1. What makes a pancreas allograft marginal? Peter J Friend University of Oxford

2. Do we need marginal grafts? What is a marginal graft – conventionally? What is a marginal graft – evidence-based? How can we use marginal grafts safely? The future

3. Pancreas transplantation in the UK – the current situation

4. Pancreas transplantation (UK) 1999 - 2009 Donor BMI criterion introduced August 2008

5. Pancreas transplantation from DBD – UK Age range 8 to 60 years * Percent of HB donors aged 8 to 60 resulting in transplant Donors aged 8 to 60 years - decreasing Expanding age criteria - offers and retrievals have increased Transplant conversion rate -declined by 7 percentage points

6. Pancreas transplantation from DBD – UK Include BMI less than 30 * Percent of HB donors aged 8 to 60 with a BMI ≤ 30 resulting in transplant Donors within age & BMI criteria - decreasing Including age and BMI criteria, conversion rate still below 50%

7. Pancreas transplantation from DBD (2009) The influence of age * Percent of HB donors aged 8 to 60 with a BMI ≤ 30 resulting in transplant Highest conversion rate - donors aged 18 to < 30 years Very low conversion rates - donors aged over 50 years

8. Pancreas transplantation from DBD (2009) The influence of BMI * Percent of HB donors aged 8 to 60 with a BMI ≤ 30 resulting in transplant Lower BMI associated with higher conversion rates

9. What factors make a graft marginal? Uncontrollable factors: Age Obesity Cardiovascular disease Alcohol Amylase Controllable factors: Inotropes (Warm ischaemia) Cold ischaemia Rewarming time Retrieval technique ‘Standard’ criteria vs. ‘Extended’ criteria

13. University of Minnesota 1994-2003 937 transplants – 327 SPK – 399 PAK – 211 PTA 624 functioning (66.5%) - mean follow-up 45 months 123 (13%) lost due to ‘technical’ complications - – 52% thrombosis6.5% leaks – 19% sepsis2.4% bleeding – 20% pancreatitis Humar et al Transplantation 2004

14. Risk factors for technical failure Recipient BMI>302.42 Preservation time>24 hr.1.87 Donor deathNon-trauma1.58 DrainageEnteric1.68 Donor BMI>301.66 Humar et al Transplantation 2004

15. The extended criteria donor - results

16. Oxford data Single centre retrospective analysis Extended criteria Age less than 12, more than 45 years Non-heart-beating donors All pancreas transplant recipients 2004 – 2009 End points: –Graft & patient survival –Delayed graft function –Complications (re-admissions, re-operations) Muthusamy et al

17. Patients & Methods 265 transplants (261 pts) – 155 male, 106 female – 176 SCD, 89 ECD – Enteric-systemic drainage of grafts Immunosuppression: – Campath / Tac / MMF (n = 249) – (ATG n=8, Basiliximab n=4) / Tac/MMF/Steroids (all SCD)

18. Clinical details SCDECDP value Creatinine – donor85 ± 3185 ± 28NS Cause of death: vascular43%66%0.0006 Cause of Death: head injury30%16%0.013 Donor Body Mass Index24 ± 325 ± 9NS Recipient age (years)42±746±8<0.0001 Recipient Body mass index24±426 ± 40.03 Recipient ethnicity % Caucasian/Asian/Afro-Caribbean 90/ 7 /394 / 6 / 0NS HLA (median)44NS Cold Ischemia (mins)692±159717±177NS Hospital stay (days)19 ±1220 14NS Median F/U (months)23160.0043

19. Results - Outcomes SCDECDP value DGF - kidney11%19%0.13 DGF - pancreas1.7%6.7%0.06 PNF - kidney00NS PNF - pancreas01.5%NS Re-operation25% NS Re-admission20%33%0.03 Rejection episodes15%10%NS

20. Patient & graft survival: SCD vs ECD

21. Graft function SCD vs. ECD

22. Conclusions – the expanded criteria donor pancreas Equivalent graft and patient survival Equivalent pancreatic & renal graft function at 3 months Higher risk of delayed graft function of kidney & pancreas Greater morbidity related to pancreatitis Feasible source to expand the organ pool

23. Pre-procurement pancreas suitability score (P-PASS) - Eurotransplant Vinkers et al 2008

24. P-PASS predicts organ acceptance, not viability

25. But – more complications and longer hospital stay Bochum, Germany

26. Analysis of 24,703 donors 2000 – 2004 (OPTN) 44,529 kidney transplants 21,079 liver transplants 5521 solid organ pancreas transplants 1041 pancreases used for islets

27. Reasons for non-retrieval of pancreas in 64% multi-organ donors Poor organ function33% Donor medical history12% No recipient7% Intra-operative evaluation6% Hepatitis serology6% Anatomical anomaly3% Unstable haemodynamics3% Time constraints2% Other28% Stegall et al 2007

28. Effect of donor age AgePAKSPK Less than 5079.785.6* More than 5066.775.5 * p=0.05 Stegall et al 2007 1 year graft survival

29. Effect of donor BMI BMIPAKSPK Less than 3079.685.7* More than 3078.182.7 *p=0.06 1 year graft survival Stegall et al 2007

30. Effect of cold ischaemia time Cold ischaemia (hrs) PAKSPK 0 – 1279.786.7 12 – 1879.385.2 18 – 2475.785.8 24 +79.376.2 Stegall et al 2007 (UK results show significant effect of cold ischaemia time at 3 months)

31. The effect of donor age OPTN data Salvalaggio et al (St Louis) 2007 Increased complications of older donors (+/- 45 years) more than compensated by reduced morbidity whilst waiting longer

32. Paediatric donors University of Wisconsin 1986 – 2001 680 SPK including 142 paediatric donors – 47 aged 3 to 12 years – 95 aged 12 – 17 years 10 year survival and function better in paediatric donors No difference between smaller and larger cohorts Fernandez et al 2004 (Concerns about islet mass & technical complications)

33. Pancreas graft survival Fernandez et al 2004

34. Kidney graft survival Fernandez et al 2004

35. Pancreas transplantation from NHB donors Salvalaggio et al 2006 Analysis of UNOS data 1993 to 2003 – 57 NHBD (47 SPK, 10 PA) – 4038 HBD (2431 SPK, 1607 PA) Equivalent patient & graft survival rates Shorter time on waiting list Longer hospital stay More pancreas thrombosis (12.8% vs. 6.1%) More renal DGF (28.2% vs. 7.6%)

36. Kidney graft survival Pancreas graft survival Patient survival Salvalaggio et al 2006

37. Higher-risk transplants Postoperative mortality Waiting list mortality

38. Mortality on Tx waiting list Mortality after pancreas Tx IPTR, UNOS data Gruessner et al 2004

39. The future Improved method of assessment needed – Objective rather than subjective Improved graft protection needed – Prevent ischaemia-reperfusion Minimise cold ischaemia Free radical scavenging; Haemoxygenase-1; Complement inhibition etc. Machine perfusion +/- normothermia

40. Conclusions Pancreas donor organs poorly utilised Marginal donor organs are the reality Published data are inconsistent Risk-benefit analysis favours early transplant Innovative preservation and viability assessment methods needed