Machine preservation of the liver

1. Machine preservation of the liver Peter J Friend University of Oxford

2. Disclosure I am co-founder and medical director of the Oxford University spin-out company, OrganOx, that has been set up to develop normothermic organ preservation.

3. Centre G Centre D Centre E Centre B Centre F Centre C Centre A Liver transplant survival – UK From transplantation

4. Centre G Centre D Centre G Centre E Centre B Centre F Centre C Centre B Centre A Centre F Centre D Centre E Centre A Centre C Liver transplant survival – UK From listing From transplantation Patients more likely to die on waiting list than postoperatively

5. Trends in liver transplantation • Increasing organ donation, but mostly in high risk donors • Increasing incidence of liver disease • Waiting lists increasing faster than transplants • Long waiting lists, restricted access, mortality The challenge – to transplant greater numbers of higher risk organs without compromising the outcome

6. Utilisation of donor livers 45% livers offered are accepted 76% livers accepted are transplanted (50% of DCD)

7. Limitations of static cold storage • Cooling • Loss of cell membrane functions • No oxygen delivery • Anaerobic metabolism • Accumulation of metabolites • Ischaemia-reperfusion • Limited viability assessment • Injury occurs at time of reperfusion Acceptable for high quality, but not marginal organs

8. DCD liver transplants have poorer outcomes Primary non-function Ischaemic cholangiopathy

9. Inferior outcomes - graft failure & biliary complications Patient Graft P<0.01 P<0.001 Foley. D’Alessandro et al et al 2011

10. Ischaemic cholangiopathy after DCD liver transplantation Success has been achieved at the price of selectivity

11. 11 studies • Unrandomised control groups • 489 DCD (Maastricht 3) • 4455 DBD controls • Isch. cholangiopathy 16% vs. 3% (O/R 10.8) • Biliary complications 29% vs. 17% (O/R 2.4) • Retransplant (O/R 2.6) • Primary non-function (O/R 3.6) Jay, Skaro et al (2011), Northwestern, Chicago

12. Internalisation of membrane proteins during ATP depletion to reduce energy demand • Structural but lack of functional recovery after energy restoration (unlike renal tubular cells) Hepatology 2000, 31(5): 1045-54

13. Liver preservation – the key issues • Oxygen delivery • Machine perfusion (versus static) • Temperature

14. Oxygen delivery

15. Am J Trans 2011, 11:2627-34 • Oxygen insufflation via IVC, exit via pin-pricks in capsule • Superior function; survival; transaminase release

16. (Rat liver reperfusion model) Trans Int 2010, 23: 944-50

17. Machine perfusion Hypothermic Normothermic

18. Pig DCD liver transplant model (60 min WI) 7 hr cold storage versus 6 hr CS + 1 hr HOPE Ann Surg 2009, 250 (5): 674-83

19. 90 min warm ischaemia • 4 hours CS or HMP • Liver transplantation • Better immediate function with HMP • Progressive cellular injury • 20% survival Transplantation 2012, 94 (1): 22-29

20. Columbia University, New York Am J Trans 2010, 10: 372-381

21. Low risk donors • <65 yr, <25% steatosis, DBD • 20 HMP preserved organs (3-7 hr), matched controls • No difference in early histological appearances • Lower transaminase & lower cytokine expression in HMP Larger-scale clinical trial in progress

22. Normothermic machine perfusion Recreate physiological environment Physiological temperature Deliver oxygen Provide nutrients Allow normal metabolic activity Avoid ischaemia-reperfusion Assess viability

24. Survival after normothermic preservationDBD vs. DCD (40 min) DBD DCD

25. Normothermic DBD vs. DCD (40 min) ALT release DCD (n=6) DBD (n=7) P=NS

26. Viability assessment – Base excess DBD 5 hours DBD 20 hours DCD (40) 20 hours DCD (60) 20 hours * p<0.05 * * * *

27. Pig liver transplant model • 90 minutes warm ischaemia • 60 min normothermic recirculation (ECMO) • 4 hours normothermic preservation • 100% survival

28. Preservation or reconditioning? Recirculation Re-conditioning Organ retrieval Transplant Preservation Must the perfusion machine be transportable?

29. 60 mins warm ischemia 4 hr UW 20 hours NP Liver retrieval Reperfuse 24 hr 24 hours NP

30. Bile output AST levels Base excess After 60 minutes warm ischaemia, 4 hours cold storage causes significant damage Reddy et al 2004

31. Pig liver DCD model • ATP levels • 30% after 60 min WI • 0% after 2 hr CS • 80% after 4 hr NMP J Surg Res 2011, 173: 83-88

32. From laboratory to clinic Commercial perfusion systems

33. Product specification: What matters? • Physical parameters: weight, size, materials • Usability: transportability, automation, ease of setup • Functionality (what features are essential?): • Blood or oxygen carrier? • In-line or off-line blood gas analysis? • Gas bottles or on-board gas production? • Mains power/DC power/battery power? • Parameters measured and displayed to the user? • Regulatory compliance • Cost

34. Hypothermic or normothermic?

35. Organ Recovery SystemsHypothermic machine perfusion

36. Organ Assist – liver perfusion

37. OrganOx metra

38. Automated, transportable, self-contained

39. The OrganOx metra™ - start of perfusion Start After 10 secs After 60 secs Clinical trial in progress

40. Where will we be in 5 years? • Routine machine perfusion of all/most livers • Cold or warm? • Portable or static? • Logistic demands – retrieval teams • Cost implications • More donors and increased utilisation

41. Conclusions • Static cold preservation does not meet the challenges of marginal donor organs • Hypothermic machine perfusion • Benefits in pig model • Clinical studies in progress • Normothermic machine perfusion • Resuscitation, prolonged preservation & viability assessment (in pig models) • Cold preservation must be avoided (even in transit) • Clinical trials in progress Machine perfusion …. not whether, but how?