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 at- tempts 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 in- creased 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