The aim of this study was to assess whether preformed donor-specific HLA antibodies (DSA) are associated with graft loss after liver transplantation. We conducted a prospective multicenter study at four liver transplant centers. Presence of preformed HLA antibodies was analyzed using Single-antigen bead assay and a virtual crossmatch unknown to clinicians at a central laboratory. Graft survival was assessed using Kaplan-Meier analysis and Cox regressions during a 2-year follow-up. Class I DSA were observed in 106 of 832 patients (13%) and showed no association with graft loss. Class II DSA were detected in 131 of 831 patients (16%), and DQ in 79 (10%). Class II DQ subtype was the only independent predictor of graft loss (adjusted HR 2.0, 95% CI: 1.1-3.6, P = 0.02) with a 2-year graft loss rate of 23% (95% CI: 15-34%) compared to 10% (95% CI: 8-12%) without class II DSA and 7% (95% CI: 2 - 20%) for DR-specific antibodies (log-rank P = 0.002). Mean fluorescence intensity was not independently associated with graft loss after adjustment for DQ status. Preformed class II DQ DSA are independently associated with an increased risk of graft loss even at low mean fluorescence intensity.
Living donor kidney transplantation is the preferred standard of care for most patients with kidney failure. We sought to quantify variation in access to living donor transplantation across referral networks for patients in Australia & New Zealand. We included adults who initiated kidney replacement therapy between 2002-2022. Each patient was mapped to a transplant referral network. For each network, we calculated a standardized living donor transplant ratio by comparing the observed number of living donor transplants within 12 months with the expected number. The expected number was estimated using multivariate Poisson regression with a random effect for each referral network. Overall, 53,313 patients were included. The ratio of observed to expected living donor transplants ranged from 0.36 to 2.11. Of 21 networks, 4 (19%) performed below expected. Initiating treatment at a center with direct transplant unit affiliation, non-metropolitan residence and timely nephrology referral were associated with increased living kidney donor transplantation. Access to living donor kidney transplantation varies substantially across transplant referral networks in Australia & New Zealand. Identifying center-level barriers and facilitators underpinning this variation will be critical to developing targeted center-based strategies to enhance living donation rates.
Leveraging the Transplant Pregnancy Registry International, we conducted a retrospective study of children born to liver transplant (LT) recipients between 1986-2023 to evaluate long term health outcomes of offspring. Child data were collected primarily from bi-yearly maternal phone interviews. Descriptive statistics and multivariate analyses were used to evaluate risk factors for adverse child outcomes. There were 599 children with follow-up data, born to 435 LT recipients of whom 73% were white and 13.1% Hispanic with a median age at conception of 29.4 yrs. The most common LT indications were autoimmune hepatitis (14.2%) and biliary atresia (13.9%); Time from LT to delivery was median 6.9 yrs (IQR 3.1, 14.2); 21.0.% of mothers required anti-hypertensives in pregnancy, 20.7% developed preeclampsia, and 46.1% had cesarean delivery. Most (68.3%) children were healthy and developing well at median 7.6 (IQR: 3.3, 14.9) years of follow up. The most common pediatric conditions in offspring were allergies (6.5%), asthma/reactive airway disease (4.7%), attention deficit hyperactivity disorder/ attention deficit disorder (ADHD/ADD) (2.3%), mild developmental delay (2.7%), autism spectrum disorder (2.0%), and mood disorders (1.2%). Most school-age children of LT recipients were healthy overall, without greater risk for growth or cognitive conditions than the general pediatric population.
Ex situ normothermic machine perfusion (NMP) of the liver offers considerable promise for both transplant and non-transplant purposes, including repair, regenerative conditioning, therapeutic testing, disease modeling, and diverse bioengineering applications. While some functions of the liver may be maintained during NMP for periods lasting from days to weeks, a fundamental "blind spot" in prolonged liver NMP protocols remains their near universal failure to reproduce the temporal variability in liver inputs and physical conditions normally directed by circadian rhythms in the in vivo environment. In this narrative review article, we examine key aspects of hepatic circadian rhythmicity and describe how circadian regulation sustains liver health and homeostasis. We consider current liver NMP protocols and explore potential consequences of chronodisruption - the failure to reproduce or meaningfully mimic normal chronobiological conditions - during these procedures. Ultimately, we aim to establish a conceptual framework for understanding how temporal synchronization may influence the success of liver NMP and highlight potential strategies for incorporating temporal cues into future NMP applications.
Persistent proteinuria remains a major barrier to successful pig-to-nonhuman primate (NHP) kidney xenotransplantation and may become an important issue in clinical renal xenotransplantation. However, published human renal xenotransplant reports to date have not established severe proteinuria as a consistent clinical finding, and its relevance in living human recipients should therefore be regarded as an important unresolved question.In pig-to-NHP models, severe proteinuria may also be accompanied by urinary loss of therapeutic monoclonal antibodies, including anti-CD154, potentially compromising rejection prophylaxis. Proteinuria in this setting may occur in association with heterogenous and overlapping patterns of immune-mediated and non-immune mediated injury, including rejection-associated endothelial, microvascular, and humoral lesions such as thrombotic microangiopathy, capillaritis, C4d deposition, and xenograft glomerulopathy. Hemodynamic mismatch should currently be regarded as a possible but unproven contributor rather than a dominant initiating trigger.We therefore propose a unifying hypothesis based on an evidence-informed, testable framework rather than a definitive causal cascade, which we hope will stimulate discussion. Clarifying the dominant mechanisms in individual cases, correlating proteinuria with biopsy findings, and prospectively monitoring urinary drug loss will be essential for developing rational preventive and therapeutic strategies.
Frailty predicts adverse outcomes in kidney transplant candidates, but it remains unclear whether different frailty tools identify the same or distinct at-risk patients. In this retrospective cohort study, 953 kidney transplant candidates listed between 2018 and 2022 underwent frailty assessment using both the FRAIL (Fatigue, Resistance, Ambulation, Illnesses, Weight Loss) scale and Short Physical Performance Battery (SPPB). In a subset with available CT imaging, body composition was analyzed using AI-based tools. Frailty prevalence differed by instrument: 6.2% by FRAIL versus 24% by SPPB. Waitlist mortality occurred in 9.5% (91/953) of candidates. Both tools independently predicted waitlist mortality (FRAIL:aHR 2.38, 95%CI 1.34-4.20,p=0.003; SPPB:aHR 1.66, 95%CI 1.07-2.60,p=0.025). SPPB-defined frailty showed stronger associations with post-transplant outcomes, including longer hospital stay, and 30-day and one-year readmissions. CT analysis revealed that SPPB-defined, but not FRAIL-defined, frailty was associated with lower muscle density and increased visceral adiposity, suggesting a mechanistic basis. The FRAIL scale and SPPB capture distinct dimensions of frailty with complementary strengths. FRAIL better reflects symptom burden and candidates at risk for waitlist mortality, while SPPB more closely associates with post-transplant complications. Results support systematic use of both instruments to optimize risk stratification and identify candidates who may benefit from targeted prehabilitation.
These updated guidelines of the AST IDCOP review safe living practices including routine vaccinations, travel vaccinations including general travel advice, as well as non-pharmacological strategies for safe living. General principles of vaccination as well as the use of specific vaccines in this population are discussed. Vaccination status should be reviewed and updated in the pre-transplant setting and when travel is planned. The optimal timing of vaccination post-transplant should be taken into account. There are accumulating data that live-attenuated vaccines can also be given to select post-transplant pediatric and young adult patients. Since the last update of the guidelines in 2019, several new vaccines are recommended such as those for COVID-19 and RSV. In addition, newer formulations of pneumococcal, meningococcal, and hepatitis B vaccinations are available. There are expanded age indications for recombinant zoster vaccine. Close contacts of transplant patients can receive most routine live and inactivated vaccines. For travel, location, duration, and activity during the trip determines the vaccine requirements as well as the need for malaria chemoprophylaxis. Other strategies for safe living include considerations for food, water, pets, and sexual activity. Detailed recommendations surrounding these are included in these guidelines.
The availability and structure of donor care units (DCUs) at OPO level may influence lung utilization and transplant outcomes. Adult first-time lung transplant recipients and donors with lung disposition data from January 1, 2018, through August 31, 2025 were abstracted from Scientific Registry of Transplant Recipients database. Mixed-effects logistic regression and frailty-adjusted Cox models were performed to examine lung utilization and graft survival respectively across no DCU available (DCU-negative), hospital-based DCU available (DCU-hospital available), and independent DCU available (DCU-independent available) groups. An OPO performance visualization tool was developed (http://opolung2025.com/). Among 108,502 donors, lung utilization increased stepwise by available DCU structure. DBD donors recovered by OPOs with DCU-hospital available (OR=1.11, 95% CI 1.01-1.22) and DCU-independent available (OR=1.21, 95% CI 1.08-1.36) had higher odds of utilization than DBD donors recovered by DCU-negative OPOs, whereas no significant DCU association was observed among DCD donors. Among 18,271 lung transplant recipients, graft survival did not differ between DCU-positive and DCU-negative groups (HR= 1.03, 95% CI 0.96-1.11) or between DCU-independent available and DCU-hospital available groups within the DCU-positive cohort (HR=1.00, 95% CI 0.87-1.15). DCU availability was associated with higher DBD donor lung utilization but not recipient graft survival.
The long-term impact of kidney delayed graft function (DGF) following simultaneous pancreas-kidney (SPK) transplantation, and its frequency in the postkidney allocation system (KAS 250) era, remains incompletely understood. We analyzed adult SPK recipients (2014-2025) in the Scientific Registry of Transplant Recipients, stratified by DGF status, with follow-up censored at 7.5 years. Multivariable logistic regression identified predictors of DGF, and Cox proportional hazards models evaluated associations with kidney and pancreas death-censored graft survival and recipient survival. Among 5474 recipients, 472 (8.6%) developed DGF. Independent predictors included pretransplant dialysis (odds ratio, 3.98; 95% confidence interval [CI], 2.43-6.52; P < .001), longer cold ischemia time (odds ratio, 1.03 per hour; 95% CI, 1.01-1.05; P = .01), and transplantation in the post-KAS 250 era (odds ratio, 1.53; 95% CI, 1.22-1.92; P < .001). DGF was not associated with acute rejection or kidney (HR, 0.92; 95% CI, 0.62-1.37; P = .69) or pancreas graft survival (HR, 1.27; 95% CI, 0.88-1.82; P = .20). In contrast, DGF was independently associated with worse recipient survival (HR, 1.66; 95% CI, 1.24-2.21; P < .001), including in analyses conditioned on one-year pancreas and kidney graft survival (HR, 1.52; 95% CI, 1.03-2.23; P = .034). DGF represents an important marker of post-transplant risk with implications for long-term recipient outcomes.
Chronic lung allograft dysfunction (CLAD) is a major barrier to long-term lung transplantation success. Microbial factors have been linked to CLAD risk, and sequence-based methods have been applied recently to identify potential microbial drivers, although patient heterogeneity and follow-up time have been limitations. We undertook a longitudinal cohort study of 186 patients transplanted for diseases other than cystic fibrosis. Dense lung sampling was carried out over the first year, and patients were followed for a median of 6.04 years. Bronchoalveolar lavage was analyzed by bacterial 16S ribosomal RNA gene sequencing and quantification. Postimplant bronchoalveolar lavage was assayed for cytokines and underwent metabolomics analysis. Seventy patients (38%) developed CLAD. CLAD development and shorter time to CLAD were associated with higher lung bacterial burden, particularly 6 months posttransplant, low Streptococcus/Prevotella ratio in lung 6 weeks posttransplant, and elevated lung IP10/CXCL10 immediately after implantation. Each factor was associated with distinct timing of CLAD onset. These factors, together with previously recognized clinical features, stratified patients into groups differing by >3-fold CLAD risk. Thus, increased lung bacteria and altered composition during the first year posttransplant and of IP10/CXCL10 immediately after implantation are associated with CLAD after transplantation for non-cystic fibrosis lung disease. Early events in the allograft may establish conditions affecting later graft failure, identify potentially modifiable mechanisms of injury, and provide biomarkers for CLAD risk.
Late liver allograft rejection is under-recognized because it is often clinically silent, liver tests are insensitive, protocol biopsies are uncommon, and the histology differs from classic early acute T cell-mediated rejection (TCMR) manifesting in the initial weeks after transplantation. Differences in tempo and pathogenesis lead to distinct clinical and histologic manifestations. Late- compared with acute-TCMR is characterized by more prevalent interface and perivenular inflammatory activity, a lymphocyte-predominant infiltrate and fibrosis, with less conspicuous portal duct-centered and subendothelial venular inflammation. The traditional Banff RAI scheme that works consistently well to diagnose acute-TCMR is less well calibrated to account for these later shifts of inflammatory target and density, risking under-diagnosis of clinically significant late-TCMR. This document lays out the histopathologic characteristics of acute- vs. late-TCMR and the rationale for updating the Banff scoring system for liver allograft rejection to better incorporate currently unrepresented histology features correlating with a molecular rejection signature into the Banff rejection scheme.
Transplant recipients have an elevated risk of actinic keratosis (AK), a precursor of squamous cell carcinoma. We assessed whether an AK polygenic risk score (PRS) can identify transplant-naive individuals and transplant recipients at risk of multiple AKs who may benefit from early prevention. Using genome-wide association data (140 339 cases; 1 430 776 controls), we developed an AK PRS and evaluated it in cohort studies of European descent individuals in the QSkin Sun and Health Study (QSkin) (N = 12 843), Skin Tumors in Allograft Recipients Study (STAR) (N = 357), UK Biobank (N = 963), and All of Us (N = 1859). The PRS was strongly associated with higher AK burden in transplant-naive individuals, conferring a 5-fold increased risk of developing ≥20 AKs (odds ratio [OR] per standard deviation [SD] increase in the PRS = 5.06, 95% confidence interval [CI] = 4.69-5.46). In transplant recipients, it was associated with up to a 2.5-fold increased risk of developing ≥1 AK (United Kingdom Biobank [UKB] OR per SD = 2.49, 95% CI = 1.91-3.23; STAR OR per SD = 1.79, 95% CI = 1.10-2.91; All of Us OR per SD = 1.52, 95% CI = 1.35-1.70). The PRS improved prediction of ≥20 AKs by 13% beyond age and sex (AUC 0.90 vs 0.77) and identified the highest-risk 20% with a 9-fold increased risk in transplant-naive individuals (OR = 8.61, 95% CI = 7.26-10.22) and a 2-fold increased risk in transplant recipients (OR = 2.23, 95% CI = 1.26-4.20), compared to the middle-risk 60%. Incorporating PRS into pretransplant and posttransplant care could enable earlier, personalized prevention.
Controlled donation after circulatory determination of death has markedly expanded the lung donor pool; however, the biological consequences of donor warm ischemia on mitochondrial injury and systemic danger signaling remain uncertain. Cell-free mitochondrial DNA (cf-mtDNA) has been implicated in ischemia-reperfusion injury, yet its systemic behavior in ventilated human lungs is incompletely characterized. We conducted a prospective, multicenter observational study in matched adult lung transplant recipients from controlled donation after circulatory determination of death and donation after brain death to characterize donor and recipient plasma cf-mtDNA kinetics and evaluate their relationship with warm ischemic exposure. Serial plasma samples were obtained from donors and from recipients. Donor plasma cf-mtDNA levels were comparable between groups. A divergence emerged at 72 hours after transplantation, reflected by a significant donor type-by-time interaction in adjusted longitudinal analysis. Neither total nor functional warm ischemia time was associated with cf-mtDNA concentrations. In multivariable analysis restricted to 72 hours, donor type was not independently associated with absolute systemic cf-mtDNA levels. Exploratory analysis of donor-derived cf-mtDNA demonstrated a decline in graft-derived mitochondrial DNA between reperfusion and 72 hours despite a concurrent increase in total cf-mtDNA. These findings suggest that posttransplant systemic cf-mtDNA dynamics reflect recipient-driven inflammatory processes rather than a direct surrogate of donor warm ischemic injury.
Chronic antibody-mediated rejection is a leading cause of allograft loss, with limited therapies that effectively target humoral immunity. Current immunosuppressive regimens primarily target T cells, leaving a critical gap in strategies to suppress antibody-driven rejection. Marginal zone (MZ) B cells are innate-like cells that can rapidly generate antibodies, but their role in donor-specific antibody generation and chronic rejection remains unclear. We developed novel murine models of chronic antibody-mediated rejection using HLA-A2 transgenic heart and kidney transplants that recapitulate clinical features of human disease. Using an anti-Notch2 antibody to selectively target MZ B cells, we observed reduced antigen-specific humoral responses, including decreases in germinal center B cells, plasma cells, donor-specific antibodies, and C4d deposition, alongside improved graft structure and function. Mechanistically, the reduction of MZ B cells disrupted antigen shuttling to follicular dendritic cells, leading to decreased follicular dendritic cell-associated alloantigen clusters and impaired germinal center reactions. These findings establish MZ B cells as key drivers of alloantibody formation and highlight Notch2 as a promising therapeutic target.
Graft-vs-host disease (GvHD) remains a key challenge in allogeneic transplantation, underscoring the need for effective therapies to establish immune tolerance. Adoptive regulatory T cell (Treg) therapy shows promise but is restricted by the limited expansion of natural Tregs (nTregs) and the instability of induced Tregs (iTregs). The latter are prone to losing forkhead box protein 3 expression and suppressive function in inflammatory microenvironments. Here, we developed membrane-anchored transforming growth factor-β1 (MAT) and interleukin (IL)-10 (IL-10)-secreting iTregs (MAT-iTregs), a novel engineered iTreg platform designed to enhance lineage stability and suppressive potency. MAT-iTregs express membrane-anchored transforming growth factor-β1 and produce high levels of interleukin-10 to amplify immunosuppression and maintain functional stability. We optimized construct design and manufacturing processes to yield highly enriched MAT-iTregs. In preclinical studies, MAT-iTregs outperformed conventional iTregs in safety profiles and therapeutic efficacy. MAT-iTregs significantly prolonged survival, reduced tissue injury, and attenuated pathogenic effector T cell responses in xenogeneic GvHD mice. Notably, MAT-iTregs maintained suppressive function, durable persistence, and a favorable safety profile in mouse models, with no evidence of converting to effector T cells and minimal tissue toxicity. Together, these findings support MAT-iTregs as a clinically translatable cell therapy to promote transplant tolerance and improve outcomes in GvHD.
