Impact of preservation method on delayed graft function

1. Cold Machine Perfusion versus Static Cold Storage for SCD, ECD and DCD Kidneys Session 6: Devices for Kidney Flushing, Transport and Preservation William Irish, PhD CTI Clinical Trial and Consulting Services September 9, 2011

2. Disclosure Consultant: Y’s Therapeutics

3. Outline Delayed graft function Incidence and clinical impact Risk factors – role of ischemia time Kidney preservation Preservation solutions Storage modalities – cold storage vs. machine perfusion Outcomes Cost-effectiveness Sources of variability Unanswered questions/unresolved issues Approaching resolution

4. Delayed Graft Function by Donor Status Donation after cardiac death ECD deceased donors All deceased donors SCD deceased donors Living donors U.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. Endpoint With DGF No DGF (N=203) (N=298) % AR by 6 months post - 33.5 20.1 transplant Odds Ratio* (95% CI) 1.9 (1.2 – 2.8) 1.0 AR, Graft failure or death** Hazard rate ratio* (95% CI) 2.1 (1.5 – 3.1) 1.0 Graft 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-transplant Clinical Impact of Delayed Graft Function Danovich 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 continued Systematic Review and Meta Analysis Pooled estimates using random effects model Yarlagadda et al. Nephol Dial Transplant 24: 1039-1047, 2009

7. Clinical Impact of Delayed Graft Function by Donor Type 0.5 ECD DGF % Yes Yes 5.3 Yes No 9.6 No Yes 19.4 No No 65.7 0.4 0.3 Hazards of Graft Failure 0.2 0.1 0.0 0 1 2 3 4 5 Years Post-Transplant Source: UNOS/OPTN data as of April 29, 2011

8. 0 10 20 30 40 50 60 70 80 90 100 Continuous Variables Peak PRA (%) 0 60 Duration Dialysis (days) 0 1000 2000 3000 4000 5000 6000 7000 8000 Duration Dialysis Squared 8000 7000 6000 5000 4000 3000 1000 Recipient BMI (kg/m2) 0 5 10 15 20 25 30 35 40 45 1 5 HLA Mismatch 0 4 CIT (hours) 0 5 10 15 20 25 30 35 40 45 WIT (minutes) 0 30 60 90 Donor Terminal Creatinine (mg/dL) 0 0.5 1 1.5 2 2.5 3 3.5 4 Donor Age (years) 0 10 25 40 55 Donor Weight (kg) 200 160 120 80 40 0 Donor Weight Squared 0 60 80 100 120 140 Comprehensive Risk Model to Predict Risk of DGF Points Points Categorical Variables 6 Black Recipient 9 Male Recipient 5 Previous Transplant 8 Recipient Diabetes 6 Recipient Pre -transplant Transfusion 27 Donation after Cardiac Death 6 Donor History of Hypertension 6 Donor Cause of Death -Anoxia 6 Donor Cause of Death -Cardiovascular 160 180 200 Total Points 0 50 100 150 200 250 300 350 Risk of DGF 0.10 0.20 0.50 0.70 0.90 Irish et al. Am J Transplant 2010;10(10):2279-2286

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

10. Potential Role of Warm Ischemia Timeas a Risk Factor for DGF Warm 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 Modalities Static Cold Storage1: US: 80% Eurotransplant: 100% LifePort™ Kidney Transporter for hypothermic machine perfusion 1Hartono 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 Transplantation de 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 Transplantation Roels et al. Transplantation. 1998; 66(12): 1660-64 Agarwal et al. Transplantation 2006; 81(3): 480-82 Lynch et al. Am J Transplant 2008; 8: 567-73

15. Impact of HTK on Long-term Graft Survival Following Deceased Donor Kidney Transplantation Stewart 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 size Non-randomized comparisons subject to: Confounding by indication Selection and reporting biases Differential center-effects Changing patient management practices Prospective, 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-S35 Sung 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 methods Wight 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 days in the first week after transplantation. This category did not include patients in whom acute rejection, CNI toxicity, or both developed 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 Category Moers C et al N Engl J Med 2009; 360:7-19

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

22. Unanswered Questions

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 2003 Matsuoka Am J Transplant 2006; 6:1473-1478;

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

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

30. Primary clinical endpoint (utility) is graft survival at one-year post-transplant Garfield et al. Transplant Proceedings 2009; 41:3531-36

31. Approaching Resolution

32. Sources of Variability Definitions of DGF1 Lack of a standardized definition Dialysis-dependent: requirement within 7-10 days Creatinine-dependent: increase/insufficient reduction within 3 days Study design Randomized vs. non-randomized comparison Insufficient sample size Center effects Kidney discard rate Staff resources and experience Patient management strategies Donor type SCD vs. ECD DBD vs. DCD Organ treatment Variable cold ischemia time Warm ischemia time (sp. uncontrolled DCD) not adequately studied Early exposure to calcineurin inhibitors 1Yarlagadda SG et al Nephrol Dial Transplant 2008; 23:2995-3003

33. Accounting for Variability How it: Affects outcome Choice of preservation modality Type of donor organ