Extracorporeal liver cross-circulation (ELC) using gene-edited porcine liver xenografts offers a potential bridge therapy for liver failure. We previously performed five ELC procedures in four brain-dead human decedents, during which the recipients developed severe thrombocytopenia. The porcine liver xenografts maintained their parenchymal structure, with immune cell infiltration and detectable IgM deposition on endothelial cells. Here, to investigate the underlying host-xenograft interactions, we performed longitudinal proteomic, lipidomic and metabolomic profiling of 64 blood samples, alongside spatial transcriptomics and histology of 25 porcine liver xenograft and 3 native human liver biopsies. Spatial transcriptomic analysis revealed progressive infiltration of human immune cells (predominantly inflammatory macrophages and neutrophils) in the xenografts, concurrent with the loss of porcine Kupffer-like macrophages and T cells. Distinct human and porcine complement dynamics were observed, with suppressed human but elevated porcine complement levels, accompanied by increased levels of porcine acute-phase proteins and coagulation factors. Moreover, multiomics analyses identified candidate cellular and molecular factors associated with thrombocytopenia. Human platelets colocalized with activated porcine endothelial cells, which showed increasing porcine vWF expression over time, as well as with immune cells (primarily macrophages and neutrophils) and hepatocytes in the xenografts. Integrative analyses indicated that ELC procedures provided hepatic support for apolipoprotein synthesis, bilirubin clearance, energy metabolism and detoxification, although circulating lipid levels remained low under anhepatic conditions. Collectively, these findings yield insights into the complex interplay between human and xenograft systems during ELC and inform strategies to improve liver xenograft biocompatibility for clinical translation.

Background:Understanding center-level decision-making for suboptimal kidney (SOK) offers is critical to ensure utilization of all transplantable kidneys. Methods:We quantified center-level variation in accepting SOK deceased donor kidney transplant (DDKT) offers using 2021-2023 national registry data. SOK subtypes included: donor age >60, ultimate cold ischemia time >24 h, hepatitis C positive, terminal serum creatinine >2.0 mg/dL, donation after circulatory death, kidney donor profile index >85%, and public health service increased risk donors. Gini coefficient (Gini) was used to analyze inequality in DDKT utilization by SOK subtype. Multilevel logistic regression models were used to calculate the median odds ratio (mOR), measuring center-level variation in accepting SOK donor offers among adult centers. Results:Of all DDKTs, 72.6% were from donors with at least 1 SOK characteristic. Inequality persisted in utilization of SOK DDKTs (Gini of all SOKs: 0.53, Gini of all non-SOKs: 0.47). The 193 adult centers accepted a median (interquartile range) of 12.5% (8.4%-19.2%) offered non-SOK donors and 7.2% (4.6%-10.8%) offered SOK donors. Non-SOK donors and SOK donors were refused by a median (interquartile range) of 5 (3-10) and 9 (4-23) centers, respectively. The SOK subtypes with the least and the most center-level variance in acceptance were increased risk donor (mOR = 2.06) and cold ischemia time >36 h (mOR = 4.86), respectively. Conclusions:Centers vary sharply in their willingness to accept certain types of SOK offers. Informing centers of their patterns of accepting specific donor phenotypes compared with their peers may motivate centers to accept more SOKs for clinically suitable recipients, thus improving patient access to DDKT.

INTRODUCTION:Technological advances in organ preservation and reconditioning have enabled increased use of donation after circulatory death (DCD) organs. We aimed to characterize temporal trends in pediatric DCD (pDCD) in the United States. METHODS:We used Organ Procurement and Transplantation Network data to identify all pediatric (age < 18 years) deceased organ donors in the US, 2000-2025. We calculated the number and proportion of pediatric donation after brain death (pDBD) and pDCD donors by year. We calculated the number and type of recovered and transplanted pDBD and pDCD organs by year. RESULTS:The annual number of pDBD donors fell from 985 in 2000 to 530 in 2025, whereas pDCD donors increased from 21 to 244. The rise in pDCD recovery was observed for all organs: 32%, 19%, 16%, 14%, and 12% of recovered pediatric kidneys, livers, lungs, hearts, and pancreata by 2025. Among transplants with pediatric recipients in 2000, there was 1 pDCD liver transplant and no pDBD kidney, heart, lung, or pancreas transplants. By 2025, pDCD transplants accounted for 3%, 2%, and 8% of kidney, liver, and heart transplants with pediatric recipients. CONCLUSION:pDBD donors have fallen over the last 25 years, whereas pDCD donors have increased over 10-fold over the same period. Given the ongoing need for pediatric organ transplantation and the ethical importance of preserving opportunities for donation, there is an urgent need to develop a parallel communication and ethical framework to support families, clinicians, and transplant teams in navigating these donation opportunities.

This study describes secular trends in organ donation after circulatory death in the United States between 2000 and 2025.

Artificial intelligence (AI) is rapidly transforming healthcare, and the field of kidney transplantation (KT) is no exception. While much of the AI-related work has focused on deceased donor KT, there is a growing body of research applying AI tools to living kidney donation (LKD). This review explores AI’s current and potential roles in LKD, focusing on predictive and social applications of AI in LKD. Additionally, we discuss the challenges and limitations of implementing AI in clinical settings and highlight emerging research trends. This review consolidates existing research and provides a foundation for both transplant professionals and data scientists seeking to integrate AI responsibly into living donor programs.

ABSTRACTPurposeIn October 2018, the OPTN changed adult heart transplant (HT) allocation policy, increasing the number of adult candidates that had higher priority than pediatric candidates, potentially disadvantaging pediatric waitlist registrants.MethodsTo understand the impact of this policy change, we used SRTR data to identify 1469 pre‐policy (7/2016–9/2018) and 2901 (10/2018–12/2022) post‐policy pediatric (< 18 years) HT registrants. We quantified mortality and transplant risks using weighted cause‐specific hazard models, and then using weighted competing risks regression. We further stratified these analyses by age to understand risks for those in direct competition with adults for organs (≥ 12 years).ResultsPost‐policy, patients were more likely to need VAD prior to HT. There were no changes in post‐policy access to HT (weighted hazard ratio [wHR] = 0.96 1.03 1.11, p = 0.43). Mortality risk censoring for transplantation declined by 20% post‐policy (wHR = 0.64 0.80 1.02, p = 0.05). When accounting for competing risks of transplantation, post policy, mortality decreased by 24% compared to pre‐policy (weighted subdistribution HR [wSHR] = 0.61 0.76 0.94, p = 0.02). Post policy, 1‐year transplant rate did not change in those < 12years (68.2%–71.0%, p = 0.77), but in those ≥ 12years, transplant rate increased (77.3%–81.0%, p = 0.003).ConclusionsMortality on the waitlist decreased and access to HT for pediatric registrants did not decline following the 2018 policy change. The decreased mortality rate may reflect changes in patient casemix and/or improved patient care. Continued surveillance is important in ensuring equity in pediatric, and adult, HT.

Historically, liver transplant (LT) candidates with human immunodeficiency virus (HIV) have experienced high waitlist mortality. Since the HIV Organ Policy Equity (HOPE) Act expands access to organs from donors with HIV, we assessed the impact of HOPE on LT rate and wait time for this population. We linked data from a multicenter HOPE in Action study to Scientific Registry of Transplant Recipients (February 21, 2019 to June 1, 2024) and used Poisson regression to compare transplant rates among 99 candidates willing to accept HOPE donors (HOPE candidates) to 13 495 candidates with or without HIV not listed as willing to accept HOPE donors (non-HOPE candidates) matched on transplant center. The median time to any deceased donor liver transplant (DDLT) was 2.3 months for HOPE and 1.1 years for non-HOPE candidates. Within 2 years of listing, 90.9% of HOPE versus 58.5% of non-HOPE candidates received a DDLT (P < .001). HOPE was associated with an overall 3.11-fold higher DDLT incident rate ratio (95% CI 2.48-3.88, P < .001). Stratified by model for end-stage liver disease score categories 6 to 14, 15 to 24, 25 to 34, and 35 to 40/status 1; HOPE candidates had 10.12-fold, 5.31-fold, 1.41-fold and 2.90-fold higher DDLT rates, respectively. Willingness to accept livers from donors with HIV improves access to liver transplantation for candidates with HIV.

Organ shortage remains a major challenge in transplantation, and gene-edited pig organs offer a promising solution1-3. Despite gene editing, the immune reactions following xenotransplantation can still cause transplant failure4. To understand the immunological response of a pig-to-human kidney xenotransplantation, we conducted large-scale multi-omics profiling of the xenograft and the host's blood over a 61-day procedure in a brain-dead human (decedent) recipient. Blood plasmablasts, natural killer cells and dendritic cells increased between postoperative day (POD) 10 and 28, concordant with an expansion of IgG and IgA B cell clonotypes and subsequent biopsy-confirmed antibody-mediated rejection (AMR) at POD33. Human T cell frequencies increased from POD14 and peaked between POD33 and POD49 in the blood and xenograft, which coincided with T cell receptor diversification, expansion of a restricted TRBV2 and TRBJ1 clonotype and histological evidence of combined AMR and cell-mediated rejection at POD49. At POD33, the most abundant human immune population in the graft was CXCL9+ macrophages, which aligned with interferon-γ-driven inflammation and a T helper 1-type immune response. There was also evidence of interactions between activated pig-resident macrophages and infiltrating human immune cells. Xenograft tissue showed pro-fibrotic tubular and interstitial injury marked by S100A6 (ref. 5), SPP1 (also known as osteopontin)6 and COLEC11 (ref. 7) expression at POD21-POD33. Proteomic profiling revealed activation of human and pig complement, with a decreased human component after AMR therapy, in which complement was inhibited. Collectively, these data delineate the molecular orchestration of human immune responses to a porcine kidney and reveal potential immunomodulatory targets for improving xenograft survival.

BackgroundTo encourage high-quality, reduced-cost care for total joint arthroplasty (TJA), the Centers of Medicare & Medicaid Services mandated a pay-for-performance model, the Comprehensive Care for Joint Replacement (CJR), as part of the Patient Protection and Affordable Care Act (PPACA). The CJR incentivizes cost containment, and it was anticipated that its implementation would reduce access to TJA for high-cost populations. Patients with end-stage kidney disease (ESKD) undergoing kidney replacement therapy (dialysis and kidney transplant) are costly compared with healthier patients, but it was unknown whether this population lost access to hip and knee replacement because of CJR implementation. This population allows study of whether TJA is accessible for medically complex patients whose risk of surgical complications has been mitigated, as kidney transplantation improves outcomes compared with dialysis, allowing evaluation as to whether access improved when patients crossed over from dialysis to transplantation. Because all patients with ESKD are included in a mandated national registry, we can quantify whether access changed for patients who underwent dialysis and transplantation.Questions/purposes(1) How did the rate of TJA change amid the shift to bundled payments for patients with ESKD receiving dialysis? (2) How did the rate of TJA change amid the shift to bundled payments for patients with ESKD after kidney transplant?MethodsThis was an observational cohort study from 2008 to 2018 using the United States Renal Data System, a mandatory national registry that allows for the opportunity to study all individuals with ESKD. During the study period, we identified 1,324,614 adults undergoing routine dialysis and 187,212 adult kidney transplant recipients; after exclusion for non-Medicare primary insurance (n = 785,224 for dialysis and 78,011 for transplant), patients who were 100 years or older (n = 79 and 0, respectively), those who resided outside of 50 US states and Puerto Rico (n = 781 and 87, respectively), missing dialysis status for the dialysis cohort (n = 8658), and multiorgan transplant recipients for the transplant cohort (n = 2442), our study population was 40% (529,872) of patients who underwent routine dialysis and 57% (106,672) of adult kidney transplant recipients, respectively. TJA was ascertained using Medicare Severity Diagnosis Related Groups and ICD-9 and ICD-10 codes. We divided the study period by PPACA (January 1, 2014, to March 31, 2016) and CJR (April 1, 2016, to December 31, 2018) implementation and compared the incidence of TJA by era using mixed-effects Poisson regression adjusting for calendar time and clinical and demographic variables.ResultsAfter adjustment for linear temporal trend and patient case mix, there was no evidence of association between policy implementation and the incidence of TJA. In the dialysis cohort, the adjusted incidence rate ratio (IRR) for TJA was 1.06 (95% confidence interval [CI] 0.98 to 1.14; p = 0.2) comparing PPACA with the previous period and 1.02 (95% CI 0.96 to 1.08; p = 0.6) comparing CJR with the previous periods. Similarly, in the transplant cohort, the adjusted IRR for TJA was 0.82 (95% CI 0.67 to 1.02; p = 0.07) comparing PPACA with the previous period and 1.10 (95% CI 0.94 to 1.28; p = 0.9) comparing CJR with the previous periods.ConclusionThere was no loss in access to TJA for medically complex patients receiving kidney replacement therapy. The increase in TJA incidence for patients after kidney transplant and decrease for patients receiving dialysis suggest that surgeons continued to provide care for higher risk patients whose risk of morbidity or mortality with total joint replacement has been maximally improved after transplantation.Level of EvidenceLevel III, prognostic study.

BACKGROUND:Access to liver transplantation (LT) for pediatric registrants is complex and impacted by many factors. Assessing the state of pediatric LT requires understanding the balance between policy, the availability of livers, and the quantity of pediatric patients requiring LT. METHODS:Using Scientific Registry of Transplant Recipients data with Cox regression (to compare rates) and competing risk regression (to compare cumulative incidence), we evaluated pediatric patient characteristics, number of registrants transplanted, and waitlist mortality from (January 1, 2017-February 4, 2020) to (May 1, 2020-June 4, 2023) using the implementation of acuity circles to divide the eras. RESULTS:In 4314 pediatric LT registrants, transplantation rate increased in the post-policy era, compared with the pre-policy era (adjusted hazard ratio [HR], 1.05 1.12 1.20 ; P  < 0.001). When accounting for competing risks, the increase was attenuated and not statistically significant (adjusted subdistribution HR, 0.99 1.06 1.14 ; P  = 0.08); recipients were no more likely to die on the waitlist (adjusted subdistribution HR, 0.78 1.01 1.30 ; P  = 0.99). Importantly, the prevalent pediatric waitlist dropped from 396 (2017) to 225 (2023), the rate of deceased donor LT from pediatric donors increased (weighted HR, 1.20 1.31 1.42 ; P  < 0.001), and access to living donor LT increased, compared with the pre-policy era (weighted HR, 1.11 1.33 1.59 ; P  = 0.002). The transplant rate for pediatric patients did not decrease during the study period despite the introduction of acuity circles. During the study period, the prevalent waitlist shrank, access to LT from pediatric donors increased, and access to living donor LT increased. CONCLUSIONS:Comprehensive assessment following the policy change is necessary to ensure that pediatric candidates maintain priority. Changes in pediatric transplantation are modest and likely related to changes in the pool, rather than to the policy of acuity circles.

Orthotopic heart transplantation is considered to be the best treatment for end-stage heart failure, with improved survival and quality of life for patients.1 Despite the number of adult and pediatric heart transplants performed in the US having reached >4000 annually, the number of patients waiting for a heart allograft continues to exceed the available supply.2 Xenotransplantation has emerged as a promising alternative to address the demand by providing a source of organs that is readily available and practically inexhaustible.3 Given their anatomical and physiological similarity to humans, pigs are considered the most suitable donor species for xenotransplantation,4 with immunologic barriers steadily being overcome through advances in targeted genetic engineering of the porcine genome and immunosuppression therapies.4, 5 In 2022, two brain-dead human recipients "decedents" received 10-gene-edited porcine hearts. Over the two ∼3-day studies, there was sustained cardiac function, without evidence of acute-onset rejection or zoonotic transmission.6 To better elucidate the molecular processes in the peripheral blood and pig heart xenograft tissues, Schmauch and colleagues recently reported in Nature Medicine the dynamic molecular interactions following these pig heart to human decedent xenotransplants using comprehensive, longitudinal multi-omic profiling.7 This commentary dissects their key findings, emphasising the clinical translational implications and highlighting future research avenues in this evolving field. Over the last decade, methodological and technical advances have led to the development of high-throughput, low-cost technologies where millions of biomolecules spanning nucleic acids, proteins, lipids and metabolites can be measured simultaneously.8 This includes advances in high-throughput sequencing, with current platforms able to produce large high-quality human and pig whole genome sequencing (WGS), RNA-sequencing, epigenetic and genomic structure profiling e.g., bisulfite WGS and Assay for Transposase-accessible chromatin with sequencing (ATAC-seq), a technique that assesses chromatin accessibility across the genome. A number of these sequencing approaches can be performed in tissues as well as in cell-free fractions of DNA and RNA in peripheral fluids including blood and urine. Concomitantly, advances in biochemical preparation and mass spectrometry technologies have enabled the large-scale quantitative profiling of proteins (proteomics), metabolites (metabolomics) and lipids (lipidomics) in tissues and bodily fluids. Current advances have afforded the ability to perform a variety of assays at single cell resolution, for example, scRNA-seq and scATAC-seq, which allow new insights into specific cell-types and cell–cell interactions that drive different types of rejection which would be otherwise masked at the level of 'bulk' RNA profiling. The latest advances in single-cell analyses also allow spatial cellular profiling in tissues, further adding key contextual information related to donor and recipient cell interactions in vivo. Leveraging these methodologies, Schmauch and colleagues used peripheral blood mononuclear cells (PBMCs) and pig heart xenograft tissue collected every 6 h to perform an integrated analysis of the transcriptome, lipidome, proteome, and metabolome, as well as histologic and transcriptomic profiling. Their findings revealed distinct molecular signatures. Decedent 1 (D1) exhibited a pronounced immune response characterised by increased CD4+ and CD8+ T cell as well as NK cell activity observed with scRNA-seq, and upregulation of inflammatory pathways was observed using bulk RNA-seq. Additionally, an early surge of B cell subtypes, following an increase in plasma cells, was observed, indicating a potential humoral immune response in the early stages of xenotransplantation. In contrast, D2 exhibited a relatively muted response, with a substantial decrease in T cells and stable B cell population after a second dose of rabbit anti-thymocyte globulin (rATG). Detailed single-cell transcriptomic analysis of PBMCs revealed a complex interplay of immune cell populations. The increase in CD8+ and CD4+ T cells in D1, along with the pathways, indicates a robust cellular immune response to the xenograft. This observation is further supported by the upregulation of inflammatory pathways in the bulk RNA-seq datasets. These findings highlight the critical role of immunosuppression in modulating the decedent's immune response and the potential for personalised therapeutic strategies based on individual immune profiles. Thus, in the xenotransplant setting we have confirmatory evidence that immunosuppressant regimes can effectively modulate the immune response. With the advent of multi-omic technologies 'druggable' targets can be identified to help personalise drug development for xenotransplant and/or optimise dosing of immunosuppressant regimens at the pre-and post-transplant stages. These studies also showed ischemia reperfusion injury (IRI) through RNAseq which identified transcriptional signatures, including hypoxia related genes, with spatial transcriptomics showing vascular remodeling. This is important because IRI is a major mechanism by which an inflammatory response can be generated in the heart, which may lead to earlier and more pronounced neoantigen exposure to the immune system, which may amplify immune response(s). Furthermore, this IRI state in the xenograft and the resulting decedent's immune response is an opportunity for intervention e.g. through known interventions/mitigations of IRI such as optimising organ preservation/perfusion to reduce graft dysfunction. Additionally, the integration of single-nuclei RNA-seq data from the xenograft with a publicly available dataset of pig hearts subjected to IRI allowed the identification of specific transcriptional signatures associated with IRI in the xenograft. Specifically, the upregulation of hypoxia-related genes, damage-associated molecular patterns (DAMP), and inflammatory pathways in D1's heart tissue points to a significant IRI component. Furthermore, spatial transcriptomic analyses revealed a distinct pattern of vascular remodeling and damage in the xenograft, particularly in D1. The enrichment of vascular markers, DAMPs, and inflammatory signals in specific spatial clusters suggests localised tissue injury and repair processes. This observation underscores the importance of optimising organ preservation and surgical techniques to minimise IRI in xenotransplantation. Using additional open-source RNA profiling from pig heart xenotransplantation in the non-human primate setting the Schmauch et al. paper showed that the top mRNA and pathway signals were consistent with the phenotype of perioperative cardiac xenograft dysfunction (PCXD), a complication that can occur during a heart xenotransplantation where the xenograft has significant dysfunction immediately after surgery, with expanded T-cell proliferation evident on the background of IRI.9 A size mismatch between the donor heart and D1's chest cavity, coupled with prolonged cold ischemia time and the use of bovine pericardial patches, also exacerbated IRI and contributed to the observed PCXD. PCXD can be managed in the xenotransplant setting using approaches including optimised organ preservation strategies to mitigate PCXD in future xenotransplants. The importance of this study lies in its use of longitudinal multi-omics, which provides a powerful framework for elucidating complex molecular events, facilitating a more holistic understanding of biological processes (Figure 1). The findings highlight early molecular and immune responses following xenotransplantation, particularly as they relate to IRI and PCXD. This knowledge can offer critical insights in identifying potential biomarkers and therapeutic targets, including druggable genes, to optimise immunosuppression and patient outcomes. It can also help identify genes that can be knocked out in subsequent porcine models, as well as human transgenes that can be 'knocked in' to reduce immune recognition in human patients. Future long-term studies are needed to assess the longevity and functionality of xenografts, with expansion to other omics layers, such as the epigenome, to further characterise pig-to-human heart xenotransplantation. Overall, this study represents a substantial step forward, helping pave the way for successful clinical xenotransplantation. All coauthors helped with writing and editing of this manuscipt. Michael P. Snyder is a co-founder and the scientific advisory board member of Personalis, SensOmics, Qbio, January AI, Fodsel, Filtricine, Protos, RTHM, Iollo, Marble Therapeutics, Crosshair Therapeutics, NextThought and Mirvie. He is a scientific advisor of Jupiter, Neuvivo, Swaza, Mitrix, Yuvan, TranscribeGlass, Applied Cognition. The other coauthors have no declarations. The authors have nothing to report. Development of the multi-omics platform and analyses was supported by NIAID-NIH R01 AI144522 (to B.J.K., M.P.S. and B.P.).

ABSTRACTIntroductionSome living organ donors will decide to donate again at a later date. Evidence has indicated that this practice may have increased in recent years. We evaluated the incidence and outcomes of this practice to inform counseling of potential repeat donors.MethodsUsing SRTR data from 1994 to 2023, we identified 220 repeat living donors and their 415 recipients. We constructed donor comparison groups using weighting by the odds. We described clinical and lab results at 6 months, 1 year, and 2 years post‐donation separately for kidney‐second donors and liver‐second donors. We compared all‐cause graft failure for their recipients with those of comparison donors.ResultsThe annual count of repeat living donors increased from 5 in 2018 to 25 in 2019 (p < 0.001). Of 220 donors, 159 were liver‐second donors (72.3%) and 55 were kidney‐second donors (25.0). The percentage of nondirected donations increased from 30.5% at first donation to 53.2% at second donation (p < 0.001). Liver‐second donors had one death approximately 2.5 years post‐donation. Seventeen were re‐admitted and 20 experienced complications requiring an interventional procedure or re‐operation. Among kidney‐second donors, no deaths, re‐admissions, or post‐donation complications were reported. Post‐donation outcomes in both groups were comparable when evaluated against organ‐specific comparison donors. Recipients of repeat living donors experienced graft survival similar to recipients of comparison donors.ConclusionsRepeat living donation may be a safe practice for carefully selected living donors in the short term; however, long term safety is unknown. Outcomes for recipients are similar to recipients of comparison donors.

BACKGROUND:Organ Procurement and Transplantation Network (OPTN) policy requires 2 years of follow-up for living kidney donors (LKDs); however, many transplant hospitals struggle to meet this requirement. We developed and tested a mobile health (mHealth) system for LKD follow-up in a pilot randomized-controlled trial (RCT). METHODS:LKDs were randomly assigned to either the intervention (mHealth + standard of care) or control arm (standard of care). We assessed OPTN policy-defined completeness and timeliness of 6-month, 1-year, and 2-year follow-ups. Four hundred LKDs were enrolled in the study (June 2018 to February 2021). RESULTS:At 6-month follow-up, a higher proportion of the intervention arm participants completed composite visits (97.5% vs. 91.5%, p = 0.01). Both arms had similar compliance rates at 1- and 2-year follow-up (92.0% vs. 89.5%, p = 0.49, and 66.5% vs. 65.0%, p = 0.83). Intervention arm participants completed 6-month follow-up 11 days earlier than their counterparts (p = 0.009). CONCLUSION:mHealth technologies improved 6-month follow-up, but did not impact 1- and 2-year LKD follow-up in this single-center RCT. Other strategies, such as providing services beyond data collection, may be necessary to improve donor engagement and support LDK's long-term follow-up.

This study uses a national registry study to characterize temporal trends in perioperative mortality in donors and risk factors associated with this event.