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Treatment with vaptans may be considered in patients with severe hypervolemic hyponatremia (<125 mmol/l). Tolvaptan is licensed in some countries for oral treatment. Convivaptan is only licensed in some countries for short-term intravenous treatment. Treatment with tolvaptan should be started in the hospital and the dose titrated to achieve a slow increase in serum sodium. Serum sodium should be monitored closely particularly during the first days of treatment and whenever the dose of the drug is increased. Rapid increases in serum sodium concentration (>8-10 mmol/day) should be avoided to prevent the occurrence of osmotic demyelination syndrome. Neither fluid restriction nor administration of saline should be used in combination with vaptans to avoid a too rapid increase in serum sodium concentration. Patients may be discharged after serum sodium levels are stable and no further increase in the dose of the drug is required. Concomitant treatment with drugs that are either potent inhibitors or inducers of the CYP3A should be avoided. The duration of treatment with vaptans is not known. Safety has only been established for short-term treatment (one month) (B1).

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]. These are that vasodilatation mainly occurs in the splanchnic arterial bed, that the cardiac output in patients with HRS may be low or normal (infrequently high), but insufficient for the patient’s needs, that the most important trigger for the development of type 1 HRS is bacterial infection, and that renal function can be improved by drug therapy [192].

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

33 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. 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 > 133µmoles/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 in two types: type 1 HRS, characterized by a rapid and progressive impairment