RESUMO
BACKGROUND: Xenografts from genetically modified pigs have become one of the most promising solutions to the dearth of human organs available for transplantation. The challenge in this model has been hyperacute rejection. To avoid this, pigs have been bred with a knockout of the alpha-1,3-galactosyltransferase gene and with subcapsular autologous thymic tissue. METHODS: We transplanted kidneys from these genetically modified pigs into two brain-dead human recipients whose circulatory and respiratory activity was maintained on ventilators for the duration of the study. We performed serial biopsies and monitored the urine output and kinetic estimated glomerular filtration rate (eGFR) to assess renal function and xenograft rejection. RESULTS: The xenograft in both recipients began to make urine within moments after reperfusion. Over the 54-hour study, the kinetic eGFR increased from 23 ml per minute per 1.73 m2 of body-surface area before transplantation to 62 ml per minute per 1.73 m2 after transplantation in Recipient 1 and from 55 to 109 ml per minute per 1.73 m2 in Recipient 2. In both recipients, the creatinine level, which had been at a steady state, decreased after implantation of the xenograft, from 1.97 to 0.82 mg per deciliter in Recipient 1 and from 1.10 to 0.57 mg per deciliter in Recipient 2. The transplanted kidneys remained pink and well-perfused, continuing to make urine throughout the study. Biopsies that were performed at 6, 24, 48, and 54 hours revealed no signs of hyperacute or antibody-mediated rejection. Hourly urine output with the xenograft was more than double the output with the native kidneys. CONCLUSIONS: Genetically modified kidney xenografts from pigs remained viable and functioning in brain-dead human recipients for 54 hours, without signs of hyperacute rejection. (Funded by Lung Biotechnology.).
Assuntos
Rejeição de Enxerto , Transplante de Rim , Transplante Heterólogo , Animais , Animais Geneticamente Modificados/cirurgia , Morte Encefálica , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Rejeição de Enxerto/prevenção & controle , Xenoenxertos/transplante , Humanos , Rim/patologia , Rim/fisiologia , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , Suínos/cirurgia , Transplante Heterólogo/efeitos adversos , Transplante Heterólogo/métodosRESUMO
Xenotransplantation (XTx) presents a potential clinical alternative to the shortage of human organs for transplantation. Before clinical trials occur in the United States, public assessments are crucial to understand potential barriers to acceptance. The purpose of this study was to explore barriers and identify characteristics associated with attitudes toward XTx. A survey assessing demographic characteristics and attitudes toward XTx was distributed to a nationally representative sample of adults aged ≥18 years in the United States. Regression analysis was employed to identify characteristics associated with attitudes toward XTx. Between May 25 and June 14, 2023, 5008 respondents completed the survey. Importantly, half of the respondents expressed low or no knowledge of either transplantation or XTx. Approximately 40% expressed discomfort with receiving a pig organ for themselves or a loved one. Despite a lack of xenotransplant outcome data, 36% were open to experimental XTx if they needed a transplant. However, 57% rated lack of current evidence of success or fear of complications as top concerns. Regression models consistently associated being younger, female, not needing an organ, or being a member of a racial minority group with lower acceptance. This survey is the largest to date exploring public attitudes toward XTx. Despite overall acceptance, concerns persist. Increasing public acceptance is key as the field advances.
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Xenotransplantation offers the potential to meet the critical need for heart and lung transplantation presently constrained by the current human donor organ supply. Much was learned over the past decades regarding gene editing to prevent the immune activation and inflammation that cause early organ injury, and strategies for maintenance of immunosuppression to promote longer-term xenograft survival. However, many scientific questions remain regarding further requirements for genetic modification of donor organs, appropriate contexts for xenotransplantation research (including nonhuman primates, recently deceased humans, and living human recipients), and risk of xenozoonotic disease transmission. Related ethical questions include the appropriate selection of clinical trial participants, challenges with obtaining informed consent, animal rights and welfare considerations, and cost. Research involving recently deceased humans has also emerged as a potentially novel way to understand how xeno-organs will impact the human body. Clinical xenotransplantation and research involving decedents also raise ethical questions and will require consensus regarding regulatory oversight and protocol review. These considerations and the related opportunities for xenotransplantation research were discussed in a workshop sponsored by the National Heart, Lung, and Blood Institute, and are summarized in this meeting report.
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Transplante de Coração , Transplante de Pulmão , Transplante Heterólogo , Transplante Heterólogo/ética , Humanos , Transplante de Pulmão/ética , Animais , Estados Unidos , Transplante de Coração/ética , National Heart, Lung, and Blood Institute (U.S.) , Pesquisa Biomédica/ética , Doadores de Tecidos/provisão & distribuição , Doadores de Tecidos/éticaRESUMO
Over the past year, 3 scientific teams conducted experiments of genetically edited porcine organs into human recipients, 3 of whom were deceased and 1 living. In this editorial, we describe challenges for the design of initial xenotransplantation clinical trials and focus on patient selection, consent, and requisite post-transplant follow-up. Given the uncertain clinical benefit of xenotransplantation, we propose that patient selection criteria might include novel elements, such as approaching patients who have a low quality of life and a strong aversion to continued dialysis therapy. We set expectations related to the importance of informing and protecting family members and medical teams who could be exposed to zoonotic viral infection from the donor organ and/or receive unwanted publicity. Meeting these challenges in trial design and oversight will require multidisciplinary expertise, a conceptual model that extends beyond the individual patient, and creative collaboration between scientists and regulatory agencies.
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Qualidade de Vida , Diálise Renal , Humanos , Animais , Suínos , Transplante Heterólogo , Rim , Doadores de TecidosRESUMO
US correctional facilities operate under a binary interpretation of gender, which can yield inherent risks and conflicts for incarcerated transgender people. We conducted a scoping literature review on challenges unique to transgender individuals within US correctional settings. Online databases were searched to identify papers that addressed the challenges of incarcerated transgender adults age 18 + within US correctional institutions. A concurrent analysis of legal literature was reviewed with key policy recommendations extracted. A total of 33 papers (21 scientific studies and 12 legal analyses) met criteria for inclusion. Of the 21 scientific studies, the majority of papers (n = 14) focused on transgender women and most (n = 13) utilized qualitative methods. Emerging themes revealed challenges in key domains of violence, health, healthcare access, housing, and a pervasive culture of transphobia. Legal analyses supported policy changes such as implementing case-by-case housing classification systems, providing all forms of gender-affirming care, and safeguarding gender expression. Transgender persons face distinct obstacles while incarcerated in US correctional facilities and are in need of expanded protections. Working in tandem with efforts to decarcerate and reduce criminal legal involvement, widespread institutional policy change, such as redefining housing assignment policies, ensuring gender-affirming healthcare, and expanding transgender-specific competency trainings for correctional staff, is necessary.
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Criminosos , Pessoas Transgênero , Adulto , Humanos , Feminino , Adolescente , Prisões , Identidade de Gênero , Atenção à SaúdeRESUMO
Use of extracorporeal membrane oxygenation (ECMO) in cardiopulmonary resuscitation, termed eCPR, offers the prospect of improving survival with good neurological function after cardiac arrest. After death, ECMO can also be used for enhanced preservation of abdominal and thoracic organs, designated normothermic regional perfusion (NRP), before organ recovery for transplantation. To optimize resuscitation and transplantation outcomes, healthcare networks in Portugal and Italy have developed cardiac arrest protocols that integrate use of eCPR with NRP. Similar dissemination of eCPR and its integration with NRP in the USA raise novel ethical issues due to a non-nationalized health system and an opt-in framework for organ donation, as well as other legal and cultural factors. Nonetheless, eCPR investigations are ongoing, and both eCPR and NRP are selectively employed in clinical practice. This paper delineates the most pressing relevant ethical considerations and proposes recommendations for implementation of protocols that aim to promote public trust and reduce conflicts of interest. Transparent policies should rely on protocols that separate lifesaving from organ preservation considerations; robust, centralized eCPR data to inform equitable and evidence-based allocations; uniform practices concerning clinical decision-making and resource utilization; and partnership with community stakeholders, allowing patients to make decisions about emergency care that align with their values. Proactively addressing these ethical and logistical challenges could enable eCPR dissemination and integration with NRP protocols in the USA, with the potential to maximize lives saved through both improved resuscitation with good neurological outcomes and increased organ donation opportunities when resuscitation is unsuccessful or not in accordance with individuals' wishes.
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Reanimação Cardiopulmonar , Oxigenação por Membrana Extracorpórea , Parada Cardíaca Extra-Hospitalar , Obtenção de Tecidos e Órgãos , Humanos , Preservação de Órgãos , Reanimação Cardiopulmonar/métodos , Oxigenação por Membrana Extracorpórea/métodos , Estudos RetrospectivosRESUMO
This manuscript reports on a landmark symposium on the ethical, legal and technical challenges of xenotransplantation in the UK. King's College London, with endorsement from the British Transplantation Society (BTS), and the European Society of Organ Transplantation (ESOT), brought together a group of experts in xenotransplantation science, ethics and law to discuss the ethical, regulatory and technical challenges surrounding translating xenotransplantation into the clinical setting. The symposium was the first of its kind in the UK for 20 years. This paper summarises the content of the expert lectures showcasing the progress which has been made in xenotransplantation including-the history of xenotransplantation, advances in gene edited animals and progress towards clinical xenotransplantation. We then set out the ethical and legal issues still to be resolved. Finally, we report the themes of the roundtable discussion highlighting areas of consensus and controversy. While the detail of the legal discussion was directed towards the UK, the principles and summary reported here are intended to be applicable to any jurisdiction seeking to implement clinical xenotransplantation.
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Research involving recently deceased humans that are physiologically maintained following declaration of death by neurologic criteria-or 'research involving the recently deceased'-can fill a translational research gap while reducing harm to animals and living human subjects. It also creates new challenges for honouring the donor's legacy, respecting the rights of donor loved ones, resource allocation and public health. As this research model gains traction, new empirical ethics questions must be answered to preserve public trust in all forms of tissue donation and in the practice of medicine while respecting the legacy of the deceased and the rights of donor loved ones. This article suggests several topics for immediate investigation to understand the attitudes and experiences of researchers, clinical collaborators, donor loved ones and the public to ensure research involving the recently deceased advances ethically.
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Donation after circulatory determination of death (DCDD) has increased organ donation rates in the US over the past decade within an established legal framework, which is consistent with and supports individual and family decisions regarding organ donation in the context of end-of-life care. A new application, controlled DCDD donation utilizing thoracoabdominal normothermic regional perfusion (NRP) protocols (cDCDD-NRP), provides the opportunity to maximize a donation decision by recovering additional organs for transplant, including the heart, and to limit the detrimental impact of warm ischemic time by perfusing organs in situ following the declaration of circulatory death. In this viewpoint, we narrate our rationale for why cDCDD-NRP is consistent within the existing legal framework for organ donation in the United States and recommend no changes to the Uniform Determination of Death Act.
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Preservação de Órgãos , Obtenção de Tecidos e Órgãos , Morte , Humanos , Preservação de Órgãos/métodos , Perfusão/métodos , Doadores de Tecidos , Estados UnidosRESUMO
This paper responds to the position statement released by the American College of Physicians (ACP) entitled "Ethics, Determination of Death, and Organ Transplantation in Normothermic Regional Perfusion (NRP) with Controlled Donation after Circulatory Determination of Death (cDCD): American College of Physicians Statement of Concern." The ACP's statement engages with critical ethical issues surrounding cDCD NRP, but several of their conclusions are flawed. Contrary to the statement, the practice respects the dead donor rule and the legal definition of death while honoring the wishes of the deceased and their loved ones to help save the lives of those in need of organ transplants. cDCD NRP is well established in many countries, it can enhance trust in medical practice and organ donation, and will increase the availability of optimal organs for life-saving transplants.
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Médicos , Obtenção de Tecidos e Órgãos , Morte , Humanos , Preservação de Órgãos , Perfusão , Doadores de Tecidos , Estados UnidosRESUMO
Solid organ transplant (SOT) candidates and recipients were not included in the COVID-19 vaccine trials that have justified vaccine administration to millions worldwide and will be critical to ending the pandemic. The risks of COVID-19 for SOT candidates and recipients combined with data about this population's response to other vaccines has led to transplant centers recommending vaccination for their candidates and recipients in accordance with guidance from major transplant organizations. Relevant ethics considerations include: weighing the low risk of vaccination causing transplant complications against potentially limited antibody response of vaccines for transplant recipients; the equitable distribution of vaccines among vulnerable populations; the duty to steward and respect organs as limited resources; the duty to support vaccination; and patient autonomy. Vaccinated transplant patients and candidates should also consider participating in research studies to better understand the efficacy and potential long-term risks in this patient population. There are difficult scenarios, like timing transplant after second vaccine dose, when to administer the second dose to a partially vaccinated candidate who gets an organ match, whether to vaccinate a recent transplant recipient with low exposure risk and which vaccine to use. Here we provide ethics considerations for vaccinating different groups within the transplant population.
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COVID-19 , Transplante de Órgãos , Vacinas contra COVID-19 , Humanos , SARS-CoV-2 , Transplantados , VacinaçãoRESUMO
Innovative research in deceased donation and transplantation often presents ethical challenges for researchers and those responsible for ethical governance of research. These challenges have been recognized as potential barriers to the conduct of research. We review the literature to identify and describe ethical considerations that may cause confusion or uncertainty in the context of research involving potential deceased donors or deceased donor transplantation. We normatively examine these considerations and discuss their implications for the ethical conduct of research. In addition to the complexities of research involving critically ill, dying or recently deceased individuals, uncertainty may arise regarding the ethical status of various individuals who may be involved in research aimed at improving availability and outcomes of organ transplantation. Consequently, routine ethical guidelines for clinical research may fail to provide clear guidance with regards to the design, conduct and governance of some deceased donation or transplantation studies. Ethical uncertainty may result in delays or barriers to research, or neglect of important ethical considerations. Specific ethical guidance is needed to support research in deceased donation and transplantation as the ethical considerations that arise in the design and conduct of such research may not be addressed in the existing guidelines for human research.
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Transplante de Órgãos , Obtenção de Tecidos e Órgãos , Humanos , Doadores de TecidosRESUMO
As the USA contends with another surge in COVID-19 cases, hospitals may soon need to answer the unresolved question of who lives and dies when ventilator demand exceeds supply. Although most triage policies in the USA have seemingly converged on the use of clinical need and benefit as primary criteria for prioritisation, significant differences exist between institutions in how to assign priority to patients with identical medical prognoses: the so-called 'tie-breaker' situations. In particular, one's status as a frontline healthcare worker (HCW) has been a proposed criterion for prioritisation in the event of a tie. This article outlines two major grounds for reconsidering HCW prioritisation. The first recognises trust as an indispensable element of clinical care and mistrust as a hindrance to any public health strategy against the virus, thus raising concerns about the outward appearance of favouritism. The second considers the ways in which proponents of HCW prioritisation deviate from the very 'ethics frameworks' that often preface triage policies and serve to guide resource allocation-a rhetorical strategy that may undermine the very ethical foundations on which triage policies stand. By appealing to trust and consistency, we re-examine existing arguments in favour of HCW prioritisation and provide a more tenable justification for adjudicating on tie-breaker events during crisis standards of care.
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COVID-19/terapia , Alocação de Recursos para a Atenção à Saúde/ética , Pessoal de Saúde , Política de Saúde , Hospitais/ética , Pandemias , Triagem/ética , Atitude Frente a Saúde , COVID-19/virologia , Tomada de Decisões/ética , Dissidências e Disputas , Ética , Ética Clínica , Prioridades em Saúde/ética , Humanos , Ética Baseada em Princípios , Saúde Pública/ética , Alocação de Recursos , SARS-CoV-2 , Confiança , Estados UnidosRESUMO
Controlled heart donation after circulatory determination of death (cDCD) is well established internationally with good outcomes and could be adopted in the United States to increase heart supply if ethical and logistical challenges are comprehensively addressed. The most effective and resource-efficient method for mitigating warm ischemia after circulatory arrest is normothermic regional perfusion (NRP) in situ. This strategy requires restarting circulation after declaration of death according to circulatory criteria, which appears to challenge the legal circulatory death definition requiring irreversible cessation. Permanent cessation for life-saving efforts must be achieved to assuage this concern and ligating principal vessels maintains no blood flow to the brain, which ensures natural progression to cessation of brain function. This practice-standard in some countries-raises unique concerns about prioritizing life-saving efforts, informed authorization from decision-makers, and the clinician's role in the patient's death. To preserve public trust, medical integrity, and respect for the donor, the donation conversation must not take place until after an un-coerced decision to withdraw life-sustaining treatment made in accordance with the patient's treatment goals. The decision-maker(s) must understand cDCD procedure well enough to provide genuine authorization and the preservation/procurement teams must be kept separate from the clinical care team.
Assuntos
Parada Cardíaca , Transplante de Coração , Obtenção de Tecidos e Órgãos , Morte , Humanos , Preservação de Órgãos , Perfusão , Doadores de Tecidos , Estados UnidosRESUMO
Implementing uncontrolled donation after circulatory determination of death (uDCDD) in the United States could markedly improve supply of donor lungs for patients in need of transplants. Evidence from US pilot programs suggests families support uDCDD, but only if they are asked permission for using invasive organ preservation procedures prior to initiation. However, non-invasive strategies that confine oxygenation to lungs may be applicable to the overwhelming majority of potential uDCDD donors that have airway devices in place as part of standard resuscitation. We propose an ethical framework for lung uDCDD by: (a) initiating post mortem preservation without requiring prior permission to protect the opportunity for donation until an authorized party can be found; (b) using non-invasive strategies that confine oxygenation to lungs; and (c) maintaining strict separation between the healthcare team and the organ preservation team. Attempting uDCDD in this way has great potential to obtain more transplantable lungs while respecting donor autonomy and family wishes, securing public support, and enabling authorized persons to affirm or cease preservation decisions without requiring evidence of prior organ donation intent. It ensures prioritization of life-saving, the opportunity to allow willing donors to donate, and respect for bodily integrity while adhering to current ethical norms.
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Seleção do Doador/ética , Consentimento Livre e Esclarecido/ética , Preservação de Órgãos/ética , Doadores de Tecidos/ética , Morte , Seleção do Doador/métodos , Seleção do Doador/organização & administração , Humanos , Preservação de Órgãos/métodos , Relações Profissional-Família , Doadores de Tecidos/provisão & distribuição , Estados UnidosRESUMO
Over 115 000 people are waiting for life-saving organ transplants, of whom a small fraction will receive transplants and many others will die while waiting. Existing efforts to expand the number of available organs, including increasing the number of registered donors and procuring organs in uncontrolled environments, are crucial but unlikely to address the shortage in the near future and will not improve donor/recipient compatibility or organ quality. If successful, organ bioengineering can solve the shortage and improve functional outcomes. Studying manufactured organs in animal models has produced valuable data, but is not sufficient to understand viability in humans. Before risking manufactured organ experimentation in living humans, study of bioengineered organs in recently deceased humans would facilitate evaluation of the function of engineered tissues and the complex interactions between the host and the transplanted tissue. Although such studies do not pose risk to human subjects, they pose unique ethical challenges concerning the previous wishes of the deceased, rights of surviving family members, effective operation and fair distribution of medical services, and public transparency. This article investigates the ethical, legal and social considerations in performing engineered organ research on the recently deceased.