permeability to water 6. Loss of collecting eluct water permeability in Tesponse to ADI-! 7. Enhanced collecting' cluct water permeability (in water diuresis)

2.

995

TOH 2 O

OH2 O

FENa

N

N

,J.

,J.

<J% >2%

N

,J.

>2%

N

,J.

<2%

,J.

,J.

<1%

,J.

N

<1%

N

<1%

996

Pathophysiology of the Kidney

livery of solute to the distal nephron were decreased or medullary blood 110w significantly increased over normal. The former situation deprives the diluting segments of the substrate for free-water generation and thus reduces the ability to both concentrate and dilute the urine (Umax and Umin). TCHzO ancl cHzO curves, however, would be perfectly normal, since these are obtained over a range of solute deliveries. Increased medullary blood How, on the other hand, will result in washout of the corticomedullary gradien t, thus reducing concentrating ability alone. This defect would influence both Umax and the normal TCHzO curve, I t should be noted here that small decreases in medullary blood flow, which do not limit cellular metabolism, should actually enhance concentrating ability since interstitial osmolality will rise.

PATHOPHYSIOLOGICAL MECHANISM

Abnormal NaCl Transport By the Loop of Henle Despite in vitro evidence indicating that the thin ascending limb of the loop of Henle does not carry out active sodium chloride transport (10-11), these structures when presen t, * particularly in nephrons dipping into the inner medulla, are important [or the excretion of a maximally concentrated urine (14-18). The main function of thin limbs, however, appears to arise from the permeabili ty characteristics o[ their walls to sodium, urea, and wa tel', combinecl with urea trapping in the interstitium of the inner medulla. Urea and "As shown by the comparative sLUdies of Tisher and his collaborators (12-13), thin loops may be absen t and yet concentrated urine will be excreted. On the other hand, ablation of long' thin loops when present abolishes the elaboration of maximally concentrated urine.

sodium chloride will largely determine the steepness of the corticornedull ary concentration gradient, insuring maximal water abstraction from fluid traversing the collecting duct:. The major determinant of the metlullary accumulation of urea, in addition to adequate dietary protein illtake, appears to be the transfer of energy from the thick ascending limb, to the inner medulla in its process of active sodium chloride transport:. It is clear, therefore, that the "single effect" is responsible not only for a sodium chloride corticomedullary gradient but will also influence the urea gradient (16,18). In situations wherein collecting duct permeabili ty is normal, in the presence or absence of ADH, and medullary blood flow rate is unchanged from the control state, the integrity of the NaCl reabsorptive mechanism in the thick portion of the loop will determine the excretion of a maximally concentrated urine (Umax). Furthermore, during infusion of hypertonic saline, the reabsorption of solute-free water (TOH 2 0) as solute excretion rises will also depend on the intactness of the NaCl reabsorptive process in the thick limb* (19). Similarly, the capacity to excrete a maximally dilute urine, in the absence of ADH, will be significantly curtailed. IE NaCl reabsorption in the loop were impaired, the presence of both a concentrating and diluting defect would occur iF the thick limb were involved throughout its length or in its outer medullary region. If the involvement were confined to its cortical portion, only dilu ting capacity would be impaired. This is the case because very little free-water reabsorption takes place in the cortex even in the pres*Often, during hypertonic saline infusion, TOI-IoO will plateau or actually fall as osmolar clearal~ce mounts. This is due to the failure of the large volumes of hypotonic urine which enter the collecting duct to achieve equilibrium with the interstitium (20).

Pathophysiology

of Clinical DisOl'de1"S of Urine

encc of ADH. The nature of the reabsorptive process in the thick limb is largely unknown. Al­ though in ,JilTO studies of these structures appear to indicate that chloride is the major actively transported ion species (10, 2] ,22), the cellular and molecular details of this event are obscure at best. It is possi­ ble that a Na+-K+-stimulated membrane adenosine triphosphatase (Na+-I<'-ATPase) is involved (23-25), but its relationship to the movement of chloride has not been examined closely and remains to be eluci­ dated. In the clinical context it is c1ifficuJ t to assess whether pure defects in urine con­ centration or dilution exist which are clue ta diminution in sodium transport by the thick ascending limb wi thout alterations in collecting duct permeability or intra­ renal hemodynamics. Nevertheless, in this part of our discussion we shall focus on dis­ turbances far which there is both clinical and experimental evidence that a transport defect may be involved in its genesis.

Hypercalcemia Inability to concentrate the urine and to maximally reabsorb solute-free water during hypertonic saline infusion or to maximally generate free water during water diuresis has been observed clinically and experimentally in hypercalcemic subjects (26-29). Experimentally, the defect may be reproduced by the administration of calcium, ergocalciferol, or parathyroid ex­ tract (27-29). Clinically, hypercalcemia secondary to hyperparathyroidism, hyper­ thyroidism, Addison's disease, vitamin D intoxication, sarcoidosis, and milk alkali syndrome has been observed to lead to re­ duced Umax and abnormal TCH 2 0 and cH 2 0 curves (30). There is evidence, to be discussed later, that the impaired ability to concentrate or

997

dilute the urine observed in hypercalcemia may result from alterations in collecting duct permeability to water or changes in renal hemodynamics. EvicJence also exists suggesting that sodium reabsorption per se is impaired. The content of sodium in the medullary interstitium of rats and dogs made hypercalcemic by vi tamin D or calci­ um loads is markedly diminished (31-33). Although possibly the resul t of climinishetl GFR with reduced sodium delivery to the loop of Henle, the observation that abso­ lute and fractional sodium excretion is greatly increased during brief periods of hypercalcemia suggests a direct inhibitory effect of calcium on the renal tubular epi­ thelium (29). Also, acute hypercalcemia in the dog, in contrast to prolonged hyper­ calcemia, reduces free-water clearance at any level of distal delivery when compared to normal animals (29). Failure to observe this change ill animals with chronic eleva­ tion of serum calcium may be the result of reduction in nephron mass with severe de­ creases in GFR. Of note is the fact that changes in GFR induced by reduction in aortic blood flow to levels observed in acute hypercalcemia do not lead to reductions in cH 2 0 of the same magnitude, suggesting that the elevated calcium per se may impair sodium reabsorption (29). Studies in the rabbit seem to strengthen the suggestion of a direct effect of hypercalcemia on renal tubular sodium reabsorption. In this species the differences between hypertonic saline and mannitol TCH 2 0 curves are abolished, indicating diminished sodium reabsorption by the loop despite adequate distal delivery (Figure 26-2) (34). Studies in renal and other epithelia have provided some evidence for an inhibitory eHeet of calcium on sodium transport. In frog skin, calcium reduces the permeability of the epithelium to sodium (35) while it does not alter vasopressin-induced sodium trans­

998

Pathophysiology of the Kidney

port in toad bladder (36). :rvIicropuncture experiments in the rat have also indicated that acute hypercalcemia or the presence of high calcium in the filtrate is associated with a pronounced reduction in tubular fluid reabsorption, indicating reduced sodi­ um transport (37-39). The interference with transepithelial sodium transport may be the result of a number of cellular changes. Calcium has been shown to re­ duce Na+-K:-ATPase activity ('10) which, particularly in the ascending limb (25), seems to playa central role in transcellular sodium transport. This would result in cHminished extrusion of sodium entering the cell from luminal !tuid, which would eventually lead to reduced sodium move­ men t from lumen to cell interior. On the other hand, calcium may directly inhibit the active transport of chloride at the luminal membrane, thus reducing both Na+ and Cl- reabsorption. The inhibition of NaCI reabsorption may also be the result of uncoupling of medullary mitochondria resulting in reduced high energy phosphate supply to either Na+ or CI- pumps. Lastly, the apical or basal permeabilities to chlor­ ide or sodium may be altered resulting in diminished entry of Na+ or diminished exit of Cl'- from the cell. Singly or combined, the above possibilities would result in de­ creased net NaCI transport (Figure 26-3). It is of interest that the renal concen­ trating defect produced by clinical or ex­ perimental hypercalcemia may be reversi­ ble in periods ranging from hours to days (29,30,41). This finding strongly suggests that the changes observed, as described above, are predominantly functional or bio­ chemical, in contrast to morphological. This is not to say that in chronic forms of hypercalcemia, even as early as twenty-four to forty-eight hours, morphological changes are not important. In fact, observations of

ASCENDING LIMB CELL PERITUBULAR SPACE

LUMEN

No'

---------

-+ -

(I)

...

Fig'ure 26-3. Schematic representation of as­ cending limb (thick portion) cell showing possible changes which may be reduced NaCl reabsorption. (1) Inhibition of Na+K+ATPase; (2) Inhibition of luminal active Cl-pump; (3) Inhibition of metabolism (oxidative phosphor­ lylation or glycolysis); and (4) Changes in ion permeability of either luminal or periluminal cell membrane.

the cellular alterations, which eventually take place, may provide indirect evidence that calcium concentration is high at the sites of the proposed functional derange­ ments. For example, the concentration oE calcium is normally greater in the medulla than in the cortex, and medullary changes tend to occur earlier and to be more severe in hypercalcemia (30). Focal lesions in the loop of Henle and distal tubules including calcification of cell cytoplasm, basement membrane, and mitochondria have also been observed (42). Although far from settled, hypercal­ cemia may affect renal concentrating and diluting ability by reducing net reabsorp­ tion of Nael from lumen to interstitium. In the intact kidney the evidence is in­ conclusive, but information which sheds light on the issue may be forthcoming from the use of isolated perfused tubules.

u

Pathoj)hysiology of Clinical Disorders of Urine

Potassium Depletion The mechani~m by which potassium de­ pletion leads to a reduced Umax has at­ tracted the interest of a number of in­ vestigators, yet it still remains unclear (t13­ 53). A principal problem is that there may be some significant species differences; in many instances, clearance studies have pro­ vided different results depending upon the experimental animal. A Umax defect ha~ been described in man (43,4'1). In the dog', demonstration of a defect in the generation of TCH 2 0 or cH 2 0 has been inconsistent (51,52) , while a serious disturbance of both has almost always been uncovered in the hamster, the rat, and the rabbit ('15·'J7,49­ 51). It is apparently clear that in rodents the effect of potassium deficiency on renal function is different from that in carn­ ivores. The role played by reduced filtered load to the diluting site is not clear. Al­ though this may well be the cause of the concentrating defect under some circum­ stances, most investigators have almost al­ way~ observed a disorder of TCH 2 0 in po­ tassium deficiency de~pite a normal GFR An exception to this may be found in studies in the dog by Bennett (52). This investigator, however, utilized mannitol infusion~ which, per se, may impose a limit on the generation of TCH 2 0 as a function of Cosmo In fact, all curves depicting this relationship in his study are flat and, there­ fore, difficul t to in terpre t. Despi te the possibility that part of the defect in urine concentration and dilution observed in hypokalemic animals may be the result of enhanced proximal tubular reabsorption secondary to diminished GFR, it is ob· viously not the entire explanation. An important aspect of the defect in urine concentration seen in hypokalemia is that sodium content of the renal medulla has been shown to be diminished in some

999

species such as the rat (45,50). Studies by Eknoyan and his collaborators in this species (50) have demonstrated a defect in loop transport manifested by alterations in both TCH 2 0 and cH 2 0, which, if present in other species, could explain the reduc­ tion in tissue sodium concentration. Hypo­ kalemia is known to lead to disorders of ion transport in other cell systems so that re­ duced NaCl reabsorption in the distal tubule, if not likely, is entirely possible. Evidence also exists to indicate that hypo­ kalemia leads to reduction in the content of enzymes involved in oxidative phos­ phorylation in the renal medulla of the rat (54). Therefore, the supply of high energy phosphate compounds for the transport process may be defective in hypokalemia. An alternative to deficiencies in ion transport or solute delivery as causes of the concen trating or diluting defect is the pos­ sibility that the anatomical lesions induced by hypokalemia may result in diminished epithelial permeability to water in the dis­ tal parts of the nephron. The resultant in tense vacuolization of the cytoplasm of the collecting duct cells could alter the tubular response to the effect of circulating ADH. Evidence has been advanced from potassium-depleted hamsters that despite gross histological lesions in the collecting ducts, osmotic equilibration is achieved across this structure under circumstances in which a defect in urine concentration is demonstrable (47). It does not appear likely, therefore, that altered permeabili ty of the distal nephron ~econclary to the sig­ nificant anatomical alterations in hypo­ kalemia is responsible for the Umax defect in the rodent. On the other hand, the possibility persists that in both man and dog the presence of prolonged hypokalemia may result in anatomical or biochemical defects which render the collecting duct

1000

PalhojJhysiolog)I of the Kidney

less responsive or refractory to the circu­ lating effects of ADH. Evidence for this has been advanced by the demonstration that patients wi th potassium deficiency, when administered ADH, excrete less cyclic AMP in the urine than normal subjects or pa­ tients wi th other disorders of urine con­ centration, such as sickle cell disease (55). One other possible mechanism by which hypokalemia could result in reduced Umax could be related to enhancement oE medul­ lary blood flow. Enhanced medullary blood How, by washing out medullary solute, could explain the findings of a re­ duced tissue sodium and abnormal Dmax and TOH 2 0, as has been shown when a variety of renal vasodilators are infused directly into the renal artery (56-58). It could also explain why, in some species (dog and man) during water diuresis, a defect in cH 2 0 might not be apparent or why Dmin might be normal, since medul­ lary washout is maximal in water diuresis. 1£ diminished solute content were second­ ary to increased medullary blood flow, how­ ever, it could not explain data on medul­ lary metabolism obtained by Kannegiesser and Lee (59) and those of Weiner et aI. (5'1). The demonstration by V\Teiner that medullary mitochondrial enzymes have diminished specific activities and that sodi­ um-potassium-ATPase is normal in hypo­ kalemia would suggest that both TOH 2 0 and 0H 2 0 may be impaired through inter­ ference with transport processes. Yet Kannegiesser and Lee have demonstrated that hypokalemic animals (rabbits) have a defect in oxidative phosphorylation which is only manifest in hyperosmotic environ­ ments but not under hypoosmotic or isosmotic conditions, as would be the case during water diuresis. Should renal medul­ lary blood How be increased under basal conditions, thus preventing the formation of a hyperosmotic interstitium, it would

tend to limit the defect in TCH 2 0 rather than enhance it. Further studies in this direction are needed, however, before the cellular events occurring in hypokalemia arc clearly elucidated.

Hypertension An increasing body of evidence points to the possibility that intrarenal physical forces (so-called Starling forces) play an important part in the regulation of sodium reabsorption (60). Nevertheless, it is ap­ parent that increases in peri tubular hydro­ static pressure may lead to diminished tubular reabsorption of NaCI and water. The experimental work generated by the interest in the role of physical factors in the maintenance of salt and water home­ ostasis has provided a theoretical explana­ tion Eor the observation that hypertensive man excretes a sodium chloride load faster than his normotensive counterpart (61-6"1). The fact that raising systemic blood pres­ sure by occlusion of the carotid arteries (G5) or by the infusion of a variety of pressor agents could reproduce the situation ob­ served in hypertensive man suggests tha t the elevated blood pressure is responsible for the observed natriuresis (66). Similar results have been obtained in experimental animals, particularly under circums tances where renal vasodilatation precedes the elevation o[ blood pressure (66-69). The relaxation of pre- and postglomerular capil­ lary sphincters permits the more eI-Iective transmission of pressure to the peri tubular capillaries, leading to a greater reduction in net reabsorption of salt and water. Micropuncture and clearance studies sug­ gest that the proximal convoluted tubule is an important site where elevated hydro­ static pressure acts to diminish reabsorp­ tion (67-7]). In addition to this, evidence exists indicating inhibition of reabsorption along the distal tubule or loops of Henle

PathojJhysiology of Clinical Disorders of Urine (72-76). Despite the fact that direct micro­ puncture data have indicated a diminished fractional proximal tubular rea bsorption in hypertension, many of these studies have failed to provide information as to what happens to absolute reabsorption in this segment. In a recent study, elevation of blood pressure in the rat was accompanied by a rise in peri tubular capillary hydro­ static pressure, hut protein concentration in efferent arteriolar blood rose sufficiently to result in enhanced net peritubular re­ absorptive force; yet, natriuresis still re­ sulted (77,78). These findings suggest that, in the absence of prior vasodilatation, the effect of hypertension is beyond the super­ ficial proximal convoluted tubule. On the other hanel, data as to what may be happen­ ing in juxtamedullary nephrons is not available. Conceivably, because of the anatomical location of these nephrons, pres­ sure changes may be translated more elIec­ tively and lead to a reduced reabsorptive rate. Studies in man have demonstrated that the presence of hypertension leads to in­ ability to maximally concentrate the urine. This reduction in Umax is accompanied by diminished TCH 2 0 and cH 2 0 when exam­ ined as functions of C'osm and V respective­ This combination of findings ly (79). points to reduced N 'lCI reabsorption by the ascending limb of Henle's loop which Buckalew and his collaborators suggest is the result of transmission of elevated hydro­ static pressure to the peri tubular capillaries of the outer medulla. This attractive hypo­ thesis received some experimental support from the studies of Daugherty and his co­ workers (74). As was the case in hyper­ tensive patients, cH 2 0 at any rate of distal delivery was less in dogs made acutely hy­ pertensive by the infusion of angiotensin than in control dogs. It is clear that the reduced NaCI transport in the distal neph­

1001

ron, whether in the loop or in more distal diluting sites, is not the result of an In­ trinsic abnormality of the transport mech­ anism but rather an indirect dfect of the elevated blood pressure. As has been de­ scribed for the proximal tubule, an eleva­ tion of peri tu bular hydrostatic pressure could reduce net reabsorptive force by in­ creasing back flux of Nael and entry of water into the lumen. The net result will be a greater volume of luminal fluid of higher than normal sodium concentration. Direct evidence for the effect of physical factors on loop reabsorption, however, is lacking, at present.

Diuretics The most commonly utilized diuretics, such as thiazides and their derivatives in­ cluding furosemide, affect the active trans­ port of sodium chloride in the distal parts of the mammalian nephron (1,21,22). Such is also the case for ethacrynic aciel (22). The administration of these drugs, there­ fore, leads to a sharp reduction in the capacity to concentrate and dilute the urine. Because 0 f inability to pump sodi· urn chloride into the interstitium of the renal medulla, fluid emerging into the early portion of the distal convolution is less hypotonic than normal and remains essen­ tially unchanged as it enters the collecting duct. Since the medullary interstitium is less hypertonic than normal and the tubu­ lar fluid less hypotonic there is a reduc­ tion in the removal of water leading to the formation of urine which, in the hydro­ penic state, will be less concentrated than normal. During water diuresis the differ­ ence in the gradient between lumen and interstitium is narrowed, and the degree of hypotonicity of the final urine will be de­ pendent on the removal of solu te in the as­ cending limb. Interference with this pro­ cess will resul t in urine having a higher

1002

Pathoj)hysiology of the Kidney

osmolality than normal. Under some circumstances patients taking diuretics for ill-advised weight-reducing schemes, (un­ known to the physician) , may present with polyuria. The precise mechanisms of action of diuretics are still unknown. It is conceiv­ able, however, that they may affect, directly or indirectly, a sodium-potassium-activated adenosine triphosphatase related to Na' or CI- translocation across the tubular cel1 epithelium (80-84). The relationship of this enzyme to chloride transport remains to be clarified, but, conceivably, the move­ ment of chloride across the cel1, particular­ ly in the ascending limb of Henle's loop where CI- transport appears to be the primary event in NaCI reabsorption, is linked in some fashion to the activity of the enzyme which is known to be present at the basal side of the cell (85). It is of interest that the ascending limbs of Henle's loop contain the highest concentrations of enzyme found in the nephron (25). Diuret­ ics may also interfere wi th energy-pro­ ducing mechanisms in the tubule, includ­ ing the production of ATP by mito­ chondria (86). Irrespective of the effects of diuretics on metabolism it is also known that they may alter the ability to concen trate or dilu te the urine through reduction in extracellular fluid volume (ECFV). The shrinkage of ECFV, which occurs after prolonged diuretic therapy leads to reductions in renal blood flow and glomerular filtration rate (87). This, in turn, leads to reduced delivery of NaCI to the loop of Henle, reducing concentrating and dilu ting function. Enhanced or avid reabsorption of sodium chloride proximal to the diluting and concentrating sites will also have the same effect (Figure 26-1). Fortunately, recovery of these functions is usually swift after discontinuation of the medication, and in the individual that had

otherwise normal renal function and is hemodynamically stable, the changes are completely reversible. It should be noted that in patients with a prior concentrating defect such as central or nephrogenic dia­ betes insipidus, diuretic therapy, by a re­ duction in ECFV, results in the excretion of a concentrated urine by decreasing so­ lute load to the diluting site (88).

Decreased Delivery of Solute to Diluting or Concentrating Sites As in the case of diuretics, other condi­ tions which reduce delivery of sodium chloride to the distal nephron wil1 limit the amount of substrate arriving at the diluting and concentrating sites (see Fig­ ure 26-4). This will lead to a lower than normal Umax in hydropenia and a higher NoCI

@NoCI

No cr

®

HIO

H,O H20 H,O No CI

®

Figure 26-4. Schematic representation of the nephron. Decreases in G.F.R. (1) and in­ creases in NaCI reabsorption; (2) proximal to diluting segment will result in alterations in urine concentration and dilution by climin­ ishing delivery. Distal tubular reabsorption may be decreased at sites (3), (3'), and (3") and will alter renal dilution. Decreased NaCl reabsorption at (3) will also reduce urine con­ cen lration. Concen tratiOll will also be reduced by changes in the secretion or the response to ADH «4) collecting dUCl).

than normal Umin during water diuresis. Experimental evidence that this may hap­

Pathophysiology

of Clinical Disorders of Urine

pen, despite the presence of antidiuretic hormone and of normal response to it of the dis tal nephron, was obtained in the classical experiments of Levinsky, David­ son, and Berliner (89) and Berliner and Davidson (90). These autI-lars clemon­ strated that reduction in GFR to around 30 percent or less of normal, during hydro­ penia, resulted in a dilute urine. During maximal water diuresis, reduction of GFR in one kidney led to the excretion of urine of a higher osmolality (isotonic or slightly hypertonic to plasma) while the contralateral kidney continued to excrete maximally dilute urine. Clinically speaking there are three major situations in which reduced distal delivery may result in ab­ normal urine dilution and concentration. These are salt-retaining states such as con­ gestive heart failure, cirrhosis of the liver and nephrotic syndrome, hypothyroidism (myxedema), and low salt diet.

Salt-Retaining States Controversy still exists as to the site in the nephron of increased salt reabsorption in the salt-retaining states. It appears clear that the inability to excrete a maximally concentrated or a maximally dilute urine in these circumstances must be the conse­ quence of some malfunction of the distal nephron. In view of the fact that retention may occur anywhere between the glomer­ ulus and the turn of the loop, these concli­ tions will be equivalent to having reduced sodium chloride presented to the reab­ sorptive sites in the ascending limb. Clin­ ical studies have been suggestive of distal sodium retention (91,92). If the increased reabsorption takes place in the ascending limb of Henle's loop, some other impor­ tant feature of the countercurrent mech­ anism must be at fault in order to re­ sult in decreases in dilution or concentra­ tion. Changes in permeability character­

1003

is tics of the ascending limb and collccting duct might be involved, yet evidence for these changes is not available. On the other hanel, changes in intrarenal hemo­ dynamics Inight be an important cletennin­ ant of the defect. For example, in all the sodium-retaining states medullary blood flow might be increased so as to continu­ ously maintain reduced solute content of the medulla, resulting in the defect already described. In most of the conditions being examined total renal blood flow is usually reduced, and it is unlikely that there is
1001

Pathophysiology of the Kidney

not allow precise knowledge of the changes occurring in the filtered fluid prior to the descending limb.

Sodimn Restriction (Low Salt Diet or Acute Salt Depletion) The consequences of salt restriction on renal function, particularly on the ability to maximally concentrate the urine, is still incompletely understood. One of the re­ sults of acute sodium depletion is a limita­ tion of the ability to reabsorb solu te-free water (TCH 2 0). This disturbance is of such extent that it may be noticeable at moderate urine Haws and may even be accompanied by the excretion of hypotonic urine (97). These observations in the clog are in accord with those in man (98). Of interest is that Umax may be altered in a trivial way or not at all. Two major ex­ planations have been advanced to explain these findings: first, a decreased penneabil­ ity to water in the distal convoluted tubule (97); second, a decreased rate of sodium delivery resulting from a lowered plasma soclium ancl reduced GFR (98). For this last possibility to be strongly considered one would expect to find a diminished solute (sodium, possibly urea) concentra­ tion in the medulla. A priori this seems unlikely, in view of the fact that Umax is normal. Conceivably, since Umax repre­ sen ts fluid equilibration with papillary tissue interstitium, if the defect is confined to the outer medulla, TCI-I 2 0 might be im­ paired, but not Umax. To examine this, Khoyi et a1. (99) measured renal tissue solutes in acutely salt depleted and control animals. Four hours after acute salt de­ pletion there was a marked reduction in solute content of outer and inner medulla. On the other hand, at twenty-four and forty-eight hours, inner medullary solute concentration had been restored to normal, while outer medullary solute concentration

remained low. Of particular note was the fact that inner medulla sodium concentra­ tion was normal, but urea concentration was almost double that seen during con­ trol periods. These observations in the dog deserve to be corroborated since they imply that in this species, the thin ascending limbs might generate the "single effect" and act as countercurrent multipliers. Alternatively, under some circumstances, such as acute salt depletion, the collecting duct may be capa ble of enhancing its capacity for sodi­ um chloride transport into the medullary interstitium (129,130). The acute salt depletion state could perhaps make the papillary collecting duct more permeable to urea than it normally is, even in the presence of ADH. The issue remains un­ settled. As far as we know, studies de­ termining cH 2 0 have not been performed. The explanation as to why the defect would be restricted to the outer medulla is not clear. '!\Te are not aware of data bear­ ing on the possibility that the permeability of the collecting duct is altered.

Hypothyroidism (Myxedema) Deficiency in the secretion of thyroid hormone usually results in profound alter­ ations in renal function. Decreases in glo­ merular filtration rate (GFR) , in eJIec­ tive renal plasma How, and reduced tubular transport maximum for Diodrast and para­ aminohippurate (PAH) have been reported (100,101). A marked impairment in excre­ tion of water loads has been described in myxedematous patients (102-105) and in experimental animals rendered hypothy­ roid by organ ablation or by antithyroid agents (106-108). Accompanying these findings is a low Umax and, at least in man, abnormal free-water generation and reab­ sorption (109-110). Clinically, the most important consequence of the alteration in

PathojJhysiology of Clinical Disorders of Urine

1005

renal function is water retention and hy­ in hypothyroid rats than in controls during ponatremia (105). Several mechanisms administration of massive sodium loads. have been proposed to explain this defect. Nevertheless, in the same experiments, net (a) defective sodium excretion remained unchanged. Al­ Suggestions have included: distal sodium reabsorption (106,109), (b) so, both net and fractional sodium excre­ relative deficiency of adrenocortical hor­ tion were lower in hypothyroid rats during mones (104), (c) inappropriate secretion water diuresis experiments in which the of or increased tubular sensitivity to vaso­ amount of sodium infused was smaller. pressin (111-113), and (el) decreased de­ The significance of the finding' of impaired renal sodium handling in either man or livery of filtrate to the diluting site (l08). In man, DiScala and Kinney (109) have rat is not apparent and remains to be clari· The relationship between filtered demonstrated that both °H2 0 and TCH 2 0, fiecI. when examined as a function oE V and load and distal soclium reabsorption has Cosm respectively, are abnormal in myx­ been Eurther examined by Katz and Lind­ edema. Although at the moment when heimer (lOS). In an ingenious study these patients were studied GFR was low, it investigators demonstrated that in the ex­ was clemonstra ted that during therapy, perimentally-hypothyroid rat, the reduc­ tion in N a+·I(+·ATPase activity observed in TUH 2 0 remained abnormal at a time when GFR had returned to control values. In both cortex and medulla results from the fact, the defect in diluting the urine was diminished filtered load of N aCI. Thus, also retained after CFR had been cor­ the concentrating defect is not the result rected. In contrast, from studies in the rat, of the reduced enzyme activity but of the Holmes and DiScala (107) and Michael et reduced distal delivery of Na+. The find­ al. (114) have concluded that in this ings with Na-·K!-ATPase conform with species, as in man, the main fault lies in other findings by Katz and Epstein (1l6), the capacity for distal nephron sodium demonstrating that enzyme activity is in­ reabsorption. A striking finding in these fluenced importantly by the filtered load studies was the demonstration of a substan­ of NaG!. Experiments by Reville and Stephan tial leak of sodium by the kidney. For in­ stance, early during 5% saline infusion, (117,118) have shown that the defect in when cosm, cNa, and TCI-I 2 0 were com­ sodium metabolism is unchanged in the parable in hypothyroicl and control rats, hypothyroid l"at, despite adrenalectomy. the filtered load of sodium was 31 percent Furthermore, addi tion oE mineralocorticoid lower in the hypothyroid animals (107). A hormones did not abolish the alterations in similar finding was obtained in Michael's sodium excretion, making it unlikely that experiments. This also seems to be the adrenal conical hormones playa major role case in man. Vaamonde and his coworkers in the abnormality of renal function. More conclusive data from the studies (106) have observed that in severely myx­ edematous patients, there is a prolongation of Emmanouel and his colleagues (115) of the time required to reduce Na' excre­ have eliminated the possibility that inap­ tion by 50 percent (Na tl/2) following a propriate secretion of, or undUly high sen­ natriuresis, and cumulative Na+ losses are sitivity to, ADH can explain the findings increased when compared to euthyroid pa­ of altered water metabolism in the experi­ tients. In the study of Emmanouel et al. mental animal. Studies in the hypothy­ (115), fractional Na clearance was higher roid Brattleboro rat, a strain with can­

1006

Pathophysiology of the Kidney

genital absence of ADH, have shown that the changes in Umax and in absolute values for cH 2 0 and T G f-I 2 0 are identical to those occurring in hypothyroid rats from normal strains. Furthermore, in this species, tissue osmolality and sodium concentration of cortex, medulla, and papilla in rats made hypothyroid is identical to that of control rats. Perhaps of greater significance is the fact that fractional TCH 2 0 curves are identical in hypothyroid and normal rats regardless of the species utilized, indicating that at low rates of urine flow, the llefect is primarily the result of diminished delivery to the diluting site. In addition, during hypotonic (0."15%) saline infusion, abso­ lute sodium delivery to the diluting seg­ ment and free-water clearance were marked­ ly lower in hypothyroid rats. Despite this, hypothyroid and control animals had simi­ lar fractional distal sodium delivery and fractional free-water clearance, suggesting also that the reduction in absolute free­ water formation in hypothyroid rats was due to decreased net distal delivery.

Alterations in Medullary Blood Flow Altered renal blood flow is possibly re­ sponsible for the defects in urine concen­ tration seen in sickle cell disease, multiple myeloma, and pyelonephritis.

Sickle Cell Hemoglobinopathies Inability to maximally concentrate the urine is one of the characteristics of HbS in its homozygous (HbSS) or heterozygous state (HbSA), as well as of HbSC disease. The observation has also. been made that the administration of vasopressin does not raise urine concentration above the mb­ maximal levels attained by dehydration (119,120). Although less consistently, simi­ lar observations have been made in patients with sickle cell trait (119) and sickle cell dis­ ease (120). An early report demonstrated

that the inability to excrete maximally con­ cen trated urine is directly related to the sick­ ling phenomenon, rather than to other inherited or acquired defects (121). It was shown that urine can be concentrated fol­ lowing exchange transfusions of normal blood to young (five years of age or less) sickle cell anemia patients. Also demon­ strated in this importan t study was that with time, the defect becomes irreversible, being permanent in the adult suffering from HbSS disease. It is also of importance that there is a significant progressive de­ crease in renal concentrating ability with age in HbSA subjects (lIS). A possible mechanism for the develop­ ment of the defect could be direct or in­ direct in terference by the sickling process with active NaCI transport in the ascending limb of Henle's loop. Several lines of evi­ dence mitigate against this possibility. Measurements of free water reabsorption (TOH 2 0) during mannitol diuresis in HbSS adults and children have been found to be essentially identical to those of normal in­ Initially, during dividuals (122,123). manni tol loading, TCH 2 0 rises progressive­ ly with increasing rates of osmolar clear­ ance (Cosm) until TCI-I 2 0 either levels off in plateau fashion or slowly declines (19). The flat or descending portion of the curve describing the TOH 2 0 to °osm relationship during mannitol diuresis, is the conse­ quence of the l'eduction in tubular fluid sodium chloride COllcell tration caused by the osmotic agent. This imposes a limita­ tion on the transport of NaCI into the medullary interstitium by the ascending limb (19). Therefore, at rates of cosm prior to the plateau, NaCl transport by the ascending limb must be normal in HbSS disease. Because of the possibility that the flattening of the curve imposed by mannitol may obscure a NaCI transport defect in the loop at higher rates of cosm,

Pathoj)hysiology of Clinical Disorders of Urine

1007

Hatch and his collaborators (124) exam­ late secretion of the hormone might be so ined the effects of 3% NaCl infusion 011 the involved by microinfarction, that despite In this the appropriate stimulus, circulating titers TCI-I:!O to Gosm relationship. circumstance, TOH:!O rises with increasing might be suboptimal. This seems unlikely, cosm without any evidence of a limit be­ in view oE the fact that water loading is ing reached, since luminal sodium chlo­ promptly accompanied by reductions in ride concentration in the loop does not fall urine osmolality to levels equal to those (19). It was found that in HbSS subjects, seen in normals (120,124,125). Disruption in contrast to normal individuals, TCH 2 0 of anatomical pathways sufficient to result reached a maximum at levels of cosm in altered honnone secretion would not similar to those at which a plateau occurred be expected to be accompanied by main­ during mannitol infusion. Although this tenance of an intact feedback mechanism. suggests impairecl sodium reabsorption at Furthermore, in HbSA subjects, it would high rates of sodium chloride delivery to be difficult to invoke vascular involvement the loop, free-water clearance (OH 2 0) was of the bypothalamic-posterior pituitary found to be normal throughout wide ranges axis, in view of the lack of thrombotic of dis tal delivery, indicated by the rate of episodes in this group (126,127). urine flow (V). Furthermore, the fraction­ On the basis of the experience with al excretion of sodium during mannitol, young patients, similar arguments may be saline, or water diuresis or at control rates leveled against the suggestion that the basic of solute excretion dill not differ between defect is one of diminished responsiveness control and HbSS subjects (124). These of the collecting duct to ADH. Since the results make it unlikely that a gross defect defect becomes progressively worse with in­ in active sodium chloride transport by the creasing age (120,128), an effect on the ascending segment of the loop of Henle is cellular actions of ADH at the level of the the cause of the concentrating disorder. collecting duct may be involved. The The combination of a diminished nature of this alteration is probably not in Umax and the impaired TOH 2 0 during the response of the collecting duct to ADH. hypertonic saline diuresis could be ex­ The urinary excretion of cyclic AMP in })lained on the basis of an abnormal perme­ sickle cell anemia patients underg'oing ability to water in the collecting duct. De­ water diuresis reaches levels similar to those ficient secretion of ADH, diminished re­ of normals following the intravenous ad­ sponsiveness of the collecting duct to ADH, ministration of vasopressin (55). Also, or a primary alteration in the permeability urinary osmolality rises albeit less than in of the distal nephron to water could lead normals (55). This indicates that there is some cellular response to endogenously to the findings in sickle cell patients. Absence or decreased secretion of ADH formed cyclic AMP, the presumed physio­ by sickle cell patients does not seem to be logical messenger of ADH. In view of the responsible for the concen trating defect. fact that urine is not maximally concen­ As already noted, transfusion of normal trated, structural defects in some cells may blood into young patients leads to 11m-mal make them refractory to the action of cyclic Umax (121,123). Thus, secretion of ADH AMP, thus contributing to the reduced must be normal at least at an early age. Umax. Nevertheless, this alone cannot en­ Conceivably, at later stages of the disease, tirely explain the defect. A primary alteration in the permeabil­ the areas of the hypothalamus which regu­

1008

Pathophysiology

ity o[ the distal nephron appears even less plausible in older patients with the sickling phenomenon. Reduced permeability to water (to account for diminished Umax) would not allow the generation of normal TCH 2 0 during mannitol diuresis nor would TCH 2 0 values reach levels shown to occur before a defect is demonstrated dur­ ing 3% saline diuresis. Furthermore, cH 2 0 would be supernormal, since the volume of water which is normally reabsorbed from the collecting duct during water diuresis (1,8,129,130) would be excreted in the urine. In 1961, Herbin and his collaborators (131) demonstrated that sickling could be induced in vitro by placing erythrocytes of patients with HbS in hyperosmolar solu­ tions. They postulated that entry of cells into the medulla leads to sickling, sludging of cells because of increased viscosity, and diminished medullary and papillary blood flow with disruption of the concentration profile. Perillie and Epstein (132) ex­ tended these observations by careful analy­ sis o[ the different factors which may lead to sickling in the renal medulla. It was shown by these investigators that other factors which are usually associated with the production of sickle cells, such as low pH and hypoxia, are superceded by the effect of hyperosmolar salt solutions under all conditions in which this situation was tested. Furthermore, the viscosity of the solution of sickle cell anemia blood and hypertonic sodium chloride was greater than that of thalassemia major or normal blood mixed with hypertonic saline. Of particular importance was the finding that unlike the sickling promoted by low oxygen tension, which takes two to four minutes to become apparent at body temperature, sickling induced by hypertonic solutions oc­ curs and may be reversed practically in­ stantaneously. These investigators there­

of the Kidney

fore suggested a sequence of alterations produced by the sickling of erythrocytes similar to those postulated by Herbin et '11. (131). In the model proposed by Herbin et al. (131) and Perillie and Epstein (132), fail­ ure to excrete a maximally concentrated urine would be the consequence of inter­ ference with active sodium chloride trans­ port in the ascending limb of Henle's loop or alterations in the impermeability to water of this structure. Evidence has al­ ready been cited which does not support the notion that active sodium chloride re­ absorption in the ascending limb is re­ sponsible for the defect in urine concentra­ tion. Changes in the impermeability to water of the ascending limb would not be associated with normal TOH~O during mannitol diuresis nor with normal cH~O during water diuresis. ·Were water reab­ sorption to follow sodium chloride reab­ sorption in the loop, the osmolality of inter­ stitial fluid would be reduced, and free­ water reabsorption would be severely limited throughout wide ranges of cosmo During water diuresis, water reabsorption in the ascending limb would permit Huid of higher osmolali ty to emerge into the distal convolution and enter the collecting duct. Throughout a wide range of V, urine would be less dilute than normal, and cH 2 0 would be lower than normal. Furthermore, maximal urine diluting abil­ ity would be impaired, which is not the case in sickling hemoglobin disease. The findings of a low Umax amI an abnormal TCH 2 0 at high rates of cosm may be explai ned if the disease has selec­ tively destroyed juxtamedullary nephrons with long thin limbs of Henle which de­ scend into the papilla. In view of the normal capacity to excrete maximally dilute urine, the assumption must be made that long thin loops arc not necessary for

Pathophysiology of Clinical Disorders of Urine

the elaboration of a maximally dilute urine. In order for this to be the case, the major site of active NaGI transport in the ascending limb, if not the only site, has to be the thick portion. Long thin loops dip­ ping into the papilla would only be in­ volved in the concentration of urine at low rates of flow by a mechanism other than active transport. Kokko and Rector (18) have proposed that the permeability char­ acteristics of thin loops with respect to Nael, urea, and water, rather than active sodium transport by these structures, arc what determines urine concentration. In this model, papillary accumulation of urea and active NaCI transport by the thick as­ cending limb play the central role in urine concentration at low rates of urine flow. Similar proposals have been made by Stephenson (16) and by Stewart and Valtin (17). Elimination of the papilla would re­ move the major mechanism of urea recircu­ lation, in addition to reducing the length of the collecting duct. This last feature would also explain the finding of an ab­ normal TOHzO at high rates of flow. The large volumes of hypotonic fluid entering into the shortened collecting duct will have less time to equilibrate with the intersti­ tium as flow rises. Consequently, cosm will rise, but TCHzO will either plateau or fall. The evidence that thin ascending limbs are not essential for the excretion of maximal­ ly concentrated urine, and that their func­ tion may not involve active NaGl transport, can be naturally found or artificially created. In Macaque (13) and Rhesus (12) monkeys, Tisher and his collaborators have shown that long thin loops are SCal"ce; yet, Umax is normal as is TOHzO at low rates of flow, but at high rates of osmolar clearance, reductions in TCHzO are appar­ ent. By surgical ablation of the papilla in the rat, Lief et al. (14) and Martinez­ Maldonado et al. (15) have shown that

1009

Umax is reduced, but TCHzO remains normal during solute loading until high levels of °osm are achieved. Furthermore, in this model, as in the case of sickle cell states, °1-1 2 0 remains intact throughout a wide range of urine flow (15). One may visualize that therecluction in blood flow to the papilla, which occurs as a result of increased viscosity induced by sickled erythrocytes, results in a functional papillectomy. This is reversible in the early stages by transfusions, but, as time elapses, irreversible damage takes place and blood exchanges will not correct the defect. On the other hanel, the changes in Umax and TCH 2 0 described above will persist.

Multiple Myeloma Changes in urine concentration and dilution may take place during the course of multiple myeloma as a consequence of its various complications. Thus, hyper­ and renal in­ calcemia, pyelonephritis, sufficiency may all be found as causes of Umax defects (41). Of interest is the possibility that when hyperviscosity secondary to hypergam­ maglobulinemia is found, it may interfere with the function of the countercunent system. In fact, two subjects with this syn­ drome in whom Umax was affected have been reported (133). The hyperviscosity syndrome, however, is a life-threatening condition, the treatment of which takes precedence over any desires to solve the mechanism by which the countercurrent system is affected. Should there be massive plasma cell infil tra tion of the kidney, and were this to predominate in the medulla, a Umax de­ fect might develop. The authors are aware of one patient in which this may have con­ tributed to abnormal renal function (41). A curious possibility is that amyloid

1010

Pathophysiology of the Kidney

})roduced by the myeloma cells may selec­ tively surround some of the structures with­ in the medulla. This, as in the case re­ ported by Carone and Epstein (13"1), could lead to a syndrome of nephrogenic diabetes insipidus (should it involve the collecting duct) , or a disorder of reduced filteredloacL to the diluting site if the glomeruli are beavily involved.

Pyelonephritis The association between chronic urin­ ary tract infection and an impairment in renal concentrating ability is well known. In the past fifteen years it has also been found that normal and pregnant women with acute pyelonephritis or asymptomatic bacteriuria have a defect in urine-concen­ trating ability (136-138). The reduced Umax, in fact, is probably the earliest evi­ dence of the invasion by bacteria of the renal medulla. Experimentally, a similar functional disorder has been reproduced in rats innoculated intravenously with gram positive cocci or gram negative bacilli (140, )41). The direct relationship between the localization of the bacteria in the genito­ urinary tract and its functional and thera­ peutic import may be appreciated from the studies of Ronald et al. (142) and Clark et al. (143). Utilizing selective catheteriza­ tion of the ureters, these authors deter­ mined the precise site of bacteriuria in ap­ proximately sixty-six individuals in which this had been a recurrent problem. It was established beyond doubt that renal but not bladder bacteriuria is associated with decreased urinary concentrating ability. Patients in whom bacteriuria had a renal origin presented, in addition to the low Umax, [771 ± 122(SD)mOsmjKg; n:::::38] , a reduced urine urea concentration (Uurea). It has been sugges ted that this reduction in Umax may be the consequence of increased renal blood flow (particularly medullary

blood flow) as a result of the pyrogenic re­ action (144). In acute pyelonephritis of animals or man this may well be the case. In fact, Gonick et a1. (145) studied rats with acute pyelonephritis induced by enterococci and found that in the medulla, the concentration of sodium was normal and that of urea markedly reduced. Since the initial event may be a marked increase in renal medullary blood flow, this would lead first to increased U urea, yet, with time, should the hemodynamic alteration persist, Uurea would fall. The pyrogen response need not be systemic but could be localized to the medulla. Evidence for this may be gleaned from patients with unilateral renal bacteriuria where the control kidney con­ tinued to excrete urine with an osmolality comparable to normal, while Umax was distinctly lower in the diseased kidney de­ spite comparable GFR in both (1"12,1'13). This finding also rules out the possibility that dietary factors, such as protein or water intake, may determine the presence of the Umax defect. The direct relation­ ship between the abnormal Umax and the bacteriuria is also suggested by the fact that appropriate therapy tends to revert Umax to normal as the bacteria are eradica teel (1'16,147) . Studies attempting to elucidate the na­ ture of the concentrating defect were per­ formed in patients with acute pyelonephri­ tis by Suki, Axelrad, Eknoyan, and Mart­ inez-Nlalclonado (148). The subjects were, in general, women who presented with fever, flank pain, dysuria and positive urine culture (bacterial counts: 100,000 coloniesjm1 urine). Within twenty-four hours of subsidence of acute symptomatol­ ogy, a Umax was performed. Despite an average GFR value of 125 mljmin / 1.73 m 2 (control 120 mljminj1.73m 2 ) there was a severe limitation in Umax (468 to 850 mOsmjKg as compared to controls of

Pathophysiology of Clinical Disorden of UTine

904 to 1072 mOsm/Kg). TCH 2 0 at any level of cosm was less in patients with acute pyelonephritis than in controls. On the other hand, cH 2 0 versus V was identical in controls and patients. 1n view of the clata on Uurea in humans and experimental ani­ mals, these results are best explained by ei ther increased medullary blood flow with urea washout or altered permeability of the collecting duct to urea and water. An alternative is that both these mechanisms may be operative. Clearly, this is related to the bacteria. ·Whether these interfere directly, through the production of toxins or pyrogens, or by disrupting the normal archi tecture of the medulla is, at present, still a matter of conjecture.

Changes in Nephron Membrane Permeability Figure 26-5 demonstrates the supposed effect of ADH on a renal tubular cell and the presumed physiological consequences that follow. It is now well accepted that cyclic AMP is the physiological messenger of the cellular actions of ADH, and that this nucleotide is responsible for changes in tubular permeability and ion transport POSSIBLE SITElS) OF ACTION OF SUBSTANCES WHICH MAY LEAD TO NEPHROGENIC OIABETES INSIPIDUS

(SEROSA) BLOOD

r@

;'0\0''"la!". ,,,...,,1

AlP,

;:;.'

....

~:

HtO

~'!

Cyclic AMP

J

(""'O'AI UfllHE

~' AMP

Figure 26-5. lecting duct drug effects nephrogenic

Schematic representation of a col­ all indicating possible sites where may lead to the generation of diabetes insipidus.

1011

(149). By blocking any of the steps which follow the release oE ADH into the cirCllla­ tion, a variety of therapeutic compounds may lead to abnormal urine concentration and/or dilution. The most common clinic­ ally utilized agents responsible for function­ al disorders involving the adenylate cyclase­ cyclic AMP system include lithium salts, tetracycline, amphotericin-B, and methoxy­ flurane.

Lithium Therapy Lithium salts, which have their main clinical usage in the treatment of manic­ depressive states, has been observed to lead to polyuria and a defect in urine concentra­ tion (150,151). Even when doses are pre­ scribed to maintain serum levels in the range between 0,5 and 1.5 mEg /1, it may lead to the procluction of polyuria and polydipsia. III man it has been shown that the reduced Umax is accompanied by a de­ fect in TCH 2 0 formation, but that the 01-1 2 to V relationship is no different than that of controls (152). Experimental evi­ dence advanced by Martinez-Maldonado and his collaborators (153) and by Forrest et al. (154) has corroborated that this is also the case in rats. It is clear that lithium polyuria cannot be completely abolished by the administration of large doses of vaso­ pressin. In fact, the excretion of urinary cyclic AMP, a measure oE the responsive­ ness of the distal nephron to ADH, is diminished under basal conditions or in response to exogenous ADH. A finding of great interest is that the change in water excretion in response to cyclic AMP in animals which have been rendered poly­ uric by the administration of lithium, ap­ pears to be somewhat better than those pro­ duced by vasopressin (153). This suggests that the defect is in the formation of cyclic AMP or at the site of hormone stimulation oE the adenyl cyclase receptor. On the

°

I!

I

f_

I

1012

Pathophysiology of the Kidney

other hand, there might also be some defect at a step beyond the forma60n of cyclic Al\J[P since the observation has been made that some doses of cyclic AMP do not revert the Uosm defect to normal (154). Studies in isolated anuran epithelia have been eq uivocal (155-] 58). In these studies an eHect of Li+ has been proposed before cyclic AMP formation and after this step. As in the case of other drugs leading to nephrogenic diabetes insipidus, the possi­ bility that, in the whole animal, the defect may result from the loss of another ion needs to be considered. The possibility that prolong-ed lithium therapy may lead to potassium depletion with subsequent in­ ability to concentrate the urine has been suggested, but it appears quite clear that this is a specific effect of the lithium ion. Usually, there are no changes in GFR and renal blood How, so that hemodynamic alterations as the cause of the defect seem unlikely.

Tetracycline TheralJy Demethylchlortetracycline (demeclocy­ cline) has been reported to produce a syn­ drome of nephrogenic diabetes insipidus in some patients (159-161). The use of other tetracyclines have been implicated 111 several renal tubular syndromes, and nephrotoxic effects have been observed dur­ ing utilization of outdated (degraded) tetracyclines (162,163). The renal changes produced by degraded and other tetra­ cyclines simulate the Fanconi Syndrome and involve, in addition to polyuria, hypo­ kalemia and defects in the renal transport of P0 4 , urate, and glucose. By contrast, the changes produced by demeclocycline appear limited to the distal nephron. "Vil­ son et aI. (1M) studied three patients re­ ceiving demeclocydine and two patients re­ ceiving non degraded tetracycline. In the former, Umax, after sixteen hours of clehy­

dration, fell to 48 percent of control, while it only fell by 9 percent in the latter. Similarly, TOH 2 0 was markedly reducecl by the usc of clemeclocycline, while it was not altered in the subjects ingesting tetra­ cycline. Urinary cyclic Arvrp excretion after the administration of vasopressin to patien ts on demecIocycline, was essen tiaIly unchanged, indicating lack of response to the hormone in these patients. Further evidence for a major effect of demeclo­ cycIine in the permeability of the distal tubule to water was advanced by Singer and Rotenberg (165). In eight out of twenty-four patients receiving clemecIocy­ cline for acne, there was a clearly abnormal Umax. Further studies on three patients in whom Umax was below 450 mOsm/Kg revealed grossly abnormal TCH 20 to cosm curves in two, while it was borderline in the other. Proof that ascending limb func­ tion was normal was provided by the fact that Dmin, °H 2 0 and urine flow rate were equal when control and demeclocycline­ treated subjects with abnormal Umax were compared. In vitro studies by Singer and Rotenberg (165) disclosed that addition of demeclocycline to the serosal side of toad urinary bladders resulted in inhibition of ADH-inducecl and cyclic-AMP-induced water flow. Water How induced by ADH was inhibited more significantly. These findings suggest that demeclocycline proba­ bly inhibits both cyclic-AMP production and cyclic-AIVIP action. Of clinical import:­ ance was that the effect was rapidly reversi­ ble after removal of the antibiotic from the serosal bath. Supporting evidence for in ter­ ference of demeclocycline with the cellular action of ADH has been accrued by Dousa and '\'\Tilson (166). Renal medullary ex­ tracts containing adenylate cyclase, protein kinase, and cyclic AMP phosphodiesterase activity were isolated and exposed to vari­ ous concentrations of demecIoeycline.

Pathophysiology of Clinical Disorders of Urine

Basal and Huoride and ADH-stimulated adenylate cyclase activity were inhibited. Similar doses of the antibiotic also pro­ duced inhibition of the cyclic AMP- de­ penclen t cytosol protein kinase. These findings indicate that clemeclocycline has the potential to inhibit cyclic AMP forma­ tion and its accumulation in the renal medulla in response to AD H. It also has the potential to inhibit the cyclic AMP-de­ pendent phosphorylation of proteins in the renal medulla. An important observation in these studies was that tetracycline and chlortetracycline can produce in vitro in similar concentrations, the same effect as demeclocycline, yet in vivo they do not pro­ duce nephrogenic diabetes insipidus. Al­ though not clear, it is likely that the pene­ tration of these other tetracyclines into dis­ tal renal tubular cells may well be poor or of lesser degree than in the case of clemeclo­ cyeline.

Anesthesia (Fluoride Toxicity) Patients who have received methoxy­ flurane (Penthrane@) anesthesia, with the usual anesthetic adjuvants, have developed dose-related abnormalities in renal func­ tion (167). Exposure to minimum alveolar concentration of the anesthetic for 2.5 to 3 Ius, i.e. 2.5 to 3 MAC/hr (serum inorganic fluoride above 50 fLmol I I) has resulted in subclinical toxicity. By contrast, all pa­ tients in whom doses greater than 5 MACI hr (serum inorganic fiuoride above 90 jLmol/l) have been utilized, have developed clinical toxicity (167,168). The major manifestation of this clinical toxicity ap­ pears to be the development of a polyuric syndrome which is resistan t to the effect of vasopressin (169). Most likely associ­ ated with the presence of the fluoride ion, it is conceivable that this is a result of in­ abili ty to reabsorb sodium in the ascending limb of the loop of Henle since fluoride, a

1013

well-known inhibitor of anaerobic metabol­ ism, might interfere with sodium reab­ sorption at this site (170). On the other hanel, inhibitors of anaerobic metabolism may also result in inabili ty of the papillary collecting duct to respond to vasopressin (171). Studies utilizing inhibitors of an­ aerobic metabolism in the toad bladder and frog skin have shown that both the hydro­ osmotic eiTect and the stimulation of sodi­ um transport induced by ADH afe blocked (172) .

AmphQtericin-B Therapy The antifungal agent amphotericin-B has also been demonstrated to induce a defect in maximal urine concentration (173). Polyuria and nocturia occur fre­ quently, and there is resistance to the effect of exogenous vasopressin (174). It should be clear, however, that the Umax defect is associated with marked impairment in GFR (173). The fall in filtration rate often represents as much as 50 percent of normal which, by reducing distal delivery, could curtail the development of a hyper­ tonic medullary interstitium and result in a reduced Umax. Furthermore, potassium depletion is a frequent companion of amphotericin nephrotoxicity and could be the sole or compounding factor in the de­ velopment of the urine-concentrating de­ fect (175-177). Another contributing fac­ tor may be an actual reduction in the number of functioning nephrons, particu­ larly juxtamedullary, as a result of struc­ tural defects produced by the drug (173, 17'1). Lastly, amphotericin-B may directly interfere with the permeability or solute selectivity of the distal nephron mem­ branes. Furthermore, the effect of anti­ diuretic hormone on the collecting duct may be altered. Studies in isolated mem­ branes such as toad bladder, have demon­ strated that amphotericin-B increases the

101 <1:

Pathophysiology of the Kidney

permeability of the plasma membranes to urea, thiourea, potassium, and chloride (178). Other membranes are also known to be affected. In erythrocytes, amphoteri­ cin-B increases the permeability to potassi­ um, sodium, and chloride and to hydro­ philic nonelectrolytes smaller than sucrose (179). It is possible, therefore, that an en­ hancement of the permeability of the nephron cell membranes to these ions, to­ gether with conformational changes which prevent normal water movement across the cells of medullary structures, may result in an inability to concentrate the urine. Also, it is entirely conceivable that the same effects noticed in the collecting duct may take place in the ascending limb of Henle's loop, making this structure less imperme­ able to water. This would result in diminished genera tion of free water and re­ duced interstitial solute concentration. Tvlore precise knowledge of the mechanism of amphotericin-B-induced nephrotoxicity is clearly needed.

Defects Resulting from Alterations in

Medullary Architecture

Cystic Disease of the Kidneys A number of inherited and acquired diseases may result in alterations of the anatomical interrelationships between the loop of Henle collecting-duct system and the medullary vasculature, leading to de­ fects in urine concentration and dilution. Classical examples of congenital anomalies which are accompanied by defects in Umax are polycystic kidneys, medullary cystic dis­ ease, and medullary sponge kidney. Some acquired disorders, in particular obstructive uropathy, may well represent situations in which architectural derangements in the medulla are the major reason for changes in concentration and dilution. Clinically, all these patients may have polyuria and hyposthenuria, even in the absence of

severe renal failure. Inability to maximally concentrate the urine is probably the earliest functional disturbance in patients with polycystic kid­ neys and medullary cystic disease (180,181). Hyposthenuria in these states may be un­ covered in the absence of renal insufficiency (180,182). In view of the low Umax, de­ spite normal GFR, one of the possible mechanisms leading to the defect is ab­ normal sodium chlorille transport in the distal nephron. In the case of polycystic kidney disease this does not appear to be the case since patients, throughout a wide range of renal function, possesses the abili ty to dilute the urine maximally, and they exhibit normal free-water clearances (I 80). The authors are not aware of detailed studies bearing on this point in patients with medullary cystic disease. Neverthe­ less, in one case of sponge kidneys, both Umin and free-water clearance were per­ fectly normal in the presence of a low Umax. A priori, it is conceivable that urinary diluting ability and capacity in me­ dullary cystic disease are abnormal. This disorder is accompanied by salt-losing neph­ ritis, suggesting a defect in the handling of NaCl in the distal nephron. Utilizing a similar reasoning, one might infer that TOH 2 0 as a function of °osm is also im­ paired. Despite this speculative argument, one cannot discard the fact that a signif­ icant anatomical derangement exists which may compound the functional disorder.

Obstructive Nephropathy Obstruction of the urinary tract results in impaired ability to excrete a maximally concentrated urine (183). This abnormali­ ty depends on the duration and complete­ ness of the obstruction (184-189) ancl of the presence or absence of infection (190,191). Acute complete obstruction is accompanied by loss of the ability to maximally concen­

Pathophysiology of Clinical Disorders of Urine

trate the urine, so that Umax on the affected side is considerably lower than in the contralateral kidney (186,187). In this case the associated finding that tissue con­ centration of solute is sharply reduced has led to the suggestion that medullary blood How is increased and thus leach to washout of solute (192). This conclusion, however, was based on the demonstration that the renal extraction of PAH from renal arterial blood was decreased. This inference is at best tenuous, since incomplete extraction does not necessarily represent perfusion of tissue (medulla) incapable of secreting PAR (193). Studies employing 851(1' wash­ out (191,195) and indocyanine green mean transit time (196) have not corroborated that medullary blood flow is increased. The origin of the low Umax is most likely the result of two other factors: first, a sharp reduction in GFR, leading to re­ duced NaCI delivery to the diluting site which, in turn, would explain the reduced medullary tissue solute concentration if the analysis were made without the reestab­ lishment of urine flow; second, should urine flow be reestablished, and then analy­ sis of Umax and tissue solute concentra­ tion done, the time to replenish medullary solute and raise Umax might be insufficient. "When obstruction has been present for twelve to twenty-four hours, changes in collecting duct function may already be present. At this time, studies in the rat (197) and the rabbit (198) have demon­ strated dilation of the collecting duct at the inner stripe of the outer zone. In addi­ tion, engorgement and dilation of the radi­ cals of the renal veins and numerous small hemorrhages can be seen. These altera­ tions may result in failure of these struc­ tures to respond to ADH in a normal way and lead, even after replenishment of me­ dullary solute concentration, to low Umax. In contrast to complete acute obstruc­

1015

tion, partial acute obstruction is not associ­ ated with a reduced Umax (188). This appears to be the case in the hydropenic an tidiuretic animal, as well as during en­ hanced distal delivery through the infusion of hypertonic saline. Since, in these two models, medullary blood flow increases [as measured by fiber-optics (196)], it is clear that it is most unlikely that this hemody­ namic change can explain the fll1dings in complete obstruction. The maintenance of Umax during acute incomplete obstruc­ tion suggests, in fact, enhanced NaCl reab­ sorption in the ascending limb (188,199). The duration of urinary tract obstruc­ tion in man is difficult to ascertain so that, by necessity, most of the aforementioned studies have been in the experimental ani­ mal. Nevertheless, it is dear that accord­ ing to the alterations in I'enal function, one may clinically categorize obstruction into acute and chronic. Clinically, the latter may be characterized by polyuria with in­ ability to concentrate the urine and mim­ icking nephrogenic diabetes insipidus (200­ 203) , while the former will be accompanied by reduced urine flow, and diminished free­ water excretion with a higher Uosm (188). The differences between acute and chronic obsti'uction have been best characterized by the classical studies of Suki, Eknoyan, Rector, and Seldin (204). Studies in dogs revealed that acute unilateral ureteral elevation led to reduced urinary sodium concentration, sodium excretion, and cH 2 0/100 ml GFR, a pattern similar to that of renal arterial constriction and thus suggesting diminished delivery of NaCI to the ascending limb. On the other hand, unilateral chronic hydronephrosis resulted in an increase in urinary solute com:entra· tion and urinary sodium excretion, Abso­ lute 0HzO was decreased but °HzOjlOO ml GFR was actually increased, indicating increased solute delivery to the diluting

1016

Pathophysiology of the Kidney

site. The possibility that back-diffusion of free water in the collecting duct may have played a role was also considered. Further evidence that loop function is intact was obtained by Eknoyan, Suki, Martinez­ Maldonado, and Anhalt (205). In dogs with unilateral chronic obstruction it was demonstrated that free-water reabsorption is normal, as was the renal tissue content of Na. In fact, despite marked reduction of GFR and RPF, the corticopapillary gradient for sodium during hypertonic saline diuresis was essentially the same in the hydronephrotic and control kidneys. This finding ellectively eliminates reduced GFR as a factor in this case. Other factors, therefore, must be responsible for the low Umax. It is possible that, as has been mel1lioned, cellular atrophy secondary to the increased intraluminal pressure ren­ ders the collecting duct hypo- or unrespon­ sive to ADH. This seems unlikely, in view of the normal TDH~O during hypertonic saline diuresis. The nephron hyperperfu­ sian state (increased GFR per nephron), on the other hand, may be responsible. Be­ cause of the increased distal delivery, large volumes of hypotonic fluid will el1ler the distal tubule following the removal of solute in the ascemling limb. The fluid will en tel' the collecting duct and be ex­ creted without attaining equilibrium with the interstitium. Alternatively, the most attractive possibility is that the normal eq uilibration of fluid between collecting duct and interstitium is not attained, be­ cause the normal architecture of the me­ dulla and the physiological charatceristics of its structures have been disrupted. Per­ haps the solute transported into the me­ dulla is, in a sense, "compartmentalized", because the distances from its site or: ac­ cumulation to the collecting duct do not permi t an effective osmotic pressure to be exerted under these circumstances. This

will lead to polyuria, which is unresponsive to ADH administration.

Analgesic Nephropathy Disrup tion of medullary architecture is also responsible for the abnormality of urine concentration seen in analgesic neph­ ropathy. In most cases, the defect in urine­ concentrating ability seen in these patients is the result of reductions in glomerular filtration rate (206). Nevertheless, in some patients, the magnitude of the reduction in urine concentnuion is greater than can be accounted for by diminished GFR (207). It is in these patients that the functional defect may result from anatomical changes in the area of the medulla. It is also clear that papillary necrosis, which is a common consequence of analgesic abuse, amply ex­ plains the abnormality in urine concentra­ tion in some cases. In fact, marked me­ dullary interstitial sclerosis and loss of tu­ bules, as well as tubular basement mem­ brane sclerosis, are frequently observed even in patients whose creatinine clearance is as high as 90 ml/min or more. Histo­ logical changes may lead to the observed defect without the need to invoke a direct toxic effect of the analgesic on inherent functional parameters 0 f the cell. N ever­ theless, Bluemlc and Goldberg (208) have advanced evidence suggesting that accumu­ lation of metabolites of phenacetin may have toxic effects on the cells of the me­ dulla. Since a defect in urine acidification is frequently seen under these conditions, structural or functional damage to the col­ lecting duct may well be of importance in the concentrating defect (209).

Miscellaneous Another condition in which medullary interstitial swelling and edema may inter­ fere with normal concentration, by in­ creasing pressure in the area, is lympho­

Pathophysiology of Clinical Disorders of Urine

matous infiltration of the kidney. A case representing this phenomenon has been observed by one of the authors (210), and a similar case has been recently reported by Steele and his associates (211). In the latter case, X-ray therapy of the involved kidney reduced cellular infiltration by the tumor and reverted the Umax toward normal, demonstrating the direct relationship between edema of the medullary area and the abnormality in urinary concentration.

Acquired Chronic Renal Disease The ability to concentrate the urine is impaired in chronic renal disease. In contrast to the case in chronic obstruction, this aberration rarely takes the form of nephrogenic diabetes insipidus but rather urine, most likely reduced in volume, has an osmolality which approaches and becomes isotonic to plasma. On some occasions urine may become hypotonic to plasma and will remain so despite the administration of vasopressin. This syndrome of vasopressin-resistant hyposthenuria had been described rarely in patients with chronic pyelonephritis (212,213) and in children with chronic renal disease (214). More recently, Tannen and his collaborators (215) have demonstrated that this disorder is not as rare as previously thought. Vasopressin-resistant hyposthenuria was present in eleven of thirteen patients with chronic renal disease of various etiologies studied by this group. The mechanisms by which these changes in urine concentration arise are not perfectly clear. Of interest is that urine dilution remains intact even after Far-advanced renal failure is present (21'1-216), suggesting that function of the loop of Henle is intact. The experimental studies of Bricker et al. (217) have provided strong evidence for the in tegrity of function of the ascending limb. In dogs

1017

with three varieties of unilateral experimental renal disease, the values for TCH 2 0 and cH 2 0, when expressed as a fraction of the GFR, were within normal limits. In fact, cH 2 0, whether fractional or absolute, tended to be higher in the diseased kidney than in the control. By contrast, in subjects with GFR's ranging from "1 to 127 mIl min, the administration of hypotonic mannitol under conditions of maximal hydration resulted in an increased fractional sodium excretion in those with a low GFR. Because fractional distal sodium reabsorption (or-I 20 /GFR) appeared lower in subjects with low GFR than in those with normal GFR, it was concluded that an alteration in distal sodium reabsorption was present in chronic renal disease (216). This conclusion seems unwarranted, since it only demonstrates that flooding of the distal nephron by fluid contalning a nonreabsorbable solu te will limi t cH 2 0 generation more in subjects with low GFR than in normals. This may well be compounded by the increased delivery of proximal tubular Iiuid, which may be normally present in patients with chronic renal insufficiency (218). The importance of solute load per nephron on distal sodium reabsorption in chronic renal disease has been demonstra teel by Coleman and his collaborators (219). These authors were able to reduce the excretion of sodium by reducing filtered load in subjects with chronic renal disease. On the other hand, as in the studies of Kahn et al. (216), infusion of mannitol led again to a fixed amount of sodium loss in the urine. In addition to solute load per nephron, it is possible that uremic toxins render ineffective the action of ADH. This possibility has not been thoroughly explored, although circumstantial evidence suggests that, if present, the toxin is not llialyzable (215) .

1018

Pathophysiology of the Kidney

More important may be alterations in the normal relationship between tubules and their vascular supply. The marked distortion of anatomical relationships in the diseased kidney is well known, and the likelihood that water movement is markedly altered could well explain some of the findings. This would be particularly the case if nephrons with long loops of Henle were involved out of proportion to short loop nephrons.

4.

5.

SUMMARY STATEMENT In the preceding discussion we have attempted to characterize the pathophysiology of disorders of urine concentration and dilution. Clearly, there are areas in which our knowledge of the mechanisms involved are incomplete and in which further clarification is needed. Some subjects we have purposely dissected in more detail than others. Concerning sickle cell hemoglobinopathies, we feel that these clinical entities provide a model to which the latest theoretical analyses of the countercurrent system may be applied. Other clinical entities, such as drug-induced nephrogenic diabetes insipidus, may not continue to be observed clinically, through avoidance of their lise. Their use in experimental models, however, may provide further insight into the molecular mechanisms involved in one of the kidney's most important functions.

6.

7.

8.

9.

10.

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11.

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1019

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1020

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