1. HLA for renal allocation in the modern immunosuppressive era Jose M. Morales Hospital 12 de Octubre Madrid (Spain) Buenos Aires 29 Nov 2011 2011 ORGAN DONATION CONGRESS

3. Renal transplantation from living vs deceased donors UNOS DATA

4. 67 51 Cecka, Clinical Transplants 2004 (p.2) Graft Survival by Donor Source (1999-2003) Years Posttransplant Percent Graft Survival 10 100 0 1 2 3 4 5 6 7 8 9 10 80 60 20 40 n t1/2 LD 17.8 28,260 SCD 10.8 33,118 ECD 5,943 6.8 Donor p<0.001 33

5. First cadaver renal transplants 1986-1996 P< .0001 Transplant Proc 1999; 31: 717-720

6. First cadaver kidney transplants (1986-1996) p>.0001 Transplant Proc 1999; 31: 717-720

7. HLA matching improved patient survival after transplantation from cadaveric donors

8. Influence of HLA matching and cold ischemia time on graft survival G Opelz, TP 1999

9. Effect of HLA matching on outcome of first kidney transplantation in black recipients G Opelz, TP 1999

10. UNOS point system for allocation of deceased donor kidneys (2009) Danovitch, 2010 ECD longest waiting patient 4 Organ donor Pediatric recipient priority for donors younger than 35 yr +80% PAR and Neg CM 4 PAR Zero DR MM One DR MM 2 1 Quality of HLA match 0-a, B, DR mismatch 1 for each yr Of waiting time Time waiting CONDITION POINTS FACTOR

12. Retransplantation and HLA matching

14. Conclusions. DR matching is critically important in kidney retransplantation. There was no significant difference in survival of zero ABDR mismatched retransplants compared with one to four AB and zero DR mismatched retransplants. On the other hand, kidney graftsurvival of all one to four AB and zero DR mismatches Exceed ed that of one or two DR mismatched retransplants. We propose that the association of decreasing regraft survival with increasing PRA reflects undetected sensitization to class II, and possibly class I, antigens.

16. Transplantation 2007;84: 722–728

19. SUPERVIVENCIA RETRASPLANTES POR ÉPOCAS - EUROPA Retransplantation improved with new immunosupresive drugs

21. Patient Survival for Patients With a Functioning Graft and After Graft Loss Adjusted Patient Survival (%) Time Since Transplant/Graft Loss (months) 100 90 80 70 60 50 40 30 0 12 24 36 48 60 72 84 96 108 120 Meier-Kriesche H-U et al. Am J Transplant. 2003. Patients with transplant Patients after return to dialysis

24. Mortality rates relevant for donation and Deceased Donors per cause of death in Spain

25. Deceased Donor age in Spain

26. Transplants & Waiting list for kidney and liver in Europe* along time (Newsletter Transplant) *EuroTx, France, ScandiaTx, Spain, United Kingdom, 1989 1994 2001 2009 1989 1994 2001 2009 KIDNEY LIVER 928 patients dead while on the liver WL in 2009

27. Improvements in acute rejection and graft survival are associated with more efficient immunosuppression Acute rejection/Graft survival rates (%) 100 80 60 40 20 0 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 Year of transplantation 1yr graft survival Acute rejection Azathioprine Antilymphocyte Antibodies Prednisone Radiation Cyclosporine Tacrolimus Mycophenolate mofetil Rapamycine Thymoglobuline Daclizumab Basiliximab 95% 10% Graft Survival Acute Rejection Courtesy Dr H Ekberg

29. 12.5 21.8 Long-term Graft Survival Improvements Half-life (years): Europe

30. Patient and graft projected half life in Spain 1990-1998 Serón, Arias, Campistol, Morales et al.Transplantation 2003;76:1588 Long-term results improved is spite of an increase of donor age and poor HLA matching (3.4 mean MM). Why?  Acute rejection New immunosuppressive drugs  VHC statins? a 1994 or 1998 vs 1990, p<0.05. b 1998 vs 1994, p<0.05

31. In spite of a minor HLA compatibility Transplant Int 2010

33. Graft and patient survival according recipient age at 5 years (2600 from Spain 2000-2002) 95% received S+CNI+ MMF 88% 84.2% 79.1% (death censored) (death not censored) 97% 91% 78% Morales et al, ESOT Congress Glasgow 2011 Patient survival Graft survival 64.7% 80.3% 82.1%

35. AJKD 2008;52:553-586 Graft Survival Country, n Donor age, years of GS, % Morris 1999 UK, 6363 >60 5a 44% vs 18-39 68% Miranda 2003 Spain (Cat), 4008 60-69 5a 57% vs 40-49 76% >69 5a 50% Oppenheimer 2004 Spain (1 año funcionando), 3365 RR Graft loss 61-70 2.89 ; >70 4.19 (RR 1 si <20 a) Andreoni 2007 USA ECD 5a 53% vs SCD 5 a 70% Miles 2007 USA, 2908 retrasplantes No más supervivencia con reTR que siguiendo en lista si el reTR es con ECD Leichtman 2008 USA ECD 5a 55.1% vs SCD 5 a 70%

36. Projected half-life: standard renal transplantatation vs ECD vs waiting list Age group UNOS 2002 years

37. Mortality RR* for 23,275 first cadaveric transplant versus 46,164 wait-listed (WL) dialysis patients * Adjusted for age, sex, race, end-stage renal disease (ESRD) cause, WL year, region and time to WL 0 106 183 244 365 548 0.32 2.84 Equal risk Equal survival Transplant WL dialysis = reference Days since transplantation (equal time since WL) Relative risk (RR) 1 Wolfe RA, et al. N Engl J Med 1999;341:1725–30

38. Old for old Meier-Kriesche HU et al. AJT 2005; 5: 1725. Posttransplant years Donor age <50

39. Transplant Proc 2009; 41: 2376-2378 Transplantation better survival than WL/HD

42. Prospective Age-Matching in Elderly Kidney Transplant Recipients—A 5-Year Analysis of the Eurotransplant Senior Program 1. The ESP age matching of elderly donors and recipients is an effective organ allocation system for the use of organs from elderly donors. 2. The principles of decreasing the importance of HLA matching and emphasizing shorter CIT may be a promising option for other regional and national kidney allocation systems to increase the utilization of kidneys that would otherwise be at risk of being discarded. 3. Graft and patient survival were not negatively affected by the ESP allocation when compared to the standard allocation. Frei U.et al. Am J Transplant 2008; 8: 50-57

43. Dual transplantation from older donors Diaz Gonzalez R

47. Irreversible Cardiac Arrest Occurring on the Street: A Source of Transplantable Kidneys Sánchez Fructuoso et al, Ann Internal Med 2006 BD (donor < 60 y) N=458 BD (donor  60 y) N=126 Uncontroled NHBD N=320 p Donor age 35.4 ± 14.2 65.4 ± 4.6 36.4 ± 11.5 <0.001 Donor Sex (%M) 64.3 54.0 88.1 <0.001 Recipient age 47.0 ± 13.1 55.1 ± 11.6 48.8 ± 13.6 <0.001 Recipient sex (%M) 63.5 63.5 61.9 0.89 HLA matching 1.83 ± 1.04 1.90 ± 1.13 1.45 ± 1.07 <0.001 PRA 6.0 ± 17.3 5.5 ± 15.0 5.3 ± 17.2 0.84 % Retransplants 14.2 13.5 14.4 0.97 Cold ischemia 18.7 ± 5.5 19.5 ± 5.7 17.7 ± 3.5 0.001

48. GRAFT SURVIVAL BD (donor < 60 y.) NHBD p=0.0006 BD < 60 y vs BD>=60 p=0.0001 BD < 60 y vs NHBD p=ns NHBD vs BD >=60 p=0.014 BD (donor >= 60 y.) months Cum. survival Sanchez-Fructuoso et al, Ann Intern Med 2006

50. Non-Heart Beating Donors N 67% 77 108 130 12 64 55 81 87 35 88 35 43 36 32 32 18 51 55 71 71 76 58 50 55 8 47 46 16 20 18 23 19 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Total Spain Community of Madrid

51. NON-HEART BEATING DONATION PROGRAMS SUMMA 112-E.SESCAM-HOSPITAL 12 DE OCTUBRE Transfer by helicopter and by ambulance Transfer by Helicopter only

52. Outcomes of kidney transplant with non-heart beating donors who died in the street or at home (31/12/2010 ) NON-HEART BEATING DONOR GROUP N=151 DBD DONOR CONTROL GROUP N=93 p HLA Incompatibilities 4.4 ± 1.2 (1-6) 2.2 ± 1.6 (0-6) 0.001 Cold Ischemia Time (hours) 12.7 ± 5.7 (3-28) 16 ± 6.9 (2.6-30) 0.001 Primary non-function 13/151 (8.6%) 2/93 (2.2%) 0.04 Immediate kidney function 23/151 (15.2%) 40/93 (43%) 0.001 Delayed graft function 128/151 (84.8%) 53/93 (57%) 0.001 Number of HD 3 ± 2.6 (0-9) 2.1 ± 2.8 (0-14) 0.02 Days until onset of decrease of SCr 13.9 ± 6.7 (0-38) 8.2 ± 7.6 (1-41) 0.001