Abstracts
Abstract
Precision medicine can put clinicians in a position where they must act more as resource allocators than their traditional role as patient advocates. In the allocation of transplantable organs and tissues, the use of eplet matching will enhance precision medicine but, in doing so, generate a tension with the present reliance on rule of rescue and justice-based factors for allocations. Matching donor and recipient human leukocyte antigens (HLA) is shown to benefit virtually all types of solid organ transplants yet, until recently, HLA-matching has not been practical and was shown to contribute to ethnic/racial disparities in organ allocation. Recent advances using eplets from the HLA molecule has renewed the promise of such matching for predicting patient outcomes. The rule of rescue in organ allocation reflects a combination of ethical, policy, and legal imperatives. However, the rule of rescue can impede the allocation strategies adopted by professional medical associations and the optimal use of scarce transplant resources. While eplet-matching seeks to improve outcomes, it may potentially frustrate current ethics-motivated initiatives, established patient-practitioner relationships, and functional conventions in the allocation of medical resources such as organ and tissue transplants. Eplet-matching allocation schemes need to be carefully and collaboratively designed with clear, fair and equitable guidelines that complement functional conventions and maintain public trust.
Keywords:
- organ and tissue donation and transplantation,
- resource allocation,
- rule of rescue,
- HLA eplet-matching,
- personalized medicine
Résumé
La médecine de précision peut placer les cliniciens dans une position où ils doivent agir davantage comme des répartiteurs de ressources que dans leur rôle traditionnel de défenseurs des patients. Dans l’attribution d’organes et de tissus transplantables, l’utilisation de l’appariement eplet renforcera la médecine de précision mais, ce faisant, créera une tension avec la dépendance actuelle au devoir d’assistance et des facteurs fondés sur la justice pour l’attribution des ressources. L’appariement des antigènes leucocytaires humains (HLA) du donneur et du receveur est bénéfique pour pratiquement tous les types de greffes d’organes solides. Pourtant, jusqu’à récemment, l’appariement HLA n’était pas pratique et il a été démontré qu’il contribuait aux disparités ethniques/raciales dans l’attribution des organes. Des avancées récentes utilisant des eplets de la molécule HLA ont renouvelé la promesse d’un tel appariement pour prédire les résultats pour les patients. Le devoir d’assistance dans l’attribution d’organes reflète une combinaison d’impératifs éthiques, politiques et juridiques. Cependant, le devoir d’assistance peut entraver les stratégies d’attribution adoptées par les associations médicales professionnelles et l’utilisation optimale des ressources limitées en matière de transplantation. Alors que l’appariement d’eplet cherche à améliorer les résultats, il peut potentiellement contrecarrer les initiatives actuelles motivées par l’éthique, les relations établies entre patients et praticiens et les conventions fonctionnelles dans l’attribution des ressources médicales telles que les transplantations d’organes et de tissus. Les systèmes d’attribution de l’eplet doivent être conçus avec soin et en collaboration, avec des lignes directrices claires, justes et équitables qui complètent les conventions fonctionnelles et maintiennent la confiance du public.
Mots-clés :
- don et transplantation d’organes et de tissus,
- allocation des ressources,
- devoir d’assistance,
- appariement HLA,
- médecine personnalisée
Appendices
Bibliography
- 1. Canadian Medical Association. Framework for Ethical Decision Making During the Coronavirus Pandemic. Apr 2020.
- 2. CMPA. Scarce resources: Caring for patients during COVID-19. Jun 2020.
- 3. CMPA. Navigating triage protocols amid COVID-19. Jun 2020.
- 4. Mckie J, Richardson J. The rule of rescue. Social Science & Medicine. 2003;56(12):2407-19.
- 5. Caulfield T, Murdoch B, Sapir-Pichhadze R, Keown P. Policy challenges for organ allocation in an era of “precision medicine”. Can J Kidney Heal Dis. 2020;20(7):2054358120912655.
- 6. Vogenberg FR, Barash CI, Pursel M. Personalized medicine: part 1: evolution and development into theranostics. Pharm Ther. 2010;35(10):560-76.
- 7. Pray L. Personalized medicine: hope or hype? Nat Educ. 2008;1(1):72.
- 8. Einav S, O’connor M, Chavez LO. Visit to intensive care of 2050. Intensive Care Med. 2017;43:97-100.
- 9. Montréal Declaration for a Responsible Development of Artificial Intelligence. 2018.
- 10. Ahmad MA, Eckert C, Teredesai A. Interpretable machine learning in healthcare. In: 2018 IEEE International Conference on Healthcare Informatics (ICHI). New York, NY; 2018. p. 447-8.
- 11. Chouchane L, Mamtani R, Dallol A, Sheikh JI. Personalized medicine: a patient - centered paradigm. J Transl Med. 2011;9:206.
- 12. Caulfield T, Toews M. Rare diseases and resource allocation policy: the role of Canadian legal and ethical norms. UBC L Rev. 2016;49(2):11.
- 13. Jasseron C, Francoz C, Antoine C, et al. Impact of the new MELD-based allocation system on waiting list and post-transplant survival – a cohort analysis using the French national CRISTAL database. Transpl Int. 2019;32(10):1061-73.
- 14. Ahearn A. Ethical dilemmas in liver transplant organ allocation: is it time for a new mathematical model? AMA J Ethics. 2016;18(2):126-32.
- 15. Duquesnoy RJ. Should epitope-based HLA compatibility be used in the kidney allocation system? Hum Immunol. 2017;78(1):24-9.
- 16. Naesens M, Anglicheau D. Precision transplant medicine: biomarkers to the rescue. J Am Soc Nephrol. 2018;29(1):24-34.
- 17. Süsal C, Opelz G. Current role of human leukocyte antigen matching in kidney transplantation. Curr Opin Organ Transplant. 2013;18(4):438-44.
- 18. Shi X, Lv J, Han W, et al. What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients. BMC Nephrol. 2018;19:116.
- 19. Zachary AA, Leffell MS. HLA mismatching strategies for solid organ transplantation - a balancing act. Front Immunol. 2016;7:575.
- 20. Robinson J, Barker DJ, Georgiou X, Cooper MA, Flicek P, Marsh SGE. IPD-IMGT/HLA database. Nucleic Acids Res. 2020;48(D1):D948-55.
- 21. Johnson RJ, Fuggle SV, Mumford L, et al. A new UK 2006 national kidney allocation scheme for deceased heart-beating donor kidneys. Transplantation. 2010;89(4):387-94.
- 22. Crafter SR, Bell L, Foster BJ. Balancing organ quality, HLA-matching, and waiting times: Impact of a pediatric priority allocation policy for deceased donor kidneys in Quebec. Transplantation. 2007;83(11):1411-5.
- 23. Tambur AR, Kosmoliaptsis V, Claas FHJ, Mannon RB, Nickerson P, Naesens M. Significance of HLA-DQ in kidney transplantation: time to reevaluate human leukocyte antigen–matching priorities to improve transplant outcomes? An expert review and recommendations. Kidney Int. 2021;100(5):1012-22.
- 24. Hariharan S, Israni AK, Danovitch G. Long-term survival after kidney transplantation. N Engl J Med. 2021;385(8):729-43.
- 25. Pamboukian SV, Costanzo MR, Meyer P, Bartlett L, McLeod M, Heroux A. Influence of race in heart failure and cardiac transplantation: mortality differences are eliminated by specialized, comprehensive care. J Card Fail. 2003;9(2):80-6.
- 26. Hall EC, Massie AB, James NT, et al. Effect of eliminating priority points for HLA-B matching on racial disparities in kidney transplant rates. Am J Kidney Dis. 2011;58(5):813-6.
- 27. Duquesnoy RJ, Takemoto S, De Lange P, et al. HLAmatchmaker: a molecularly based algorithm for histocompatibility determination. III. Effect of matching at the HLA-A,B amino acid triplet level on kidney transplant survival. Transplantation. 2003;75(6):884-9.
- 28. Duquesnoy RJ, Askar M. HLAmatchmaker: a molecularly based algorithm for histocompatibility determination. V. Eplet matching for HLA-DR, HLA-DQ, and HLA-DP. Hum Immunol. 2007;68(1):12-25.
- 29. Wiebe C, Pochinco D, Blydt-Hansen TD, et al. Class II HLA epitope matching—a strategy to minimize de novo donor-specific antibody development and improve outcomes. Am J Transplant. 2013;13(12):3114-22.
- 30. Tafulo S, Malheiro J, Santos S, et al. HLA class II eplet mismatch load improves prediction of dnDSA development after living donor kidney transplantation. Int J Immunogenet. 2021;48(1):1-7.
- 31. Smith JD, Banner NR, Hamour IM, et al. De novo donor HLA-specific antibodies after heart transplantation are an independent predictor of poor patient survival. Am J Transplant. 2011;11(2):312-9.
- 32. Bryan CF, Chadha V, Warady BA. Donor selection in pediatric kidney transplantation using DR and DQ eplet mismatching: A new histocompatibility paradigm. Pediatr Transplant. 2016;20(7):926-30.
- 33. Khon R, Rubenfeld GD, Mitchell ML, Ubel PA, Halpern SD. Rule of rescue or the good of the many? An analysis of physicians’ and nurses’ preferences for allocating ICU beds. Intensive Care Med. 2011;37(7):1210-7.
- 34. Mathews KS, Rodriguez SM, Nelson JE, Richardson LD. Triage and ongoing care for critically ill patients in the emergency department: results from a national survey of emergency physicians. West J Emerg Med. 2020;21(2):313-21.
- 35. Persad G, Wertheimer A, Emanuel EJ. Principles for allocation of scarce medical interventions. The Lancet. 2009;373(9661):423-31.
- 36. Emanuel EJ, Persad G, Upshur R, et al. Fair allocation of scarce medical resources in the time of Covid-19. N Engl J Med. 2020;382(21):2049-55.
- 37. Egan TM. Ethical issues in thoracic organ distribution for transplant. 2003;3(4):366-72.
- 38. Scheunemann LP, White DB. The ethics and reality of rationing in medicine. Chest. 2011;140(6):1625-32.
- 39. Bickenbach, J. Disability and health care rationing. In: Zalta EN, editor. Stanford Encyclopedia of Philosophy. (Spring 2021 Edition). 29 Jan 2016.
- 40. NICE Citizens Council. Rule of Rescue. London. Citizens Council Reports No. 6. 28 Jan 2006.
- 41. Charlton V. Does NICE apply the rule of rescue in its approach to highly specialised technologies? J Med Ethics. 2022;48(2):118-25.
- 42. Gottlieb J, Greer M, Sommerwerck U, et al. Introduction of the lung allocation score in Germany. Am J Transplant. 2014;14(6):1318-27.
- 43. Alberta v. Elder Advocates of Alberta Society. 2011 SCC 24 (CanLII), [2011] 2 SCR 261.
- 44. Norberg v. Wynrib. 1992 CanLII 65 (SCC), [1992] 2 SCR 226.
- 45. Law Estate v. Simice, 1994 CanLII 3068 (BC SC).
- 46. Caulfield T, Robertson G. Cost containment mechanisms in health care: a review of private law issues. Manit Law J. 1999;27(1):1-16.
- 47. CMPA. Medical-legal handbook for physicians in Canada. May 2021 (rev Mar 2023).
- 48. Kopar PK, Lui FY. Surgeon as double agent: perception of conflicting expectations of patient care and stewardship of resources. J Am Coll Surg. 2020;231(2):239-243.e4.
- 49. Persad G. Evaluating the legality of age-based criteria in health care: from nondiscrimination and discretion to distributive justice. Bost Coll Law Rev. 2019;60(3):889-949.
- 50. American Medical Association. Allocating Limited Health Care Resources. Opinion 11.1.3.
- 51. Duda L. National organ allocation policy: the final rule. Virtual Mentor. 2005;7(9):604-7.
- 52. OPTN. Ethical Principles in the Allocation of Human Organs. Jun 2015
- 53. American Medical Association. Guidelines for Organ Transplantation. Opinion 6.2.1
- 54. Canadian Medical Association. CMA Policy: Organ and tissue donation and transplantation. 7 Dec 2019.
- 55. Canadian Medical Association. Background to CMA Policy: Organ and tissue donation and transplantation. 7 Dec 2019.
- 56. White DB, Lo B. Mitigating inequities and saving lives with ICU triage during the COVID-19 pandemic. Am J Respir Crit Care Med. 2021;203(3):287-95.
- 57. Ferrari P, Cantwell L, Ta J, Woodroffe C, D’Orsogna L, Holdsworth R. Providing better-matched donors for HLA mismatched compatible pairs through kidney paired donation. Transplantation. 2017;101(3):642-8.
- 58. Wall AE, Veale JL, Melcher ML. Advanced donation programs and deceased donor-initiated chains-2 innovations in kidney paired donation. Transplantation. 2017;101(12):2818-24.
- 59. Wadmann S, Hauge AM. Strategies of stratification: Regulating market access in the era of personalized medicine. Soc Stud Sci. 2021;51(4):628-53.
- 60. Cavallo J. Has the promise of precision medicine been oversold? The ASCO Post. 25 Oct 2018.
- 61. Gottlieb J. Lung allocation. J Thorac Dis. 2017;9(8):2670-4.
- 62. Mathews KS, Rodriguez SM, Nelson JE, Richardson LD. “Breaking” the emergency department: Does the culture of emergency medicine present a barrier to self-care? West J Emerg Med. 2020;21(2):313-21.
- 63. Howard RJ, Cornell DL. Ethical Issues in organ procurement and transplantation. In: Clark PA, editor. Bioethics - Medical, Ethical and Legal Perspectives. InTech; 2016.
- 64. Kahn JM. The utility of cost-utility analyses in critical care. Crit Care Med. 2021;49(4):702-4.
- 65. Lewis J, Lipworth W, Kerridge I. Ethics, evidence and economics in the pursuit of “personalized medicine”. J Pers Med. 2014;4(2):137-46.
- 66. Alexander GC, Sehgal AR. Barriers to cadaveric renal transplantation among Blacks, women, and the poor. JAMA. 1998;280(13):1148-52.
- 67. Mistretta A, Veroux M, Grosso G, et al. Role of socioeconomic conditions on outcome in kidney transplant recipients. Transplant Proc. 2009;41(4):1162-7.
- 68. Purnell TS, Luo X, Crews DC, et al. Neighborhood poverty and sex differences in live donor kidney transplant outcomes in the United States. Transplantation. 2019;103(10):2183-9.
- 69. Slomp C, Edwards L, Burgess M, Sapir-Pichhadze R, Keown P, Bryan S. Public values and guiding principles for implementing epitope compatibility in kidney transplantation allocation criteria: results from a Canadian online public deliberation. BMC Public Health. 2023;23:844.
- 70. Swetz KM, Stulak JM, Dunlay SM, Gafford EF. Management of advanced heart failure in the elderly: ethics, economics, and resource allocation in the technological era. Cardiol Res Pract. 2012;2012:524961.
- 71. Mckneally MF, Dickens BM, Meslin EM, Singer PA. Bioethics for clinicians: 13. Resource allocation. 1997;157(2):163-7.
- 72. Lanken PN, Terry PB, Adler DC, et al. Fair allocation of intensive care unit resources. Am J Respir Crit Care Med. 1997;156(4):1282-301.
- 73. Fleck LM. Pharmacogenomics and personalized medicine: wicked problems, ragged edges and ethical precipices. N Biotechnol. 2012;29(6):757-68.