In hepatorenal syndrome (HRS), renal insufficiency is often progressive, and the prognosis is extremely poor under standard medical therapy. The molecular adsorbent recirculating system (MARS) is a modified dialysis method using an albumin-containing dialysate that is recirculated and perfused online through charcoal and anion-exchanger columns. MARS enables the selective removal of albumin-bound substances. A prospective controlled trial was performed to determine the effect of MARS treatment on 30-day survival in patients with type I HRS at high risk (bilirubin level, > or =15 mg/dL) compared with standard treatment. Thirteen patients with cirrhosis with type I HRS were included from 1997 to 1999. All were Child's class C, with Child-Turcotte-Pugh scores of 12.4 +/- 1. 0, United Network for Organ Sharing status 2A, and total bilirubin values of 25.7 +/- 14.0 mg/dL. Eight patients were treated with the MARS method in addition to hemodiafiltration (HDF) and standard medical therapy, and 5 patients were in the control group (HDF and standard medical treatment alone). None of these patients underwent liver transplantation or received a transjugular intrahepatic portosystemic shunt or vasopressin analogues during the observation period. In the MARS group, 5.2 +/- 3.6 treatments (range, 1 to 10 treatments) were performed for 6 to 8 hours daily per patient. A significant decrease in bilirubin and creatinine levels (P <.01) and increase in serum sodium level and prothrombin activity (P <.01) were observed in the MARS group. Mortality rates were 100% in the control group at day 7 and 62.5% in the MARS group at day 7 and 75% at day 30, respectively (P <.01). We conclude that the removal of albumin-bound substances with the MARS method can contribute to the treatment of type I HRS.

The single pass albumin dialysis (SPAD) was reported to be an alternative to the Molecular Adsorbent Recirculating System (MARS) for the effective removal of protein bound substances in liver failure. Three SPAD experiments using different albumin concentrations and dialysate flow rates were performed. In each experiment, 1000 ml human donor plasma, spiked with 250 mg unconjugated bilirubin, 200 mg sulfobromophthalein (BSP) and 115 mg glycocholic acid (N-[3alpha,7alpha,12alpha-trihydroxy-24-oxycholan-24-yl]glycine) - a conjugated bile acid (BA), circulated in a closed loop with 150 ml/min and was dialysed against albumin solution. These substances are bound to the different binding sites of albumin and have different association constants. For the comparison, the standard MARS experiment was performed using the same plasma flow rate of 150 ml/min. Moreover, the clearances of bilirubin for MARS and SPAD during clinical treatments were calculated using own data and those reported by Seige, Kreymann, Jeschke, et al. in Transplant Proc 1999; 31: 1371-5. The concentrations of bilirubin, BSP and BA were measured in plasma and dialysate and for these substances clearances (Cl) were calculated. It is known that the elimination rate of bilirubin is not very high during albumin dialysis in comparison to other substances, like bile acids, due to the high association constant. An increase of albumin concentration or the flow rate improved the efficacy but also raised the costs substantially. In this study, we have shown that MARS is the more effective kind of albumin dialysis for the important substances like bile acids. By SPAD an improvement of efficacy can be reached only by dramatic increase of the costs. Also, the earlier experiments showed that MARS is safer because of the removal of the stabilizers, which are normally included in the commercial albumin solutions.

Abstract.Liver failure resulting from different causes and its concomitant complications represent difficult-to-treat conditions with high mortality rates, despite improved therapeutic modalities in intensive care medicine. The accumulation of albumin-bound metabolites that are normally cleared by the liver, such as bilirubin and bile acids, contributes substantially to the development of multiorgan dysfunction in these clinical situations. The molecular adsorbent recirculating system (MARS) represents a cell-free, extracorporeal, liver assistance method for the selective removal of albumin-bound substances. Moreover, it enables the removal of excess water and water-soluble substances via an inbuilt dialysis step. Since 1993, >400 patients have been treated in 53 centers in Europe, the United States, and Asia. Diseases treated with MARS included acute exacerbation of chronic hepatic failure, hepatorenal syndrome, acute hepatic failure, and primary nonfunction/poor function after liver transplantation and major liver resection. Treatments were well tolerated. No severe adverse events were observed. Six- to 8-h MARS treatments resulted in significant (P< 0.05) removal of bilirubin, bile acids, tryptophan, shortand middle-chain fatty acids, aromatic amino acids, and ammonia. Clearance rates for strongly albumin-bound substances were between 10 and 60 ml/min. The removal of albumin-bound toxins resulted in decreases in hepatic encephalopathy, increases in mean arterial pressure, and improvements in kidney and liver function. In the first randomized clinical trial of the MARS method for treatment of the hepatorenal syndrome, significant prolongation of survival was observed for the MARS-treated group. It is concluded that the MARS method can contribute to the treatment of critically ill patients with liver failure and different underlying diseases.

In liver diseases the pharmacokinetics and pharmacodynamics of drugs may be changed to a different degree. At present, there is no satisfactory test for the quantitative determination of metabolic liver function. Child-Pugh scoring is a poor predictor of drug-metabolising capacity. In patients with liver disease the grade of reduction of the metabolic capacity (dependent on hepatic blood flow and enzyme activity) and of plasma protein binding rate as well as the influence of extrahepatic elimination is difficult to foresee. Precise determination of drug dosage in liver insufficiency requires information on physicochemical and pharmacokinetic properties of the drugs, their particular metabolic pathway (e. g. enzymes involved), the effect of liver disease on the ›› Drugs in liver disease and during albumin dialysis -MARS

Background and Objectives: Albumin binding of the loop diuretic furosemide forms the basis for its transport to the kidney and subsequent tubular secretion, which is a prerequisite for its therapeutic effects. Accordingly, high albumin concentrations should result in higher efficacy of furosemide. However, study results on the combination of furosemide in conjunction with albumin, and on the efficacy of furosemide in hypoalbuminemia, did not confirm this hypothesis. The aim of this study was to determine the efficacy of furosemide not only in relation to albumin concentration, but also taking albumin function into account. Materials and Methods: In a prospective and non-interventional clinical observational trial, blood and urine samples from 50 intensive care patients receiving continuous intravenous furosemide therapy were evaluated. Albumin binding capacity (ABiC) determination allowed conclusions to be drawn about the binding site-specific loading state of albumin, by quantifying the unbound fraction of the fluorescent marker dansylsarcosine. In addition, assessment of the total concentration of furosemide in plasma and urine, as well as the concentration of free furosemide fraction in plasma, was performed by HPLC–MS. The efficacy of furosemide was evaluated by the ratio of urine excretion to fluid intake. Results: In patients with an ABiC ≥ 60% free furosemide fraction was significantly lower compared to patients with a lower ABiC (p < 0.001), urinary furosemide concentration was higher (p = 0.136), and a significantly higher proportion of infused furosemide was excreted renally (p = 0.010). ABiC was positively correlated (r = 0.908, p = 0.017) with increase in the urine excretion to fluid input ratio after initiation of furosemide therapy. Conclusions: ABiC could serve as a marker for individual response to furosemide and could be used to generate patient-specific therapeutic regimens. In view of the relatively low number of patients in this study, the relationship between furosemide efficacy and albumin function should be investigated in larger studies in the future.

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Background: Liver Cirrhosis complicated by severe cholestasis (bilirubin > 20 mg/dl) is associated with accumulation of toxic albumin bound substances, like lipophilic bile acids, bilirubin, tryptophane and its metabolites, endogenous vasodilatators like Nitric oxide, prostaglandins, neurotoxins like endogenous benzodiazepines etc. Elevated levels of these substances exhibit toxic effects or/and increase the unbound fraction of other, usually albumin bound toxins, thus creating a cumulative toxic effect on the brain, the kidneys, the cardiovascular system and the liver itself.