Molecular Adsorbent
Recirculating System
Patrick Brophy MD
Director Pediatric Nephrology,
University of Iowa Children’s
Hospital
Outline
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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 Therapies
Current Opin in Crit Care. 2007; 13:215-21
MARS™
MARS™ ADSORPTION
Flux Filter COLUMNS
Patient
Blood
Circuit
DIALYSIS
DiaFlux Filter
20-25% Albumin Dialysis
Circuit
Circuit
MARS Flux Filter
Kapoor D., Journal of Gastroenterology and Hepatology, 2002
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
pCRRT Rome 2010
Albumin Bound Toxins
Removed During MARS
Therapy
• Aromatic Amino Acids
• Bilirubin
• Bile Acids
• Copper
• Middle and Short Chain
Fatty Acids
• Nitric Oxide (SNitrosothiol)
• 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
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
12
Indications
• Intoxications (US ***)
• Acute Liver Failure (ALF)
– Hepatorenal Syndrome
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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
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
1
cumulative survival
0,8
p = 0,0123
0,6
» Mitzner SR., Liver Transpl 6: 277-286,
2000
0,4
0,2
0
0
5
10
15
20
25
treatm ent days
MARS(n=8)
HDF(n=5)
30
Acute Liver Failure
1
Weight
Kg
9
Age
month
10
Liver
disease
Biliary atresia
2
7
7
3
9,5
28
Fulminant
hepatitis
Biliary cirrhosis
4
13
36
Byler disease
5
6,3
9
Biliary atresia
6
7
50
55
166
180
Wilson disease
Biliary atresia
8
37
189
9
6,8
6
10
11
12
20
30
50
139
135
181
Fulminant
hepatitis
Fulminant
hepatitis
Wilson disease
Wilson disease
Wilson disease
Priamary graft
dysfunction
Underlying
disase
Graft
dysfunction
Cystic
fibrosis
End stage
renal failure
Chronic graft
rejection
Biliary
Cirrhosis
Chronic graft
rejection
Graft
Dysfunction
Indication
Transplantation
Outcome
ALF
Living donor
ALF
Cadaveric Donor
Severe
disabilities
Died
AoCLF
Liver-Kidney
Alive
RP
Living donor
Alive
Cadaveric Donor
Alive
ALF
RP
Living donor
Living donor
Alive
Alive
RP
Living donor
Alive
ALF
Living donor
Alive
ALF
ALF
ALF
Cadaveric Donor
Cadaveric Donor
Cadaveric donor
X2
Alive
Alive
Alive
AoCLF/RP
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
Hepatic Encephalopathy
LIVER FAILURE
MARS
Fischer Index
Ammonia
Nitric Oxide
Endogenous
Benzodiazepine
Glutamine
Glutamate
Cerebral
Edema
Intracranial
Hypertension
Loss of Cerebral
Auto-regulation
Cerebral
Ischemia
Herniation
Benefits of MARS
• Improvement in Hepatic Encephalopathy
Hassanein T., Hepatology 46: 1853-1862, 2007
Tolerance and efficacy
ALF
Weight
kg
9
Age
month
10
7
6,8
Tolerance
Efficacy
Indication Hemodynamic Transfusion Neurological Pruritus Humor
ALF
Moderate
Yes
(+/-)
7
ALF
Bad
No
NA
6
ALF
Bad
Yes
NA
AoCLF/RP
9,5
13
6,3
55
37
28 AoCLF
36
RP
9 AoCLF/RP
180
RP
189
RP
Good
Good
Good
Good
Good
No
No
Yes
No
No
Yes
Yes
Stable
Yes
Yes
Wilson disease
50
166
ALF
Good
Yes
Stable
20
30
50
139
135
181
ALF
ALF
ALF
Graft
dysfunction
Good
Good
Good
Atrial
tachycardia
Yes
Yes
yes
NA
Sable, no EH
Yes
Yes
Yes
Stable
Yes
Yes
Yes
Yes
NA
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
• 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
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Pediatric Dialysis Staff
Mary Lee Neuberger
Critical Care physicians/Nursing
Pharmacy
Appendix