[Organ donation and organ assessment after primary circulatory death and secondary brain death]. / Organspende und Organassessment nach primärem Herz-Kreislauf-Stillstand und sekundärem Hirntod.

BACKGROUND: The global organ shortage is the biggest obstacle to expand urgently needed liver transplantation activities. In addition to donation after brain death (DBD), donation after primary circulatory death (DCD) has also been introduced in many European countries to increase the number of donated organs. OBJECTIVE: This article summarizes the legal and ethical aspects of DCD, the practical donation process of DCD, the clinical results of DCD liver transplantation with a special focus on organ assessment before a planned DCD liver transplantation. RESULTS: In Europe 11 countries have active DCD liver transplantation programs and a total of 1230 DCD liver transplantations were performed in Europe in 2023. The highest proportion of DCD liver transplantations were recorded in Belgium (52.8%), the Netherlands (42.8%) and Switzerland (32.1%). The adequate selection of donors and recipients is crucial in DCD transplantation and the use of DCD livers particularly depends on the preparedness of the healthcare system for routine machine perfusion. The leaders are Belgium, France and Italy which implant around 68-74% of DCD organs. With an adequate organ assessment, the long-term results of DBD and DCD liver transplantations are comparable. To assess mitochondrial damage and thus organ quality, hypothermic oxygenated machine perfusion (HOPE) was introduced and has the secondary benefit of mitochondrial protection through oxygenation. The establishment of aerobic metabolism in mitochondria under hypothermia leads to a reduction of toxic metabolites and the restoration of ATP storage, which subsequently leads to a reperfusion light during implantation. CONCLUSION: Expanding the donor pool with DCD donors can counteract the global organ shortage. With adequate patient selection and routine organ assessment short-term and also long-term outcomes of DBD and DCD liver transplantation are comparable.

Increasing Utilization of Extended Criteria Donor Hearts for Transplantation: The OCS Heart EXPAND Trial.

BACKGROUND: Extended criteria donor (ECD) hearts available with donation after brain death (DBD) are underutilized for transplantation due to limitations of cold storage. OBJECTIVES: This study evaluated use of an extracorporeal perfusion system on donor heart utilization and post-transplant outcomes in ECD DBD hearts. METHODS: In this prospective, single-arm, multicenter study, adult heart transplant recipients received ECD hearts using an extracorporeal perfusion system if hearts met study criteria. The primary outcome was a composite of 30-day survival and absence of severe primary graft dysfunction (PGD). Secondary outcomes were donor heart utilization rate, 30-day survival, and incidence of severe PGD. The safety outcome was the mean number of heart graft-related serious adverse events within 30 days. Additional outcomes included survival through 2 years benchmarked to concurrent nonrandomized control subjects. RESULTS: A total of 173 ECD DBD hearts were perfused; 150 (87%) were successfully transplanted; 23 (13%) did not meet study transplantation criteria. At 30 days, 92% of patients had survived and had no severe PGD. The 30-day survival was 97%, and the incidence of severe PGD was 6.7%. The mean number of heart graft-related serious adverse events within 30 days was 0.17 (95% CI: 0.11-0.23). Patient survival was 93%, 89%, and 86% at 6, 12, and 24 months, respectively, and was comparable with concurrent nonrandomized control subjects. CONCLUSIONS: Use of an extracorporeal perfusion system resulted in successfully transplanting 87% of donor hearts with excellent patient survival to 2 years post-transplant and low rates of severe PGD. The ability to safely use ECD DBD hearts could substantially increase the number of heart transplants and expand access to patients in need. (International EXPAND Heart Pivotal Trial [EXPANDHeart]; NCT02323321; Heart EXPAND Continued Access Protocol; NCT03835754).

[Heart transplantation : Current situation]. / Herztransplantation : Ein aktueller Stand.

Heart transplantation is the gold-standard in the treatment of terminal heart failure. The shortage of donor hearts represents the major obstacle in patient care and necessitates the creation of waiting lists and allocation algorithms. The Transplantation Act regulates donor heart allocation according to the urgency and the prospects of success. Donor hearts can be implanted following the classical biatrial or the modern bicaval valve implantation technique with a slightly lower spectrum of complications. Modern mechanical perfusion systems enable extended transport times. After heart transplantation rejection reactions must be controlled by an individually adjusted immunosuppression to guarantee long-term survival with as few complications as possible.

Construction and validation of a prediction model for public acceptance of kidney xenotransplantation in China / 器官移植

Objective To explore the public attitude towards kidney xenotransplantation in China by constructing and validating the prediction model based on xenotransplantation questionnaire. Methods A convenient sampling survey was conducted among the public in China with the platform of Wenjuanxing to analyze public acceptance of kidney xenotransplantation and influencing factors. Using random distribution method, all included questionnaires (n=2 280) were divided into the training and validation sets according to a ratio of 7:3. A prediction model was constructed and validated. Results A total of 2 280 questionnaires were included. The public acceptance rate of xenotransplantation was 71.3%. Multivariate analysis showed that gender, marital status, resident area, medical insurance coverage, religious belief, vegetarianism, awareness of kidney xenotransplantation and whether on the waiting list for kidney transplantation were the independent influencing factors for public acceptance of kidney xenotransplantation (all P<0.05). The area under the curve (AUC) of receiver operating characteristic (ROC) of the prediction model in the training set was 0.773, and 0.785 in the validation set. The calibration curves in the training and validation sets indicated that the prediction models yielded good prediction value. Decision curve analysis (DCA) suggested that the prediction efficiency of the model was high. Conclusions In China, public acceptance of kidney xenotransplantation is relatively high, whereas it remains to be significantly enhanced. The prediction model based on questionnaire survey has favorable prediction efficiency, which provides reference for subsequent research.

Trends in pediatric donor heart discard rates and the potential use of unallocated hearts for allogeneic valve transplantation.

Objectives: Allogeneic valve transplantation is an emerging therapy that delivers a living valve from a donor heart. We reviewed the national discard rate of pediatric and young adult (aged 25 years or younger) donor grafts to estimate the number of hearts potentially available to source valve allotransplantation. Methods: We queried the United Network for Organ Sharing database to identify pediatric and young adult heart donors from 1987 to 2022. Donor heart discard was defined as nontransplantation of the allograft. Results: Of 72,460 pediatric/young adult heart donations, 41,065 (56.7%) were transplanted and 31,395 (43.3%) were unutilized. The average annual number of discarded hearts in era 1 (1987-2000), era 2 (2000-2010), and era 3 (2010-2022) was 791 (42.8%), 1035 (46.3%), and 843 (41.2%), respectively. From 2017 to 2021, the average annual number of discards by age was: 39 (31.8%) neonates/infants, 78 (38.0%) toddlers, 41 (49.4%) young children, 240 (38.0%) adolescents, and 498 (40.1%) young adults. High-volume procurement regions had the greatest proportion of nonutilization, with the national average discard rate ranging from 39% to 49%. The most frequently documented reasons for nonallocation were distribution to the heart valve industry (26.5%), presumably due to suboptimal graft function, poor organ function (22.7%), and logistical challenges (10.8%). Conclusions: With ∼900 pediatric/young adult donor hearts discarded annually, unutilized grafts represent a potential source of valves for allogeneic valve transplant to supplement current conduit and valve replacement surgery. The limited availability of neonatal and infant hearts may limit this technique in the youngest patients, for whom cryopreserved homografts or xenografts will likely remain the primary valve substitute.

Past, Current, and Future Perspectives on Transplanting Acute Kidney Injury Kidneys.

(1) Background: Acute kidney injury (AKI) kidneys have high non-utilization rates due to concerns regarding unfavorable outcomes. In this paper, we aimed to review the past, present, and future opinions on AKI kidneys. (2) Methods: A PubMed search was conducted for topics relevant to AKI kidney transplantation. (3) Results: Current short- and long-term data on AKI kidneys have demonstrated good outcomes including favorable graft function and survival. The role of procurement biopsies is controversial, but they have been shown to be beneficial in AKI kidneys by allowing clinicians to differentiate between reversible tubular injury and irreversible cortical necrosis. Machine perfusion has also been applied to AKI kidneys and has been shown to reduce delayed graft function (DGF). The incidence of DGF increases with AKI severity and its management can be challenging. Strategies employed to counteract this have included early initiation of dialysis after kidney transplantation, early targeting of adequate immunosuppression levels to minimize rejection risk, and establishment of outpatient dialysis. (4) Conclusions: Despite good outcomes, there continue to be barriers that impact AKI kidney utilization. Successful strategies have included use of procurement biopsies or machine perfusion and expectant management of DGF. With increasing experience, better use of AKI kidneys can result in additional opportunities to expand the donor pool.

Advancing Perfusion Models: Dual-Vessel Ex Vivo Rat Liver Perfusion Based on a Clinical Setup.

Normothermic ex vivo liver machine perfusion (NEVLP) has been developed to address the increasing organ shortage in liver transplantation, through optimal preservation, assessment, and conditioning of grafts from extended criteria donors. There remains a need to establish simple and standardized animal models that simulate clinical NEVLP to test novel therapies. Liver grafts from 36 Sprague-Dawley rats were perfused for 6 h in a dual-vessel NEVLP system with a Dulbecco's modified Eagles medium-based perfusate supplemented with rat plasma and erythrocytes. Varying doses of the clinically used vasodilator epoprostenol, Kupffer cell inhibitor glycine, and a Steen™-based perfusate were assessed. Perfusion pressures and bile production were recorded, and perfusate was analyzed for transaminase secretion. Tissue samples were evaluated histologically, and levels of cytokines and 8-Isoprostane were measured. Increasing levels of epoprostenol and the addition of glycine resulted in a stepwise decrease of transaminase secretion and improved bile production. Steen further decreased transaminase release and interleukin 1 beta levels. Liver grafts perfused with the optimized Steen-based protocol exhibited lowest levels of oxidative stress and best-preserved liver integrity. In conclusion, epoprostenol seemed to ameliorate liver function and prevent cellular damage beyond its vasodilatory effect, with glycine acting synergistically. The anti-inflammatory and antioxidative properties of Steen further improved the outcome of perfusion. Our rodent NEVLP system may be used to rapidly test new agents for the pharmacologic conditioning of livers and help translate findings from bench-to-bedside.

Evaluation of Physician's Attitudes and Knowledge Regarding the Diagnosis of Brain Death in Deceased Organ Transplantation in Northern Cyprus.

Introduction Increasing deceased organ transplantation rates is an important strategy to overcome the organ shortage. Prior to the pandemic in Northern Cyprus, there were more transplants from deceased donors than from living donors. However, after the pandemic, living donor organ transplants were almost equal to cadaveric organ transplants. The purpose of this study was to explore the knowledge, attitudes, and experiences of hospital-based clinicians involved in the diagnosis of brain death and donor care in order to raise the deceased organ transplantation rate. Methods The study population consisted of three departments: physicians' anesthesiology, neurology, and neurosurgeons, who signed off on the brain death report. The demographic information of the participants was recorded. A total of 31 questions in the questionnaire were about personal experiences, attitudes toward brain death, organ donation, and donor care, and the level of knowledge and expertise required for the identification and care of potential organ donors. The answers are "agree," "indecisive," and "disagree." Results A total of 29 physicians, seven (24.1%) neurologists, six (20.7%) neurosurgeons, and 16 (55.2%) anesthesiologists answered the questionnaire. Although all of the participants stated that brain death is a definite death, it was determined that they did not agree on how the process should proceed for non-donors after the diagnosis of brain death. Conclusion Physicians' attitudes towards deceased organ transplantation are positive. It is pointed out that society's insensitivity and indifference to the decrease in organ donation rates. Multidisciplinary work motivation may increase deceased organ transplant rates.

Reassessing Geographic, Logistical, and Cold Ischemia Cutoffs in Liver Transplantation.

INTRODUCTION: Liver acceptance patterns vary significantly between transplant centers. Data pertaining to outcomes of livers declined by local and regional centers and allocated nationally remains limited. PROJECT AIM: The objective was to compare post-liver transplant outcomes between liver allografts transplanted as a result of national and local-regional allocation. DESIGN: This was a retrospective evaluation of 109 nationally allocated liver allografts used for transplant by a single center. Outcomes of nationally allocated grafts were compared to standard allocation grafts (N = 505) during the same period. RESULTS: Recipients of nationally allocated grafts had lower model for end stage liver disease scores (17 vs 22, P = .001). Nationally allocated grafts were more likely to be post-cross clamp offers (29.4% vs 13.4%, P = .001) and have longer cold ischemia times (median hours 7.8 vs 5.5, P = .001). Early allograft dysfunction was common (54.1% vs 52.5%, P = .75) and did not impact hospital length of stay (median 5 vs 6 days, P = .89). There were no differences in biliary complications (P = .11). There were no differences in patient (P = .88) or graft survival (P = .35). In a multivariate model, after accounting for differences in cold ischemia time and posttransplant biliary complications, nationally allocated grafts were not associated with increased risk for graft loss (HR 0.9, 95% CI 0.4-1.8). Abnormal liver biopsy findings (33.0%) followed by donor donation after circulatory death status (22.9%) were the most common reasons for decline by local-regional centers. CONCLUSION: Despite longer cold ischemia times, patient and graft survival outcomes remain excellent and comparable to those seen from standard allocation grafts.

Expanding Liver Transplant Opportunities in Older Patients With Nonconventional Grafts.

INTRODUCTION: Broader use of donation after circulatory death (DCD) and nonconventional grafts for liver transplant helps reduce disparities in organ availability. Limited data, however, exists on outcomes specific to nonconventional graft utilization in older patients. As such, this study aimed to investigate outcomes specific to conventional and nonconventional graft utilization in recipients > 70 y of age. METHODS: 1-to-3 matching based on recipient sex, Model for End-Stage Liver Disease score, and donor type was performed on patients ≥70 and <70 y of age who underwent liver transplant alone at Mayo Clinic Arizona between 2015 and 2020. Primary outcomes were posttransplant patient and liver allograft survival for recipients greater than or less than 70 y of age. Secondary outcomes included grafts utilization patterns, hospital length of stay, need for reoperation, biliary complications and disposition at time of hospital discharge. RESULTS: In this cohort, 36.1% of grafts came from DCD donors, 17.4% were postcross clamp offers, and 20.8% were nationally allocated. Median recipient ages were 59 and 71 y (P < 0.01). Recipients had similar Intensive care unit (P = 0.82) and hospital (P = 0.14) lengths of stay, and there were no differences in patient (P = 0.68) or graft (P = 0.38) survival. When comparing donation after brain death and DCD grafts in those >70 y, there were no differences in patient (P = 0.89) or graft (P = 0.71) survival. CONCLUSIONS: Excellent outcomes can be achieved in older recipients, even with use of nonconventional grafts. Expanded use of nonconventional grafts can help facilitate transplant opportunities in older patients.

Ex Vivo Liver Machine Perfusion: Comprehensive Review of Common Animal Models.

The most common preservation technique for liver grafts is static cold storage. Due to the organ shortage for liver transplantation (LT), extended criteria donor (ECD) allografts are increasingly used-despite the higher risk of inferior outcome after transplantation. Ex vivo liver machine perfusion (MP) has been developed to improve the outcome of transplantation, especially with ECD grafts, and is currently under evaluation in clinical trials. We performed a literature search on PubMed and ISI Web of Science to assemble an overview of rodent and porcine animal models of ex vivo liver MP for transplantation, which is essential for the present and future development of clinical liver MP. Hypothermic, subnormothermic, and normothermic MP systems have been successfully used for rat and pig LT. In comparison with hypothermic systems, normothermic perfusion often incorporates a dialysis unit. Moreover, it enables metabolic assessment of liver grafts. Allografts experiencing warm ischemic time have a superior survival rate after MP compared with cold storage alone, irrespective of the temperature used for perfusion. Furthermore, ex vivo MP improves the outcome of regular and ECD liver grafts in animal models. Small and large animal models of ex vivo liver MP are available to foster the further development of this new technology. Impact Statement Ex vivo machine perfusion is an important part of current research in the field of liver transplantation. While evidence for improve storage is constantly rising, the development of future applications such as quality assessment and therapeutic interventions necessitates robust animal models. This review is intended to provide an overview of this technology in common large and small animal models and to give an outlook on future applications. Moreover, we describe developmental steps that can be followed by others, and which can help to decrease the number of animals used for experiments based on the replace, reduce, refine concept.

The liver transplant surgeon Mondays blues: an Italian perspective.

Poor data exist on the influence of holidays and weekdays on the number and the results of liver transplantation (LT) in Italy. The study's main objective is to investigate the impact of holidays and the different days of the week on the LT number and early graft survival rates in a multi-centric Italian series. We performed a retrospective analysis on 1,026 adult patients undergoing first deceased-donor transplantation between January 2004 and December 2018 in the three university centers in Rome. During the 4,504 workdays, 881 LTs were performed (85.9%; one every 5.1 days on average). On the opposite, 145 LTs were done during the 975 holidays (14.1%; one every 7.1 days on average). Fewer LTs were performed on holidays (P = 0.004). There were no substantial differences in donor-, recipient- and transplant-related characteristics in LTs performed on weekdays or holidays. On Monday, fewer transplants were performed (vs. other weekdays: P < 0.0001; vs. Sunday: P = 0.03). At multivariable Cox regression analysis, LTs performed during the holiday or during the different days of the week were not found to be independent risk factors for the risk of 3- and 12-month graft loss. At three-month survival curves, no differences were observed among the transplants performed during the holidays versus the workdays (86.2 vs. 85.0%; P-0.70). The range of graft survival rates based on the day of the week was 81.6-86.9%, without showing any significant differences (P = 0.57). Fewer transplants are performed on holidays and Mondays. Survivals are not affected by holidays or the day the transplant is performed.

Unaddressed regulatory issues in xenotransplantation: a hypothetical example.

The last few years have seen a significant increase in the use of technology to manipulate genetic sequences and generate animals as a source of xeno-organs. This has made the generation of genetically bespoke organisms a reality. This paper will analyze the regulatory and practical aspects of such an innovative approach to xenotransplantation on the basis of a hypothetical case study applied to Germany and highlight the gaps in the current regulation. This paper thus provides the basis for legal debate within a specific country. In addition, the identified gaps also pose a barrier toward the harmonization of international regulation. This publication therefore lays the groundwork for guiding the international debate regarding the regulatory framework for solid organ xenotransplantation toward specific issues.

Transmission of porcine endogenous retrovirus in xenotransplantation / 器官移植

Organ transplantation is the most effective treatment for various types of end-stage diseases. To resolve the problem of donor shortage in organ transplantation, the possibility of xenotransplantation has been gradually explored by surgeons. Pig is one of the common donor sources for xenotransplantation. As a bridge between two species, the viruses carried by pig organs may be transmitted between species and cause the risk of zoonosis. Porcine endogenous retrovirus (PERV) is integrated into the genome, which is a category of retrovirus featuring cross-species transmission. In this article, the influencing factors of transmission characteristics of PERV, the transmission risk of PERV and its recombinant virus, and the detection and transmission risk assessment of PERV in xenotransplantation test were reviewed, aiming to provide reference for alleviating severe shortage of donor organs and driving the advancement of xenotransplantation technologies.

Attitudes and influencing factors of transplantation-related populations towards kidney xenotransplantation / 器官移植

Objective To investigate the attitudes and influencing factors of transplantation-related populations towards kidney xenotransplantation. Methods From June 2022 to January 2023, stratified random sampling was performed from patients awaiting kidney transplantation, patients after kidney transplantation, patients' relatives and medical students. Four hundred subjects were collected from each population and 1600 subjects were investigated using a self-designed questionnaire. Baseline data of the respondents, their attitudes towards kidney xenotransplantation and the reasons of rejecting kidney xenotransplantation were analyzed. The influencing factors of attitudes towards kidney xenotransplantation were also identified. Results A total of 1 493 valid questionnaires were collected, and the questionnaire retrieval rate was 93.31%. About 93.10% of the respondents accepted allogeneic kidney transplantation, and 66.78% had heard of kidney xenotransplantation. Seven hundred and ninety-five respondents suggested that they could accept kidney xenotransplantation "when kidney xenotransplantation and allogeneic kidney transplantation yielded the same results and risks". Six hundred and ninety-eight respondents indicated that they were "unable" or "uncertain" whether they could accept kidney xenotransplantation (χ2=16.409，P=0.001). Among these 698 respondents, the proportion of them who were willing to accept kidney xenotransplantation when they did not meet the conditions of allogeneic kidney transplantation was 10.9%. About 35.8% of respondents were willing to accept kidney xenotransplantation if it yielded less risk and better prognosis compared with allogeneic kidney transplantation. If the time of awaiting kidney xenotransplantation was shorter than that of allogeneic kidney transplantation, 21.2% were willing to accept kidney xenotransplantation. If the cost of kidney xenotransplantation was less than that of allogeneic kidney transplantation, 24.5% of them were willing to accept kidney xenotransplantation. The main reasons of rejecting kidney xenotransplantation included surgical risk and other unknown risks. Multivariate analysis showed that respondents residing in cities and towns for a long period of time, those who accept allogeneic kidney transplantation and those who have heard of kidney xenotransplantation showed more positive attitudes towards kidney xenotransplantation. Conclusions Different transplantation-related populations have different attitudes towards kidney xenotransplantation, and the overall attitudes are positive. Active promotion of kidney xenotransplantation research and carrying out relevant popular science education contribute to improving public attitudes towards the acceptance of kidney xenotransplantation.

Ethical construction of recipients’ rights and interests protection in organ transplantation from expanded criteria donors / 器官移植

Under the background of severe shortage of donor organs and organ donation after citizen's death becoming the main source of donor organs in China, expanded criteria donor (ECD) has been widely applied in clinical practice. However, ECD has the disadvantages of basic diseases, old age, trauma, shock or infection, which will affect the quality of donor organs to varying degrees and become one of critical factors affecting clinical efficacy of organ transplantation. The recipients of ECD organ transplantation will also bear the additional risk and uncertainty of efficacy brought by ECD organs. Hence, it is necessary to pay attention to the protection of the recipients’ rights and interests. In this article, ethical issues faced by ECD organ transplantation in recipient protection and the shortcomings in the ethical review of organ ethics committee were reviewed, and suggestions on the ethical review institution and system construction of the rights and interests of organ transplantation recipients were elucidated, aiming to provide reference for promoting the advancement of ECD organ transplantation.

The past, present and future of heart transplantation / 器官移植

Heart transplantation is one of the most effective strategies to treat end-stage heart failure. Multiple challenges, such as difficulty in preservation of heart allograft, rejection and postoperative complications, emerge in heart allotransplantation. After decades of research and practice, most problems have been resolved. Nevertheless, the shortage of donor organs has become increasingly prominent. To alleviate the shortage of donor organs, artificial heart and heart xenotransplantation have captivated attention, and obtained significant progress in recent years. The application of artificial heart in clinical practice has significantly enhanced the survival rate of patients with end-stage heart failure, which is expected to become the standard treatment for end-stage heart failure. Heart xenotransplantation still faces many challenges, which is still far from clinical application. In this article, the history of heart transplantation, development of heart allotransplantation, use of artificial heart and research progress on heart xenotransplantation were reviewed, and the future development direction of heart transplantation was predicted.

Ethical Solutions to the Problem of Organ Shortage.

Organ shortage is a major survival issue for millions of people worldwide. Globally 1.2 million people die each year from kidney failure. In this paper, we critically examine and find lacking extant proposals for increasing organ supply, such as opting in and opt out for deceased donor organs, and parochial altruism and paired kidney exchange for live organs. We defend two ethical solutions to the problem of organ shortage. One is to make deceased donor organs automatically available for transplant without requiring consent from the donor or their relatives. The other is for society to buy nonvital organs in a strictly regulated market and provide them to people in need for free.