Extracorporeal liver support by recirculating albumin dialysis: analysing the effect of the first clinically used generation of the MARSystem

Albumin dialysis with the MARSystem is used in many hospitals to support excretory hepatic function in acute or acute on chronic liver failure. Potential pathogenic albumin bound substances accumulated in excretory liver insufficiency can be removed from patients blood by dialysis against albumin solution. A specific membrane enables the selective transport of albumin bound metabolites to the albumin containing dialysate compartment, where the loaded transport albumin is cleared and regenerated at the same time by adsorption columns and a second dialyser. Between 1993 and 1995 different membranes, set-ups and components in albumin dialysis were tested and led finally to the recirculating MARSystem with a modified polysulphone based membrane (P3/5S Gambro, Hechingen) and two adsorption columns (N350 and BR 350, ASAHI Medical Ltd.), which showed the best performance at this time. This first generation of MARSystems was used clinically between 1995 and 1998 with only minor changes in 15 patients with acute (n = 1) or acute deterioration of chronic liver disease in our department until the improved next generation of MARSystems has been available (MARS set and monitor, Teraklin AG, Rostock, Germany). Changes in blood tests pre/post during 95 single MARS treatments and in clinical status over treatment period were evaluated retrospectively. RESULTS: A significant decrease of albumin bound substances (average reduction during single MARS treatments: bilirubin -18%, bile acids -43.7%) as well as of water soluble metabolites (creatinine -32%, urea -31%) was observed. During extracorporeal therapy also a significant drop in platelets (- 15.4%) and a prolongation of activated prothrombin time (- 21%) was documented, whereas haemoglobin, WBC, electrolytes as well as transaminases and albumin were not affected significantly. Conclusion: Albumin dialysis with the first generation of MARS enables the removal of albumin bound and water soluble toxins. Unwanted side-effects and changes in laboratory tests are comparable to conventional haemodialysis (drop of platelets and prolongation of coagulation tests). The elimination of albumin bound and water soluble substances was accompanied by an improvement of clinical status.     

Reduction of Elevated Cytokine Levels in Acute/Acute‐on‐Chronic Liver Failure Using Super‐Large Pore Albumin Dialysis Treatment: An In Vitro Study

The removal of small water soluble toxins and albumin‐bound toxins in acute liver failure patients (ALF) or acute‐on‐chronic liver failure (AocLF) patients has been established using extracorporeal liver support devices (e.g. Molecular Adsorbents Recirculating System; MARS). However, reduction of elevated cytokines in ALF/AocLF using MARS is still not efficient enough to lower patients' serum cytokine levels. New membranes with larger pores or higher cut‐offs should be considered in extracorporeal liver support devices based on albumin dialysis in order to address these problems, as the introduction of super‐large pore membranes could counterbalance high production rates of cytokines and further improve detoxification in vivo. Using an established in vitro two compartment albumin dialysis model, three novel membranes of different pore sizes were compared with the MARS Flux membrane for cytokine removal and detoxification qualities in vitro. Comparing the membranes, no improvement in the removal of water soluble toxins was found. Albumin‐bound toxins were removed more efficiently using novel large (Emic2) to super‐large pore sized membranes (S20; HCO Gambro). Clearance of cytokines IL‐6 and tumor necrosis factor‐α was drastically improved using super‐large pore membranes. The Emic2 membrane predominantly removed IL‐6. In vitro data suggest that the usage of larger pore sized membranes in albumin dialysis can efficiently reduce elevated cytokine levels and liver failure toxins. Using large to super‐large pore membranes might exert effects on patients' serum cytokine levels. Combined with increased detoxification this could lead to higher survival in ALF/AocLF. Promising membranes for clinical evaluation have been identified.     

Application of Molecular Adsorbent Recirculating System in patients with severe liver failure after hepatic resection or transplantation: initial single-centre experiences

Acute liver failure after hepatic surgery is still plaqued with high mortality rate. Recently, a liver dialysis system (MARS) that allows detoxification of albumin-bound substances and may hereby support liver regeneration and patient's recovery has been developed. In the present study, we report our experiences with MARS dialysis in patients with liver failure after hepatic resection or transplantation. Between September 1999 and January 2001, five patients were treated with MARS (2-5 courses). Though beneficial effects such as improvement of encephalopathy and renal function as well as reduced bilirubin levels were recorded during MARS therapy, only one patient survived. Neither significant technical problems nor adverse effects occurred by using MARS dialysis. We conclude that in surgical patients, acute liver failure is usually part of a complicated clinical course affecting multipleorgan systems. Thus, it is difficult to determine the specific influence of MARS on patient's outcome. However, beneficial effects observed in our patients justify its continuous use and may stimulate further evaluation in controlled studies with surgical patients.     

Increase of Octanoate Concentrations During Extracorporeal Albumin Dialysis Treatments

Extracorporeal liver support procedures based on albumin dialysis require the use of pharmaceutical‐grade human serum albumin (HSA). Those preparations contain octanoate, which is added as stabilizer during the production process. For octanoate, a direct involvement in the pathogenesis of liver failure complications as well as an indirect influence by competitive displacement effects at the albumin molecule have been described. During five Single Pass Albumin Dialysis (SPAD) and three Molecular Adsorbent Recirculating System (MARS) treatments the changes of octanoate concentrations in blood and dialysate were investigated. An octanoate increase in patient blood was observed during passage of the filter for both SPAD (585 µmol/L [338–1022 µmol/L]) (median [range]) and MARS (182 µmol/L [71–437 µmol/L]) during the first three hours of treatment. The molar ratio of octanoate/albumin at the blood outflow was significantly higher during SPAD treatments (1.73 [0.86–2.64] vs. 0.54 [0.31–1.1]; P = 0.001) during MARS. Changes of octanoate blood levels during SPAD were significantly higher than during MARS (P < 0.001). The shift of octanoate from the dialysate to the patient was persistent during SPAD (median 67.6 µmol/min), whereas during MARS a decrease over time was observed (from 25.5 to 7.5 µmol/min). During albumin dialysis procedures a transfer of octanoate into patient blood occurs. The time‐course and extent are different between both albumin dialysis procedures. Given the positive clinical effects reported mainly for MARS, the clinical impact of albumin dialysis‐associated transfer of octanoate during extracorporeal liver support needs to be evaluated further.     

Effect of Extracorporeal Liver Support by Molecular Adsorbents Recirculating System and Prometheus on Redox State of Albumin in Acute‐on‐Chronic Liver Failure

Oxidative stress is believed to play an important role in acute‐on‐chronic liver failure (AoCLF). Albumin, an important transport vehicle, was found to be severely oxidized in AoCLF patients. Extracorporeal liver support systems may exert beneficial effects in AoCLF via removal of albumin‐bound toxins. At present, two systems are commercially available, the molecular adsorbents recirculating system (MARS) and fractionated plasma separation, adsorption and dialysis (FPAD, also known as Prometheus). The aim of this study was to compare the effect of MARS and Prometheus treatments on the redox state of human serum albumin. Eight patients with AoCLF underwent alternating treatments with either MARS or Prometheus in a randomized cross‐over design. Sixteen treatments (eight MARS and eight Prometheus) were available for analysis. The fraction of human mercaptalbumin (HMA), human nonmercaptalbumin‐1 (HNA1), and human nonmercaptalbumin‐2 (HNA2) were measured before and after single MARS and Prometheus treatments and during follow‐up. In AoCLF patients the oxidized fractions of albumin, HNA1, and HNA2 were markedly increased. Both MARS and Prometheus treatments resulted in a shift of HNA1 to HMA, while HNA2 was not significantly affected. This shift in albumin fractions was transient and disappeared within 24 h after treatment. There were no significant differences between MARS and Prometheus treatments with respect to the redox state of albumin. Both MARS and Prometheus treatments lead to transient improvements of the redox state of albumin, which could be beneficial in the treatment of AoCLF.     

Albumin dialysis has a favorable effect on amino acid profile in hepatic encephalopathy

According to one popular theory, hepatic encephalopathy (HE) is partly caused by an imbalance in plasma amino acid levels. The Fischer's ratio between branched chain amino acids (BCAAs) and aromatic amino acids (AAAs) correlates with the degree of HE; the lower Fischer's ratio, the higher the grade of HE. Extra-corporeal liver support systems, like MARS(R)-albumin dialysis (Molecular Adsorbents Recirculating System), can improve HE. The MARS(R) system uses a hyperosmolar albumin circuit to remove both water-soluble and albumin-bound substances. Plasma levels of neuroactive amino acids were analyzed in 82 consecutive patients with life-threatening liver failure admitted to our ICU. All patients fulfilled our indications for MARS treatment and most also fulfilled the criteria for liver transplantation (LTx). In patients with acute liver failure (ALF), as compared to those with acute decompensation of chronic liver failure (AcOChr), levels of leucine and isoleucine were significantly higher before MARS(R) treatment. In all patients, before MARS(R) treatment the higher the grade of HE grade the lower was the Fischer's ratio and higher were the levels of inhibitory neuroactive amino acids. During MARS(R) treatments the Fischer's ratio increased, and the grade of HE decreased. The increase in Fischer's ratio was mainly due to the decrease in AAAs. The plasma levels of neuroactive amino acids, methionine, glutamine, glutamate, histidine and taurine decreased during MARS(R)-treatment. In this study MARS(R)-albumin dialysis had a favorable effect on the plasma amino acid profile of patients with HE.     

Emerging indications for albumin dialysis

The accumulation of albumin-bound toxins in liver failure is believed to be responsible for the development of associated end-organ dysfunctions (kidney, circulation, brain). Albumin dialysis utilizes the scavenging functions of albumin for the removal of toxins. The Molecular Adsorbents Recirculating System (MARS) is one such extracorporeal liver support device where blood is dialyzed across an albumin-impregnated membrane against 20% albumin. Charcoal and anion exchange resin columns in the circuit cleanse and regenerate the albumin dialysate. Clinical studies in the last decade have demonstrated proven reduction in hyperbilirubinemia, along with an improvement in encephalopathy in liver failure patients, as well as apparent improvement in survival. Some studies have also reported improvement of systemic hemodynamics and renal function in these patients. Amelioration of intractable pruritus and treatment of toxicities with albumin-bound substances are some of the newer indications emerging. However, the specific underlying pathophysiological mechanisms are still not clear. Two other systems based on the removal of albumin-bound toxins, the Prometheus (using the principle of fractionated plasma separation and adsorption [FPSA]), and the single pass albumin dialysis (SPAD) are also currently under development but available clinical data are limited.     

Albumin Dialysis in Liver Failure: Comparison of Molecular Adsorbent Recirculating System and Single Pass Albumin Dialysis—A Retrospective Analysis

Despite improvement in critical care, liver failure is still associated with high mortality. Therapeutic concepts are aimed at restoring endogenous liver function or to bridge the time to liver transplantation. In addition to standard medical treatment, extracorporeal liver support with albumin dialysis is used for this purpose. The aim of this study was to analyze the efficacy of single pass albumin dialysis (SPAD) in comparison to the molecular adsorbent recirculating system (MARS) in patients treated at our university hospital intensive care unit between July 2004 and August 2008. In this retrospective analysis we studied patients presenting with liver failure who were treated with albumin dialysis. Laboratory parameters, daily health scoring, the number of transfusions, and mortality were recorded. The (paired) t‐test, Mann–Whitney U‐test, and Wilcoxon test were used for statistical analysis. In all, 163 albumin dialysis treatments, 126 with MARS and 37 with SPAD, in 57 patients were performed. MARS resulted in a significant decrease in bilirubin (?38 ± 66.5 µmol/L from a baseline of 301 ± 154.6 µmol/L), γ‐glutamyltransferase (γ‐GT), alanine aminotransferase, creatinine, and urea. SPAD resulted in a significant decrease in bilirubin (?41 ± 111.2 µmol/L from a baseline of 354 ± 189.4 µmol/L) and γ‐GT, while lactate levels increased. No differences in the need for blood transfusion, health scoring, or mortality between the two treatment modalities were detected. This retrospective analysis suggests equal efficacy of MARS and SPAD; however, prospective assessment to further define the role of SPAD in the treatment of acute or acute‐on‐chronic liver failure is needed.     

Albumin dialysis with MARS for the treatment of anabolic steroid-induced cholestasis

Background and aims. Steroid-related hepatotoxicity has become one of the most relevant causes of drug induced liver cholestasis. Some patients do not improve after standard medical treatment (SMT) and may therefore require other approaches, like extracorporeal liver support.Material and methods. We report four cases of patients with pruritus, abnormal liver function tests and biopsy-proven anabolic steroid-induced cholestasis who were unresponsive to SMT. They underwent treatment with albumin dialysis (Molecular Adsorbent Recirculating System -MARS®-). A minimum of two MARS sessions were performed.Results. After MARS® procedure, patients’ symptoms improved, as well as liver function tests, thus avoiding liver transplantation.Conclusion. Albumin dialysis appears as a valuable therapeutic option for the management of anabolic steroid-induced cholestasis in patients that are unresponsive to SMT.     

Molecular adsorbent recirculating system treatment for patients with liver failure: the Hong Kong experience.

BACKGROUND: The molecular adsorbent recirculating system (MARS) is an extracorporeal liver dialysis system that allows selective removal of bilirubin and other albumin-bound toxins. We reported here our experience with the use of this technique for management of liver failure at Queen Mary Hospital, Hong Kong. METHODS: From December 2002 to 2004, a total of 74 MARS sessions were performed on 22 patients. The cause of liver failure included acute liver failure (n = 2), acute on chronic liver failure (n = 12), posthepatectomy liver failure (n = 4), and posttransplantation allograft failure (n = 4). RESULTS: MARS treatment showed significant reduction in total bilirubin level, serum ammonia level and blood urea, and nitrogen (P < 0.001 for all three parameters). Five patients (22.7%) were able to bridge to transplantation and one patient (4.5%) made a spontaneous recovery. The 30-day mortality rate was 72.7%. CONCLUSIONS: Our results indicated that MARS can effectively improve serum biochemistry and is suitable for temporarily supporting patients with liver failure where transplantation is not immediately available. There is, however, no clear evidence showing that MARS can increase survival, improve the chance of transplantation or assist liver regeneration. Future studies in the form of randomized-controlled trials are crucial to characterize the true potential of this treatment.     

Albumin dialysis: effective removal of copper in a patient with fulminant Wilson disease and successful bridging to liver transplantation: a new possibility for the elimination of protein-bound toxins

BACKGROUND: Acute liver failure may be the first manifestation of Wilson disease. If copper elimination fails, liver transplantation is the only remaining therapeutic option. Albumin dialysis, a new method for the removal of protein-bound toxins, was performed in a patient with fulminant Wilson disease. METHODS: An 18-year-old man with Wilson disease presented with hyperacute liver failure, hepatic encephalopathy III, oligo-anuric renal failure, haemolytic anaemia, rhabdomyolysis, pancreatitis and thrombocytopenia. He was treated with albumin dialysis using a 44 g/l albumin-containing dialysate and a slow dialysate flow rate (1-2 l/h). The other details of the technique used are similar to routine continuous veno-venous haemodiafiltration. RESULTS: One hundred and five milligrams of copper were removed by albumin dialysis within the first six treatments, resulting in normalisation of blood-copper levels. Successful treatment of the multiorgan failure was achieved. Hepatic encephalopathy improved within 2 days. The patient initially refused liver transplantation. Therefore 35 additional albumin dialysis treatments were performed. Forty-three grams of bilirubin (an indicator of detoxified substances in the liver) and 196 mg of copper were removed. Multiorgan failure, in particular hepatic encephalopathy, did not recur during 59 days of treatment. Eventually, the patient agreed to liver transplantation and that was successful. CONCLUSION: Albumin dialysis is a new method for the effective treatment of fulminant Wilson disease, resulting in the removal of protein-bound toxins copper and bilirubin. It may serve as a new treatment option in hyperacute liver failure of other origin, acting as an extracorporeal detoxifier.     

Non biological artificial devices: what do they mean and what is their role today?

Chronic liver diseases affect 10% of the world population. Five million people per year have acute liver failure in occidental countries. Since more than 30 years now, orthotopic liver transplantation has been the treatment of choice for selected patients with these diseases, but the lack of enough organs to satisfy the increasing need oftransplantations as well as the elevated mortality of the operation in patients in critical condition, has led to search for additional therapies. Within the last years several therapies aiming to support liver function have developed in order to serve as a bridge to liver transplantation or as replace therapy allowing regeneration of the injured live. Biological and non biological devices providing liver support have been developed. The aim of this review is to analyze the technical aspects and the potential indications of the artificial non biological systems of liver support. In order to provide an adequate extracorporeal liver replacement, more complex and advanced techniques are needed, combining diffusion facilitated hemodialysis with adsorption and/or pheresis. Among these therapies, the more developed techniques are Single Pass Albumin Dialysis (SPAD), Molecular Adsorption Recirculating System (MARS) and the recently developed extracorporeal liver support combining albumin pheresis and fractioned adsorption (Prometheus).     

Liver dialysis in acute-on-chronic liver failure: current and future perspectives

Patients with acute-on-chronic liver failure (ACLF) are known to have a very high mortality rate as the majority of these patients succumb to multiorgan failure. Liver transplant remains the only option for these patients; however, there are problems with its availability, cost and also the complications and side effects associated with immunosuppression. Unlike advanced decompensated liver disease, there is a potential for hepatic regeneration and recovery in patients with ACLF. A liver support system, cell or non-cell based, logically is likely to provide temporary functional support until the donor liver becomes available or the failing liver survives the onslaught of the acute insult and spontaneously regenerates. Understanding the pathogenesis of liver failure and regeneration is essential to define the needs for a support system. Removal of hepatotoxic metabolites and inhibitors of hepatic regeneration by liver dialysis, a non-cell-based hepatic support, could help to provide a suitable microenvironment and support the failing liver. The current systems, i.e., MARS and Prometheus, have failed to show survival benefits in patients with ACLF based on which newer devices with improved functionality are currently under development. However, larger randomized trials are needed to prove whether these devices can enable restoration of the complex dysregulated immune system and impact organ failure and mortality in these patients.     

Albumin dialysis reduces portal pressure acutely in patients with severe alcoholic hepatitis

BACKGROUND/AIMS: In patients with alcoholic hepatitis (AH), inflammation contributes to the severity of portal hypertension. This study evaluates the acute effects of albumin dialysis, using the Molecular Adsorbents Recirculating System (MARS), on portal pressure in AH. METHODS: Eleven patients with AH and portal hypertension were treated with MARS (n=8) or haemofiltration (n=3). All patients had associated organ failure manifested by hepatic encephalopathy (Grade 2 or more) or renal failure. Hepatic venous pressure gradient (HVPG) was measured before, during and after the treatment session. RESULTS: A rapid significant reduction of HVPG was observed by 6 h (falling by > or =20% in 7/8 patients, reaching 12 mmHg in 6/8), which was sustained up to 18 h after stopping dialysis. Similar rapid sustained improvements of systemic haemodynamics were also observed. No changes occurred in three patients receiving haemofiltration alone. CONCLUSIONS: Albumin dialysis produces clinically significant, acute reduction in portal pressure but the mechanism by which this effect is achieved is not clear. Our results suggest that MARS may be a useful adjunct in management of portal hypertension, particularly in patients with severe AH with associated organ failure.     

Liver failure due to mushroom poisoning: clinical course and new treatment perspectives

Mushroom poisoning, mainly due to the Amanita genus, is an infrequent cause of liver failure in our environment. However, because of its high morbidity and mortality, it constitutes a medical emergency. The characteristic initial symptoms of vomiting, abdominal pain, and diarrhea are nonspecific and may be confused with gastroenteritis. If correct and early treatment is not given, renal and hepatic failure can develop, sometimes requiring liver transplantation. We present three cases of mushroom poisoning, which presented a different clinical course ranging from complete recovery with traditional medical treatment to severe acute liver failure requiring transplantation in one patient and albumin dialysis (molecular absorbent recycling system [MARS]) in another with favorable outcome. Although controlled clinical studies of the treatment of mushroom poisoning are lacking, recommendations based on the experience of various authors have been established. Penicillin G and silymarin seem to be useful. The development of new techniques of extracorporeal detoxification, mainly MARS, may represent an important support system in the treatment of these patients.     

Albumin regeneration in liver support-comparison of different methods

Albumin is the most abundant human plasma protein. Among many other functions it is an important transporter of hydrophobic internal and external substances such as intermediate and end products of metabolism and drugs. In liver failure the albumin binding capacity is decreased because of a disproportion between available albumin molecules caused by decreased hepatic synthesis and hydrophobic toxins because of decreased hepatic clearance. The resulting increase in plasma and tissue concentrations of these substances is associated with multiple organ dysfunctions frequently seen in severe liver failure. The scope of the present article is to compare different liver support strategies with regard to their ability to regenerate the patients albumin pool by removing albumin-bound toxins. Most prominent technique in this group is the molecular adsorbent recirculating system (MARS). It will be compared with single pass albumin dialysis (SPAD), fractionated plasma separation and adsorption system (FPSA, Prometheus), and plasma perfusion/bilirubin adsorption with special regard to efficacy and selectivity.     

Early Molecular Adsorbents Recirculating System Treatment of Amanita Mushroom Poisoning

Acute poisoning due to ingestion of hepatotoxic Amanita sp. mushrooms can result in a spectrum of symptoms, from mild gastrointestinal discomfort to life‐threatening acute liver failure. With conventional treatment, Amanita phalloides mushroom poisoning carries a substantial risk of mortality and many patients require liver transplantation. The molecular adsorbent recirculating system (MARS) is an artificial liver support system that can partly compensate for the detoxifying function of the liver by removing albumin‐bound and water‐soluble toxins from blood. This treatment has been used in acute liver failure to enable native liver recovery and as a bridging treatment to liver transplantation. The aim of the study is to evaluate the outcome of 10 patients with Amanita mushroom poisoning who were treated with MARS. The study was a retrospectively analyzed case series. Ten adult patients with accidental Amanita poisoning of varying severity were treated in a liver disease specialized intensive care unit from 2001 to 2007. All patients received MARS treatment and standard medical therapy for mushroom poisoning. The demographic, laboratory, and clinical data from each patient were recorded upon admission. The one‐year survival and need for liver transplantation were documented. The median times from mushroom ingestion to first‐aid at a local hospital and to MARS treatment were 18 h (range 14–36 h) and 48 h (range 26–78 h), respectively. All 10 patients survived longer than one year. One patient underwent a successful liver transplantation. No serious adverse side‐effects were observed with the MARS treatment. In conclusion, MARS treatment seems to offer a safe and effective treatment option in Amanita mushroom poisoning.     

Emerging indications for MARS dialysis

MARS stands for Molecular Adsorbent Recirculating System and represents an interesting option in treating patients with liver disease. There is still little known about the best time point of initiating this treatment and the exact selection criteria for patients who may benefit from this therapy. The list of potential applications using this procedure is expanding. We report on the experience in seven patients being treated with MARS dialysis for chronic cholestatic liver disease and acute on chronic liver failure. From August 2000 to October 2001 seven patients received 27 MARS treatments in our clinic, ranging from 2 to 12 treatments per subject. Presented cases were diagnosed as steatohepatitis because of alcoholism (n = 3), vanishing bile duct disease (n = 1), metabolic liver disease (n = 1), primary biliary cirrhosis (n = 1) and drug-induced hepatitis (n = 1). Based on this experience, we discuss the ongoing questions of various indications and the decision to initiate MARS dialysis.     

The challenges of providing renal replacement therapy in decompensated liver cirrhosis

Development of renal failure requiring renal replacement therapy (RRT) in the cirrhotic patient is a devastating complication. Survival without RRT is less than 10% on average at 6 months. However, it is now appreciated that all renal failure in this group of patients is not due solely to hepatorenal syndrome, and the cause of the renal failure affects the prognosis. This paper reviews the prognosis depending on cause and points out the difficulty in making the correct diagnosis. Provision of RRT is difficult in this group of patients due to hypotension and coagulopathy which is highly prevalent. Survival with RRT is still poor with only 30-60% of patients surviving to liver transplant. Provision of RRT should be offered as a bridge to patients awaiting liver transplant or those undergoing liver transplant evaluation. Provision of long-term RRT is usually not indicated in other cirrhotic patients who develop a need for RRT except as a trial to see if renal function will return. The decision between intermittent hemodialysis or continuous renal replacement therapy (CRRT) is usually based on the clinical characteristics of the patient. Neither has been demonstrated to be superior to the other, although CRRT may be better tolerated in the unstable patient. CRRT is clearly indicated in cases of fulminant hepatic failure as it does not raise intracranial pressure. Provision of intraoperative CRRT during liver transplant may be indicated to help control volume and electrolytes in those patients presenting for liver transplant with renal failure. Newer extracorporeal support systems, such as extracorporeal albumin dialysis (MARS) and fractional plasma separation and adsorption with hemodialysis (Prometheus), have recently been developed to provide both renal and liver support in this group of patients. These are still considered experimental, although the MARS system has been utilized to treat patients with hepatorenal syndrome, and is available outside the United States.