American Journal of Transplantation最新文献

Disparities in deceased donor liver transplant (DDLT) may be due to geographic imbalances of organ supply-to-demand ratios and/or center organ acceptance practices. We evaluated the relative contribution of centers versus broader geographic units (donor service areas [DSAs]/states/organ procurement and transplantation network regions/census divisions) to variability in DDLT rate. Using Scientific Registry of Transplant Recipients data on adult, first-time, non-Status1A, period-prevalent waitlist candidates, we conducted multilevel Poisson regression with center-level and DSA-level intercepts to model DDLT rates across 3 eras: preacuity circles (pre-AC) (May 1, 2017 to April 30, 2019), initial post-AC (February 4, 2020 to February 3, 2022), and recent post-AC (February 4, 2022 to December 31, 2024), adjusting for candidate factors. We calculated center-level and DSA-level median incidence rate ratios (MIRRs) and their relative contributions to total geographic variation. DSA-level MIRR declined from _1.471.52_1.58 to _1.321.37_1.42 to _1.171.23_1.28 from pre-AC to initial post-AC to recent post-AC. The center-level, within-DSA MIRR increased from _1.561.61_1.64 to _1.761.82_1.84 to _1.921.96_2.05 across eras. The DSA-level contribution to total center-level variation declined from 43.7% to 21.5% to 8.4% across eras. Similarly, the contribution of other broad, geographic units (states/organ procurement and transplantation network regions/census divisions) to total geographic variation in DDLT rates decreased after AC. Further allocation changes are unlikely to substantially reduce geographic disparities because DDLT rate variation is predominantly driven by center-level differences, which were associated with highly variable advanced preservation practices.

As hepatitis C virus (HCV) infection is now curable, HCV-positive donor organs have expanded the deceased donor pool. Using Organ Procurement and Transplantation Network data, we identified adult kidney, liver, heart, and lung candidates listed between 2016 and 2025 and evaluated rates of consent to accept HCV antibody-positive (Ab+) and HCV viremic (nucleic acid testing [NAT]+) organs. Temporal trends were described, and multilevel modified Poisson regression with center-level random effects was used to estimate adjusted risk ratios for candidate factors and quantify center variation using median incidence rate ratios (MIRRs). Rates of consent to accept both HCV Ab+ and NAT+ organs rose over time. By the end of follow-up, consent rates for HCV Ab+ organs were 63.1% for kidney, 80.6% for liver, 73.3% for heart, and 72.1% for lung candidates, and consent rates for NAT+ organs were 44.9%, 70.7%, 50.5%, and 46.1%, respectively. Associations between candidate characteristics and consent were small after adjustment for center, whereas center effects were large. For HCV Ab+ organs, MIRRs were 6.31 (kidney), 2.48 (liver), 2.90 (heart), and 4.36 (lung); for NAT+ organs, MIRRs were even higher, 9.65, 3.19, 4.00, and 7.30, respectively, indicating marked between-center variability. Our analyses suggest that access to HCV-positive organs is influenced more by center practices than patient characteristics.

CD4⁺ forkhead box P3⁺ (Foxp3⁺) regulatory T cells (Treg) are essential for maintaining immune tolerance in both lymphoid and nonlymphoid tissues, including transplanted organs. Understanding the mechanisms that regulate Treg suppressor function and tissue migration remains a major focus in transplantation immunobiology. Here, we showed that under minimal effector T cell (Teff) response settings, Treg were unexpectedly inefficient at migrating to inflamed allografts despite circulatory presence. In contrast, Teff infiltration into inflamed allografts induced a multifold increase in intragraft Treg accumulation. These observations were confirmed in 2 lymphoreplete murine models in which Treg trafficking can be assessed with or without concurrent Teff activity. Intravital microscopy revealed that although Treg transferred alone remained confined to perivascular spaces, the presence of Teff enabled Treg migration deep into graft tissue. Mechanistically, Teff increased graft inflammation, and Teff-driven Treg migration to allografts required chemokine receptor signaling in Treg. In addition, we demonstrated that Teff-conditioned media directly promoted chemokine receptor-dependent Treg transmigration in vitro. Collectively, our findings demonstrate that Treg exhibit restricted migration and accumulation within inflamed allografts under controlled Teff responses, emphasizing the need to optimize Treg therapy designs to improve their trafficking to allografts under immunosuppression.

Aging donor livers (age ≥60 years) are increasingly used in liver transplantation but remain highly vulnerable to ischemia-reperfusion injury (IRI). Sustained activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome and macrophage pyroptosis are key features of hepatic IRI, yet the upstream mechanism responsible for persistent NLRP3 activation in aging liver macrophages is unclear. Analysis of human liver graft samples revealed the clinical association of CD38-related nicotinamide adenine dinucleotide (NAD)⁺ dysregulation with transplantation-associated injury, although mechanistic investigations using mouse models and macrophage systems identified the CD38-NAD⁺-sirtuin 1(SIRT1)-estrogen-related receptor (ERR)α-NLRP3 pathway underlying aging-associated IRI. Consistently, aging grafts developed more severe IRI and macrophage pyroptosis than young grafts, whereas conditional deletion of CD38 in Kupffer ells partially alleviated these changes in vivo and in vitro. Mechanistically, CD38-associated NAD⁺ depletion impaired SIRT1 activity, reduced ERRα deacetylation at lysine 129, and affected ERRα-mediated regulation of NLRP3 transcription. Moreover, a nanodelivery system carrying the CD38 inhibitor 78c effectively reduced Kupffer cell pyroptosis and attenuated IRI in aging donor livers. These findings identify the CD38/NAD⁺/SIRT1/ERRα/NLRP3 signaling pathway as a potential regulatory axis linking aging-associated metabolic dysfunction with graft susceptibility to IRI.

The availability and structure of donor care units (DCUs) at the Organ Procurement Organization (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 the 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. Donation after brain death donors recovered by OPOs with DCU-hospital available (odds ratio = 1.11; 95% confidence interval (CI), 1.01-1.22) and DCU-independent available (odds ratio = 1.21; 95% CI, 1.08-1.36) had higher odds of utilization than donation after brain death donors recovered by DCU-negative OPOs, whereas no significant DCU association was observed among donation after circulatory death donors. Among 18 271 lung transplant recipients, graft survival did not differ between DCU-positive and DCU-negative groups (hazard ratio = 1.03; 95% CI, 0.96-1.11) or between DCU-independent-available and DCU-hospital-available groups within the DCU-positive cohort (hazard ratio = 1.00; 95% CI, 0.87-1.15). DCU availability was associated with higher donation after brain death donor lung utilization but not recipient graft survival.

Innate immune memory is increasingly recognized as a regulator of immune responses in solid organ transplantation. Following an initial stimulus, innate immune cells and their progenitors can undergo epigenetic and metabolic reprogramming, resulting in enhanced or suppressed proinflammatory responses upon subsequent encounters, termed trained immunity and innate immune tolerance, respectively. These antigen-independent forms of innate immune memory are complemented by donor-specific innate immune memory. Importantly, innate immune memory may influence alloimmune responses by shaping adaptive T cell activation through altered cytokine production, antigen presentation, and costimulatory signals. Conversely, adaptive immune cells can regulate the induction of innate immune memory, highlighting a bidirectional innate-adaptive crosstalk. In this review, we discuss the interplay of innate immune memory with adaptive immunity, and the potential to harness this mechanism to promote graft survival and long-term tolerance.

Kidney transplant benefit is limited by delayed graft function, a syndrome stemming from severe ischemia-reperfusion injury (IRI). Natural killer (NK) cells have been implicated in rejection and injury pathologies, motivating translatable strategies to target these cells. We investigated whether monoclonal antibody depletion of CD94-expressing immune cells attenuates injury in 2 clinically relevant mouse models of kidney IRI. High-dimensional flow cytometry demonstrated rapid expansion of NK cell populations following injury. Anti-CD94 therapy reduced NK cell frequency and activation after IRI in the kidney, and improved renal function and reduced histologic injury. Notably, kidney IRI induced acute lung injury with NK and T cell inflammation, hypoxemia, and histologic damage. Anti-CD94 therapy preceding kidney IRI abrogated all metrics of acute lung injury by 48 hours relative to isotype control. Finally, in orthotopic allogeneic kidney transplant models, anti-CD94 treatment was associated with reduced injury and improved observed survival relative to isotype control. These findings implicate CD94⁺ NK cells in early transplant-associated injury and support further evaluation of anti-CD94 treatment to potentially improve outcomes following transplantation.

Complement activation during clinical kidney normothermic machine perfusion (NMP) is poorly defined. We examined whether perfusate complement biomarker levels measured during prolonged NMP were associated with early graft recovery. Samples and outcome data were obtained from the normothermic kidney perfusion 1 phase-1 trial of prolonged kidney NMP before transplantation (n = 36). Perfusate complement component 1s, collectin-11, complement component 2, complement component 3, complement component 3d, factor B, complement factor B activation fragment Ba, and soluble terminal complement complex/membrane attack complex (C5b-9) levels were measured at hour 1 and at the end of perfusion. Associations with functional delayed graft function and the time to 50% fall in serum creatinine levels were assessed using nonparametric testing, Kaplan-Meier analysis, and Cox models incorporating the United Kingdom donor risk index (UKDRI). Paired preperfusion and postreperfusion biopsies underwent multiplex immunofluorescence for complement component 4d, C5b-9, and intercellular adhesion molecule 1 levels. Complement component 1s, collectin-11, complement component 3d, and soluble C5b-9 levels increased during NMP, whereas complement component 2 and factor B levels decreased. Kidneys developing functional delayed graft function had higher end-perfusion soluble C5b-9 and hour-1 complement component 3 levels, both significant after false discovery rate correction. Complement profiles stratified using the time to 50% fall in serum creatinine levels, including within UKDRI score strata, and an hour-1 grouping improved Cox model fit beyond UKDRI score alone. Postreperfusion tissue C5b-9 and intercellular adhesion molecule 1 levels increased, whereas complement component levels did not. Complement activation during prolonged NMP is associated with early graft outcomes and may support biomarker level-guided assessment and future targeted intervention in clinical kidney transplantation practice.

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.

Leveraging the Transplant Pregnancy Registry International, we conducted a retrospective study of children born to liver transplant (LT) recipients between 1986 and 2024 to evaluate long-term health outcomes of offspring. Child data were collected primarily from biyearly 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 73.3% were White and 13.1% Hispanic, with a median age at conception of 29.4 years. The most common LT indications were autoimmune hepatitis (14.2%) and biliary atresia (13.9%); the median time from LT to delivery was 6.9 (interquartile range, 3.1-14.2) years; 21.0% of mothers required antihypertensive medications during their pregnancy, 20.7% developed preeclampsia, and 46.1% had cesarean delivery. Most (68.3%) children were healthy and developing well at a median follow-up time of 7.6 (interquartile range, 3.4-14.9) years. The most common pediatric conditions in offspring were allergies (6.5%), asthma/reactive airway disease (4.7%), attention deficit hyperactivity disorder/attention deficit disorder (4.7%), 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.