Diagnosis and treatment of hepatorenal syndrome

BaillieÁre's Clinical Gastroenterology Vol. 14, No. 6, pp. 945±957, 2000

doi:10.1053/bega.2000.0140, available online at http://www.idealibrary.com on

5 Diagnosis and treatment of hepatorenal syndrome Pere GineÁs*

MD

Associate Professor of Medicine Liver Unit, Institut de Malalties Digestives, Hospital ClõÂnic, IDIBAPS, University of Barcelona, Catalunya, Spain

Hepatorenal syndrome (HRS) is a common complication of advanced cirrhosis characterized not only by renal failure due to a marked vasoconstriction of the renal circulation but also by marked alterations in systemic haemodynamics and activity of endogenous vasoactive systems. The pathogenesis of HRS is not completely known but it is probably the result of an extreme under®lling of the arterial circulation secondary to an arterial vasodilation located in the splanchnic circulation. Besides the renal circulation all other extrasplanchnic vascular beds appears to be vasoconstricted. The diagnosis of HRS is currently based on the exclusion of non-functional causes of renal failure. Prognosis of patients with HRS is very poor. Liver transplantation is the best option in selected patients, but is seldom applicable due to the short survival expectancy of most patients with HRS, particularly those with the progressive type (type I HRS). Therapies introduced during the last few years, such as transjugular intrahepatic portosystemic shunts or, particularly, vasoconstrictor drugs with preferential e€ect on the splanchnic circulation (V1 receptor agonists) are very e€ective in improving renal function and reverting HRS. However, the impact of the improvement of renal function on the natural course of HRS is unknown. Finally, the development of HRS after spontaneous bacterial peritonitis can be e€ectively prevented by the administration of albumin together with antibiotic therapy. Key words: cirrhosis; ascites; renal failure; oedema; portal hypertension.

Patients with cirrhosis and ascites often develop a particular form of renal failure known as hepatorenal syndrome (HRS), which is due to a marked vasoconstriction of the renal circulation.1 This disorder is of functional origin because kidneys are normal under histological examination and renal failure is reversible after liver transplantation. Besides changes in renal function, patients with HRS also show remarkable abnormalities in the systemic arterial circulation and activity of endogenous vasoconstrictor systems, which probably play a major role in the development of renal failure. In recent years, important advances have been made in the pathogenesis, diagnosis, and management of patients with HRS (Table 1). The aim of this chapter is to provide an updated review of HRS in cirrhosis. *Address for correspondence: Liver Unit, Institut de Malalties Digestives, Hospital Clõ nic, IDIBAPS, Villarroel, 170, 08036 Barcelona, Catalunya, Spain. 1521±6918/00/060945‡13 $35.00/00

c 2000 Harcourt Publishers Ltd. *

946 P. GineÁs Table 1. Landmarks in hepatorenal syndrome. 1860 1950±1960 1960±1970 1970±1980 1988 1996 1990±2000

First description Clinical characterization. Description of association with circulatory dysfunction Recognition of renal vasoconstriction Investigation of renal vasoactive factors Arterial vasodilation theory De®nition and diagnostic criteria Introduction of splanchnic vasoconstrictor drugs in clinical practice

DEFINITION The new de®nition of HRS which emphasizes the changes occurring in both the renal and extrarenal circulations is as follows: `Hepatorenal syndrome is a clinical condition that occurs in patients with advanced chronic liver disease, liver failure, and portal hypertension characterized by impaired renal function and marked abnormalities in the arterial circulation and activity of the endogenous vasoactive systems. In the kidney there is marked renal vasoconstriction that results in low glomerular ®ltration rate (GFR), whereas in the extrarenal circulation there is predominance of arterial vasodilation, which results in reduction of total systemic vascular resistance and arterial hypotension'.1 Although HRS occurs predominantly in advanced cirrhosis, it may also develop in other chronic liver diseases associated with severe liver failure and portal hypertension, such as alcoholic hepatitis, or in acute liver failure.2 PATHOGENESIS The pathophysiological hallmark of HRS is a vasoconstriction of the renal circulation.3±5 The mechanism of this vasoconstriction is incompletely understood and possibly multifactorial involving changes in systemic haemodynamics, increased pressure in the portal venous system, activation of vasoconstrictor factors and suppression of vasodilator factors acting on the renal circulation (Table 2). A detailed analysis of these alterations and their possible role in the pathogenesis of renal vasoconstriction is outside the scope of this article and may be found in recent reviews.6,7 The theory that better explains the relationship between changes in the renal circulation, activation of vasoconstrictor mechanisms and presence of marked disturbances in systemic haemodynamics is the arterial vasodilation theory.8±10 This theory proposes that renal hypoperfusion represents the extreme manifestation of under®lling of the arterial circulation secondary to a marked vasodilation of the splanchnic vascular bed (Figure 1). This arterial under®lling would result in a progressive baroreceptor-mediated activation of vasoconstrictor systems (i.e. the renin± angiotensin and sympathetic nervous systems) that would eventually cause vasoconstriction not only in the renal circulation but also in other vascular beds (lower and upper limbs, cerebral circulation; see later). The splanchnic area would escape the e€ect of vasoconstrictors and an intense vasodilation would persist because of a markedly enhanced local production of vasodilator factors. Most of the available data suggest that the most important factor responsible for splanchnic vasodilation in cirrhosis is nitric oxide, although other factors such as prostaglandins and vasodilator peptides may also play a role.11 In early phases following the development of portal

Hepatorenal syndrome 947 Table 2. Vasoactive factors potentially involved in the regulation of renal perfusion in cirrhosis and in the pathogenesis of hepatorenal syndrome. Vasoconstrictors Angiotensin II Norepinephrine Neuropeptide Y Endothelin Adenosine Cysteinyl leukotrienes F2-isoprostanes Vasodilators Prostaglandins Nitric oxide Natriuretic peptides Kallikrein±kinin system

Cirrhosis Portal hypertension Splanchnic vasodilation Reduced effective arterial blood volume Stimulation of vasoconstrictor systems Renal vasoconstriction Hepatorenal syndrome Figure 1. Proposed pathogenesis of hepatorenal syndrome in cirrhosis according to the arterial vasodilation theory.

hypertension, renal perfusion would be maintained within normal or near-normal levels despite the overactivity of vasoconstrictor systems by an increased synthesis/ activity of renal vasodilator factors. However, in later phases of the disease renal perfusion would not be maintained because of the extreme arterial under®lling causing maximal activation of vasoconstriction systems and/or decreased activity of renal vasodilator factors, and HRS would develop. The observation that the administration of drugs causing vasoconstriction of the splanchnic circulation is associated with the suppression in the activity of endogenous vasoconstrictor systems and marked improvement of GFR is a strong argument supporting the arterial vasodilation theory.12±14

948 P. GineÁs

An alternative theory proposes that renal vasoconstriction in HRS is the result of a direct relationship between the liver and the kidney and bears no pathogenic relationship with the disturbances in systemic haemodynamics. The link between the liver and the kidney would be either a vasodilator factor, the synthesis of which would be reduced as a consequence of liver failure, or a hepatorenal re¯ex causing renal vasoconstriction.15±17 Evidence supporting the sequence of events proposed by this theory in human cirrhosis is weak. CLINICAL AND LABORATORY FINDINGS Hepatorenal syndrome is a common complication of patients with cirrhosis, with a reported incidence of about 10% among hospitalized patients with ascites. The clinical manifestations include a combination of signs and symptoms related to renal, liver and circulatory failure. Renal failure may have a rapid or insidious onset (see later) and is usually associated with marked sodium and water retention which result in ascites and oedema and dilutional hyponatraemia, respectively.1,6,7 HRS may occur in two di€erent clinical patterns, according to the intensity and form of onset of renal failure (Table 3). The dominant clinical features of type I HRS are those of severe renal failure with oliguria or anuria and increased serum levels of urea and creatinine. Despite an important reduction of GFR in these patients, serum creatinine levels are commonly lower than values observed in patients with acute renal failure of similar intensity with respect to the reduction in GFR, but without liver disease.6 This is probably due to the lower endogenous production of creatinine secondary to reduced muscle mass in patients with cirrhosis compared with patients without liver disease. This type of HRS is frequently seen in patients with alcoholic cirrhosis, especially when associated with alcoholic hepatitis, but it occurs in non-alcoholic cirrhosis as well. Type I HRS is associated with a very low survival expectancy, the median survival time being of only 2 weeks.18 Type II HRS is characterized by less severe and stable reduction of GFR that does not meet the criteria proposed for type I. Patients are usually in a better clinical condition than those with type I HRS and their survival expectancy is longer. The dominant clinical feature of these patients is diuretic-resistant ascites due to the combination of intense sodium retention, reduced GFR, and marked stimulation of antinatriuretic systems.1 Severe spontaneous hyperkalaemia is an uncommon feature of HRS. However, marked hyperkalaemia may occur if patients are treated with aldosterone antagonists, specially patients with type I HRS. Severe metabolic acidosis and pulmonary oedema, which are frequent complications of acute renal failure of patients without liver disease, are uncommon ®ndings in patients with HRS. Because HRS is a form of functional renal failure, the characteristics of urine are those of pre-renal azotemia, with oliguria, low urine sodium concentration, and Table 3. Clinical types of hepatorenal syndrome. Type I. Rapid and progressive impairment of renal function as de®ned by a doubling of the initial serum creatinine to a level higher than 2.5 mg/dl or a 50% reduction of the initial 24-hour creatinine clearance to a level lower than 20 ml/minute in less than 2 weeks Type II. Impairment in renal function (serum creatinine 41.5 mg/dl) that does not meet the criteria of type I

Hepatorenal syndrome 949

increased urine osmolality and urine-to-plasma osmolality ratio.1,3,6,7 Nevertheless, there are non-oliguric forms of the syndrome and in some cases urine sodium concentration is not extremely reduced. As discussed later, urinary indices are not considered essential at present for the diagnosis of HRS.1 Circulatory failure in patients with HRS is characterized by high cardiac output, arterial hypotension (most patients have a mean arterial pressure in the range 60± 80 mmHg), and low total systemic vascular resistance (Table 4).1,3,5 This pattern of renal vasoconstriction and systemic vasodilation is very characteristic of HRS although not exclusive because it may be observed in renal failure associated with conditions other than cirrhosis, such as sepsis. Another important haemodynamic feature of HRS is that the reduction in total systemic vascular resistance and arterial pressure occurs in the setting of a markedly increased activity of vasoconstrictor systems (i.e. the renin±angiotensin system and the sympathetic nervous system), which suggests that the decrease in systemic vascular resistance and arterial pressure would be even greater if these systems were not activated.1,6,7 Most importantly, the activation of these vasoconstrictor systems provides a pathophysiological link between the disturbances in systemic haemodynamics and renal vasoconstriction. Traditionally, arterial vasodilation in patients with HRS had been considered to occur in all arterial vascular beds other than the renal circulation. However, recent data indicate that this is not the case. Studies assessing blood ¯ow and vascular resistance by duplex Doppler ultrasonography have found that blood ¯ow to the upper and lower limbs, either in absolute terms or as fraction of the cardiac output, is reduced in patients with HRS compared with values found in patients with cirrhosis and ascites without renal failure or healthy controls.19,20 Moreover, in patients with cirrhosis a direct correlation exists between GFR and brachial or femoral artery blood ¯ow, indicating that the upper and lower limb vascular beds change in parallel with the renal circulation. Likewise, the resistance to blood ¯ow in the cerebral circulation, as assessed by Doppler resistive index in the mean cerebral artery, is also increased in patients with HRS.21 The ®ndings of increased vascular resistance in the brain and upper and lower limbs, leave the splanchnic area as the only vascular bed responsible for arterial vasodilation and reduced total systemic vascular resistance in patients with HRS. As will be discussed later, this ®nding has important implications in the management of patients with HRS. Finally, the third type of clinical manifestation of HRS is related to the existence of liver failure. Most patients show ®ndings of advanced liver insuciency, particularly jaundice, coagulopathy, poor nutritional status and encephalopathy, although some patients with HRS may show only moderate liver failure. In general, patients with type I HRS have more advanced liver disease compared with patients with type II HRS. Table 4. Haemodynamic ®ndings in hepatorenal syndrome. Increased cardiac output Arterial hypotension Reduced total systemic vascular resistance Increased total blood volume Increased activity of vasoconstrictor systems Increased portal pressure Portosystemic shunting Reduced splanchnic vascular resistance Increased renal vascular resistance Increased brachial and femoral artery resistance Increased cerebral vascular resistance

950 P. GineÁs

PRECIPITATING FACTORS In some patients, HRS develops without any identi®able precipitating factor, whereas in others it occurs in close chronological relationship with bacterial infections, particularly spontaneous bacterial peritonitis (SBP).1,3,6,7 Approximately one-third of patients with SBP develop an impairment of renal function in the absence of shock and despite treatment with non-nephrotoxic antibiotics.22 The impairment in renal function is of functional origin and occurs in the setting of a further decrease in e€ective arterial blood volume, as indicated by a marked activation of vasoconstrictor systems, and increased serum and ascitic ¯uid levels of cytokines.23 In approximately one-third of patients developing renal failure after SBP, the impairment in renal function is reversible after resolution of infection. However, in the remaining patients the impairment in renal function is not reversible after the resolution of the infection and meets the criteria of HRS (type I in most cases). Patients who develop type I HRS after SBP have an in-hospital mortality close to 100%. Although uncommon, HRS has been reported after therapeutic paracentesis without plasma expansion.24 This is one of the reasons that supports the administration of intravenous albumin when large-volume paracentesis is performed.25 Gastrointestinal bleeding has been classically considered as a precipitating factor of HRS.3 However, the development of renal failure after gastrointestinal bleeding is uncommon in patients with cirrhosis (approximately 10%), and it occurs commonly in patients who have developed hypovolaemic shock, in most cases associated with ischaemic hepatitis, which suggests that renal failure in this setting is probably related to the development of acute tubular necrosis (ATN) and is not of functional origin (P GineÁs, unpublished observations). Diuretic treatment has also been classically described as a precipitating factor of HRS, but there is no clear evidence to support such pathogenic relationship. DIAGNOSIS The diagnosis of HRS is currently based on several diagnostic criteria (Table 5).1 The value of serum creatinine required for the diagnosis of HRS is 1.5 mg/dl. Although this value may seem low compared with values of serum creatinine in acute renal failure in patients without liver disease, patients with cirrhosis with a serum creatinine above 1.5 mg/dl usually have a GFR below 30 ml/minute.6 In patients receiving diuretics, creatinine measurement should be repeated after diuretic withdrawal because, in some patients, creatinine may increase during diuretic therapy even in the absence of excessive diuresis, causing volume depletion. Because no speci®c laboratory tests are available for the diagnosis of HRS, and patients with advanced cirrhosis may develop renal failure of other aetiologies (prerenal failure due to volume depletion, ATN, drug-induced nephrotoxicity and glomerulonephritis), the most important step in the diagnosis of HRS is to rule out renal failure secondary to volume depletion or organic renal causes.1 Gastrointestinal ¯uid losses, due to vomiting or diarrhoea, or renal ¯uid losses, due to excessive diuresis, should be looked for in all patients with cirrhosis presenting with renal failure. If renal failure is secondary to volume depletion, renal function improves rapidly after volume repletion and treatment of the precipitating factor. Shock is another common condition in patients with cirrhosis that may lead to renal failure due to ATN. While hypovolaemic shock related to gastrointestinal bleeding is easily recognized, the presence of septic

Hepatorenal syndrome 951 Table 5. Diagnostic criteria of hepatorenal syndrome.a Major criteria 1. Low glomerular ®ltration rate, as indicated by serum creatinine greater than 1.5 mg/dl or 24-hour creatinine clearance lower than 40 ml/minute 2. Absence of shock, ongoing bacterial infection, ¯uid losses and current treatment with nephrotoxic drugs 3. No sustained improvement in renal function (decrease in serum creatinine to 1.5 mg/dl or less or increase in creatinine clearance to 40 ml/minute or more) following diuretic withdrawal and expansion of plasma volume with 1.5 l of a plasma expander 4. Proteinuria lower than 500 mg/day and no ultrasonographic evidence of obstructive uropathy or parenchymal renal disease Additional criteria 1. Urine volume lower than 500 ml/day 2. Urine sodium lower than 10 mEq/l 3. Urine osmolality greater than plasma osmolality 4. Urine red blood cells less than 50 per high-power ®eld 5. Serum sodium concentration lower than 130 mEq/l a

All major criteria must be present for the diagnosis of hepatorenal syndrome. Additional criteria are not necessary for the diagnosis, but provide supportive evidence.

shock may be more dicult to diagnose because of the paucity of symptoms of bacterial infection in some patients with cirrhosis. Moreover, arterial hypotension due to the infection may be erroneously attributed to the underlying liver disease. In some patients with septic shock oliguria is the ®rst sign of infection. These patients may be misdiagnosed as having HRS if signs of infection (cell blood count, examination of ascitic ¯uid) are not sought. On the other hand, as discussed before, patients with cirrhosis and SBP may develop renal failure during the course of the infection, in the absence of septic shock.22 Renal failure in these patients may either improve with the antibiotic therapy or evolve into a true HRS, even after resolution of the infection has been achieved. The administration of non-steroidal anti-in¯ammatory drugs (NSAIDs) is another common cause of acute renal failure in patients with cirrhosis and ascites, which is clinically indistinguishable from a true HRS.26 Therefore, treatment with these drugs should always be ruled out before the diagnosis of HRS is made. Similarly, patients with cirrhosis are also at high risk of developing renal failure due to ATN when treated with aminoglycosides.26 Because of this high risk of nephrotoxicity and the existence of other e€ective antibiotics (i.e. third-generation cephalosporins) treatment with aminoglycosides should be avoided in patients with chronic liver disease. Finally, patients with cirrhosis may also develop renal failure due to glomerulonephritis. In these cases, proteinuria and/or haematuria are almost constant and provide a clue for the diagnosis, which may be con®rmed by renal biopsy in selected cases.

TREATMENT Many therapeutic methods have been used in patients with HRS in an attempt to improve renal failure and increase survival.3,6,27 Unfortunately, most of these methods have no, or only minor, bene®cial e€ects, except for liver transplantation, the administration of vasopressin analogues and transjugular intrahepatic portosystemic shunts (Figure 2).

952 P. GineÁs

Liver transplantation

Cirrhosis

TIPS

Ornipressin + albumin

Vasoconstrictor antagonists

Portal hypertension Splanchnic vasodilation Reduced effective arterial blood volume Stimulation of vasoconstrictor systems

Vasodilators

Renal vasoconstriction Hepatorenal syndrome

Figure 2. Proposed pathogenesis of hepatorenal syndrome in cirrhosis according to the arterial vasodilation theory with potential therapeutic interventions.

LIVER TRANSPLANTATION Because HRS is a functional disorder due to an advanced liver disease, liver transplantation is theoretically the ideal treatment for patients with HRS as it allows the cure of both the diseased liver and the associated renal failure. The long-term outcome of patients with cirrhosis and HRS treated by liver transplantation is usually good, the probability of survival being 60% after 3 years of transplantation. This survival is only slightly reduced compared with that of 70±80% for transplanted patients without HRS and markedly increased compared with the survival of non-transplanted patients with HRS, which is close to 0% after 3 years.28,29 Nevertheless, the presence of HRS is associated with an increased morbidity and early mortality compared with patients transplanted without HRS. The main problem regarding liver transplantation for patients with HRS is that, because of the poor prognosis of HRS and the prolonged waiting times in most transplant centres, a signi®cant proportion of patients with HRS, particularly those with type I HRS, die before transplantation can be done. Therefore, there is a need for e€ective therapies to increase survival of these patients until transplantation can be performed. An alternative, but not exclusive, approach to this problem is to indicate liver transplantation before the development of HRS. Several predictive factors for the development of HRS in patients with cirrhosis and ascites have been identi®ed (Table 6).18 Patients showing some of these predictive factors should be evaluated for liver transplantation before the development of HRS. Of note, the severity of liver dysfunction, as assessed by the Child±Pugh classi®cation has no predictive value for the development of HRS in patients with cirrhosis and ascites.18 PHARMACOLOGICAL TREATMENT The administration of vasoconstrictors represents the most promising pharmacological approach to therapy of HRS.12±14 The rationale behind the use of these drugs in

Hepatorenal syndrome 953 Table 6. Predictive factors of development of hepatorenal syndrome in patients with cirrhosis and ascites. Slightly increased BUN and/or serum creatinine levels Dilutional hyponatraemia Reduced free water excretion after water load Low urinary sodium excretion Arterial hypotension High plasma renin activity High plasma norepinephrine concentration Previous episodes of ascites Absence of hepatomegaly Poor nutritional status Moderately increased renal vascular resistive index

patients with HRS is to improve renal perfusion by increasing systemic vascular resistance and suppressing the activity of endogenous vasoconstrictors (Figure 2). Because arterial vasodilation in HRS is exclusively located in the splanchnic circulation, the ideal vasoconstrictor for patients with HRS would be a drug with a selective action in the splanchnic arteries without e€ect on the extrasplanchnic circulation. Although such an ideal drug is not available at present, the family of drugs that are closer to the ful®lment of these requirements are the agonists of the vasopressin V1 receptors (analogues of vasopressin with a predominant action on the V1 receptors and less e€ect on the V2 receptors). Alpha-adrenergic agonists (i.e. norepinephrine, metaraminol) and agonists of the angiotensin AT1 receptors have been used without signi®cant clinical bene®ts.27 By contrast, the administration of V1 receptor agonists, such as ornipressin or terlipressin, is associated with suppression of the activity of endogenous vasoconstrictor systems and marked improvement of renal perfusion and GFR and normalization of serum creatinine levels in most patients (Figure 3).12±14 Although information about the use of V1 agonists in patients with HRS is still very limited and based only on a few phase II studies conducted in small series of patients, the following preliminary conclusions can be drawn while awaiting for results of large randomized trials. 1. These drugs should be given for prolonged periods, usually 5±15 days, because the improvement in renal function occurs slowly. Therapy should be aimed at reducing serum creatinine below 1.5 mg/dl; when this goal has been achieved, HRS usually does not recur after discontinuation of therapy. 2. The e€ective doses of these drugs have not been de®ned precisely and may vary from patient to patient; ornipressin has been given in continuous intravenous infusion at doses ranging from 1 to 6 IU/hour while terlipressin has been used as intravenous boluses from 0.5 to 2 mg/4 hours. At present, it seems advisable to start with low doses (i.e. ornipressin 1±2 IU/hour or terlipressin 0.5±1 mg/4 hours) and increase the doses in a stepwise manner (i.e. every 2±3 days) in cases showing no response to therapy. 3. In some studies a concomitant administration of albumin has been used to improve e€ective arterial blood volume further; whether or not this manoeuvre increases the bene®cial e€ects of these drugs on renal function is not known. 4. The incidence of important ischaemic side-e€ects requiring the withdrawal of the drug is high, especially with ornipressin; the incidence of ischaemic complications seems low in patients treated with terlipressin, which has a better safety pro®le than ornipressin, but this requires con®rmation in larger studies. The risk of ischaemic complications should be weighed against the lack of alternative pharmacological therapies for HRS. 5. The potential bene®cial impact of the improvement of renal function on survival of patients with

954 P. GineÁs

8

Serum creatinine (mg/dL)

5

4

3

2

1

0

3

7 Days

10

15

Figure 3. Individual values of serum creatinine in nine patients treated with terlipressin and intravenous albumin. Reproduced from Uriz et al (2000, Journal of Hepatology) with permission.

HRS has not been assessed and requires investigation in large comparative studies. 6. Because of limited information, treatment with V1 agonists should probably be restricted at present to patients with type I HRS. Another approach to the pharmacological treatment of HRS which has been described recently consists of the administration of an orally-active alpha-adrenergic agonist (midodrine) associated with octreotide and intravenous albumin.30 The aim of this therapy is twofold: to suppress the activity of vasoconstrictor systems by increasing total systemic vascular resistance with the vasoconstrictor and improving central blood volume with albumin and reducing the release of splanchnic vasodilator factors with octreotide. Although this therapeutic approach was associated with a marked improvement of renal function in a small series of patients with HRS, its e€ectiveness requires con®rmation in further studies.

TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT Despite the existence of isolated reports of improvement of renal function in patients with HRS after side-to-side or end-to-side portacaval shunts during the 1970s, these procedures did not become an accepted therapy for HRS because of their high morbidity and mortality.27 However, the recent introduction of a non-surgical method

Hepatorenal syndrome 955

of portal decompression, the transjugular intrahepatic portosystemic shunt (TIPS), has led to reconsideration of this therapeutic approach in the management of HRS. TIPS is usually performed under analgesia and consists of the placement of a self-expandable metal stent between an hepatic vein and the intrahepatic portion of the portal vein using a transjugular approach. Because of its powerful e€ect in reducing portal pressure, TIPS has become a therapy frequently used in high-risk patients bleeding from oesophageal varices not responding to usual therapeutic measures and its use is also being evaluated in the management of refractory ascites.31 The information about the e€ect of TIPS in patients with HRS is still very limited but published studies indicate that TIPS improves renal perfusion and GFR and reduces the activity of vasoconstrictor systems.32,33 In patients with type II HRS, the improvement of renal perfusion is associated with an increase in urinary sodium excretion and improved renal response to diuretics. In patients with type I HRS, the use of TIPS is associated with a moderate increase in renal blood ¯ow and GFR and a reduction in serum creatinine levels in some, but not all, patients. As with vasoconstrictor drugs, it is not known whether the improvement in renal function is associated with an increased survival. Because the use of TIPS is frequently associated with signi®cant side-e€ects, particularly hepatic encephalopathy and impairment of liver function, its role in the management of HRS needs to be established by prospective controlled investigations.

OTHER THERAPEUTIC METHODS Drugs with renal vasodilator activity have been used in patients with HRS in an attempt to counteract the e€ect of vasoconstrictor factors on the renal circulation. Dopamine was the ®rst drug used owing to its renal vasodilatory e€ect when given in subpressor doses. Although there are isolated reports of reversal of HRS after dopamine administration, studies speci®cally assessing the e€ects of dopamine on renal function in series of patients with HRS have shown no e€ects, or only minor e€ects, on GFR.27 Despite its lack of ecacy, dopamine is still commonly used in clinical practice in patients with HRS. The second type of renal vasodilators used in patients with HRS are prostaglandins and prostaglandin analogues.27 The rationale for the use of prostaglandins was the proposal that renal vasoconstriction in HRS could be due to a reduced intrarenal synthesis of prostaglandins. Unfortunately, however, no bene®cial e€ects on renal function have been observed after the intravenous or intra-arterial administration of PGA1 or PGE2. The oral administration of misoprostol (a PGE1 analogue) was found to improve renal function in one study but this bene®cial e€ect was not con®rmed in a subsequent investigation.27 The potential ecacy of this drug deserves further investigation but its use in clinical practice may be limited by the high incidence of side-e€ects, especially diarrhoea. Peritoneovenous shunting was widely used in the past in the management of patients with cirrhosis and refractory ascites, which is commonly seen in association with type II HRS. However, the use of this method has declined markedly because of important side-e€ects and the existence of other therapeutic methods with a similar ecacy but fewer side-e€ects (i.e. therapeutic paracentesis associated with albumin). In patients with type I HRS, peritoneovenous shunting prevents the progression of renal failure but does not prolong survival compared with supportive therapy.34 For these reasons, peritoneovenous shunting is not commonly used at present in the management of patients with HRS.

956 P. GineÁs

Haemodialysis or peritoneal dialysis have been used in the management of patients with HRS, and sporadic cases of improvement of renal function have been reported.27 Unfortunately, there are no controlled studies evaluating the e€ectiveness of dialysis in HRS. Uncontrolled studies suggest that it is hardly e€ective because most patients die during treatment and there is a high incidence of severe side-e€ects, including arterial hypotension, coagulopathy and gastrointestinal bleeding. In some centres, haemodialysis is used to treat patients with HRS awaiting liver transplantation. The e€ectiveness of dialysis in this setting has not been appropriately studied. Continuous arteriovenous or veno-venous haemo®ltration have also been used but their ecacy also remains to be determined.27

PREVENTION Up to now, no e€ective methods for the prevention of HRS existed. However, recent data indicate that the development of HRS in the setting of spontaneous bacterial peritonitis can be e€ectively prevented by the administration of albumin (1.5 g/kg intravenously at the diagnosis of infection and 1 g/kg intravenously 48 hours later) together with antibiotic therapy.35 The incidence of HRS is markedly lower in patients receiving albumin compared with that in patients not receiving albumin. Most importantly, albumin administration also improves survival in these patients. The bene®cial e€ect of albumin is probably related to its capacity to prevent the impairment in the e€ective arterial blood volume and subsequent activation of vasoconstrictor systems that occurs during the infection. Acknowledgement Studies reported in this chapter have been partly supported by a grant from the Fondo de InvestigacioÂn Sanitaria (FIS 97/2073).

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