EASL Clinical Practice Guidelines

Hepatorenal syndrome

Definition and diagnosis of hepatorenal syndrome

Hepatorenal syndrome (HRS) is defined as the occurrence of renal failure in a patient with advanced liver disease in the absence of an identifiable cause of renal failure [56]. Thus, the diagnosis is essentially one of exclusion of other causes of renal failure. In 1994 the International Ascites Club defined the major criteria for the diagnosis of HRS and designated HRS into type 1 and type 2 HRS [56]. These were modified in 2007 [192]. The new diagnostic criteria are shown in Table 8. Various new concepts have emerged since the first definition and criteria for HRS were published in 1996 [56]. According to these new concepts: vasodilatation mainly occurs in the splanchnic arterial bed; the cardiac output in patients with HRS may be low or normal (infrequently high), but insufficient for the patient's needs; the most important trigger for the development of type 1 HRS is bacterial infection; and renal function can be improved by drug therapy [192].

Table 8
Criteria for diagnosis of hepatorenal syndrome in cirrhosis.

Cirrhosis with ascites
Serum creatinine >1.5 mg/dl (133 μmol/L)
Absence of shock
Absence of hypovolemia as defined by no sustained improvement of renal function (creatinine decreasing to <133 μmol/L) following at least 2 days of diuretic withdrawal (if on diuretics), and volume expansion with albumin at 1 g/kg/day up to a maximum of 100 g/day
No current or recent treatment with nephrotoxic drugs
Absence of parenchymal renal disease as defined by proteinuria <0.5 g/day, no microhaematuria (<50 red cells/high powered field), and normal renal ultrasonography

There are 2 types of HRS. Type 1 HRS is a rapidly progressive acute renal failure that frequently develops in temporal relationship with a precipitating factor for a deterioration of liver function together with deterioration of other organ function. It commonly occurs in severe alcoholic hepatitis or in patients with end-stage cirrhosis following a septic insult such as SBP, although in some patients it may occur in the absence of any identifiable triggering event. Conventionally, type 1 HRS is only diagnosed when the serum creatinine increases more than 100% from baseline to a final level of greater than 2.5 mg/dl (221 μmol/L). Type 2 HRS occurs in patients with refractory ascites and there is a steady but moderate degree of functional renal failure, often with avid sodium retention. Patients with type 2 HRS may eventually develop type 1 HRS either spontaneously or following a precipitating event such as SBP [56]. The renal community has recently re-termed acute renal failure as acute kidney injury (AKI) [193]. However, the applicability and usefulness of the AKI classification in patients with cirrhosis requires full evaluation in prospective studies.

Recommendations It is important to make the diagnosis of HRS or identify other known causes of renal failure in cirrhosis as early as possible. The causes of renal failure in cirrhosis that should be excluded before the diagnosis of HRS is made include: hypovolemia, shock, parenchymal renal diseases, and concomitant use of nephrotoxic drugs. Parenchymal renal diseases should be suspected if there is significant proteinuria or microhaematuria, or if renal ultrasonography demonstrates abnormalities in kidney size. Renal biopsy is important in these patients to help plan the further management, including the potential need for combined liver and kidney transplantation (Level B1).

HRS should be diagnosed by demonstrating a significant increase in serum creatinine and excluding other known causes of renal failure. For therapeutic purposes, HRS is usually diagnosed only when serum creatinine increases to >133 μmol/L (1.5mg/dl). Repeated measurement of serum creatinine over time, particularly in hospitalized patients, is helpful in the early identification of HRS (Level B1).

HRS is classified into two types: type 1 HRS, characterized by a rapid and progressive impairment in renal function (increase in serum creatinine of equal to or greater than 100% compared to baseline to a level higher than 2.5 mg/dl in less than 2 weeks), and type 2 HRS characterized by a stable or less progressive impairment in renal function (Level A1).

Pathophysiology of hepatorenal syndrome

There are four factors involved in the pathogenesis of HRS. These are (1) development of splanchnic vasodilatation which causes a reduction in effective arterial blood volume and a decrease in mean arterial pressure. (2) Activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system which causes renal vasoconstriction and a shift in the renal autoregulatory curve [194], which makes renal blood flow much more sensitive to changes in mean arterial pressure. (3) Impairment of cardiac function due to the development of cirrhotic cardiomyopathy, which leads to a relative impairment of the compensatory increase in cardiac output secondary to vasodilatation. (4) Increased synthesis of several vasoactive mediators which may affect renal blood flow or glomerular microcirculatory hemodynamics, such as cysteinyl leukotrienes, thromboxane A2, F2-isoprostanes, and endothelin-1, yet the role of these factors in the pathogenesis of HRS remains unknown. An extended discussion of the pathophysiology of HRS is outside the scope of these guidelines and can be found elsewhere [[165], [195], [196]].

Risk factors and prognosis of hepatorenal syndrome

The development of bacterial infections, particulary SBP, is the most important risk factor for HRS [[121], [127], [197], [198]]. HRS develops in approximately 30% of patients who develop SBP [121]. Treatment of SBP with albumin infusion together with antibiotics reduces the risk of developing HRS and improves survival [121]. The prognosis of HRS remains poor, with an average median survival time of all patients with HRS of approximately only 3 months [[195], [199]]. High MELD scores and type 1 HRS are associated with very poor prognosis. Median survival of patients with untreated type 1 HRS is of approximately 1 month [200].

Management of hepatorenal syndrome

General measures

All comments made in these guidelines with respect to treatment refer to type 1 HRS unless otherwise specified. Once diagnosed, treatment should be started early in order to prevent the progression of renal failure. General supportive measures include careful monitoring of vital signs, standard liver and renal tests, and frequent clinical assessment as well as management of concomitant complications of cirrhosis. An excessive administration of fluids should be avoided to prevent fluid overload and development/progression of dilutional hyponatremia. Potassium-sparing diuretics should not be given because of the risk of severe hyperkalemia.

Recommendations Monitoring: Patients with type 1 HRS should be monitored carefully. Parameters to be monitored include urine output, fluid balance, and arterial pressure, as well as standard vital signs. Ideally central venous pressure should be monitored to help with the management of fluid balance and prevent volume overload. Patients are generally better managed in an intensive care or semi-intensive care unit (Level A1).

Screening for sepsis: Bacterial infection should be identified early, by blood, urine and ascitic fluid cultures, and treated with antibiotics. Patients who do not have signs of infection should continue taking prophylactic antibiotics, if previously prescribed. There are no data on the use of antibiotics as empirical treatment for unproven infection in patients presenting with type 1 HRS (Level C1).

Use of beta-blockers: There are no data on whether it is better to stop or continue with beta-blockers in patients with type 1 HRS who are taking these drugs for prophylaxis against variceal bleeding (Level C1).

Use of paracentesis: There are few data on the use of paracentesis in patients with type 1 HRS. Nevertheless, if patients have tense ascites, large-volume paracentesis with albumin is useful in relieving patients' discomfort (Level B1).

Use of diuretics: All diuretics should be stopped in patients at the initial evaluation and diagnosis of HRS. There are no data to support the use of furosemide in patients with ongoing type 1 HRS. Nevertheless furosemide may be useful to maintain urine output and treat central volume overload if present. Spironolactone is contraindicated because of high risk of life-threatening hyperkalemia (Level A1).

Specific therapies
Drug therapy

The most effective method currently available is the administration of vasoconstrictor drugs. Among the vasoconstrictors used, those that have been investigated more extensively are the vasopressin analogues particularly terlipressin [[195], [201], [202], [203], [204], [205], [206], [207], [208], [209]]. The rationale for the use of vasopressin analogues in HRS is to improve the markedly impaired circulatory function by causing a vasoconstriction of the extremely dilated splanchnic vascular bed and increasing arterial pressure [[210], [211]]. A large number of studies, randomized and non-randomized, have shown that terlipressin improves renal function in patients with type 1 HRS. Treatment is effective in 40–50% of patients, approximately (reviewed in [[195], [210]]). There is no standardized dose schedule for terlipressin administration because of the lack of dose-finding studies. Terlipressin is generally started at a dose of 1 mg/4–6 h and increased to a maximum of 2 mg/4–6 h if there is no reduction in serum creatinine of at least 25% compared to the baseline value at day 3 of therapy. Treatment is maintained until serum creatinine has decreased below 1.5 mg/dl (133 μmol/L), usually around to 1–1.2 mg/dl (88–106 μmol/L). Response to therapy is generally characterized by a slowly progressive reduction in serum creatinine (to below 1.5 mg/dl–133 μmol/L), and an increase in arterial pressure, urine volume, and serum sodium concentration. Median time to response is 14 days and usually depends on pre-treatment serum creatinine, the time being shorter in patients with lower baseline serum creatinine [212]. A serum bilirubin less than 10 mg/dl before treatment and an increase in mean arterial pressure of >5 mm Hg at day 3 of treatment are associated with a high probability of response to therapy [212]. Recurrence after withdrawal of therapy is uncommon and retreatment with terlipressin is generally effective. The most frequent side effects of treatment are cardiovascular or ischemic complications, which have been reported in an average of 12% of patients treated [[195], [210]]. It is important to emphasize that most studies excluded patients with known severe cardiovascular or ischemic conditions. In most studies, terlipressin was given in combination with albumin (1 g/kg on day 1 followed by 40 g/day) to improve the efficacy of treatment on circulatory function [213].

Treatment with terlipressin has been shown to improve survival in some studies but not in others. A recent systematic review of randomized studies using terlipressin as well as other vasoconstrictors has shown that treatment with terlipressin is associated with an improved short-term survival [214]. Most clinical trials on the use of terlipressin have excluded patients with ongoing sepsis. The effectiveness of terlipressin in the treatment of HRS with concomitant sepsis is unknown. Finally, treatment with terlipressin in patients with type 2 HRS is also associated with an improvement of renal function [[209], [215]]. Nevertheless, there is still limited information on the use of terlipressin in these patients.

Vasoconstrictors other than vasopressin analogues that have been used in the management of type 1 HRS include noradrenaline and midodrine plus octreotide, both in combination with albumin. Midodrine is given orally at doses starting from 2.5 to 75 mg/8 h and octreotide 100 μg/8 h subcutaneously, with an increase to 12.5 mg/8 h and 200 μg/8 h, respectively, if there is no improvement in renal function. Although this approach has been shown to improve renal function, the number of patients reported using this therapy is very small [[216], [217]]. Noradrenaline (0.5–3 mg/h) is administered as a continuous infusion and the dose is increased to achieve a raise in arterial pressure and also improves renal function in patients with type 1 HRS [218]. Unfortunately, the number of patients treated with noradrenaline is also small and no randomized comparative studies with a control group of patients receiving no vasoconstrictor therapy have been performed to evaluate its efficacy.

There have been few studies on prevention of HRS. Short-term treatment (4 week) with pentoxifylline (400 mg three times a day) in a randomized double-blind study was shown to prevent the development of HRS in patients with severe alcoholic hepatitis [219]. In a more recent study, long-term treatment with pentoxifylline was not associated with an improved survival but with reduced frequency of some complications of cirrhosis, including renal failure, yet this was not the primary endpoint of the study [220]. More studies are needed to assess the usefulness of pentoxifylline in the prevention of HRS in patients with cirrhosis. Finally, as discussed previously a randomized double-blind study showed that norfloxacin (400 mg/day) reduced the incidence of HRS in advanced cirrhosis [156].

Transjugular intrahepatic portosystemic shunts

Transjugular intrahepatic portosystemic shunts (TIPS) have been reported to improve renal function in patients with type 1 HRS [[77], [221]]. However, the applicability of TIPS in this setting is very limited because many patients have contraindications to the use of TIPS. More studies are needed to evaluate the use of TIPS in patients with type 1 HRS. TIPS has also been shown to improve renal function and the control of ascites in patients with type 2 HRS [90]. However, TIPS has not been specifically compared with standard medical therapy in these latter patients.

Renal replacement therapy

Both hemodialysis or continuous venous hemofiltration, have been used to treat patients with type 1 HRS [[222], [223]]. However, published information is very scant and in most studies patients with type 1 HRS have not been differentiated from patients with other causes of renal failure. Moreover, no comparative studies have been reported between renal replacement therapy and other methods of treatment, such as vasoconstrictor drugs. Circumstances that call for an immediate treatment with renal replacement therapy, such as severe hyperkalemia, metabolic acidosis, and volume overload are infrequent in patients with type 1 HRS, particularly in the early stages. There are isolated reports and a small randomized study suggesting that the so-called artificial liver support systems, either the molecular adsorbents recirculating system (MARS) or Prometheus, may have beneficial effects in patients with type 1 HRS [[224], [225]]. However, these approaches should still be considered investigational until more data are available.

Liver transplantation

Liver transplantation is the treatment of choice for both type 1 and type 2 HRS, with survival rates of approximately 65% in type 1 HRS [226]. The lower survival rate compared to patients with cirrhosis without HRS is due to the fact that renal failure is a major predictor of poor outcome after transplantation. Moreover, patients with type 1 HRS have a high mortality whilst on the waiting list and ideally should be given priority for transplantation.

There seems to be no advantage in using combined liver–kidney transplantation versus liver transplantation alone in patients with HRS, with the possible exception of those patients who have been under prolonged renal support therapy (>12 weeks) [[227], [228]].

Although not studied prospectively, treatment of HRS before transplantation (i.e., with vasoconstrictors) may improve outcome after transplantation [229]. The reduction in serum creatinine levels after treatment and the related decrease in the MELD score should not change the decision to perform liver transplantation since the prognosis after recovering from type 1 HRS is still poor.

Recommendations Management of type 1 hepatorenal syndrome

Drug therapy of type 1 hepatorenal syndrome Terlipressin (1 mg/4–6 h intravenous bolus) in combination with albumin should be considered the first line therapeutic agent for type 1 HRS. The aim of therapy is to improve renal function sufficiently to decrease serum creatinine to less than 133 μmol/L (1.5 mg/dl) (complete response). If serum creatinine does not decrease at least 25% after 3 days, the dose of terlipressin should be increased in a stepwise manner up to a maximum of 2 mg/4 h. For patients with partial response (serum creatinine does not decrease <133 μmol/L) or in those patients without reduction of serum creatinine treatment should be discontinued within 14 days (Level A1).

Contraindications to terlipressin therapy include ischemic cardiovascular diseases. Patients on terlipressin should be carefully monitored for development of cardiac arrhythmias or signs of splanchnic or digital ischemia, and fluid overload, and treatment modified or stopped accordingly. Recurrence of type 1 HRS after discontinuation of terlipressin therapy is relatively uncommon. Treatment with terlipressin should be repeated and is frequently successful (Level A1).

Potential alternative therapies to terlipressin include norepinephrine or midodrine plus octreotide, both in association with albumin, but there is very limited information with respect to the use of these drugs in patients with type 1 HRS (Level B1).

Non-pharmacological therapy of type 1 hepatorenal syndrome: Although the insertion of TIPS may improve renal function in some patients, there are insufficient data to support the use of TIPS as a treatment of patients with type 1 HRS.

Renal replacement therapy may be useful in patients who do not respond to vasoconstrictor therapy, and who fulfill criteria for renal support. There are very limited data on artificial liver support systems, and further studies are needed before its use in clinical practice can be recommended (Level B1).

Management of type 2 hepatorenal syndrome

Terlipressin plus albumin is effective in 60–70% of patients with type 2 HRS. There are insufficient data on the impact of this treatment on clinical outcomes (Level B1).

Liver transplantation

Liver transplantation is the best treatment for both type 1 and type 2 HRS. HRS should be treated before liver transplantation, since this may improve post-liver transplant outcome (Level A1).

Patients with HRS who respond to vasopressor therapy should be treated by liver transplantation alone. Patients with HRS who do not respond to vasopressor therapy, and who require renal support should generally be treated by liver transplantation alone, since the majority will achieve a recovery of renal function post-liver transplantation. There is a subgroup of patients who require prolonged renal support (>12 weeks), and it is this group that should be considered for combined liver and kidney transplantation (Level B2).

Prevention of hepatorenal syndrome

Patients who present with SBP should be treated with intravenous albumin since this has been shown to decrease the incidence of HRS and improve survival (Level A1).

There are some data to suggest that treatment with pentoxifylline decreases the incidence of HRS in patients with severe alcoholic hepatitis and advanced cirrhosis and treatment with norfloxacin decreases the incidence of HRS in advanced cirrhosis, respectively. Further studies are needed (Level B2).