1. Eurotransplant- Principles of Organ Allocation Dr. Axel Rahmel Medical Director Eurotransplant International Foundation Meeting with Representatives from the Ministry of Health and the Republic Expert Commissions Belgrade, Serbia – 10.08.2009

2. The key problem in organ transplantation in Europe is organ shortage…

3. Kidney waiting list and transplants Eurotransplant 1969 - 2007 11308 3703 1032

4. Each day, 9 European citizens die whilst waiting for a suitable organ transplant* *3.262 deaths on the waiting list in 2007, Council of Europe data 2008 Grim facts…

5. ...and organ donation rates are not equally distributed over Europe

6. > 20 15-20 10-15 < 10 Donors pmp Council of Europe; Newsletter Transplant, Vol.13 No. 1, September 2008

7. PMP Organ donation – Eurotransplant and Republic of Serbia - 2008

8. WHO GUIDING PRINCIPLES ON HUMAN CELL, TISSUE AND ORGAN TRANSPLANTATION Guiding Principle 9 Where donation rates do not meet clinical demand, allocation criteria should be defined at national or subregional level by a committee that includes experts in the relevant medical specialties, bioethics and public health…Where donation rates do not meet clinical demand, allocation criteria should be defined at national or subregional level by a committee that includes experts in the relevant medical specialties, bioethics and public health…

9. WHO GUIDING PRINCIPLES ON HUMAN CELL, TISSUE AND ORGAN TRANSPLANTATION Guiding Principle 9 The allocation of organs, cells and tissues should be guided by clinical criteria and ethical norms, not financial or other considerations.The allocation of organs, cells and tissues should be guided by clinical criteria and ethical norms, not financial or other considerations. Allocation rules, defined by appropriately constituted committees, should be equitable, externally justified, and transparent.Allocation rules, defined by appropriately constituted committees, should be equitable, externally justified, and transparent.

10. Allocation principles

11. Organ allocation principles Equity: every patient the same chanceEquity: every patient the same chance Queuing: longest waiting firstQueuing: longest waiting first Utility: best post-Tx outcome firstUtility: best post-Tx outcome first Need: sickest patient firstNeed: sickest patient first Net benefit: balancing urgency and outcomeNet benefit: balancing urgency and outcome

12. Organ allocation principles Equity: every patient the same chanceEquity: every patient the same chance Sense of fairness or impartialitySense of fairness or impartiality Lack of bias or discriminationLack of bias or discrimination Queuing: longest waiting firstQueuing: longest waiting first Need/urgency: sickest patient firstNeed/urgency: sickest patient first Utility: best post-Tx outcome firstUtility: best post-Tx outcome first Net benefit: balancing urgency and outcomeNet benefit: balancing urgency and outcome Lottery Equal/similar patients have to be treated equal/similar

13. Equity: every patient the same chanceEquity: every patient the same chance Queuing: longest waiting firstQueuing: longest waiting first Waiting time is easy to understandWaiting time is easy to understand “first come first served” is a fair way to do things“first come first served” is a fair way to do things Need/urgency: sickest patient firstNeed/urgency: sickest patient first Utility: best post-Tx outcome firstUtility: best post-Tx outcome first Net benefit: balancing urgency and outcomeNet benefit: balancing urgency and outcome Organ allocation principles

14. Important factors in allocation Public opinion Important factors in allocation Public opinion No priority Gender (95%)Gender (95%) Income (97%)Income (97%) Employment status (95%)Employment status (95%) Profession (92%)Profession (92%) High priority Waiting time (87%)Waiting time (87%) Post-tx outcome (79%)Post-tx outcome (79%) Young age (66%)Young age (66%) Parental status (56%)Parental status (56%) Social Science and Medicine 2001; 52:853-861

15. Queuing: longest waiting first Emergency department ?

16. Urgency vs. outcome in allocation The „net-benefit“-concept Need/urgency: sickest patient firstNeed/urgency: sickest patient first Direct organs to those most in need, i.e. most at risk of death without a transplant (medical urgency) Utility: patient with best outcome firstUtility: patient with best outcome first Transplanting patients who will not survive is a waste of a limited resourceTransplanting patients who will not survive is a waste of a limited resource Net benefit-concept: Balancing urgency and outcome in allocationNet benefit-concept: Balancing urgency and outcome in allocation Urgency Outcome

17. Balancing urgency and outcome “Transplant window“-concept -> Increasing organ failure -> Mortality Med. Therapy Transplantation benefit “too early” “too late” “Transplantation window”

18. Organ exchange between the European Organ Exchange Organizations (EOEO)

19. Scandiatransplant UK Transplant AdB, France Swiss Transplant Lusotransplante ONT, Spain EurotransplantBalttransplantPoltransplantCzechtransplantHungarotransplant CNT, Italy HNTO, Greece European organ exchange organizations (EOEO)

20. 596 6 OEOs, by number of deceased donor transplants in 2003

21. Organ allocation Offering to other Organ Exchange Organizations Allocation within the own country / Organ Exchange Organization No suitable recipient within own country/OEO

22. Origin of donor organs transplanted in ET 01.01.2001 – 31.12.2005

23. Organ offers from other OEO‘s to ET Kidney transplantation 2001-2005 (n = 207)

24. Principles of organ exchange between EOEOs Organ exchange between European OEO‘s is mainly „donor-driven“:Organ exchange between European OEO‘s is mainly „donor-driven“: Donor organ exchange only if no suitable recipient for this donor is available in donor countryDonor organ exchange only if no suitable recipient for this donor is available in donor country Difficult to allocate donorDifficult to allocate donor Extended criteria donor (ECD)Extended criteria donor (ECD) Rare blood group, size or ageRare blood group, size or age -> Reduction of loss of donor organs-> Reduction of loss of donor organs -> No balancing of exchanged donor organs-> No balancing of exchanged donor organs Main benefit for countries/EOEOs withMain benefit for countries/EOEOs with Large waiting listLarge waiting list Liberal organ acceptance policyLiberal organ acceptance policy

25. Principles of organ exchange within ET Organ exchange within the Eurotransplant area is also „recipient driven“:Organ exchange within the Eurotransplant area is also „recipient driven“: Donor organ exchange for special patient groups and medical reasonsDonor organ exchange for special patient groups and medical reasons High urgent patientsHigh urgent patients Immunized patientsImmunized patients Pediatric patients etc.Pediatric patients etc. -> Supports special patient groups / improves outcome-> Supports special patient groups / improves outcome -> Optimization of donor organ usage-> Optimization of donor organ usage

26. Origin of donor organs transplanted in ET 01.01.2001 – 31.12.2005

27. Principles of organ exchange within ET Solidarity principle between Eurotransplant member countriesSolidarity principle between Eurotransplant member countries Exchange when medically indicatedExchange when medically indicated National, regional or local allocation when possible and/or medically indicated (short ischemic time)National, regional or local allocation when possible and/or medically indicated (short ischemic time) ET Senior programET Senior program Extended criteria donor organsExtended criteria donor organs National balancing mechanismsNational balancing mechanisms

28. Kidney allocation

29. Kidney waiting list and transplants Eurotransplant 1969 - 2007 11308 3703 1032

30. ET Organ allocation - renal Highly immunized - Acceptable Mismatch (AM) - Program Zero Mismatch (“full house”) ETKAS Point Score System (including HU) A Pediatric Donor (< 10 a) to Pediatric Recipient (< 6 a) when HLA-DR-identical Eurotransplant Senior Program (ESP) B/LDHRNLSLO

31. ET Organ allocation - renal Highly immunized - Acceptable Mismatch (AM) - Program Zero Mismatch (“full house”) ETKAS Point Score System (including HU) A Pediatric Donor (< 10 a) to Pediatric Recipient (< 6 a) when HLA-DR-identical Eurotransplant Senior Program (ESP) B/LDHRNLSLO

32. Chance of every new highly sensitized patient to receive a suitable crossmatch negative organ within 12 months (real life data) Offer [%] Standard allocation AM

33. Claas et al. Transplantation, 2004

34. ET Organ allocation - renal Highly immunized - Acceptable Mismatch (AM) - Program Zero Mismatch (“full house”) ETKAS Point Score System (including HU) A Pediatric Donor (< 10 a) to Pediatric Recipient (< 6 a) when HLA-DR-identical Eurotransplant Senior Program (ESP) B/LDHRNLSLO

35. Role of HLA-matching for graft survival after kidney transplantation CTS Newsletter 2004:1 6.2 yrs. difference

36. Influence of HLA-A,B,DR matching for primary transplant on subsequent sensitization (CDC) %

37. 100%10073total 0,4%446 2,4 % 2445 10,5 % 10554 30,2%30433 26,6 % 26792 8321 2176 0 Percentage No. of transplantations No. of mismatches HLA-matching in kidney transplantation ET 2000-2004, non-ESP patients 8,3 % 21,6 %

38. ET Organ allocation - renal Highly immunized - Acceptable Mismatch (AM) - Program Zero Mismatch (“full house”) ETKAS Point Score System (including HU) A Pediatric Donor (< 10 a) to Pediatric Recipient (< 6 a) when HLA-DR-identical Eurotransplant Senior Program (ESP) B/LDHRNLSLO

39. ETKAS - Pediatric allocation factors

40. Probability of receiving a kidney transplant ET, Registration WL 01.01.1999 – 31.12.2000 Waiting time (yrs) Recipient age

41. Mortality on the kidney waiting list ET, Registration WL 01.01.1999 – 31.12.2000 Recipient age

42. ET Organ allocation - renal Highly immunized Acceptable Mismatch (AM) - Program Zero Mismatch (“full house”) ETKAS Point Score System (including HU) A Pediatric Donor (< 10 a) to Pediatric Recipient (< 6 a) when HLA-DR-identical Eurotransplant Senior Program (ESP) B/LDHRNLSLO

43. Development in organ donation for different donor age groups Reported kidney donors, Eurotransplant, 2000-2006 Donor age groups Number of donors (in relation to 2000)

44. Eurotransplant Senior Program (ESP) Rationale HLA-matching probably less important in older recipientsHLA-matching probably less important in older recipients Reduced risk of repeated re-transplantationReduced risk of repeated re-transplantation Older patients might be less prone to rejection after transplantationOlder patients might be less prone to rejection after transplantation Short ischemic time might reduce risk of graft loss from older donorsShort ischemic time might reduce risk of graft loss from older donors For older recipients shorter waiting time might be especially importantFor older recipients shorter waiting time might be especially important

45. Eurotransplant Senior Program (ESP) Practical implementation Priority allocation for kidneys from donors over age 65 years to recipients over age 65 years -> “old for old” programPriority allocation for kidneys from donors over age 65 years to recipients over age 65 years -> “old for old” program First transplantFirst transplant No HLA-matchingNo HLA-matching Regional allocationRegional allocation Short ischemic timeShort ischemic time

46. Kidney discard rate by donor age: US vs. Eurotransplant 0 10 20 30 40 50 60 39185055606566+ Donor Age Percent Discarded Eurotransplant US

47. Patient survival for ESP patients vs. control Eurotransplant, 1999-2004 Frei et al.. AJT 2007; 7:1-8 = ETKAS 60-64 y

48. ET organ allocation - renal Highly immunized - Acceptable Mismatch (AM) - Program Zero Mismatch (“full house”) ETKAS Point Score System (including HU) A Pediatric Donor (< 10 a) to Pediatric Recipient (< 6 a) when HLA-DR-identical Eurotransplant Senior Program (ESP) B/LDHRNLSLO

49. ETKAS allocation factors

50. International organ exchange in kidney transplantation Impact for selected patient groups Eurotransplant 01.01.2002 -31.12.2006

51. Impact of kidney organ exchange on special patient groups Belgium, 01.01.2001 - 31.12.2005

52. Non-renal organs

53. Organ allocation International HU (Accepted) Combined Organs Elective Other Organ Exchange Organizations National HU Eurotransplant

54. Liver allocation

55. Liver waiting list and transplants Eurotransplant 1995 – 2008 2442

56. ET Organ allocation – Liver International HU Accepted combined organs (ACO) Elective (labMELD) A, SlG, CrNLB Elective center- oriented allocation Elective MatchMELD (labMELD SE, NSE) Elective MatchMELD (labMELD SE, (NSE)) Elective MatchMELD (labMELD SE, NSE) PediatricMELD

57. n=201 (16%)n=1053 (84%) Waiting time HU liver-transplant First HU liver-tx [n=1254] Pediatric (<16 yrs) Adult (16+ yrs) Median waiting time: 2 d (both groups)

58. Probability of dying on the liver waiting list or removal due to clinical deterioration Elective liver-tx candidates, ET Jan 2002 – Jun 2009 Probability of dying on the liver waiting list or removal due to clinical deterioration Elective liver-tx candidates, ET Jan 2002 – Jun 2009

59. Thoracic organ allocation

60. Heart waiting list and transplants Eurotransplant 1995 - 2007 959

61. Lung waiting list and transplants Eurotransplant 1995 - 2007 856

62. Thoracic allocation rules Eurotransplant Three active urgency groupsThree active urgency groups High urgentHigh urgent UrgentUrgent Transplantable = electiveTransplantable = elective Uniform „international“ HU-rules + separate national HU-rulesUniform „international“ HU-rules + separate national HU-rules Organ exchange with national balancing within different urgency tiersOrgan exchange with national balancing within different urgency tiers

63. New member countries - Prerequisites

64. Legal prerequisites for new ET member countries Non-commercialization of organ donationNon-commercialization of organ donation Brain death definition and diagnostic proceduresBrain death definition and diagnostic procedures Accreditation of transplant centersAccreditation of transplant centers Data safety and protection principles / legislationData safety and protection principles / legislation Collection and delivery of transplant follow-up data to improve organ allocationCollection and delivery of transplant follow-up data to improve organ allocation Legislation allowing organ exchange with ET partner countries based on commonly agreed ET allocation principlesLegislation allowing organ exchange with ET partner countries based on commonly agreed ET allocation principles Adherence to EU standards on organ transplantation (EU directive)Adherence to EU standards on organ transplantation (EU directive)

65. Logistical prerequisites for new ET member countries 24/7 duty for organ procurement, organ offering and HLA-typing and cross-matching24/7 duty for organ procurement, organ offering and HLA-typing and cross-matching Clearly defined contact persons for ETClearly defined contact persons for ET Official language inside ET is EnglishOfficial language inside ET is English Reporting of all donors to EurotransplantReporting of all donors to Eurotransplant Standardized transport logisticsStandardized transport logistics Donor organsDonor organs HLA seraHLA sera Defined responsibilities and contact institutions for financial settlementsDefined responsibilities and contact institutions for financial settlements Registration and procurement costsRegistration and procurement costs

66. Medical prerequisites for new ET member countries Standardized and qualifiedStandardized and qualified Brain death definition and diagnostic proceduresBrain death definition and diagnostic procedures Donor evaluation and pretreatmentDonor evaluation and pretreatment Donor organ explantation by experienced teamsDonor organ explantation by experienced teams Donor organ packing and transportationDonor organ packing and transportation Accreditation of HLA-laboratory by European Foundation for Immunogenetics (EFI)Accreditation of HLA-laboratory by European Foundation for Immunogenetics (EFI)

67. PMP Organ donation – Eurotransplant and Republic of Serbia - 2008 Reducing the gap

68. Integration of Croatia into Eurotransplant

69. Cooperation ET – Croatia Stepwise Approach Partial membership for one yearPartial membership for one year Cooperation in the field of special patient groups (HU, AM, pediatrics)Cooperation in the field of special patient groups (HU, AM, pediatrics) Zero-national balanceZero-national balance All donors reportedAll donors reported Participation in the Organ Advisory CommitteesParticipation in the Organ Advisory Committees Aiming at full membership after one yearAiming at full membership after one year

70. Cooperation ET – Croatia Stepwise Approach II HU liver programHU liver program Kidney acceptable mismatch programKidney acceptable mismatch program Consecutive listing of all eligable highly immunized patientsConsecutive listing of all eligable highly immunized patients HU heart and HU kidneyHU heart and HU kidney Elective pediatric heart and liver transplantationElective pediatric heart and liver transplantation Full membershipFull membership

71. Organ Exchange with Croatia Kidney Transplantation 2007 Net-Import to Croatia: 16 Kidneys

72. Summary Collaboration offers mutual benefits to participating centers and countries, e.g.Collaboration offers mutual benefits to participating centers and countries, e.g. Improved allocationImproved allocation Transparent patient oriented allocationTransparent patient oriented allocation Zero mismatch 20%, high urgency patients…Zero mismatch 20%, high urgency patients… Scientifically based evolution of allocation rulesScientifically based evolution of allocation rules Reduced loss of donor organsReduced loss of donor organs Multinational scientific cooperationMultinational scientific cooperation Data registry accessible to participantsData registry accessible to participants

73. Thank you for your attention