1. Hepatic Failure and Hemofiltration Timothy E Bunchman Professor Pediatric Nephrology & Transplantation

2. Outline Hepatic Failure-definition(s) Indications-when do we use them?
What are hepatic support therapies
Recent Literature

3. 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 failure, death

4. 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

5. Indications Bridge to liver transplantation
Bridge to allow sufficient time for hepatic regeneration
Improve clinical stability of patient

6. What & Why are they? Two main approaches to liver support
Non-biological
Filtration of potentially harmful molecules
Hybrid Biological artificial support (hepatic cells in a synthetic framework)

7. Non-Biological Filtration Techniques
Hemofiltration:
First attempt (hemodialysis) 1956 Kiley et al (Proc. Soc. Exp. Biol. Medical 1956)
Noted Hemodialysis improved clinical (4/5-patients) neurological function, didn’t change outcome though

8. Non-Biological Filtration Techniques
Hemofiltration:
CRRT support can buy time, help prevent further deterioration/complication and allow
Potential recovery of functional critical cell mass
Management of precipitating events that lead to decompensated disease
Bridge to liver transplantation

9. CVVHD for NH4 Bridge to Hepatic Transplantation
Successful Liver
Transplantation
micromoles/L
NH4
Time
(days)

10. Non-Biological Filtration Techniques
Hemofiltration:
CRRT may not improve overall outcome of liver failure- provide stability and prolongs life in the setting of hepatic failure
Primary applications include use in control of elevated ICP in fulminant hepatic failure (Davenport Lancet 1991:2:1604)
Management of Cerebral Edema through middle molecule removal- reversal of Coma (Matsubara et.al. Crit Care Med1990:8:1331)

11. Hepatic Failure-Role of CRRT
Others:
Fluid Balance
Nutritional support
Uremic Clearance

12. Non-Biological Filtration Techniques
Hemoperfusion:
Historically Charcoal gave rise to current cartridge chambers in use today
PolyAcryloNitrile-Initially noted to remove substances up to 15000Da (initial study) found clinical but not statistical survival improvement
Issues:
Non-specific removal of growth factors
Reactivity with the membranes

13. Non-Biological Filtration Techniques
Hemoperfusion:
Development of Resin Exchange Columns:
Amberlite- removal of cytokines, bilirubin, bile acids
Polymixin-endotoxin removal
Hydrophilic Membranes- for removal NH4, phenols and fatty acids
Downside- also effective at removing leucocytes and platelets

14. Non-Biological Filtration Techniques
Plasma Exchange:
Allows removal of hepatic toxins with replacement with equivalent volume of Fresh Frozen Plasma
Improved clinical response but no significant increase in survival rates
In general- get limited toxin removal and high FFP replacement volumes are required over time- costly

15. Non-Biological Filtration Techniques
Molecular Adsorbents Recycling System (MARS)
Commercially available-premise based on filtering out albumin bound toxins
Uses albumin-enriched dialysate combined with a charcoal filter and an ion exchange resin
Utilizes existing Renal Dialysis Machinery along with the MARS device

16. Non-Biological Filtration Techniques
Albumin dialysis pumps the blood out of the body and into a plastic tube filled with hollow fibers made of a membrane that has been coated with albumin.
On one side of the fiber's membrane is the blood; on the other, a dialysis solution containing more albumin.

17. Non-Biological Filtration Techniques
The toxins on the albumin in the patient's blood are attracted to the albumin on the membrane, which is "stickier" because it has more room for molecules to attach.
Then, the albumin on the membrane passes the toxins along to the albumin in the solution as it flows by.

18. Non-Biological Filtration Techniques
Meanwhile, smaller toxin molecules that don't stick to albumin flow through the membrane's tiny pores into the less-concentrated dialysis solution.
The patient's own albumin, too large to fit through the membrane's pores, returns to the body with the blood.

19. Hepatic Support Devices

22. Hybrid Biological artificial support
Rooted in Cross Circulation Studies- using Dogs and Human subjects & Porcine, Baboon extracorporeal liver perfusion
Conceptually: liver function-including synthesis and homeostasis are replaced by hepatocytes in an exogenous environment
Peritoneal placement of hepatocytes
Extracorporeal perfusion (cells in synthetic frame)

23. Hybrid Biological artificial support
Implantation: (using coated microcarrier beads)
Within liver resulted in cell aggregation and portal hypertension
Within peritoneum/spleen (animal models)
Benefits: relatively simple to do
Problems: delayed onset of function (less useful in Acute Hepatic Failure), Lose function over time-need re-implantation (animal studies), require immunosuppresion

24. Hybrid Biological artificial support
Implantation: (using coated microcarrier beads)
Problems: Human pilot (Bilir et al. Liver Transplantation 2000,6,32-40)
8 patients transplanted- no survivors, 3/8 showed some neuro improvement

25. Hybrid Biological artificial support
Extracorporeal Bioartificial Liver Support Devices:
Extracorporeal systems that combine hepatocytes in a plastic cartridge and semi-permeable membrane
Problems: 1) maintaining cell viability and numbers
2) Membrane type and structure
3) cell mass and type of hepatocyte

26. Hybrid Biological artificial support
Extracorporeal Bioartificial Liver Support Devices:
Types:
HepatAssist 2000
ELAD (extracorporeal liver assist device)
BLSS (bioartificial liver support system)
MELS (Modular extracorporeal liver system)
LiverX2000 system
AMC-BAL (academic medical centre) Chamuleau

27. Hybrid Biological artificial support
All of these therapies combine replacement hepatocytes (human, porcine, immortalized, inducible) within a structured meshwork fiber
Each has a different cell mass and nourishment system for the cells
Several provide charcoal columns for toxin removal, and/or albumin dialysate along with the ability to add in a dialysis unit

28. Hybrid Biological artificial support
Most are in Phase I/II clinical trials
Initial studies have been mixed with respect to outcomes (end points differ between studies)
Data just starting to emerge on these devices

29. Hybrid 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
Possibility of introducing viruses with live cell use
Need to standardize end points in these studies

30. What is the recent literature?

31. Artificial Liver Support System
+ ALSS
- ALSS N
338
312
30 day survival
48%
37%
Decrease in encephalopathy
71%
52%
OLT
31/338
Du et al, Transpl Proc 37, , 3005

32. MARS N = 116 Bili drop 23-12 mg/dl NH4 drop 238-115 microgms/dl
Lactate drop 3.48 – 1.76 mmol/L
Creatinine drop mg/dl
No comment on survival, bridge to Tx
Novelli et al, Trans Proc 37, , 2005

33. ARF and Liver Failure 66 patients with ARF and LF Rx with CVVH
26 – OLT with 9.5 avg CVVH days, ICU and Hospital mortality of 15% and 23%
40 – no OLT 5 avg CVVH days, ICU and Hospital mortality of 63% and 70%
Naka et al, ISAO, , 2004

34. Device Review Review of all devices to date (semi meta-analysis)
Conclusion = Hepatic support systems use is not justified as an ongoing support but may be best use for OLT bridge
Wigg & Padbury, J Gastro & Hepatol 20: , 2005

35. PCRRT 4 Abstract Ringe et al
8 children Rx with Single Pass albumin hemofiltration (SPAD)
Improvement in Hepatic Encephalopathy
Stable hemodynamics

36. Conclusion Hepatic Support Devices are still in their infancy
Use of CVVH with or without albumin may be “equally” effective
Future research in this area is on goin
OLT only definitive Rx of ALF