Porcine kidney xenotransplantation for end-stage renal disease (ESRD) has reached the stage of clinical testing following major advances in donor pig genetic modifications and effective immunosuppressive strategies through decades of rigorous translational research. Reports of pig kidney xenograft survival beyond 1 year post-transplant in nonhuman primate (NHP) models justify optimism for its potential as an alternative to allotransplantation. In the United States, experimental transplantations of genetically engineered (GE) porcine kidneys into brain-dead subjects and a small number of ESRD patients have shown no evidence of hyperacute rejection and adequate pig kidney function for up to several months. Here we discuss pre-clinical/clinical results, infectious disease, ethical, and regulatory considerations, and propose evidence-based recommendations. For initial clinical trials in kidney xenotransplantation, we make the following recommendations: (i) transplantation with organs from a triple knockout (TKO) donor pig, preferably with added human transgenes, (ii) an immunosuppressive regimen with induction therapy to deplete T (and possibly B) cells, and maintenance therapy based on a cluster of differentiation (CD)40/CD154 co-stimulation pathway blockade, (iii) the patient should be fully acceptable as a candidate for allotransplantation but should be unlikely ever to receive an allograft. Patients aged 60-69 years (extendable to 40-75 years, if one of the criteria mentioned below is present), of blood group B or O, and with diabetes are most at risk in this regard. Other patients who could be considered are (i) those who have lost two or more previous kidney allografts from recurrent disease in the graft, (ii) those with broad human leukocyte antigen (HLA)-reactivity but no evidence of anti-pig antibodies, including swine leukocyte antigen (SLA), and (iii) those with failing vascular access. Clinical pilot studies in carefully and highly selected patients with no alternative therapy will provide the foundation upon which to base subsequent formal expanded clinical trials.

The standard treatment for end-stage organ failure is transplantation, but demand for organs has always vastly outstripped supply. Discussions are ongoing about the feasibility of addressing the organ shortage through measures like increasing organ donations, improving post-transplant outcomes, and xenotransplantation. This paper examines the rationale, risks, and costs of xenotransplantation, such as xenozoonoses, creating a new form of industrialized animal farming, abandoning animal ethics principles, and the opportunity costs of investing finite research dollars in xenotransplantation instead of investing in more viable strategies. Alternative strategies that can ethically and effectively address the demand for heart, kidney, and other transplants are recommended: Improving disease prevention and management to reduce demand for transplant organs, improving transplantation methods, and systemic changes to donor policies and organ recovery methods to increase overall supply. Upon careful exploration of the full landscape of organ transplantation, it is considered whether these alternative strategies that do not impose the definite harms and significant risks of xenotransplantation are the most ethical and effective means to increase life-saving options and improve clinical outcomes for patients in organ failure.

Recent advancements in genetic engineering have propelled the field of xenotransplantation from preclinical models to early compassionate use cases. As first-in-human clinical trials (FIHCTs) approach, we examine recent developments, ethical and regulatory challenges, immunological considerations, and the clinical infrastructure necessary for successful xenotransplantation trials.

Expanded access transplants of pig hearts, kidneys, and livers have identified key challenges. Heart xenotransplants revealed risks of antibody-mediated rejection and zoonotic infections, while kidney xenotransplants suggest that patient selection, rather than immune rejection, may have caused failures. While there has been a report of auxiliary liver transplantation conducted abroad, profound thrombocytopenia poses an obstacle. As FIHCTs draw near, critical clinical challenges include determining the optimal donor genetic constructs and immunosuppressive regimens. Enrollment criteria and patient selection pose additional complexity, alongside ethical concerns such as lifelong zoonosis monitoring. Only a limited number of centers have the expertise needed to conduct these complex trials.

Xenotransplantation holds great promise as a solution to organ shortages, but success in FIHCTs will require careful design, multidisciplinary collaboration, and strong infrastructure. Addressing immunologic, ethical, and patient selection challenges will be critical. With proper preparation, xenotransplantation could transform organ transplantation.

Porcine kidney xenotransplantation for end-stage renal disease (ESRD) has reached the stage of clinical testing following major advances in donor pig genetic modifications and effective immunosuppressive strategies through decades of rigorous translational research. Reports of pig kidney xenograft survival beyond 1 year posttranplant in nonhuman primate (NHP) models justify optimism for its potential as an alternative to allotransplantation. In the United States, experimental transplantations of genetically engineered (GE) porcine kidneys into brain-dead subjects and a small number of ESRD patients have shown no evidence of hyperacute rejection and adequate pig kidney function for up to several months. Here we discuss pre-clinical/clinical results, infectious disease, ethical, and regulatory considerations, and propose evidence-based recommendations. For initial clinical trials in kidney xenotransplantation, we make the following recommendations: (i) transplantation with organs from a triple knockout (TKO) donor pig, preferably with added human transgenes, (ii) an immunosuppressive regimen with induction therapy to deplete T (and possibly B) cells, and maintenance therapy based on a cluster of differentiation (CD)40/CD154 co-stimulation pathway blockade, (iii) the patient should be fully acceptable as a candidate for allotransplantation but should be unlikely ever to receive an allograft. Patients aged 60-69 years (extendable to 40-75 years, if one of the criteria mentioned below is present), of blood group B or O, and with diabetes are most at risk in this regard. Other patients who could be considered are (i) those who have lost two or more previous kidney allografts from recurrent disease in the graft, (ii) those with broad human leukocyte antigen (HLA)-reactivity but no evidence of anti-pig antibodies, including swine leukocyte antigen (SLA), and (iii) those with failing vascular access. Clinical pilot studies in carefully and highly selected patients with no alternative therapy will provide the foundation upon which to base subsequent formal expanded clinical trials.

First-in-human pig xenotransplant clinical trials may soon begin, which raises ethical concerns about patients' decision-making to participate in such trials. We assessed kidney transplant candidates' attitudes and hypothetical decision-making about participating in xenotransplant trials through semi-structured telephone interviews and an online survey. We analyzed qualitative data by thematic analysis and quantitative data by descriptive statistics. Twenty-eight patients participated in interviews; 142 patients participated in the survey. Most interview and survey respondents were male (68%, 56%), White (54%, 61%), or Black (36%, 22%). Although interview participants appreciated xenotransplantation research's potential to advance science, they expressed concerns about infection transmission and graft function. Few survey respondents were willing to participate in a pig kidney trial to test the safety of pig kidneys (12.6%) or pig kidney function (16.9%). Interview participants would be more likely to participate in a first-in-human pig kidney trial if receiving a human kidney was unlikely and their health status declined. Willingness would also depend on how long the pig kidney would function. Most interview participants were receptive to long-term monitoring, but not to family monitoring. Transplant programs planning xenotransplant trials should anticipate these types of concerns for optimizing human subject protections and conducting a robust informed consent process.

Advancements in xenotransplantation intersecting with modern machine perfusion technology offer promising solutions to patients with liver failure providing a valuable bridge to transplantation and extending graft viability beyond current limitations. Patients facing acute or acute chronic liver failure, post-hepatectomy liver failure, or fulminant hepatic failure often require urgent liver transplants which are severely limited by organ shortage, emphasizing the importance of effective bridging approaches. Machine perfusion is now increasingly used to test and use genetically engineered porcine livers in translational studies, addressing the limitations and costs of non-human primate models. Current reports about artificial and bioartificial liver support combined with xenografts showcase the potential in ex vivo xenogeneic perfusion. Breakthroughs, such as the perfusion of genetically modified porcine liver with FDA-approved machine perfusion systems connected to human blood circulation, underscore the interest and potential feasibility of a "liver dialysis" bridge to allotransplantation or recovery. This review provides an overview of the past and current research in the field of ex vivo pig liver xenoperfusion.

Liver transplantation represents a pivotal intervention in the management of end-stage liver disease, offering a lifeline to countless patients. Despite significant strides in surgical techniques and organ procurement, ethical dilemmas and debates continue to underscore this life-saving procedure. Navigating the ethical terrain surrounding this complex procedure is hence paramount. Dissecting the nuances of ethical principles of justice, autonomy and beneficence that underpin transplant protocols worldwide, we explore the modern challenges that plaques the world of liver transplantation. We investigate the ethical dimensions of organ transplantation, focusing on allocation, emerging technologies, and decision-making processes. PubMed, Scopus, Web of Science, Embase and Central were searched from database inception to February 29, 2024 using the following keywords: "liver transplant", "transplantation", "liver donation", "liver recipient", "organ donation" and "ethics". Information from relevant articles surrounding ethical discussions in the realm of liver transplantation, especially with regards to organ recipients and allocation, organ donation, transplant tourism, new age technologies and developments, were extracted. From the definition of death to the long term follow up of organ recipients, liver transplantation has many ethical quandaries. With new transplant techniques, societal acceptance and perceptions also play a pivotal role. Cultural, religious and regional factors including but not limited to beliefs, wealth and accessibility are extremely influential in public attitudes towards donation, xenotransplantation, stem cell research, and adopting artificial intelligence. Understanding and addressing these perspectives whilst upholding bioethical principles is essential to ensure just distribution and fair allocation of resources. Robust regulatory oversight for ethical sourcing of organs, ensuring good patient selection and transplant techniques, and high-quality long-term surveillance to mitigate risks is essential. Efforts to promote equitable access to transplantation as well as prioritizing patients with true needs are essential to address disparities. In conclusion, liver transplantation is often the beacon of hope for individuals suffering from end-stage liver disease and improves quality of life. The ethics related to transplantation are complex and multifaceted, considering not just the donor and the recipient, but also the society as a whole.

One objection to xenotransplantation is that it will require the large-scale breeding, raising and killing of genetically modified pigs. The pigs will need to be raised in designated pathogen-free facilities and undergo a range of medical tests before having their organs removed and being euthanised. As a result, they will have significantly shortened life expectancies, will experience pain and suffering and be subject to a degree of social and environmental deprivation. To minimise the impact of these factors, we propose the following option for consideration-ethically defensible xenotransplantation should entail the use of genetic disenhancement if it becomes possible to do so and if that pain and suffering cannot be eliminated by other means. Despite not being a morally ideal 'solution', it is morally better to prevent unavoidable pain until a viable non-animal alternative becomes available.

The transplantation of non-human organs into humans, or xenotransplantation (XTx), has recently garnered new attention and is being developed to help address the problem of organ scarcity in transplantation. Ethical issues surrounding XTx have been studied since initial interest arose decades ago and have experienced renewed discussion in the literature. However, the distinct and relevant differences when applied to children has largely been overlooked with few groups attending to the concerns that XTx in children raises. In this paper, we explore ethical challenges to be expected in paediatric XTx, in particular exploring organ sizing concerns, infectious risks, psychological burdens, and issues of moral hazard. We review these domains with the aim of highlighting the implications of pursuing paediatric XTx and the cross-disciplinary approach needed to solve these issues. Children require a unique analysis from a bioethical perspective to best prepare for the issues XTx presents.

Xenotransplant patient selection recommendations restrict clinical trial participation to seriously ill patients for whom alternative therapies are unavailable or who will likely die while waiting for an allotransplant. Despite a scholarly consensus that this is advisable, we propose to examine this restriction. We offer three lines of criticism: (1) The risk-benefit calculation may well be unfavorable for seriously ill patients and society; (2) the guidelines conflict with criteria for equitable patient selection; and (3) the selection of seriously ill patients may compromise informed consent. We conclude by highlighting how the current guidance reveals a tension between the societal values of justice and beneficence.

This report comprises the contents of the presentations and following discussions of a workshop of the German Heart Transplant Centers in Martinsried, Germany on cardiac xenotransplantation. The production and current availability of genetically modified donor pigs, preservation techniques during organ harvesting, and immunosuppressive regimens in the recipient are described. Selection criteria for suitable patients and possible solutions to the problem of overgrowth of the xenotransplant are discussed. Obviously microbiological safety for the recipient and close contacts is essential, and ethical considerations to gain public acceptance for clinical applications are addressed. The first clinical trial will be regulated and supervised by the Paul-Ehrlich-Institute as the National Competent Authority for Germany, and the German Heart Transplant Centers agreed to cooperatively select the first patients for cardiac xenotransplantation.

Early in 2022 the first pig to human cardiac xenotransplant was performed. The graft initially performed well, and rejection was well controlled. However, the graft failed, and the patient died 60 days after the procedure. The ethical issues relating to xenotransplantation include the risk/benefit to the individual, the risk of porcine-derived infectious agents crossing into humans, animal welfare and rights, issues of human and animal identity and concerns relating to fair allocation of organs and appropriate use of resources.These ethical issues are often addressed using emotional arguments, or through consequentialist or deontological lens. An alternative is to use approaches based on virtue ethics to understand the moral purpose (telos) of the research and the virtues (character traits) needed to be a good research clinician. In this review we will consider the virtues of justice, courage, temperance and practical wisdom, as well as the role of clinical curiosity, and their application to xenotransplantation. This provides an alternative approach for the clinical academic and others involved in the research to reflect on their practice.

Every year, hundreds of patients in England die whilst waiting for a kidney transplant, and this is evidence that the current system of altruistic-based donation is not sufficient to address the shortage of kidneys available for transplant. To address this problem, we propose a monopsony system whereby kidney donors can opt-in to receive financial compensation, whilst still preserving the right of individuals to donate without receiving any compensation. A monopsony system describes a market structure where there is only one 'buyer'-in this case the National Health Service. By doing so, several hundred lives could be saved each year in England, wait times for a kidney transplant could be significantly reduced, and it would lessen the burden on dialysis services. Furthermore, compensation would help alleviate the common disincentives to living kidney donation, such as its potential associated health and psychological costs, and it would also help to increase awareness of living kidney donation. The proposed system would also result in significant cost savings that could then be redirected towards preventing kidney disease and reducing health disparities. While concerns about exploitation, coercion, and the 'crowding out' of altruistic donors exist, we believe that careful implementation can mitigate these issues. Therefore, we recommend piloting financial compensation for living kidney donors at a transplant centre in England.

Dementia currently affects more than 55 million people worldwide, and scientists predict that this number will continue to rise. The most common form is Alzheimer's disease (AD), which is triggered, among other things, by dysfunctional cells in the human brain. Stem cell research attempts to counteract neurodegenerative processes, for example by replacing or treating diseased cells. In addition to human embryonic stem cells, since the successes of Takahashi and Yamanaka in 2006, there has been an increased focus on human induced pluripotent stem cells (hiPS cells). These cells avoid ethically challenging questions about the moral status of human embryos, but there are numerous problems, such as high production costs, side effects from the reprogramming process, or a potentially new moral status. These ethical issues will be examined primarily in relation to AD. The first part will be a discussion of hiPS cells and their importance for stem cell research, after which the focus turns to AD. Based on scientific studies, the relationship between hiPS cells and AD will be outlined as well as ethical implications presented. While potential limitations of hiPS cells have been discussed by numerous authors, an ethical perspective on the link between hiPS cells and AD seems to be neglected in the scientific community. The following risk analysis aims to identify a possible research agenda. In conclusion, the focus on individuals with AD may help to adopt an ethical stance that recognizes existing limitations and constructively engages with the possibilities of research.

Non-human animal chimeras, containing human neurological cells, have been created in the laboratory. Despite a great deal of debate, the status of such beings has not been resolved. Under normal definitions, such a being could either be unconventionally human or abnormally animal. Practical investigations in animal sentience, artificial intelligence, and now chimera research, suggest that such beings may be assumed to have no legal rights, so philosophy could provide a different answer. In this vein, therefore, we can ask: What would a chimera, if it could think, think about? Thinking is used to capture the phenomena of a novel, chimeric being perceiving its terrible predicament as no more than a laboratory experiment. The creation of a thinking chimera therefore forces us to reconsider our assumptions about what makes human beings (potentially) unique (and other sentient animals different), because, as such, a chimera's existence bridges our social and legal expectations about definitions of human and animal. Society has often evolved new social norms based on different kinds of (ir)rational contrivances; the imperative of non-contradiction, which is defended here, therefore requires a specific philosophical response to the rights of a thinking chimeric being.

It is envisioned that one day xenotransplantation will bring about a future where transplantable organs can be safely and efficiently grown in transgenic pigs to help meet the global organ shortage. While recent advances have brought this future closer, worries remain about whether it will be beneficial overall. The unique challenges and risks posed to humans that arise from transplanting across the species barrier, in addition to the costs borne by non-human animals, has led some to question the value of xenotransplantation altogether. In response, we defend the value of xenotransplantation research, because it can satisfy stringent welfare conditions on the permissibility of animal research and use. Along the way, we respond to the alleged concerns, and conclude that they do not currently warrant a cessation or a curtailing of xenotransplantation research.

The future of xenotransplantation is promising. However, the scientific process behind xenotransplantation, shown through the methodology of history and bioethics, involves stakeholders beyond the laboratory. We present three short vignettes, the history of a 20th-century pioneer in solid organ transplantation, the xenoheart received by David Bennett, and a global system of illegal organ procurement, to highlight the complexity of biomedical practice. Current solid organ transplantation systems are seemingly unsustainable and ineffective in satisfying a growing global demand for organs. Despite the shortcomings of current systems, we argue that the discourse surrounding xenotransplantation science is insufficient to construct a long-lasting and equitable replacement for solid organ transplantation. Xenotransplantation is more than a surgical technique, an interdisciplinary health concern, or a biomedical technology-it is deeply dependent on a series of cultural, historical, and social factors. Incorporating a greater variety of perspectives and disciplines into ongoing discussions of xenotransplantation science, while potentially frustrating in the short term, will act to maximize its potential as a paradigm-shifting science.

The knowledge accumulated throughout the years about liver regeneration has allowed a better understanding of normal liver physiology, by reconstructing the sequence of steps that this organ follows when it must rebuild itself after being injured. The scientific community has used several interdisciplinary approaches searching to improve liver regeneration and, therefore, human health. Here, we provide a brief history of the milestones that have advanced liver surgery, and review some of the new insights offered by the interdisciplinary work using animals, in vitro models, tissue engineering, or mathematical models to help advance the knowledge on liver regeneration. We also present several of the main approaches currently available aiming at providing liver support and overcoming organ shortage and we conclude with some of the challenges found in clinical practice and the ethical issues that have concomitantly emerged with the use of those approaches.