1. Facing the Organ Shortage Crisis: Business as Usual vs Non- Conventional Solutions? Richard Perez MD Division of Transplant Surgery UC Davis Medical Center

2. Rationale for Transplantation Survival benefit vs dialysis Survival benefit vs dialysis Improvement in quality of life Improvement in quality of life Economic benefit to health care system Economic benefit to health care system

3. Merion, et al. JAMA 2005

4. Survival benefit with use of extended criteria donor kidneys Merion, et al. JAMA 2006

5. Our Goal To make transplantation a safe option for as many patients as possible

6. Patients waiting for kidney transplantation on October 2, 2013 97,916

7. A National Crisis Waiting list growing – 97,916 today Transplant rate flat – 16,000+/yr x 8yrs

8. Transplantation - A victim of its own success: UC Davis waiting list 200520002010 SRTR July 2012 California kidney wait list 18,219

9. UC Davis Kidney Transplantation More transplants but the donor gap widens

10. Clinical J American Society of Nephrology 2009

11. Crisis Response Business as usual vs non-conventional solutions?

12. Deceased Donor Transplantation Making the most of every opportunity

13. Organ preservation method matters Machine preservation may increase availability of organs for transplantation vs

14. Hypothermic Pulsatile Pump Preservation: Rationale – Hypothermic conditions with decreased metabolism – Simulates normal circulation – Continuous provision of micro-nutrients – Removal of toxic waste products and free radicals – Pulsatile flow stimulates endothelial expression of vasoprotective genes

15. Pulsatile Pump Preservation Rationale for initiation of pump preservation – Improved early allograft function – Lower DGF rates – Able to exclude kidneys at high risk for primary non- function – Particularly important in ECD and DCD kidneys – Shorter hospital stay?

16. Improved graft survival with machine perfusion Moers, et al. N Engl J Med 2012

17. Question How does pulsatile perfusion preservation impact long term Extended Criteria Donor allograft survival? American Transplant Congress 2009

18. Machine preservation improves survival of extended criteria donor kidneys Patients at risk: PP 60 45 30 20 16 CS 31 21 13 9 9 Pulsatile Perfusion Cold Storage American Transplant Congress 2009

19. University of California, Davis Kidney and Pancreas Transplant Program Options for Expanding the Deceased Donor Pool Expanded Criteria Donors (ECD) Donation after Circulatory Death (DCD) Pediatric en-bloc kidneys (peds-en-bloc) Dual Adult Kidneys Donors with Acute Kidney Injury (AKI) HCV positive donors Hepatitis B core Ab positive donors

20. Making more organs available: Extended Criteria Donors Age > 60 years old Or Age 50 -60 years old + 2 factors below: 1.Death by stroke 2.History of hypertension 3.High serum creatinine

21. General evaluation of kidneys from extended criteria donors All organ offers evaluated by txp surgeon All organ offers evaluated by txp surgeon History History – General health maintenance, lifestyle – Presence of co-morbidities – History of tobacco use Inspection of organs at time of procurement Inspection of organs at time of procurement Biopsy results Biopsy results Pump flow and resistance Pump flow and resistance

22. Selection of appropriate recipients of ECD or “non- conventional” kidneys Wait list management important to maintain a pool of patients eligible for ECD kidneys Wait list management important to maintain a pool of patients eligible for ECD kidneys Ensure appropriate patients in all blood groups Ensure appropriate patients in all blood groups For certain kidneys with limited renal mass consider allocation of organ to patients with: For certain kidneys with limited renal mass consider allocation of organ to patients with: – Presumed lower metabolic needs Older age group Older age group Low BMI Low BMI – Low immunologic risk Primary transplants Primary transplants Non-sensitized patients Non-sensitized patients

23. Extended Criteria vs Standard Criteria Donors: 2006-2011 SCD(n = 344) ECD (n = 133) p = 0.012; Log rank test 84% 76% SCD = Standard Criteria Donor ECD = Expanded Criteria Donor

24. Dual Transplantation of ECD Kidneys Offered to patients who will accept ECD kidneys Donor > 55 yo Creat Cl 50 – 90 ml/min Must be able to tolerate longer surgical procedure Standard immunosuppresion protocol

25. Dual kidney transplantation with single arterial and venous anastomoses D Nghiem, J Urol 2006 Ex vivo vascular reconstruction prior to transplantation

26. Dual adult donation equivalent to standard criteria donation UCD graft survival (1996-2010) 1 2 3 4 5 SCD (n = 469) ECD (n = 101) Dual-ECD (n = 15) p = 0.009, log-rank test

27. Hepatitis B Core Ab+ Kidneys – Informed consent at time of listing – Offered to patients are immunized (HbsAb+) – All HbcAb+ donors are tested for viremia (HBV DNA by PCR) – Recipient prophylactic antiviral treatment: Hepatitis B Immune Globulin pre-transplant. Hepatitis B Immune Globulin pre-transplant. Entecavir starting POD 1 Entecavir starting POD 1 – Continuation of Entecavir depends on results of donor HBV DNA and recipient quantitative HBsAb titer

28. Deceased Donors with Acute Kidney Injury

29. Deceased Donors with AKI: UC Davis Experience AKI group: n= 83 AKI group: n= 83 Control group: n= 620 Control group: n= 620 Outcome measures: Outcome measures: - rate of DGF (dialysis during 1 st week post-txp) - rate of DGF (dialysis during 1 st week post-txp) - renal allograft function - renal allograft function - acute rejection in the first year post-transplant - acute rejection in the first year post-transplant - patient and graft survival - patient and graft survival Santhanakrishnan, et al. Amer Transplant Congress 2013

30. Donor Demographics 2005-2012 AKI (n = 83)No-AKI (n=620) p value Donor age (years) 42 ± 14.440 ± 16.40.18 Cold ischemic time (hours) 23.6 ± 7.4619.8 ± 9.81<0.001 Donor Terminal Creat (mg/dl) 3.2 ± 1.370.98 ± 0.39<0.001 Donor e-GFR (mg/min) 26 ± 9.3105 ± 79.3<0.001 Expanded Criteria Donor (%) 26.518.40.08 Imported graft (%) 7638<0.001 Donation Circulatory Death (%) 3.5180.005 Santhanakrishnan, et al. Amer Transplant Congress 2013

31. Recipients of AKI kidneys were older and less sensitized AKI (n = 83)No-AKI (n = 620)p value Recipient age (years) 57 ± 13.654 ± 12.80.024 Years on dialysis (mean ± SD) 3.8 ± 3.113.8 ± 2.740.9 PRA at Transplant (%) 7 ± 20.417 ± 30<0.001 Santhanakrishnan, et al. Amer Transplant Congress 2013

32. More Delayed Graft Function in Recipients of Kidneys with Acute Injury AKI (n = 83)No-AKI (n = 620) p value Delayed Graft Function30 (36%)124 (20%)0.001 Graft Failure within 90 days2 (2.4%)28 (4.5%)0.6 Recipient Death - 90 days0 (0%)10 (1.6%)0.6 Acute Rejection within 1 st yr3 (3.6%)33 (5.3%)0.79 Santhanakrishnan, et al. Amer Transplant Congress 2013

33. Excellent survival of allografts with acute renal injury Donors with AKI (n = 83) Donors without AKI (n = 620) P = 0.38; Log rank test 1 year graft survival was 95.9% (AKI) vs 93.3% (control) p = 0.38 Santhanakrishnan, et al. Amer Transplant Congress 2013

34. Excellent patient survival of allografts with acute kidney injury vs donors with normal function Donors with AKI (n = 83) Donors without AKI (n = 620) P = 0.68; Log rank test Pt survival at 1 yr – 98.2 (AKI) vs 96.4% Pt survival at 3 yr – 89.9% (AKI) vs 92.1% Santhanakrishnan, et al. Amer Transplant Congress 2013

35. Slower recovery of AKI kidneys e-GFR (ml/min) 7 days 30 days 90 days 1 year 2 years AKI (n = 83) No-AKI (n = 608) p<.001 p=.7 p=.017 p=.03 p=.4 Santhanakrishnan, et al. Amer Transplant Congress 2013

36. Kidneys from Small Pediatric Donors

37. Study Patient Cohort Recipients of deceased donor kidneys from small pediatric donors (<20kg) from June 2007 to November 2012 Recipients of deceased donor kidneys from small pediatric donors (<20kg) from June 2007 to November 2012

38. Results 146 patients received kidneys from donors <20kg 146 patients received kidneys from donors <20kg 89% imported from distant OPOs 89% imported from distant OPOs 88% transplanted en bloc 88% transplanted en bloc 55% donors age <6 months old 55% donors age <6 months old 35% donors weighed <5kg 35% donors weighed <5kg 34% donors after circulatory death 34% donors after circulatory death

39. Graft survival of kidneys from small pediatric donors 93% 89% Patients 76 36 24

40. Addressing the organ shortage crisis: Importing kidneys that require further assessment UC Davis Region 5 U.S. Transplant rate 21%*10%12% Imported kidneys 64.4%24.6%21.8% Dialysis in 1 st week 21.2%27.8%23.6% Waitlist mortality 3.0%*5.0%6.0% Graft survival (1 yr) 92.86%92.04% SRTR July 2012

41. University of California, Davis Kidney and Pancreas Transplant Program Demographic Data II Year of Transplantation Total # of DDTx # of NCDTx% of NCDTx 200549714% 2006702029% 2007773647% 2008793747% 2009975355% 20101298163% 201121314367% 2012 (partial)14210775% Total85648457% p < 0.001, Chi-squared test

42. University of California, Davis Kidney and Pancreas Transplant Program Demographic Data: 1/2005-7/2012 Non-Conventional Deceased Donors n% of total DDTx % of NCDDTx Expanded Criteria Donors15118%31% Donors with Circulatory Death15118%31% Pediatric en-bloc donors11513%24% Dual-kidney adult donors192%4% Donors with Acute Kidney Injury12014%25% HCV Donors223%4.5% HBcAb positive Donors647.5%13% Total48457%*>100% due to dual classification

43. University of California, Davis Kidney and Pancreas Transplant Program Delayed Graft and 90 Day Complications NDGF90 Day Graft Failure 90 Day Surgical Complications SCD4121.0 (reference) ECD1512.7 (1.73-4.29) 2.2 (0.98-5.08) 1.4 (0.85 -2.22) DCD1033.4 (2.07-5.62) 2.2 (0.87-5.76) 1.3 (0.71-2.21) Peds-en- bloc 1141.7 (0.98-2.87) 1.7 (0.63-4.59) 1.7 (1.03-2.86) AKI753.3 (1.90-5.80) 0.8 (0.19-3.80) 0.7 (0.30-1.44) Hazard Ratio (95% Confidence Interval)

44. University of California, Davis Kidney and Pancreas Transplant Program Patient and Graft Survival, 3 yr eGFR *p-value is for eGFR for group vs SCD

45. University of California, Davis Kidney and Pancreas Transplant Program Graft Survival 2005 – 2012 by Type of Donor Living Donors (n = 366) DCD (n = 103) Pediatric en-bloc (n = 114) SCD (n = 412) ECD (n = 151) p < 0.001, log-rank test for trend (ECD) SCD/AKI (n = 75)

46. University of California, Davis Kidney and Pancreas Transplant Program Estimated-GFR by Type of Deceased-Donor e-GFR (ml/min) 7 days 30 days 90 days 1 year 2 years NCD (n = 484) Conv (n = 372) 3 years p<.001 p=.04 p=.2 p=.9 437 vs 404 165 vs 249 111 vs 194 426 vs 392 291 vs 338 429 vs 398

47. University of California, Davis Kidney and Pancreas Transplant Program Conclusions 1.The use of non-conventional donors (NCDD) is a viable option for expanding the deceased donor pool 2.Delayed graft function or slow graft function is more common with NCDD 3.Surgical complications are greater at 90 days with the pediatric en bloc 4.The long term outcome with NCDD transplants is comparable to SCD outcomes at 3 years.

48. New technologies for deceased donor transplantation?

51. Normothermic perfusion for organ preservation/pre-conditioning Maintain body temperature Maintain body temperature Oxygenation Oxygenation Support aerobic metabolism Support aerobic metabolism Normal physiologic function Normal physiologic function Advantages Advantages – Restore ATP (energy source) – Regeneration and repair processes initiated – Able to assess organ function – Minimize cold ischemia injury

52. Hosgood / Nicholson, Transplantation 2011

53. Normothermic Machine Perfusion: “ECMO for the kidney”

54. Normothermic Perfusion: Future Directions Routine assessment of high risk/marginal organs Routine assessment of high risk/marginal organs Normothermic perfusion as a means to intervene and optimize organ function pre-transplant Normothermic perfusion as a means to intervene and optimize organ function pre-transplant – Pharmacologic – Gene therapy – Stem cells Development of “Organ Repair Centers” Development of “Organ Repair Centers”

55. The Future of Transplantation: Organ Assessment at Regional Repair Centers ♦ ♦ ♦ ♦ - Donor Hospitals UC Davis ♦ ♦ ♦♦ ♦ ♦ ♦ - Organ Repair Center ♦

56. The Future of Transplantation: Organ Reconditioning at Regional Repair Centers ♦ ♦ ♦ ♦ ♦♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ - Transplant Center UC Davis - Organ Repair Center

57. Normothermic kidney perfusion at UC Davis! April 18, 2013

58. Making the most of every opportunity in deceased donor transplantation Why? – There is a survival advantage with deceased donor renal transplantation – Improvement in quality of life

59. Going the extra mile! In the face of the organ shortage crisis, we cannot continue in “business as usual” mode In the face of the organ shortage crisis, we cannot continue in “business as usual” mode Expansion of donor pool by identifying new organ sources Expansion of donor pool by identifying new organ sources “Non-conventional” organ sources “Non-conventional” organ sources – More resources necessary up front – Slower recovery of the kidney and management of patient expectations Newer technologies needed Newer technologies needed