Molecular Adsorbent Recirculating System Patrick Brophy MD Director Pediatric Nephrology, University of Iowa Children’s Hospital

Outline Hepatic Dialysis- Liver Support MARS™ Rationale Indications Outcomes Future Directions

Hepatic Failure Definition: Loss of functional liver cell mass below a critical level results in liver failure (acute or complicating a chronic liver disease) Results in: hepatic encephalopathy & coma, jaundice, cholestasis, ascites, bleeding, renal injury, death

Hepatic Failure Production of Endogenous Toxins & Drug Metabolic Failure Bile Acids, Bilirubin, Prostacyclins, NO, Toxic fatty acids, Thiols, Indol-phenol metabolites These toxins cause further necrosis/apoptosis and a vicious cycle Detrimental to renal, brain and bone marrow function; results in poor vascular tone

History Two main approaches to liver support Non-biological: Filtration of potentially harmful molecules Hybrid Biological artificial support: hepatic cells in a synthetic framework Stadlbauer and Jalan. Acute Liver Failure: liver support Therapies Current Opin in Crit Care. 2007; 13:215-21

MARS™ MARS™ Flux Filter ADSORPTION COLUMNS DIALYSIS DiaFlux Filter The system consists of a blood circuit, an albumin circuit, and a classic ‘renal’ circuit. Blood is dialysed across an albumin Impregnated high-flux dialysis membrane; 600 ml of 25% human albumin in the albumin circuit acts as the dialysate. Albumin-bound toxins in blood are released to the membrane. These are subsequently picked up by albumin in the dialysate, which then undergoes hemodialysis/hemofiltration if required. The albumin dialysate is subsequently cleansed via passage across two sequential adsorbent columns containing activated charcoal and anion exchange resin. Blood Circuit 20-25% Albumin Circuit Dialysis Circuit Patient

MARS Flux Filter Kapoor D., Journal of Gastroenterology and Hepatology, 2002

Technical Aspects Filters : Flow Rates : Anticoagulation: MARS™ flux : 2m2 ECV = 150 ml + lines, 600ml 20% Alb MARSMini™: 0.6m2 ECV = 56ml + lines, 500ml 20% Alb *** (not Available in US) PRISMARS™ 1 kit = $ 2700 (USD) Flow Rates : Blood flow rate: 4-10 ml/kg/min Albumin dialysate Flow Rate = BFR UFR : 2000ml/h/1.73m2 in CVVH or in CVVHDF mode Anticoagulation: No anticoagulation Heparin (5 U/kg/h) Citrate pCRRT Rome 2010

Albumin Bound Toxins Removed During MARS Therapy Water Soluble Substances Removed During MARS Therapy Aromatic Amino Acids Bilirubin Bile Acids Copper Middle and Short Chain Fatty Acids Nitric Oxide (S-Nitrosothiol) Protoporphyrin Ammonia Creatinine Tryptophan Tumor Necrosis Factor Alpha Urea IL-6 Spectrum of substances removed based on clinical and animal experimental data sets

Substances Not Removed During MARS™ Clotting Factors (Factor VII 50,000 Daltons) Improvement in Factor VII levels after repeated treatments in small studies Immunoglobulin G (150,000 Daltons) Hormone binding proteins Albumin This is in contrast to Plasmapheresis, in which the patient’s serum is replaced by Albumin and/or FFP

Rationale To provide an environment facilitating recovery- isolated or as a component of MOSF Therapy To prolong the window of opportunity for LTx : Bridge to Transplantation To allow waiting for the native liver recovery: Bridge to recovery The rationale for supportive therapy and extracorporeal systems is to provide an environment facilitating recovery, to prolong the window of opportunity for LT as a Bridge to LT or sometimes to allow waiting for the native liver recovery as a bridge to liver recovery Liver transplantation is required most of the time

Indications Intoxications (US ***) Acute Liver Failure (ALF) Hepatorenal Syndrome Acute on Chronic Liver Failure (AoCLF) Hepatic Encephalopathy Refractory Pruritus in Liver Failure Sepsis / SIRS / MODS

Intoxications leading to Acute Liver Failure Exogenous: Acetaminophen Amanita Toxin Endogenous: Inborn Error Metabolism Wilson disease, neonatal hemochromatosis Removal of inflammatory Toxins Sepsis/SIRS MOSF See appendix for references Multiple studies have shown MARS to be an effective therapy in these types of toxin induced ALF Sometimes LF occurs because of the accumulation of copper or iron in the organism: as in the Wilson disease and neonatal hemochromatosis LF amy be also due to drugs intoxications, mushrooms poisoning and herbs intoxication. The removal of inflammatory markers and cytokines in the context of MOF or sirs are controversial and requires more studies. Nevertheless the majority of toxins in LF are water insoluble and albumin bound.

Acute Liver Failure Improvement in native liver function? Increased avoidance of liver transplant in adult patients with fulminate hepatic failure Camus, C., Ther Apher Dial 2009 Dec, 13(6): 549-55 Improvement in survival: 67% survival in MARS group at 7 days 25% survival in MARS group at 30 days 0% survival in control group at 7 days Mitzner SR., Liver Transpl 6: 277-286, 2000 Evidence to date is somewhat equivocal in terms of survival outcomes using MARS– however the symptomatic relief appears clear.

Acute Liver Failure 12 children– 88 sessions in total Data -2000-2009 PICU at Pédiatriques Hôpital Femme Mère Enfant, Lyon, France: Dr. E Javouhey- presented ppCRRT meeting 2010

Acute on Chronic Liver Failure Increased Survival 24 adult patients with AoCLF 92% 30 day survival in MARS group 50% 30 day survival in control group Heemann U., Hepatology 36: 949-958, 2002

Benefits of MARS Improvement in Hemodynamic Stability Increased systemic vascular resistance Increased mean arterial pressure Decreased portal venous pressure in AoCLF Improvement in renal blood flow (RBF) Laleman W., Critical Care 10:R108, 2006 Schmidt LE., Liver Transpl 9: 290-297, 2003 Kapoor D., Journal of Gastroenterology and Hepatology 2002, 17: S280 – 86, 2002 Mitzner SR., J Am Soc Nephrol 12: S75-82, 2006 Patients in advanced liver failure demonstrate a Hyperdynamic Circulation, which many propose is secondary to increased serum Nitric Oxide content in this patient population. Indeed, MARS has shown to remove Nitric Oxide from the circulation and may even decrease total body nitric oxide production.

Hepatic Encephalopathy LIVER FAILURE MARS Fischer Index Ammonia Loss of Cerebral Auto-regulation Nitric Oxide Endogenous Benzodiazepine Cerebral Ischemia Glutamine Glutamate Fischer Index: Serotonin, NE, Dopamine. Glutamine/Glutamate: NMDA Herniation Cerebral Edema Intracranial Hypertension

Benefits of MARS Improvement in Hepatic Encephalopathy This graph illustrates advanced improvement in MARS treated patients with vs standard medical therapy based on HE grade (scale from 0 to 4). This and other studies have also shown similar results with Glasgow Coma Scores in patients with HE who undergo MARS therapy. Improvement with Mars : 64% p 0,04 Improvement with SMT : 38% Hassanein T., Hepatology 46: 1853-1862, 2007

Tolerance and efficacy The tolerance of the MARS session largely varied between liver disease groups. All infants treated by MARS for an ALF as a bridge to liver transplantation had a poor hemodynamic tolerance of the extracorporeal treatment and required many blood product transfusions. However, all weighted less than 9kg and were treated with haemodialysis. The two first patients were treated using the MARS membrane of more than 2m2 of size, corresponding to a extracorporeal volume of 220ml. The level of consciousness assessed by the GCS and the EEG was improved in 4 children with AoCLF or RP, and was stabilized in two others children. As we will show it, the MARS therapy was effective to improve the itching and the humor of the children who presented refractory prurity due to a chronic cholestasis. Data -2000-2009 PICU at Pédiatriques Hôpital Femme Mère Enfant, Lyon, France: Dr. E Javouhey- presented ppCRRT meeting 2010

Risks Hemodynamic Instability Has been seen primarily in children weighing < 10kg also undergoing hemodialysis Overall improvement with continued therapy Thrombocytopenia Bleeding Complications Transfusion of Blood Products In acute liver failure, it seemed to us that MARS treatment is able to provide a slight improvement or at least a stabilization of the hepatic encephalopathy. Moreover, this allows us to better control the fluid balance of the children in this severe situation. Finally, this treatment allowed us to bridge 12 children to liver transplantation. However, sthis system has some technical limitations. Because the size of the membrane is too large, the hemodynamic tolerance was poor in infants. Consequently, they required fluid bolus and inotropic drugs. The better tolerance observed when we combined the miniMARS membrane with a haemodiafiltration machine suggests that it would be interesting to develop a miniPRISMARS system. The most interesting impact of the MARS therapy was observed for children with acute-on chronic LF and those with refractory pruritus. Our observation of chronic use of MARS suggests that improving the pruritus and its consequences, the quality of life and the nutrional status of the child was improved. However this therapy is very expensive and require a long term haemodialysis catheter so that we reserved this treatment for the children with the most severe diseases, particularly when they have an associated renal failure and when they are registered on liver transplantation list.

Cost Benefit Positive benefit in terms of health cost reductions using MARS Kantola et.al. Cost-utility of MARS treatment in ALF. World Journal of Gastroenter 2010; 16; 2227-34 Hessel et.al. Cost-effectiveness of MARS in patients with acute-on-chronic liver failure. Gastroenterol Hepatol 2010; 22: 213-20 Positive impact on reduction of Pharmacy utilization (albumin)- compared to SPAD Drexler et. al. Albumin dialysis MARS: impact of albumin dialysate concentration on detoxification efficacy. Ther Apher Dial 2009; 13; 393-8

Non-Biological artificial support Issues: Still don’t understand the complexity of the liver and the causes of hepatic encephalopathy/coma May be removing both good (growth factors-for liver regeneration) and bad substances Need to standardize end points in these studies Multicenter RCTs are desperately required in Pediatrics

Future Horizons Huge potential Impact on critical care & Transplantation Potential for managing patients chronically as an outpatient with intractable pruritus- High impact on quality of life: Leckie et.al. Outpatient albumin dialysis for Cholestatic patients with intractable pruritus Aliment Pharmacol Ther 2012; 35: 696-714 Schaefer et.al. MARS dialysis in children with cholestatic pruritus. Pediatr Nephrol 2012; 27: 829-34

Thank You Pediatric Dialysis Staff Mary Lee Neuberger Critical Care physicians/Nursing Pharmacy

Appendix