The time is right for the use of liver dialysis devices in patients with hepatorenal syndrome.

Abstract

Hepatorenal syndrome is, unfortunately, a common and severe complication of cirrhosis. It is associated with marked renal vasoconstriction resulting in a low glomerular filtration rate. In the splanchnic circulation, there is arteriolar vasodilation resulting in reduced systemic vascular resistance and arterial hypotension. There is progressive renal insufficiency, and the prognosis is poor with routine medical therapies. Orthotopic liver transplantation is considered the best treatment option for patients with hepatorenal syndrome. Transjugular intraheptic portosystemic shunt (TIPS) and vasopressin analogue (ornipressin or terlipressin) infusions are promising nontransplant approaches for this problem. Recently, a liver dialysis method that permits removal of albumin-bound toxins from the circulation was reported to prolong survival in patients with hepatorenal syndrome (Liver Transplantation 2000;6:277–86). In a prospective, randomized controlled trial, five patients with rapid-onset hepatorenal syndrome received standard medical therapy while eight patients received standard therapy plus treatment with a molecular adsorbent recirculating system (MARS). Dr. Steffen R. Mitzner and colleagues of the University of Rostock in Germany report that MARS uses an albumin-containing dialysate that is recirculated and perfused online through charcoal and anion-exchanger columns. All thirteen adult patients were listed as a status 2A according to United Network for Organ Sharing Criteria and had Child's class C cirrhosis. The mean Child-Turcotte-Pugh score was 12.4 and mean total serum bilirubin level was 25.7 mg/dL (439.5 μmol/L). Thirty-day survival was defined as the primary end point of the study. Patients in the MARS arm of the study had significant decreases in serum bilirubin (mean 26.8 mg/dL pretreatment vs. 17.3 mg/dL posttreatment, P < 0.01) and creatinine (3.8 vs. 2.3 mg/dL, P < 0.01) levels and increases in serum sodium (130 vs. 139 mmol/L, P < 0.01) and prothrombin activity (32% vs. 44% of control, P < 0.01). In the MARS treatment group, mortality was 62.5% at 7 days and 75% at 30 days. In the standard therapy group, all patients (100%) died within 7 days. None of the patients received a liver transplant, transjugular intrahepatic portosystemic shunt, or vasopressin infusion during the observation period. The MARS treatment was well tolerated throughout the trial period. Side effects included mild thrombocytopenia, which was reversible and did not require platelet transfusion. The authors conclude that MARS might be particularly useful as a bridge to transplantation for patients with hepatorenal syndrome until a liver becomes available for transplantation. Furthermore, MARS might be indicated in patients who are ineligible for placement of a transjugular intrahepatic portosystemic shunt. In an accompanying editorial (Liver Transplantation 2000;6:287–9), Dr. Vicente Arroyo from the University of Barcelona in Spain cautions that the study involved very few patients. Further, the biochemical improvements observed might merely represent the effect of the dialysis process and not reflect a significant change in hepatic or renal functions. A major flaw in the design of the study is that only standard liver and renal function studies were determined before, during, and after treatment. Parameters estimating systemic hemodynamics and renal function (such as cardiac output, peripheral vascular resistance, renal blood flow, and glomerular filtration rate) and neurohumoral measurements (such as plasma renin activity, plasma norepinephrine and antidiuretic hormone concentrations) were not reported. While the probability of survival was longer in the MARS group, the improvement in survival, although statistically significant, is of little clinical relevance. There was only one long-term (greater than one month) survivor. It cannot be excluded that this survival was unrelated to the MARS treatment. A multicenter randomized trial in large numbers of patients is now needed to determine the utility of this potential treatment option. While the end-point should be survival, systemic hemodynamics and renal and hepatic functions also must be carefully investigated. A number of bioartificial liver support devices are currently undergoing various phases of investigation. These include the HepatAssist (Circe Biomedical, Lexington, MA, U.S.A.) in a phase II, III trial and the ELAD Artificial Liver (VitaGen, La Jolla, CA, U.S.A.) in a phase I trial. One device, the Liver Dialysis Unit (HemoTherapies, San Diego, CA, U.S.A.), is approved by the United States Food and Drug Administration for use in America in the treatment of acute hepatic encephalopathy due to decompensation of chronic liver disease or fulminant hepatic failure or for the treatment of drug overdose and poisonings. None of these devices are currently approved for use in the treatment of the hepato-renal syndrome. Until the results of large, randomized, controlled trials are reported, use of these devices should be limited to investigational protocols. It is likely that in the near future, bioartificial liver support will be included in our armamentarium to combat liver failure. However, only by careful investigation using controlled, randomized large trials will the true potential of these techniques be realized.