Therapy Insight: management of hepatorenal syndrome

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1 Therapy Insight: management of hepatorenal syndrome Andrés Cárdenas and Pere Ginès* SUMMARY Hepatorenal syndrome (HRS), a feared complication of advanced cirrhosis, is characterized by functional renal failure, secondary to renal vasoconstriction in the absence of underlying kidney pathology. Extreme underfilling of the arterial circulation, caused by arterial vasodilation of the splanchnic circulation, activates vasoconstrictor systems, which lead to intense renal vasoconstriction and HRS. Factors predictive for the development of HRS include intense urinary sodium retention, dilutional hyponatremia, low blood pressure, decreased cardiac output, and increased activity of systemic vasoconstrictors. The prognosis for patients with HRS is extremely poor, especially for those with the acute, progressive (type 1) form. Liver transplantation is the best treatment for suitable candidates and should always be the management option considered first. Pharmacologic therapies are aimed at improving renal function to enable patients to survive until transplantation is possible. These therapies are based on plasma expansion with albumin, combined with the use of either vasopressin analogs or α-adrenergic agonists. Other nonpharmacologic therapies, such as transjugular intrahepatic portosystemic shunts and albumin dialysis show promise, but experience with these treatments is limited. For prevention of HRS, albumin infusion is recommended in patients with spontaneous bacterial peritonitis, and pentoxifylline treatment is recommended in patients with acute alcoholic hepatitis. KEYWORDS ascites, cirrhosis, dilutional hyponatremia, portal hypertension, renal failure REVIEW CRITERIA PubMed was searched in July 2005, January 2006 and again in March 2006 with the terms cirrhosis, hepatorenal syndrome, renal failure, liver transplantation, vasopressin analogues, or transjugular intrahepatic portosystemic shunts alone or in combination. The names of specific agents available in Europe and the US, including terlipressin, midodrine, octreotide, albumin and norepinephrine, were also matched with the terms above. The search was limited to English-language articles published in the past 25 years. Abstracts from the American Association for the Study of Liver Disease and the European Association for the Study of Liver Disease meetings were also included. A Cárdenas is an Associate Researcher, and P Ginès is an Associate Professor of Medicine and Chief of the Liver Unit at the Institut de Malalties Digestives, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain. Correspondence *Liver Unit, Hospital Clinic, Villaroel 170, Barcelona 08036, Spain gines@medicina.ub.es Received 31 October 2005 Accepted 20 March doi: /ncpgasthep0517 INTRODUCTION Renal failure is a common complication in patients with advanced cirrhosis, and can occur in patients with advanced liver disease as functional renal failure in the absence of parenchymal kidney disease. Hepatorenal syndrome (HRS) is defined as functional renal failure that develops in patients with liver failure and portal hypertension. 1 HRS is the final consequence of events that lead to a reduction in renal blood flow, mediated by circulatory failure associated with severe hepatic injury. 1 Although HRS occurs predominantly in patients with advanced cirrhosis, it can also develop in patients with alcoholic hepatitis or acute liver failure. 1 4 Patients with ascites and marked sodium and solute-free water retention with DILUTIONAL HYPONATREMIA, a high MODEL FOR END-STAGE LIVER DISEASE (MELD) score, as well as those with marked arterial hypotension, have a high risk of developing HRS. 5,6 Two types of HRS have been described: type 1 HRS, an acute form of the disease with a poor prognosis, and type 2 HRS, a more subtle form of the disease that develops slowly over weeks. 1 Liver transplantation remains the best treatment for suitable candidates, but its use is limited because of the poor survival of patients with HRS. Over the past decade, several studies have demonstrated that splanchnic vasoconstrictors (e.g. terlipressin, midodrine, octreotide, and norepinephrine), combined with albumin expansion or TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT (TIPS) PLACEMENT, are effective in improving renal function in patients with HRS. This syndrome can be prevented in the setting of SPONTANEOUS BACTERIAL PERITONITIS (SBP) by administering intravenous albumin, and in the setting of alcoholic hepatitis by administering oral pentoxifylline. 3,7 This remainder of this review focuses on the pathogenesis, clinical features, diagnosis, and current management of HRS in patients with cirrhosis. 338 NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY JUNE 2006 VOL 3 NO 6

2 PATHOGENESIS HRS is characterized by a severe vasoconstriction of the renal circulation. 8,9 In patients with advanced cirrhosis there are several mechanisms underlying the development of HRS, including changes in systemic arterial circulation, increased portal pressure, and activation of systemic and renal vasoconstrictors that act on the renal circulation, and eventually lead to renal vasoconstriction. In patients with portal hypertension there is an increased production of local vasodilators, including nitric oxide, which leads to the development of splanchnic arterial vasodilation. 10 The blood that pools in the splanchnic bed triggers an important compensatory response: it activates systemic vasoconstrictor and antinatriuretic systems such as the renin angiotensin aldo sterone system (RAAS), the sympathetic nervous system (SNS), and arginine vasopressin (AVP) which account for sodium and water retention, as well as renal vasoconstriction In the initial stages of cirrhosis with ascites, there is a subtle degree of renal vasoconstriction that can only be detected by measuring renal plasma flow; however, as cirrhosis progresses, significant renal vasoconstriction becomes more evident, with increasing levels of serum creatinine. Renal vasoconstriction causing HRS (currently defined by an elevated serum creatinine concentration) is the functional renal abnormality that develops last in patients with cirrhosis and ascites. The pathogenesis of HRS seems to be explained best by the ARTERIAL VASODILATION THEORY, which states that HRS is the ultimate consequence of an unrelenting activation of vasoconstrictors acting on the kidney, secondary to splanchnic vasodilation. 9 In the early stages of cirrhosis, renal blood flow can be kept within normal limits because there is an increased production of systemic and renal vasodilators. As cirrhosis progresses, the effect of the circulating vasoconstrictors overcomes the effect of the renal vasodilators, leading to severe renal vasoconstriction and a reduction in the glomerular filtration rate (GFR). 9,14 In some patients, precipitating factors, such as bacterial infections, worsen circulatory dysfunction and, therefore, might aggravate renal vasoconstriction. 7,15 Once renal vasoconstriction occurs, intrarenal mechanisms are likely to perpetuate HRS, because hypoperfusion leads to an imbalance in local vasoactive systems that, in turn, cause more vasoconstriction (Figure 1). Arterial underfilling does not, however, seem to be the only factor leading to renal dysfunction. Some studies suggest that the development of HRS occurs in the setting of a reduction in cardiac output. 16,17 This finding indicates that the progression of circulatory and renal dysfunction in cirrhosis is not only caused by splanchnic vasodilation, but also by a reduction in cardiac output. 16,17 The reduction in cardiac output is present at the time of diagnosis of HRS, in contrast to patients with cirrhosis and ascites without HRS, who have an elevated cardiac output. Current evidence suggests that the reduction in cardiac output might be caused by a fall in cardiac preload, impaired chronotropic function, and impaired left ventricular function, and that it is a final consequence of the so-called cirrhotic cardiomyopathy. 17,18 Together, this evidence suggests that HRS might be the consequence of a fall in cardiac output in the presence of marked splanchnic vasodilation (Figure 1). 16 CLINICAL FEATURES HRS occurs in about 10% of hospitalized patients with cirrhosis and ascites. 5 The probability of developing HRS in patients with cirrhosis and ascites is 18% at 1 year and increases to 39% at 5 years. 5 Most patients who develop HRS have features of advanced liver disease, as well as a low arterial blood pressure and tachycardia. Patients usually have a low urine volume, and intense urinary sodium retention (urine sodium 20 mmol/l). Spontaneous dilutional hyponatremia (serum sodium 130 mmol/l) is a common consequence of increased solute-free water retention, which is caused by elevated levels of AVP. 19 Although an elevated concentration of serum creatinine is considered the sole defining marker of HRS, the concentration is usually lower than in patients with acute renal failure without liver disease, because of the reduced muscle mass and low endogenous production of creatinine in patients with cirrhosis. 20,21 The two types of HRS differ in the time they take to develop, aggresiveness, and prognosis (Box 1). 1 Type 1 HRS is characterized by a rapid impairment in renal function and an increase in serum creatinine concentration to a level higher than 2.5 mg/dl (220 μmol/l) in less than 2 weeks. Without treatment, the median survival time of patients with type 1 HRS is approximately 2 weeks, and practically all patients die within 3 months from the onset of renal failure GLOSSARY DILUTIONAL HYPONATREMIA A fluid and electrolyte imbalance caused by excessive release of antidiuretic hormone; patients are unable to excrete dilute urine so they retain water and have low sodium levels MODEL FOR END-STAGE LIVER DISEASE (MELD) A liver disease severity score based on serum bilirubin and creatinine levels and the international normalized ratio for prothrombin time; used for liver allocation in US transplant centers TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT (TIPS) PLACEMENT A nonsurgical method of portal decompression that acts as a side-to-side portocaval shunt; it reduces portal pressure, decreases ascites, and improves renal function in some patients with decompensated cirrhosis SPONTANEOUS BACTERIAL PERITONITIS (SBP) A common and severe complication of cirrhosis with ascites; characterized by infection of ascitic fluid in the absence of any intra-abdominal source of infection ARTERIAL VASODILATION THEORY The theory that renal hypoperfusion is the extreme manifestation of an underfilling of the arterial circulation secondary to a marked vasodilatation of the splanchnic area JUNE 2006 VOL 3 NO 6 CÁRDENAS AND GINÈS NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY 339

3 Elevated levels of splanchnic nitric oxide Cirrhosis and portal hypertension Central hypovolemia and impaired chrontropic function Splanchnic arterial vasodilation and decreased systemic vascular resistance Decrease in cardiac preload and cardiac output SBP, bacterial infections, LVP Decreased effective arterial blood volume SBP and bacterial infections Stimulation of systemic vasoconstrictors RAAS, SNS, AVP Renal vasoconstriction Late stages of cirrhosis Early stages of cirrhosis Decreased production of local vasodilators and increased production of local vasoconstrictors Increased production of systemic and local vasodilators counteracts vasoconstriction Hepatorenal syndrome Preserved renal perfuson Figure 1 The pathogenesis of hepatorenal syndrome and its precipitating factors. Portal hypertension is the main factor responsible for the development of splanchnic arterial vasodilation, which is caused mainly by increased production of extrahepatic nitric oxide. Bacterial infections, particularly spontaneous bacterial peritonitis, and large-volume paracentesis without plasma expansion are triggers that worsen splanchnic vasodilation and decrease cardiac output. The vasodilation caused by pooling blood in the splanchnic bed triggers an important compensatory response by activating vasoconstrictor and antinatriuretic systems. These include the renin angiotensin aldosterone system, the sympathetic nervous system, and arginine vasopressin, and account for sodium and water retention as well as renal vasoconstriction. Coupled with decreased cardiac output, vasoconstriction seems to have an equally important role in the decreased renal perfusion that leads to functional renal failure. In the early stages of the disease, renal perfusion is maintained by the increased production of local renal vasodilators; however, as the disease progresses, the circulating and local vasoconstrictors overcome the effect of renal vasodilators, leading to severe renal vasoconstriction and a reduction in the glomerular filtration rate leading to hepatorenal syndrome. AVP, arginine vasopressin; LVP, large-volume paracentesis; RAAS, renin angiotensin aldosterone system; SBP, spontaneous bacterial peritonitis; SNS, sympathetic nervous system. Box 1 Types of hepatorenal syndrome. Type 1 Rapid and progressive impairment of renal function, as defined by a doubling of the initial serum creatinine concentration to >2.5 mg/dl (220 μmol/l) or a 50% reduction of the initial 24-h creatinine clearance rate to <20 ml/min in less than 2 weeks. Type 2 Impairment in renal function with a serum creatinine concentration >1.5 mg/dl (130 μmol/l) that does not meet the criteria for type 1. (Figure 2). 5,16,22 Both the MELD score and the type of HRS have an independent prognostic value for survival. 6 Most patients with type 1 HRS have a MELD score Type 2 HRS takes longer to develop than type 1, and patients have serum creatinine levels between mg/dl ( μmol/l). 1,22 Patients with type 2 HRS usually have diureticresistant ascites and a better chance of survival, compared with patients with type 1 HRS. The median survival time of a patient with type NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY CÁRDENAS AND GINÈS JUNE 2006 VOL 3 NO 6

4 HRS is approximately 6 months, if they do not undergo transplantation (Figure 2). 5,6,22 In patients with type 2 HRS, a MELD score 20 is associated with a poorer outcome, compared with a MELD score <20. 6 Type 1 HRS can develop without there being an identifiable precipitating factor, but it can be precipitated by bacterial infections such as SBP or sepsis, acute alcoholic hepatitis, or large-volume paracentesis without albumin expansion. 3,7,15,23,24 SBP precipitates type 1 HRS in up to 30% of cases, despite appropriate treatment and resolution of the infection. 7,24,25 Nearly 20% of patients who undergo largevolume paracentesis ( 5 l) without albumin expansion develop type 1 HRS. 23 Renal failure occurs in 10% of cirrhotic patients who have gastrointestinal bleeding; 26 however, in most cases, renal failure is associated with hypovolemic shock, which suggests that renal failure in these patients is probably related to the development of acute tubular necrosis (ATN) and not HRS. 26 Although contrast media for radiologic procedures was previously felt to be a precipitant of renal failure in cirrhotic patients with ascites, this does not seem to be the case. In a study of patients with cirrhosis and ascites, administration of contrast media was not associated with renal failure, suggesting that it probably does not represent a risk factor for renal failure in these patients. 27 Predictive factors associated with a greater risk of developing HRS have also been described in cirrhotic patients with ascites but without renal failure. 5,16 Patients with intense sodium retention (<10 mmol/l per day), spontaneous dilutional hyponatremia (serum sodium <130 mmol/l), low mean arterial blood pressure (<85 mmhg), decreased cardiac output (<6.0 l/min), increased plasma renin activity, and increased aldosterone and norepinephrine levels have a high probability of developing HRS. 5,16 Other parameters, such as the degree of liver failure, as assessed by serum bilirubin and albumin levels and prothrombin time, have not been consistently shown to predict the development of type 1 HRS. DIAGNOSIS Although the International Ascites Club (IAC) proposed specific diagnostic criteria for the diagnosis of HRS (Box 2), clinicians do not seem to diagnose HRS accurately in the setting of cirrhosis in all patients. In one study, only Probability of survival Time (months) 59% of those patients with cirrhosis and renal failure labeled as having HRS fulfilled the proposed criteria. 28 In a report from a large referral center, 140 patients were diagnosed as having HRS, but only 29% met all the criteria proposed by the IAC; most mislabeled cases were caused by ATN and sepsis. 29 The diagnosis of HRS is one of exclusion of other causes of renal failure in cirrhosis, and is currently based on criteria defined in 1996 by the IAC (Box 2). 1 It is considered that a low GFR corresponds to a serum creatinine concentration greater than 1.5 mg/dl (130 μmol/l) with no diuretic therapy for 5 days. Other criteria defined by the IAC include the absence of precipitants of renal failure, no improvement of renal function following diuretic withdrawal and plasma expansion, no proteinuria, and a normal renal ultrasound. Other causes of renal failure in cirrhosis, such as prerenal:renal failure secondary to volume depletion, ATN, drug-induced nephrotoxicity (mainly from nonsteroidal anti-inflammatory agents or aminoglycosides), and glomerulonephritis in patients with hepatitis B or C, or chronic alcoholism, should be excluded before the diagnosis of HRS is made. Prerenal:renal failure can occur in patients with gastrointestinal bleeding, vomiting, or diarrhea, or those with renal fluid losses caused by excessive diuretic therapy. In prerenal:renal failure caused by volume depletion, renal function usually P < Type 2 HRS Type 1 HRS Figure 2 Probability of survival of patients with cirrhosis according to the type of hepatorenal syndrome. Reproduced with permission from ref 6 (2005) John Wiley & Sons, Ltd. HRS, hepatorenal syndrome. 12 JUNE 2006 VOL 3 NO 6 CÁRDENAS AND GINÈS NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY 341

5 Box 2 Major diagnostic criteria for hepatorenal syndrome. Low glomerular filtration rate, as indicated by a serum creatinine concentration >1.5 mg/dl (130 μmol/l) Exclusion of shock (either septic or hypovolemic), volume depletion, and use of nephrotoxic drugs (mainly nonsteroidal anti-inflammatory drugs) No improvement in renal function, despite stopping diuretics and volume repletion with intravenous albumin a No proteinuria or ultrasonographic evidence of obstructive uropathy or parenchymal renal disease a The arbitrary dose of albumin is considered to be between 20 g and 40 g. improves after plasma expansion, whereas no improvement occurs in patients with HRS. Shock preceding the development of renal failure usually indicates ATN. Proteinuria (>500 mg per day) and/or ultrasonographic abnormalities seen in the kidneys indicate parenchymal renal disease or obstructive uropathy. MANAGEMENT Prevention HRS can be prevented in patients with SBP and alcoholic hepatitis; however, data on prophylaxis in these conditions are based on only two studies. In patients with SBP, the administration of albumin (1.5 g/kg body weight at diagnosis of infection and 1 g/kg body weight 48 h later) prevents circulatory dysfunction and subsequent development of HRS. The rationale for albumin administration is to prevent further arterial underfilling and subsequent activation of vasoconstrictor systems, which usually occur in the presence of bacterial infections in patients with cirrhosis. 7 It seems that plasma expanders other than albumin, such as hydroxyethyl starch, are not effective in preventing renal failure in the setting of SBP. 30 The incidence of HRS in patients with SBP who receive albumin together with antibiotic therapy is 10%, compared with an incidence of 33% in those not receiving albumin. 7 More importantly, there is improved survival in those receiving albumin (10%) versus those not receiving albumin (29%). 7 In patients with acute alcoholic hepatitis, the use of pentoxifylline, an inhibitor of tumor necrosis factor, (400 mg orally, three times daily for 28 days) reduces the incidence of HRS and mortality (8% and 24%, respectively), with respect to a control group (35% and 46%, respectively). 3 The exact mechansim by which this drug prevents HRS in patients with alcoholic hepatitis is unknown, but it is possible that it improves the microcirculation, as it does in patients with lower-extremity claudication. Pentoxifylline might, therefore, improve functional renal failure in the setting of alcoholic hepatitis. 3 Although there are no follow-up studies confirming the above results, these two approaches are widely used in the clinical setting because of the wide accessibility of albumin and pentoxifylline. Liver transplantation Liver transplantation offers the possibility of a cure for both the liver disease and the circulatory and renal dysfunction. The survival of cirrhotic patients with HRS treated by liver transplantation is 85% at 1 year and 73% at 3 years, although the presence of HRS is associated with increased morbidity and early mortality after transplantation. 31 Unfortunately, transplantation for type 1 HRS is limited by the fact that a significant proportion of patients die before the operation, because they have a short survival and there is a prolonged waiting time for donor organs in most centers. 5,16,32 Since patients with type 1 HRS have a very poor prognosis, this group of patients should be given high priority for transplantation. 32 In addition, patients with type 2 HRS and a MELD score 20 have a poor outcome and should also be prioritized for transplantation. 6 If patients are successfully treated with pharmacologic therapy before undergoing liver transplantation their outcome seems to be similar to that of patients without HRS. 32,33 Pharmacologic therapy Patients with HRS (particularly type 1) should be hospitalized and closely monitored. A nutritionist should be consulted to make sure these patients are receiving proper nutrition because they are frequently malnourished. 2 If patients have dilutional hyponatremia (serum sodium concentration < 130 mmol/l), fluid restriction to 1 l per day is recommended. 19 As most HRS patients have ascites, diagnostic paracentesis must be performed to rule out SBP. 2 Diuretics must be stopped as they can worsen renal failure. In patients with tense ascites, a small therapeutic tap of less than 5 l, along with an albumin infusion (8 g/l tapped) might help to make the patient more comfortable. 22 The most important aspect of management is to assess the patient for candidacy for liver 342 NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY CÁRDENAS AND GINÈS JUNE 2006 VOL 3 NO 6

6 Liver transplantation Diagnosis of cirrhosis, portal hypertension, and HRS Lower portal pressure TIPS Intravenous splanchnic vasoconstrictors Reverse splanchnic arterial vasodilation Reverse decrease in cardiac output Plasma expansion with intravenous albumin Improvement of effective arterial blood volume Improvement of HRS Figure 3 Therapeutic options and the aim of therapy for hepatorenal syndrome. When a diagnosis of hepatorenal syndrome is made, liver transplantation should be the first treatment option considered. Once transplantation is considered, pharmacologic therapy with intravenous splanchnic vasoconstrictors (see Box 3 for doses), aimed at reversing splanchnic vasodilation, and intravenous albumin, aimed at increasing cardiac preload and cardiac output, are effective. This therapy should help ensure a better outcome for those patients who respond and who will undergo liver transplantation. By reducing portal pressure, transjugular intrahepatic portosystemic shunt placement improves circulatory function and hepatorenal syndrome in a subset of patients with preserved liver function. Shunt placement is, therefore, not an option for patients with a Child Turcotte Pugh score >12. HRS, hepatorenal syndrome; TIPS, transjugular intrahepatic portosystemic shunt. transplantation. In an attempt to obtain a better outcome after transplantation, renal function should be improved before transplantation, if possible. Available therapies for type 1 HRS include the use of splanchnic vasoconstrictors combined with plasma expansion and TIPS (Figure 3). Patients with type 2 HRS are less sick than those with type 1; some can be managed as outpatients, with their ascites treated with largevolume paracentesis and albumin. 2 Patients with type 2 HRS also need to be evaluated for liver transplantation. Limited data suggest that patients with type 2 HRS respond well to vasoconstrictors and TIPS Renal vasodilator drugs Renal vasodilator drugs were used in the past for patients with HRS in an attempt to counteract the effect of vasoconstrictors on the renal circulation. Dopamine was felt to be an ideal drug owing to its renal vasodilator properties at low doses; however, studies assessing its effect on renal function in series of patients with HRS showed no beneficial effects on the GFR. 37,38 The use of prostaglandins such as misoprostol (a prostaglandin E 1 analog) as renal vasodilators improved renal function in one study, but this beneficial effect was not confirmed in a subsequent investigation. 39,40 Other treatments, such as the use of endothelin blockers (BQ123, Clinalfa, Merck Biosciences AG, Läufelfingen, Switzerland) and N-acetylcysteine seem to be promising, but larger noncontrolled and controlled studies are needed to confirm their role in the therapy of HRS. 41,42 Vasoconstrictor therapy Systemic vasoconstrictors combined with plasma expansion are currently the most used form of pharmacologic therapy, because several studies have confirmed a beneficial role in HRS, particularly type ,43 57 Splanchnic vasoconstrictors are used in conjunction with albumin because they counteract the intense vasodilation in the splanchnic bed, thereby improving effective arterial blood volume. This improvement, JUNE 2006 VOL 3 NO 6 CÁRDENAS AND GINÈS NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY 343

7 Table 1 Treatment of patients with type 1 hepatorenal syndrome using terlipressin. Reference (author/year) Proportion of patients who responded a (%) Proportion of patients who had recurrent hepatorenal syndrome b (%) Proportion of patients who reported side effects c (%) Percentage of patients who underwent liver transplantation Survival at 1 month d (%) Uriz et al. (2000) 46 7/9 (77) 0/7 (0) 1/9 (11) 33 6/9 (67) Mulkay et al. (2001) 49 11/12 (92) 6/11 (55) 0/12 (0) 25 10/12 (80) Moreau et al. (2002) 47 53/91 (58) NR 18/99 (18) 13 40/99 (40) Colle et al. (2002) 51 11/18 (61) 7/11 (64) 0/18 (0) 11 7/18 (40) Halimi et al. (2002) 50 13/18 (72) NR 4/18 (22) 11 NR Ortega et al. (2002) 48 14/21 (66) 2/12 (17) 1/21 (5) 14 11/21 (52) Solanki et al. (2003) 52 5/12 (42) NR 3/12 (25) NR NR a The definition of a response varies between studies. b Recurrence of hepatorenal syndrome after treatment withdrawal in patients who respond to treatment; the definition of recurrence varies between studies. c Severe side effects reported only; most patients presented with self-limited abdominal cramps and/or diarrhea during the administration of the first doses of terlipressin, which were not counted as severe side effects. d 1 month survival. NR, not reported. in turn, suppresses the endogenous vasoconstrictors (e.g. RAAS, SNS) that are responsible for renal vasoconstriction (Figure 3). It seems that when splanchnic vasoconstrictors are used alone there is a suboptimal increase in the GFR. 37,48,58 By expanding the circulating blood volume, albumin administration seems to increase cardiac preload and cardiac output (Figure 3). 58 This increase would result in an improvement in effective arterial bood volume leading to an amelioration of vasoctive systems and improvement of GFR. 58 Vasoconstrictors used for HRS include vasopressin analogs (ornipressin and terlipressin), somatostatin analogs (octreotide), and the α-adrenergic agonists (midodrine and norepinephrine). In most studies, vasoconstrictors were given in combination with a plasma expander (albumin). 37 Vasopressin analogs have a marked vasoconstrictor effect on the splanchnic circulation. Ornipressin and vasopressin, although effective in HRS, caused significant ischemic side effects in 30 40% of patients and were abandoned. 37,43,44 Terlipressin has significantly fewer side effects (in approximately 5 10% of cases) than vasopressin or ornipressin, and several uncontrolled studies support its use in HRS. 37,45 55 The administration of terlipressin and intravenous albumin improves renal function, with a reduction in serum creatinine concentrations to below 1.5 mg/dl and improvement in GFR in 42 92% of patients with type 1 HRS (Table 1). 37,45 55 In most cases, improvement in urine volume occurs within the first 1 2 days, but changes in serum creatinine concentrations and GFR take longer. Patients with Child Turcotte Pugh scores 13 and those who do not receive albumin expansion do not seem to respond well to this treatment. 47,48 Recurrence after stopping treatment is variable (Table 1) and a repeat course of terlipressin with albumin is usually effective. 46,48 Survival at 1 month ranges from 40 80% in most reported studies The use of midodrine in association with octreotide (an inhibitor of the release of glucagon and other vasodilator peptides) and albumin also improves renal function in cirrhotic patients with HRS, although information about this therapeutic approach is limited to only two studies with a total of 19 patients. 38,56 In all cases there was a marked improvement in renal perfusion and GFR, and a suppression of renin, aldosterone, norepinephrine, and AVP levels to normal or near-normal levels. Octreotide is, however, ineffective when administered alone. 59 These results require confirmation in a larger group of patients. The administration of norepinephrine (0.5 3 mg/h) for a minimum of 5 days in association with intravenous albumin resulted in a significant improvement of renal function in a small group of 12 cirrhotic patients with type 1 HRS. 57 Reversal of HRS was observed in 10 patients in association with an increase in mean arterial pressure and a marked reduction in renin and aldosterone levels. There was an episode of 344 NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY CÁRDENAS AND GINÈS JUNE 2006 VOL 3 NO 6

8 reversible myocardial hypokinesia, and no other ischemic side effects. 57 One of the primary goals of pharmacologic therapy is to reverse renal failure succesfully so that suitable candidates for liver transplants can undergo transplantation with less morbidity and similar survival to patients without HRS. Patients treated sucessfully with terlipressin and albumin before liver transplantation seem to have a similar post-transplantation outcome and survival to those who undergo liver transplantion but who do not have HRS. 33 Nontransplant candidates also seem to benefit from this pharmocologic therapy. In three studies, patients who responded to therapy for HRS (a decrease in creatinine concentration to <1.5 mg/dl) with terlipressin and albumin and octretide, midodrine and albumin, or terlipressin alone had an increased survival compared with those who did not respond to this therapy. 47,48,56 The information about the use of vasoconstrictors in patients with HRS is somewhat limited, because there are no largescale, placebo-controlled studies showing that they are superior to no treatment. On the basis of published studies, however, recommendations can be made (Box 3) mainly for patients with Type 1 HRS while awaiting the results of large, randomized, controlled trials. Transjugular intrahepatic portosystemic shunt TIPS placement is a nonsurgical way to achieve portal decompression; it is used as an alternative therapy for cirrhotic patients bleeding from esophageal or gastric varices who are refractory to endoscopic and medical treatment. 60 Although the use of TIPS has been evaluated for the treatment of refractory ascites, there are few data regarding its use in the management of HRS. 34,35,56,61 The rationale for using TIPS in this setting is based on the fact that reducing portal pressure can improve circulatory function and suppress RAAS and SNS activity. 60 Small, uncontrolled studies indicate that TIPS can improve renal function and GFR, and reduce the activity of RAAS and SNS in cirrhotic patients with type 1 HRS. 34,35,56,61 Improvement in renal function after TIPS placement alone is generally slow, with success in approximately 60% of patients. 34,35,56,61 Studies assessing TIPS for treating patients with type 1 HRS have included patients with mostly preserved liver function. Patients with a Child Turcotte Pugh score 12 were excluded Box 3 Recommendations for the use of vasoconstrictors in patients with type 1 hepatorenal syndrome. The goal of treatment is to reduce serum creatinine concentrations to 1.5 mg/dl (130 μmol/l). Recommendations Terlipressin 0.5 mg should be given intravenously every 4 h; the dose can be increased in a stepwise fashion (i.e. every 2 days) to 1 mg/4 h and then up to 2 mg/4 h in cases where there is no reduction in the serum creatinine concentration Alternatively, a continuous infusion of terlipressin 2 mg per day can be given; when the serum creatinine concentration does not reduce by at least 30%, the dose can be increased every 2 days up to 12 mg per day Midodrine mg should be given orally three times daily, increasing to 12.5 mg three times daily if needed; octreotide 100 μg should be given subcutaneously three times daily, increasing to 200 μg three times daily if needed Norepinephrine titrated to mg/h should be given as a continuous intravenous infusion Concomitant intravenous albumin infusion (1 g/kg body weight on the first day, followed by g per day) a is recommended Contraindications include coronary artery disease, peripheral vascular disease and/or cerebrovascular disease, because of the potential risk of ischemic events The duration of therapy should be approximately 7 14 days a This dose of albumin was arbitrarily proposed. It is not known if smaller doses of albumin or use of other plasma expanders are beneficial in HRS. because of the risk of worsening liver failure and/or hepatic encephalopathy. Unfortunately, most patients with type 1 HRS fall into this category. Combination therapy using vasoconstrictors with TIPS for treatment of type 1 HRS has been reported. Patients with preserved liver function (Child Turcotte Pugh score <12), who responded to oral midodrine plus subcutaneous octreotide and intravenous albumin, and then underwent TIPS placement, had an excellent outcome, with renal function that continued to improve and eventually became completely normalized. 56 Larger studies are needed in order to confirm these results. In patients with type 2 HRS, TIPS placement improves renal function and reduces ascites. 34,35,62,63 Experience from a large series of cirrhotic patients undergoing TIPS placement for refractory ascites indicates, however, that TIPS placement does not improve prognosis compared with repeated large-volume paracentesis in patients with refractory ascites and associated type 2 HRS. 62,63 JUNE 2006 VOL 3 NO 6 CÁRDENAS AND GINÈS NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY 345

9 Dialysis Small uncontrolled studies of hemodialysis and peritoneal dialysis suggest that both are ineffective in the management of HRS, mainly because there is a high incidence of severe side effects, including arterial hypotension, coagulo pathy, and gastrointestinal bleeding. 64,65 Continuous arterio-venous or veno-venous hemofiltration have also been used, but their efficacy remains to be determined. Although hemodialysis is not routinely recommended for patients with HRS, it might be a reasonable option in candidates suitable for liver transplant as a bridge to transplantation when there is no response to vasoconstrictors or TIPS, or when patients develop severe volume overload, metabolic acidosis, refractory hyperkalemia, or signs of uremia. According to the available data (from one study), the extracorporeal albumin dialysis system (Molecular Adsorbent Recirculating System; MARS) seems to be beneficial in this setting. In this study of 13 patients with Child class C cirrhosis, and type 1 HRS, the authors reported a significant decrease in bilirubin and creatinine concentrations, an improvement in serum sodium concentrations, urine volume, mean arterial blood pressure and decreased mortality. 66 The mean survival was 25.2 ± 34.6 days, and two of the eight patients reached the primary endpoint of the study, which was 30-day survival. 66 In addition, a study that used Prometheus, another KEY POINTS Hepatorenal syndrome (HRS) is at the end of a spectrum of functional renal abnormalities caused by a severe vasoconstriction of the renal circulation Splanchnic vasodilation causing arterial underfilling, a compensatory neurohormonal response that leads to renal vasoconstriction, and a reduction in cardiac output seem to be the main factors responsible for the development of HRS Type 1 HRS is an acute and rapidly progressive form with a very poor prognosis; type 2 HRS is a more stable form with a slightly better prognosis HRS that develops in patients with cirrhosis after spontaneous bacterial peritonitis can be prevented by intravenous albumin and antibiotic therapy Patients with HRS who are transplant candidates should be given high priority for liver transplantation Therapy of HRS should be aimed at reversing the intense splanchnic arteriolar vasodilation with splanchnic vasoconstrictors and plasma expansion as a bridge to liver transplantation; the use of transjugular intrahepatic portosystemic shunt also seems to be effective in selected cases of HRS extracorporeal liver support system that combines removal of albumin-bound substances and water-soluble substances, was reported to be safe and beneficial in a small group of patients with type 1 HRS; 67 however, these results require further evaluation to be able to consider albumin dialysis as an effective therapy for HRS. CONCLUSIONS HRS is an outstanding clinical event that can develop as part of decompensated cirrhosis. The most characteristic feature of the syndrome is functional renal failure due to renal vasoconstriction in the absence of underlying kidney pathology. There are two types of HRS: type 1 HRS, the acute form with a very poor prognosis, and type 2 HRS, which is characterized by a progressive impairment in circulatory and renal function, and has a slightly better prognosis than type 1. The pathogenesis of HRS is related to a worsening of effective arterial blood volume, caused by splanchnic arterial vaso dilation and a reduction in venous return and cardiac output. Liver transplantation is the best treatment option for suitable candidates, but is not always feasible owing to the number of candidates who do not survive the wait for a donor organ. Pharmacologic therapies based on the use of vasoconstrictor drugs (terlipressin, midodrine, octreotide, or norepinephrine) combined with albumin expansion are the most promising in terms of successfully offering a bridge to liver transplantation. Other treatments, such as TIPS placement and albumin dialysis, seem to be effective, but experience with these treatments is still limited. For prevention of HRS, albumin infusion is recommended in patients with spontaneous bacterial peritonitis, and pentoxifylline treatment is recommended in patients with acute alcoholic hepatitis. Research efforts in this field should focus on identifying which patients with decompensated liver disease are at a high risk of developing HRS, so they can be given priority on a transplant list. In addition, newer, safer, and more-effective pharmacologic therapies that can counteract the intense vasodilation of the splanchnic circulation and/or the intense renal vasoconstriction universally present in patients with HRS are needed to improve the grim outcome patients have once they develop the syndrome. 346 NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY CÁRDENAS AND GINÈS JUNE 2006 VOL 3 NO 6

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