Clinical Challenge

New Challenge of Hepatorenal Syndrome: Prevention and Treatment

FLORENCE WONG1 AND LAURENCE BLENDIS1,2

Hepatorenal syndrome (HRS) remains one of the major therapeutic challenges in hepatology today. The pathogenesis is complex, but the nal common pathway seems to be that sinusoidal portal hypertension, in the presence of severe hepatic decompensation, leads to splanchnic and systemic vasodilatation and decreased effective arterial blood volume. Renal vasoconstriction increases concomitantly, renal hemodynamics worsens, and renal failure occurs. Renal failure was shown 15 years ago to be potentially reversible after liver transplantation. This potential reversibility together with increased understanding of the pathogenesis has led to successful preliminary attempts to reverse HRS nonsurgically with combinations of splanchnic vasoconstrictors and colloid volume expansion, insertion of transjugular intrahepatic portovenous shunt radiologically, and improved forms of dialysis. Recent classication of HRS into the acute onset or severe type 1 with virtually 100% mortality and the more insiduous less severe type II promises to shed more light on the pathogenesis of HRS, especially on the currently unrecognized precipitating factors. It is hoped that this classication will be included in the necessary and carefully performed clinical trials, which should lead to clearer indications for the available therapies. The challenge now is to use all this information to improve our management of cirrhotic patients to prevent occurrence of HRS in the future. (HEPATOLOGY 2001;34:1242-1251.) Progressive oliguric renal failure is a common and severe complication in patients with advanced liver disease. In a large prospective follow-up study of cirrhotic patients with ascites, development of renal failure occurred in 18% and 39% of the patients at 1 year and at 5 years, respectively, with a median survival of 1.7 weeks or a 90% mortality at 10 weeks.1 Hepatorenal syndrome (HRS) originally referred to occurrence of renal failure following biliary surgery.2 The denitions of HRS gradually evolved to describe the renal failure observed in patients with liver failure associated with low urinary sodium levels and absence of renal pathology.3 A recent consensus conference further dened HRS as types I and

II with the following diagnostic criteria: type I HRS is characterized by rapidly progressive renal failure with a doubling of serum creatinine to a level greater than 2.5 mg/dL or a halving of the creatinine clearance to less than 20 mL/min in less than 2 weeks; type II HRS is a more chronic form with a slowly progressive increase in serum creatinine level to greater than 1.5 mg/dL or a creatinine clearance of less than 40 mL/min4 and has a corresponding better prognosis. Until recently, liver transplantation was the only denitive treatment for HRS.5,6 However, even then, the reported survival rates of these HRS patients posttransplantation have been less than in transplanted patients with normal renal function, and the return of renal function to normal may be delayed for months or years.7,8 Furthermore, liver transplantation is not readily available to every patient, nor is every patient with HRS a suitable candidate for this surgery. We review herein possible ways of preventing HRS and how the new therapies for HRS9-12 have shed light on the pathophysiology resulting in improvement in the prognosis of patients with HRS.
THE PATHOPHYSIOLOGY OF HRS AND ITS ROLE IN PREVENTION

Abbreviations: HRS, hepatorenal syndrome; TIPS, transjugular intrahepatic portosystemic shunt; NOS, nitric oxide synthase; PRA, plasma renin activity; SBP, spontaneous bacterial peritonitis; MARS, molecular adsorbent recirculating system. From the 1Division of Gastroenterology, Department of Medicine, The Toronto General Hospital, University of Toronto, Ontario, Canada; and 2Institute of Gastroenterology, Souraksy Tel Aviv Medical Centre, Tel Aviv, Israel. Received March 9, 2001; accepted July 9, 2001. Address reprint requests to: Laurence Blendis, M.D., Institute of Gastroenterology, Souraksy Tel Aviv Medical Centre, Tel Aviv, Israel. E-mail: maxin@netvision.nel.il; fax: 416-340-5019. Copyright 2001 by the American Association for the Study of Liver Diseases. 0270-9139/01/3406-0023$35.00/0 doi:10.1053/jhep.2001.29200

The hallmark of HRS is hypoperfusion of the kidney resulting from combined renal vasoconstriction and decreased total renal blood ow13 in response to generalized systemic arterial vasodilatation.14 Patients with advanced cirrhosis and liver failure have a hyperdynamic circulation with lowered systemic vascular resistance and increased cardiac output.15,16 As a result of splanchnic and systemic arterial vasodilatation, there is relative underlling of the systemic circulation and a fall in mean arterial pressure.17,18 Consequently, renal perfusion pressure is reduced, leading to decreased renal blood ow.19 Compensatory activation of various vasoconstrictor systems maintains hemodynamic stability, whereas vasoconstriction occurs in some nonsplanchnic vascular beds including the kidneys,20 thereby further reducing renal perfusion with consequent reduction in glomerular ltration rate.21 However, two patients with similarly reduced renal blood ow may or may not have HRS.22 Dagher et al.23 suggested that mesangeal contraction due to increased circulating levels of renal vasoconstrictors (Fig. 1) lowers the glomerular capillary ultraltration coefcient (Kf) causing further reduction of glomerular ltration. Such vasoconstrictors include endothelin-1,24,25 leukotrienes,26,27 and products of lipid peroxidation.28 However, the role of these vasoconstrictors in causing mesangeal contraction is unclear because levels of immunoreactive endothelins do not correlate with the extent of renal dysfunction in these patients29 or with the improvement of renal function following insertion of a transjugular intrahepatic portosystemic shunt (TIPS).30 The suggestion that sinusoidal or postsinusoidal portal hypertension is an important factor in the development of renal

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FIG. 1. The pathophysiology of hepatorenal syndrome.

dysfunction31 is supported by recent reports of patients in whom HRS was successfully treated by reduction of portal pressure by a TIPS.12 Furthermore, occlusion of a TIPS by an angioplasty balloon was associated with acute reduction of renal blood ow.32 Upon release of the balloon, with elimination of portal hypertension, renal blood ow returned to baseline levels. Portal hypertension with portosystemic shunts and splanchnic dilatation leads to development of hyperdynamic circulation with attendant systemic arterial vasodilatation and effective arterial underlling and hence renal hypoperfusion. However, this is unlikely to be the whole explanation. Presinusoidal portal hypertension due to portal vein thrombosis, nodular regenerative hyperplasia, or schistosomiasis is associated with hemodynamic changes similar to those of compensated cirrhosis17,33 but not associated renal sodium retention34 or HRS. Animal studies suggest the important afferent factor for the development of HRS is sinusoidal portal hypertension. For example, infusion of glutamine into the portal vein, which induces hepatocyte swelling and hence increases sinusoidal portal pressure, was associated with a signicant decrease of both renal plasma ow and glomerular ltration rate. These effects were abolished by sectioning the renal sympathetic nervous supply.35 Furthermore, increased intrahepatic pressure resulted in greater efferent renal sympathetic nervous activity,36 and renal sympathectomy improved glomerular ltration rate in cirrhotic rats.37,38 Finally, renal sympathetic block resulted in transient improvement in renal blood ow and function in patients with HRS.39 Bataller et al.14 proposed that renal hypoperfusion in cirrhosis could also be related to liver dysfunction, which inuences the synthesis or release of renal vasodilators such as the renal prostaglandins40,41 from the kidney. In decompensated cirrhosis but without renal failure, increased renal production of prostaglandins has been reported.42 In HRS, urinary excre-

tion of prostaglandin E2 (PGE2) and prostacyclin metabolite 6-oxo-PGF1 are decreased compared with patients with ascites alone.43 This may partly result from a fall in glomerular ltration rate44 and decreased renal production of PGE2 and 6-oxo-PGF1 .45 In addition, the use of nonsteroidal anti-inammatory drugs, which are cyclo-oxygenase inhibitors, in patients with cirrhosis and ascites can precipitate HRS.46 Another renal vasodilator that could be involved in the pathogenesis of HRS is nitric oxide.47 In portal hypertension endothelial nitric oxide synthase (NOS) activity is signicantly increased, leading to increased circulating levels of nitric oxide.48 In normal animals and humans, short-term inhibition of NOS results in renal vasoconstriction and reduced renal plasma ow.49,50 In contrast, NOS inhibition in cirrhotic rats with ascites does not affect renal blood ow or function51,52 despite an increased systemic pressor effect.53 Furthermore, renal vasoconstriction may occur in the presence of increased glomerular nitrite production54 and increased urinary nitrate excretion55 in ascitic patients compared with compensated nonascitic cirrhotics. This suggests that renal microcirculation in ascites is less sensitive to nitric oxide.56 However, infusion of nitric oxide substrate L-arginine in cirrhotic patients with ascites, in contrast to controls, causes increased natriuresis with increased urinary nitrate/nitrite excretion.57 Finally, there is a possible role of natriuretic peptides.58 In experimental cirrhosis with ascites in rats, blockade of natriuretic peptide receptors was followed by a signicant reduction of both renal blood ow and glomerular ltration rate.59 Renal vasodilatation with acetylcysteine improved renal function in patients with HRS without affecting liver function or systemic hemodynamics.60 Furthermore, not all patients with seemingly equally severe hepatic dysfunction develop HRS. Therefore, the role of liver dysfunction in the pathogenesis of

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FIG. 2. The rst hit and the second hit hypothesis of hepatorenal syndrome.

HRS appears to be an important background factor, or rst hit, that requires an additional factor, or second hit, to initiate HRS (Fig. 2). In the same way splanchnic and systemic vasodilation and sinusoidal portal hypertension appear to be primary factors in the pathogenesis, but all require additional factors to initiate HRS.
DEFINITION OF HRSITS ROLE IN CLARIFYING THE PATHOGENESIS AND PREVENTION

The recent consensus conference of the International Ascites Club clearly posed the diagnostic criteria of HRS (Table 1) and dened types I and II. Although the denition describes renal failure complicating liver failure, and helps in the clinical management of these patients, it is not clear whether types I and II HRS are two different stages on the same conTABLE 1. Denition of Hepatorenal Syndrome Major criteria Chronic or acute liver disease with liver failure and portal hypertension Low glomerular ltration rate as indicated by a serum creatinine 1.5 mg/dL or a creatinine clearance of 40 mL/min Absence of shock, ongoing bacterial infection, and recent treatment with nephrotoxic drugs. Absence of excessive uid loss including gastrointestinal loss No sustained improvement in renal function following expansion with 1.5 L of isotonic saline Proteinuria of 0.5 g/d and no ultrasonagraphic evidence of renal tract disease Minor criteria Urine volume 500 mL/d Urine sodium 10 mmoL/d Urine osmolality plasma osmolality Urine red cell count 50 per high power eld Serum sodium 130 mmol/L

tinuum of the end-stage cirrhotic process or two distinct entities. The denition does not explain what determines whether a patient with normal serum creatinine will gradually evolve into type II HRS with progressively worsening glomerular ltration rate or acutely develop renal failure with its grave prognosis. Finally, the denition does not explain why most but not all patients with HRS have ascites. We will attempt to answer some of these questions while focusing on the two types of HRS from a pathogenetic point of view. We also are taking the opportunity to suggest certain recommendations in the literature for prevention of HRS.
TYPE I

Gines et al.1 reported that hyponatremia and high plasma renin activity (PRA) are independent predictors for development of type 1 HRS in cirrhotic patients with ascites. They suggested that it is the extent of the systemic arterial vasodilatation with consequent effective arterial underlling (the rst hit), causing a rise in the PRA that is important in the pathogenesis of type 1 HRS. Indeed, HRS frequently develops as a consequence of precipitating events (the second hit), which exaggerate the effective arterial underlling. Such events may include the overzealous use of diuretics,61 large volume paracentesis, or development of spontaneous bacterial peritonitis (SBP) in ascitic patients as well as in patients with gastrointestinal bleeding. However, at least 24% of patients with type 1 HRS develop renal failure without any obvious precipitating factor.62 This suggests that other as yet unrecognized factors may also be involved in the pathogenesis of HRS, which we shall address later.
Diuretics

Patients with refractory ascites have signicantly higher PRA63 compared with patients with responsive ascites, sug-

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gesting reduction in effective arterial blood volume. Furthermore, these patients have a poor natriuretic response to furosemide.63 Gines et al. reported a signicantly higher incidence of reversible renal impairment in hospitalized patients with tense ascites treated with diuretics compared with those treated with large-volume paracentesis,64 which is associated with further increases in PRA. These ndings support the contention that diuretics cause a further contraction of intravascular volume with compensatory increases in the vasoconstrictor activities predisposing patients to development of renal failure. However, the same investigators also reported that diuretics do not increase the incidence of postparacentesis circulatory dysfunction (dened as an increase in renin of greater than 50% over baseline levels up to a value higher than 4 ng/mL/h on the third day after paracentesis).65 The possibility remains that diuretic therapy in nonhospitalized, severely decompensated patients might induce the onset of HRS. In hospitalized patients, addition of a colloid solution such as albumin to diuretic therapy prevented a diuretic-induced rise in serum creatinine and blood urea nitrogen despite an unchanged hematocrit and lack of protection from a fall in systemic blood pressure,66 indicating an unchanged intravascular volume. Thus albumin may have a local effect on the physical factors of the tubule.67 This suggests that diuretics may also induce renal impairment via mechanisms other than reduction in intravascular volume.67 This may occur via some local effects of diuretics on the nephron, as structural changes have been observed following prolonged diuretic therapy.68 Although overzealous use of loop diuretics in particular can cause a rise in serum urea and creatinine, it is nearly always reversible with cessation of diuretics.69 Furthermore, patients with peripheral edema appear to be protected by more rapid mobilization of edema uid.70 Therefore, the indication for the protective and synergistic use of albumin with diuretics remains controversial.71 Recommendation. In patients with ascites, spironolactone should not be increased above 400 mg daily. The pharmacodynamics of loop diuretics in cirrhotic ascitic patients are altered, and the diminished response to furosemide is not enhanced by large doses.72 These patients should be treated with divided doses of furosemide of up to 160 mg daily and be followed closely with monitoring of electrolytes and serum creatinine, especially in the absence of peripheral edema. Patients who do not respond to these generally accepted maximal doses of diuretic therapy should not have their diuretic doses increased further, but other treatment options for ascites should be considered. In the future, simple tests such as the natriuretic response to an acute intravenous infusion of furosemide63 may help to predict diuretic nonresponsiveness and possibly avoid unrecognized precipitation of HRS, especially in outpatients.
Large-Volume Paracentesis

tesis. Because PRA is one of the independent predictors for development of HRS,1 those patients with higher baseline PRA (rst hit) are more likely to develop HRS after largevolume paracentesis (second hit). However, use of albumin as a volume expander after large-volume paracentesis does not always prevent postparacentesis renal failure. Recommendation. Before starting a course of repeated paracenteses, it is important to measure serum creatinine levels and, if possible, perform PRA determinations to identify patients at greatest risk of developing postparacentesis circulatory dysfunction. Such patients should be maximally protected with 6 to 8 grams of intravenous albumin per liter of ascites.
Gastrointestinal Bleeding

Ruiz-del-Arbol et al.73 described development of circulatory dysfunction after large-volume paracentesis that led to deterioration in renal function. They interpreted this as an exaggeration of the arterial vasodilatation already present in cirrhotic patients with ascites, with further activation of the already stimulated vasoconstrictor systems74 leading to further renal vasoconstriction. The intriguing observation is that only 32% of patients had activation of the vasoconstrictor systems after large-volume paracentesis.74 The answer may lie in the extent of the hemodynamic instability before paracen-

Acute blood loss leads to acute blood volume contraction with decreased renal perfusion and acute tubular necrosis. However, the pathogenesis of acute renal failure secondary to variceal bleeding has been poorly documented, and some patients are diagnosed as having (type 1) HRS. For example, in a recent study 46% of 85 patients with decompensated cirrhosis (rst hit) and variceal bleeding developed a systemic inammatory response syndrome, manifesting with increased temperature, tachycardia, tachypnea, and leukocytosis, with or without an infection,75 associated with exacerbation of the hyperdynamic circulation (second hit). The inammatory response is associated with activation of many cytokines,76 some of which stimulate production of nitric oxide and other vasodilators.76 Thus, the patient with gastrointestinal bleeding is also predisposed to further exaggeration of systemic arterial vasodilation because the accompanying inammatory response will yield more vasodilators and aggravate the effective arterial underlling. Superimposition of this systemic inammatory response (second hit) on decompenasated liver disease can lead to organ failure. In one report, 3 patients died of documented HRS after acute gastrointestinal bleeding.75 However, in such cases, the classic differentiation of acute tubular necrosis from HRS by an active urinary sediment with casts and urinary sodium concentration greater than 20 mmol/L may be blurred. Development of renal failure after gastrointestinal bleeding is related to an advanced stage of cirrhosis77 and renal impairment before the bleeding is a predictor of mortality.77 Cirrhotic patients with marked systemic arterial vasodilatation and effective underlling are less able to tolerate intravascular volume depletion, predisposing them to development of renal failure and a poor outcome. Recommendation. Cirrhotic patients with acute gastrointestinal bleeding and poor liver function and/or decreased renal function should be managed in an intensive care unit where optimal monitoring can provide maximum protection of their effective circulating blood volume and renal perfusion. In addition, cirrhotic patients, particularly those with ascites, with acute variceal bleeding, should be given a prophylactic course of antibiotics.78 Recommended antibiotic regimens include noroxicin, 400 mg 12 hourly for a minimum of 7 days, or a combination of ciprooxacin, 400 mg daily, and amoxicillinclavulanic acid, 3 g daily, intravenously and then orally and continued for 3 days after the bleeding stops. In a meta-analysis of randomized controlled trials,79 prophylactic antibiotics signicantly reduced the incidence of SBP and consequently mortality from septic shock and renal failure.80

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SBP is another common precipitant of HRS. At least 30% of patients with SBP develop HRS despite adequate treatment of infection.81,82 Previous renal impairment and a marked inammatory response, indicated by the polymorphonuclear cell count and cytokine concentrations in ascitic uid, result in further arterial vasodilatation and are important predictors for development of type 1 HRS.83 Sepsis decreases both spontaneous and agonist-induced vascular contractile activity in the cirrhotic rat.84 Sort et al.85 postulated that sepsis in cirrhosis induces an increased production of various cytokines and endotoxins, which in turn stimulate the production of nitric oxide and other vasodilators86 causing further arterial vasodilatation. Indeed, intestinal decontamination with oral antibiotics in cirrhotic patients was associated with improvement in systemic hemodynamics and reduction in systemic arterial vasodilatation,87 probably as a result of a reduction of nitric oxideinduced systemic arterial vasodilatation.88 Thus, circulatory dysfunction in patients with SBP is in many ways similar to that observed in patients with gastrointestinal bleeding: the inammatory response leads to further reduction of effective arterial blood volume resulting in incremental activation of the already elevated neurohumoral vasoconstrictor systems with development of renal vasoconstriction and dysfunction.85 Therefore, it is not surprising that the same investigators reported signicant reduction in the incidence of renal impairment when patients with SBP were given volume expansion in the form of intravenous albumin85 in a randomized controlled study. However, circulatory dysfunction worsened, indicated by rising PRA, despite adequate treatment of the infection. It appears that a precipitant will only induce type I HRS in a susceptible patient. For example, renal impairment in patients with SBP only occurred in those with a direct bilirubin level greater than 4 mg/dL.85 Recommendation. Patients who develop SBP with evidence of renal impairment or with serum bilirubin levels greater than 4 mg/dL should be managed in a setting that allows optimal monitoring to protect volume status and renal function and should be treated initially with intravenous albumin 1.5 g/kg per day.
Cholestasis

impairment.95 They postulated that the increased production of F2-isoprostanes in cholestasis was responsible for the development of renal failure because F2-isoprostanes are potent renal vasoconstrictors, and administration of antioxidants that reduced F2-isoprostanes levels was associated with improvement of renal function.95 HRS is also a common cause of death in patients with severe acute alcohol-induced hepatitis96 in whom sinusoidal portal hypertension is exacerbated and liver function deteriorates further. Severity in this context can be dened using the Maddrey discriminant function97: 1 of the 2 components is serum bilirubin level and the other is prothrombin time, i.e., 4.6 (prothrombin time control time in seconds) serum bilirubin in mg/dL. Therefore, the onset of cholestatic jaundice in advanced cirrhosis may be a less well recognized second hit, contributing to the development of type 1 HRS in patients. Recommendation. Cirrhotic patients who as a consequence of decompensation have developed signicant cholestasis, e.g., serum bilirubin greater than 4 mg/dL, should be considered at increased risk for developing HRS in the presence of a second hit, SBP, or variceal bleeding and treated accordingly. In patients with severe acute alcohol-induced hepatitis and jaundice, further control trials are needed to conrm the use of pentoxifylline to prevent onset of HRS and to reduce mortality96 in these patients.
TYPE II

The presence of cholestatic jaundice may be an unrecognized factor in the development of type 1 HRS. This is not surprising because historically obstructive jaundice can be an important factor (rst hit) in patients subjected to circulatory changes, such as surgery (second hit), and can lead to renal failure.89 It is now well accepted that cholestasis per se, in the absence of portal hypertension, causes vasodilatation and a hyperdynamic circulation associated with impaired vascular responsiveness to circulating vasoconstrictors.90 Therefore, cholestasis superimposed on cirrhosis and portal hypertension is likely to compound the circulatory changes,91 thus predisposing the patient to HRS. It is not surprising to nd both elevated bilirubin levels as a major component of prognostic indexes, such as the Child-Pugh score, and creatinine clearance frequently decreased to 60% of normal with biliary obstruction.92 The mechanism is still unknown, but could include endotoxemia, nephrotoxic effects of elevated levels of bile acids,93 and/or disturbances of renal prostaglandin/ thromboxane synthesis.94 Holt et al. observed that acute biliary obstruction was associated with the development of renal

Type II HRS has been regarded as an extension of the stage of refractory ascites in cirrhosis and shares the same pathophysiology, namely, splanchnic and systemic vasodilatation with renal vasoconstriction, leading to progressive deterioration in renal function.4 However, Papper et al. reported on a series of 200 patients with HRS, in which only 75% of the patients had massive ascites.98 Furthermore, in the only longterm follow-up study of Gines et al.1 assessing the natural history of a cohort of ascitic cirrhotic patients, the presence of ascites was not an independent predictor for development of HRS. Newer predictive factors such as renal-resistive index, measured by doppler ultrasound,99,100 or the Mayo End-Stage Liver Disease Index (MELD),101 based on the initial elevation of serum creatinine together with total bilirubin and a reduction in prothrombin time, may increase our ability to predict the onset of HRS in these patients. Despite this, patients with refractory ascites are poised to develop renal failure. Subtle factors such as a further deterioration in liver function with increasing cholestatic jaundice, which in itself causes systemic vasodilatation,90 further compromises the pathophysiology of refractory ascites and triggers development of renal failure.96 It is clear that while the denition separates HRS into two clinically distinct entities, for some patients both types of HRS are a continuum of the same condition: type II HRS can evolve into type I HRS, especially in the presence of precipitating factors.
NEW THERAPIES FOR HRS

Although liver transplantation remains the only effective permanent treatment for HRS,5,6 preoperative renal dysfunction frequently reduces patient and graft survival after liver transplantation.6-8,102 Therefore, medical treatments have attempted to reverse HRS, either denitively or to improve renal function sufciently to allow liver transplantation to proceed. All manipulate some aspects of the pathophysiology of HRS,

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with varying degrees of success. We therefore will examine various nonsurgical treatments for HRS from a pathophysiologic standpoint with the aim of improving prevention and overall management of HRS.
Vasopressin Analogues

Endothelin Antagonists

The rationale for using vasopressin analogues as a treatment for HRS is based on the observation that the vasopressin-1 receptor agonist, 8-ornithin vasopressin or ornipressin, a vasoconstrictor, increased splanchnic and systemic vascular resistance in cirrhotic patients with impaired renal function, resulting in redistribution of circulating blood volume. This improved systemic blood pressure and therefore renal perfusion pressure, thereby increasing renal plasma ow and glomerular ltration rate after only 4 hours of intravenous infusion.103,104 Infusion longer than 48 hours further improved renal function, resulting in a suppression of the renin-angiotensin and sympathetic activities with consequent further improvement in renal plasma ow and glomerular ltration rate. When ornipressin was infused for up to 15 days, together with plasma volume expansion with intravenous albumin, the improvement in renal function was even more impressive, but serious life-threatening ischemic complications limited the use of this therapy.11 In contrast, infusion of another vasopressin analogue, terlipressin, over 48 hours improved renal function, suppressed PRA and aldosterone levels, and increased the atrial natriuretic factor levels without increasing sodium excretion, all without serious side effects.105 Lack of a natriuretic response after improvement of renal function may be related to severe liver dysfunction in these patients, as onset of natriuresis has been shown to be related to a threshold of liver function.106-109 When terlipressin was combined with either intravenous albumin110 or a renal vasodilator such as low-dose dopamine,10 the result was even more encouraging, with suppression of the renin-angiotensin activity and normalization of serum creatinine in a number of patients without serious ischemic side effects. These observations further support the concept that both splanchnic and systemic arterial vasodilatation with effective arterial underlling, resulting in increased circulating levels of vasoconstrictors, play pathogenetic roles in the development of HRS. However, in some patients improvement in renal function persisted despite discontinuation of the vasopressin analogue, yet vasoconstrictor levels returned to their previously elevated levels.11
-Adrenergic Agonists

Endothelin has been postulated as one such mediator of intrarenal vasoconstriction in HRS. Therefore, an endothelin antagonist was assessed in a preliminary study to determine its efcacy in reversing HRS. Consecutive and increasing doses of an endothelin antagonist, BQ123, were infused for 60 minutes in 3 patients with HRS.115 All patients showed a doserelated increase in both glomerular ltration rate and renal plasma ow that approached 100% with the highest dose. However, these results have only appeared in the form of a Letter to the Editor and therefore cannot be recommended outside a clinical trial setting.
Antioxidants

Another group of intrarenal vasoconstrictors, the products of lipid peroxidation such as F2-isoprostanes, have been implicated in the pathogenesis of HRS.28,116 The synthesis of F2-isoprostanes is regulated through products of lipid peroxidation. In a recent study, 12 patients received continuous infusion of N-acetylcysteine, an antioxidant, for 5 days. Creatinine clearance improved from 24 3 mL/min to 43 4 mL/min without any change in liver function or systemic hemodynamics,60 suggesting that it was the reduction in oxidant stress per se that caused the improvement in renal function. Again, these are preliminary data and they need to be conrmed by clinical controlled trials. We cannot recommend this therapy outside the setting of a clinical trial.
Moleculular Adsorbent Recirculating System

In HRS, systemic vasoconstrictors such as metaraminol improved urinary sodium excretion but not renal function,111 whereas norepinephrine112 or dopamine10 were ineffective. Oral administration of an -adrenergic agonist, midodrine, improved systemic and renal hemodynamics in nonazotemic cirrhotic patients but had no effect in patients with HRS.113 However, when midodrine was combined with plasma volume expansion and octreotide, a nonspecic inhibitor of the release of endogenous vasodilators, there was signicant improvement in both the systemic and renal hemodynamics and urinary sodium excretion9 although renal function did not return to normal despite suppression of all measured neurohormonal systems to within the normal range. This may be because of continued renal hypoperfusion, maintained as a result of persistent intrarenal activation of vasoconstrictors.114

Molecular adsorbent recirculating system (MARS) is a modied dialysis method that uses an albumin-containing dialysate that selectively removes albumin-bound substances. The device consists of a dialysis module with an asymmetric permeable polysulfone-saturated membrane with human albumin on both the patient and dialysate sides of the membrane. During dialysis, a closed loop dialysate circuit allows the transfer of albumin-bound toxins from plasma onto the membrane. The membrane-bound albumin plus toxin is recycled by continuous deligandization. Water-soluble toxins can also be removed by using charcoal columns and ion-exchange resins as the adsorbents. The system is connected to a continuous venovenous hemoltration system to remove most molecules except those with a molecular weight greater than 50 kd. Although conventional dialysis has not been shown to be effective in the treatment of HRS,117,118 the use of albuminenriched dialysate uid seems to help in the management of HRS. In a randomized controlled trial of MARS-assisted dialysis versus conventional hemodialysis and standard medical therapy,119 the patients who received MARS-assisted dialysis had a signicant reduction in serum bilirubin and creatinine (from 3.8 1.6 mg/dL to 2.3 1.5 mg/dL) that was associated with a prolongation of survival; however, survival was still low (40%) at 2 weeks. Although hemodynamic measurements were not performed, mean arterial pressure did not change in the MARS patients. MARS dialysate removes cytokines, such as tumor necrosis factors and interleukin 6,120,121 among other substances, that have been implicated in the production of various vasodilators.76 Therefore, excessive toxins such as cytokines appear to be important in the pathogenesis of HRS but only via the intermediary of arterial vasodilatation. At the very least, MARS appears to have potential as bridging therapy for HRS patients awaiting denitive treat-

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ment. In addition, it may open up new avenues of research into the pathogenesis of HRS. We must await further conrmatory trials of this exciting approach. Therefore, MARS should not be used in the treatment of patients with HRS except in the context of a clinical trial.
TIPS

Successful insertion of a TIPS, which lowers portal pressure, was associated with improved renal function in patients with HRS,11,12,122-124 thereby supporting a central role of sinusoidal portal hypertension in the pathogenesis of renal dysfunction in these patients. From a pathophysiologic point of view, TIPS returns a signicant portion of the splanchnic volume into the systemic circulation, suppressing various vasoactive neurohormones, and thus improves renal hemodynamics.125 However, TIPS does not reverse every case of HRS, and even in those patients who do respond, it does not completely normalize renal function. This may be related to the fact that TIPS acutely exacerbates the hyperdynamic circulation.125,126 Many of the systemic vasoconstrictors such as ET1 also remained elevated post-TIPS despite relling of the systemic circulation122; this can also explain the slow recovery of renal function. In the rst small controlled trial of TIPS for 25 patients with refractory ascites, a forerunner of HRS, that included 8 jaundiced Child class C patients, the mortality rate after 2 years in patients treated with TIPS was 56%, which was signicantly greater than in patients treated with repeat largevolume paracentesis (29%).127 This nding was recently reversed, with TIPS signicantly improving the chances of survival in patients with refractory ascites compared with paracentesis.128 However, the second study excluded cholestatic patients with serum bilirubin greater than 5 mg/dL and serum creatinine greater than 3 mg/dL. In the largest study of TIPS for HRS to date, the survival rate at 2 years was 35%.12 Of further interest, the patients were separated into types I and II HRS. Survival was 70% at 1 year for type II HRS patients and signicantly greater than the 20% for type I HRS patients. Thus, Cox regression analysis found both HRS type (P .05) and serum bilirubin (P .001) to be independent survival predictors post-TIPS. It still remains to be seen whether further correction of the pathophysiology, such as reduction of portal pressure into the normal range or infusion of volume expanders, such as albumin, in the post-TIPS period, may help to return renal function to normal. We obviously still do not understand every pathophysiologic change that occurs after TIPS nor do we know what determines which patients will or will not respond to TIPS placement. Perhaps there are critical levels of renal dysfunction and cholestatic jaundice that determine no response no matter what medical treatment is provided. The answers to these questions will have to await the results of randomized controlled trials. After that, we may be able to select the ideal candidates for TIPS insertion.129 Recommendation. TIPS therapy for HRS should only be performed in the setting of a clinical trial, optimally with types I and II patients being studied separately.
SUMMARY

more electively. Furthermore, by improving renal function before liver transplantation, we may improve patient and graft survival after transplantation6,102 and avoid the necessity of liver-kidney transplants.8 Alternatively, by identifying patients at risk earlier in the natural history of HRS, by using predictive indices such as the renal arteriolar-resistive index or MELD,101 we may be able to develop management strategies to further prevent development of HRS and thereby reduce the morbidity and mortality of these severely ill patients. Finally, future clinical trials in HRS should separate types I and II patients to clarify the therapeutic responses for both groups. These considerations are important because clinical investigators will nd randomized placebo-controlled trials difcult to conduct ethically in this group of patients because of the virtual 100% mortality of HRS type I.
REFERENCES 1. Gines A, Escorsell, Gines P, Salo J, Jimenez W, Inglada L, Navasa M, et al. Incidence, predictive factors and prognosis of the hepatorenal syndrome in cirrhosis and ascites. Gastroenterology 1993;105:229-236. 2. Helwig FC, Schutz CB. A liver kidney syndrome. Clinical pathological and experimental studies. Surg Gynecol Obstet 1932;55:570-580. 3. Hecker R, Sherlock S. Electrolyte and circulatory changes in terminal renal failure. Lancet 1956;2:1121-1125. 4. Arroyo V, Gines P, Gerbes AL, Dudley FJ, Gentilini P, Laf G, Reynolds TB, et al. Denition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. HEPATOLOGY 1996;23:164-176. 5. Iwatsuki S, Popovtzer MM, Corman JL, Ishikawa M, Putnam CW, Katz FH, Starzl TE. Recovery from hepatorenal syndrome after orthotopic liver transplantation. N Engl J Med 1973;289:1155-1159. 6. Gonwa TA, Morris CA, Goldstein RM, Husberg BS, Klintmalm GB. Long-term survival and renal function following liver transplantation in patients with and without hepatorenal syndrome experience in 300 patients. Transplantation 1991;51:428-430. 7. Brown RS, Lombardero M, Lake JR. Outcome of patients with renal insufciency undergoing liver or liver-kidney transplantation. Transplantation 1996;62:1788-1793. 8. Jeyarajah DR, Gonwa TA, McBride M, Testa G, Abbasoglu O, Husberg BS, Levy MF, et al. Hepatorenal syndrome: combined liver kidney transplants versus isolated liver transplant. Transplantation 1997;64:17601765. 9. Angeli P, Volpin R, Gerunda G, Craighero R, Merenda R, Bottaro S, Amodio P, et al. Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. HEPATOLOGY 1999;29: 1690-1697. 10. Gulberg V, Bilzer M, Gerbes AL. Long-term therapy and retreatment of hepatorenal syndrome type 1 with ornipressin and dopamine. HEPATOLOGY 1999;30:870-875. 11. Guevara M, Gines P, Fernandez-Esparrach G, Sort P, Salmeron JM, Jimenez W, Arroyo V, Rodes J. Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion. HEPATOLOGY 1998;27:35-41. 12. Brensing KA, Textor J, Perz J, Schiedermaier P, Raab P, Strunk H, Klehr HU, et al. Long term outcome after transjugular intrahepatic portosystemic stent-shunt in non-transplant cirrhotics with hepatorenal syndrome: a phase II study. Gut 2000;47:288-295. 13. Cardenas A, Uriz J, Gines P, Arroyo V. Hepatorenal syndrome. Liver transplantation 2000;6(suppl 1):S63-S71. 14. Bataller R, Sort P, Gines P, Arroyo V. Hepatorenal syndrome: denition, pathophysiology, clinical features and management. Kidney Int 1998; 53(suppl 66):S47-S53. 15. Bernardi M, Fornale L, Di Marco C, Trevisani F, Baraldini M, Gasbarrini A, De Collibus C, et al. Hyperdynamic circulation of advanced cirrhosis: a re-appraisal based on posture-induced changes in hemodynamics. J Hepatol 1995;22:309-318. 16. Groszmann, RJ. Hyperdynamic circulation of liver disease 40 years later: pathophysiology and clinical consequences. HEPATOLOGY 1994;20: 1359-1363. 17. Albillos A, Colombato LA, Groszmann RJ. Vasodilatation and sodium retention in prehepatic portal hypertension. Gastroenterology 1992; 102:931-935. 18. Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodes J. Peripheral arterial vasodilation hypothesis: a proposal for the initiation

Recent advances made in the understanding of the pathophysiology of HRS have improved the prognosis of many patients. However, there is still a great deal to be learned about HRS. Treatments now available prolong the survival of many of these patients and allow liver transplantation to proceed

HEPATOLOGY Vol. 34, No. 6, 2001 of renal sodium and water retention in cirrhosis. HEPATOLOGY 1988;8: 1151-1157. Stein J. Regulation of the renal circulation. Kidney Int 1990;38:571-576. Maroto A, Gines P, Arroyo V, Gines A, Salo J, Claria J, Jimenez W, et al. Brachial and femoral artery blood ow in cirrhosis: relationship to kidney dysfunction. HEPATOLOGY 1993;17:788-793. Moore K. Hepatorenal syndrome. Clin Sci 1997;92:433-443. Ring-Larsen H. Renal blood ow in relation to systemic and portal hemodynamics and liver function. Scand J Clin Lab Invest 1977;37:635642. Dagher L, Patch D, Marley R, Moore K, Burrough A. Review article: pharmacological treatment of hepatorenal syndrome in cirrhotic patients. Aliment Pharmacol Ther 2000;14:515-521. Uchihara M, Izumi N, Sato C, Marumo F. Clinical signicance of elevated plasma endothelin concentration in patients with cirrhosis. HEPATOLOGY 1992;16:95-99. Moore K, Wendon J, Frazer M, Karani J, Williams R, Badr K. Plasma endothelin immunoreactivity in liver disease and the hepatorenal syndrome. N Engl J Med 1992;327:1774-1778. Huber M, Kastner S, Scholmerich J, Gerok W, Keppler D. Analysis of cysteinyl leukotrienes in human urine: enhanced excretion in patients with liver cirrhosis and hepatorenal syndrome. Eur J Clin Invest 1989; 19:53-60. Uemura M, Buchholz U, Kojima H, Keppler A, Hafkemeyer P, Fukui H, Tsujii T, et al. Cysteinyl leukotrienes in the urine of patients with liver diseases. HEPATOLOGY 1994;20:804-812. Morrow JD, Moore KP, Awad JA, Ravenscraft MD, Marini G, Badr K, Williams R, et al. Marked overproduction of non-cyclo-oxygenase derived prostanoids (F2-isoprostanes) in the hepatorenal syndrome. J Lipid Mediators 1993;6:417-420. Salo J, Fernandez-Esparrach G, Gines P, Gines A, Guevara M, Sort P, Jimenez W, et al. Urinary endothelin like immunoreactivity in patients with cirrhosis. J Hepatol 1997;27:810-816. Guevara M, Gines P, Bandi JC, Gilabert R, Sort P, Jimenez W, GarciaPagan JC, et al. Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: effect on renal function and vasoactive systems. HEPATOLOGY 1998;28:416-422. Campbell V, Greig PD, Cranford J, Langer B, Silverman M, Blendis LM. A comparison of acute reversible pre- and post-sinusoidal portal hypertension on salt and water retention in the dog. HEPATOLOGY 1982;2: 54-58. Jalan R, Forrest EH, Redhead DN, Dillon JF, Hayes PC. Reduction in renal blood ow following acute increase in the portal pressure: evidence for the existence of a hepatorenal reex in man? Gut 1997;40: 664-670. Lebrec D, Bataille C, Bercoff E, Valla D. Hemodynamic changes in patients with portal venous obstruction. HEPATOLOGY 1983;3:550-553. Rayner BL, Robson SC, Kirsch RE, Voigt M. Renal function, sodium and water homeostasis in patients with idiopathic extrahepatic portal vein thrombosis compared with normal healthy controls. S Afr Med J 2001; 91:61-65. Lang F, Tschernko E, Schulze E, Ottl I, Ritter M, Valkl H, et al. Hepa` torenal reex regulating kidney function. HEPATOLOGY 1991;14:590594. Kostreva D, Castaner A, Kampine J. Reex effects of hepatic baroreceptors on renal and cardiac sympathetic nerve activity. Am J Physiol 1980; 238:R390-R394. Di Bona GF. Renal nerve activity in hepatorenal syndrome. Kidney Int 1984;25:841-853. Koepke JP, Jones S, Di Bona GF. Renal nerves mediate blunted natriuresis to atrial natriuretic peptide in cirrhotic rats. Am J Physiol 1987;252: R1019-R1023. Solis-Herruzo JA, Duran A, Favela G, Castellano G, Madrid JL, MunozYague MT, Morillas JD, et al. Effects of lumbar sympathetic block on kidney function in cirrhotic patients with hepatorenal syndrome. J Hepatol 1987;5:167-173. Epstein M. Renal prostaglandins and the control of renal function in liver disease. Am J Med 1986;80:46-61. Guarner C, Colina I, Guarner F, Corzo J, Prieto J, Vilardi F. Renal prostaglandins in cirrhosis of the liver. Clin Sci 1986;70:477-484. Laf G, La Villa G, Pinzani M, Ciabattoni G, Patrignani P, Mannelli M, Cominelli F, et al. Altered renal and platelet arachidonic acid metabolism in cirrhosis. Gastroenterology 1986;90:274-282. Rimola A, Gines P, Arroyo V, Camps J, Peres-Ayuso RM, Quintero E, et al. Urinary excretion of 6-keto-prostaglandin F1alpha, thromboxane B2

WONG AND BLENDIS

1249

19. 20.

44.

21. 22.

45.

23.

46. 47. 48.

24.

25.

26.

49. 50.

27. 28.

51. 52. 53. 54.

29. 30.

31.

55. 56. 57. 58. 59. 60. 61. 62. 63. 64.

32.

33. 34.

35. 36. 37. 38. 39.

40. 41. 42. 43.

65.

66.

and prostaglandin E2 in cirrhosis with ascites: relationship to functional renal failure (hepatorenal syndrome). J Hepatol 1986;3:111-117. Moore K, Ward PS, Taylor GW, Williams R. Systemic and renal production of thromboxane A2 and prostacyclin in decompensated liver disease and hepatorenal syndrome. Gastroenterology 1991;100:10691077. Govindarajan S, Nast CC, Smith WL, Koyle MA, Daskalopoulos G, Zipser RD. Immunohistochemical distribution of renal prostaglandin endoperoxidase synthase and prostacyclin synthase: diminshed endoperoxidase synthase in the hepatorenal syndrome. HEPATOLOGY 1987; 7:654-659. Boyer T, Zia P, Reynolds T. Effect of indomethacin and prostaglandin A, on renal function and plasma renin activity in alcoholic liver disease. Gastroenterology 1979;77:215-222. Bomzon A, Blendis LM. The nitric oxide hypothesis and the hyperdynamic circulation in cirrhosis. HEPATOLOGY 1994;20:1343-1350. Guarner C, Soriano G, Tomas A, Bulbena O, Novella MT, Balanzo J, Vilardell F, et al. Increased serum nitrite and nitrate levels in patients with cirrhosis: relationship to endotoxemia. HEPATOLOGY 1993;18: 1139-1143. Raij L, Baylis C. Glomerular actions of nitric oxide. Kidney Int 1995;48: 20-32. Bech JN, Nielsen CB, Pedersen EB. Effects of systemic nitric oxide synthesis inhibition on renal plasma ow, glomerular ltration rate, urinary sodium excretion, and vasoactive hormones in healthy humans. Am J Physiol 1996;270:F845-F851. Ros J, Claria J, Jimenez W, Bosch-Marce M, Angeli P, Arroyo V, Rivera F, et al. Role of nitric oxide and prostacyclin in the control of renal perfusion in experimental cirrhosis. HEPATOLOGY 1995;22:915-920. Arucha NM, Garcia-Estan J, Ramirez A, Perez MC, Quesada T, Romero JC. Renal effects of nitric oxide synthesis inhibition in cirrhotic rats. Am J Physiol 1994;267: R1454-R1460. Claria J, Jimenez W, Ros J, Asbert M, Castro A, Arroyo V, Rivera F, et al. Pathogenesis of arterial hypotension in cirrhotic rats with ascites: role of endogenous nitric oxide. HEPATOLOGY 1992;15:343-349. Criado M, Flores O, Ortiz MC, Hidalgo F, Rodriguez-Lopez AM, Eleno N, Atucha NM, et al. Elevated glomerular and blood mononuclear lymphocye nitric oxide production in rats with chronic bile duct ligation: role of inducible nitric oxide sythase activation. HEPATOLOGY 1997;26: 268-276. Campillo B, Bories PN, Benvenuti C, Dupeyon C. Serum and urinary nitrate levels in liver cirrhosis: endotoxemia, renal function and hyperdynamic circulation. J Hepatol 1996;24:707-714. Martin PY, Gines P, Schrier RW. Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis. N Engl J Med 1998;339:533-541. Tajiri K, Miyakawa H, Izumi N, Marumo F, Sato C. Systemic hypotension and diuresis by L-arginine in cirrhotic patients with ascites: role of nitric oxide. HEPATOLOGY 1995;22:1430-1435. Gulberg V, Moller S, Henriksen AL, Gerbes AL. Increased renal production of C-type natriuretic peptide (CNP) in patients with cirrhosis and functional renal failure. Gut 2000;47:852-857. Angeli P, Jimenez W, Arroyo V, Mackenzie HS, Zhang PL, Claria J, Rivera F, et al. Renal effects of natriuretic peptide receptor blockade in cirrhotic rats with ascites. HEPATOLOGY 1994;20:948-954. Holt S, Goodier D, Marley R, Patch D, Burroughs A, Fernando B, Harry D, Moore K. Improvement in renal function in hepatorenal syndrome with N-acetylcysteine. Lancet 1999;353:294-295. Rasool A, Palevsky PM. Treatment of edematous disorders with diuretics. Am J Med Sci 2000;319:25-37. Papper S. The hepatorenal syndrome. In: Epstein M, ed. The Kidney in Liver Disease. 2nd Edition. New York: Elsevier Biomedical 1983:87106. Spahr L, Villeneuve JP, Tran HK, Pomier-Layrargues G. Furosemideinduced natriuresis as a test to identify cirrhotic patients with refractory ascites. HEPATOLOGY 2001;33:28-31. Gines P, Arroyo V, Quintero E, Planas R, Bory F, Cabrera J, Rimola A, et al. Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites. Results of a randomized study. Gastroenterology 1987;93:234-241. Fernandez-Esparrach G, Guevara M, Sort P, Pardo A, Jimenez W, Gines P, Planas R, et al. Diuretic requirements after therapeutic paracentesis in non-azotemic patients with cirrhosis. A randomized double-blind trial of spironolactone versus placebo. J Hepatol 1997;26:614-620. Gentilini P, Casini-Raggi V, Di Fiore G, Romanelli RG, Buzzelli G, Pinzani M, La Villa G, Laf G. Albumin improves the response to di-

1250 WONG AND BLENDIS

uretics in patients with cirrhosis and ascites. Results of a randomized control trial. J Hepatol 1999;30:639-645. Blendis L, Wong F. Intravenous albumin with diuretics. Protean lessons to be learnt? J Hepatol 1999;30:727-730. Loon NR, Wilcox CS, Unwin RJ. Mechanism of impaired response to furosemide during prolonged therapy. J Clin Invest 1989;83:113-126. Gregory PB, Broekelschen PH, Hill MD, Lipton AB, Knauer CM, Egger M, Miller R. Complications of diuresis in the alcoholic patient with ascites: a controlled trial. Gastroenterology 1977;73:534-538. Pockros PJ, Reynolds TB. Rapid diuresis in patients with ascites from chronic liver disease: the importance of peripheral edema. Gastroenterology 1986;90:1827-1833. Gines P, Arroyo V. Is there still a need for albumin infusions to treat patients with liver disease? Gut 2000;46:588-590. Brater DC. Diuretic therapy. N Engl J Med 1998;339:387-395. Ruiz-del-Arbol L, Monescillo A, Jimenez W, Garcia-Plaza A, Arroyo V, Rodes J. Paracentesis-induced circulatory dysfunction: mechanism and the effect on hepatic hemodynamics in cirrhosis. Gastroenterology 1997;113:579-586. Salo J, Gines A, Gines P, Piera C, Jimenez W, Guevara M, FernandezEsparrach G, et al. Effect of therapeutic paracentesis on plasma volume and transvascular escape rate of albumin in patients with cirrhosis. J Hepatol 1997;27:645-653. Afessa B, Kublis PS. Upper gastrointestinal bleeding in patients with hepatic cirrhosis: clinical course and mortality prediction. Am J Gastroenterology 2000;95:484-489. Paterson RL, Webster NR. Sepsis and the systemic inammatory response syndrome. J R Coll Surg Edinb 2000;45:178-182. Del Olmo JA, Pena A, Serra MA, Wassel AH, Benages A, Rodrigo JM. Predictors of morbidity and mortality after the rst episode of upper gastrointestinal bleeding in liver cirrhosis. J Hepatol 2000;32:19-24. Rimola A, Garcia-Tsao G, Navasa M, Piddock LJ, Planas R, Bernard B, Inadomi JM. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol 2000;32:142-153. Bernard B, Grange JD, Khac EN, Amiot X, Opolon P, Poynard T. Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis. HEPATOLOGY 1999;29:1655-1661. Pauwels A, Mostefa-Kara N, Debenes B, Degoutte E, Florent C, Levy VG. Antimicrobial prophylaxis after gastrointestinal hemorrhage for cirrhotic patients with a high risk of infection. HEPATOLOGY 1996;24: 802-806. Follo A, Llovet JM, Navasa M, Planas R, Forns X, Francitorra A, Rimola A, et al. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis. HEPATOLOGY 1994;20:1495-1501. Navasa M, Rodes J. Management of ascites in the patient with portal hypertension with emphasis on spontaneous bacterial peritonitis. Semin Gastrointest Dis 1997;8:200-209. Navasa M, Follo A, Filella X, Jimenez W, Francitorra A, Planas R, Rimola A, et al. Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis. Relationship with the development of renal impairment and mortality. HEPATOLOGY 1998;27:1227-1232. Mastrangelo D, Frossard JL, Hadengue A, Pastor CM. Sepsis decreases the spontaneous and agonist-induced contractile activities in the rat portal vein. J Hepatol 2000;33:933-940. Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-del-Arbol, Castells L, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;341:403-409. Jimenez W, Ros J, Morales-Ruiz M, Navasa M, Sole M, Colmenero J, Sort P, et al. Nitric oxide production and inducible nitric oxide synthase expression in peritoneal macrophages of cirrhotic patients. HEPATOLOGY 1999;30:670-676. Rasaratnam B, Kaye D, Chin-Dusting J, Gennings G, Dudley F. Effect of selective intestinal decontimation on the peripheral arterial vasodilatation in cirrhosis [Abstract]. HEPATOLOGY 2000;32(part 2 of 2):310A. Chin-Dusting J, Rasaratnam B, Gennings G, Dudley F. Effect of uoroquinolone on the enhanced nitric oxide induced peripheral arterial vasodilatation seen in cirrhosis. Ann Int Med 1997;127:985-988. Dixon JM, Armastrong CP, Duffey, Davies GC. Factors affecting morbidity and mortality after surgery for obstructive jaundice: a review of 373 patients. Gut 1983;24:845-852. Bomzon A, Rosenberg M, Gali D, Binah O, Mordechovitz D, Better OS, Greig PD, Blendis LM. Systemic hypotension and decreased pressor

HEPATOLOGY December 2001 response in dogs with chronic bile duct ligation. HEPATOLOGY 1986;6: 595-600. Lee SS, Girod C, Braillon A, Hadengue A, Lebrec D. Hemodynamic characterization of chronic bile duct-ligated rats: effect of pentobarbital sodium. Am J Physiol 1986;251:G176-G180. Thompson JN, Edwards WH, Winearls CG, Blenkharn JI, Benjamin IS, Blumgart LH. Renal impairment following biliary tract surgery. Br J Surg 1987;74:843-847. Bomzon A, Green J, Better OS. Jaundice and the kidney. In: Epstein M, ed. The Kidney in Liver Disease. Philadelphia: Hanley & Belfast 1996; 423-446. Kramer HJ, Scharting K, Backer A. Impaired renal function in obstructive jaundice. Clin Sci & Mol Med 1995;88:39-45. Holt S, Marley R, Fernando B, Harry D, Anand R, Goodier D, Moore K. Acute cholestasis-induced renal failure: effects of antioxidants and ligands for the thromboxane A2 receptor. Kidney Int 1999;55:271-277. Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology 2000;119: 1637-1648. Maddrey WC, Boitnott JK, Bedline MS, Weber FLJ, Mezey E, Whire RI. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology 1978; 75:193-199. Papper S, Belsky JL, Bleifer KH. Renal failure in Laennecis cirrhosis of the liver: (1) Description of clinical and laboratory features. Ann Int Med 1959;51:759-773. Maroto A, Gines A, Salo J, Claria J, Gines P, Anibarro L, Jimenez W, et al. Diagnosis of functional kidney failure of cirrhosis with Doppler sonography: prognostic value of resistive index. HEPATOLOGY 1994;20: 839-844. Platt JF, Ellis JH, Rubin JM, Merion RM, Lucey MR. Renal duplex doppler ultrasonography: a non invasive predictor of kidney dysfunction and hepatorenal failure in liver disease. HEPATOLOGY 1994;20:362-369. Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg C, DAmico G, et al. A model to predict survival in patients with end-stage liver disease. HEPATOLOGY 2001;33:464-470. Lafayette RA, Pare G, Schmid CH, King AJ, Rohrer RJ, Nasraway SA. Pre-transplant renal dysfunction predicts poorer outcome in liver transplantation. Clin Nephrol 1997;48:159-164. Lenz K, Hortnagl H, Druml W, Grimm G, Laggner A, Schneeweisz B, Kleinberger G. Benecial effects of 8-ornithin vasopressin on renal dysfunction in decompensated cirrhosis. Gut 1989;30:90-96. Lenz K, Hortnagl H, Druml W, Reither H, Schmid R, Schneeweisz B, Laggner A, et al. Ornipressin in the treatment of functional renal failure in decompensated liver cirrhosis, effects on renal hemodynamics and atrial natriuretic factor. Gastroenterology 1991;101:1060-1067. Hadengue A, Gadano A, Moreau R, Giostra E, Durand F, Vella D, Erlinger S, Lebrec D. Benecial effects of the 2-day administration of terlipressin in patients with cirrhosis and hepatorenal syndrome. J Hepatol 1998;29:565-570. Wong F, Massie D, Hsu P, Dudley F. The renal response to a saline load in well compensated alcoholic cirrhosis. HEPATOLOGY 1994;20:873-881. Wensing G, Sabra R, Branch RA. Renal and systemic hemodynamics in experimental cirrhosis in rats: relation to hepatic function. HEPATOLOGY 1990;12:13-19. Wensing G, Sabra R, Branch RA. The onset of sodium retention in experimental cirrhosis in rats is related to a critical threshold of liver function. HEPATOLOGY 1990;11:779-786. Jalan R, Hayes PC. Sodium handling in patients with well compensated cirrhosis is dependent on the severity of liver disease and portal pressure. Gut 2000;46:527-533. Uriz J, Gines P, Cardenas A, Sort P, Jimenez W, Salmeron JM, Bataller R, et al. Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome. J HEPATOLOGY 2000;33:43-48. Lancestremere RG, Klinger EL Jr, Frisch E, Papper S. Simultaneous determinations of cardiac output and renal function in patients with Laennecs cirrhosis during the administration of the pressor amine, metaraminol. J Lab Clin Med 1963;61:820-825. Badalamenti S, Borroni G, Lorenzano E, Incerti P, Salerno F. Renal effects in cirrhotic patients with avid sodium retention of atrial natriuretic factor injection during norepinephrine infusion. HEPATOLOGY 1992;15:824-829. Angeli P, Volpin R, Piovan D, Bortoluzzi A, Craighero R, Bottaro S, Finucci GF, et al. Acute effects of the oral administration of midodrine, an -adrenergic agonist, on renal hemodynamics and renal function in cirrhotic patients with ascites. HEPATOLOGY 1998;28:937-943.

67. 68. 69. 70. 71. 72. 73.

91. 92. 93. 94. 95. 96.

74.

97. 98. 99.

75. 76. 77. 78.

100. 101. 102. 103. 104.

79.

80.

81.

105.

82. 83.

106. 107. 108. 109. 110. 111.

84. 85.

86.

87. 88. 89. 90.

112.

113.

HEPATOLOGY Vol. 34, No. 6, 2001 114. Arroyo V, Jimenez W. Complications of cirrhosis. II. Renal and circulatory dysfunction. Lights and shadows in an important clinical problem. J Hepatol 2000;32(suppl 1):157-170. 115. Soper CP, Latif AB, Bending MR. Amelioration of hepatorenal syndrome with selective endothelin-A antagonist [Letter]. Lancet 1996;347:18421843. 116. Holt S, Marley R, Goodier D, Harry D, Fernando B, Moore K. Oxidant stress and renal dysfunction in cholestasis. Gut 1998;43:153. 117. Wilkinson SP, Weston MJ, Parsons V, Williams R. Dialysis in the treatment of renal failure in liver disease. Clin Nephrol 1977;8:287-292. 118. Perez GO, Oster JR. A critical review of the role of dialysis in the treatment of liver disease. In: Epstein M, ed. The Kidney in Liver Disease. First Edition. New York: Elsevier 1978;325-335. 119. Mitzner SR, Stange J, Klammt S, Risler T, Erley CM, Bader BD, Berger ED, et al. Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: results of a prospective randomized, controlled clinical trial. Liver Transpl 2000;6:277-286. 120. Awad SS, Sawada S, Soldes OS, Ricj PB, Klein R, Alarcon WH, Bartlett RH. Can the clearance of tumor necrosis factor and interleukin 6 be enhanced using an albumin dialysate hemodialtration system? ASAIO J 1999;45:47-49. 121. Rahman TM, Hodgson HJF. Liver support systems in acute hepatic failure. Aliment Pharmacol Ther 1999;13:1255-1272. 122. Brensing KA, Textor J, Strunk H, Klehr HU, Schild H, Saverbruch T, et al. Transjugular intrahepatic portosystemic stent-shunt for hepatorenal syndrome. Lancet 1997;349:697-698.

WONG AND BLENDIS

1251

123. Lake JR, Ring EJ, LaBerge JM, Gordon R, Roberts J, Ascher N. Transjugular intrahepatic portasystemic stent shunts in patients with renal insufciency. Transplant Proc 1993;25:1766-1767. 124. Spahr L, Fenyves D, Nguyen VV, Roy L, Legault L, Dufresne MP, Pomier-Layrarques G, et al. Improvement of hepatorenal syndrome by transjugular intrahepatic portosystemic shunt. Am J Gastroenterology 1995;90:1169-1171. 125. Wong F, Sniderman K, Liu P, Allidina Y, Sherman M, Blendis LM. The effects of transjugular intrahepatic portasystemic shunt on systemic and renal hemodynamics and sodium homeostasis in cirrhotic patients with refractory ascites. Ann Int Med 1995;122:816-822. 126. Azoulay D, Casting D, Dennison A, Martino W, Eyraud D, Bismuth H. Transjugular intrahepatic portosystemic shunt worsens the hyperdynamic circulation state of the cirrhotic: preliminary report of a prospective study. HEPATOLOGY 1994;19:129-132. 127. Lebrec D, Giuily N, Hadenque A, Vilgrain V, Moreau R, Poynard T, Gadano A, et al. Transjugular intrahepatic portosystemic shunt: comparison with paracentesis in patients with cirrhosis and refractory ascites: a randomized trial. J Hepatol 1996;25:135-144. 128. Rossle M, Ochs A, Gulberg V, Siegerstetter V, Holl J, Deibert P, Olschewski M, et al. A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with ascites. N Engl J Med 2000;342;1701-1707. 129. Boyer TD. Is transjugular intrahepatic portosystemic shunt a panacea for the complications of portal hypertension. HEPATOLOGY 1998;28:590592.