Fda Iri Dgf Workshop 09 Sep2011 W Irish

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Impact of preservation method on delayed graft function

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Fda Iri Dgf Workshop 09 Sep2011 W Irish

  1. 1. Cold Machine Perfusion versus Static Cold Storage for SCD, ECD and DCD Kidneys<br />Session 6: Devices for Kidney Flushing, Transport and Preservation<br />William Irish, PhD<br />CTI Clinical Trial and Consulting Services<br />September 9, 2011<br />
  2. 2. Disclosure<br />Consultant: Y’s Therapeutics<br />
  3. 3. Outline<br />Delayed graft function<br />Incidence and clinical impact<br />Risk factors – role of ischemia time <br />Kidney preservation<br />Preservation solutions<br />Storage modalities – cold storage vs. machine perfusion<br />Outcomes<br />Cost-effectiveness<br />Sources of variability<br />Unanswered questions/unresolved issues<br />Approaching resolution<br />
  4. 4. Delayed Graft Function by Donor Status <br />Donation after cardiac death<br />ECD deceased donors<br />All deceased donors<br />SCD deceased donors<br />Living donors<br />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.<br />
  5. 5. Endpoint<br />With DGF<br />No DGF<br />(N=203)<br />(N=298)<br />% AR by 6 months post<br />-<br />33.5<br />20.1<br />transplant<br />Odds Ratio* (95% CI) <br />1.9 (1.2 <br />–<br /> 2.8)<br />1.0<br />AR, Graft failure or death**<br />Hazard rate ratio* (95% CI)<br />2.1 (1.5 <br />–<br /> 3.1)<br />1.0<br />Graft failure**<br />Hazard rate ratio<br />* (95% CI)<br />3.1 (1.5 <br />–<br /> 6.5)<br />1.0<br />* Adjusted for MMF vs. no MMF, Europe vs. North America and ANTILFA vs. placebo <br />** Excludes patients who failed within the first 7 days post-transplant<br />Clinical Impact of Delayed Graft Function<br />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<br />
  6. 6. Clinical Impact of Delayed Graft Function continued<br />Systematic Review and Meta Analysis<br />Pooled estimates using random effects model<br />Yarlagadda et al. Nephol Dial Transplant 24: 1039-1047, 2009<br />
  7. 7. Clinical Impact of Delayed Graft Function by Donor Type<br />0.5<br />ECD DGF %<br />Yes Yes 5.3<br />Yes No 9.6<br />No Yes 19.4<br />No No 65.7<br />0.4<br />0.3<br />Hazards of Graft Failure<br />0.2<br />0.1<br />0.0<br />0<br />1<br />2<br />3<br />4<br />5<br />Years Post-Transplant<br />Source: UNOS/OPTN data as of April 29, 2011 <br />
  8. 8. 0<br /> 10<br /> 20<br /> 30<br /> 40<br /> 50<br /> 60<br /> 70<br /> 80<br /> 90<br />100<br />Continuous Variables<br />Peak PRA (%)<br />0<br />60<br />Duration Dialysis (days)<br />0<br />1000<br />2000<br />3000<br />4000<br />5000<br />6000<br />7000<br />8000<br />Duration Dialysis Squared<br />8000<br />7000<br />6000<br />5000<br />4000<br />3000<br />1000<br />Recipient BMI (kg/m2)<br />0<br />5<br />10<br />15<br />20<br />25<br />30<br />35<br />40<br />45<br />1<br />5<br />HLA Mismatch<br />0<br />4<br />CIT (hours)<br />0<br />5<br />10<br />15<br />20<br />25<br />30<br />35<br />40<br />45<br />WIT (minutes)<br />0<br />30<br />60<br />90<br />Donor Terminal Creatinine (mg/dL)<br />0<br />0.5<br />1<br />1.5<br />2<br />2.5<br />3<br />3.5<br />4<br />Donor Age (years)<br />0<br />10<br />25<br />40<br />55<br />Donor Weight (kg)<br />200<br />160<br />120<br />80<br />40<br />0<br />Donor Weight Squared<br />0<br />60<br />80<br />100<br />120<br />140<br />Comprehensive Risk Model to Predict Risk of DGF<br />Points<br />Points<br />Categorical Variables<br />6<br />Black Recipient<br />9<br />Male Recipient<br />5<br />Previous Transplant<br />8<br />Recipient Diabetes<br />6<br />Recipient Pre<br />-transplant Transfusion<br />27<br />Donation after Cardiac Death<br />6<br />Donor History of Hypertension<br />6<br />Donor Cause of Death<br />-Anoxia<br />6<br />Donor Cause of Death<br />-Cardiovascular<br />160<br />180<br />200<br />Total Points<br /> 0<br /> 50<br />100<br />150<br />200<br />250<br />300<br />350<br />Risk of DGF<br />0.10<br />0.20<br />0.50<br />0.70<br />0.90<br />Irish et al. Am J Transplant 2010;10(10):2279-2286<br />
  9. 9. Cold Ischemia Time and Probabilityof Delayed Graft Function<br />Slope = 0.0084 risk of DGF per 1 hr increase in CIT<br />Irish et al. Am J Transplant 2010;10(10):2279-2286<br />
  10. 10. Potential Role of Warm Ischemia Timeas a Risk Factor for DGF<br />Warm ischemic time associated with DCD transplants<br />*Time from circulatory arrest until start of cold perfusion and grouped by 10 minute intervals with <10 minutes as reference<br /># Adjusted for donor - and recipient characteristics and type of preservation method (machine perfusion versus static cold storage)<br />Jochmans et al. Ann Surg 2010; 252:756-764<br />
  11. 11. Kidney Preservation Modalities<br />Static Cold Storage1:<br />US: 80%<br />Eurotransplant: 100%<br />LifePort™ Kidney Transporter<br />for hypothermic machine perfusion<br />1Hartono C, Suthanthiran M Nat Rev Nephr 2009; 5:433-434<br />
  12. 12. Static Cold Storage<br />
  13. 13. Clinical Trials Comparing UW and HTK Solutionsin Deceased Donor Kidney Transplantation<br />de Boer et al. Transpll Int. 1999;12(6):447-53.<br />Klaus et al. Transplant Proc 2007; 39(2):353-54.<br />
  14. 14. Prolonged Cold Ischemia Time: UW versus HTK in Deceased Donor Kidney Transplantation<br />Roels et al. Transplantation. 1998; 66(12): 1660-64<br />Agarwal et al. Transplantation 2006; 81(3): 480-82<br />Lynch et al. Am J Transplant 2008; 8: 567-73<br />
  15. 15. Impact of HTK on Long-term Graft Survival Following Deceased Donor Kidney Transplantation<br />Stewart et al. Am J Transplant 2009; 9:1048-54<br />
  16. 16. What Does the Evidence Suggest?<br />Results are mixed: no clear evidence to discriminate either preservation method <br />Conflicting results, due in part, to:<br />Insufficient sample size<br />Non-randomized comparisons subject to:<br />Confounding by indication<br />Selection and reporting biases<br />Differential center-effects<br />Changing patient management practices<br />Prospective, randomized, adequately powered studies are still needed; especially in “at-risk” study populations (e.g., ECD, prolonged CIT)<br />
  17. 17. Machine Pulsatile Perfusion <br />Taylor and Baicu. Cryobiology 2010; 60(3S): S20-S35<br />Sung et al. Am J Transplant 2008; 8(Part 2): 922-34<br />
  18. 18. Influence of Machine Perfusion on Risk of DGF: Meta-analysis Results#<br />*Relative risk (MP vs. CS) of DGF (DerSimonian and Laird random effects model)<br /># Included studies in which kidney pairs were allocated between the two preservation methods<br />Wight et al Clin Transplant 2003; 17:293-307<br />
  19. 19. Clinical Trial Comparing Static versus Active Perfusion in Deceased Donor Kidney Transplantation<br />*Defined as the absence of a decrease in the serum creatinine level of at least 10% per day for at least 3 consecutive days<br />in the first week after transplantation. This category did not include patients in whom acute rejection, CNI toxicity, or both<br />developed in the first week.<br />Moers C et al N Engl J Med 2009; 360:7-19<br />
  20. 20. Impact of Machine Perfusion on Risk of DGF by Donor Risk Category<br />Moers C et al N Engl J Med 2009; 360:7-19<br />
  21. 21. Clinical Trial Comparing Static versus Active Perfusion in DCD Kidney Transplantation<br />Watson et al Am J Transplant 2010; 10:1991-1999<br />
  22. 22. Unanswered Questions<br />
  23. 23. Does Machine Perfusion Make a Difference Following DCD Only in Older Recipients?<br /><ul><li> OPTN database analysis; N=6,057 DCD recipients transplanted between 1993-2008
  24. 24. Mean follow up: 2.2±2.6 years</li></ul>Cantafio et al Clin Transplant 2011; DOI: 10.1111/j.1399-0012.2011.01477.x<br />
  25. 25. Does Preservation Modality Affect Outcomes Following Transplantation of ECD Kidneys?<br />UNOS database analysis of ECD kidneys transplanted between 2000 and 2003<br />Matsuoka Am J Transplant 2006; 6:1473-1478; <br />
  26. 26. Does Preservation Modality AffectLong-Term Graft Survival?<br />Results of a Meta-analysis<br /> MP CS<br />DBD<br />DCD<br />CS – cold storage; DBD – donation after brain death; DCD – donation after cardiac death; MP – machine perfusion <br />Wight et al Clin Transplant 2003; 17:293-307<br />
  27. 27. What About Cost-Effectiveness?<br /><ul><li> Modeling inputs based mostly on the European Machine Preservation Trial
  28. 28. Assumes a higher utilization of machine perfusion (80%) for ECD kidneys than for SCD kidneys (20%)
  29. 29. Cost drivers: DGF, dialysis, acquisition cost, transplant hospitalization, transplant maintenance
  30. 30. Primary clinical endpoint (utility) is graft survival at one-year post-transplant </li></ul>Garfield et al. Transplant Proceedings 2009; 41:3531-36<br />
  31. 31. Approaching Resolution<br />
  32. 32. Sources of Variability<br />Definitions of DGF1<br />Lack of a standardized definition<br />Dialysis-dependent: requirement within 7-10 days<br />Creatinine-dependent: increase/insufficient reduction within 3 days<br />Study design<br />Randomized vs. non-randomized comparison<br />Insufficient sample size<br />Center effects<br />Kidney discard rate<br />Staff resources and experience<br />Patient management strategies<br />Donor type<br />SCD vs. ECD<br />DBD vs. DCD<br />Organ treatment<br />Variable cold ischemia time<br />Warm ischemia time (sp. uncontrolled DCD) not adequately studied<br />Early exposure to calcineurin inhibitors<br />1Yarlagadda SG et al Nephrol Dial Transplant 2008; 23:2995-3003<br />
  33. 33. Accounting for Variability<br />How it: <br />Affects outcome <br />Choice of preservation modality<br />Type of donor organ <br />

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