1. Nine‐yr experience of 700 hand‐assisted laparoscopic donor nephrectomies in Japan Clinical Transplantation Volume 26, Issue 5, pages 797-807, 26 MAR 2012 DOI: 10.1111/j.1399-0012.2012.01617.x http://onlinelibrary.wiley.com/doi/10.1111/j.1399-0012.2012.01617.x/full#ctr1617-fig-0001 Volume 26, Issue 5, http://onlinelibrary.wiley.com/doi/10.1111/j.1399-0012.2012.01617.x/full#ctr1617-fig-0001

2. Organ Transplantation Lloyd E Ratner MD MPH Department of Surgery Columbia University New York-Presbyterian Hospital New York, NY

3. Disclaimer: I am a transplant surgeon, not an ethicist

5. Topics Brain death Allocation Transplant center interests versus patient interests – Patient selection Living Donation – Risk acceptance/aversion – Misattributed paternity – Kidney paired donation Compatible pair participation Organ equity Donor safety oversight – Living donor list exchange – Living organ donation in terminally ill patients – Donor/Recipient risk/benefit ratio Utilization of vulnerable populations as donors – Transplant commercialism – Transplant tourism – Prisoners as donors Living Executed – Children as donors Deceased donor experimentation

6. Brain Death: History 1954 Murray kidney transplant from an identical twin 1962 Murray first successful cadaveric kidney transplant 1963 Starzl first human liver transplant 1963 Hardy first lung transplant 1967 Barnard first heart transplant Brain death donor was brought to the OR, ventilator was stopped and everyone waited for the donors heart to stop, therefore these donors were not brain death at the time of organ retrieval

7. Brain Death: History cont. 1959 Wertheimer et al. characterized the death of the nervous system 1959 Mollaret and Goulon coined the term “ coma depasse ” (beyond coma) for and irreversible state of coma and apnea June 3,1963 Guy Alexandre introduced the first set of Brain Death Criteria based on description of coma depasse and performed the first kidney transplantation from a heart beating brain death donor The recipient, who was maintained on PD, died of sepsis on post op day 87 1968 Ad hoc Committee at HMS defined irreversible coma and transplantation from brain death donors begins in the US 1970 ’ s only 20 stated had adopted the criteria 1981 the presidents commission for the study of ethical problems in medicine and biomedical and behavioral research published its guidelines adopting “ whole brain ” formulation All 50 states accepted these guidelines

8. Brain Death Harvard Ad Hoc Committee 1968 – “ With its pioneering interest in organ transplantation, I believe the faculty of Harvard Medical School is better equipped to elucidate this area than any other single group” – Dean Robert Ebert – 13 Members Technological progress – “Life” support (e.g. mechanical ventillation) – Diagnostics (e.g. EEG) – Cardiac arrest & cardiopulmonary bypass in cardiac surgery Transplantation’s need for organs – 1 st heart transplant 1967 – Kidney procurement from heart beating donors 1960s Public distrust of the medical profession – Fear of premature burial (ancient fear) Resource utilization of “comatose” patients Benefit to the donor

9. “Any modification of the means of diagnosing death to facilitate transplantation will cause the whole procedure to fall into disrepute…….” Discussion regarding establishing brain death criteria 1966

10. Defining Brain Death: 4 Major Questions 1.Under what circumstances, if ever, shall extraordinary means of support be terminated, with death to follow? (Answer: When the criteria of irreversible coma described above have been fulfilled.) 2.From the earliest times the moment of death has been recognized as the time the heartbeat ceased. Is there adequate evidence now that the "moment of death" should be advanced to coincide with irreversible coma while the heart continues to beat? (Answer: Yes.) 3.When, if ever, and under what circumstances is it right to use for transplantation the tissues and organs of a hopelessly unconscious patient? (Answer: When the criteria of irreversible coma described above have been fulfilled.) 4.Can society afford to discard the tissues and organs of the hopelessly unconscious patient when they could be used to restore the otherwise hopelessly ill but still salvageable individual? (Answer: No.)

11. Renewal: Finds Living Kidney Donors In the Orthodox Jewish Community

12. Directed Donation Donor or decedent’s family stipulate who the organs will go to – Individual – Specific group of people Race, Religion, Ethnic group, Geographic location, etc Non-directed donation Living donor giving purely altruistically without a connection to any individual recipient

13. Organ Allocation

14. Structuring Analytic discussion that spells out a variety of conflicting ethical principles in order to isolate and ultimately clarify the pivotal concepts involved in the decision

15. Rationing Goal: Maximize # of lives saved 1Produce the greatest benefit 2Give the most deserving 3Give to those who make the greatest contribution to society 4Give to individuals who have the greatest responsibility to others 5Assign by random choice 6(Select those willing to pay the most)

16. Distributive Justice Goal: Maximize quality-adjusted life years saved 1Utility (length & quality of life produced) 2Neutral queuing (first-in-first-out) 3Principle of rescue – Absolute – save life above all else – Modified – triage for expected length of survival or quality related issues – Modified Utility Principle

17. Value-Based System 1Urgency – Pro or Con – Saving the most lives vs Longest possible functional period per organ 2Loyalty to patient – Influences judgement 3Fairness

18. Medical Considerations Age Potential for recurrent disease Retransplantation Non-adherence Immunologic compatibility Waiting time

19. United States Organ Allocation National Organ Transplant Act – Sponsored by Al Gore Governed by OPTN – UNOS is the OPTN contractor Membership organization – Transplant centers Public members (e.g. patients, organ donors, etc.) Organ specific differences in allocation

20. Sickest patients prioritized – Liver – Heart – Lung Post-transplant outcomes not included in allocation Kidney largely based on waiting time & longevity matching United States Organ Allocation

21.  Over time, waiting time has become the primary driver of kidney allocation  Histocompatibility components have diminished over time  This overreliance led to a system that does not accomplish any goal other than transplanting the candidate waiting the longest  Doesn’t recognize that not all can wait the same length of time  Fails to acknowledge different needs for different candidates (e.g., speed over quality) Unbalanced System Components

22.  Make the most of every donated kidney without diminishing access  Promote graft survival for those at highest risk of retransplant  Minimize loss of potential graft function through better longevity matching  Improve efficiency and utilization by providing better information about kidney offers Proposed Policy Objectives

23.  Provide comprehensive data to guide transplant decision making  Reduce differences in access for ethnic minorities and sensitized candidates Proposed Policy Objectives

24. Kidney Donor Profile Index (KDPI) KDPI Variables Donor age Height Weight Ethnicity History of Hypertension History of Diabetes Cause of Death Serum Creatinine HCV Status DCD Status KDPI values now displayed with all organ offers in DonorNet®

25. Sequence A KDPI <=20% Sequence B KDPI >20% but <35% Sequence C KDPI >=35% but <=85% Sequence D KDPI>85% Highly Sensitized 0-ABDRmm (top 20% EPTS) Prior living donor Local pediatrics Local top 20% EPTS 0-ABDRmm (all) Local (all) Regional pediatrics Regional (top 20%) Regional (all) National pediatrics National (top 20%) National (all) Highly Sensitized 0-ABDRmm Prior living donor Local pediatrics Local adults Regional pediatrics Regional adults National pediatrics National adults Highly Sensitized 0-ABDRmm Prior living donor Local Regional National Highly Sensitized 0-ABDRmm Local + Regional National *all categories in Sequence D are limited to adult candidates

26.  Estimated Post-Transplant Survival  Candidate age, time on dialysis, prior organ transplant, diabetes status  Top 20% of candidates by EPTS to receive kidneys matched on longevity  Applies only to kidneys with KDPI scores <=20% not allocated for multi-organ, very highly sensitized, or pediatric candidates Proposed Classification: Longevity Matching

27. Sequence A KDPI <=20% Sequence B KDPI >20% but <35% Sequence C KDPI >=35% but <=85% Sequence D KDPI>85% Highly Sensitized 0-ABDRmm (top 20% EPTS) Prior living donor Local pediatrics Local top 20% EPTS 0-ABDRmm (all) Local (all) Regional pediatrics Regional (top 20%) Regional (all) National pediatrics National (top 20%) National (all) Highly Sensitized 0-ABDRmm Prior living donor Local pediatrics Local adults Regional pediatrics Regional adults National pediatrics National adults Highly Sensitized 0-ABDRmm Prior living donor Local Regional National Highly Sensitized 0-ABDRmm Local + Regional National *all categories in Sequence D are limited to adult candidates Proposed Longevity matching

28.  Candidates with CPRA >=98% face immense biological barriers  Current policy only prioritizes sensitized candidates at the local level.  Proposed policy would give following priority  To participate in Regional/National sharing, review & approval of unacceptable antigens will be required Proposed Classifications: Very Highly Sensitized CPRA=100%National CPRA=99%Regional CPRA=98%Local

29. Sequence A KDPI <=20% Sequence B KDPI >20% but <35% Sequence C KDPI >=35% but <=85% Sequence D KDPI>85% Highly Sensitized 0-ABDRmm (top 20% EPTS) Prior living donor Local pediatrics Local top 20% EPTS 0-ABDRmm (all) Local (all) Regional pediatrics Regional (top 20%) Regional (all) National pediatrics National (top 20%) National (all) Highly Sensitized 0-ABDRmm Prior living donor Local pediatrics Local adults Regional pediatrics Regional adults National pediatrics National adults Highly Sensitized 0-ABDRmm Prior living donor Local Regional National Highly Sensitized 0-ABDRmm Local + Regional National *all categories in Sequence D are limited to adult candidates New categories for highly sensitized candidates

30.  Prior living organ donors receive the same level of priority as current policy  Requirements remain the same for registering a prior living organ donor  Policy proposal to allow priority with subsequent registrations to be considered by Board in November 2012  Proposed policy will base qualification on date of procurement not date of transplant  Would provide priority for prior donors whose organs were removed but not transplanted Unmodified Classification: Prior Living Organ Donor

31. Sequence A KDPI <=20% Sequence B KDPI >20% but <35% Sequence C KDPI >=35% but <=85% Sequence D KDPI>85% Highly Sensitized 0-ABDRmm (top 20% EPTS) Prior living donor Local pediatrics Local top 20% EPTS 0-ABDRmm (all) Local (all) Regional pediatrics Regional (top 20%) Regional (all) National pediatrics National (top 20%) National (all) Highly Sensitized 0-ABDRmm Prior living donor Local pediatrics Local adults Regional pediatrics Regional adults National pediatrics National adults Highly Sensitized 0-ABDRmm Prior living donor Local Regional National Highly Sensitized 0-ABDRmm Local + Regional National *all categories in Sequence D are limited to adult candidates Continued priority for prior living donors

32.  Current policy prioritizes donors younger than 35 to candidates listed prior to 18 th birthday  Proposed policy would  Prioritize donors with KDPI scores <35%  Eliminate pediatric categories for non 0-ABDR KPDI >85%  Provides comparable level of access while streamlining allocation system Modified Classification: Pediatric

33. Sequence A KDPI <=20% Sequence B KDPI >20% but <35% Sequence C KDPI >=35% but <=85% Sequence D KDPI>85% Highly Sensitized 0-ABDRmm (top 20% EPTS) Prior living donor Local pediatrics Local top 20% EPTS 0-ABDRmm (all) Local (all) Regional pediatrics Regional (top 20%) Regional (all) National pediatrics National (top 20%) National (all) Highly Sensitized 0-ABDRmm Prior living donor Local pediatrics Local adults Regional pediatrics Regional adults National pediatrics National adults Highly Sensitized 0-ABDRmm Prior living organ donor Local Regional National Highly Sensitized 0-ABDRmm Local + Regional National *all categories in Sequence D are limited to adult candidates Continued priority pediatric candidates (now based on KDPI)

34.  KDPI >85% kidneys would be allocated to a combined local and regional list  Would promote broader sharing of kidneys at higher risk of discard  DSAs with longer waiting times are more likely to utilize these kidneys than DSAs with shorter waiting times Modified Classification: Local + Regional for High KDPI Kidneys

35. Sequence A KDPI <=20% Sequence B KDPI >20% but <35% Sequence C KDPI >=35% but <=85% Sequence D KDPI>85% Highly Sensitized 0-ABDRmm (top 20% EPTS) Prior living organ donor Local pediatrics Local top 20% EPTS 0-ABDRmm (all) Local (all) Regional pediatrics Regional (top 20%) Regional (all) National pediatrics National (top 20%) National (all) Highly Sensitized 0-ABDRmm Prior living organ donor Local pediatrics Local adults Regional pediatrics Regional adults National pediatrics National adults Highly Sensitized 0-ABDRmm Prior living organ donor Local Regional National Highly Sensitized 0-ABDRmm Local + Regional National *all categories in Sequence D are limited to adult candidates Proposed Regional Sharing

36. Organ Allocation – Other Countries Old for old (some European countries) Israel: Prioritization given to those individuals who are designated organ donors Japan: Little acceptance of brain death, therefore minimal deceased donation

38. Transplant Center Interests Versus Patient Interests

39. Patient selection – Transplant center performance metrics Patient safety – Use of hemostatic clips in living donor nephrectomy Cost savings FDA contra-indication in US but not elsewhere Continued use in other countries

41. Transplant Volume Declined in Centers With Low Performance Schold JD et al: AJT 2013, 13(1):67-75

43. Living Donation

44. Risk acceptance/aversion Misattributed paternity Potential donor’s desire to back out Kidney paired donation – Compatible pair participation – Organ equity – Donor safety oversight Living donor list exchange Living organ donation in terminally ill patients Donor/Recipient risk/benefit ratio

45. Living Donation: Risk Acceptance/Aversion Who determines the degree of risk a donor should take? – Paternalism? – Opportunity to do good What risk? – Operative risk – Long term risk Absolute minimal risk versus risk assessment and stratification? Risk based on what comparator group? Should the relationship between donor & recipient influence risk tolerance? – Coercion? Liver versus Kidney donation

46. LIVE DONOR MORTALITY RATES Segev Trotter/Ringe

47. Truthfulness? Misattributed paternity – Medical implications – Relationship dynamics – Legal implications Potential donor’s desire to back out – Coercion – Medical excuse Ability to donate at a later date

48. ABO Compatibility Random Pairs of Individuals ABO Identical 39% ABO Compatible 25% A to O 21% B to O 4% AB to O 1.3% AB to A 1.1% B to A 5% A to B 3% AB to B 0.6%

49. Kidney Paired Donation

50. History of Kidney Paired Donation 1986 – Rapaport first proposes KPD to overcome immunologic incompatibility with live kidney donors 1991 – Establishment of KPD program at Yonsei Univ in S. Korea 1995 – First Laparoscopic Donor Nephrectomy – Johns Hopkins Univ. 1998 – Successful use of Plasmapheresis/IVIg to overcome immunologic incompatibility – Johns Hopkins Univ. – February – First international presentation of Korean PKE Program – ASTP - May 2000 – First KPD in U.S. NEOB 2001 – First KPD Johns Hopkins U – Legal Dept. requirement to anesthetize donors simultaneously 2003 – Establishment of Dutch “Crossover Transplantation Program” 2004 – Antibody Working Group 3 rd Meeting – Focus on KPD to overcome immunologic incompatibility 2007 – Rees removes logistical constraint of simultaneous operations with Nonsimultaneous, Extended, Altruistic-Donor Chain – Utilization of compatible donor/recipient pairs to facilitate KPD for incompatible donor/recipient pairs 2008 – National Kidney Registry established 2010 – UNOS Pilot Project commences

51. A Conventional Paired Exchange Donor 1 Blood Group A Donor 2 Blood Group B Recipient 1 Blood Group B Recipient 2 Blood Group A X X

52. An Unconventional Paired Exchange Donor 1 Blood Group 0 Donor 2 Blood Group A Recipient 1 Blood Group A (DSA) Recipient 2 Blood Group B X X Positive Crossmatch ABO Incompatibility

53. A Nonsimultaneous, Extended, Altruistic-Donor ChainBrief Report: Michael A Rees, Jonathan E Kopke, Ronald P Pelletier, Dorry L Segev, et al. The New England Journal of Medicine. Boston: Mar 12, 2009. Vol. 360, Iss. 11; pg. 1096

54. Compatible Pair Participation

55. Compatible Pair Participation: Background Living Kidney Donor: – a private resource for the recipient since first LD Tx in 1954 “ Good Samaritan ” or “ Undirected ” Donors: – Used with increasing frequency – Public resource (center limited?) Kidney Paired Donation (KPD): – Incompatible donors are relinquished Compatible Pair Participation (CPP) : – Compatible donors exchanged to enable more incompatible patients to be transplanted

56. Compatible Pair Participation Donor 1 Blood Group 0 Donor 2 Blood Group A Recipient 1 Blood Group A Recipient 2 Blood Group B X Compatible ABO Incompatibility

57. Compatible Pair Participation Major paradigm shift: donor from private resource to public or shared resource Potential large impact on organ supply Regional or national sharing networks not necessary to achieve AUPKEs Easily performed at any center Ross et al – ethical concerns due to potentially coercive nature – Transplantation. 2000 Apr 27;69(8):1539-43.

58. Altruistic Kidney Exchange Live Donor Renal Transplants Columbia University January 2005 – July 2006 n = 163 Donor Recip ABOAB A292210 B3960 O94740 AB2220

59. THE POTENTIAL FOR 2005-2006 DONORABOAB RECIPIENT A X X 868 B X X 403 O X X X AB 785543 Total # of Living Donor Transplants in the UNOS data base 2005-2006: 6,565 Total # of Transplants that had the Potential to Participate in AUPKE:1,447 (22%) Blood group O donors: 1314 (90.8%)

60. Compatible Pair Participation: Areas of Ethical Concern Coercion

62. Recipient: opportunity to obtain an organ with likelihood of a superior outcome Donor: primary goal of altruism fulfilled by facilitating more transplants

63. Altruistic Unbalanced Paired Kidney Exchange: Areas of Ethical Concern Coercion Donor equity or “ trading up ”

64. Compatible Pair Participation: Areas of Ethical Concern Coercion Donor equity or “ trading up ” Donor/recipient age matching

65. Compatible Pair Participation: Areas of Ethical Concern Coercion Donor equity or “ trading up ” Donor/recipient age matching Disparity in donor/recipient attitudes

66. Disparity in Donor/Recipient Attitudes Towards CPP Donor - YesDonor - No Recipient - YesYes/YesYes/No Recipient – NoNo/YesNo/No

70. Compatible Pair Participation: Areas of Ethical Concern Coercion Donor equity or “ trading up ” Donor/recipient age matching Disparity in donor/recipient attitudes Donor selection based on willingness to participate in AUPKE

71. Compatible Pair Participation: Areas of Ethical Concern Coercion Donor equity or “ trading up ” Donor/recipient age matching Disparity in donor/recipient attitudes Donor selection based on willingness to participate in AUPKE Anonymity

72. Dislike Coercion Poor outcomes

73. First Compatible Pairs Participation Columbia University 8/30/07 RecipientDonorRelationship O AB A O A Spouse Acquaintance Spouse X

74. Compatible Pairs Participation: Complex Exchange RecipientDonorRelationship AB O BO B Spouse Daughter Brother X X

75. Ethical Considerations CUMC Ethics Committee & University of Pisa Symposium: Ethically Sound & Acceptable

76. Compatible Pair Participation Definition of : – Compatible – Incompatible Immunologically incompatible Blood type Donor specific antibodies – Quasi-compatible Some advantage may be obtained in either survival (patient or graft) or risk if participate in KPD Age Serology

77. Safety Oversight in KPD What responsibility does the recipient center have to the donor? What responsibility does the donor center have to the recipient? Each patient has their own physicians to assess and counsel regarding risk What if different centers have different risk tolerances? What if organ is lost or damaged in transport?

78. Living Donor List Exchange Deceased donor organ is used to initiate a KPD chain Opportunity to increase the number of transplants by utilizing more live donors Some patients advantaged while other disadvantaged – Blood group O patients without live donor are disadvantaged – Blood group A patients will be advantaged

79. ABO Compatibility Random Pairs of Individuals ABO Identical 39% ABO Compatible 25% A to O 21% B to O 4% AB to O 1.3% AB to A 1.1% B to A 5% A to B 3% AB to B 0.6%

81. Living Organ Donation In Terminally Ill Patients Question has come up in patients with ALS (Lou Gehrig’s Ds) More and better quality organs for transplantation if taken from living donor Able to give informed consent and express individual’s wishes Decision for withdrawal of life support and subsequent donation

82. Utilization Of Vulnerable Populations As Donors Transplant commercialism – Black market – Regulated system (Iran) Transplant tourism Prisoners as donors – Living – Executed Children as donors – Child conceived as donor for ill sibling – Court as guardian

83. Transplant Commercialism US NOTA prohibits “valuable consideration” for organs Regulated system of organ sales – Government establishes non-negotiable price and pays donors – Proposal for US $100,000 – Iran only country with this system Black market How to prevent in US? What is the role of the transplant center/physician? – Suspicion – No investigative powers

85. Transplant Tourism Definition: Declaration of Istanbul “Travel for transplantation is the movement of organs, donors, recipients or transplant professionals across jurisdictional borders for transplantation purposes. Travel for transplantation becomes transplant tourism if it involves organ trafficking and/or transplant commercialism or if the resources (organs, professionals and transplant centers) devoted to providing transplants to patients from outside a country undermine the country's ability to provide transplant services for its own population.”

86. Transplant Tourism Stewardship of a scarce resource Potential for exploitation of vulnerable populations Poor follow-up care Transplant service may not be available in all localities (countries)

87. Prisoners As Donors Living prisoners – Mississippi case – Free will and informed consent? – Quid pro quo? Executed prisoners – Ethics of capital punishment? – Main source of donated organs in China – Justice of the legal system – Consent – Donor donation part of repaying debt to society – Transplant tourism in China

88. Children As Donors Ability to give informed consent Coercive nature of parental relationship 18 yo age of consent – Mature 17 yo Independent Understands risks and consequences Child conceived as donor for ill sibling Court serves as guardian for decision

89. Deceased Donor Experimentation

90. Necessary to move the field of transplantation forward – Organ supply Number of organs per donor Quality of organs Multiple potential recipients with competing needs – When in relation to organ allocation – Consent? – Which organ takes priority? Who provides oversight?

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92. Summary & Conclusions Finite resource (organs) brings transplantation to the fore for ethical considerations Everyday part of transplantation Plethora of interesting and vexing ethical issues Acceptance of various ethical issues in transplantation have evolved and will continue to do so As demand increasing and technology advances we can expect new challenging issues