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Hepatorenal syndrome is a serious life threatening complication in end stage liver disease. A recent consensus conference has agreed definitions for hepatorenal syndrome and divided the syndrome into types I and II.1 Type I is characterised by rapidly progressive renal failure with a doubling of serum creatinine to a level greater than 2.5 mg/dl or a halving of creatinine clearance to less than 20 ml/min in less than two weeks. In type II, serum creatinine must be greater than 1.5 mg/dl or creatinine clearance <40 ml/min but is more slowly progressive with a correspondingly better prognosis. Most patients pass through a sequence of ascites, followed by refractory ascites, and then hepatorenal syndrome. A large prospective study including patients with ascites demonstrated that hepatorenal syndrome developed in 18% at one year and in 39% at five years.2 Prognosis was poor with median survival of 1.7 weeks and 90% mortality at 10 weeks. The pathogenesis of hepatorenal syndrome is believed to involve splanchnic vascular dilatation with resultant vasoconstriction in other vascular beds particularly affecting the kidney.1 Therapies such as head out water immersion or liver transplantation can reverse this process but are not practical or rapidly available for many patients.3 4
Recent studies suggest that transjugular intrahepatic portosystemic stent-shunt (TIPS) or pharmacological therapy may be useful in this syndrome. The study by Brensing et al in this issue of Gut 5 describes the long term outcome in cirrhotics with hepatorenal syndrome treated with TIPS (see page 288). They divided their patients into those with hepatorenal syndrome types I and II. Three quarters responded to TIPS with improvement in renal function. One year survival in the treated group was 48%. On an intention to treat basis, one year survival was 39%. The survival of type II patients after TIPS was significantly better than that of type I patients (one year survival approximately 70% v 20%). These results are very encouraging. However, it is important to remember that this was not a controlled trial. In addition, we are told little about the selection criteria for this cohort of patients. It is difficult to judge whether this group is directly comparable with the cohort identified prospectively by Gines et al, which most comprehensively defined the natural history of this syndrome.2 It is likely that the group with type I hepatorenal syndrome most closely resemble classical hepatorenal syndrome. Extrapolating from the graphs supplied, survival at 10 weeks in the type I hepatorenal syndrome group, by intention to treat, was 53% compared with 10% described by Gines et al.
These results are very encouraging but controlled trials are required to confirm improvement in prognosis. The results of a small controlled trial of TIPS compared with large volume paracentesis in 25 patients with refractory ascites would cause some concern in this regard. It is probably directly relevant as refractory ascites is frequently a forerunner of hepatorenal syndrome. While ascites improved in many treated patients, overall survival was significantly lower in the TIPS group (29% v 56%) at two years.6 Four patients in each group had Pugh grade C liver disease. In the current study patients with serum bilirubin >15 mg/dl, a Pugh score >12, or spontaneous severe encephalopathy were excluded, which probably selected out some of the highest risk patients and may have improved the results.
Another choice for treating hepatorenal syndrome is long term vasoconstrictor therapy. A number of studies have shown that long term vasoconstrictor therapy improves renal function in patients with hepatorenal syndrome. These studies used the vasopressin analogues ornipressin or terlipressin (glypressin) or the alpha adrenoceptor agonist midodrine.7-9 Intravenous 20% albumin was used to increase intravascular volume. The long acting somatostatin analogue octreotide was added in one study to inhibit production of endogenous vasodilator peptides. Renal function improved in the majority of patients treated and one study suggested improved survival compared with historical controls treated with low dose dopamine and volume repletion.7 Ischaemic complications led to treatment withdrawal in a small number of patients.
Hepatorenal syndrome is a manifestation of advanced decompensated liver disease. It may be unrealistic to expect TIPS or pharmacological therapy to improve long term prognosis if underlying liver disease is unaffected. Acute alcoholic hepatitis may be an exception where liver function could improve substantially with abstinence. The gold standard treatment for hepatorenal syndrome in patients with cirrhosis is likely to remain liver transplantation. Long waiting lists or contraindications such as active alcoholism may preclude this option in many patients, at least in the short term. TIPS or pharmacological therapy may act as a bridge to transplantation for these patients. There may also be additional benefits. Renal failure remains a major adverse prognostic factor for survival following liver transplantation.10 If renal failure per se is a critical determinant of prognosis following liver transplant, reversal of hepatorenal syndrome prior to transplantation could improve prognosis after transplant.
These are exciting times for the treatment of hepatorenal syndrome. Future clinical trials will need to confirm that these new therapies actually improve prognosis. Studies will also need to address how best to use these treatments and to determine whether they should be viewed as alternative or complementary therapies. It is also important to remember that hepatorenal syndrome frequently develops in hospital and may be precipitated by over diuresis, infection, or use of nephrotoxic drugs such as aminoglycosides, etc. Renal failure may be preventable in many of these patients. A recent trial has shown that intravenous albumin reduces the risk of renal failure and mortality in cirrhotic patients with spontaneous bacterial peritonitis.11 Hopefully we will see more advances in prevention and treatment of this syndrome.
See article on page 288
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