Clin Liver Dis 10 (2006) 371385

Hepatorenal Syndrome
Andres Cardenas, MD, MMSc, Pere Gines, MD*
Liver Unit, Institut de Malalties Digestives Hospital Clinic, Institut dInvestigacions Biome`diques August Pi i Sunyer, University of Barcelona, Villaroel 170, Barcelona 08036, Spain

Renal failure in the setting of advanced cirrhosis continues to be a common complication that accounts for signicant morbidity and mortality. Among the many causes of renal failure in patients who have advanced liver disease, functional renal failure occurring in the absence of parenchymal kidney disease, better known as hepatorenal syndrome (HRS), is the most frequent cause of renal dysfunction in patients who have cirrhosis [1]. HRS is the consequence of a series of hemodynamic events that occur because of the presence of cirrhosis and portal hypertension. In most cases HRS occurs in advanced cirrhosis, but it occasionally occurs in patients who have alcoholic hepatitis or acute liver failure [14]. Cirrhotic patients who have ascites and marked sodium retention as well as dilutional hyponatremia have a high risk of developing HRS [5]. Two types of HRS were originally dened by the International Ascites Club (IAC); type 1 HRS is an acute form with very poor prognosis, and type 2 HRS is a steady form that develops slowly over weeks with better survival [16]. Although important advances in pharmacologic therapy for HRS were made in the past decade, liver transplantation remains the best treatment in suitable candidates; unfortunately its use might be limited because of the high mortality these patients carry. In recent years uncontrolled studies in patients who had HRS demonstrated that the use splanchnic vasoconstrictors, such as terlipressin, midodrine, octreotide, and noradrenaline, in combination with albumin administration or the use of transjugular intrahepatic portosystemic shunts (TIPS), is eective in improving renal function as bridge to liver transplantation. HRS can be prevented in the setting of spontaneous bacterial peritonitis (SBP) with intravenous albumin and in alcoholic hepatitis with oral pentoxifylline [3,7]. This article focuses on the
* Corresponding author. Liver Unit, Hospital Clinic, Villaroel 170, Barcelona 08036, Spain. E-mail address: pgines@clinic.ub.es (P. Gines). 1089-3261/06/$ - see front matter 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.cld.2006.05.006 liver.theclinics.com

372

CARDENAS & GINES

pathogenesis, clinical features, diagnostic approach, and current treatment of HRS in cirrhosis. Pathogenesis Renal vasoconstriction is the main hemodynamic derangement that denes HRS [8,9]. This event occurs late in the natural history of cirrhosis and ascites and is the end product of a continuous process in which several underlying mechanisms, including changes in systemic arterial circulation, an increased portal pressure, and activation of systemic and renal vasoconstrictor factors that modulate renal circulation, eventually lead to renal dysfunction without histologic damage in the kidneys. The main factor responsible for these hemodynamic derangements is portal hypertension in the setting of cirrhosis causing a splanchnic arterial vasodilation. This vasodilation occurs mainly because of the production of nitric oxide as a consequence of endothelial stretching and possibly bacterial translocation [10]. The accumulation of plasma volume in the splanchnic bed causes a compensatory response because of a decrease in central blood volume with activation of systemic vasoconstrictor and antinatriuretic systems such as the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system (SNS), and arginine vasopressin (AVP) accounting for sodium and water retention as well as renal vasoconstriction as the kidney senses a relative hypovolemic state (Fig. 1) [1113]. A constant activation of vasoconstrictor factors acting on the kidney because of splanchnic vasodilation leads to HRS. This activation occurs because, although in the early stages of cirrhosis renal blood ow may be kept within normal limits because of the eect of local renal vasodilators, with time circulating vasoconstrictors overcome the eect of renal vasodilators, leading to severe renal vasoconstriction and reduction in glomerular ltration rate (GFR) [9,14]. In some patients, precipitating factors such as bacterial infections worsen circulatory dysfunction and aggravate renal vasoconstriction [7,15]. Once vasoconstriction occurs, intrarenal mechanisms perpetuate HRS through the development of local vicious cycles in which decreased perfusion leads to an imbalance between intrarenal vasoactive systems that in turn cause more vasoconstriction. As discussed previously, a complex interplay between the splanchnic, systemic, and renal circulation takes place once portal hypertension is established. In the initial stages of cirrhosis (compensated state) in the process of progressive vasodilation both intravascular volume and cardiac output increase to maintain hemodynamic homeostasis. With progression to decompensated cirrhosis there is more vasodilation, and cardiac output still increases. This high-output state eventually cannot maintain perfusion pressure, and renal blood ow decreases. Recent studies suggest that the development of HRS occurs in the setting of a reduction in cardiac output, indicating that the progression of circulatory and renal dysfunction in cirrhosis is caused

HEPATORENAL SYNDROME

373

CIRRHOSIS
Elevated splanchnic nitric oxide Portal hypertension SBP, bacterial infections, LVP, Alcoholic hepatitis

Splanchnic Arterial Vasodilation

Arterial underfilling

Decreased total systemic vascular resistance

Decreased effective arterial blood volume

Sodium and water retention

Stimulation of vasoconstrictors:
RAAS, SNS, AVP

Central hypovolemia & impaired cardiac function

Increase in plasma volume Development of severe renal vasoconstriction

Fall in cardiac output

Hepatorenal Syndrome

Fig. 1. Pathogenesis of hepatorenal syndrome (HRS) in cirrhosis. Extrahepatic nitric oxide production is secondary to endothelial stretching and bacterial translocation. The major and precipitating factors are spontaneous bacterial peritonitis (SBP), other bacterial infections, large-volume paracentesis (LVP) without plasma expanders, and alcoholic hepatitis. Splanchnic vasodilation arising from portal hypertension, an increased plasma volume, and a decreased cardiac output seem to play an equally important role in the decreased renal perfusion leading to HRS. AVP, arginine vasopressin; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system.

not only by splanchnic vasodilation but also by a reduction in cardiac output [16,17]. This nding suggests that HRS may be the consequence of a fall in cardiac output in the setting of marked splanchnic vasodilation (see Fig. 1) [16]. Clinical features A study undertaken more than a decade ago indicated that HRS occurred in about 10% of hospitalized patients who had cirrhosis and ascites, but there are no recent studies that conrm this estimate [5]. Additionally the same study indicated that the probability of developing HRS in patients who had cirrhosis and ascites was 18% at 1 year and increased to 39% at 5 years [5]. Again, there are no updated studies addressing these numbers, but the authors suspect they remain stable. Individuals who develop HRS for the most part exhibit clinical features of advanced cirrhosis along with low arterial blood pressure, low urine volume, and severe urinary sodium retention (urine sodium % 10 meq/L). Spontaneous dilutional hyponatremia (serum sodium % 130 meq/L) is almost always present because of an increased solute-free water retention related to elevated levels of AVP [18]. Serum creatinine levels are elevated and in fact dene HRS; however, these

374

CARDENAS & GINES

levels usually are lower than those seen in noncirrhotic patients who have acute renal failure because of reduced muscle mass and low endogenous production of creatinine in cirrhosis [19,20]. Two types of HRS, which dier in time course, aggressiveness, and prognosis, were dened by the IAC in 1996 (Box 1) [1]. In type 1 HRS there is an acute decline in renal function with an increase in serum creatinine to a level higher than 2.5 mg/dL (220 mmol/L) in less than 2 weeks. This type of HRS, if not treated, is associated with a grim prognosis, because the median survival time is approximately 2 weeks, and in most cases patients die within 2 to 3 months after the onset of renal failure (Fig. 2) [5,6,21]. Most patients who have type 1 HRS have a Model for End Stage Liver Disease (MELD) score of 20 or higher and a ChildPugh score of 12 or higher [6]. Type 2 HRS has a subtler course, and serum creatinine levels range between 1.5 and 2.5 mg/dL (132220 mmol/L) [1,6,21]. Most patients who have type 2 HRS usually have diuretic-resistant ascites and also have better survival than patients who have type 1 HRS with a median survival time of approximately 6 months without transplantation (see Fig. 2) [5,6,21]. In patients who have type 2 HRS, a MELD score of 20 or higher is associated with a poor outcome compared with that of patients who have a MELD score of less than 20 [6]. Type 1 HRS may develop spontaneously, but in many cases it can be precipitated by bacterial infections such as SBP or sepsis, acute alcoholic hepatitis, or large-volume paracentesis without albumin expansion [3,7,15,22]. Bacterial infections and SBP may precipitate type 1 HRS in up to 30% of cases despite appropriate treatment and resolution of the infection [7,15,23]. Therapeutic paracentesis (R5 L) without albumin expansion may precipitate type 1 HRS in nearly 20% of cases [22]. Renal failure may occur in up to 10% of cirrhotic patients who have gastrointestinal bleeding, but in most cases this renal failure is caused by acute tubular necrosis (ATN) and not HRS [24]. Contrary to prior belief, contrast media for radiologic procedures used in patients who have cirrhosis and ascites is not associated with renal failure and probably does not represent a risk factor for renal failure for these patients [25]. Box 1. Clinical types of hepatorenal syndrome Type 1: rapid and progressive impairment of renal function dened by a doubling of the initial serum creatinine to a level higher than 2.5 mg/dL (220 mmol/L) or a 50% reduction of the initial 24-hour creatinine clearance to a level lower than 20 mL/min in less than 2 weeks Type 2: impairment in renal function with serum creatinine levels higher than 1.5 mg/dL (132 mmol/L) that does not meet criteria for type 1 hepatorenal syndrome

HEPATORENAL SYNDROME

375

1.0

Probability of survival

.8

.6

Type 2 HRS

.4 P<0.0001 .2 Type 1 HRS

0.0 0 3 6 9 12

months
Fig. 2. Probability of survival of patients who have cirrhosis according to type of hepatorenal syndrome (HRS). (From Alessandria C, Ozdogan O, Guevara M, et al. MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation. Hepatology 2005;41:1287; with permission).

Diagnosis Although the IAC proposed specic diagnostic criteria for the diagnosis of HRS (Box 2), these criteria are not always used in the clinical setting. In one study, only 60% of those patients who had cirrhosis and renal failure labeled as having HRS fullled the proposed criteria [26]. A recent report from a large tertiary care center indicated that only 29% of 140 patients diagnosed as having HRS met all the criteria proposed by IAC, and the majority of misdiagnosed cases were caused by ATN- and sepsis-related renal failure [27]. The diagnosis of HRS is still based on excluding other causes of renal failure in cirrhosis (see Box 2) [1]. Other causes of renal failure in cirrhosis that should be excluded before the diagnosis of HRS is made include

Box 2. Diagnostic criteria for hepatorenal syndrome 1. Low glomerular ltration rate, as indicated by serum creatinine levels greater than 1.5 mg/dL or 132 mmol/L 2. Absence of shock (sepsis or hypovolemia), volume depletion, and use of nephrotoxic drugs (ie, nonsteroidal anti-inammatory drugs) 3. No improvement in serum creatinine level despite stopping use of diuretics for at least 4 to 5 days and volume repletion with 40 g intravenous albumin 4. Absence of proteinuria or ultrasonographic evidence of obstructive uropathy or parenchymal renal disease

376

CARDENAS & GINES

prerenal renal failure secondary to volume depletion, ATN secondary to shock, drug-induced renal failure (mainly from nonsteroidal anti-inammatory agents), and glomerulopathies in patients who have cirrhosis caused by alcohol or hepatitis viruses. If prerenal renal failure is caused by volume depletion, renal function usually improves after plasma expansion with albumin. Lack of improvement in serum creatinine levels with plasma expansion indicates HRS. Proteinuria (O500 mg/d) or ultrasonographic abnormalities of the kidneys indicate parenchymal renal disease or obstructive uropathy and preclude the diagnosis of HRS. Management Initial measures The initial approach to patients who have advanced cirrhosis and who develop hepatorenal failure must always take into account the type of HRS. In type 1 HRS it is always recommended that patients be hospitalized in a closely monitored care unit. Although the information provided by a central line is extremely helpful in assessing volume status after patients receive plasma expansion, it is not always required for ruling out other causes of renal failure. On the other hand, most patients who have type 2 HRS can be managed as outpatients. Box 3 provides a checklist that is helpful when providing care for patients who have type 1 HRS. Because patients who have HRS frequently are malnourished and require a sodium-restricted diet, a nutritionist should be included in the team taking care of the patient. If patients have dilutional hyponatremia, which is almost always the case, uid restriction of 1 L/d is recommended [18]. In addition to routine blood tests, all patients must undergo a diagnostic paracentesis too rule out SBP. The use of diuretics must be stopped because they can worsen renal failure and might cause severe hyperkalemia (in the case of spironolactone). It is unclear whether it is safe to perform a therapeutic paracentesis in patients who have grade 3 (tense) ascites and type 1 HRS, but the authors believe it is reasonable to carry out a small-volume tap (%5 L) associated with an albumin infusion (8 g/L tapped) because it provides comfort for the patient [21]. The most important aspect of providing care to patients who have HRS is assessment of candidacy for orthotopic liver transplantation. In patients who are candidates for liver transplantation, all eorts should be made to improve renal function to obtain a better outcome after transplantation. Current available therapies for type 1 HRS include the use splanchnic vasoconstrictors or TIPS. Patients who have type 2 HRS usually are managed with large-volume paracentesis and albumin expansion or with TIPS. Pharmacologic interventions Vasoconstrictors used for HRS include vasopressin analogues (ornipressin and terlipressin), somatostatin analogues (octreotide), and the

HEPATORENAL SYNDROME

377

Box 3. Initial management checklist for patients suspected of having type 1 hepatorenal syndrome 1. Admission to monitored care setting with strict measurement of arterial pressure, pulse, intake and outtake, and daily weight 2. Central line placement to measure central venous pressure is helpful but not mandatory 3. Blood tests: complete blood cell count, coagulation studies, liver tests, serum albumin, serum electrolytes, serum blood urea nitrogen, and serum creatinine levels 4. Abdominal ultrasound to examine the liver and kidneys to rule out any parenchymal nephropathy, masses, or obstructive uropathy 5. Twenty-fourhour urine collection to measure urine sodium and volume as well as urine sediment; urine analysis, and urine culture 6. Diuretics always discontinued 7. Diagnostic paracentesis including albumin measurement and cell count with culture of uid in blood culture bottles 8. Plasma expansion with albumin to rule out prerenal renal failure 9. Nutrition consultation 10. Evaluation for orthotopic liver transplantation

alpha-adrenergic agonists (midodrine and noradrenaline), all used along with intravenous albumin as a plasma expander [2846]. These drugs are used with albumin because they work against the intense vasodilation of the splanchnic bed and improve eective arterial blood volume. This eect subsequently suppresses endogenous vasoconstrictor factors (RAAS and SNS) responsible for renal vasoconstriction and improves renal function. It seems that albumin coadministration with vasoconstrictors is important to obtain an optimal response [35,42,44,46,47]. Albumin administration by expanding circulating blood volume seems to increase cardiac preload and cardiac output, which results in an improvement of eective arterial blood volume leading to increased GFR [47]. Terlipressin Vasopressin analogues have a marked vasoconstrictor eect in the splanchnic circulation. Ornipressin and vasopressin, although eective in HRS, caused signicant ischemic side eects in about one third of patients and were abandoned [28,29,46]. Terlipressin is a newer and safer synthetic analogue of vasopressin with fewer side eects (in approximately

378

CARDENAS & GINES

5%10% of cases). This agent has been used successfully for the past 7 years, and several uncontrolled studies support its use in the treatment of type 1 HRS [3033,3541,46]. The administration of terlipressin and intravenous albumin improves renal function with a reduction of serum creatinine and improvement in GFR in approximately 75% of patients who have type 1 HRS [3033,3541,46]. In most cases the rst signs of response might be an improvement in urine volume, which occurs within the rst 48 hours. The main of endpoint of treatment is a reduction in serum creatinine to a value less than 1.5 mg/dL or 132 mmol/L, but changes in serum creatinine may take up to 3 days. In one study, recurrence after stopping treatment was 17%, and a repeat course of terlipressin with albumin was eective in normalizing renal function [35]. One-month survival among most studies has ranged from 40% to 80% [3033,3541,46]. Other vasoconstrictors The use of midodrine (an alpha-adrenergic agonist) in association with octreotide, an inhibitor of the release of glucagon, and albumin also improves renal function in cirrhotic patients who have HRS. The available data about this therapeutic approach are limited to only two studies with a total of 19 patients [42,43]. In both studies there was a marked improvement in renal function and GFR with suppression of renin, aldosterone, norepinephrine, and AVP to normal or nearly normal levels in 80% of cases (15/19 patients). One study showed that octreotide was ineective when administered alone [48]. The administration of a continuous infusion of noradrenaline (0.53 mg/h) for 5 days in association with intravenous albumin resulted in a signicant improvement of renal function in a small group of 12 cirrhotic patients who had type 1 HRS [44]. Improvement in renal function 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 one episode of reversible myocardial hypokinesia, but there were no other ischemic side eects [44]. Goals of therapy Perhaps the most important goal of treating HRS is to provide a successful bridge to liver transplantation by reversing renal failure (reduction in serum creatinine levels to ! 1.5 mg/dL or 132 mmol/L) so that suitable candidates can undergo liver transplantation with less morbidity and side effects caused by posttransplantation medications and have survival rates similar to those of patients who do not have HRS. Patients treated successfully with terlipressin and albumin before liver transplantation have outcomes after transplantation and survival similar to those of patients receiving transplantation who did not have HRS [49]. In three studies, patients who responded to therapy of HRS with terlipressin and albumin and octreotide, midodrine, and albumin had a better survival rate than patients who did not respond to therapy [33,35,43]. Although the information available on

HEPATORENAL SYNDROME

379

vasoconstrictor therapy in HRS is still limited, based on current data, the authors propose a treatment algorithm mainly for patients who have type 1 HRS while awaiting results of large, randomized, controlled trials (Fig. 3). Nonpharmacologic interventions Transjugular Intrahepatic portosystemic shunt TIPS has been used successfully as a treatment of refractory ascites, but there are very scarce data regarding its use in the management of HRS [43,5052]. Four studies indicate that TIPS improves renal function and GFR as well as reduces the activity of RAAS and SNS in cirrhotic patients who have HRS [43,5052]. Improvement in renal function after TIPS placement alone is generally slow, with success in approximately 60% to 70% of patients. Studies assessing TIPS for treatment of type 1 HRS have included only patients who have relatively preserved liver function and have excluded those who have Child-Pugh scores of 12 or higher because of their higher risk of death. A novel approach using the combination of vasoconstrictors with TIPS for treatment of type 1 HRS revealed that patients who had

Diagnosis of Hepatorenal Syndrome

Evaluation for Liver Transplantation

Vasoconstrictors and Albumin (Intravenous albumin: 40 g/day )

Terlipressin:
0.5 mg IV every 4 or hours; may increase dose to 1 mg/4h and then up to 2 mg/4h or 2 -12 mg/day intravenous continuous infusion

Midodrine & Octreotide:

Midodrine: 2.5-7.5 mg p.o. t.i.d with an increase to 12.5 mg t.i.d daily if needed & Octreotide:100 ug s.c. t.i.d. with an increase to 200 ug t.i.d. if needed

Noradrenaline: or
0.5-3mg/hr continuous IV infusion

Duration of therapy: between 5 15 days

Consider TIPS in patients with Child-Pugh score <12 not responding to vasoconstrictors

GOAL: Reduction of serum creatinine < 1.5 mg/dL

Fig. 3. Proposed therapies and treatment endpoints for patients who have type 1 hepatorenal syndrome (HRS). Liver transplantation should be considered rst when the diagnosis of HRS is made. Intravenous splanchnic vasoconstrictors are aimed at reversing the intense splanchnic vasodilation, and intravenous albumin seems to increase cardiac preload and cardiac output. Although octreotide, midodrine, and noradrenaline are commonly available in most centers, terlipressin, which is widely used in Europe, is not available in some countries, including the ` United States. (Adapted from Cardenas A, Gines P. Management of complications of cirrhosis in patients awaiting liver transplantation. J Hepatol 2005;42:S127; with permission.)

380

CARDENAS & GINES

preserved liver function (Child-Pugh score ! 12) and who responded to oral midodrine plus subcutaneous octreotide and intravenous albumin and then had a TIPS had an excellent outcome, with renal function that continued to improve and completely normalized [43]. Dialysis The use hemodialysis is ineective mainly because of a high incidence of severe side eects, including arterial hypotension, coagulopathy, and gastrointestinal bleeding [53,54]. Although dialysis is not routinely recommended in HRS, it may be a reasonable option in patients who have no response to vasoconstrictors or TIPS or in those who develop severe volume overload, metabolic acidosis, or refractory hyperkalemia. Data on the extracorporeal albumin dialysis system seems to be promising. In one small study of 13 patients who had Child C cirrhosis and type 1 HRS, there was a signicant decrease in bilirubin and creatinine, an improvement in serum sodium levels, urine volume, and mean arterial blood pressure, and decreased mortality [55]. Additionally, a small study using Prometheus (Fresenius, Germany), another extracorporeal liver support system, which combines removal of albumin-bound substances and water-soluble substances, was reported to be safe and benecial in a small group of 10 patients who had type 1 HRS [56]. These results require further evaluation to consider any type of dialysis an effective therapy for HRS. Liver transplantation Orthotopic liver transplantation is the best treatment for HRS. The survival of cirrhotic patients who have 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 [57]. Transplantation for type 1 HRS is limited, however, because a signicant proportion of patients die before the operation as the result of their short survival and prolonged waiting times in most centers [58]. In fact, a recent study demonstrated that it was the duration and not the cause of renal dysfunction that predicted outcome of renal function after transplantation, supporting the role of prompt treatment in HRS [59]. Therefore, because patients who have type 1 HRS have a very poor prognosis, this group of patients should be given higher priority for transplantation [58]. Additionally, patients who have type 2 HRS and a MELD score of 20 or higher also have a poor outcome and should also be prioritized for transplantation [6]. If patients are treated successfully with pharmacologic therapy, the outcome after transplantation seems to be similar to that of patients who do not have HRS [49]. Prevention One of the most important advances in the eld of HRS has been the ability to predict which patients are at risk and how to prevent HRS. The

HEPATORENAL SYNDROME

381

two clinical settings in which prevention has been successful are SBP and alcoholic hepatitis. It is unknown if HRS can be prevented in the presence of other bacterial infections; a prospective randomized, controlled trial evaluating the role of intravenous albumin in preventing HRS in unrelated SBP bacterial infections in cirrhosis is being performed at the authors institution (www.clinicaltrials.gov). In SBP, intravenous albumin (1.5 g/kg at diagnosis of infection and 1 g/kg 48 hours later) prevents the development of HRS because it counteracts the enhanced arterial splanchnic vasodilation causing underlling and subsequent activation of vasoconstrictor systems that might occur in the setting of bacterial infections in cirrhosis [7]. In the only study published so far, the incidence of HRS in patients who had SBP without albumin administration was 33% and was only 10% in those who received albumin [7]. More importantly, there was less inhospital mortality in those receiving albumin (10%)than in those not receiving albumin (29%) (Fig. 4) [7]. Other plasma expanders such as hydroxyethyl starch are not effective in preventing renal failure in the setting of SBP [60]. In patients who have acute alcoholic hepatitis, the use of oral pentoxifylline (400 mg three times daily for 1 month) was shown to reduce the incidence and mortality of HRS [3]. There are no follow-up studies conrming these results; however, these two methods of prevention are widely accepted in the clinical setting because of their ease of administration and the availability of albumin and pentoxiphylline.
Hepatorenal Syndrome (%)
30 30

Mortality (%)

20

p=0.02

20

p=0.01

10

10

Cefotaxime

Cefotaxime + albumin

Cefotaxime

Cefotaxime + albumin

Fig. 4. The administration of albumin (1.5 g/kg at diagnosis of infection and 1 g/kg 48 hours later) and cefotaxime prevents the circulatory dysfunction and subsequent development of hepatorenal syndrome (HRS) in cirrhotic patients presenting with spontaneous bacterial peritonitis (SBP). The incidence of HRS in patients who have SBP receiving albumin together with antibiotic therapy is 10%, compared with an incidence of 33% in patients not receiving albumin. Additionally, inhospital mortality is lower in patients receiving albumin (10%) than in those not receiving plasma expansion (29%). (Data from Sort P, Navasa M, Arroyo V, et al. Eect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;341:407.)

382

CARDENAS & GINES

Summary HRS is a common complication of advanced cirrhosis characterized by renal failure, changes in systemic blood pressure, and increased activity of endogenous vasoactive systems. Renal failure is caused by severe renal vasoconstriction developing in the late stages of cirrhosis. The pathogenesis of HRS is related to a worsening of eective arterial blood volume caused by a splanchnic arterial vasodilation and a reduction in venous return and cardiac output. Liver transplantation is the best therapy, but it is not always feasible. The use of vasoconstrictors (terlipressin, midodrine, octreotide, or noradrenaline) plus albumin is the therapy of choice because data are available supporting their use, particularly in type 1 HRS. Prophylaxis of HRS with albumin infusion is recommended in patients who have SBP and with pentoxifylline in patients who have acute alcoholic hepatitis. References
` [1] Arroyo V, Gines P, Gerbes A, et al. Denition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 1996;23:16476. ` [2] Gines P, Cardenas A, Arroyo V, et al. Management of cirrhosis and ascites. N Engl J Med 2004;350:164654. [3] Akriviadis E, Botla R, Briggs W, et al. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology 2000; 119:163748. [4] Moore K. Renal failure in acute liver failure. Eur J Gastroenterol Hepatol 1999;11:96775. ` ` [5] Gines A, Escorsell A, Gines P, et al. Incidence, predictive factors, and prognosis of hepatorenal syndrome in cirrhosis. Gastroenterology 1993;105:22936. [6] Alessandria C, Ozdogan O, Guevara M, et al. MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation. Hepatology 2005;41: 12829. [7] Sort P, Navasa M, Arroyo V, et al. Eect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;5:4039. [8] Moreau R, Lebrec D. Hepatorenal syndromeddenitions and diagnosis. Aliment Pharmacol Ther 2004;20(Suppl 3):248. [9] Schrier RW, Arroyo V, Bernardi M, et al. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 1988;8: 11517. [10] Iwakiri Y, Groszmann R. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology 2006;43:S12131. ` [11] Bernardi M, Domenicali M. The renin-angiotensin-aldosterone system in cirrhosis. In: Gines P, Arroyo V, Rodes J, et al, editors. Ascites and renal dysfunction in liver disease. Oxford (UK): Blackwell Publishing; 2005. p. 4353. ` [12] Dudley F, Esler M. The sympathetic nervous system in cirrhosis. In: Gines P, Arroyo V, Rodes J, et al, editors. Ascites and renal dysfunction in liver disease. Oxford (UK): Blackwell Publishing; 2005. p. 5472. [13] Ishikawa S, Schrier RW. Pathophysiological roles of arginine vasopressin and aquaporin-2 in impaired water excretion. Clin Endocrinol (Oxf) 2003;58:117. [14] Arroyo V, Colmenero J. Ascites and hepatorenal syndrome in cirrhosis: pathophysiological basis of therapy and current management. J Hepatol 2003;38(Suppl 1):S6989.

HEPATORENAL SYNDROME

383

[15] Terra C, Guevara M, Torre A, et al. Renal failure in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis. Value of MELD score. Gastroenterology 2005; 129:194453. [16] Ruiz del Arbol L, Monescillo A, Arocena C, et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 2005;42:43947. [17] Ruiz-del-Arbol W, Urman J, Fernandez J, et al. Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 2003; 38:12108. ` ` [18] Cardenas A, Gines P. Management of hyponatremia in cirrhosis. In: Gines P, Arroyo V, Rodes J, et al, editors. Ascites and renal dysfunction in liver disease. Oxford (UK): Blackwell Publishing; 2005. p. 30514. [19] Caregaro L, Menon F, Angeli P, et al. Limitations of serum creatinine level and creatinine clearance as ltration markers in cirrhosis. Arch Intern Med 1994;154:2015. [20] Sherman D, Fish DN, Teitelbaum I. Assessing renal function in cirrhotic patients: problems and pitfalls. Am J Kidney Dis 2003;41:26978. [21] Cardenas A. hepatorenal syndrome: a dreaded complication of end-stage liver disease. Am J Gastroenterol 2005;100:18. ` [22] Gines P, Tito L, Arroyo V, et al. Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology 1988;94:1493502. [23] Follo A, Llovet JM, Navasa M, et al. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis. Hepatology 1994;20:1495501. ` [24] Cardenas A, Gines P, Uriz J, et al. Renal failure after upper gastrointestinal bleeding in cirrhosis. Incidence, clinical course, predictive factors and short-term prognosis. Hepatology 2001;34:6716. [25] Guevara M, Fernandez-Esparrach G, Alessandra C, et al. Eects of contrast media on renal function in patients with cirrhosis: a prospective study. Hepatology 2004;40:64651. [26] Watt K, Uhanova J, Minuk GY. Hepatorenal syndrome: diagnostic accuracy, clinical features, and outcome in a tertiary care center. Am J Gastroenterol 2002;97:204650. [27] Servin-Abad L, Regev A, Contreras G, et al. Retrospective analysis of 140 patients labeled as hepatorenal syndrome in a referral center. Hepatology 2005;42:543A. ` [28] Guevara M, Gines P, Fernandez-Esparrach G, et al. Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion. Hepatology 1998;27:3541. [29] Gulberg V, Bilzer M, Gerbes AL. Long-term therapy and retreatment of hepatorenal syndrome type 1 with ornipressin and dopamine. Hepatology 1999;30:8705. [30] Hadengue A, Gadano A, Moreau R, et al. Benecial eects of the 2-day administration of terlipressin in patients with cirrhosis and hepatorenal syndrome. J Hepatol 1998;29: 56570. ` [31] Uriz J, Gines P, Cardenas A, et al. Terlipressin plus albumin infusion: an eective and safe therapy of hepatorenal syndrome. J Hepatol 2000;33:438. [32] Mulkay JP, Louis H, Donckier V, et al. Long-term terlipressin administration improves renal function in cirrhotic patients with type 1 hepatorenal syndrome: a pilot study. Acta Gastroenterol Belg 2001;64:159. [33] Moreau R, Durand F, Poynard T, et al. Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study. Gastroenterology 2002;122: 92330. [34] Alessandria C, Venon WD, Marzano A, et al. Renal failure in cirrhotic patients: role of terlipressin in clinical approach to hepatorenal syndrome type 2. Eur J Gastroenterol Hepatol 2002;14:13638. ` [35] Ortega R, Gines P, Uriz J, et al. Terlipressin therapy with and without albumin for patients with hepatorenal syndrome. Results of a prospective, non-randomized study. Hepatology 2002;36:9418.

384

CARDENAS & GINES

[36] Halimi C, Bonnard P, Bernard B, et al. Eect of terlipressin (Glypressin) on hepatorenal syndrome in cirrhotic patients: results of a multicentre pilot study. Eur J Gastroenterol Hepatol 2002;14:1538. [37] Colle I, Durand F, Pessione F, et al. Clinical course, predictive factors and prognosis in patients with cirrhosis and type 1 hepatorenal syndrome treated with Terlipressin: a retrospective analysis. J Gastroenterol Hepatol 2002;17:8828. [38] Solanki P, Chawla A, Garg R, et al. Benecial eects of terlipressin in hepatorenal syndrome: a prospective, randomized placebo-controlled clinical trial. J Gastroenterol Hepatol 2003; 18:1526. [39] Saner F, Kavuk I, Lang H, et al. Terlipressin and gelafundin: safe therapy of hepatorenal syndrome. Eur J Med Res 2004;9:7882. [40] Saner FH, Fruhauf NR, Schafers RF, et al. Terlipressin plus hydroxyethyl starch infusion: an eective treatment for hepatorenal syndrome. Eur J Gastroenterol Hepatol 2003;15: 9257. [41] Gluud LL, Kjaer M, Taastroem, et al. Terlipressin for hepatorenal syndrome: a Cochrane systematic review. J Hepatol 2005;42:206A. [42] Angeli P, Volpin R, Gerunda G, et al. Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology 1999;29:16907. [43] Wong F, Pantea L, Sniderman K. Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology 2004;40:5564. [44] Duvoux C, Zanditenas D, Hezode C, et al. Eects of noradrenaline and albumin in patients with type 1 hepatorenal syndrome: a pilot study. Hepatology 2002;36:37480. [45] Kiser TH, Fish DN, Obritsch MD, et al. Vasopressin, not octreotide, may be benecial in the treatment of hepatorenal syndrome: a retrospective study. Nephrol Dial Transplant 2005;20: 181320. [46] Arroyo V, Terra C, Torre A, et al. Hepatorenal syndrome in cirrhosis: clinical features, di` agnosis, and management. In: Gines P, Arroyo V, Rodes J, et al, editors. Ascites and renal dysfunction in liver disease. Oxford (UK): Blackwell Publishing; 2005. p. 34159. [47] Arroyo V, Ruiz del Arbol, Gines P. Circulatory dysfunction in cirrhosis. In: Arroyo V, Navasa M, Forns X, et al, editors. Update in treatment of liver disease. Barcelona (Spain): Ars Medica; 2005. p. 1928. [48] Pomier-Layrargues G, Paquin SC, Hassoun Z, et al. Octreotide in hepatorenal syndrome: a randomized, double-blind, placebo-controlled, crossover study. Hepatology 2003;38: 23843. [49] Restuccia T, Ortega R, Guevara M, et al. Eects of treatment of hepatorenal syndrome before transplantation on posttransplantation outcome. A case-control study. J Hepatol 2004; 40:1406. ` [50] Guevara M, Gines P, Bandi JC, et al. Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: eects on renal function and vasoactive systems. Hepatology 1998;28: 41622. [51] Brensing KA, Textor J, Perz J, et al. Long-term outcome after transjugular intrahepatic portosystemic stent-shunt in non-transplant cirrhotics with hepatorenal syndrome: a phase II study. Gut 2000;47:28895. [52] Testino G, Ferro C, Sumberaz A, et al. Type-2 hepatorenal syndrome and refractory ascites: role of transjugular intrahepatic portosystemic stent-shunt in eighteen patients with advanced cirrhosis awaiting orthotopic liver transplantation. Hepatogastroenterology 2003; 50:17535. [53] Kapling RK, Bastani B. The clinical course of patients with type 1 hepatorenal syndrome maintained on hemodialysis. Ren Fail 2004;26:5638. [54] Keller F, Heinze H, Jochimsen F, et al. Risk factors and outcome of 107 patients with decompensated liver disease and acute renal failure (including 26 patients with hepatorenal syndrome): the role of hemodialysis. Ren Fail 1995;17:13546.

HEPATORENAL SYNDROME

385

[55] Mitzer SR, Stange J, Klammt S, et al. Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: results of a prospective, randomized, controlled clinical trial. Liver Transpl 2000;6:27786. [56] Rifai K, Ernst T, Kretschmer U, et al. The Prometheus device for extracorporeal support of combined liver and renal failure. Blood Purif 2005;23:298302. [57] Rimola A, Navasa M, Grande L, et al. Liver transplantation for patients with cirrhosis and ` ascites. In: Gines P, Arroyo V, Rodes J, et al, editors. Ascites and renal dysfunction in liver disease. Oxford (UK): Blackwell Publishing; 2005. p. 27185. ` [58] Cardenas A, Gines P. Management of complications of cirrhosis in patients awaiting liver transplantation. J Hepatol 2005;42:S12433. [59] Campbell MS, Kotlyar DS, Brensinger CM, et al. Renal function after orthotopic liver transplantation is predicted by duration of pretransplantation creatinine elevation. Liver Transpl 2005;11:104855. [60] Fernandez J, Monteagudo J, Bargallo X, et al. A randomized unblinded pilot study comparing albumin versus hydroxyethyl starch in spontaneous bacterial peritonitis. Hepatology 2005;42:62734.