Renal prostaglandins and the control of renal function in liver disease

Renal Prostaglandins and the Control of Renal Function in Liver Disease

MURRAY EPSTEIN, M.D. Miami,

Recent evidence suggests that renal prostaglandins play a major role in the control of renal hemodynamics and function in patients with advanced liver disease. The available data suggest that alterations in renal prostaglandin metabolism participate in the pathogenesis of at least three prominent renal complications of liver disease: sodium retention, impaired renal diluting ability, and the hepetorenai syndrome. Nonsteroidal anti-inflammatory agents that inhibit cyciooxygenase activity favor sodium retention and diminish renal plasma flow and glomerular filtration rate in patients with decompensated cirrhosis. The clinical caveat emerging from these observations is that nonsteroidal anti-inflammatory agents, which inhibit cyclooxygenase activity, should not be prescribed for sodium-retaining patients with decompensated liver disease.

Florida

it is well established that derangements in renal function commonly complicate primary disorders of the liver. These complications comprise a wide continuum, including decreased renal blood flow and giomeruiar filtration rate, sodium retention, and an impairment in renal diluting capacity [l]. The mechanisms responsible for the changes in renal function have not been completely elucidated. Recent studies have suggested that, in analogy with their role in various cardiovascular and renal diseases [2,3], prostagiandins may play an important role in the control of renal function and hemodynamics in patients with cirrhosis. RENAL PROSTAGLANDINS AND SODIUM RETENTION

From the Nephrology Division, Department of Medicine, University of Miami School of Medicine, Miami, Florida. Requests for reprints should be iddressed to Dr. Murray Epstein, Nephrology Section, Veterans Administration Medical Center, 1201 Northwest 16 Street, Miami, Florida 33125.

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Patients with Laennec’s cirrhosis have a remarkable capacity for sodium chloride retention; indeed, they frequently excrete urine that is virtually free of sodium (4-71. Extracellular fluid accumulates excessively and eventually becomes evident as clinically detectable ascites and edema. Weight gain, ascites formation, and edema occur in cirrhotic patients who are unable to excrete sodium as long as dietary sodium content exceeds maximal urinary sodium excretion. if access to sodium is not curtailed, the relentless retention of sodium may lead to the accumulation of vast amounts of ascites (on occasion up to 20 to 25 liters). Weight gain and ascites formation promptly cease when sodium intake is sufficiently iimited 151. The-possibility that prostagiandins participate in mediating the sodium retention of cirrhosis is receiving more and more consideration. Obsewations from several studies have raised the possibility that alterations in prostagiandin release may constitute a determinant of the natriuretic reof Medlclne

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sponse to extracellular fluid volume expansion in normal humans [8], suggesting that alterations in renal prostaglandin synthesis may contribute to the derangements in renal sodium handling. Attempts to investigate the role of renal prostaglandins in mediating the sodium retention in cirrhosis have encompassed two manipulations: administration of exogenous prostaglandins, and alteration of the endogenous production of prostaglandins by inhibition of prostaglandin synthesis. Initially, the problem was approached by examining the renal hemodynamic response to the administration of exogenous prostaglandins [9-l 11. Unfortunately, the relevance of such studies in patients with cirrhosis is tenuous, since available studies suggest that any action of prostaglandins on the kidney must be as a local tissue hormone [12]. Thus, any evaluation of the physiologic role of prostaglandins on renal function necessitates an experimental design in which the endogenous production of the lipids is altered. Within the past several years, a number of investigators have demonstrated that the administration of inhibitors of prostaglandin synthetase, both indomethacin and ibuprofen, results in significant decrements in glomerular filtration rate and renal plasma flow in patients with alcoholic liver disease [11,13]. In the study by Boyer et al [I I], indomethacin (200 mg in 24 hours) was administered to 27 patients with alcoholic liver disease. In patients with ascites, indomethacin caused a decrease in para-aminohippurate clearance of up to 67 percent, and a decrease in creatinine clearance of up to 58 percent (Figure 1). Renal function generally returned to basal values within 24 hours after discontinuing indomethacin. It is interesting that in ttie study of Zipser et al [13], the decrement in renal hemodynamics was demonstrated to vary directly with the degree of sodium retention, that is, patients with the greatest sodium retention manifested the largest decrements in glomerular filtration rate. In addition to the increased dependence on renal synthesis of prostaglandins for maintenance of normal renal hemodynamics, the susceptibility of patients with cirrhosis to the nephrotoxic effects of nonsteroidal anti-inflammatory drugs may be amplified by pharmacokinetic changes induced by hepatic dysfunction per se. Since most nonsteroidal anti-inflammatory drugs are eliminated by hepatic metabolism, patients with liver disease might be expected to have an impairment in the disposal of these drugs (see article by Brater elsewhere in this issue). In addition, patients with cirrhosis frequently have decreased plasma albumin concentrations, which could reduce the protein binding of nonsteroidal anti-inflammatory drugs, resulting in higher concentrations of the unbound drug. Thus, patients who are most susceptible to the adverse effects of nonsteroidal anti-inflammatory drugs have insult added to injury by being, in effect, overdosed. Since the studies just cited have examined the effect of inhibiting endogenous production of renal prostaglandins, January

17, 1996

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ASCITES

NO ASCITES

)

FTgure 1. Changes in creatinine clearance

after indomethatin adminisfrafion to patients with alcoholic liver disease. Patients are classified as those with ascites and those without ascites. lndomethacin induced a profound decrease in creatinine clearance in patients with ascites. The differences between each mean creatinine clearance in the ascitic group are significant (p cO.05). Reproduced with permission from (1 I].

it was of great interest to assess an opposite experimental manipulation, one that examined the effects on renal function of augmentation of endogenous prostaglandins [14]. Epstein and associates [8] have utilized water immersion to the neck, an experimental maneuver that redistributes blood volume with concomitant central hypervolemia and enhances prostaglandin E excretion in normal humans. It was demonstrated that decompensated cirrhotic patients manifested an increase in mean prostaglandin E excretion three times greater than that observed in normal subjects studied under identical conditions [14]. This was attended by a marked natriuresis and an increase in creatinine clearance. Furthermore, an examination of the relationship of cumulative prostaglandin E excretion with cumulative sodium excretion during the four-hour immersion period disclosed a significant correlation. Finally, recent studies from our laboratory have assessed the effects of immersion when 6-keto-prostaglandin F,, is used as an index of prostaglandin I2 (prostacyclin) production [15]. Studies in 12 patients with cirrhosis disclosed that immersion induced a marked increase in 6-keto-prostaglandin F,, from a mean of 3.2 & 0.6 ng per minute to a peak of 9.1 2 1.2 ng per minute (p ~0.001). This observation suggests that both vasodilatory prostaglandins may modulate renal function in patients with decompensated cirrhosis. Does the increase in prostaglandin E excretion reflect an increase in prostaglandin E production, or does it merely mirror the immersion-induced increase in urine flow. rate? Several lines of evidence support the formulaThe

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tion that the augmentation of prostaglandin E during immersion reflects an increase in renal prostaglandin E production. Studies in normal subjects undergoing immersion befDre and after indomethacin administration unmasked a striking dissociation between urine flow rates and prostaglandin E excretory rates [a]. Short-term indomethacin administration (50 mg every 6 hours) induced a striking diminution in urinary prostaglandin E excretion despite similar diuretic responses. The demonstration that the suppression of prostaglandin E excretion occurred in the absence of changes in urine flow rates suggests that in the setting of immersion, prostaglandin excretory rates are not solely a reflection of urine flow rates but must in part reflect renal prostaglandin E production. Additional evidence suggesting that prostaglandin excretory rates reflect renal prostaglandin E production is derived from comparisons of the immersion responses of 48

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Figure 2. Effect of water immersion to the neck on creatinine &arance (CcJ and prostaglandin E excretion (UPGEV) in 12 patients with cirrhosis. Shaded area represents the mean + SE for 15 normal subjects undergoing an identical study while receiving an identical diet of 10 meq of sodium and 100 meg of potassium. Data are expressed as the absolute changes from the preimmersion hour (A&J. The immersion-induced increments in creatinine clearance were profound, exceeding those seen in normal subjects. Cessation of immersion (recovery hour) was associated with prompt decrements in creatinine clearance. Concomitant/y, immersion induced marked increments in prostaglandin E excretion and, presumably, renal prostaglandin synthesis.

the cirrhotic patients with those of a group of normal subjects studied previously while ingesting an identical diet of 10 mmol of sodium and 100 mmol of potassium [14]. Despite a similar level of basal prostaglandin E excretion during the prestudy hour, patients with cirrhosis manifested a markedly greater augmentation in prostaglandin E excretion than did the normal subjects (Figure 2). Since the greater increase in prostaglandin E excretion was associated with similar urine flow rates, the current studies strongly suggest that the immersion-induced augmentation in prostaglandin E excretion was not solely attributable to an increase in urinary flow rate but reflected an increase in renal prostaglandin E production. One may inquire whether the augmentation of prostaglandin E excretion and the natrjuresis are causally related and not merely pari passu events. Several lines of evidence are consistent with a causal role for prosta80 (euppl

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glandins. Lianos et al [16] reported that angiotensin II induced a natriuretic response in half of a group of patients with cirrhosis and ascites, and antinatriuretic responses in the remainder. The natriuresis was accompanied by an increase in prostaglandin E2 excretion, whereas the antinatriuresis was associated with a decrease in prostaglandin EP excretion. After partial inhibition of renal prostaglandin synthetase by indomethacin, the angiotensin II-induced natriuretic responses were attenuated or reversed. The demonstration that the natriuretic response of angiotensin II correlates with renal prostaglandin synthesis or release, or both, supports my interpretation that renal prostaglandin E2 production constitutes one of the determinants of renal sodium handling in decompensated cirrhosis. This is consistent with the concept that a diminution in renal prostaglandin E excretion (and presumably in synthesis) contributes to renal sodium retention in patients with decompensated cirrhosis. When interpreted in concert with the earlier studies utilizing prostaglandin synthetase inhibitors [l 1,131, the findings during water immersion suggest that derangements in renal prostaglandin E production contribute to the renal dysfunction of cirrhosis, including sodium retention. Specifically, it is tempting to postulate that, in cirrhosis of the liver, the ability to enhance prostaglandin synthesis constitutes a compensatory or adaptive response to incipient renal ischemia. The corollary of this formulation is that the administration of agents that impair or attenuate such an adaptation might result in a clinically important deterioration of renal function, including sodium retention [2,3]. Additional studies are necessary to characterize further the role of prostaglandins as determinants of the sodium retention in cirrhosis. If this formulation is valid, one may inquire how it can be reconciled with discrepant reports of both elevated and depressed prostaglandin E levels in patients with advanced cirrhosis and sodium retention. Although it has previously been proposed that urinary prostaglandin E excretory levels are elevated in cirrhotic patients with ascites [l 1,131, a review of the available data discloses that this is not necessarily so. As I and my colleagues have noted [14], other investigators have demonstrated urinary excretory levels to be either normal or depressed in patients with advanced cirrhosis [17,18]. In our view, the enhanced prostaglandin E excretory levels in some patients with decompensated cirrhosis should be viewed as an insufficient (and thus a failing) attempt at natriuresis. Patients with “normal” or modestly elevated levels are considered to be unable to mount a sufficient compensatory response; thus, they may be at an even higher risk of renal failure and sodium retention than patients without liver disease who are volume replete. The finding of elevated prostaglandin levels in some patients with decompensated cirrhosis does not militate against the theory that an impairment in a compensatory response of renal prostaglandins contributes to the sodium retention. January

17,1988

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The role of renal prostaglandins as modulators of several aspects of renal function has implications for the management of patients with cirrhosis and sodium retention. A mainstay of managing such patients is the frequent use of diuretics to mobilize excessive extracellular fluid. In the past few years, several investigators have demonstrated that the inhibition of prostaglandins by nonsteroidal anti-inflammatory drugs markedly alters the natriuretic response to such agents. Thus, indomethacin, naproxen, and aspirin blunt the natriuretic and hemodynamic effects of furosemide. More recently, Mirouze et al [19] demonstrated that such effects are not unique to furosemide, since nonsteroidal agents also attenuate the natriuretic response to spironolactone. These observations support the formulation that renal prostaglandins modulate renal function in patients with sodium retention and liver disease. As a clinical caveat, these findings emphasize the importance of avoiding the use of nonsteroidal anti-inflammatory drugs in cirrhotic patients with sodium retention. ALTERED RENAL PROSTAGLANDIN METABOLISM AND DERANGED RENAL WATER HANDLING

Alterations in renal prostaglandins may contribute to the antidiuresis of cirrhosis by several mechanisms [20-221. The overall action of prostaglandins appears to be that of promoting free water excretion, and several different mechanisms have been proposed to account for this effect. These include inhibition of the action of vasopressin in stimulating cyclic adenosine monophosphate and causing a “washout” of medullary interstitial tonicity. Studies by the Barcelona group, as well as studies in our laboratory utilizing the water immersion model, suggest that a relative diminution of renal prostatglandins may contribute to the antidiuresis of cirrhosis [20,23]. It should be emphasized that such a formulation does not necessarily imply an absolute decrease in renal prostaglandins. Rather, a relative deficiency characterized by levels that may be appropriate in absolute terms, but insufficient in light of the marked elevation of vasoconstrictor hormones, may contribute to the pathogenesis of renal water retention [20]. HEPATORENAL

SYNDROME

Several acute azotemic syndromes occur with increased frequency in patients with hepatic and biliary disease [l]. Although acute azotemia often represents classic acute renal failure, patients with cirrhosis may also develop a unique form of renal failure for which a specific cause cannot be elucidated-the hepatorenal syndrome [24,25]. This condition has been designated by many names, including “functional renal failure,” and “the renal failure of cirrhosis,” but the more appealing, albeit less specific, term “hepatorenal syndrome” has been utilized commonly to describe this condition. For the purposes of this discussion, the hepatorenal syndrome may be defined as The American

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Ygure 3. Left: Selective renal arteriogram obtained on i vati with oliguric renal failure and cirrhosis. Note the extreme abnormality of the intrarenal vessels, including the prima9 ranches off the main renal artery and the interlobar arteries. The arcuate and cortical arterial system is not recognizable, nor is a distinct cortical nephrogram present. Arrow indicates the edge of the kidney. Right: Angiogram obtained postmortem on the same kidney with the intra-arterial injection of micropaque in gelatin as the contrast agent. Note filling of the renal arterial system throughout the vascular bed to the periphery of the cortex. The peripheral arterial tree that did not opacify in vivo now fills completely. The vascular attenuation and tortuosity is no longer with permission from 1271. present. The vessels were also histologically normal. Reproduced

the hepatorenal syndrome remains obscure. Many studies utilizing diverse hemodynamic techniques have documented a significant reduction in renal perfusion. Since a similar reduction in renal perfusion is compatible with urine volumes exceeding 1 liter per day in many patients with chronic renal failure, it is unlikely that a reduction in mean blood flow per se is responsible for the encountered oliguria. Our laboratory has applied the xenon 133 washout technique and selective renal arteriography to the study of the hepatorenal syndrome and demonstrated a significant reduction in mean renal blood flow, as well as a preferential reduction in cortical perfusion [27]. In addition, I and co-workers [27] performed simultaneous renal arteriography to delineate further the nature of the hemodynamic abnormalities. Selective renal arteriograms disclosed marked beading and tottuosity of the interlobar and proximal arcuate arteries, and an absence of both distinct cortical nephrograms and vascular filling of the cortical vessels (Figure 3). Postmortem angiography performed on the kidneys of five patients who had been studied while they were still alive, disclosed a striking normalization of the vascular abnormalities, with reversal of all the vascular

unexplained progressive renal failure occurring in patients with liver disease in the absence of clinical, laboratory, or anatomic evidence of other known causes. Patients with this syndrome manifest a rather characteristic urinary excretory pattern, voiding urine that is practically sodiumfree and retaining the capacity to concentrate urine to a modest degree. There is compelling support for the concept that the renal failure in hepatorenal syndrome is functional in nature [26,27& Despite the severe derangement of renal function, pathologic abnormalities are minimal and inconsistent. Furthermore, tubular functional integrity is maintained during renal failure, as manifested by excessive sodium reabsorption and relatively unimpaired concentrating ability. Finally, more direct evidence is derived from studies entailing the transplantation of the kidneys and livers of patients with hepatorenal syndrome. The demonstration that kidneys removed at the time of death and transplanted from patients with hepatorenal syndrome are capable of resuming normal function in a recipient with a normal liver [26] emphasizes the functional nature of the derangement. Despite extensive study, the precise pathogenesis of 60

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abnormalities in the kidneys (Figure 3). The peripheral vasculature filled completely, and the previously irregular vessels became smooth and regular. These findings provide additional strong evidence for the functional basis of the renal failure operating through active renal vasoconstriction. Although renal hypoperfusion with preferential renal cortical ischemia has been shown to underlie the renal failure of the hepatorenal syndrome [27], the factors responsible for sustaining reduction in cortical perfusion and for suppression of filtration in the hepatorenal syndrome have not been elucidated. Increasing evidence suggests that prostaglandins participate in mediating the renal failure of cirrhosis. Studies conducted by Zipser et al [28] disclosed that prostaglandin E2 levels were decreased in patients with hepatorenal syndrome. These investigators compared prostaglandin excretory rates in 14 patients with hepatorenal syndrome to rates in patients with acute renal failure (both nonoliguric and oliguric) and with chronic renal failure, as well as to rates in patients with alcoholic hepatitis and cirrhosis with ascites. Patients with hepatorenal syndrome consistently excreted very little prostaglandin EP, 2.2 ? 0.3 ng per hour, compared with fluid-restricted normal subjects, 8.2 + 1.2 ng per hour (p
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4. Comparison of the effects of water immersion on renal prostaglandin E (UP,&) and renal water handling (V) between patients with alcoholic liver disease and six normal subjects (shaded areas), previously reported [8]. Cirrhotic patients manifested a markedly greater increase in renal prostaglandin E than did normal subjects. An examination of the changes in urine flow rate (lower panel) disclosed that peak renal water handling was virtually identical in the two study populations during the period of maximal prostaglandin E excretion (Hour 2). Results are reported as means + SE and significance (p values) of differences are indicated. Reproduced with permission from [14].

striction of the hepatorenal syndrome. Urinary excretion of prostaglandin E2 and thromboxane B2 (the nonenzymatic metabolite of thromboxane A,,,)were measured in 14 patients with hepatorenal syndrome. Although prostaglandin E2 levels were decreased in comparison with those of healthy control subjects and patients with acute renal failure, it was observed that thromboxane B2 levels were markedly elevated. The investigators interpreted their data to suggest that an imbalance between vasodilator and vasoconstrictor metabolites of arachidonic acid contributes to the pathogenesis of the hepatorenal syndrome. Additional studies are needed to confirm such alterations. Of interest is a recent attempt to modify the course of

Studies conducted by Zipser et al [28] suggest that the ratio of the vasodilator prostaglandin E2 to the vasoconstrictor thromboxane A2, rather than the absolute levels of prostaglandin EP, may modulate the renal vasocon17,1986

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nearly four times that of controls. The implications of such findings should be considered in prescribing sulindac to patients with hepatic disease.

hepatorenal syndrome by administration of selective inhibitors of thromboxane synthesis [30]. Whereas nonspecific cyclooxygenase inhibitors, such as indomethacin and aspirin, reduce both thromboxane and prostaglandin synthesis to varying degrees in different biologic systems, selective inhibitors of thromboxane synthesis preserve or possibly increase the production of other metabolites of arachidonic acid, such as the potent vasodilator prostacyclin [31]. Zipser et al [30] administered the thromboxane synthetase inhibitor dazoxiben to patients with alcoholic hepatitis and progressive azotemia. Although administration of dazoxiben reduced the urinary excretion of the thromboxane metabolite thromboxane B2 by approximately 50 percent, prostaglandin E2 and 6-keto-prostaglandin F,, were essentially unaltered. Despite a reduction in thromboxane excretion, there was no consistent reversal of the progressive renal deterioration [30]. Unfortunately, in most of the patients, disease had progressed to an advanced degree and they may not have been capable of responding to therapeutic interventions. Additional studies with selective thromboxane inhibitors in patients with widely varying degrees of acute renal insufficiency will be required to establish definitively the role of thromboxane A2 as a major determinant of the renal vasoconstriction in hepatorenal syndrome.

DO NONSTEROIDAL ANTI-INFLAMMATORY DRUGS DIFFER IN THEIR RENAL EFFECTS IN PATIENTS WITH LIVER DISEASE?

Recently, it has been suggested that sulindac differs from other nonsteroidal anti-inflammatory drugs by sparing renal but inhibiting systemic prostaglandins [33]. This is reflected in the lack of an effect on urinary prostaglandin EP excretion and on other putative end points of renal prostaglandin synthesis, such as renin release and response to furosemide, whereas inhibition of systemic prostaglandins is reflected by the decreased production of thromboxane by platelets (see article by Brater elsewhere in this issue). Ciabottoni et al [33] compared one week of treatment with 1.2 g per day of ibuprofen to 400 mg per day of sulindac in a large group of women with chronic glomerular diseases. Sulindac did not affect urinary excretion of prostaglandin E2 or 6-keto-prostaglandin F,,, or cause renal function to deteriorate; however, serum thromboxane B2 decreased 85 percent. In contrast, ibuprofen caused approximately 80 percent decreases in both urinary prostaglandins, a 30 percent decrease in the creatinine clearance and a 35 percent decrease in the clearance of para-aminohippurate. In a recent study in normal subjects, Brater et al [34] demonstrated that sulindac did not differ from ibuprofen in its ability to decrease urinary prostaglandin E2 and that both decreased the pharmacodynamics of response to furosemide. In light of these disparate findings, studies in patients with cirrhosis and ascites are needed. Recently, Daskalopoulos et al [35] compared the effects of sulindac and indomethacin on furosemide-induced augmentation of prostaglandin E2 and renal sodium, and on water handling. Although only indomethacin reduced creatinine clearance, urinary volume, sodium, and prostaglandin E2 before administration of furosemide, these differences were virtually abolished after furosemide administration. That is, indomethacin appeared only slightly more potent in reducing the diuresis (55 percent versus 38 percent), natriuresis (67 percent versus 52 percent), and prostaglandin E2 release (81 percent versus 74 percent). Thus, under conditions of furosemide-enhanced prostaglandin activity, sulindac does affect renal function. To the extent that the ability to augment renal prostaglandin synthesis constitutes an important adaptive response in disorders characterized by decreased renal perfusion, the observations of Daskalopoulos et al [35] merit attention. It would appear that additional studies are necessary in order to define the differences between sulindac, on the one hand, and indomethacin and ibuprofen in patients with cirrhosis, both under basal conditions and during maneuvers that

ALTERED PHARMACOKINETICS OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS IN LIVER DISEASE

Drug metabolism may be influenced by the functional capabilities of the liver. Changes in hepatic blood flow or in bile secretion, as well as direct damage to the cellular organelles responsible for biochemical alterations of drugs, are potential sources of altered kinetics in persons with liver disease. Recent studies have indicated that liver disease per se may alter the metabolism and pharmacokinetics of some nonsteroidal anti-inflammatory drugs. Juhl et al [32] observed that ibuprofen follows a relatively straightforward metabolic pathway. Approximately 60 to 90 percent of the drug is excreted in the urine as metabolites or their conjugates. In contrast, the complex metabolism of sulindac is responsible for altered kinetics of the drug. Sulindac is a pro-drug that is inactive itself and relies on reduction to the sulfide metabolite for its biologic activity. Reformation of the parent compound, conversion to an inactive sulfone derivative, and enterohepatic recirculation of all three forms of the drug complicate the metabolic pathway of sulindac. Juhl et al [32] demonstrated that in patients with severe liver disease, there is delayed activation of sulindac and reduced conversion to inactive products. Thus, plasma concentration of the active sulfide is maximal about eight hours after an oral dose of sulindac in patients with liver disease, compared with about two hours in healthy subjects. Nonetheless, plasma levels of the active sulfide are

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alter (that is, augment) renal prostaglandin production. Do these data imply that sulindac is indeed renal sparing, even for patients with decompensated cirrhosis? It would appear that a definitive answer cannot yet be offered. The renal-sparing effect of sulindac may simply reflect the fact that common clinical doses are at the low end of the dose-response curve in terms of inhibition of renal prostaglandins, whereas relatively higher doses of other nonsteroidal anti-inflammatory drugs are used. Furthermore, different disease states, including advanced liver disease, may manifest different susceptibilities to the inhibition of prostaglandin synthesis. Thus, not only may different nonsteroidal anti-inflammatory drugs have different potencies, but also different sites of prostaglandin synthesis. For example, renal interstitium, vascular endothelium, and platelets probably have differing sensitivities to prostaglandin inhibition. Large doses of any nonsteroidal antiinflammatory drug will probably inhibit all prostaglandins, whereas differences among drugs will become manifest at lower doses and in different disease states. Additional studies are necessary to address this important issue. EXPERIMENTAL

MODELS

In an attempt to define further the role of renal prostaglandins in mediating the renal abnormalities of liver disease, several investigators have resorted to the use of animal models. Prominent among these is the model of chronic ligation of the bile duct. Ligation of the canine bile duct causes hepatic alterations consistent with obstructive jaundice and early biliary cirrhosis with portal hypertension [36]. Renal vasoconstriction appears to be present in rats, baboons, and rabbits with chronic ligation of the bile duct. Some, but not all, observers have documented a decrease in glomerular filtration rate in dogs with chronic ligation of the bile duct. Zambraski and Dunn [37) were the first to examine prostaglandin excretory rates in an animal model of liver disease. They observed increases in prostaglandin EP, prostaglandin F&, and 6-keto-prostaglandin F,, excretion rates after chronic ligation of the bile duct, by approximately 100,80, and 500 percent, respectively. In contrast, prostaglandin excretion rates were unchanged in shamligated animals. Sequential measurements of urine prostaglandins in six dogs indicated that prostaglandin E2 and 6-keto-prostaglandin F,, excretion were significantly increased at two, four, and six weeks after ligation, whereas the increase in prostaglandin FPaexcretion was not significant until six weeks. Levy et al [38] studied dogs with chronic ligation of the bile duct and documented significant reductions in glomerular filtration rate and renal plasma flow after administration of indomethacin (2 mg/kg), regardless of the presence of ascites, but dependent on portal hypertension. Collectively, these data demonstrate that, in dogs with

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experimental liver disease produced by chronic bile duct ligation, renal prostaglandin synthesis is increased. They suggest that the enhanced synthesis of vasodilatory prostaglandins serves to maintain renal blood flow and glomerular filtration rate. Experimental models of liver disease have also been utilized to examine the effects of nonsteroidal anti-inflammatory drugs in hepatic disorders. To test the hypothesis that sulindac may be renal sparing, Zambraski et al [39] administered the active form of the drug, sulindac sulfide (5 mg/kg intravenously) to four sham-ligated dogs and four dogs with chronic ligation of the bile duct. In both groups of animals, sulindac sulfide caused a 60 to 90 percent reduction in prostaglandin Fp, prostaglandin F&, and 6-keto-prostaglandin F,, excretion rates. In the same animals, subsequent treatment with another cyclooxygenase inhibitor, naproxen (10 mg/kg, intravenously), did not result in any further decrease in prostaglandin E2 or prostaglandin Fti excretion but did decrease 6-keto-prostaglandin F,, excretion. In the animals with chronic ligation of the bile duct, sulindac sulfide treatment decreased renal plasma flow, glomerular filtration rate, and urine volume and resulted in the urinary excretion of large amounts of the sulindac sulfide. Similar changes in prostaglandin excretion and in renal function were observed in animals with chronic ligation of the bile duct treated solely with naproxen (10 mg/kg intravenously) or with ibuprofen (20 mg/kg intravenously). Thus, these studies demonstrate that in either normal animals or in animals with liver dysfunction produced by chronic ligation of the bile duct, both sulindac sulfide and sulfoxide administered intravenously decrease renal prostaglandin synthesis. In animals with chronic ligation of the bile duct the changes in renal hemodynamics and in water and electrolyte excretion with sulindac treatment were similar to those observed with other nonsteroidaj antiinflammatory compounds. It is possible that the apparent renal-sparing effect of sulindac sulfoxide in humans may be dependent on oral administration with less rapid increments in plasma sulindac sulfide, thereby allowing more efficient renal oxidation of sulfide to sulfoxide.

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The available data suggest that alterations in renal prostaglandin metabolism participate in the pathogenesis of at least three prominent renal complications of liver disease; sodium retention, impaired renal diluting ability, and the hepatorenal syndrome. Although the data are highly suggestive, additional studies will be required to establish the role of prostaglandins in mediating these renal abnormalities. These would include experimental manipulations that augment vasodilatory prostaglandins while diminishing vasoconstrictor metabolites of arachidonic acid. The clinical caveat emerging from these observations is that drugs

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inhibition of crucial prostaglandin functions by the use of nonsteroidal anti-inflammatory drugs may eventuate in excessive salt and water retention and acute renal insuff iciency.

that possess cyclooxygenase inhibitory activity should not be prescribed for patients with decompensated liver disbask who are sodium retentive. Finally, recent evidence indicates that the alterations in renal function associated with cirrhosis of the liver are not unique but may be associated with a wide range of disease states characterized by diminished effective \iolume, including congestive heart failure and nephrotic syndrome. In these conditions,

ACKNOWLEDGE&&NT

I am indebted to Gilda Manicourt for her expert preparation of the manuscript.

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Epstein M, ed. The kidney in liver disease, ed 2. New York: Elsevier, 1983. Epstein M, Lifschitz M: Volume status as a determinant of the influence of renal PGE on renal function. Nephron 1980; 25: 157-159. Clive DM, Stoff JS: Renal syndromes associated with non-steroidal anti-inflammatory drugs. N Engi J Med 1984; 310: 583-572. Epsiein M: Deranged sodium homeostasis in cirrhosis. Gastroenterology 1979; 76: 622-835. Epstein M: Renal sodium handling in cirrhosis. in: Epstein M, e@ The kidney in liver disease, ed 2. New York: Elsevier, 1983; 35-53. Klingler EL Jr, Vaamonde CA, Vaamonde LS, et al: Renal function changes iti cirrhosis of the liver. Arch Intern Med 1970; 125: 1016-1015. Gabuzda GJ: Cirrhosis, ascites, and edema. Clinical course related to management. Gastroenterology 1970; 58: 546-553. Epstein M, Lifschitz M, Hoffman DS, et al: Relationship between renal prostaglandin E and renal sodium handling during water immersion in normal man. Circ Res 1979; 45: 71-80. Arieff Al, Chidsey CA: Renal function in cirrhosis and the effects bf prostaglandin A,. Am J Med 1974; 56: 695-703. Zusman RM, Axelrod L, Tolkoff-Rubin N: The treatment of the hepatorenal syndrome with intrarenal administration of prostaglandin E. Prostaglandins 1977; 13: 819-830. Bayer TD, Zia P, Reynolds TB: Effect of indomethacin and prostaglandin At on renal function and plasma renin activity in alcoholic liver disease. Gastroenterology 1979; 77: 215-222. McGiff JC, ltskovitz HD: Prostaglandins and the kidney. Circ Res 1973; 33: 479-488. Zipser RD, Hoefs JC, Speckarl PF, et al: Prostaglandins. J Clin Endocripoi Metab 1979; 48: 895-900. Epstein M, Lifschitz M, Ramachandran M, et al: Characterization of renal PGE responsiveness in decompensated cirrhosis. Clin Sci 1982; 63: 555-563. Epstein M, Lifschitz M; Larios 0: Dissociation of renin from prostaglandins in patients with cirrhosis. Kidney Int 1983; 23: 277. Lianos EA, Aivai N, Tobin M, et al: Angiotensin-induced sodium excretion patterns in cirrhosis. Kidney Int 1982; 21: 70-77. Wernze H, Muller G, Goehrig M: Relationship between urinary prostaglandin (PGEp and PGF,) and sodium excretion in various stages of chronic liver disease. Adv Prostagiandin Thromboxane Res 1980; 7: 1089-1096. Robhe J, Chambaz EM, Hostein J, et al: Role des prostaglandines PGEz dans I’insuffisance ienale fonctionelle de la cirrhose. Nouv Presse Med 1980; 9: 2259-2260. Mirouze b, Zipser RD, Reynolds TB: Effect of inhibitors of prostagiandin synthesis on induced diuresis in cirrhosis. Hepatoiogy 1983; 3: 50-55. Epstein M: Derangements of renal water handling in liver disease. Gastroenterology 1985; 89: 1415-1425. Gross PA, Schrier RW, Anderson RJ: Prostagiandins and water metabolism. Kidney Int 1981; 19: 839-858. Stokes JB: Integrated actions of renal medullary prostaglandins in the control of water excretion. Am J Physioll981; 9: F471-

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F480. Perez Ayuso RM, Arroyo V, Camps J, et al: Evidence that renal prostaglandins are involved in renal water metabolism in cirrhosis. Kidney Int 1984; 26: 72-80. Papper S: Hepatorenal syndrome. In: Epstein M, ed.: The kidney in liver disease, ed 2. New York: Elsevier, 1983; 87-106. Shear L, Kleinerman J, Gabuzda GJ: Renal failure in patients with cirrhosis of the liver. Am J Med 1985; 39: 184-198. Koppel MH, Cobum JW, Mims MM, et al: Transplantation of cadaveric kidneys from patients with hepatorenal syndrome. Evidence for the functional nature of renal failure in advanced liver disease. N Engl J Med 1989; 280: 1367-1371. Epstein M, Berk DP, Hollenberg NK, et al: Renal failure in the patient with cirrhosis. Am J Med 1970; 49: 175-185. Zipser RD, Radvan GH, Kronborg KJ, et al: Urinary thromboxane B2 and prostagiandin E2 in the hepatorenal syndrome. Gastroenterology 1983; 84: 697-703. Arroyo V, Planas R, Gaya J, et al: Sympathetic nervous activity, renin-angiotensiri system, and renal excretion of prostaglandins E2 in cirrhosis. Eur J Ciin Invest 1983; 13: 271-278. Zipser RD, Kronborg I, Rector W, et al: Therapeutic trial of thromboxane synthesis inhibition in the hepatorenal syndrome. Gastroenterology 1984; 87: 1228-l 232. Tyler HM, Saxton CAPD, Parry MJ: Administration to man of UK-38248, a selective inhibitor of thromboxane synthetase. Lancet 1981; I: 629-632. Juhl RP, Van Thiei DH, Dittert LW, et al: Ibuprofen and suiindac kinetics in alcoholic liver disease. Clin Pharmacol Ther 1983; 34: 104-109. Ciabattoni G, Cinotti GA, Pierucci A, et al: Effects of sulindac and ibuprofen in patients with chronic glomerular disease. Evidence for the dependence of renal function on prostacyclin. N Engl J Med 1984; 310: 279-283. Brater DC, Anderson S, Baird B, et al: Effects of ibuprofen, naproxen, and sulindac on prostaglandins in men. Kidriey Int 1985; 27: 86-73. Daskalopoulos G, Kronborg I, Katkov, et al: Sulindac and indomethacin suppress the diuretic action of furosemide in patients with cirrhosis and ascites: evidence that sulindac affects renal prostaglandins. Am J Kidney Dis 1985; 8: 217221. Better OS: Bile duct ligation: an experimental model of renal dysfunction secondary to liver disease. In: Epstein M, ed. The kidney in liver disease, ed 2. New York: Elsevier, 1983; 295311. Zambraski EJ, Dunn MJ: Importance of renal prostaglandins in control of renal function after chronic ligation of the common bile duct ih dogs. J Lab Clin Med 1984; 103: 549-559. Levy M, Wexler MJ, Fechner C: Renal perfusion in dogs with experimental hepatic cirrhosis: role of prostaglandins. Am J Physiol 1983; 245: F521 -F529. Zambraski EJ, Chremos AN, Dunn MJ: Comparison of the effects of suiindac with other cyclooxygenase inhibitors on prostaglandin excretion and renal function in normal and chronic bile duct-ligated dogs and swine. J Pharmacol Exp Therap 1984; 228: 560-566.

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AND THE KIDNEY-EPSTEIN

gerate the effects of the nonsteroidal anti-inflammatory drug. If we give aspirin to patients with cirrhosis, there is no decrease in glomerular filtration rate; however, we still block the effect of furosemide and of spironolactrone. If we give them sulindac, we get similar results even though, at least in our hands, it appears to be a relatively weak cyclooxygenase inhibitor. When given concomitantly with furosemide, sulindac most profoundly blocks the natriuretic and diuretic responses. Perhaps patients with cirrhosis and ascites who receive diuretics or who are on sodium-restricted diets are the most sensitive to these nonsteroidal agents. Dr. Dunn: Dr. Epstein, you showed that immersion augments glomerular filtration rate in about half of your patients with cirrhosis. Such increments are striking and difficult to achieve with other maneuvers. Have you prevented the increase in glomerular filtration rate by prior administration of a cyclooxygenase inhibitor? Dr. Epstein: That is precisely what we are currently attempting to do. We have just initiated a major study with the following sequential studies: immersion without drug, followed several days later by immersion with ibuprofen administration, and several days later, immersion with sulindac pretreatment. We are attempting to ascertain two major questions: whether we can attentuate or prevent the augmentation in glomerular filtration rate with the cyclooxygenase inhibitor and whether there are relative differences between the two cyclooxygenase inhibitors. Dr. Zipser: Have you ever immersed a patient with the hepatorenal syndrome? Dr. Epstein: We have not, although we would like to. We never encountered a patient who was sufficiently stable with regard to absence of asterixis or gastrointestinal bleeding at the time that we would want to undertake immersion. Dr. Morrison: Was there any suggestion that the immersed individuals who responded with the largest increment in glomerular filtration rate had the lowest initial (basal) glomerular filtration rate? Dr. Epstein: The preliminary answer is no. To our surprise, someone whose basal glomerular filtration rate is 120 to 140 ml per minute is just as apt to have an increase to 200 ml per minute as is the patient with a basal rate of 60 ml per minute. When we correlated the basal glomerular filtration rate versus the subsequent change in the glomerular filtration rate there was no correlation. Indeed, some of the most striking increments in creatinine clearance, 60 or 70 ml per minute, were observed in patients whose basal glomerular filtration rate was 130 ml per minute. We have not yet completed the analysis of these data.

Dr. Dunn: The issue about ascites as a risk factor for nonsteroidal anti-inflammatory drug nephrotoxicity seems indisputable. However, I wonder whether we can state that a patient without ascites will not have a decrement in renal function when nonsteroidal anti-inflammatory drugs are administered. That is certainly what Boyer and Reynolds stated in their article and possibly what Zipser believes. In our animal studies with bile duct ligation and early biliary cirrhosis [37], only about half the animals had ascites, and we could not distinguish between the adverse effects that the nonsteroidal anti-inflammatory drugs had on the renal function of the ascitic group and the effects they had on the nonascitic group. Although we did not directly measure portal pressure, we presume all dogs had portal hypertension. I would therefore be concerned about using a nonsteroidal anti-inflammatory agent in patients with significant portal hypertension, even in the absence of overt ascites. Dr. Zipser: Is 6-keto-prostaglandin F,, a better index of susceptibility to nonsteroidal anti-inflammatory drugs in liver disease than prostaglandin E? Dr. Dunn: Let me first reinforce the concept that urinary prostaglandins originate from diverse parts of the kidney. The major urinary prostaglandin, prostaglandin EP,comes from the medulla, which has little to do with the control of cortical events, glomerular filtration rate, and renal blood flow, factors that we measure and worry about in patients receiving a nonsteroidal anti-inflammatory drug. Although prostacyclin can be synthesized by the medulla of the human kidney in vitro, it is undoubtedly derived mostly from the cortex and particularly from cortical vasculature when measured in the urine. Perhaps it is a better predictor of renal eicosanoid production than prostaglandin E. However, animal work in areas such as sodium depletion give us insight into what to predict clinically in patients with cirrhosis and ascites, and into their susceptibility to these nonsteroidal agents. Blasingham and Nasjletti (Am J Physiol 1980; 239: F360-F365) found that animals can be rendered susceptible to nonsteroidal anti-inflammatory drugs by sodium depletion despite the absence of changes in urinary prostaglandins. The lesson, at least for me, is that the kidney can be prostaglandin dependent without large changes in the urinary level of prostaglandins. Patients with cirrhosis are clearly prostaglandin dependent, as defined by decreases in glomerular filtration rate induced by nonsteroidal agents, even if urinary levels of prostaglandin E2 or 6-keto-prostaglandin F,, do not change. Dr. Zipser: In our experience, diuretics unmask or exag-

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