The 50 most-cited articles in Transplantation, 2024

BK polyomavirus (BKPyV) remains a significant challenge after kidney transplantation. International experts reviewed current evidence and updated recommendations according to Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Risk factors for BKPyV-DNAemia and biopsy-proven BKPyV-nephropathy include recipient older age, male sex, donor BKPyV-viruria, BKPyV-seropositive donor/-seronegative recipient, tacrolimus, acute rejection, and higher steroid exposure. To facilitate early intervention with limited allograft damage, all kidney transplant recipients should be screened monthly for plasma BKPyV-DNAemia loads until month 9, then every 3 mo until 2 y posttransplant (3 y for children). In resource-limited settings, urine cytology screening at similar time points can exclude BKPyV-nephropathy, and testing for plasma BKPyV-DNAemia when decoy cells are detectable. For patients with BKPyV-DNAemia loads persisting >1000 copies/mL, or exceeding 10 000 copies/mL (or equivalent), or with biopsy-proven BKPyV-nephropathy, immunosuppression should be reduced according…

On June 3, 2023, the American Society of Transplant Surgeons convened a meeting in San Diego, California to (1) develop a consensus statement with supporting data on the ethical tenets of thoracoabdominal normothermic regional perfusion (NRP) and abdominal NRP; (2) provide guidelines for the standards of practice that should govern thoracoabdominal NRP and abdominal NRP; and (3) develop and implement a central database for the collection of NRP donor and recipient data in the United States. National and international leaders in the fields of neuroscience, transplantation, critical care, NRP, Organ Procurement Organizations, transplant centers, and donor families participated. The conference was designed to focus on the controversial issues of neurological flow and function in donation after circulatory death donors during NRP and propose technical standards necessary to ensure that this procedure is performed safely and effectively. This article discusses major topics and conclusions addressed at the meeting.

BACKGROUND: Standard-of-care biomarkers for renal allograft rejection are lagging indicators, signaling existing organ injury. This precludes early intervention, when immunological cascades leading to rejection are most susceptible. Donor-derived cell-free DNA (dd-cfDNA) shows promise as an early indicator of rejection, allowing earlier and possibly more effective treatment. This analysis was designed to assess this promise using real-world dd-cfDNA testing evidence. METHODS: This retrospective analysis of the prospective, observational ProActive registry study (NCT04091984) assessed dd-cfDNA and serum creatinine levels before biopsy in 424 patients with ≥1 dd-cfDNA test (n = 1013) in the 6 mo before biopsy. RESULTS: Of 4667 enrolled patients, 1631 patients had ≥18 mo of follow-up data, of which 424 had a biopsy and were included in this analysis. Twenty-six biopsies showed antibody-mediated rejection (ABMR), 62 showed T cell-mediated rejection, and 336 showed nonrejection; each from a unique patient. dd-cfDNA fractions were significantly elevated 5 mo before ABMR biopsies, and 2 mo…

BACKGROUND: The availability of in situ normothermic regional perfusion (NRP) or ex situ normothermic machine perfusion (NMP) has revolutionized donation after circulatory death (DCD) liver transplant (LT). While some have suggested that NRP and NMP may represent competing technologies for DCD LT, there are many scenarios where these technologies can function in a complementary manner. METHODS: Between January 2022 and March 2024, 83 DCD LTs were performed using NRP (62 NRP alone and 21 NRP + NMP) and were compared with 297 static cold storage (SCS) DCD LTs. NRP + NMP was used in scenarios with (1) long travel distances, (2) complicated transplant recipients, or (c) the need for additional liver graft recovery in "marginal" cases. RESULTS: Ischemic cholangiopathy was lower in the NRP alone group (0%) and the NRP + NMP group (0%) compared with the SCS group (16.8; P < 0.001 and P = 0.04, respectively). In addition, early allograft dysfunction, number of packed red blood cells transfused, and acute kidney injury were lower in the NRP alone and NRP + NMP groups compared with the SCS…

BACKGROUND: Ex situ machine perfusion of the donor liver, such as dual hypothermic oxygenated machine perfusion (DHOPE), is increasingly used in liver transplantation. Although DHOPE reduces ischemia/reperfusion-related complications after liver transplantation, data on cost-effectiveness are lacking. Our objective was to evaluate the cost-effectiveness of DHOPE in donation after circulatory death (DCD) liver transplantation. METHODS: We performed an economic evaluation of DHOPE versus static cold storage (SCS) based on a multicenter randomized controlled trial in DCD liver transplantation (DHOPE-DCD trial; ClinicalTrials.gov number, NCT02584283). All patients enrolled in the 3 participating centers in the Netherlands were included. Costs related to the transplant procedure, hospital stay, readmissions, and outpatients treatments up to 1 y posttransplant were calculated. The cost for machine perfusion was calculated using 3 scenarios: (1) costs for machine perfusion, (2) machine perfusion costs plus costs for personnel, and (3) scenario 2 plus depreciation expenses for a dedicated…

Normothermic regional perfusion (NRP) is a surgical technique that can improve the quality and number of organs recovered for donation after the determination of death by circulatory criteria. Despite its promise, adoption of NRP has been hindered because of unresolved ethical issues. To inform stakeholders, this scoping review provides an impartial overview of the major ethical controversies surrounding NRP. We undertook this review according to a modified 5-step methodology proposed by Arksey and O'Malley. Publications were retrieved through MEDLINE and Embase. Gray literature was sourced from Canadian organ donation organizations, English-language organ donation organization websites, and through our research networks. Three reviewers independently screened all documents for inclusion, extracted data, and participated in content analysis. Disagreements were resolved through consensus meetings. Seventy-one documents substantively engaging with ethical issues in NRP were included for full-text analysis. We identified 6 major themes encompassing a range of overlapping ethical…

In kidney transplantation, ongoing alloimmune processes-commonly triggered by HLA incompatibilities-can trigger chronic transplant rejection, affecting the microcirculation and the tubulointerstitium. Continuous inflammation may lead to progressive, irreversible graft injury, culminating in graft dysfunction and accelerated transplant failure. Numerous experimental and translational studies have delineated a complex interplay of different immune mechanisms driving rejection, with antibody-mediated rejection (AMR) being an extensively studied rejection variant. In microvascular inflammation, a hallmark lesion of AMR, natural killer (NK) cells have emerged as pivotal effector cells. Their essential role is supported by immunohistologic evidence, bulk and spatial transcriptomics, and functional genetics. Despite significant research efforts, a substantial unmet need for approved rejection therapies persists, with many trials yielding negative outcomes. However, several promising therapies are currently under investigation, including felzartamab, a monoclonal antibody targeting the…

BACKGROUND: Over the past 20 y, robotic surgery has entered nearly all surgical disciplines, aiming to improve patient outcomes. Liver transplantation has evolved with these advancements, and fully robotic liver transplants represent the latest innovation in this field. This study reports on the world's first series of fully robotic recipient liver transplants from robotic living donors, comparing them with matched cases from the standard open transplant approach. METHODS: A case-control study was conducted at our center from August to December 2023. Patient selection criteria for robotic recipient liver transplantation included a Model for End-stage Liver Disease score of ≤25, specific anatomical characteristics, and logistics. A propensity score analysis with a 1:4 matching ratio was used. RESULTS: The study analyzed 10 fully robotic living donor and robotic recipient liver transplant pairs with a median donor age of 29 y and a recipient age of 61 y. The main indication for transplantation was nonalcoholic steatohepatitis (6/10). There was 1 robotic to open conversion, and the…

BACKGROUND: In Italy, 20 min of continuous, flat-line electrocardiogram are required for death declaration. Despite prolonged warm ischemia time, Italian centers reported good outcomes in controlled donation after circulatory death (cDCD) liver transplantation by combining normothermic regional and end-ischemic machine perfusion (MP). The aim of this study was to evaluate the safety and feasibility of the use of septuagenarian and octogenarian cDCD donors with this approach. METHODS: All cDCD older than 70 y were evaluated during normothermic regional perfusion and then randomly assigned to dual hypothermic or normothermic MP. RESULTS: In the period from April 2021 to December 2022, 17 cDCD older than 70 y were considered. In 6 cases (35%), the graft was not considered suitable for liver transplantation, whereas 11 (65%) were evaluated and eventually transplanted. The median donor age was 82 y, being 8 (73%) older than 80. Median functional warm ischemia and no-flow time were 36 and 28 min, respectively. Grafts were randomly assigned to ex situ dual hypothermic oxygenated MP in 6…

BACKGROUND: Glucagon-like peptide 1 receptor agonists (GLP1-RAs) reduce cardiovascular events and mortality in type 2 diabetes. Limited data are available on diabetes treatment after solid organ transplantation. We aimed to explore the effect of GLP1-RAs on cardiovascular outcomes in transplanted recipients with diabetes. METHODS: We extracted data on adult transplant recipients (kidney, lungs, liver, heart) insured in a large health maintenance organization. Death-censored patients with diabetes treated with GLP1-RAs were matched with nonusers. The primary outcome was a composite of major cardiovascular events (MACEs): a nonfatal cardiac event (myocardial infarction, stable/unstable angina, coronary bypass, and coronary angiography), ischemic stroke and all-cause mortality. Secondary outcomes were MACE or peripheral vascular disease (MACE-PVD), and all-cause mortality. Safety outcomes included biliopancreatic adverse events. RESULTS: We included 318 patients (69% males, average age 58.3 ± 11.0 y) with a 3.1-y median follow-up. The incidence of MACE was 101 of 1000 patient-years in…

BACKGROUND: The outcomes after kidney transplantation (KT), including access, wait time, and other issues around the globe, have been studied. However, issues do vary from one country to another. METHODS: We obtained data from several countries from North America, South America, Europe, Asia, and Australia, including the number of patients awaiting KT from 2015, transplant rate per million population (pmp), proportion of living donor and deceased donor (LD/DD) KT, and posttransplant survival. We also sought opinions on key difficulties faced by each of these countries with respect to KT and long-term survival. RESULTS: Variation in access to KT across the globe was noted. Countries with the highest rates of KT pmp included the United States (79%) and Spain (71%). A higher proportion of LD transplants was noted in Japan (93%), India (85%), Singapore (63%), and South Korea (63%). A higher proportion of DD KTs was noted in Spain (90%), Brazil (90%), France (85%), Italy (85%), Finland (85%), Australia-New Zealand (80%), and the United States (77%). The 5-y graft survival for LD was…

BACKGROUND: Normothermic regional perfusion (NRP) has emerged as a vital technique in organ procurement, particularly in donation after circulatory death (DCD) cases, offering the potential to optimize organ utilization and improve posttransplant outcomes. Recognizing its significance, the American Society of Transplant Surgeons (ASTS) convened a work group to develop standardized recommendations for abdominal NRP in the United States. METHODS: The workgroup, comprising experts in NRP, DCD, and transplantation, formulated recommendations through a collaborative process involving revisions and approvals by relevant committees and the ASTS council. Four key areas were identified for standardization: Preprocedure communication, NRP procedure, Terminology and documentation, and Mentorship/credentialing. RESULTS: The recommendations encompass a range of considerations, including preprocedure communication protocols to facilitate informed decision-making by transplant centers and organ procurement organizations, procedural guidelines for NRP teams, uniform terminology to clarify the NRP…

BACKGROUND: This study compares selection criteria for liver transplant (LT) for hepatocellular carcinoma (HCC) for inclusivity and predictive ability to identify the most permissive criteria that maintain patient outcomes. METHODS: The Scientific Registry of Transplant Recipients (SRTR) database was queried for deceased donor LT's for HCC (2003-2020) with 3-y follow-up; these data were compared with a 2-center experience. Milan, University of California, San Francisco (UCSF), 5-5-500, Up-to-seven (U7), HALT-HCC, and Metroticket 2.0 scores were calculated. RESULTS: Nationally, 26 409 patients were included, and 547 at the 2 institutions. Median SRTR-follow-up was 6.8 y (interquartile range 3.9-10.1). Three criteria allowed the expansion of candidacy versus Milan: UCSF (7.7%, n = 1898), Metroticket 2.0 (4.2%, n = 1037), and U7 (3.5%, n = 828). The absolute difference in 3-y overall survival (OS) between scores was 1.5%. HALT-HCC (area under the curve [AUC] = 0.559, 0.551-0.567) best predicted 3-y OS although AUC was notably similar between criteria (0.506 < AUC < 0.527, Mila n =…

BACKGROUND: Donation after circulatory death (DCD) heart transplantation (HTx) significantly expands the donor pool and reduces waitlist mortality. However, high-level evidence-based data on its safety and effectiveness are lacking. This meta-analysis aimed to compare the outcomes between DCD and donation after brain death (DBD) HTxs. METHODS: Databases, including MEDLINE, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials, were systematically searched for randomized controlled trials and observational studies reporting the outcomes of DCD and DBD HTxs published from 2014 onward. The data were pooled using random-effects models. Risk ratios (RRs) with 95% confidence intervals (CIs) were used as the summary measures for categorical outcomes and mean differences were used for continuous outcomes. RESULTS: Twelve eligible studies were included in the meta-analysis. DCD HTx was associated with lower 1-y mortality rate (DCD 8.13% versus DBD 10.24%; RR = 0.75; 95% CI, 0.59-0.96; P = 0.02) and 5-y mortality rate (DCD 14.61% versus DBD 20.57%; RR = 0.72; 95% CI,…

A strategic vision toward global convergence in transplantation must encourage and remove barriers to living organ donation and transplantation. Here, we discuss deliberations of a working group of the 2023 Santander Summit charged with formulating recommendations for the safe expansion of living donor kidney transplantation and living donor liver transplantation worldwide. Living donor kidney transplantation has grown to be the preferred treatment for advanced kidney failure. Living donor liver transplantation emerged more recently as a strategy to reduce waitlist mortality, with adoption influenced by cultural factors, regional policies, clinical team experience, and the maturity of regional deceased donor transplant systems. Barriers to living donor transplantation span domains of education, infrastructure, risk assessment/risk communication, and financial burden to donors. Paired donor exchange is a growing option for overcoming incompatibilities to transplantation but is variably used across and within countries. Effectively expanding access to living donor transplantation…

Controlled donation after the circulatory determination of death (cDCDD) has emerged as a strategy to increase the availability of organs for clinical use. Traditionally, organs from cDCDD donors have been subject to standard rapid recovery (SRR) with poor posttransplant outcomes of abdominal organs, particularly the liver, and limited organ utilization. Normothermic regional perfusion (NRP), based on the use of extracorporeal membrane oxygenation devices, consists of the in situ perfusion of organs that will be subject to transplantation with oxygenated blood under normothermic conditions after the declaration of death and before organ recovery. NRP is a potential solution to address the limitations of traditional recovery methods. It has become normal practice in several European countries and has been recently introduced in the United States. The increased use of NRP in cDCDD has occurred as a result of a growing body of evidence on its association with improved posttransplant outcomes and organ utilization compared with SRR. However, the expansion of NRP is precluded by…

BACKGROUND: Thoracoabdominal normothermic regional perfusion (TA-NRP) has emerged as a powerful technique for optimizing organ procurement from donation after circulatory death donors. Despite its rapid adoption, standardized guidelines for TA-NRP implementation are lacking, prompting the need for consensus recommendations to ensure safe and effective utilization of this technique. METHODS: A working group composed of members from The American Society of Transplant Surgeons, The International Society of Heart and Lung Transplantation, The Society of Thoracic Surgeons, and The American Association for Thoracic Surgery was convened to develop technical guidelines for TA-NRP. The group systematically reviewed existing literature, consensus statements, and expert opinions to identify key areas requiring standardization, including predonation evaluation, intraoperative management, postdonation procedures, and future research directions. RESULTS: The working group formulated recommendations encompassing donor evaluation and selection criteria, premortem testing and therapeutic…

BACKGROUND: Plasma donor-derived cell-free DNA (dd-cfDNA) is used to screen for rejection in heart transplants. We launched the Trifecta-Heart study ( ClinicalTrials.gov No. NCT04707872), an investigator-initiated, prospective trial, to examine the correlations between genome-wide molecular changes in endomyocardial biopsies (EMBs) and plasma dd-cfDNA. The present report analyzes the correlation of plasma dd-cfDNA with gene expression in EMBs from 4 vanguard centers and compared these correlations with those in 604 kidney transplant biopsies in the Trifecta-Kidney study ( ClinicalTrials.gov No. NCT04239703). METHODS: We analyzed 137 consecutive dd-cfDNA-EMB pairs from 70 patients. Plasma %dd-cfDNA was measured by the Prospera test (Natera Inc), and gene expression in EMBs was assessed by Molecular Microscope Diagnostic System using machine-learning algorithms to interpret rejection and injury states. RESULTS: Top transcripts correlating with dd-cfDNA were related to genes increased in rejection such as interferon gamma-inducible genes (eg, HLA-DMA ) but also with genes induced by…

BACKGROUND: Hepatic ischemia/reperfusion (I/R) injury is a major cause of complications in clinical liver surgery. AXL receptor tyrosine kinase (AXL) is a member of the TAM receptor tyrosine kinase family (TYRO3, AXL, and MERTK). Our previous study has shown that AXL expression was markedly upregulated in liver transplantation patients. However, the underlying mechanism of AXL in hepatic I/R injury remains unclear. METHODS: A mouse liver warm I/R model and a primary hepatocyte hypoxia/reoxygenation model were established to investigate the role of AXL activation and ferroptosis in hepatic I/R injury by pretreating with recombinant mouse growth arrest-specific protein 6 (AXL activator) or R428 (AXL inhibitor). Moreover, we used LY294002 (phosphatidylinositol 3-kinase [PI3K] inhibitor) to evaluate the relationship between the PI3K/AKT (the Ser and Thr kinase AKT) pathway and ferroptosis in hepatic I/R injury. RESULTS: Hepatic I/R injury decreased phosphorylation AXL expression and enhanced ferroptosis in liver transplantation patients and hepatic I/R-subjected mice. AXL activation…

BACKGROUND: To overcome organ shortages, donation after circulatory death (DCD) kidneys are being increasingly used for transplantation. Prior research suggests that DCD kidneys have inferior outcomes compared with kidneys donated after brain death. Normothermic machine perfusion (NMP) and normothermic regional perfusion (NRP) may enhance the preservation of DCD kidneys and improve transplant outcomes. This study aimed to review the evidence surrounding NMP and NRP in DCD kidney transplantation. METHODS: Two independent reviewers conducted searches for all publications reporting outcomes for NMP and NRP-controlled DCD kidneys, focusing on delayed graft function, primary nonfunction, graft function, graft survival, and graft utilization. Weighted means were calculated for all relevant outcomes and controls. Formal meta-analyses could not be conducted because of significant heterogeneity. RESULTS: Twenty studies were included for review (6 NMP studies and 14 NRP studies). Delayed graft function rates seemed to be lower for NRP kidneys (24.6%) compared with NMP kidneys (54.3%). Both…

BACKGROUND: Xenotransplantation using pig organs is now a clinical reality. However, the process for xenograft recipient screening lacks clarity and scientific rigor: no established thresholds exist to determine which levels of preformed antipig natural antibodies (Nabs) will be safe for clinical xenograft transplantation, and hyperacute rejection (HAR) or acute humoral xenograft rejection (AHXR), which still impacts pig-to-primate kidney xenograft survivals, may impede broader application of pig-to-human clinical xenograft transplantation. METHODS: We retrospectively examined 28 cases of pig-to-baboon kidney xenotransplantation using GalTKO±human complement regulatory protein (hCRP)-transgenic (Tg) pig donors, as well as 6 cases of triple-KO multi-Tg (10GE) pig donors, and developed screening algorithms to predict risk of HAR/AHXR based on recipient antipig Nab levels. Preformed Nabs were evaluated using both complement-dependent cytotoxicity and antibody (IgM and IgG) binding flow-cytometry assays. RESULTS: High complement-dependent cytotoxicity was associated with HAR/AHXR as…

The human microbiome is associated with human health and disease. Exogenous compounds, including pharmaceutical products, are also known to be affected by the microbiome, and this discovery has led to the field of pharmacomicobiomics. The microbiome can also alter drug pharmacokinetics and pharmacodynamics, possibly resulting in side effects, toxicities, and unanticipated disease response. Microbiome-mediated effects are referred to as drug-microbiome interactions (DMI). Rapid advances in the field of pharmacomicrobiomics have been driven by the availability of efficient bacterial genome sequencing methods and new computational and bioinformatics tools. The success of fecal microbiota transplantation for recurrent Clostridioides difficile has fueled enthusiasm and research in the field. This review focuses on the pharmacomicrobiome in transplantation. Alterations in the microbiome in transplant recipients are well documented, largely because of prophylactic antibiotic use, and the potential for DMI is high. There is evidence that the gut microbiome may alter the pharmacokinetic…

BACKGROUND: Machine perfusion (MP) for liver transplantation has become more widespread in the United States, but national studies on this growing practice are lacking. We investigated national use and outcomes of MP for liver transplantation. METHODS: Adult (≥18 y) liver recipients transplanted between January 1, 2016 and September 30, 2023 in the United Network for Organ Sharing database were included. We used Cox regression to compare 1-y posttransplant recipient survival and all-cause graft failure by use of MP and performed subgroup analyses among circulatory death (DCD) and brain death (DBD) donors. RESULTS: Of 52 626 deceased donors with liver recovery, 1799 (3.5%) utilized MP. The proportion of all liver transplants using MP increased from 0.3% in 2016 to 15.5% in 2023. MP for DCD transplants increased from 0.8% in 2016 to 50.0% in 2023. Donors of MP grafts were older (47 [34-57] versus 42 [29-55] y, P < 0.001), had higher body mass indexes (28.3 [24.4-33.3] versus 27.3 [23.7-31.8] kg/m 2 , P < 0.001), and were more likely to be DCD (47.1% versus 9.3%, P < 0.001). Among DBD…

The last decade has seen an explosion in clinical research focusing on the use of noninvasive biomarkers in kidney transplantation. Much of the published literature focuses on donor-derived cell-free DNA (dd-cfDNA). Although initially studied as a noninvasive means of identifying acute rejection, it is now clear that dd-cfDNA is more appropriately described as a marker of severe injury and irrespective of the etiology, elevated dd-cfDNA ≥0.5% portends worse graft outcomes. Blood gene expression profiling is also commercially available and has mostly been studied in the context of early identification of subclinical rejection, although additional data is needed to validate these findings. Torque teno virus, a ubiquitous DNA virus, has emerged as a biomarker of immunosuppression exposure as peripheral blood Torque teno virus copy numbers might mirror the intensity of host immunosuppression. Urinary chemokine tests including C-X-C motif chemokine ligand 9 and C-X-C motif chemokine ligand 10 have recently been assessed in large clinical trials and hold promising potential for early…

BACKGROUND: There is conflicting evidence regarding the efficacy of normothermic machine perfusion (NMP) in suboptimal deceased donor kidneys. We aimed to assess the feasibility and short-term efficacy of brief preimplantation NMP in circulatory death (DCD) kidneys. METHODS: In this nonrandomized, single-center, prospective clinical trial, DCD kidneys underwent 1 to 3 h of NMP before implantation, aiming to achieve short ischemic times off NMP. The primary outcomes included feasibility and safety. Secondary outcomes included efficacy outcomes (delayed graft function and estimated glomerular filtration rate (eGFR) at 1, 6, and 12 mo), which were compared with the contralateral kidney that did not receive NMP. RESULTS: Eighteen DCD kidneys underwent NMP between 2020 and 2022, with at least 1 h completed in 16 (88.9%) of these kidneys (median 1 h); 1 kidney was removed after 5 min because of cannula failure and another at 54 min because of a sudden drop in blood flows. There was no episode of graft loss on the machine or postoperative vascular thromboses. All 18 kidneys were…

On November 9 and 10, 2023, the Organización Nacional de Trasplantes (ONT), under the Spanish Presidency of the Council of the European Union, convened in Santander a Global Summit entitled "Towards Global Convergence in Transplantation: Sufficiency, Transparency and Oversight." This article summarizes two distinct but related challenges elaborated at the Santander Summit by Working Group 2 that must be overcome if we are to develop and expand deceased donation worldwide and achieve the goal of self-sufficiency in organ donation and transplantation. Challenge 1: the need for a unified concept of death based on the permanent cessation of brain function. Working group 2 proposed that challenge 1 requires the global community to work toward a uniform, worldwide definition of human death, conceptually unifying circulatory and neurological criteria of death around the cessation of brain function and accepting that permanent cessation of brain function is a valid criterion to determine death. Challenge 2: reducing disparities in deceased donation and increasing organ utilization through…

BACKGROUND: The current landscape of organ donation and transplantation (ODT) registries is not well established. This narrative review sought to identify and characterize the coverage, structure, and data capture of ODT registries globally. METHODS: We conducted a literature search using Ovid Medline and web searches to identify ODT registries from 2000 to 2023. A list of ODT registries was compiled based on publications of registry design, studies, and reports. Extracted data elements included operational features of registries and the types of donor and recipient data captured. RESULTS: We identified 129 registries encompassing patients from all continents except Antarctica. Most registries were active, received funding from government or professional societies, were national in scope, included both adult and pediatric patients, and reported patient-level data. Registries included kidney (n = 99), pancreas (n = 32), liver (n = 44), heart (n = 35), lung (n = 30), intestine (n = 15), and islet cell (n = 5) transplants. Most registries captured donor data (including living versus…

Living kidney donors make a significant contribution to alleviating the organ shortage. The aim of this article is to provide an overview of mid- and long-term (≥12 mo) living donor psychosocial outcomes and highlight areas that have been understudied and should be immediately addressed in both research and clinical practice. We conducted a narrative review by searching 3 databases. A total of 206 articles were included. Living donors can be divided into those who donate to an emotionally or genetically related person, the so-called directed donors, or to an emotionally or genetically unrelated recipient, the so-called nondirected donors. The most commonly investigated (bio)psychosocial outcome after living donation was health-related quality of life. Other generic (bio)psychological outcomes include specific aspects of mental health such as depression, and fatigue and pain. Social outcomes include financial and employment burdens and problems with insurance. Donation-specific psychosocial outcomes include regret, satisfaction, feelings of abandonment and unmet needs, and benefits…

BACKGROUND: The TWO Study (Transplantation Without Overimmunosuppression) aimed to investigate a novel approach to regulatory T-cell (Treg) therapy in renal transplant patients, using a delayed infusion protocol at 6 mo posttransplant to promote a Treg-skewed lymphocyte repopulation after alemtuzumab induction. We hypothesized that this would allow safe weaning of immunosuppression to tacrolimus alone. The COVID-19 pandemic led to the suspension of alemtuzumab use, and therefore, we report the unique cohort of 7 patients who underwent the original randomized controlled trial protocol. This study presents a unique insight into Treg therapy combined with alemtuzumab and is therefore an important proof of concept for studies in other diseases that are considering lymphodepletion. METHODS: Living donor kidney transplant recipients were randomized to receive autologous polyclonal Treg at week 26 posttransplantation, coupled with weaning doses of tacrolimus, (Treg therapy arm) or standard immunosuppression alone (tacrolimus and mycophenolate mofetil). Primary outcomes were patient…

Organ transplantation remains the most optimal strategy for patients with end-stage organ failure. However, prevailing methods of immunosuppression are marred by adverse side effects, and allograft rejection remains common. It is imperative to identify and comprehensively characterize the cell types involved in allograft rejection, and develop therapies with greater specificity. There is increasing recognition that processes mediating allograft rejection are the result of interactions between innate and adaptive immune cells. Macrophages are heterogeneous innate immune cells with diverse functions that contribute to ischemia-reperfusion injury, acute rejection, and chronic rejection. Macrophages are inflammatory cells capable of innate allorecognition that strengthen their responses to secondary exposures over time via "trained immunity." However, macrophages also adopt immunoregulatory phenotypes and may promote allograft tolerance. In this review, we discuss the roles of macrophages in rejection and tolerance, and detail how macrophage plasticity and polarization influence…

BACKGROUND: Recent evidence highlights the pivotal role of natural killer (NK) cells in allograft rejection. METHODS: We explored associations of missing self and gene polymorphisms determining the phenotype and/or functionality of NK cells with microvascular inflammation (MVI) in a single-center cohort of 507 consecutive kidney transplant recipients. Patients were genotyped for killer cell Ig-like receptors and polymorphisms in 4 selected genes ( FCGR3AV/F158 [rs396991], KLRC2wt/del , KLRK1HNK/LNK [rs1049174], and rs9916629-C/T). RESULTS: MVI was detected in 69 patients (13.6%). In a proportional odds model, the KLRC2del/del variant reduced MVI risk (odds ratio [OR] 0.26; 95% confidence interval [CI], 0.05-0.93; P = 0.037) independent of donor-specific antibodies, HLA class II eplet mismatch, and number of biopsies. Conversely, missing self (OR 1.40; 95% CI, 1.08-1.80; P = 0.011) and the rs9916629 T/T gene variant increased the risk (OR 1.70; 95% CI, 1.08-2.68; P = 0.021). Graft loss tended to be more frequent among patients with missing self ≥2 (hazard ratio 1.97; 95% CI,…

BACKGROUND: There are few interventional studies using CMV cell-mediated immunity (CMI) to guide antiviral prophylaxis. We assessed the Quantiferon-CMV (QTF-CMV) assay to guide CMV prophylaxis duration in high-risk organ transplant recipients. METHODS: A single-arm, multicenter, prospective interventional study including high-risk kidney, pancreas, liver, and heart transplant recipients who were either donor CMV-seropositive, recipient-seronegative (D + /R - ) or recipient-seropositive with antithymocyte globulin (R + /ATG) induction. CMI testing was performed using the QTF-CMV assay at months 3, 4, 5, and 6 posttransplant. Prophylaxis was discontinued for a positive CMI but continued for a negative result up to a maximum of 6 mo. The primary endpoint was CMV viremia ≥1000 IU/mL up to 1 y posttransplant. RESULTS: One hundred eight patients were included, comprising kidney (n = 89), kidney-pancreas (n = 7), liver (n = 10), and heart (n = 2) transplants. Eighty-nine patients (82.4%) completed the study protocol (n = 39 D + /R - and n = 50 R + /ATG). In the D + /R - group, only 1 of 39…

BACKGROUND: Guidelines advise eculizumab prophylaxis for most kidney transplant recipients with atypical hemolytic uremic syndrome (aHUS). However, recurrence rates may be overestimated, and starting eculizumab at relapse ("rescue therapy") may prevent graft loss. Randomized controlled trials have not compared the efficacy, safety, and costs of different treatment strategies. We performed a comparative study, including a previously described Dutch cohort treated with rescue therapy and a UK cohort using eculizumab prophylaxis. METHODS: In the Netherlands, we selected all adult patients with aHUS who received a kidney transplant between 2010 and 2021 in the Radboud University Medical Center (n = 30) and enriched this cohort with 8 patients who received rescue therapy in other centers. The UK cohort included all adult patients with aHUS at moderate or high risk of recurrence, transplanted between 2013 and 2017 with prophylactic eculizumab. RESULTS: We included 38 Dutch patients and 35 UK patients. Characteristics were comparable, although the UK cohort included more patients with a…

BACKGROUND: Baseline lung allograft dysfunction (BLAD) is characterized by the failure to achieve normal baseline lung function after double lung transplantation (DLTX) and is associated with a high risk of mortality. In single lung transplant (SLTX) recipients, however, cutoff values and associated factors have not been explored. Here, we aimed to define BLAD in SLTX recipients, investigate its impact on allograft survival, and identify potential risk factors for BLAD in SLTX recipients. METHODS: We performed a retrospective, single-center analysis of the LTX cohort of LMU Munich between 2010 and 2018. In accordance with DLTX cutoffs, BLAD in SLTX recipients was defined as failure to achieve percentage of forced expiratory volume in 1 s and percentage of forced vital capacity of >60% on 2 consecutive tests >3 wk apart. Survival analysis and regression analysis for potential predictors of BLAD were performed. RESULTS: In a cohort of 141 SLTX recipients, 43% of patients met BLAD criteria. SLTX recipients with BLAD demonstrated impaired survival. Native lung hyperinflation was…

BACKGROUND: The number of deceased donor kidney transplants has been increasing and is at a record high, yet nonuse of kidneys recovered for transplantation has risen to 25.8% following circular kidney allocation system based on 250-nautical-mile circles implemented on March 15, 2021 (KAS250). METHODS: Using Scientific Registry of Transplant Recipients data, we studied all deceased donor kidneys recovered for transplant from March 15, 2019, to January 31, 2023. We calculated the association of multiple factors with kidney nonuse, including increasing recovery of kidneys from nonideal donors, delays in offer acceptance observed under KAS250, and impacts of COVID-19. RESULTS: In the 2 y before KAS250, the nonuse rate was 21.2%. Had this rate continued, 2334 more kidneys would have been transplanted through January 2023. We estimated that about 769 of these nonused kidneys (33%) were associated with offer acceptance delays under KAS250; about 994 of these nonused kidneys (43%) were associated with increased prevalence of nonideal donors: donation after circulatory death donors, older…

BACKGROUND: The global shortage of solid organs for transplantation is exacerbated by high demand, resulting in organ deficits and steadily growing waiting lists. Diverse strategies have been established to address this issue and enhance organ availability, including the use of organs from individuals who have undergone extracorporeal cardiopulmonary resuscitation (eCPR). The main aim of this work was to examine the outcomes for both graft and recipients of solid organ transplantations sourced from donors who underwent eCPR. METHODS: We performed a systematic literature review using a combination of the terms related to extracorporeal life support and organ donation. Using Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, PubMed and Scopus databases were searched up to February 2024. RESULTS: From 1764 considered publications, 13 studies comprising 130 donors and 322 organ donations were finally analyzed. On average, included patients were 36 y old, and the extracorporeal life support was used for 4 d. Kidneys were the most often transplanted organs…

In controlled organ donation after circulatory determination of death (cDCDD), accurate and timely death determination is critical, yet knowledge gaps persist. Further research to improve the science of defining and determining death by circulatory criteria is therefore warranted. In a workshop sponsored by the National Heart, Lung, and Blood Institute, experts identified research opportunities pertaining to scientific, conceptual, and ethical understandings of DCDD and associated technologies. This article identifies a research strategy to inform the biomedical definition of death, the criteria for its determination, and circulatory death determination in cDCDD. Highlighting knowledge gaps, we propose that further research is needed to inform the observation period following cessation of circulation in pediatric and neonatal populations, the temporal relationship between the cessation of brain and circulatory function after the withdrawal of life-sustaining measures in all patient populations, and the minimal pulse pressures that sustain brain blood flow, perfusion, activity, and…

For children with complex congenital heart problems, cardiac allotransplantation is sometimes the best therapeutic option. However, availability of hearts for pediatric patients is limited, resulting in a long and growing waitlist, and a high mortality rate while waiting. Cardiac xenotransplantation has been proposed as one therapeutic alternative for neonates and infants, either in lieu of allotransplantation or as a bridge until an allograft becomes available. Scientific and clinical developments in xenotransplantation appear likely to permit cardiac xenotransplantation clinical trials in adults in the coming years. The ethical issues around xenotransplantation of the heart and other organs and tissues have recently been examined, but to date, only limited literature is available on the ethical issues that are attendant with pediatric heart xenotransplantation. Here, we summarize the ethical issues, focusing on (1) whether cardiac xenotransplantation should proceed in adults or children first, (2) pediatric recipient selection for initial xenotransplantation trials, (3) special…

BACKGROUND: Emerging evidence has highlighted the role of macrophages in heart transplant rejection (HTR). However, the molecular signals modulating the immunometabolic phenotype of allograft-infiltrating macrophages (AIMs) during HTR remain unknown. METHODS: We analyzed single-cell RNA sequencing data from cardiac graft-infiltrating immunocytes to characterize the activation patterns and metabolic features of AIMs. We used flow cytometry to determine iNOS and PKM2 expression and MEK/ERK signaling activation levels in AIMs. We then generated macrophage-specific Mek1/2 knockout mice to determine the role of the MEK1/2-PKM2 pathway in the proinflammatory phenotype and glycolytic capacity of AIMs during HTR. RESULTS: Single-cell RNA sequencing analysis showed that AIMs had a significantly elevated proinflammatory and glycolytic phenotype. Flow cytometry analysis verified that iNOS and PKM2 expressions were significantly upregulated in AIMs. Moreover, MEK/ERK signaling was activated in AIMs and positively correlated with proinflammatory and glycolytic signatures. Macrophage-specific…

BACKGROUND: Induced pluripotent stem cells (iPSCs) offer the potential to generate autologous iPSC-derived islets (iPSC islets), however, remain limited by scalability and product safety. METHODS: Herein, we report stagewise characterization of cells generated following a bioreactor-based differentiation protocol. Cell characteristics were assessed using flow cytometry, quantitative reverse transcription polymerase chain reaction, patch clamping, functional assessment, and in vivo functional and immunohistochemistry evaluation. Protocol yield and costs are assessed to determine scalability. RESULTS: Differentiation was capable of generating 90.4% PDX1 + /NKX6.1 + pancreatic progenitors and 100% C-peptide + /NKX6.1 + iPSC islet cells. However, 82.1%, 49.6%, and 0.9% of the cells expressed SOX9 (duct), SLC18A1 (enterochromaffin cells), and CDX2 (gut cells), respectively. Explanted grafts contained mature monohormonal islet-like cells, however, CK19 + ductal tissues persist. Using this protocol, semi-planar differentiation using 150 mm plates achieved 5.72 × 10 4 cells/cm 2 (total 8.3…

BACKGROUND: Few studies have examined the long-term outcomes of recipients in minimally invasive donor hepatectomies, particularly comparing robotic and laparoscopic donor procedures. Understanding these outcomes is crucial for optimizing surgical approaches and improving the overall success of living donor liver transplantation. This study aimed to compare the feasibility and safety of robotic donor right hepatectomy (RDRH) and laparoscopic donor right hepatectomy (LDRH) by evaluating total follow-up patient outcomes. METHODS: This retrospective, single-center study included 117 and 118 donors who underwent RDRH and LDRH between March 2016 and June 2023, respectively. After performing 1:1 propensity score matching, 71 donor-recipient pairs were included in each group. Donor and recipient complications were divided into early (within 90 d) and late (after 90 d) biliary and vascular complications. RESULTS: In the matched cohort, major complication rates of donors were similar in both groups. Bile duct (BD) variation was not significantly different; however, the rates of multiple BD…

BACKGROUND: Donation after circulatory death livers are more susceptible to ischemia/reperfusion injury (IRI) because of a longer period of warm ischemia. Growing evidence now suggests that ferroptosis plays a key regulatory role in the development of IRI, so targeting ferroptosis may be an effective strategy to alleviate IRI in liver transplantation (LT). METHODS: Using donation after circulatory death LT models in rats and oxygen-glucose deprivation/reoxygenation (OGD/R) models in BRL-3A cells, we tested the effect of the Chinese medicine monomer wogonin on liver IRI and explored the specific mechanism. RESULTS: Wogonin attenuated liver IRI and increased the survival rate of rats by inhibiting lipid peroxidation and ferroptosis. Mechanistically, arachidonic acid 15-lipoxygenase-1 (ALOX15) and inducible nitric oxide synthase (iNOS) were identified as potential targets of baicalein through bioinformatics analysis combined with in vivo and in vitro experiments. This result was further confirmed by molecular docking and cellular thermal shift assays. Finally, we silenced ALOX15 and…

BACKGROUND: Warm ischemia time (WIT) and ischemia-reperfusion injury are limiting factors for vascularized composite allograft (VCA) transplantation. Subnormothermic machine perfusion (SNMP) has demonstrated the potential to extend WIT in organ transplantation. This study evaluates the effect of SNMP on VCA viability after prolonged WIT. METHODS: Rat hindlimbs underwent WIT for 30, 45, 60, 120, 150, or 210 min, followed by 3-h SNMP. Monitoring of perfusion parameters and outflow determined the maximum WIT compatible with limb viability after SNMP. Thereafter, 2 groups were assessed: a control group with inbred transplantation (Txp) after 120 min of WIT and an experimental group that underwent WIT + SNMP + Txp. Graft appearance, blood gas, cytokine levels, and histology were assessed for 21 d. RESULTS: Based on potassium levels, the limit of WIT compatible with limb viability after SNMP is 120 min. Before this limit, SNMP reduces potassium and lactate levels of WIT grafts to the same level as fresh grafts. In vivo, the control group presented 80% graft necrosis, whereas the…

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease and frequently recurs after kidney transplantation. Recurrent FSGS (rFSGS) is associated with poor allograft and patient outcomes. Bleselumab, a fully human immunoglobulin G4 anti-CD40 antagonistic monoclonal antibody, disrupts CD40-related processes in FSGS, potentially preventing rFSGS. METHODS: A phase 2a, randomized, multicenter, open-label study of adult recipients (aged ≥18 y) of a living or deceased donor kidney transplant with a history of biopsy-proven primary FSGS. The study assessed the efficacy of bleselumab combined with tacrolimus and corticosteroids as maintenance immunosuppression in the prevention of rFSGS >12 mo posttransplantation, versus standard of care (SOC) comprising tacrolimus, mycophenolate mofetil, and corticosteroids. All patients received basiliximab induction. The primary endpoint was rFSGS, defined as proteinuria (protein-creatinine ratio ≥3.0 g/g) with death, graft loss, or loss to follow-up imputed as rFSGS, through 3 mo posttransplant. RESULTS:…

Regulatory T cells (Treg), a subset of CD4 + T cells, are potent regulators of immune reactions, which have been shown to be a promising therapeutic alternative to toxic immunosuppressive drugs. Data support the utility of Treg in managing immunopathologies, including solid organ transplant rejection, graft-versus-host disease, and autoimmune disorders. Notably, reports suggest that interleukin-2 (IL-2) is critical to survival of Treg, which constitutively express high levels of CD25, that is, the IL-2 receptor α-chain, and are exquisitely sensitive to IL-2, even at very low concentrations in contrast to effector T cells, which only upregulate IL-2 receptor α-chain on activation. This has led to the notion of using low doses of exogenous IL-2 therapeutically to modulate the immune system, specifically Treg numbers and function. Here, we summarize developments of clinical experience with low-dose IL-2 (LD-IL-2) as a therapeutic agent. So far, no clinical data are available to support the therapeutic use of LD-IL-2 therapy in the solid organ transplant setting. For the latter,…

Innovation is a hallmark of organ, tissue, and cell transplantation. The development of new treatments derived from these substances of human origin (SoHO) has rapidly evolved in recent years. Despite the great benefits that these innovative therapies could bring to patients, significant difficulties have arisen in making them equitably and widely accessible. Herein, we identify and address 4 challenges to promote innovation in this field in a collaborative, sustainable, and transparent manner and propose some concrete solutions applicable to SoHO-derived treatments, ranging from cell therapies to solid organ transplantation. Regulators, health policymakers, and government officials are recommended to incorporate specific elements into the regulatory frameworks of their respective jurisdictions, although regulatory convergence and equivalent quality and safety standards applicable to SoHO at a global level would be needed. An innovation-driven regulatory environment, respectful with the human origin and in accordance with the altruistic donation of SoHO, should be encouraged to…

BACKGROUND: In November 2023, in the context of the Spanish Presidency of the Council of the European Union, the Organization National de Transplante organized a global summit discussing global action in transplantation for the next decade. This article reports the recommendations supporting the need to prioritize transplantation in healthcare systems. METHODS: The working group investigated how transplantation addresses noncommunicable disease mortality, particularly related to kidney and liver disease. They also investigated how transplantation can contribute to the achievement of several of the United Nations Sustainable Development Goals, especially Goal 3 (good health and well-being), Goal 8 (sustained, inclusive, and sustainable economic growth and employment for all), and Goal 13 (combat climate change and its impact). RESULTS: By prioritizing transplantation, the increased availability and accessibility of life-saving organs and tissues to the public will not only lead to saving more lives and improving health outcomes for individual patients but also contribute to the…

The transplantation of human organs, tissues and cells is a life-saving and live-enhancing procedure for the treatment of conditions that mostly result from noncommunicable diseases (NCDs).1 Organ transplant activities have been steadily increasing during the last decades, an evolution only interrupted by the COVID-19 pandemic.2,3 However, the volume of organ transplants barely covers 5%–10% of the global needs.4,5 For tissues and cells, the current understanding of the world landscape is fragmented and incomplete. This applies not only to those tissues and cells obtained and distributed within individual countries but also to those exchanged internationally. Public health interventions are fundamental to diminish the burden of diseases treatable with transplantation and to reduce progression to end-stage organ failure. However, the demand for the transplantation of human organs, tissues, and cells must also be addressed, and the expansion of transplantation is critical to decreasing premature mortality caused by NCDs. Figure 1 displays 2022 national organ transplant rates in…

BACKGROUND: Transarterial radioembolization (TARE) is an effective treatment to control tumor growth and improve survival in hepatocellular carcinoma (HCC). The role of TARE in downstaging patients to liver transplantation (LT) is unclear. The aim of this study was to investigate the downstaging efficacy of TARE for intermediate and advanced HCC. METHODS: Intention-to-treat analysis with multistate modeling was performed. Patients moved through 5 health states: (1) from TARE to listing, (2) from TARE to death without listing, (3) from listing to LT, (4) from listing to death without LT, and (5) from transplant to death. Factors affecting the chance of death after TARE were considered to stratify outcomes. RESULTS: Two hundred fourteen patients underwent TARE. Of those, 43.9% had radiological response, 29.9% were listed, and 22.8% were transplanted. The probability of being alive without LT was 40.5% 1 y after TARE and 11.5% at 5 y. The chance of being listed was 9.4% at 1 y and 0.9% at 5 y. The probability of dying after TARE without LT was 38% at 1 y and 73% at 5 y. The overall…

BACKGROUND: The American Society of Transplant Surgeons convened a multidisciplinary working group to address operational, ethical, and legal considerations surrounding normothermic regional perfusion (NRP) procurement. METHODS: The working group, comprising members from American Society of Transplant Surgeons and AST across various disciplines including transplant surgery, hepatology, critical care, and bioethics, collaborated to formulate recommendations and guidance for NRP procurement. RESULTS: The following topics were identified by the group as essential standards that need to be addressed for ethical, legal, and operational conformance: terminology; conceptualization of death in the context of NRP; and communication, logistics, and training and competency. CONCLUSIONS: Fourteen recommendations that support the ethical and legal acceptability of NRP in the United States and set expectations for the conduct of NRP procedures are provided.