Over the course of the last century, organ transplantation has overcome major technical limitations to become the success it is today. The breakthroughs include developing techniques for vascular ...anastomoses, managing the immune response (initially by avoiding it with the use of identical twins and subsequently controlling it with chemical immunosuppressants), and devising preservation solutions that enable prolonged periods of ex vivo storage while preserving function. One challenge that has remained from the outset is to overcome the shortage of suitable donor organs. The results of organ transplantation continue to improve, both as a consequence of the above innovations and the improvements in peri- and postoperative management. This review describes some of the achievements and challenges of organ transplantation.
Several groups have reported extended survival of genetically engineered pig organs in nonhuman primates, varying from almost 10 months for life-supporting kidney grafts and more than 2 years for ...non-life-supporting heart grafts to less than 1 month for life-supporting liver and lung grafts. We have attempted to define groups of patients who may not have an option to wait for an allograft. These include kidney, heart, and lung candidates who are highly-allosensitized. In addition, some kidney candidates (who have previously lost at least 2 allografts from rapid recurrence of native kidney disease) have a high risk of further recurrence and will not be offered a repeat allotransplant. Patients with complex congenital heart disease, who may have undergone previous palliative surgical procedures, may be unsuitable for ventricular assist device implantation. Patients dying of fulminant hepatic failure, for whom no alternative therapy is available, may be candidates for a pig liver, even if only as a bridge until an allograft becomes available. When the results of pig organ xenotransplantation in nonhuman primates suggest a realistic potential for success of a pilot clinical trial, highly selected patients should be offered participation.
The coronavirus disease 2019 (COVID-19) pandemic has had a major global impact on solid organ transplantation (SOT). An estimated 16% global reduction in transplant activity occurred over the course ...of 2020, most markedly impacting kidney transplant and living donor programs, resulting in substantial knock-on effects for waitlisted patients. The increased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection risk and excess deaths in transplant candidates has resulted in substantial effort to prioritize the safe restart and continuation of transplant programs over the second year of the pandemic, with transplant rates returning towards prepandemic levels. Over the past 2 y, COVID-19 mortality in SOT recipients has fallen from 20%-25% to 8%-10%, attributed to the increased and early availability of SARS-CoV-2 testing, adherence to nonpharmaceutical interventions, development of novel treatments, and vaccination. Despite these positive steps, transplant programs and SOT recipients continue to face challenges. Vaccine efficacy in SOT recipients is substantially lower than the general population and SOT recipients remain at an increased risk of adverse outcomes if they develop COVID-19. SOT recipients and transplant teams need to remain vigilant and ongoing adherence to nonpharmaceutical interventions appears essential. In this review, we summarize the global impact of COVID-19 on transplant activity, donor evaluation, and patient outcomes over the past 2 y, discuss the current strategies aimed at preventing and treating SARS-CoV-2 infection in SOT recipients, and based on lessons learnt from this pandemic, propose steps the transplant community could consider as preparation for future pandemics.
This overview traces the history of regenerative medicine pertinent to organ transplantation, illustrates potential clinical applications reported to date, and highlights progress achieved in the ...field of complex modular organ engineering. Regenerative medicine can now produce relatively simple tissues such as skin, bladders, vessels, urethras, and upper airways, whereas engineering or generation of complex modular organs remains a major challenge. Ex vivo organ engineering may benefit from complementary investigations in the fields of developmental biology and stem cells and transplantation before its full potential can be realized.
Prolonging the lifespan of transplanted organs is critical to combat the shortage of this life‐saving resource. Chronic rejection, with irreversible demise of the allograft, is often caused by the ...development of donor‐specific HLA antibodies. Currently, enumerating molecular (amino acid) mismatches between recipient and donor is promoted to identify patients at higher risk of developing HLA antibodies, for use in organ allocation, and immunosuppression‐minimization strategies. We have counseled against the incorporation of such approaches into clinical use and hypothesized that not all molecular mismatches equally contribute to generation of donor‐specific immune responses. Herein, we document statistical shortcomings in previous study design: for example, use of individuals who lack the ability to generate donor‐specific‐antibodies (HLA identical) as part of the negative cohort. We provide experimental evidence, using CRISPR‐Cas9‐edited cells, to rebut the claim that the HLAMatchmaker eplets represent “functional epitopes.” We further used unique sub‐cohorts of patients, those receiving an allograft with two HLA‐DQ mismatches yet developing antibodies only to one mismatch (2MM1DSA), to interrogate differential immunogenicity. Our results demonstrate that mismatches of DQα05‐heterodimers exhibit the highest immunogenicity. Additionally, we demonstrate that the DQα chain critically contributes to the overall qualities of DQ molecules. Lastly, our data proposes that an augmented risk to develop donor‐specific HLA‐DQ antibodies is dependent on qualitative (evolutionary and functional) divergence between recipient and donor, rather than the mere number of molecular mismatches. Overall, we propose an immunological mechanistic rationale to explain differential HLA‐DQ immunogenicity, with potential ramifications for other pathological processes such as autoimmunity and infections.
The availability of direct‐acting antiviral agents for the treatment of hepatitis C virus (HCV) infection has resulted in a profound shift in the approach to the management of this infection. These ...changes have affected the practice of solid organ transplantation by altering the framework by which patients with end‐stage organ disease are managed and receive organ transplants. The high level of safety and efficacy of these medications in patients with chronic HCV infection provides the opportunity to explore their use in the setting of transplanting organs from HCV‐viremic patients into non–HCV‐viremic recipients. Because these organs are frequently discarded and typically come from younger donors, this approach has the potential to save lives on the solid organ transplant waitlist. Therefore, an urgent need exists for prospective research protocols that study the risk versus benefit of using organs for hepatitis C–infected donors. In response to this rapidly changing practice and the need for scientific study and consensus, the American Society of Transplantation convened a meeting of experts to review current data and develop the framework for the study of using HCV viremic organs in solid organ transplantation.
This article summarizes key points from a recent multidisciplinary meeting addressing the expansion of transplanting hepatitis C virus–infected donor organs in solid organ recipients. Fishman and Forns respond in an editorial on page 2755, and the conversation continues in the Letters to the Editor section (pages 2986, 2988, 2989).
The COVID‐19 pandemic has rapidly evolved and changed our way of life in an unprecedented manner. The emergence of COVID‐19 has impacted transplantation worldwide. The impact has not been just ...restricted to issues pertaining to donors or recipients, but also health‐care resource utilization as the intensity of cases in certain jurisdictions exceeds available capacity. Here we provide a personal viewpoint representing different jurisdictions from around the world in order to outline the impact of the current COVID‐19 pandemic on organ transplantation. Based on our collective experience, we discuss mitigation strategies such as donor screening, resource planning, and a staged approach to transplant volume considerations as local resource issues demand. We also discuss issues related to transplant‐related research during the pandemic, the role of transplant infectious diseases, and the influence of transplant societies for education and disseminating current information.
The authors discuss the impact of COVID‐19 on donation and transplantation and provide a global framework for donor screening and management of transplant activity during the pandemic.
Background Solid organ transplant recipients are at increased risk of skin cancer, but population-based mortality data are limited. Objective Mortality and predictors of skin cancer death ...posttransplantation were investigated. Methods All US organ transplant recipients between 1987 and 2013, identified through the Organ Procurement and Transplantation Network Standard Transplant Analysis and Research file, were included. Mortality and hazard ratios (HR) were calculated for the overall population and patient subgroups. Results The overall mortality was 5308 per 100,000 person-years and the skin cancer–specific mortality was 35.27 per 100,000 person-years. Risk factors associated with skin cancer death included thoracic versus abdominal transplantation (HR 2.90, 95% confidence interval CI 2.52-3.34), age over 50 years (HR 2.86, CI 2.43-3.38), white race (HR 6.29, CI 4.63-8.53), and male sex (HR 1.85, CI 1.57-2.19). Mortality was highest for malignant melanoma (mortality of 11.48), followed by squamous cell carcinoma (mortality of 4.94) and Merkel cell carcinoma (mortality of 4.59). Limitations Limitations of this study included potential underreporting and misclassification of death from skin cancer in the data set. Conclusion Mortality from posttransplantation skin cancer is reported. Older patients, male patients, white patients, and thoracic transplant recipients had increased mortality from skin cancer.
The procedure combining medical assistance in dying (MAiD) with donations after circulatory determination of death (DCDD) is known as organ donation after euthanasia (ODE). The first international ...roundtable on ODE was held during the 2021 WONCA family medicine conference as part of a scoping review. It aimed to document practice and related issues to advise patients, professionals, and policymakers, aiding the development of responsible guidelines and helping to navigate the issues. This was achieved through literature searches and national and international stakeholder meetings. Up to 2021, ODE was performed 286 times in Canada, the Netherlands, Spain, and Belgium, including eight cases of ODE from home (ODEH). MAiD was provided 17,217 times (2020) in the eight countries where ODE is permitted. As of 2021, 837 patients (up to 14% of recipients of DCDD donors) had received organs from ODE. ODE raises some important ethical concerns involving patient autonomy, the link between the request for MAiD and the request to donate organs and the increased burden placed on seriously ill MAiD patients.
This comprehensive overview of organ donation after medical assistance in dying and its attendant issues reports an increasing frequency of this practice internationally.
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