This document discusses cold machine perfusion versus static cold storage for preserving kidneys from standard criteria, extended criteria, and donation after cardiac death donors for transplantation. It summarizes the incidence and impact of delayed graft function, outlines kidney preservation methods and clinical trials comparing outcomes between cold storage and machine perfusion. It identifies unanswered questions around how preservation method may differentially impact outcomes based on donor and recipient risk factors.

1. Cold Machine Perfusion versus Static Cold Storage for SCD, ECD and DCD KidneysSession 6: Devices for Kidney Flushing, Transport and PreservationWilliam Irish, PhDCTI Clinical Trial and Consulting ServicesSeptember 9, 2011

2. DisclosureConsultant: Y’s Therapeutics

3. OutlineDelayed graft functionIncidence and clinical impactRisk factors – role of ischemia time Kidney preservationPreservation solutionsStorage modalities – cold storage vs. machine perfusionOutcomesCost-effectivenessSources of variabilityUnanswered questions/unresolved issuesApproaching resolution

4. Delayed Graft Function by Donor Status Donation after cardiac deathECD deceased donorsAll deceased donorsSCD deceased donorsLiving donorsU.S. Renal Data System, USRDS 2010 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2010.

5. EndpointWith DGFNo DGF(N=203)(N=298)% AR by 6 months post-33.520.1transplantOdds Ratio* (95% CI) 1.9 (1.2 – 2.8)1.0AR, Graft failure or death**Hazard rate ratio* (95% CI)2.1 (1.5 – 3.1)1.0Graft failure**Hazard rate ratio* (95% CI)3.1 (1.5 – 6.5)1.0* Adjusted for MMF vs. no MMF, Europe vs. North America and ANTILFA vs. placebo ** Excludes patients who failed within the first 7 days post-transplantClinical Impact of Delayed Graft FunctionDanovich G and Irish W for the DGF Study Group. Program and Abstract from the American Society of Nephrology 2000, October 11-16, Toronto, Canada

6. Clinical Impact of Delayed Graft Function continuedSystematic Review and Meta AnalysisPooled estimates using random effects modelYarlagadda et al. Nephol Dial Transplant 24: 1039-1047, 2009

7. Clinical Impact of Delayed Graft Function by Donor Type0.5ECD DGF %Yes Yes 5.3Yes No 9.6No Yes 19.4No No 65.70.40.3Hazards of Graft Failure0.20.10.0012345Years Post-TransplantSource: UNOS/OPTN data as of April 29, 2011

8. 0 10 20 30 40 50 60 70 80 90100Continuous VariablesPeak PRA (%)060Duration Dialysis (days)010002000300040005000600070008000Duration Dialysis Squared8000700060005000400030001000Recipient BMI (kg/m2)05101520253035404515HLA Mismatch04CIT (hours)051015202530354045WIT (minutes)0306090Donor Terminal Creatinine (mg/dL)00.511.522.533.54Donor Age (years)010254055Donor Weight (kg)20016012080400Donor Weight Squared06080100120140Comprehensive Risk Model to Predict Risk of DGFPointsPointsCategorical Variables6Black Recipient9Male Recipient5Previous Transplant8Recipient Diabetes6Recipient Pre-transplant Transfusion27Donation after Cardiac Death6Donor History of Hypertension6Donor Cause of Death-Anoxia6Donor Cause of Death-Cardiovascular160180200Total Points 0 50100150200250300350Risk of DGF0.100.200.500.700.90Irish et al. Am J Transplant 2010;10(10):2279-2286

9. Cold Ischemia Time and Probabilityof Delayed Graft FunctionSlope = 0.0084 risk of DGF per 1 hr increase in CITIrish et al. Am J Transplant 2010;10(10):2279-2286

10. Potential Role of Warm Ischemia Timeas a Risk Factor for DGFWarm ischemic time associated with DCD transplants*Time from circulatory arrest until start of cold perfusion and grouped by 10 minute intervals with <10 minutes as reference# Adjusted for donor - and recipient characteristics and type of preservation method (machine perfusion versus static cold storage)Jochmans et al. Ann Surg 2010; 252:756-764

11. Kidney Preservation ModalitiesStatic Cold Storage1:US: 80%Eurotransplant: 100%LifePort™ Kidney Transporterfor hypothermic machine perfusion1Hartono C, Suthanthiran M Nat Rev Nephr 2009; 5:433-434

12. Static Cold Storage

13. Clinical Trials Comparing UW and HTK Solutionsin Deceased Donor Kidney Transplantationde Boer et al. Transpll Int. 1999;12(6):447-53.Klaus et al. Transplant Proc 2007; 39(2):353-54.

14. Prolonged Cold Ischemia Time: UW versus HTK in Deceased Donor Kidney TransplantationRoels et al. Transplantation. 1998; 66(12): 1660-64Agarwal et al. Transplantation 2006; 81(3): 480-82Lynch et al. Am J Transplant 2008; 8: 567-73

15. Impact of HTK on Long-term Graft Survival Following Deceased Donor Kidney TransplantationStewart et al. Am J Transplant 2009; 9:1048-54

16. What Does the Evidence Suggest?Results are mixed: no clear evidence to discriminate either preservation method Conflicting results, due in part, to:Insufficient sample sizeNon-randomized comparisons subject to:Confounding by indicationSelection and reporting biasesDifferential center-effectsChanging patient management practicesProspective, randomized, adequately powered studies are still needed; especially in “at-risk” study populations (e.g., ECD, prolonged CIT)

17. Machine Pulsatile Perfusion Taylor and Baicu. Cryobiology 2010; 60(3S): S20-S35Sung et al. Am J Transplant 2008; 8(Part 2): 922-34

18. Influence of Machine Perfusion on Risk of DGF: Meta-analysis Results#*Relative risk (MP vs. CS) of DGF (DerSimonian and Laird random effects model)# Included studies in which kidney pairs were allocated between the two preservation methodsWight et al Clin Transplant 2003; 17:293-307

19. Clinical Trial Comparing Static versus Active Perfusion in Deceased Donor Kidney Transplantation*Defined as the absence of a decrease in the serum creatinine level of at least 10% per day for at least 3 consecutive daysin the first week after transplantation. This category did not include patients in whom acute rejection, CNI toxicity, or bothdeveloped in the first week.Moers C et al N Engl J Med 2009; 360:7-19

20. Impact of Machine Perfusion on Risk of DGF by Donor Risk CategoryMoers C et al N Engl J Med 2009; 360:7-19

21. Clinical Trial Comparing Static versus Active Perfusion in DCD Kidney TransplantationWatson et al Am J Transplant 2010; 10:1991-1999

22. Unanswered Questions

23. Does Machine Perfusion Make a Difference Following DCD Only in Older Recipients? OPTN database analysis; N=6,057 DCD recipients transplanted between 1993-2008

24. Mean follow up: 2.2±2.6 yearsCantafio et al Clin Transplant 2011; DOI: 10.1111/j.1399-0012.2011.01477.x

25. Does Preservation Modality Affect Outcomes Following Transplantation of ECD Kidneys?UNOS database analysis of ECD kidneys transplanted between 2000 and 2003Matsuoka Am J Transplant 2006; 6:1473-1478;

26. Does Preservation Modality AffectLong-Term Graft Survival?Results of a Meta-analysis MP CSDBDDCDCS – cold storage; DBD – donation after brain death; DCD – donation after cardiac death; MP – machine perfusion Wight et al Clin Transplant 2003; 17:293-307

27. What About Cost-Effectiveness? Modeling inputs based mostly on the European Machine Preservation Trial

28. Assumes a higher utilization of machine perfusion (80%) for ECD kidneys than for SCD kidneys (20%)

29. Cost drivers: DGF, dialysis, acquisition cost, transplant hospitalization, transplant maintenance