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

Stadlbauer and Jalan. Acute Liver Failure: liver support TherapiesCurrent Opin in Crit Care. 2007; 13:215-21

MARS™MARS™ Flux Filter

ADSORPTION COLUMNS

DIALYSISDiaFlux Filter

Patient BloodCircuit

20-25% AlbuminCircuit

DialysisCircuit

MARS Flux Filter

Kapoor D., Journal of Gastroenterology and Hepatology, 2002

pCRRT Rome 2010

Technical Aspects• Filters :

– 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

Albumin Bound Toxins Removed During MARS Therapy

• Aromatic Amino Acids• Bilirubin• Bile Acids• Copper• Middle and Short Chain

Fatty Acids• Nitric Oxide (S-

Nitrosothiol)• Protoporphyrin

Water Soluble Substances Removed During MARS Therapy

• Ammonia• Creatinine• Tryptophan• Tumor Necrosis Factor

Alpha• Urea• IL-6

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

12

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

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– MOSFSee appendix for references

Multiple studies have shown MARS to be an effective therapy in these types of toxin induced ALF

Acute Liver Failure

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0,4

0,6

0,8

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0 5 10 15 20 25 30

treatment days

cum

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tive

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rviv

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MARS(n=8) HDF(n=5)

p = 0,0123

Acute Liver Failure

Data -2000-2009 PICU at Pédiatriques Hôpital Femme Mère Enfant, Lyon, France: Dr. E Javouhey- presented ppCRRT meeting 2010

Weight Kg

Age month

Liver disease

Underlying disase

Indication Transplantation Outcome

1 9 10 Biliary atresia Graft dysfunction

ALF Living donor Severe disabilities

2 7 7 Fulminant hepatitis

Cystic fibrosis

ALF Cadaveric Donor Died

3 9,5 28 Biliary cirrhosis End stage renal failure

AoCLF Liver-Kidney Alive

4 13 36 Byler disease Chronic graft rejection

RP Living donor Alive

5 6,3 9 Biliary atresia Biliary Cirrhosis

AoCLF/RP Cadaveric Donor Alive

6 50 166 Wilson disease ALF Living donor Alive 7 55 180 Biliary atresia Chronic graft

rejection RP Living donor Alive

8 37 189 Fulminant hepatitis

Graft Dysfunction

RP Living donor Alive

9 6,8 6 Fulminant hepatitis

ALF Living donor Alive

10 20 139 Wilson disease ALF Cadaveric Donor Alive 11 30 135 Wilson disease ALF Cadaveric Donor Alive 12 50 181 Wilson disease

Priamary graft dysfunction

ALF

Cadaveric donor X2

Alive

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

Hepatic Encephalopathy

Endogenous Benzodiazepine

LIVER FAILURE MARS

Ammonia

Nitric Oxide

Fischer Index

Glutamine Glutamate

Loss of CerebralAuto-regulation

IntracranialHypertension

CerebralEdema

CerebralIschemia

Herniation

Benefits of MARS• Improvement in Hepatic Encephalopathy

Hassanein T., Hepatology 46: 1853-1862, 2007

Tolerance and efficacy Tolerance Efficacy Weight

kg Age

month Indication Hemodynamic Transfusion Neurological Pruritus Humor

9 10 ALF Moderate Yes (+/-)

7 7 ALF Bad No NA

ALF

6,8 6 ALF Bad Yes NA

9,5 28 AoCLF Good No Yes Yes Yes 13 36 RP Good No Yes Yes Yes

6,3 9 AoCLF/RP Good Yes Stable Stable NA 55 180 RP Good No Yes Yes Yes

AoCLF/RP

37 189 RP Good No Yes Yes Yes

50 166 ALF Good Yes Stable Wilson disease 20 139 ALF Good Yes NA

30 135 ALF Good Yes Sable, no EH 50 181 ALF

Graft dysfunction

Good Atrial

tachycardia

yes Yes

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

Cost Benefit

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 HorizonsHuge 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