MARS Therapy for Successful Bridging to Liver Transplantation

Albumin Regeneration for Extracorporeal Liver Support Using Prometheus: A Step in the Right Direction

Toward an Improved Definition of Acute-on-Chronic Liver Failure

See “Effect of Molecular Adsorbents Recirculating System Treatment in Children With Acute Liver Failure Caused by Wilson Diseas” by Rustom et al on page 162. Molecular adsorbents recirculating system (MARS) is a form of dialysis using albumin-enriched dialysate to remove albumin-bound toxins via a specialised membrane. The dialysate is then regenerated through activated charcoal and anion exchange resin columns. Haemofiltration is required simultaneously to control the blood and dialysate circuits. Single-pass albumin dialysis is another form of albumin dialysis, without a perfusion pump. The accumulation of albumin-bound toxins (eg, bilirubin, bile salts) in liver failure has led to the curiosity behind the potential use of MARS in improving the overall clinical condition for successful bridging to transplantation, or even avoiding transplantation, in cases of acute liver failure (ALF) or acute-on-chronic liver failure (AoCLF). In this study, Rustom et al (1) have set out to show that MARS therapy may be useful as a bridge to transplantation in acute Wilson disease (WD) in children. The concept of MARS as a method for removing liver failure–associated albumin-bound toxins, as well as the increased fraction of toxic albumin-bound copper in acute WD, is the basis for their hypothesis. Data were retrospectively analysed (2004–2009) for all of the children who presented with acute WD and had MARS treatment in a single centre. All of the patients (n = 4) had encephalopathy, renal failure, and a Wilson prognostic index >11. Hence, all of the patients were listed for transplantation. Biochemical data were available for 3 patients and showed reduction in bilirubin, ammonia, aspartate aminotransferase, creatinine, and serum copper levels after MARS sessions. Data available for 2 patients showed an improvement in the Fischer index. All 4 patients were reported to have stable or improved encephalopathy after MARS treatment. Platelet count was significantly reduced in all of the patients and 1 patient had an adverse incident secondary to vascular catheter insertion. There was no improvement in hepatic synthetic function. The median time for transplantation was 5.5 days. Rustom et al suggest that the observed improvement in biological and clinical parameters render MARS a promising treatment modality in acute WD in children; however, the group recognises the shortcomings of such a small sample size and the incomplete dataset. They also acknowledge that the treatment effect is difficult to determine in the absence of a control group and the presence of simultaneous haemofiltration. The exact methodology of encephalopathy measurement in the 2 ventilated cases was unclear. Furthermore, although there is a postulated association with a higher Fischer index and improved encephalopathy, this is, as yet, not a known validated tool in liver failure. Most crucially, this article is unable to shed further light on the following clinically relevant question: Do the observed improved biological and clinical parameters correlate to improved survival and/or morbidity outcomes? Small randomised controlled trials (2–4) in adult studies of AoCLF concur with Rustom et al, namely, biological and clinical improvement is demonstrated in the MARS treatment group compared with the standard medical treatment group. Similarly, some small uncontrolled adult studies of ALF (5) and MARS therapy have observed such improvement. With respect to acute WD, case reports (using MARS or single-pass albumin dialysis) (6–8) have documented enhanced biochemical parameters with or without improved encephalopathy while being successfully bridged to transplantation. One common feature among all of the studies was the acceptable safety profile of MARS, with only complications of thrombocytopaenia and vascular catheter insertion being noted. Two recent large multicentre randomised controlled trials have shown that the survival benefit of MARS remains uncertain. Bañares et al (9) have shown no beneficial effect on survival at 28 days in MARS compared with a standard medical treatment group for AoCLF, despite improved biochemistry and encephalopathy in this group. Saliba et al (10) did show a statistically nonsignificant improved 6-month posttransplant and nontransplant survival rate in patients with ALF in the MARS therapy group, but no improvement in biochemical or clinical parameters. In paediatrics, Dhawan et al (11) revealed a median time of 3.5 days for transplantation of acute WD. This brief period to transplantation raises the question of the need for MARS as a bridging technique. Paediatric data for MARS are limited. Auth et al (12) used MARS as a bridging technique to transplantation for 2 paediatric cases of acute WD. They demonstrated that the MARS circuit could extract toxic metabolites; however, this was not consistently reflected by reduced serum levels of certain metabolites (copper, ammonia, bilirubin), suggesting saturation of the albumin-binding capacity. Essential growth factors and precursors to glutathione synthesis were also noted to be extracted by the albumin circuit, which could negatively affect mortality and liver regeneration. MARS does not prevent transplantation, and survival outcome posttransplantation is unclear. There is no robust evidence to justify the financial implications of this intervention in a clinical setting. The present role of MARS remains within the research setting. Alas, the quest for “life on MARS” continues.

Besides orthotopic liver transplantation (OLT) there is no long-term and effective replacement therapy for severe liver failure. Artificial extracorporeal liver supply devices are able to reduce blood toxin levels, but do not replace any synthetic function of the liver. Molecular adsorbent recirculating system (MARS) is one of the methods that can be used to treat fulminant acute liver failure (ALF) or acute on chronic liver failure (AoCLF). The primary non-function (PNF) of the newly transplanted liver manifests in the clinical settings exactly like acute liver failure. MARS treatment can reduce the severity of complications by eliminating blood toxins, so that it can help hepatic encephalopathy (HE), hepatorenal syndrome (HRS), and the high rate mortality of cerebral herniation. This might serve as a bridging therapy before orthotopic liver retransplantation (reOLT). Three patients after a first liver transplantation became candidate for urgent MARS treatment as a bridging solution prior to reOLT in our center. Authors report these three cases, fo-cusing on indications, MARS sessions, clinical courses, and final outcomes.

Objective. The CC chemokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-3 alpha (MIP3-alpha) may be involved in the pathogenesis of acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). In ALF and ACLF, the molecular adsorbent recirculating system (MARS) has been used to support liver function. Enhancement of MCP-1, as seen in other extracorporeal support systems such as haemodialysis, might thus have mitigated the beneficial effects of the MARS system in acute hepatic failure. Material and methods. Serum concentrations of MCP-1 and MIP3-alpha were measured in 10 patients with ALF or ACLF treated with MARS. Thirteen patients suffering from chronic hepatic failure (CHF) and 15 healthy individuals served as controls. Results. Baseline MCP-1 serum concentrations were significantly increased in ALF and ACLF patients as compared to patients with CHF (p=0.0027 and p=0.0046, respectively) and controls (p=0.0006 and p=0.0012, respectively). MIP3-alpha serum concentrations were also significantly enhanced in the ALF and ACLF groups as compared with those in CHF patients (p=0.0002 and p=0.0003, respectively) and controls (p<0.0001 and p<0.0001, respectively). Moreover, MIP3-alpha levels were significantly increased in CHF patients as compared to controls (p=0.0002). MCP-1 and MIP3-alpha concentrations did not change significantly during MARS treatment in ALF and ACLF patients. Conclusions. The CC chemokines MCP-1 and MIP3-alpha are increased in ALF and ACLF patients. MARS had no effect on MCP-1 and MIP3-alpha serum concentrations in patients with ALF and ACLF, and yielded no evidence of any harmful effects of the increase of these potentially hepatocidal chemokines.

The molecular adsorbent recirculating system removes water-soluble and albumin-bound toxins and may be beneficial for acute liver failure patients. We compared the rates of 21-day transplant-free survival in acute liver failure patients receiving molecular adsorbent recirculating system therapy and patients receiving standard medical therapy. Propensity score-matched retrospective cohort analysis. Tertiary North American liver transplant centers. Acute liver failure patients receiving molecular adsorbent recirculating system at three transplantation centers (n = 104; January 2009-2019) and controls from the U.S. Acute Liver Failure Study Group registry. Molecular adsorbent recirculating system treatment versus standard medical therapy (control). One-hundred four molecular adsorbent recirculating system patients were propensity score-matched (4:1) to 416 controls. Using multivariable conditional logistic regression adjusting for acute liver failure etiology (acetaminophen: n = 248; vs nonacetaminophen: n = 272), age, vasopressor support, international normalized ratio, King's College Criteria, and propensity score (main model), molecular adsorbent recirculating system was significantly associated with increased 21-day transplant-free survival (odds ratio, 1.90; 95% CI, 1.07-3.39; p = 0.030). This association remained significant in several sensitivity analyses, including adjustment for acute liver failure etiology and propensity score alone ("model 2"; molecular adsorbent recirculating system odds ratio, 1.86; 95% CI, 1.05-3.31; p = 0.033), and further adjustment of the "main model" for mechanical ventilation, and grade 3/4 hepatic encephalopathy ("model 3"; molecular adsorbent recirculating system odds ratio, 1.91; 95% CI, 1.07-3.41; p = 0.029). In acetaminophen-acute liver failure (n = 51), molecular adsorbent recirculating system was associated with significant improvements (post vs pre) in mean arterial pressure (92.0 vs 78.0 mm Hg), creatinine (77.0 vs 128.2 µmol/L), lactate (2.3 vs 4.3 mmol/L), and ammonia (98.0 vs 136.0 µmol/L; p ≤ 0.002 for all). In nonacetaminophen acute liver failure (n = 53), molecular adsorbent recirculating system was associated with significant improvements in bilirubin (205.2 vs 251.4 µmol/L), creatinine (83.1 vs 133.5 µmol/L), and ammonia (111.5 vs 140.0 µmol/L; p ≤ 0.022 for all). Treatment with molecular adsorbent recirculating system is associated with increased 21-day transplant-free survival in acute liver failure and improves biochemical variables and hemodynamics, particularly in acetaminophen-acute liver failure.

IMPAIRED CEREBRAL AUTOREGULATION IN PATIENTS WITH ADVANCED LIVER FAILURE: AN UNDER-RECOGNIZED PHENOMENON

Introduction: Molecular adsorbent recirculating system (MARS) for albumin liver dialysis has been used as a bridge to liver transplantation in patients with fulminant hepatic failure (FHF). This review examines the available data on its clinical use, its technical aspects and present gaps in knowledge. Methods: Peer-reviewed journals and monographs on the subject were covered. Results: FHF is associated with elevation in various substances including bilirubin, ammonia, lactate, free fatty acids and aromatic amino acids. Some of these toxic metabolites, such as ammonia and bilirubin, are believed to be central to the clinical manifestations of hepatic encephalopathy and acute renal failure. MARS ameliorates both biochemical and clinical manifestations of FHF by removing both water-soluble and protein-bound toxins. Among the benefits of MARS is the attenuation of severe cerebral oedema and raised intracranial pressure found in FHF, possibly through reduction in high concentrations of these toxins. Although MARS has been shown to be useful in FHF, its clinical efficacy in subfulminant hepatic failure and less severe forms of acute liver failure (ALF) remains uncertain. The current literature also suggests that it may be beneficial to treat cases of acute-on-chronic liver failure (AoCLF). Deranged systemic chemistries can be similarly ameliorated, but the impact of MARS on the natural history of AoCLF remains uncertain. The difficulty lies in being able to accurately quantify residual liver function and variability in the course of acute intercurrent events. The broader question is whether MARS can favourably change the natural history of ALF and FHF. For this, large multi-centre, randomised controlled trials are needed. Furthermore, it is also uncertain how hepatic excretory-assist devices, such as MARS, compare with bio-artificial liver-assist devices which have both synthetic and excretory hepatic functions in ALF treatment in intensive care unit patients. Nevertheless, MARS has proven to be a valuable homeostatic tool that may be useful in restoring the biochemical and clinical status quo in much the same way that continuous veno-venous haemofiltration and mechanical ventilation provide temporary artificial organ support while these organs are in distress. This is the evolving concept of multi-organ support therapy. Other major unresolved issues with MARS include the timing of initiation of albumin liver dialysis, the clinical and/or biochemical parameters to base this decision on, the intensity of MARS therapy (continuous versus intermittent) and the saturation capacity of the system for different metabolites in intermittent MARS. Conclusions: MARS is an effective and, thus far, safe homeostatic tool in treating FHF. More studies are needed to delineate its role as a homeostatic tool in less severe forms of ALF, including that which occurs in multi-organ failure and in AoCLF. Other studies need to focus on the optimal timing of initiation of and intensity of MARS albumin liver dialysis. The larger issue is to compare MARS with bio-assist liver devices in treating the whole spectrum of ALF.

Nucleosome Serum Levels in Acute Hepatic Failure and MARS Treatment

OBJECTIVES To develop evidence-based recommendations for clinicians caring for adults with acute or acute on chronic liver failure in the ICU. DESIGN The guideline panel comprised 29 members with expertise in aspects of care of the critically ill patient with liver failure and/or methodology. The Society of Critical Care Medicine standard operating procedures manual and conflict-of-interest policy were followed throughout. Teleconferences and electronic-based discussion among the panel, as well as within subgroups, served as an integral part of the guideline development. SETTING The panel was divided into nine subgroups: cardiovascular, hematology, pulmonary, renal, endocrine and nutrition, gastrointestinal, infection, perioperative, and neurology. INTERVENTIONS We developed and selected population, intervention, comparison, and outcomes questions according to importance to patients and practicing clinicians. For each population, intervention, comparison, and outcomes question, we conducted a systematic review aiming to identify the best available evidence, statistically summarized the evidence whenever applicable, and assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence to decision framework to facilitate recommendations formulation as strong or conditional. We followed strict criteria to formulate best practice statements. MEASUREMENTS AND MAIN RESULTS In this article, we report 29 recommendations (from 30 population, intervention, comparison, and outcomes questions) on the management acute or acute on chronic liver failure in the ICU, related to five groups (cardiovascular, hematology, pulmonary, renal, and endocrine). Overall, six were strong recommendations, 19 were conditional recommendations, four were best-practice statements, and in two instances, the panel did not issue a recommendation due to insufficient evidence. CONCLUSIONS Multidisciplinary international experts were able to formulate evidence-based recommendations for the management acute or acute on chronic liver failure in the ICU, acknowledging that most recommendations were based on low-quality indirect evidence.

The molecular adsorbents recirculating system (MARS®) is a form of artificial liver support that has the potential to remove substantial quantities of albumin-bound toxins that have been postulated to contribute to the pathogenesis of liver cell damage, haemodynamic instability and multi-organ failure in patients with acute liver failure (ALF) and acute-on-chronic liver failure (AoCLF). These toxins include fatty acids, bile acids, tryptophan, bilirubin, aromatic amino acids and nitric oxide. Data from controlled clinical trials are limited so far. One of two studies performed on small numbers of patients with AoCLF suggest a survival benefit, but no controlled data are available in the ALF setting. Our preliminary experience with MARS therapy, instituted late in the clinical course of five patients with severely impaired liver function, including three with AoCLF precipitated by sepsis and two with liver dysfunction due to sepsis in the absence of pre-existing chronic liver disease, indicates some clinical efficacy. However, the overall survival rate (1 of 5; 20%) remained poor. More data obtained from larger cohorts of patients enrolled in randomised controlled studies will be required in both the AoCLF and ALF settings to identify categories of liver failure patients who might benefit most from MARS treatment, to ascertain the most appropriate timing of intervention and to determine the overall impact on outcome, including cost-effectiveness.

See Article on Page 369 Children with acute liver failure (ALF) are among those highest at risk for death without the intervention of liver transplantation. Unfortunately, there continues to be a donor organ shortage, so not all children who could benefit from liver transplantation have timely access to this lifesaving therapy. As a result, extracorporeal liver‐support systems have been developed to address this issue. Several different systems, including cell‐based and non–cell‐based systems, have been used in an attempt to support the failing liver to either recover liver function or bridge the patient to transplantation.1 One system that has been used for more than 10 years, predominantly in Europe and Asia, is the Molecular Adsorbent Recirculating System (MARS).2 This system, originally developed in Germany, consists of 2 circuits. The first circuit is composed of human serum albumin in contact with a patient's blood through a semipermeable membrane and filters that clean the albumin after it has removed toxins from the patient's blood. The second circuit consists of a dialysis machine that cleans the albumin in the first circuit before it is recirculated to the semipermeable membrane coming in contact with the patient's blood. There are 2 sorbent columns in the system: an activated charcoal column and an anion exchanger. MARS has 510(k) approval from the US Food and Drug Administration for the treatment of drug overdoses and poisoning and has been available in the United States since 2005.3 It is required that the drug or chemical be dialyzable (in an unbound form) and be bound by charcoal and/or ion‐exchange resins. Notably, the US Food and Drug Administration has stated that MARS is not indicated as a bridge to liver transplantation because its safety and efficacy have not been demonstrated in clinical randomized controlled trials. The standard treatment for ALF involves supportive care that focuses on bridging patients to either transplantation or spontaneous recovery. The etiologies of ALF in children are not the same as those in adults with ALF, so drawing conclusions from adult data may be inappropriate.4 No large, prospective, multicenter randomized controlled trial has been performed with non–cell‐based systems in children. Most reports on the use of MARS in children are case reports or small case series.5 In this issue of Liver Transplantation, Lexmond et al.11 from the Netherlands describe their experience with MARS in treating 20 children in need of high‐urgency liver transplantation over the course of 10 years. The authors conclude that MARS therapy was relatively safe in these sick subjects; that serum bilirubin, creatinine, ammonia, and bile acid levels significantly decreased; and that 80% of these selected children survived long enough to undergo liver transplantation. The authors clearly acknowledge that their study, though large by pediatric standards, was not randomized, and that drawing any significant conclusions is difficult. No survival benefit could be demonstrated statistically. They advocate large, prospective trials and registration studies to answer important questions about pediatric ALF. They support strategies to increase the acquisition of high‐quality donor organs to improve the survival of children with ALF. One issue not mentioned in this article is the cost associated with MARS treatment. MARS therapy is costly.12 In the current climate of cost containment, financial aspects are an important consideration. Without a demonstrated statistically significant survival benefit, it is unlikely that insurers will be willing to pick up the costs of a single treatment, let alone repeated treatments, with MARS. Although MARS therapy has been available for more than a decade, there have been no randomized controlled trials of its use in children. Who is responsible for appropriately studying this potentially lifesaving therapy? Is it the responsibility of the manufacturer? Is it the responsibility of pediatric hepatologists or pediatric intensivists? Do government agencies have an ethical and moral responsibility to determine the safety and efficacy of the system? Should insurers insist on data? How long should it take to acquire the necessary data to assess the safety and efficacy of this system in children? I do not have the answers to these questions, but I believe that the time has come to get the data necessary to prove whether MARS has utility or not. I hope that multicenter randomized controlled trials will be inaugurated to answer important questions about the efficacy of MARS in children.

Plasma exchange (PE) is a promising therapeutic option in patients with acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). However, the impact of PE on patient survival in these syndromes is unclear. We aimed to systematically investigate the use of PE in patients with ALF and ACLF compared with standard medical therapy (SMT). We searched PubMed/Embase/Cochrane databases to include all studies comparing PE versus SMT for patients ≥ 18 years of age with ALF and ACLF. Pooled risk ratios (RR) with corresponding 95% CIs were calculated by the Mantel-Haenszel method within a random-effect model. The primary outcome was 30-day survival for ACLF and ALF. Secondary outcomes were overall and 90-day survival for ALF and ACLF, respectively. Five studies, including 343 ALF patients (n = 174 PE vs. n = 169 SMT), and 20 studies, including 5,705 ACLF patients (n = 2,856 PE vs. n = 2,849 SMT), were analyzed. Compared with SMT, PE was significantly associated with higher 30-day (RR 1.41, 95% CI 1.06-1.87, p = 0.02) and overall (RR 1.35, 95% CI 1.12-1.63, p = 0.002) survival in ALF patients. In ACLF, PE was also significantly associated with higher 30-day (RR 1.36, 95% CI 1.22-1.52, p < 0.001) and 90-day (RR 1.21, 95% CI 1.10-1.34, p < 0.001) survival. On subgroup analysis of randomized controlled trials, results remained unchanged in ALF, but no differences in survival were found between PE and SMT in ACLF. In conclusion, PE is associated with improved survival in ALF and could improve survival in ACLF. PE may be considered in managing ALF and ACLF patients who are not liver transplant (LT) candidates or as a bridge to LT in otherwise eligible patients. Further randomized controlled trials are needed to confirm the survival benefit of PE in ACLF.

The needle in the haystack: deciphering diagnostic data in a case of acute on chronic liver failure

Acute liver failure (ALF) carries significant morbidity and mortality, for both pediatric and adult patients. Albumin dialysis via the molecular adsorbent recirculating system (MARS) is a form of extracorporeal liver support (ELS) that can reduce hepatic encephalopathy (HE), a main driver of mortality in ALF. However, data on MARS and its benefit on mortality have been inconsistent. We sought to report our experiences and patient outcomes from the first 2 years of operation of a new ELS program, within an established pediatric liver transplantation center. Retrospective review of outcomes in pediatric and adult patients treated with MARS therapy for ALF, from 2021 to 2022. Outcomes included reduction in HE and biochemical markers of ALF after MARS therapy, survival, and transplant-free survival. Comparisons were made via Wilcoxon signed-rank test. Five pediatric and two adult patients underwent MARS for ALF. Ages ranged from 2 to 29 years. Overall, 21 MARS runs were performed (median 3 runs per patient, 12.4 hr per run [interquartile range, IQR 10.1-17]). Overall survival was 85.7%, and transplant-free survival was 71.4%. There was a statistically significant reduction in HE score with MARS therapy (median 3 [IQR 3-4] to 1 [IQR 0-1], p = 0.03), and in ALF biomarkers including ammonia (256 µL/dL [195-265] to 75 µL/dL [58-101], p = 0.02), aspartate aminotransferase (6,362 U/L [920-8,305] to 212 U/L [72-431], p = 0.02), alanine aminotransferase (8,362 U/L [3,866-9,189] to 953 U/L [437-1,351], p = 0.02), and international normalized ratio (4.5 [3.3-6.7] to 1.3 [1.2-1.4], p = 0.02). MARS therapy for ALF was well tolerated by both pediatric and adult patients, and resulted in significant improvement in clinical and biochemical parameters. We demonstrated encouraging overall and transplant-free survival, suggesting that early initiation of MARS with relatively long and frequent cycle times may be of significant benefit to ALF patients, and is worthy of additional study in larger cohorts.