Molecular adsorbents recirculating system (MARS) and the failing liver: A negative editorial for a positive trial?

Abstract

We read with interest the article by Hassanein et al.1 and the editorial by Ferenci and Kramer2 and found the editorial too negative for a positive trial. A frequent problem in the assessment of artificial liver support systems (ALSSs) is that they are unconsciously compared to the artificial renal support systems (ARSSs). This has no justification. First, although we are in the golden era of ARSS, the molecular adsorbents recirculating system (MARS) had been introduced only a few years ago. We still do not know the best indication, time of application, and treatment schedule for this device. Second, whereas chronic liver failure (CLIF) is an extremely complex syndrome, chronic renal failure (CRF) is the result of a single defect, an intense reduction in glomerular filtration rate leading to retention of water-soluble substances that are easily removed with current technology. Finally, we have excellent markers of CRF that facilitate indication and dosing of ARSS. However, this is not the case for CLIF. CLIF involves not just impaired liver excretory function but also reduced hepatic synthetic function. Moreover, most problems associated with CLIF are related to a circulatory dysfunction due to splanchnic arterial vasodilation and reduction in cardiac function.3 There is marked stimulation of the renin-angiotensin and sympathetic nervous systems and vasopressin, which maintain arterial pressure by producing vasoconstriction in extrasplanchnic organs.4 Renal vasoconstriction causes hepatorenal syndrome. Cerebral vasoconstriction may contribute to cerebral dysfunction.5, 6 Relative adrenal insufficiency is also a common event in CLIF.7 Intrahepatic vasoconstriction leading to increase in portal pressure and decrease in hepatic blood flow has been reported in CLIF.3, 8 Finally, the increased sympathetic activity impairs intestinal motility and induces bacterial overgrowth, translocation of bacterial products, and chronic inflammatory reaction.9 The observation that parameters estimating systemic hemodynamics are better markers of CLIF severity than those estimating hepatic function is a clear indication of the complexity of the syndrome. Which parameters should then be used to evaluate ALSS? Survival is important. In fact, one of the arguments given by Ferenci and Kramer to suggest a lack of benefit of MARS was the similar mortality observed by Hassanein et al. in the MARS and standard medical therapy (SMT) groups. However, the design of the trial was to assess the effect of MARS on hepatic encephalopathy and not on survival. It would have been a miracle to get differences in survival after a mean of 2.7 dialysis sessions in the MARS group. A second approach is to assess the effect of MARS on complications associated with CLIF, and here we have evidence that we are dealing with a potentially effective device. Despite the methodological criticisms raised by Ferenci and Kramer, the study by Hassanein et al. supports a significant benefit of MARS on encephalopathy. There were more patients responding in the MARS group and they improved faster. Arguments given by Ferenci and Kramer to negate a benefit of MARS were weak and could be used in the opposite sense. For example, they consider that the longer period on SMT prior to randomization in the MARS group (5.6 versus 2.6 days) could partially account for the better response of encephalopathy in this group. However, because all patients had grade III-IV encephalopathy at randomization, an alternative possibility is that there were more patients with encephalopathy refractory to SMT in the MARS group. MARS treatment is also associated with clear improvement in cardiovascular function (increase in arterial pressure and vascular resistance and suppression of renin, noradrenaline, and vasopressin).10-12 Finally, MARS removes water-soluble substances and can replace renal function in severe hepatorenal syndrome. In summary, treatment of CLIF is more complex than treatment of CRF. In addition to extracorporeal devices to replace the hepatic excretory function, it is important to treat the impaired synthetic function and multiorgan failure associated with CLIF. We need more research on CLIF to identify potential targets for treatment. MARS, in addition to being a potentially useful device, could be an important tool to explore the pathogenesis of CLIF. Vicente Arroyo*, Javier Fernandez*, Antoni Mas*, Angels Escorsell*, * Liver Unit, Hospital Clinic, University of Barcelona, Spain.