abstract: Prior to the first successful allogeneic organ transplantation in 1954, virtually every attempt at transplanting organs in humans had resulted in death, and understanding the role of the immune mechanisms that induced graft rejection served as one of the biggest obstacles impeding its success. While the eventual achievement of organ transplantation is touted as one of the most important success stories in modern medicine, there still remains a physiological need for immunosuppression in order to make organ transplantation work. One such solution in the field of experimental regenerative medicine is interspecies blastocyst complementation, a means of growing patient-specific human organs within animals. To address the progression of immune-related constraints on organ transplantation, the first part of this thesis contains a historical analysis tracing early transplant motivations and the events that led to the discoveries broadly related to tolerance, rejection, and compatibility. Despite the advancement of those concepts over time, this early history shows that immunosuppression was one of the earliest limiting barriers to successful organ transplantation, and remains one of the most significant technical challenges. Then, the second part of this thesis determines the extent at which interspecies blastocyst complementation could satisfy modern technical limitations of organ transplantation. Demonstrated in 2010, this process involves using human progenitor cells derived from induced pluripotent stem cells (iPSCs) to manipulate an animal blastocyst genetically modified to lack one or more functional genes responsible for the development of the intended organ. Instead of directly modulating the immune response, the use of iPSCs with interspecies blastocyst complementation could theoretically eliminate the need for immunosuppression entirely based on the establishment of tolerance and elimination of rejection, while also satisfying the logistical demands imposed by the national organ shortage. Although the technology will require some further refinement, it remains a promising solution to eliminate the requirement of immunosuppression after an organ transplant. / Dissertation/Thesis / Masters Thesis Biology 2020

A tese abordou questões relacionadas à economia da saúde, particularmente à visão econômica dos transplantes renais. Foi conduzida uma análise de custo-utilidade para verificar qual tratamento, transplante renal ou hemodiálise, possui menor razão de custo por anos de vida ajustados por qualidade. O resultado obtido corrobora as evidências internacionais, as quais indicam o transplante renal como estratégia mais custo-efetiva. No caso deste estudo, a razão de custo-utilidade para o transplante renal e hemodiálise foi de R$ 18.161,00/AVAQ e R$ 40.872,00/AVAQ, respectivamente. Apesar de o transplante renal ser uma estratégia dominante, a escassez de órgãos impede que essa estratégia seja amplamente utilizada, reduzindo, assim, os ganhos de eficiência na alocação dos recursos escassos. Nesse contexto, também foi alvo desta tese a questão da escassez de órgãos. Pelo levantamento feito, há tendência de aumento do desequilíbrio entre demanda e oferta de órgãos, visto que a primeira cresce rapidamente, enquanto a segunda mostra pequena tendência de crescimento. Assim, alternativas para contornar esse problema foram analisadas, especialmente as relacionadas a mudanças institucionais na lei de doação de órgãos. Entre elas, foi argüido que a lei de consentimento presumido seria a opção mais factível, por não ferir o pressuposto do altruísmo. Objetivando estimar quanto seria o eventual incremento na doação de órgãos por doador cadáver devido à lei de consentimento presumido, fez-se uso do ferramental da econometria da saúde, aplicando, para uma amostra de 34 países ao longo de cinco anos, o método de regressão quantílica para dados de painel. Os resultados obtidos nessa aplicação indicam que há benefício na adoção da lei de consentimento presumido, que tem um efeito positivo sobre a taxa de doação de órgãos, em torno de 21-26%, comparada à lei de consentimento informado. / The thesis broaches questions related to health economics, particularly the economic vision of renal transplants. A cost-utility analysis was conducted to assess which treatment, renal transplant or hemodialysis, has a lower cost rate per quality-adjusted life years. The result obtained corroborates the international evidence, which indicates renal transplant as the most cost effective strategy. In the case of this study, the cost-utility ratio for renal transplant and hemodialysis was US$ 11,157/QALY and US$ 25,110/QALY, respectively. In spite of renal transplant being the dominant strategy, the scarcity of organs hinders this strategy to be widely used, reducing in this way, the efficiency gain in the allocation of scarce resources. Within this context, the organ shortage was also a target issue of this thesis. Through the survey performed, there is a tendency towards the increase of unbalance between the demand and supply of organs, being that the first grows rapidly while the second shows small tendency towards growth. Within this context, the investigation target of this thesis was to look into possible alternatives to by-pass this problem, especially those related to institutional changes in the organ donation law. Among them, it was argued that the law of presumed consent would be the most feasible option, since it does not harm the presupposition of altruism. With the object of estimating what would be the eventual increase in organ donation, per cadaveric donor, due to the law of presumed consent, the health econometric tool of quantile regression method for panel data was used, applied to a sample of 34 countries during a five-year period. The results obtained in this application indicate that there is benefit in adopting the law of presumed consent, which has a positive effect on the organ donation rate, around 21 – 26%, compared to the law of informed consent.

A tese abordou questões relacionadas à economia da saúde, particularmente à visão econômica dos transplantes renais. Foi conduzida uma análise de custo-utilidade para verificar qual tratamento, transplante renal ou hemodiálise, possui menor razão de custo por anos de vida ajustados por qualidade. O resultado obtido corrobora as evidências internacionais, as quais indicam o transplante renal como estratégia mais custo-efetiva. No caso deste estudo, a razão de custo-utilidade para o transplante renal e hemodiálise foi de R$ 18.161,00/AVAQ e R$ 40.872,00/AVAQ, respectivamente. Apesar de o transplante renal ser uma estratégia dominante, a escassez de órgãos impede que essa estratégia seja amplamente utilizada, reduzindo, assim, os ganhos de eficiência na alocação dos recursos escassos. Nesse contexto, também foi alvo desta tese a questão da escassez de órgãos. Pelo levantamento feito, há tendência de aumento do desequilíbrio entre demanda e oferta de órgãos, visto que a primeira cresce rapidamente, enquanto a segunda mostra pequena tendência de crescimento. Assim, alternativas para contornar esse problema foram analisadas, especialmente as relacionadas a mudanças institucionais na lei de doação de órgãos. Entre elas, foi argüido que a lei de consentimento presumido seria a opção mais factível, por não ferir o pressuposto do altruísmo. Objetivando estimar quanto seria o eventual incremento na doação de órgãos por doador cadáver devido à lei de consentimento presumido, fez-se uso do ferramental da econometria da saúde, aplicando, para uma amostra de 34 países ao longo de cinco anos, o método de regressão quantílica para dados de painel. Os resultados obtidos nessa aplicação indicam que há benefício na adoção da lei de consentimento presumido, que tem um efeito positivo sobre a taxa de doação de órgãos, em torno de 21-26%, comparada à lei de consentimento informado. / The thesis broaches questions related to health economics, particularly the economic vision of renal transplants. A cost-utility analysis was conducted to assess which treatment, renal transplant or hemodialysis, has a lower cost rate per quality-adjusted life years. The result obtained corroborates the international evidence, which indicates renal transplant as the most cost effective strategy. In the case of this study, the cost-utility ratio for renal transplant and hemodialysis was US$ 11,157/QALY and US$ 25,110/QALY, respectively. In spite of renal transplant being the dominant strategy, the scarcity of organs hinders this strategy to be widely used, reducing in this way, the efficiency gain in the allocation of scarce resources. Within this context, the organ shortage was also a target issue of this thesis. Through the survey performed, there is a tendency towards the increase of unbalance between the demand and supply of organs, being that the first grows rapidly while the second shows small tendency towards growth. Within this context, the investigation target of this thesis was to look into possible alternatives to by-pass this problem, especially those related to institutional changes in the organ donation law. Among them, it was argued that the law of presumed consent would be the most feasible option, since it does not harm the presupposition of altruism. With the object of estimating what would be the eventual increase in organ donation, per cadaveric donor, due to the law of presumed consent, the health econometric tool of quantile regression method for panel data was used, applied to a sample of 34 countries during a five-year period. The results obtained in this application indicate that there is benefit in adopting the law of presumed consent, which has a positive effect on the organ donation rate, around 21 – 26%, compared to the law of informed consent.

A tese abordou questões relacionadas à economia da saúde, particularmente à visão econômica dos transplantes renais. Foi conduzida uma análise de custo-utilidade para verificar qual tratamento, transplante renal ou hemodiálise, possui menor razão de custo por anos de vida ajustados por qualidade. O resultado obtido corrobora as evidências internacionais, as quais indicam o transplante renal como estratégia mais custo-efetiva. No caso deste estudo, a razão de custo-utilidade para o transplante renal e hemodiálise foi de R$ 18.161,00/AVAQ e R$ 40.872,00/AVAQ, respectivamente. Apesar de o transplante renal ser uma estratégia dominante, a escassez de órgãos impede que essa estratégia seja amplamente utilizada, reduzindo, assim, os ganhos de eficiência na alocação dos recursos escassos. Nesse contexto, também foi alvo desta tese a questão da escassez de órgãos. Pelo levantamento feito, há tendência de aumento do desequilíbrio entre demanda e oferta de órgãos, visto que a primeira cresce rapidamente, enquanto a segunda mostra pequena tendência de crescimento. Assim, alternativas para contornar esse problema foram analisadas, especialmente as relacionadas a mudanças institucionais na lei de doação de órgãos. Entre elas, foi argüido que a lei de consentimento presumido seria a opção mais factível, por não ferir o pressuposto do altruísmo. Objetivando estimar quanto seria o eventual incremento na doação de órgãos por doador cadáver devido à lei de consentimento presumido, fez-se uso do ferramental da econometria da saúde, aplicando, para uma amostra de 34 países ao longo de cinco anos, o método de regressão quantílica para dados de painel. Os resultados obtidos nessa aplicação indicam que há benefício na adoção da lei de consentimento presumido, que tem um efeito positivo sobre a taxa de doação de órgãos, em torno de 21-26%, comparada à lei de consentimento informado. / The thesis broaches questions related to health economics, particularly the economic vision of renal transplants. A cost-utility analysis was conducted to assess which treatment, renal transplant or hemodialysis, has a lower cost rate per quality-adjusted life years. The result obtained corroborates the international evidence, which indicates renal transplant as the most cost effective strategy. In the case of this study, the cost-utility ratio for renal transplant and hemodialysis was US$ 11,157/QALY and US$ 25,110/QALY, respectively. In spite of renal transplant being the dominant strategy, the scarcity of organs hinders this strategy to be widely used, reducing in this way, the efficiency gain in the allocation of scarce resources. Within this context, the organ shortage was also a target issue of this thesis. Through the survey performed, there is a tendency towards the increase of unbalance between the demand and supply of organs, being that the first grows rapidly while the second shows small tendency towards growth. Within this context, the investigation target of this thesis was to look into possible alternatives to by-pass this problem, especially those related to institutional changes in the organ donation law. Among them, it was argued that the law of presumed consent would be the most feasible option, since it does not harm the presupposition of altruism. With the object of estimating what would be the eventual increase in organ donation, per cadaveric donor, due to the law of presumed consent, the health econometric tool of quantile regression method for panel data was used, applied to a sample of 34 countries during a five-year period. The results obtained in this application indicate that there is benefit in adopting the law of presumed consent, which has a positive effect on the organ donation rate, around 21 – 26%, compared to the law of informed consent.

La recherche doctorale étudie le rôle du droit face à la pénurie d’organes. L’objectif central consiste à dégager des pistes de réflexion de lege ferenda quant à la façon dont la science juridique peut tenter de répondre à cette problématique d’actualité et ainsi d’énoncer des propositions pour réduire le manque de greffons.Pour ce faire, il convient d’analyser le phénomène de pénurie dans son existence, ses origines et ses prolongements. En outre, un examen des règles existantes en Belgique, mais aussi dans d’autres pays et sur le plan international, et de l’impact de celles-ci sur l’insuffisance de transplants doit être réalisé, afin de mettre en évidence les options paraissant les plus appropriées. Les pays choisis pour la comparaison l’ont été pour le nombre élevé de dons qu’ils connaissent (l’Espagne et la Croatie) ou pour l’originalité et l’efficacité de leur système face la pénurie (pour l’originalité, l’Iran, qui a mis en place un système organisé par l’Etat de dons vivants rétribués, système ayant fait l’objet de plusieurs études dans les pays occidentaux ;pour l’efficacité, les États-Unis, qui ont notamment développé différents moyens pour favoriser au maximum les dons vivants).Sur cette base, des propositions inédites, destinées à appréhender de façon pertinente l’écart entre l’offre et la demande d’organes, sont formulées. Ces propositions sont valables au niveau belge mais pourraient mutatis mutandis être intéressantes pour d’autres pays, moyennant les adaptations nécessaires à la prise en compte de leurs spécificités. / The PhD research studies the role law could play in the organ shortage. The main purpose consists in finding de lege ferenda proposals so as to the way law could try dealing with this topical issue and offering ways to reduce the lack of organs.In order to do so, the phenomenon of the shortage as a whole – its existence, causes and consequences – has to be analyzed. Besides, a study of the rules applicable in Belgium, but also in other states and on the international level, as well as of their impact on the organ deficiency has to be realized, to highlight the options that seem the most appropriate. The countries were chosen for the comparison because of their high number of donations (that is the case of Spain and Croatia) or of the originality and efficiency of their system concerning the shortage (as for the originality, Iran has put in place a state-organized system of paid living donors, which has been the topic of several studies in Western countries; as for the efficiency, the United States have developed different ways to favor living donations to a maximum).On these grounds, different proposals designed to handle the gap between demand and supply of organs in a relevant way are formulated. These proposals are valid in the Belgian context but could also be interesting for other countries as long as appropriate adaptations are made to take their specificities into account. / Doctorat en Sciences juridiques / info:eu-repo/semantics/nonPublished