Hepatorenal Syndrome: Emerging Perspectives of Pathophysiology and Therapy1

Murray Epstein2

proaches lend a note of optimism to the future man- M. Epstein, Nephrology Section, Department of Vet- agement of a syndrome that is so often incompatible erans Affairs Medical Center and Division of Nephrol- with recovery. These include the acceptance of or- ogy, University of Miami School of Medicine, Miami, FL thotopic liver transplantation as definitive treatment (J. Am. Soc. Nephrol. 1994; 4:1735-1753) for patients with end-stage liver disease and attempts to improve renal function by countervailing the decreases in systemic vascular resistance while minimizing concomitant increments in renal vascular ABSTRACT resistance. Hopefully, ongoing and future clinical Progressive oliguric renal failure (designated TMhepa- trials will establish the precise contribution of each torenai syndrome”) commonly complicates the of these treatment modalities and their respective course of patients with advanced hepatic disease. roles in the therapeutic armamentarium. Despite the severe derangement of renal function Key Words: Oliguric renal failure. cirrhosis. endothelin. nitric and ominous prognosis when renal failure develops, oxide. hepatic transplantation minimal and inconsistent pathologic abnormalities ofthe kidneys are found at autopsy. Furthermore, the he hepatorenal syndrome (HRS) is a unique form kidneys, if transplanted, are capable of normal func- T of acute renal failure occurring in patients with tion, which supports the conceptthatthe renal failure liver disease for which a specific cause cannot be Is functional and potentially reversible. in contrast to elucidated. Despite the intense clinical and investi- patients with classical acute failure (ATN), hepato- gative interest that this syndrome has stimulated, renal syndrome patients manifest characteristic al- until recently, relatively little progress had been terations of renal function including (1) relatively made in the understanding and management of this hyperosmolar urine; (2) high creatinine urine:plasma syndrome. The past several years have witnessed ratio, and (3) a very low urine sodium concentration newer insights in both the pathophysiology and ther- (<10 mEq/L). The past several years have witnessed apeutics of this syndrome. The application of newer newer insights into both the pathophysiology and the methodology such as tracer kinetics has more rigor- therapeutics of this syndrome. The application of ously delineated the role of a number of pathogenic mechanisms, including activation of the sympathetic newer methodology such as tracer kinetics has more nervous system. The characterization of endothelin rigorously delineated the role of a number of patho- and the nitric oxide (NO)-arginine pathway and their genic mechanisms including activation of the sym- roles in biology and medicine has provided additional pathetic nervous system. The characterization of en- new insights with regard to the pathogenesis of HRS. dothelin and the nitric oxide-arginine pathway and Finally, recently initiated therapeutic approaches their roles in biology and medicine has provided lend a note of optimism to the future management of additional new insights with regard to the pathogen- a syndrome that is so often incompatible with recov- esis of hepatorenal syndrome. For example, nitric ery. oxide has been proposed to constitute a mediator It is not my intent to compile an exhaustive survey of both the hyperdynamic circulation and renal of the pathophysiology and therapeutics of the HRS. Rather, emphasis will be on selective issues that I failure. Finally, recently initiated therapeutic ap- believe are timely and have recently attracted increased attention and Investigative interest. Rcelved March 29, 1993. Accepted August 10, 1993. 2Corr#{149}spondence to Dr. M. Epstetn. Nephrology 5ection, vA Medical Center. 1201 NW 16th Street, Miami, FL 33125. CLINICAL FEATURES f046-6673/0410-1735$03.00/O Progressive oliguric renal failure commonly com- Journal of the American Society of Nephrology Copyright © 1994 by the American Society of Nephrology plicates the course of advanced hepatic disease (1 -

Journal of the American Society of Nephrology 1735 Hepatorenal Syndrome

4). Although this condition has been designated by tional in nature. Despite the severe derangement of many names-including “functional renal failure,” renal function, pathologic abnormalities are minimal “hemodynamic renal failure,” “hepatic nephropathy,” and inconsistent (1 ,4,9). Furthermore, tubular func- the “renal failure of cirrhosis,” and others-the more tional integrity is maintained during the renal failure, appealing, albeit less specific, term “HRS” is the most as manifested by a relatively unimpaired sodium commonly used. For the purpose of this discussion, reabsorptive capacity and concentrating ability. Fi- HRS is defined as unexplained renal failure occurring nally, more direct evidence is derived ( 1 ) from the In patients with liver disease in the absence of clini- demonstration that kidneys transplanted from pa- cal, laboratory, or anatomic evidence of other known tients with HRS are capable of resuming normal causes of renal failure. function In the recipient (1 0) and (2) by the return of The clinical features of HRS have been detailed in renal function when the patient with HRS success- several recent reviews (1-4). In brief, HRS usually fully receives a liver transplant (1 1). occurs in cirrhotic patients who are alcoholic, a!- Despite extensive study, the precise pathogenesis though cirrhosis is not a sine qua non for the deve!- of HRS has not been delineated. Many studies using opment of HRS. HRS may complicate other liver dis- diverse hemodynamic techniques have documented eases, including acute hepatitis, fulminant hepatic a significant reduction in renal perfusion (12-14). failure, and hepatic malignancy (5-7). Although Because a similar decrement of renal perfusion is renal failure may develop in patients In whom norma! compatible with urine volumes exceeding 1 L in many serum creatinine levels have been previously docu- patients with chronic renal failure, it is unlikely that mented within a few days of the onset of HRS, this a decrease in mean blood flow per se is responsible does not imply that these patients had a normal GFR. for the encountered oliguria (15). The serum creatinine level has been shown to be a Our laboratory applied the ‘33Xe washout tech- poor index of renal function in patients with chronic nique and selective renal arteriography to the study liver disease, often masking markedly reduced GFR of HRS and demonstrated a significant reduction in (7). Implicit in such a formulation is the concept that calculated mean blood flow as well as a preferential HRS patients may have a low GFR for weeks to reduction in cortical perfusion (1 3). In addition, cir- months before coming to medical attention. We are rhotic patients manifested marked vasomotor insta- therefore dealing with kidneys that are almost cer- bility that was characterized not only by variability tainly susceptible to further insult by hemodynamic between serial xenon washout studies but also by or other stimuli. instability within a single curve (1 3). This phenome- Numerous reports have emphasized the develop- non has not been encountered in renal failure of ment of renal failure after events that reduce effec- other causes. In addition, Epstein and coworkers (13) tive blood volume, including abdominal paracentesis, performed simultaneous renal arteriography to delin- vigorous diuretic therapy, and gastrointestinal bleed- eate further the nature of the hemodynamic abnor- ing, although renal failure can occur in the absence malitles. Selective renal arteriograms disclosed of an apparent precipitating event. In this context, marked beading and tortuosity of the interlobar and several careful observers have noted that HRS pa- proximal arcuate arteries and an absence of distinct tients seldom arrive in the hospital with preexisting cortical nephrograms and vascular filling of the cor- renal failure; rather, HRS seems to develop in the tical vessels (Figure 1A). Postmortem angiography hospital, indicating that iatrogenic events in the hos- performed on the kidneys of five patients studied pital might precipitate this syndrome (1,4). during life disclosed a striking normalization of the The development of renal failure in the course of vascular abnormalities with a reversal of all of the La#{235}nnec’s cirrhosis is of grave prognostic signifi- vascular abnormalities in the kidneys (Figure 1B). cance (1,4,8). The majority of patients die within 3 The peripheral vasculature filled completely, and the wk of the onset of azotemia. Despite the bleak prog- previously irregular vessels became smooth and reg- nosis, it is difficult to attribute the poor outcome ular. These findings provide additional evidence for directly to renal failure in patients in whom azotemia the functional basis of the renal failure, operating is moderate. Such observations suggest that the renal through active renal vasoconstriction (13). failure may be more of a reflection of a broader lethal Although renal hypoperfusion with preferential event and that, in most instances, it is not in itself renal cortical ischemia has been shown to underlie the major determinant of survival. A truly uremic the renal failure of HRS (13,16), the factors respon- death is a rarity. sible for sustaining reduction in cortical perfusion and suppression of filtration in HRS have not been elucidated. A consideration of the pathogenetic PATHOGENESIS events leading to the intrarenal hemodynamic de- A substantial body of evidence lends strong support rangement and the decrease in GFR is simplified by to the concept that the renal failure in HRS is func- a consideration of the “afferent” and “efferent” events

1736 Volume 4’ Number 10’ 1994 Epstein

Figure 1. (Left panel) A selective renal arteriogram carried out in a patient with oliguric renal failure and cirrhosis (1.1.). Note the extreme abnormality of the intrarenal vessels, including the primary branches off of the main renal artery and the interlobar arteries. The arcuate and cortical arterial system is not recognizable, nor is a distinct cortical nephrogram present. The arrow indicates the edge of the kidney. (Right panel) Angiogram of the same kidney carried out postmortem with the intro-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 attentuation and tortuosity are no longer present. The vessels were also histologically normal (reproduced with permission from reference 13).

that lead to this derangement. The discussion of in stimulating volume receptors. The concept is afferent events will include a consideration of the somewhat elusive because the actual volume recep- extracellular fluid translocations or sequestration tors remain incompletely defined. A diminished ef- into serous spaces or interstitial fluid compartments fective volume may reflect subtle alterations in sys- that characterize advanced liver disease. The section temic hemodynamic factors such as decreased filling considering efferent events will encompass a survey of the arterial tree, a diminished central blood vol- of the hormonal and neural mechanisms proposed or ume, or both. Despite massive retention of salt and implicated in the pathogenesis of the renal failure. water, effective blood volume remains functionally Emphasis will be placed on recent studies character- contracted because of a disturbance in the Starling izing the sympathetic nervous system, renal throm- forces, which govern the distribution of fluid within boxanes (Tx), (NO)-arginine pathway, and the possi- the extracellular fluid compartment. ble contribution of endothelin. The mechanisms contributing to the appearance of a diminished effective volume are multiple. Tradi- tionally. it has been proposed that ascites formation Afferent Events in cirrhotic patients begins when a critical imbalance Traditionally, it has been proposed that a contrac- of Starling forces in the hepatic sinusoids and tion of the “effective” blood volume constitutes a splanchnic capillaries causes an excessive amount pivotal event in patients Deing predisposed to HRS of lymph formation, exceeding the capacity of the (1-4,17-19). In this context, it is important to note thoracic duct to return this excessive lymph to the that the term “effective plasma volume” refers to that circulation (1,17-19). Consequently, excess lymph part of the total circulating volume that is effective accumulates in the peritoneal space as ascites, with

Journal of the American Society of Nephrology 1737 Hepatorenal Syndrome

a subsequent contraction of circulating plasma vol- the most extreme elevations of vasoactive hormones, ume. Thus, as ascites develops, there is a progressive including PRA, norepinephrine (NE), and vasopres- redistribution of plasma volume. sin, and the most extreme degree of renal vasocon- Although an imbalance of Starling forces in the striction (21). hepatosplanchnic microcirculation is thought to con- Overflow Theory. An alternative hypothesis to the tribute importantly to the relative decrease in effec- two underfill theories is the overflow theory of ascites tive blood volume, it should be emphasized that this formation (22,24). In contrast to the underfill for- Is not the sole mechanism. An additional determi- mulation, the overflow theory postulates that the nant is the significant diminution of total peripheral initial primary event is the inappropriate retention resistance in most patients with cirrhosis who are of excessive amounts of sodium by the kidneys, un- retaining sodium and water (20,21). This decrease in related to defense of the plasma volume (and thought peripheral vascular resistance is no doubt partially to be due to intrahepatic hypertension). In the setting related to anatomical arteriovenous shunts, and pos- of abnormal Starling forces in the portal venous bed sibly to some undefined vasodilator (either produced and hepatic sinusoids (both portal venous hyperten- by or not inactivated by the diseased liver). Thus, sion and a reduction in plasma colloid osmotic pres- despite an increase in total plasma volume, the rela- sure), the expanded plasma volume is sequestered tive “fullness” of the arteriovenous tree is diminished. preferentially in the peritoneal space, with resultant In summary. several hemodynamic events act in con- ascites formation. Thus, renal sodium retention and cert to diminish effective volume, thereby activating plasma volume expansion precede rather than Jot- the mechanisms promoting a decrease in renal per- tow the formation of ascites. fusion and GFR. Regardless of cause, the resultant In summary, both underfill theories provide a pos- diminution of effective volume is thought to consti- sible explanation of why fluid retention often fails to tute an afferent signal to the renal tubule to augment attenuate both the stimulus for neurohormonal ac- salt and water reabsorption and to decrease GFR. tivation and the continuing sodium and water reten- Thus, the traditional underfill formulation suggests tion. Despite a progressive increase in total extracel- that the renal retention of sodium is a secondary lular fluid volume, fluid is sequestered into one or rather than a primary event. more of the other fluid compartments without suc- Peripheral Arterial Vasodilation Theory (Revised ceeding in normalizing effective blood volume. Be- Underfill Theory). The principal distinguishing fea- cause the capacity of the interstitial fluid and its ture of a newly proposed revision of the underfill associated spaces, for example, the peritoneum, is theory is that the decrease in effective blood volume largely limitless, the kidneys encounter great diffi- is attributable primarily to an early occurring in- culty in filling such a space and the sodium retention crease in vascular capacitance (2 1 ). Thus, peripheral becomes relentless. Only correction of the disturb- vasodilation is the initial determinant of intravascu- ance in the forces governing fluid distribution and lax underfilling, and an imbalance between the ex- reversing the peripheral arterial vasodilation will per- panded capacitance and available volume constitutes mit a reexpansion of effective blood volume to nor- a diminished effective volume. This concept brings ma!. Importantly, the peripheral arterial vasodilation the hypothesis into accord with some experimental theory highlights the florid systemic hemodynamic observations that were not consistent with the origi- disturbances and the importance of attempting to nal postulate. For example, recent careful balance correct not only the renal hemodynamic disturbances studies in animals with experimental cirrhosis have but the concomitant systemic hemodynamic de- clearly shown that sodium retention precedes ascites rangements as well. formation (22). An alternate formulation has emphasized that the Primary systemic hemodynamic changes charac- renal vasoconstriction is attributable to unique terized by peripheral vasodilation occur very early in events independent of a contracted volume, i.e., a experimental cirrhosis and in humans with compen- primary cause. According to this theory, advanced sated cirrhosis (20,22,23). The decrease in effective liver damage, in conjunction with some other un- volume induced by these hemodynamic alterations is known abnormality, induces a primary disorder in compounded further by an impaired pressor response one or more of the modifiers that regulate renal vas- to vasoactive agents, including exogenous angioten- cular tone. The renal ischemia, it is argued, is not an sin II and noradrenaline (4,21). Even in those pa- expression of the normal neural and hormonal re- tients who eventually develop an increase in total sponse to liver damage but rather represents either plasma volume, the relative “fullness” of the arterio- an alteration in the synthesis, degradation, or po- venous tree is decreased. tency of a vasoactive substance or a malfunction of According to the peripheral arterial vasodilation the normal feedback regulation of its release. Such hypothesis, the HRS constitutes an extreme exten- abnormalities might result from impaired hepatic sion of underfilling of the arterial circulation, with degradative or excretory capacity, portasystemic

1738 Volume 4 - Number 10 - 1994 Epstein

shunting of blood, or altered neural connections be- TABLE I . Known and postulated mechanisms that tween the liver and the kidney. may contribute to the renal failure of liver disease Although many investigators have focused on a Hormonal contraction of effective arterial blood volume (EABV) Activation of the renin-angiotensin system as a major etiologic factor in the pathogenesis of HRS, Alterations in renal eicosanoids there is lack of unanimity on this point. Some au- Diminished vasodilatory prostaglandins thors have proposed that because a diminished EABV increased vasoconstrictor Tx causes the typical syndrome of prerenal failure (eas- Enhanced NO production ily reversible with volume replacement) sometimes Elevated plasma endothelin levels leading to ATN, it cannot be considered as the pre- Endotoxemia potent etiologic factor for HRS. Although I agree that Relative impairment of renal kallikrein production because HRS is primarily a syndrome induced by a Diminished atrial natriuretic peptides unique cause for renal ischemia not necessitating a Vasoactive intestinal peptide contracted EABV, a contributory role for a contracted Glomerulopressin deficiency Neural and Hemodynamic EABV need not be excluded. Rather, it is tempting to An increase in sympathetic nervous system activity postulate that a contracted EABV or the concomitant Alterations in intrarenal blood flow distribution activation of neurohormonal mediators that attend such hypovolemia amplifies the renal vasoconstric- tive effects of the putative, as yet undefined, media- tion and plasma renin levels has disclosed that cir- tors. Indeed, because the majority of studies have rhotic patients with impaired renal function mani- reported that a reduction of EABV is a typical feature fested the most profound elevations in plasma renin of patients with HRS, this alteration in volume status levels. Although the elevation of plasma renin is may be a necessary but not sufficient factor predis- attributable in part to the decreased hepatic macti- posing patients to HRS. vation of renin, it is evident that the major determi- An alternate formulation to reconcile the presence nant is increased renin secretion by the kidney. It is of contracted EABV in both prerenal azotemia and noteworthy that the elevation of plasma renin often HRS posits that they represent differences in degree occurs despite diminished hepatic synthesis of the and occupy disparate points on a continuum (21). a2 globulin, renin substrate (25). Conceivably, patients with moderate contraction of There are at least two reasonable explanations for EABV develop prerenal azotemia, which is reversible the increased renin secretion in cirrhosis. First, it is by volume repletion. With advancing liver disease, possible that renal hypoperfusion may be the pri- the magnitude of the contraction becomes greater mary event, with a resultant activation of the renin- and at some point is no longer reversible by volume- angiotensmn system. Alternatively, activation of the expansive maneuvers. Presumably at this point, we renin-angiotensmn system may be a secondary re- are facing the transition from prerenal azotemia to sponse to a diminished effective blood volume. HRS. The observations of Barnardo et at. (29) have been interpreted as supporting the former hypothesis. Those authors infused dopamine into 1 0 patients Efferent Events whose cirrhosis was associated with various degrees The effectors that promote renal ischemia and a of renal functional impairment. Dopamine caused a decrease in GFR remain incompletely defined. Sev- consistent increase in effective RPF but little change eral major hypotheses have been implicated or sug- in GFR or sodium and water excretion. Concomi- gested, including: (1) alterations of the renin-angio- tantly, dopamine suppressed PRA. One might object tensin system; (2) an increase in sympathetic that increases in arterial pressure or cardiac output nervous system activity; (3) alterations in renal occurring during dopamine administration could con- eicosanoids, including a relative decrease in renal found the interpretation of the results. Such a pos- vasodilatory prostaglandins and an increase in vas- sibility did not pertain to this study, however, be- oconstrictor Tx; (4) enhanced NO production with cause dopammne was administered in subpressor peripheral vasodilation; (5) elevated plasma endothe- doses and the changes in cardiac output were slight lin levels; (6) a relative impairment of renal kallikrein and inconsistent. Furthermore, it has been shown production; and (7) endotoxemia (Table 1). previously that dopamine given intravenously to nor- Renin-Angiotensin System. Several lines of evi- mal subjects or directly into the renal artery of nor- dence suggest a role for the renin-angiotensin axis in mal dogs does not reduce PRA (29). It is therefore sustaining the vasoconstriction in HRS (25). Patients unlikely that dopammne reduced renin secretion by with decompensated cirrhosis frequently manifest directly affecting the juxtaglomerular apparatus. marked elevations of plasma renin levels (25-29). An Rather, the ability of dopammne to reduce PRA is most examination of the relationship between renal func- probably attributable to its ability to increase pri-

Journal of the American Society of Nephrology 1739 Hepatorenal Syndrome

manly RPF. In summary, the authors interpreted angiotensin as a determinant of the state of the renal their findings as indicating that the increased PRA vasculature (see reference 37). Unfortunately, at- of cirrhosis is secondary to the impaired renal per- tempts to block the renin-angiotensin system in cir- fusion, rather than being its cause (29). rhotic humans have been complicated by a striking Regardless of mechanism(s), the activation of the fall in blood pressure and by the intrinsic activity of renin-angiotensin system has profound implications the partial agonists in use, which may have blunted for renal function. In light of compelling experimen- the influence on GFR (35,36). The synthesis of more tal evidence that angiotensin plays an important role specific angiotensin antagonists that may act pref- in the control of the renal circulation (30), it is tempt- erentially at the level of the renal vascular bed with- ing to speculate that enhanced angiotensin levels out inducing concomitant hypotension may contrib- contribute to the renal vasoconstriction and the re- ute to the further characterization of the pathogen- duction in filtration rate seen in the renal failure in esis of HRS (37). cirrhosis. Observations by Cade et at. (3 1 ) have un- Role of Renal Prostaglandins. Alterations of renal derscored the role of angiotensmn II in mediating the prostaglandins also participate in mediating the reduction in renal perfusion and GFR in patients renal failure of cirrhosis. Attempts to investigate the with HRS. The Infusion of angiotensin II caused a role of renal prostaglandmns in modulating renal marked reduction of RPF and GFR, with a marked hemodynamics and mediating the sodium retention increase in filtration fraction. in cirrhosis have encompassed two manipulations: In addition to activation of the renin-angiotensin (1 ) the administration of exogenous prostaglandins system, attention has focused on the possibility that and (2) the alteration of the endogenous production the depletion of renin substrate may be the principal of prostaglandins by the inhibition of prostaglandin etiologic factor for the hemodynamic abnormalities synthesis. Initially, the problem was approached by that accompany HRS (32,33). Iwatsuki et at. (11) examining the renal hemodynamic response to the demonstrated that renin substrate levels rose signif- administration of exogenous prostaglandins (38). Un- icantly after hepatic transplantation and preceded fortunately, the relevance of such studies in cirrhotic the improvement in renal function by several days. humans is tenuous because any action of prostaglan- Subsequently, Berkowitz et at. (33) infused renin dins on the kidney must be as a local tissue hormone substrate-rich fresh frozen plasma into two patients (39). Thus, any evaluation of the physiologic role of with HRS and noted a prompt increase in creatinine prostaglandmns in renal function necessitates an ex- clearance and urine output coincident with a signif- perimental design in which the endogenous produc- icant rise in renin substrate and in the suppression tion of the lipids is altered. of peripheral renin concentration (34). After the ter- Several investigators have demonstrated that the mination of the infusion, both urine flow and creat- administration of inhibitors of prostaglandmn synthe- mine clearance decreased progressively over the next tase (both indomethacin and ibuprofen) resulted in 5 days as renin substrate concentrations declined significant decrements in GFR and effective RPF in toward premnfusion levels. patients with alcoholic liver disease and ascites Cade et at. (3 1 ) have extended these observations. (40,41). Of interest, the decrement in renal hemody- Those investigators administered either 750 mL of namics varied directly with the degree of sodium

stored plasma or 750 mL of fresh frozen plasma in retention, i.e. , the patients with the most avid sodium random order on successive days. The infusion of retention manifested the largest decrements in GFR fresh frozen plasma improved function more than (41-43). did stored plasma and in addition returned a very low Because the above-cited studies have examined the filtration fraction toward normal. Plasma renin sub- effect of inhibiting the endogenous production of strate concentration was uniformly low and was in- renal prostaglandmns, it was of great interest to assess creased by an infusion of fresh frozen plasma. Arte- an opposite experimental manipulation, i.e., assess- rial blood pressure, initially low, was improved by ing the effects of the augmentation of endogenous the infusion of stored plasma but increased far more prostaglandmns on renal function. Epstein and asso- when fresh frozen plasma was infused. The low fil- ciates (44) have used water immersion to the neck, tration fraction observed in all of their patients was an experimental maneuver that redistributes blood depressed even more by expansion with stored volume with concomitant central hypervolemia and plasma but returned toward normal when fresh fro- enhances prostaglandin E (PGE) excretion in normal zen plasma was infused (31). Only additional studies humans. They demonstrated that decompensated will establish the significance of these provocative cirrhotic patients manifested an increase in mean observations. PGE excretion that was threefold greater than that The availability of pharmacologic agents that in- observed in normal subjects studied under identical terrupt the renin-angiotensin axis has suggested a conditions (45). This was attended by a marked na- possible approach for defining further the role of triuresis and an increase in creatinine clearance.

1740 Volume 4’ Number 10 - 1994 Epstein

When interpreted in concert with the earlier studies Rimola et at. (49) speculated that the discrepancy using prostaglandin synthetase inhibitors, these between their own findings and those of Zipser et at. findings suggest that derangements in renal PGE (48) might have been attributable to differences in production contribute to the renal dysfunction of the patient population. Rimola et at. (49) studied cirrhosis. Specifically, it is tempting to postulate that, patients with moderate impairment of hepatic and in the setting of cirrhosis of the liver, the ability to renal function, whereas the patients in the studies enhance prostaglandin synthesis constitutes a com- of Zipser et at. (48) had hepatic failure and severe pensatory or adaptive response to incipient renal renal insufficiency. Additional studies will be re- ischemia. The corollary of this formulation is that quired to assess alterations in the differing eicosa- the administration of agents that impair such an noids with progressive renal functional impairment. adaptation can induce a clinically important deteri- In light of the above findings suggesting that oration of renal function. thromboxanes may contribute to the development of The above findings are not isolated observations. HRS, there have been attempts to modify the course As I have noted (43), one may conceive of renal of HRS by the administration of selective inhibitors prostaglandins as constituting critical modulators of of thromboxane synthesis and thromboxane receptor renal function during conditions or disease states antagonists (50-52). As detailed on page 13, such involving volume contraction. The demonstration interventions either have been negative or have that synthetase inhibition affected renal function failed to substantively augment GFR. Additional only in decompensated (presence of ascites and/or studies with thromboxane receptor antagonists in edema) and not in compensated cirrhotic subjects patients with widely varying degrees of acute renal and that the effects of synthetase inhibition vary as insufficiency will be required to further define the a function of the degree of renal sodium avidity is role of TxA2 as a major determinant of the renal consistent with this formulation (42,43). vasoconstriction in HRS. Additional studies have suggested that alterations Increase in Sympathetic Nervous System Activ- of thromboxanes may contribute to the renal dys- ity. An increase in sympathetic nervous system ac- function. Thromboxane A2 (TxA2), a potent proaggre- tivity also contributes to the renal failure of cirrhosis. gatory and vasoconstrictor substance, is synthesized It is now well established that alterations of the input by platelets and a large number of other cell types of cardiopulmonary receptors induce changes in and tissues, including the kidney (46,47). Renal TxA2 renal sympathetic activity (53-56). Thus, a decrease production is thought to be involved in the regulation in effective blood volume is sensed as a decrease in of glomerular hemodynamics by acting on glomerular left atrial pressure (the sensor of the low-pressure capillary filtration surface area (46,47) and by mod- vascular system). This “unloads” the left atrial me- ulating the tone of afferent and efferent arterioles chanoreceptors, which in turn discharge into affer- (47). It has been proposed that the ratio of the vaso- ent vagal fibers that have appropriate central nerv- dilator PGE2 to the vasoconstrictor prostaglandin ous system representation. As a consequence, effer-

TxA2, i.e. , E2/TxA2, rather than absolute levels of ent renal sympathetic nerve activity is augmented PGE2, may determine the degree of renal vasocon- (54,55,57). Such an increase in sympathetic tone striction of HRS. Zipser et at. (48) determined the would tend to produce renal vasoconstriction and urinary excretion of POE2 and TxB2 (the nonenzy- decrease GFR. matic metabolite of TxA2) in 1 4 patients with HRS. Although these theoretical considerations suggest They observed that, whereas PGE2 levels were de- a role for the sympathetic nervous system in the renal creased in comparison with those of healthy controls vasoconstriction and sodium retention of cirrhosis, as well as those of patients with acute renal failure, only recently have studies been conducted to test this TxB2 levels were markedly elevated. The authors in- possibility. Studies to assess the activity of the sym- terpreted their data to suggest that an imbalance of pathetic nervous system in cirrhotic humans have vasodilator and vasoconstrictor metabolites of ara- measured plasma catecholamine levels during basal chidonic acid contribute to the pathogenesis of HRS. conditions and after postural manipulations (55,57- It should be noted, however, that the findings of 62). Most observers agree that mean peripheral NE others of an increase in TxB2 are somewhat different. levels are elevated in cirrhotic patients (59-62): Ring- Rimola et at. (49) studied 18 normal subjects, 49 Larsen et at. (59) have determined plasma NE and cirrhotic patients with ascites (but without renal fail- epinephrine concentrations in differing vascular ure), and 20 patients with HRS. Cirrhotic patients beds of cirrhotic patients at the time of hepatic ve- without HRS had a significantly higher urinary ex- nous catheterization. On the basis of differences in cretion of 6-keto-PGF1a, TxB2, and PGE than did regional NE levels, they concluded that the elevated normal subjects. Patients with HRS failed to manifest NE levels in patients with cirrhosis were attributable increases in urinary PGE2, 6-keto-PGF1,, and TxB2; to enhanced sympathetic nervous system activity this is in contrast to the findings of Zipser et at. (48). rather than to decreased metabolism.

Journal of the American Society of Nephrology 1741 Hepatorenal Syndrome ... .. ,.

As detailed in several recent reviews (63-65), how- patients with chronic liver disease, its role in contrib- ever, the plasma concentrations of NE are an made- uttng to the development of renal failure is unclear. quate guide to either total or regional sympathetic Attempts to correlate the occurrence of renal failure activity. Global measures of sympathetic activity, with the presence of endotoxemia are conflicting. On such as plasma NE measurements, fail to identify the one hand, Clemente et at. (68) observed endotox- sources of NE release and cannot delineate regional emia in 9 of 22 patients with HRS, but not in cirrhotic patterns of sympathetic nervous activation. Re- patients with a normal GFR. On the other hand, cently, Esler et at. (65) have conducted a physiologic Gatta et at. (69) demonstrated that in patients with and neurochemical evaluation of patients with cir- cirrhosis without overt renal failure, renal vasocon- rhosis, applying tracer kinetic techniques using ra- striction did not seem to be related to endotoxemia. diolabeled NE, thereby allowing a more precise de- Coratelli et at. (70) have observed two patients scription of the regional pattern of the sympathetic before and after the development of HRS and dem- nervous derangement in cirrhosis. They demon- onstrated the appearance of endotoxemia coincident strated that the elevated plasma NE concentration in with the development of HRS. patients with cirrhosis is attributable to higher over- Despite the ostensible appeal of this hypothesis, all rates of spillover of the neurotransmitter to much additional study is required for its confirma- plasma and not to reduced plasma clearance caused tion. As has been pointed out in several reviews by liver disease. The administration of clonidine re- (66,67), the limulus tests for endotoxin have varia- duced previously elevated NE overflow rates for the tions, and their individual accuracy is controversial. whole body including kidneys, and hepatomesenteric A correlation with renal failure in cirrhosis may re- circulation. This sympathetic inhibition was accom- flect the retention of endotoxins rather than a causal panied by several potentially clinically beneficial ef- relationship of endotoxins to HRS (67). fects: the lowering of renal vascular resistance. an NO. A more recent approach to the investigation of augmentation of GFR, and the reduction of portal the pathogenesis of the HRS has focused on the florid venous pressure (65). systemic hemodynamic disturbances that invariably In summary, the available data indicate that the accompany the syndrome. These include a hyperdy- sympathetic nervous system is activated in cirrhosis, namic circulation, increased heart rate and cardiac both In the kidney and in other regional vascular output, and decreased blood pressure and systemic

beds, consequently contributing to the renal vasocon- vascular resistance (4 , 20-22). These observations striction and sodium retention of cirrhosis (57,65). have suggested the likelihood of excess production of

Endotoxins. Systemic endotoxemia may partici- a vasodilator (7 1 ). A number of vasodilators have pate in the pathogenesis of the renal failure of cir- been postulated, including prostacyclin, bradykinmn, rhosis. Endotoxins, the lipopolysaccharide constitu- substance P, and atrial natriuretic peptide, but clear ents of the cell wall of certain bacteria, are potent evidence of involvement of any of them is lacking renal vasoconstrictors (66). It has been hypothesized (4,7 1). that enteric endotoxin is liberated into the systemic Recently, attention has focused on the role of NO circulation through naturally or surgically created as a mediator of both the hyperdynamic circulation portosystemic shunts, thus bypassing the hepatic and renal failure (72). NO, a vasodilator synthesized Kupffer cells, the major site of endotoxin removal. from L-argmnine, accounts for the biologic activity of Recent studies have measured endotoxin by the lim- endothelium-derived relaxing factor (73,74). In ani- ulus lysate technique and have reported that endo- mals, the agonist-induced release of NO from the toxin is present in the portal and systemic circulation vascular endothelium leads to peripheral vasodila- of many cirrhotic patients, particularly those with tion, a fall in blood pressure, and tachycardia (75,76). ascites. Because several investigators have demon- These effects are short lived, however, and vascular strated a high frequency of positive limulus assays tone returns to normal once the agonist infusion is in cirrhotic patients with renal failure but not in stopped. On the other hand, there is a second, dis- those without renal failure, endotoxins may contrib- tinct, inducible NO synthase that occurs in response ute to the pathogenesis of the renal failure. Endotox- to bacterial lipopolysaccharide endotoxin (77). Once emia is appealing as a possible humoral agent not induced, this enzyme releases NO for many hours only because it may cause renal vasoconstriction, without the need for further stimulation. but also because it may produce vasodilation in other The in vitro incubation of vascular rings with endo- circulatory beds and may be a treatable condition toxin or cytokines leads to the induction of NO syn- (66,67). Indeed, Valiance and Moncada (see reference thase in both the endothelium and the smooth muscle 72) have proposed that endotoxemia induces nitric and to progressive vascular relaxation with dimin- oxide synthase in peripheral blood vessels with re- ished responsiveness to vasoconstrictors (78,79). sultant vasodilation (vide infra). When induced by endotoxin, these effects can be Although endotoxemia is frequently observed in prevented by cycloheximide (an inhibitor of protein

1742 Volume 4 - Number 10 - 1994 . .... -.. . . - Epstein

synthesis), poiymyxin B (an antagonist of endotoxin), 1 was directly correlated to serum creatinine (r = and NGmonomethylLarginine (an inhibitor of NO -0.58; P < 0.003). In patients who underwent liven

synthase) (77,78). Once NO synthase is induced and vein catheterization (N = 8), no significant differ- the vascular rings are relaxed, however, only NG ences were found in endothelin-1 plasma concentra- monomethyi-L-arginine will reverse these changes tions between the liver, renal, on femonal veins on (78). On the basis of these considerations, Valiance the one hand and the femoral artery on the other (P

and Moncada (72) have postulated that endotoxemia > 0. 1 ). indicating no major net elimination on release Induces a NO synthase in peripheral blood vessels in the liver, kidney, or lower limb. and that this increased NO synthesis and release Role of Biologically Active Atrial Peptides. An- accounts for the associated hyperdynamic circula- other hormone that should be included in any con- tion. If this hypothesis is correct. the inhibition of sideration of the pathogenetic mechanisms of HRS is NO synthesis should restore sensitivity to vasocon- atnial natriuretic factor (ANF) or atniopeptin. Since strictors and reverse these hemodynamic abnormal- the demonstration by DeBold et at. (83) in 1981 that Ities. Specific inhibitors of either the constitutive or saline extracts of rat heart atria, but not ventricles, the inducible NO synthase theoretically should facil- caused a marked natriuresis and diuresis when in- itate a more precise manipulation of NO synthesis jected Into normal rats, there has been much interest and help to establish the pathophysiologic impor- in the role of ANF as a mediator of volume homeosta- tance of NO in endotoxemia and cirrhosis. sis. Micropunctune studies in rats have shown that In a recent preliminary communication, those in- ANF, given by either bolus injection or continuous vestigators reported that serum nitrite and nitrate infusion, causes a significant increase in GFR levels, an index of NO production. were elevated in a (84,85), as well as natriuresis and diuresis (86). group of cirrhotic patients (80). The patients with Because ANF has thus been shown to be of impon- ascites manifested higher nitrite and nitrate levels tance In volume homeostasis and because volume than did cirrhotic patients without ascites. Further- homeostasis is of critical importance in patients with more, there was a direct correlation between serum cirrhosis and portal hypertension, a number of in- nitrite and nitrate levels and endotoxemia. Additional vestigators have sought a role for ANF In severe studies will be required to substantiate this hypoth- hepatic disease. esis. Despite proposals that ANF deficiency may contrib- Endothelin. Recently, Moore et at. (8 1 ) have sug- ute to the renal dysfunction of liver disease, the gested the possibility that alterations in endothelin available data fall to support this formulation. Most may play a pathogenetic role in the renal failure of investigators have found immunoreactive ANF levels the HRS. They reported that patients with the HRS in plasma to be either normal (87,88) or increased had markedly elevated plasma endothelin- 1 and en- (89,90) in cirrhotic patients with ascites. Morgan et dothelin-3 concentrations compared with normal at. (91) compared circulating ANF levels In seven subjects, patients having acute or chronic renal fail- patients with HRS and seven patients with advanced ure, and patients with liver disease without renal alcoholic liver disease and ascltes but normal serum dysfunction. Those investigators interpreted their re- creatinine levels. They demonstrated that ANF levels suits to support the hypothesis that these substances were twofold higher in the patients with HRS, mdi- play a role In the pathogenesis of the HRS. As I have catmng that a deficiency of ANF does not contribute noted in a recent editorial, it Is equally possible if not to the renal failure. probable that the results merely represent pan passu events (82). Thus, elevated plasma endothelin concentrations might be attributable to decreased renal disposal of endothelin. Additional studies are re- ACUTE RENAL FAILURE (ATN) quired to assess further the pathogenetic role of en- Although much attention has been directed to HRS, dothelin concentrations in this syndrome. it should be borne in mind that cirrhotic patients are Moller et at. (81a) confirmed and extended these as vulnerable as noncirrhotic patients to the devel- earlier observations. They characterized concentra- opment of ATN. Among liver disease patients in tions of endothelin- 1 in various vascular beds includ- whom renal failure developed, the etiology of renal Ing the hepatic artery/vein, the right renal artery/ failure Is more commonly ATN than HRS (1-4). The vein, and the right femoral artery/vein and related increased frequency of ATN may relate to the hypo- the findings to clinical status and hemodynamic al- tension, bleeding dyscrasias, infection, and multiple terations. Median brachial venous endothelin- 1 con- metabolic disorders that complicate the clinical centrations were substantially higher in patients course of these patients. There have been several

with cirrhosis (3.40 pg/mL; range, 1.25 to 7.84; N = attempts to develop diagnostic tests to reliably dis- 24) than in controls (1.53 pg/mL, range, 0.78 to 2.12; crimInate between acute renal failure and HRS (92-

N = 11) (P < 0.00005). In patients with cirrhosis, ET- 96). To date, these tests, which rely on enzymuria or

Journal of the American Society of Nephrology 1743 Hepatorenal Syndrome

electrolyte excretory patterns, are often suggestive as a “pseudohepatorenal” syndrome. Furthermore, as but lack sufficient selectivity to be reliable. already emphasized, it is not uncommon for patients with alcoholic cirrhosis to develop classic acute renal HRS Versus ATN: Different Diseases or a failure (ATN). In many instances, the differentiation Continuum? from HRS can be made readily by recognition of the precipitating event and by characteristic laboratory Renal function In HRS is fundamentally different findings. Table 2 lists laboratory features that are from that in ATN. In ATN, the reduction in GFR is helpful in differentiating the three principal causes generally much more severe, and the accompanying of acute azotemia in patients with liver disease. The decrease in tubular reabsorption is generally re- most uniform urinary finding of HRS patients is a garded as evidence of intrinsic tubular dysfunction. strikingly low sodium concentration, usually less In HRS, on the other hand, the reduction in GFR is than 1 0 mEq/L and occasionally as low as 2 to 5 usually not as severe, and the avid tubular reabsorp- mEq/L. Unfortunately, prerenal azotemia is associ- tion of sodium and water attests to normal intrinsic ated with similar low urinary sodium concentrations. tubular function, which appears to be responding to In contrast, patients with oligunic ATN frequently extrinsic stimuli. have urinary sodium concentrations exceeding 30 It Is immediately evident to the experienced clini- mEq/L, and usually even higher. clan that “patients don’t necessarily read textbooks.” Although avid renal sodium retention is evident in Often, the urinary indices are confusing and fall in the majority of patients with HRS, occasional pa- the “grey zone,” which spans the different presenta- tients with HRS have been recognized in whom the tions of HRS and ATN (see Differential Diagnosis, urinary sodium concentration [UNaI is consistently below). Furthermore, patients with HRS often de- greater than 1 0 mEq/L. In some of these patients. velop classic ATN as their condition deteriorates. tUNa) is initially low but increases to levels of approx- Although rigorous data are lacking, I believe that the imately 40 mEq/L as renal impairment progresses; it HRS can evolve into ATN, and in many cases, the has been suggested that this late increase in urinary natural history appears to be a continuum between sodium concentration may represent the possible the two. In terms of management, however, it is often transition to ATN. Other patients have been recog- confusing to be faced with a pattern of renal function nized in whom HRS has developed and progressed in that does not clearly fit into the categories outlined the presence of a [UNaJ persistently in the range of 20 above. Under these circumstances, the only practical to 30 mEq/L (1,4). approach is to consider the patient as being “pre- Both HRS and prerenal azotemia manifest well- renal” and search diligently for the reversible causes maintained urinary concentrating ability character- of prerenal azotemia. ized by a urine-to-plasma osmolality ratio exceeding 1.0, whereas ATN patients excrete a relatively iso- Differential Diagnosis osmotic urine (i.e., urine that is neither concentrated The abrupt onset of oliguria in a cirrhotic patient nor dilute). The urine-to-plasma creatinine ratio is does not necessarily imply the presence of HRS. Pre- greater than 30 (and at times 40:1) in both prerenal renal causes are important to differentiate, particu- failure and HRS. whereas the urine-to-plasma cre- larly because they constitute reversible conditions if atinine ratio is 20:1 or less in ATN. Proteinunia is recognized and treated in the incipient phase. Vol- absent or minimal in HRS. ume contraction or cardiac pump failure may appear In summary, the finding of a low urinary sodium

TABLE 2. Differential diagnosis of acute azotemia in the patient with liver disease: important differential urinary findings0

. Acute Renal Failure Prerenal Azotemia HRS (ATN)

Urine Sodium Concentration (mEq/L) <10 <10 >30b Urine-to-Plasma Creatinine Ratio >30:1 >30:1 <20:1 Urine Osmolaiity At least 200 mOsm> At least 200 mOsm> Relatively similar to plasma osmolality plasma osmoiality plasma osmolality Urine Sediment Normal Unremarkable Casts, cellular debris

o The numbers cited in the table are arbitrary and are meant to highlight the salient differences in these three diagnostic categories. However, the values vary. As an example. UNa occasionally may exceed 10 mEq/L. Padiocontrast agents and sepsis may lower urinary sodium concentration in the patient with ATN. When urinary output is very low, the concentration of sodium may rise. Urinary sodium levels may also rise when vasoconstriction is so severe that ATN sets in.

1744 Volume 4’ Number 10 1994 - . . .., . ., .,,- Epstein

concentration in the presence of oliguric acute renal hypovolemic. I recommend that the expanders be failure usually precludes the diagnosis of ATN. Only infused in a setting in which the alteration of clinical when prerenal failure and ATN are excluded can one status (blood pressure, urine flow rate, creatinine establish the diagnosis of HRS. clearance), as well as central hemodynamics (central venous pressure ICVPI), data derived from Swan- TREATMENT Ganz catheter) is monitored. Furthermore, it should be stressed that it is usually the change in CVP that General Considerations often is important rather than the absolute level, i.e., The management of the HRS has been discourag- although a CVP reading may not be extremely low, it ing in view of the absence of any reproducible, effec- may not change (increase) until large amounts of tive treatment modality. Because knowledge about expanders are administered. Such guidelines do not the pathogenesis of HRS is inferential and incom- presuppose that there is a correlation between cen- plete, therapy to this time has been supportive. Be- tral hemodynamics and the volume deficit. Rather, cause iatrogenic events often precipitate this syn- we use manometric determinations as a guideline to drome and because therapy is difficult once the syn- assist in assessing when to discontinue volume cx- drome is established, prevention constitutes the pansion so as to avoid overt fluid overload. Of note, linchpin of management. volume expansion carries with it the risk of opening The initial step in the management of a cirrhotic up fragile esophageal varices with secondary bleed- patient with acutely reduced renal function is to not ing, although in my experience, this is an infrequent equate decreased renal function with HRS, but rather occurrence. to search diligently for and treat correctable causes of azotemia such as volume contraction, cardiac de- Basic Management compensation, and urinary tract obstruction. The Once correctable causes of renal functional im- diagnosis of ATN (acute intrinsic renal failure) should pairment are excluded, the mainstay of the therapy clearly be considered because ATN occurs commonly for HRS to prevent clinical deterioration is careful in cirrhotic patients and they may be expected to restriction of sodium and fluid intake. A number of recover if supported with dialytic therapy. specific therapeutic measures have been attempted, Although we commonly invoke the caveat of pri- but only a few have proved to be of practical value. mum non nocere, it now takes on greater meaning in Attempts at volume expansion with different agents the HRS patient. As noted previously, it is well estab- have resulted in only transient improvement in renal lished that nonsteroidal anti-inflammatory drugs, hemodynamics without significant alteration of the which inhibit prostaglandin synthetase activity, outcome. Similarly, attempts at reinfusion of concen- often adversely influence renal function in the pa- trated ascitic fluid have not provided any lasting tient with liver disease and ascites (40,41 ,43). Simi- Improvement. Major new approaches that have at- larly, the broad-spectrum antibiotic demeclocycline tracted investigative attention and may possibly war- may induce acute azotemia in the patient with cir- rant future considerations will be enumerated. rhosis and ascites (97,98). Finally, we should recog- nize that drugs that may be indicated for the man- PARACENTESIS agement of complications of liver disease (i.e. , lac- tulose for the treatment of hepatic encephalopathy) The role of paracentesis in the treatment of HRS, are capable of inducing profound hypovolemia (sec- with or without simultaneous plasma volume expan- ondary to diarrhea) with resultant azotemia. sion, has not been established. The potential renal In excluding reversible prerenal azotemia, there are benefit of a reduction of ascitic fluid volume includes several management considerations. Because HRS diminished intra-abdominal pressure with possible and prerenal azotemia have similar urinary diagnos- relief of inferior vena caval obstruction and augmen- tic indices, one must often use a functional maneu- tation of cardiac output. Improvement in renal func- ver, i.e., the administration of volume expanders, to tion, when it occurs, is transient, because the abnor- differentiate between the two entities. In this regard, mal hydraulic pressures that sustain ascites forma- it should be underscored that our frame of reference tion are not altered by paracentesis. Continued fluid for the cirrhotic patient may be quite different from removal is necessary and may result in the progres- that pertaining to other disease states. The degree of sive depletion of intravascular volume with subse- volume expansion necessary to replete the cirrhotic quent deterioration in cardiac function and renal patient may at times be marked, occasionally requir- perfusion. Nevertheless, over the past several years, ing the infusion of massive amounts of colloid. the Barcelona group has marshaled evidence that There is no defined regimen that allows one to paracentesis may induce a more favorable renal ex- predict the amount of volume expanders necessary cretory and hormonal response than was previously to replete the cirrhotic patient suspected of being thought (99-102).

Journal of the American Society of Nephrology 1745 Hepatorenal Syndrome

DIALYSIS the central compartment is replenished despite de- creasing ascites. Unfortunately, although there have Dialysis was previously reported to be ineffective been a few well-documented “successes” ( 1 09, 1 1 1), in the management of HRS ( 1 03, 1 04). Our own recent the majority of reports have been anecdotal with experience, however, suggests that such a sweeping insufficient details to allow critical assessment. Even condemnation should be qualified ( 1 05). Although where sufficient data were available, we must con- most of the published literature indeed suggests a dude that the majority of putative “successes” oc- dismal prognosis for patients who are dialyzed, such curred in patients who were not clearly documented early reports have dealt with patients with chronic to have HRS; rather, many patients probably had end-stage liver disease. In a few instances, we have reversible azotemia secondary to a diminished effec- undertaken dialysis in HRS patients with acute he- tive blood volume (1 1 0, 1 1 1). patic disease and have been gratified by the ultimate Only two prospective, randomized studies of the favorable outcome. Our experience suggests that in role of the PVS in the treatment of HRS have been selected patients, i.e. , those with acute hepatic dys- performed ( 1 1 2, 1 1 3). Linas et at. ( 1 1 2) prospectively function in whom there is reason to believe that the compared the effects of the PV shunting (N = 1 0) or renal failure may reverse coincident with the reso- medical therapy (N = 1 0) on renal function and mor- lution of the acute hepatic insult, dialytic therapy is tality in 20 patients with the HRS associated with indicated. alcoholic liver disease. After 48 to 72 h, body weight With the recent maturation and refinement of or- and serum creatinine were increased with medical thotopic liver transplantation and its acceptance as therapy and decreased (from 3.6 ± 0.4 to 3.0 ± 0.5 the treatment of choice for end-stage liver disease, mg/dL; P < 0.05) in patients with the shunt. Despite dialysis has assumed an important ancillary role. the improvement of renal function, only one patient Dialysis is now widely used as a supportive measure with the PVS had a prolonged survival (2 1 0 days). In in the management of many patients awaiting liver the remainder, survival was 1 3.8 ± 2.2 days com- transplantation. pared with 4. 1 ± 0.6 days with medical therapy. The In addition to stabilizing renal function, it is often investigators concluded that, whereas PV shunting necessary to remove fluid, either to prevent life- often stabilizes renal function, it does not prolong threatening emergencies such as acute pulmonary life in patients with the HRS. Additional studies are edema or to permit the administration of requisite fluids such as bicarbonate solutions or hyperalimen- currently under way in HRS patients with less advanced disease. tation. Although hemodialysis often constitutes the therapeutic modality of choice for this purpose, it is In the VA Cooperative Study ( 1 1 3), although there not feasible in many patients with severe liver dis- were 7 long-term survivors in a group of 1 4 patients treated with PVS, the results were not statistically ease who have associated hemodynamic instability. significant when compared with those of a group of Unfortunately, patients with decompensated cirrho- 1 9 patients undergoing medical therapy. The mean sis frequently become hypotensive in response to half-life of patients treated with the shunt did not the institution of hemodialysis. To circumvent this differ significantly from that of controls. Of note, the problem. we have used continuous arteriovenous group of patients with the HRS was carefully se- hemofiltration as an alternative maneuver in a few lected, and patients with severe complications of patients with HRS and have been successful in chronic liver disease were excluded. mobilizing fluid without concomitant hemodynamic On the basis of the available data, it is apparent instability (106, 107). Additional experience will be that a beneficial role for the PVS in the treatment of required to clarify the role of this approach in man- the HRS has not been established. Although some aging patients with HRS. patients exhibit an improvement in renal function, further controlled studies, with larger number of patients, are necessary to delineate the effect of the Peritoneovenous (LeVeen) Shunt PVS on long-term survival, quality of life, and the An advance that has engendered major controversy incidence of complications. in the management of HRS is the development of Orthotopic Liver Transplantation. Orthotopic peritoneovenous (PV) shunting (108-111). The past liver transplantation (OLTX) has recently become the 20 yr have witnessed a flurry of enthusiasm for the accepted treatment for end-stage liver disease (114). use of PV (LeVeen) shunting in the management of Of interest, many of these patients are admitted with HRS. Because the underlying abnormality is thought varying degrees of concomitant renal dysfunction, to be a maldistribution of extracellular fluid with a including the HRS. OLTX has been reported to re- resultant diminished effective blood volume, atten- verse HRS acutely (11,115,116). Recently, Gonwa et tion has focused on developing procedures to redis- at. (114) reviewed the extensive experience of the tribute body fluids between compartments, so that Baylor University transplant group and have reported

1746 Volume 4’ Number 10 1994 Epstein

a good, long-term survival with return of acceptable Tx and prostaglandin synthesis to varying degrees in renal function for prolonged periods. They retrospec- different biologic systems, selective inhibitors of Tx tively reviewed the first 308 patients undergoing synthesis preserve or possibly increase the produc- OLTX. The incidence of HRS was 10.5%. HRS pa- tion of other metabolites of arachidonic acid, such as tients manifested an increase in GFR from a baseline the potent vasodilator prostacyclin. Zipser et at. (50) of 20 ± 4 mL/min to a mean of 33 ±3 mL/min at 6 administered the Tx synthetase inhibitor dazoxiben wk, with a further increase to 46 ± 6 mL/min at 1 to patients with alcoholic hepatitis and progressive yr. GFR remained stable at 2 yr postoperatively (38 azotemia. Although the administration of dazoxiben ± 6 mL/min). There was no difference in periopera- reduced the urinary excretion of the Tx metabolite tive (90-day) mortality between HRS and non-HRS TxB2 by approximately 50%, PGE2 and 6-keto-PGF1,, patients, despite a worse preoperative status and a excretion was essentially unaltered. Despite the re-

more unstable postoperative course. The actuarial 1 - duction in Tx excretion, there was no consistent and 2-yr survival rate for the HRS patients was 77%, reversal of the progressive renal deterioration (50). not different from that of non-HRS patients. These Gentilini et at. (5 1 ) also investigated the effects of investigators concluded that with aggressive pre- a Tx synthase inhibitor in cirrhotic patients. They transplant and posttransplant management, one can administered OKY 046, a selective TxA2 synthase anticipate excellent results after OLTX in patients inhibitor, 200 mg thrice daily for 5 days, to nine with the HRS. nonazotemic cirrhotic patients with ascites and avid Newer Experimental Modalities. As noted previ- sodium retention. OKY 046 increased inulin clear- ously, nonsteroidal anti-inflammatory drugs have ance by 19%, whereas RBF was unchanged. Drug been shown to induce reversible decrements in renal administration did not alter the avid sodium reten- perfusion and renal function in patients with decom- tion and did not affect PRA or the plasma aldosterone pensated cirrhosis (40-43). Conversely, we have level. shown that the augmentation of renal prostaglandins Unfortunately, the administration of Tx synthase induced by water immersion is associated with Inhibitors is associated with a number of confound- marked increments in creatinine clearance (44,45). Ing factors that render the results difficult to inter- The infusion of vasodilator prostaglandins to correct pret. Indeed, these drugs may lead to the accumula- a possible renal prostaglandin deficiency has been tion of the prostaglandin endoperoxides PGG2 and unrewarding (38). The widest experience has been PGH2, which mimic the renal effects of TxA2 by with PGA and PGE. Although such therapeutic ma- interacting with the same receptors. As an example, nipulations have occasionally resulted in salutary arachidonic acid-induced vasoconstriction in the rat effects on renal function, the benefits have not been kidney is only partially reduced by pretreatment with sustained. a Tx synthase inhibitor, whereas it is completely Fevery et at. (1 1 7) have recently attempted to ex- abolished by the administration of a Tx receptor tend these observations by investigating the effects antagonist (118). of the administration of a PGE1 analog (misoprostol) In an attempt to obviate these problems, Laffi et on renal function in four patients with alcoholic at. (52) have recently conducted a randomized, dou- cirrhosis and HRS. In response to misoprostol admin- ble-blind, crossover trial to characterize the effects istration (0.4 mg orally four times daily) and albumin of the Tx receptor antagonist ONO-3708 on renal infusions, urine volume increased threefold to four- hemodynamics and excretory function in 1 5 non- fold. Concomitantly, serum creatinine levels dimin- azotemic cirrhotic patients with ascites. Urinary ished. All patients had hyponatremia, which nor- TxB2 excretion was threefold higher than in healthy malized with misoprostol administration. Although subjects. The administration of ONO-3708 signifi- the experience is preliminary, it raises the possibility cantly blocked TxA2 receptors; bleeding time showed that the provision of exogenous prostaglandins may a twofold increase, and platelet aggregation to the Tx have a salutary role in the management of the HRS. receptor agonist U-46619 was abolished in all pa- Our initial enthusiasm must be tempered, however, tients studied. ONO-3708 induced an 86% increase by the subsequent failure of these investigators, or in free water clearance compared with placebo (P < other groups, to confirm these initial observations. 0.001), which was associated with a significant di- Tx Inhibitors. As detailed above (p. 7), several uresis. RPF, as measured by p-aminohippurate clear- investigators have proposed that alterations of Tx ance, increased 14% during Tx receptor blockade (P may contribute to the development of renal dysfunc- <0.05), whereas GFR, as assessed by inulin, was tion (48,50,52). Consequently, there have been at- unchanged. Additional studies with Tx receptor an- tempts to modify the course of the HRS by the ad- tagonists in patients with widely varying degrees of ministration of selective inhibitors of Tx synthesis acute renal insufficiency will be required to further (50,51). Whereas nonspecific cyclo-oxygenase inhib- define the possible utility of these agents in the treat- itors, such as indomethacin and aspirin, reduce both ment of the HRS.

Journal of the American Society of Nephrology 1747 Hepatorenal Syndrome .. ...-., J. . .

Other Treatment Modalities namic alterations that attend immersion requires close medical monitoring. (3) Finally, a patient could In view of the prominent role assigned to renal only reasonably be immersed for a small percentage cortical ischemia in the pathogenesis of HRS, it is of the day, and it is unknown if this confers a lasting not altogether surprising that there have been flu- beneficial effect. merous attempts to treat HRS with vasodilators. The The long-term effect of water immersion on central intrarenal infusion of nonspecific vasodilators such blood volume is unknown. Certainly, water immer- as acetylcholine and papaverine improve RBF but do sion constitutes a powerful and highly productive not augment GFR (1 19). Similarly, the blockade of means of investigating deranged volume homeostasis vasoconstrictor a-adrenergic nerves by the intrarenal in many edematous disorders, especially cirrhosis Infusion of phentolamine or phenoxybenzamine or ( 1 4, 1 7,27,45). We believe, however, that at this time, the stimulation of vasodilator fl-adrenergic nerves pending carefully controlled investigative pilot stud- with isoproterenol has no significant effect on GFR ies, immersion should not be used uniformly as ther- (13). apy in managing patients with decompensated cir- The direct stimulation of renal dopaminergic recep- rhosis. tors by the infusion of nonpressor doses of dopamine produces renal vasodilation, but again, GFR and urine flow are virtually unaffected, despite infusions Considerations for Future Therapeutic for as long as 24 h (29,120,121). Approaches Finally, a variety of other treatment modalities have been proposed, including prednisone, exchange An additional investigative approach that has not transfusion, charcoal hemoperfusion, xenobiotic been undertaken but that merits consideration is the cross-circulation, and ex vivo baboon liver perfusion possible role of calcium antagonists. Studies from (4, 1 22). None are of demonstrated benefit, and the several laboratories, including our own, have dem- actual and potential complications are of sufficient onstrated profound effects of these calcium antago- magnitude to dictate great hesitation in their clinical nists on renal vascular smooth muscle and concom- use. itant alterations in renal function (124,125). Specif- ically, calcium antagonists have been shown to augment and restore GFR in diverse experimental settings characterized by renal vasoconstriction. Water Immersion This effect is due, in part, to the selective reduction We are often asked in consultation if water immer- of afferent arteriolar resistance. In essence, calcium sion might be tried as a therapeutic maneuver for a antagonists may constitute selective renal vasodi- patient who has been diagnosed as having the HRS. lators that reverse or attenuate renal ischemia (126). As noted above, there has been an increasing aware- Indeed, studies from several laboratories have re- ness that the underlying abnormality in patients with cently demonstrated that calcium antagonists are decompensated cirrhosis is not solely an excess of effective in the prophylaxis of acute renal insuffi- total body fluid, but is to a greater extent a maldistri- ciency in diverse clinical settings, including cadav- bution of extracellular fluid. Consequently, much at- eric kidney transplantation and radiocontrast-in- tention has been focused on developing procedures duced renal dysfunction ( 1 26). Because patients with to redistribute body fluids, not only between com- HRS manifest a more extreme degree of preferential partments, as with the PVS, but also within the renal cortical ischemia, it appears reasonable to an- vascular compartment. ticipate that calcium antagonists can induce a similar Studies from our laboratory have provided substan- salutary effect on renal hemodynamics. If it can be tial evidence that head-out water immersion mark- demonstrated that calcium antagonists can be safely edly augments central blood volume (56,123). To the administered to patients with decompensated cirrho- extent that diminished effective blood volume con- sis without inducing concomitant hypotension, they stitutes a major determinant of renal sodium reten- may constitute an additional therapeutic approach to tion in established liver disease, one might justifiably the management of the HRS. speculate on the use of water immersion as a means Vasoconstrictor Therapy. A final therapeutic ap- of replenishing the contracted effective volume. Al- proach that warrants consideration is the adminis- though at first glance such a proposal appears at- tration of vasoactive agents that preferentially re- tractive, several arguments have been marshaled verse the decreased systemic vascular resistance against this approach. (1) The repeated use of water without increasing renal vascular resistance. As dis- immersion would be a time-consuming and costly cussed previously (21,127), there has been a resurg- procedure requiring the continuous attendance of ence of interest in the role of peripheral vasodilation paramedical personnel. (2) These patients are clini- as the primary determinant of intravascular under- cally fragile, and exposure to the marked hemody- filling. The resultant imbalance between the ex-

1748 Volume 4 Number 10’ 1994 Epstein

panded capacitance and the available volume even- SUMMARY tuates in a diminished effective volume. Such a for- In summary, despite considerable progress in the mulation dictates that therapy should be directed past three decades, we still lack a comprehensive toward a correction of the diminished systemic vas- understanding of the pathogenetic cascade that pro- cular resistance in HRS patients. Such an approach duces HRS. Although there has been some progress is not novel. Thirty years ago, Gornel et at. (128) in characterizing the pathogenesis of this condition, demonstrated that the administration of the pressor therapy is largely empirical. Much progress in the amine metaraminol in cirrhotic patients is often fol- delineation of the intrarenal hemodynamic altera- lowed by an increase in GFR, an increase in urine tions that underlie the HRS has been witnessed in flow, and the elaboration of a more dilute urine. the past two decades. The numerous attempts at Although the use of metaraminol was fraught with treating HRS empirically with vasodilators have not problems, it would appear that the general approach resulted in important therapeutic innovations. The of administering pressor agents might be valid. failure of many HRS patients to survive despite par- Twenty-five years ago, Cohn et al. (129) demon- tial correction of their renal hemodynamic abnor- strated that a synthetic analog of lysine vasopressin mality is a reflection of the precarious state of the (octapressin; PLV-2) had the unique property of pro- patient with liver failure. Hemorrhage, infection, and ducing renal vasodilation combined with systemic hepatic coma are the usual causes of death in these vasoconstriction, thereby producing a redistribution patients. of blood flow to the kidney. Those investigators stud- It is apparent that any future breakthroughs in led the systemic and renal hemodynamic effects of providing definitive treatment of HRS must be pred- PLV-2 in patients with decompensated cirrhosis of icated on a greater clarification of the mechanisms the liver. Low doses (0.004 to 0.02 U/mm) increased and a delineation of the mediators. The role of he- RBF (indicator-dilution technique), reduced renal modialysis has recently undergone reappraisal, and vascular resistance, and produced a slight increase It is apparent that dialysis clearly has a role in sup- in arterial pressure and systemic vascular resistance. porting patients awaiting hepatic transplantation. The fraction of the cardiac output delivered to the Dialysis also may be warranted as a supportive meas- kidney was increased at all dose levels. The increased ure in some patients with apparently reversible RBF was accompanied by a more rapid intrarenal dye hepatic dysfunction. Hepatic transplantation has transit time and a slight increase in the renal extrac- evolved over the past decade to the point where it tion ratio of p-aminohippurate, suggesting a rise in constitutes definitive therapy for patients with he- cortical blood flow. They concluded that PLV-2 in patic dysfunction and concomitant renal failure. Al- small doses produced renal vasodilation, and in though anecdotal information suggests that PV larger doses, it produced preferential extrarenal vaso- shunting has a role in the management of select constriction, resulting in a redistribution of blood patients with HRS, the results of available prospec- flow to the kidney. On the basis of these findings, tive studies have failed to confirm such approach. Cohn et at. (1 29) proposed a possible role for PLV-2 Finally, the advent of the peripheral vasodilation in the management of HRS. Unfortunately, addi- theory and its focus on the generalized hemodynamic tional studies were not undertaken. perturbations in the patient with the HRS have re- Recently, there has been renewed interest in the focused attention on the florid extrarenal hemody- hemodynamic derangements and attempts to im- namic derangements. This suggests that pharmaco- prove renal function by countervailing this hyperdy- logic interventions that counter the peripheral vaso- namic state. Lenz et at. (130) investigated the effects dilation may afford benefit with regard to both of the infusion of ornipressin on renal and circula- systemic hemodynamics and renal function. It is tory function. In a preliminary report, they observed hoped that future clinical trials will establish the that ornipressin reversed the hyperdynamic state. precise contribution of each of these treatment mo- Concomitantly, there was improvement in renal dalities and its respective role in the therapeutic function, as assessed by a more than 70% increase armamentarium. in creatinine clearance and a doubling in urine flow. These preliminary observations lend support to the concept that the peripheral vasodilation of liver disease contributes importantly to the renal dysfunction. Consequently, maneuvers that counter the vas- ACKNOWLEDGMENTS odilation may possibly prove to be of benefit in im- proving renal function. In this regard, clinical trials I thank Elsa V. Relna for her expert secretarial help. Portions of this review have been adapted with permission from an earlier review attempting to reverse the HRS should be undertaken by the author: Epstein M. The hepatorenal syndrome. In: Epstein M. with additional vasoactive agents that selectively in- Ed. The Kidney in Liver Disease. 3rd Ed. Baltimore: Williams & crease systemic vascular resistance. Wilkins: 1988:89-118.

Journal of the American Society of Nephrology 1749 Hepatorenal Syndrome

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Levens NR, Peach MJ, Carey RM: Role of the by para amino-hippurate extraction and re- intrarenal renin-angiotensin system in the sponse to angiotensin. Am J Med 1967:43: control of the renal function. Circ Res 887-896. 1981:48:157-167. 13. Epstein M, Berk DP, Hollenberg NK, et at.: 3 1 . Cade R, Wagemaker H, Vogel 5, et at. : Hepa- Renal failure in the patient with cirrhosis: the torenal syndrome: Studies of the effect of vas- role of active vasoconstriction. Am J Med cular volume and intraperitoneal pressure on 1970;49:175-185. renal and hepatic function. Am J Med 14. Epstein M, Schneider N, Befeler B: Relation- 1 987;82:427-438. ship of systemic and intrarenal hemodynamics 32. Berkowitz HD. Renin substrate in the hepato- in cirrhosis. J Lab Clin Med 1977;89:1 175- renal syndrome. In: Epstein M, Ed. The Kidney 1187. in Liver Disease. 1st Ed. New York: Elsevier/ 15. Hollenberg NK, Epstein M, Basch RI, Oken North Holland; 1978:251-270. DE, Merrill JP: Acute oliguric renal failure in 33. Berkowitz HD, Calvin C, Miller LD: Signifi- man: Evidence for preferential renal cortical cance of altered renin substrate in the hepato- ischemia. Medicine 1968;47:455-474. renal syndrome. Surg Forum 1 972;23:342- 16. Kew MC, Varma RR, Williams HS, Brunt PW, 343. Hourigan KJ, Sherlock 5: Renal and intrare- 34. McCombs PR, Berkowitz HD, Miller LD, Ro- nal blood flow in cirrhosis of the liver. Lancet sato EF: Renin substrate infusions in hepato- 197 1;2:504-5 10. renal syndrome. Surg Forum 1975;26:419- 17. Epstein M: Determinants of abnormal renal 421. sodium handling in cirrhosis: A reappraisal. 35. Panente EA, Bataille C, Bercoff E, Lebrec D: Scand J Clin Lab Invest 1980:40:689-694. Acute effects of captopril on systemic and renal

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M, Ed. The Kidney in Liver Disease. 3rd Ed. 84. Maack T, Marion DN, Camargo MJF, et at.: Baltimore: Williams & Wilkins; 1988:486-507. Effects of auriculin (atrial natriuretic factor) on 68. Clemente C, Bosch J, ROd#{233}SJ, Arroyo V, Mas blood pressure, renal function, and the renin- A, Maragall S: Functional renal failure and aldosterone system in dogs. Am J Med haemorrhagic gastritis associated with endo- 1984;77:1069-1075. toxaemia in cirrhosis. Gut 1977:18:556-560. 85. Cantin M, Genest J: The heart and the atrial 69. Gatta A, Milani L, Merkel C, et at. : Lack of natriuretic factor. Endocrinol Rev 1985:6:107- correlation between endotoxemia and renal hy- 127. poperfusion in cirrhotics without overt renal 86. Needleman P. Adams SP, Cole BR, et at.: failure. Eur J Clin Invest 1982:12:417-422. Atriopeptins as cardiac hormones. Hyperten- 70. Coratelli P, Passavanti G, Munno I, Fumarola sion 1 985;7:469-482. D, Amerio A: New trends in hepatorenal syn- 87. Fyhrquist F, Totterman KJ, Tikkanen I: In- drome. Kidney mt 1 985;28:S- 1 43-S- 147. fusion of atrial natriuretic peptide in liver cir- 7 1 . Bosch J, Gines P, Arroyo V, Navasa M, Rod#{233}s rhosis with asdites. Lancet 1985:2:1439. J. Hepatic and systemic hemodynamics and 88. Epstein M, Loutzenhiser R, Norsk P, Atlas S: the neurohumoral systems in cirrhosis. In: Ep- Relationship between plasma ANF responsive- stein M, Ed. The Kidney in Liver Disease. 3rd ness and renal sodium handling In cirrhotic Ed. Baltimore: Williams & Wilkins; 1988:286- humans. Am J Nephrol 1989;9:133-143. 305. 89. Epstein M: Atrial natriuretic factor in patients 72. ValIance P. Moncada S: Hyperdynamic circu- with liver disease. Am J Nephrol 1989:9:89- lation in cirrhosis: A role for nitric oxide? Lan- 100. cet 1991:337:776-778. 90. Gerbes AL, Arendt RM, Ritter D, Jungst D, 73. Palmer RMJ, Ferrige AG, Moncada S: Nitric Zahringer J, Paumgartner G: Plasma atrial oxide release accounts for the biological acitiv- natriuretic factor in patients with cirrhosis. N ity of endothelium-derived relaxing factor. Na- EnglJMed 1985:313:1609-1610. ture 1987:327:524-526. 9 1 . Morgan TR, Imada T, Hollister AS, Inagami T: 74. Palmer RMJ, Ashton DS, Moncada S: Vascular Plasma human atrial natriuretic factor in cir- endothelial cells synthesize nitric oxide from L- rhosis and asdites with and without functional arginine. Nature 1 988;333:664-666. renal failure. Gastroenterology 1 988;95: 1641- 75. Rees DD, Palmer RMJ, Moncada S: The role of 1647. endothelium-derived nitric oxide in the regula- 92. Dudley FJ, Kanel GC, Wood U, Reynolds TB: tion of blood pressure. Proc NatI Acad Sd USA Hepatorenal syndrome without avid sodium re- 1989:86:3375-3378. tention. Hepatology 1986:6:248-251. 76. Aisaka K, Gross 5G. Griffith OW, Levi R: L- 93. Zarich S, Fang LS, Diamond JR: Fractional arginine availability determines the duration of excretion of sodium. Exceptions to its diagnos- acetylcholine-induced systemic vasodilation in tic value. Arch Intern Med 1 985; 1 45: 1 08- 1 12. vivo. Biochem Biophys Res Commun 1989; 94. Sherman RA, Eisinger RP: Urinary sodium and 163:7 10-7 17. chloride during renal salt retention. Am J Kid- 77. Radlomski MW, Palmer RMJ, Moncada 5: Glu- neyDis 1983;:121-123. cocorticoids inhibit the expression of an induc- 95. Cabrera J, Arroyo V. Ballesta AM, et at.: ible, but not the constitutive, nitric oxide syn- Aminoglycoside nephrotoxicity in cirrhosis. thase in vascular endothelial cells. Proc Nat! Value of urinary f32micoglobulin to discriminate Acad Sd USA 1990;87:10043-10047. functional renal failure from acute tubular 78. Rees DD, Cellek S, Palmer RMJ, Moncada S: damage. Gastroenterology 1982:82:97-105. Dexamethasone prevents the induction by 96. Rector WG Jr, Kanel GC, Rakela J, Reynolds endotoxin of a nitric oxide synthase and the TB: Tubular dysfunction in the deeply jaun- associated effects on vascular tone. An insight diced patient with hepatorenal syndrome. He- into endotoxin shock. Biochem Biophys Res patology 1 985;5:32 1-326. Commun 1 990; 173:541-547. 97. Oster JR, Epstein M, Ulano HB: Deterioration 79 Busse R, Mulsch A: Induction of nitric oxide of renal function with demeclocycline admin- synthase by cytokines in vascular smooth mus- istration. Curr Ther Res 1976:20:794-801. DIe cells. FEBS Lett 1990:275:87-90. 98. Carrilho F, Bosch J, Arroyo V. Mas A, Viver 80. Fom#{225}s A, Sonano G, Guarner C, et at.: In- J, Rod#{233}sJ: Renal failure associated with decreased serum nitrite and nitrate in cirrhosis: meclocycline in cirrhosis. Ann Intern Med Relationship to endotoxemia [Abstractj. J He- 1977:87:195-197. patol 1992;16(Suppl 1):4. 99. Arroyo V, Gin#{233}sP, Planas R, Panes J, Rod#{233}s 81. 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DeBold AJ, Borestein HR, Veress AT, Sonnen- 70 versus albumin as plasma expanders in berg H: A rapid and potent natriuretic response cirrhotic patients with tense ascites treated to intravenous injection of atrial myocardial with total paracentesis. Results of a random- extracts in rats. Life Sd 1981:28:89-94. ized study. Gastroenterology 1990:99:1736-

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1744. transplantation Ann Surg 1 987;205:4 15-419. 102. Gin#{233}sP, Arroyo V. Quintero E, et at. : Compar- 1 16. Gunning TC, Brown MR, Swygert TH, et at.: ison of paracentesis and diuretics in the treat- Perioperative renal function in patients ment of cirrhotics with tense ascites. Results undergoing orthotopic liver transplantation. of a randomized study. Gastroenterology Transplantation 1991:51:422-427. 1987:93:234-241. 1 17. Fevery J, Van Cutsem E, Nevens F, et at.: 103. Perez GO, Oster JR. A critical review of the Reversal of hepatorenal syndrome in four pa- role of dialysis in the treatment of liver disease. tients by peroral misoprostol (prostaglandin El In: Epstein M, Ed. The Kidney in Liver Disease. analogue) and albumin administration. J He- 1st Ed. New York: Elsevier; 1978:325-336. patol l990;ll:153-158. 104. Wilkinson SP, Weston MJ, Parsons V, Wil- 1 1 8. Quilley J, McGiff JC, Nasjletti A: Role of endo- hams R: Dialysis in the treatment of renal peroxides in arachidonic acid-induced vasocon- failure in patients with liver disease. Clin Ne- striction in the isolated perfused kidney of the phrol 1977;8:287-292. rat. BrJ Pharmacol 1989:96:111-1 16. 1 05. Perez GO, Epstein M, Oster JR. Role of dialysis 1 19. Cohn JN, Tristani FE, Khatri M: Renal vaso- and ultrafiltration in the treatment of the renal dilator therapy in the hepatorenal syndrome. complications of liver disease. In: Epstein M, Med Ann DC 1970:39:1-7. Ed. The Kidney in Liver Disease. 3rd Ed. Bal- 1 20. Bennett WM, Keeffe E, Melnyk C, et at. : Re- timore: Williams & Wilkins; 1988:613-624. sponse to dopamine hydrochloride in the hep- 1 06. Epstein M, Perez GO: Continuous arterio-ve- atorenal syndrome. Arch Intern Med 1975: nous ultrafiltration in the management of the 135:964-971. renal complications of liver disease. mt J Artif 1 2 1 . Wilson JR: Dopamine in the hepatorenal syn- Organs 1986:9:217-218. drome. JAMA 1977:238:2719-2720. 107. Epstein M, Perez GO, Bedoya LA, Molina R: 1 22. Horisawa M, Reynolds TB: Exchange transfu- Continuous arterio-venous ultrafiltration in sion in hepatorenal syndrome with liver dis- cirrhotic patients with ascites or renal failure. ease. Arch Intern Med 1976;136:1 135-1137. mt J Artif Organs 1986;9:253-256. 123. Begin R, Epstein M, Sackner MA, Levinson R, 1 08. Epstein M: The peritoneovenous shunt in the Dougherty R, Duncan D: Effects of water im- management of ascites and the hepatorenal mersion to the neck on pulmonary circulation syndrome. Gastroenterology 1982:82:790- and tissue volume in man. J Appl Physiol 799. 1976:40:293-299. 109. Pladson TR, Parrish RM: Hepatorenal syn- 1 24. Loutzenhiser RD. Epstein M: The effects of drome: Recovery after peritoneovenous shunt. calcium antagonists on renal hemodynamics Arch Intern Med 1977;157:1248-1249. [Editorial Review). Am J Physiol 1985;249: 1 10. Epstein M: The LeVeen shunt for ascites and F6 19-F629. hepatorenal syndrome. N Engl J Med 1980; 1 25. Loutzenhiser RD, Epstein M, Horton C, Sonke 302:628-630. P: Reversal of renal and smooth muscle actions 1 1 1 . Epstein M. Role of the peritoneovenous shunt of the thromboxane mimetic U-44069 by dilti- in the management of asdites and the hepato- azem. Am J Physiol 1986;250:F619-F626. renal syndrome. In: Epstein M, Ed. The Kidney 1 26. Epstein M: Calcium antagonists and renal pro- in Liver Disease. 3rd Ed. Baltimore: Williams & tection: Current status and future perspectives. Wilkins; 1988:593-612. Arch Intern Med 1992:152:1573-1584. 112. Linas SL, Schaffer JW, Moore EE, Good JT 127. Epstein M. Renal sodium handling in liver dis- Jr, Giansiracusa R: Peritoneovenous shunt in ease. In: Epstein M, Ed. The Kidney in Liver the management of the hepatorenal syndrome. Disease. 3rd Ed. Baltimore: Williams & Wilkins: Kidney mt 1986;30:736-740. 1988:3-30. k 113. Stanley MM, Ochi 5, Lee KK, et at.: Perito- 128. Gornel DL, Lancestremere RG, Papper 5, neovenous shunting as compared with medical Lowenstein LM: Acute changes in renal excre- treatment in patients with alcoholic cirrhosis tion of water and solute in patients with Laen- and massive ascites. N Engl J Med 1989; nec’s cirrhosis induced by the administration 321:1632-1638. of the pressor amine, metaraminol. J Clin In- 114. Gonwa TA, Morris CA, Goldstein RM, et at.: vest 1962:41:594-605. Long-term survival and renal function follow- 129. Cohn JN, Tristani FE, Khatri IM: Systemic ing liver transplantation in patients with and vasoconstrictor and renal vasodilator effects of without hepatorenal syndrome-experience in PLV-2 (octapressin) in man. Circulation 1968; 300 patients. Transplantation 1991:51:428- 38:151-157. 430. 130. Lenz K, Hortnagl H, Druml W, et at.: Beneficial 115. Wood RP, Ellis D, Starzl TE: The reversal of effect of 8-ornithin vasopressin on renal dys- the hepatorenal syndrome in four pediatric pa- function in decompensated cirrhosis. Gut tients following successful orthotopic liver 1989:30:90-96.

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