American Journal of Transplantation最新文献

Patients awaiting liver transplantation (LT) are often frail, malnourished and at risk of poor health outcomes. Prehabilitation programs (exercise, nutrition, and psychological interventions) attempt to mitigate these co-morbidities. This study assesses the feasibility, safety, and effectiveness of such programs as primary outcomes, and their impact on physical fitness and health pre - and post- LT as secondary outcomes. We conducted a systematic review and meta-analysis and searched EMBASE, MEDLINE, CINAHL, ISI Web of Science, and CENTRAL. We included primary studies from database inception to March 2025 of adults listed for LT enrolled in prehabilitation programs. From 4762 citations, 19 studies were included. Participation in a prehabilitation program was 66% (48% to 80%; 12 studies, n=1120). Prehabilitation program completion was 75% (61% to 85%; 17 studies, n=862), and it did not differ from completion in control groups (RR 0.98, 0.95 to 1.02; 12 studies, n=753). Adverse events were 4% (2% to 9%) (8 studies, n=154). Physical fitness demonstrated improvement from pre- to post-intervention in VO₂ (SMD =0.63 (0.02 to 1.23)), 6MWT (SMD=0.71 (0.19 to 1.22)), LFI (SMD= -0.57 (-0.90 to -0.24)), and SPPB (SMD=0.88 (0.35 to 1.42)). Prehabilitation programs appear feasible and safe, with significant improvements in exercise fitness.

Organ transplant immunosuppression includes daily calcineurin inhibitors and corticosteroids, which target broad, toxic metabolic pathways. This phase 2a, open-label, single-arm trial evaluated the efficacy and safety of combining dazodalibep (cluster of differentiation (CD)154-specific, also known as CD40 ligand-specific) with belatacept (CD80/86-specific) as the sole maintenance therapy in adults undergoing first, nonidentical kidney transplants from deceased or living donors. The primary endpoint was incidence of efficacy failure, defined as treated biopsy-proven acute rejection of grade 1A or higher, graft loss, or death at week 24. Secondary endpoints assessed efficacy components at weeks 12, 24, and 48 and safety. Among 23 patients treated with at least 1 dose, 13 (56.5%) completed the study. Twenty patients received a revised dosing regimen, and 5/20 (25%) experienced treated biopsy-proven acute rejection. No antibody-mediated rejection occurred. Kidney function was similar for patients who did and did not experience transplant rejection through 24 weeks. Most patients (96% [22/23]) experienced at least 1 treatment-emergent adverse event. No thrombotic events were observed. While the prespecified primary endpoint to prevent composite efficacy failure was not met among patients who completed this study, dazodalibep and belatacept dual biologic treatment was generally safe, well tolerated, and effective as the sole maintenance antirejection therapy.

Ischemia-reperfusion injury (IRI) contributes to deleterious outcomes after lung transplantation. Although we have shown a unique protective role for eosinophils in both establishing and maintaining lung allograft tolerance, their role in IRI remains unclear. Based on previous research demonstrating a protective role for eosinophils in liver IRI, we hypothesized, they might play a similar function in the lung. Here, we show that donor-, but not recipient-derived, eosinophils worsen injury of syngeneic and allogeneic lung grafts rather than protect from it. Eosinophils in lungs stored in a low potassium dextran-based extracellular preservation solution become activated, degranulate, and die during rewarming. This damage correlates with decreased oxygenation and increased tissue injury upon reperfusion. In vitro studies confirm that eosinophils exposed to a clinically used low-potassium dextran-based preservation solution, but not to other preservation solutions, experience oxidative stress. Supplementing such a solution with the antioxidant glutathione, which is present in solutions used to preserve other solid organs, reduces activation and injury. While IRI has been attributed solely to graft damage mediated by recipient-derived cells entering the graft upon reperfusion, our new findings uncover a previously unrecognized role for donor-derived leukocytes in this process and open unexplored avenues to improve graft function.

In deceased donation, donor management and organ procurement may contribute to donor organ injury, particularly through triggering systemic inflammation. Despite the important clinical implications, the impact of circulating inflammation on donor kidney injury, and short- and long-term posttransplant outcomes are unknown. We quantified TNFα and its receptors TNFR1 and TNFR2 in 1018 longitudinal plasma samples collected during donor management from 596 deceased and 34 living donors, from multiple centres across the United Kingdom. High donor plasma TNFα levels significantly associated with 12 and up to 60 months inferior graft function and up to 96 months reduced survival, only in DBDs but not in DCDs. Associations were replicated in a validation cohort and withstood linear mixed model adjustments for donor and recipient covariates. Analysis of paired plasma and kidney biopsy samples revealed that high plasma TNFα levels correlated with increased expression of injury markers in donor kidney. Further in vitro investigations confirmed that human podocytes, exposed to TNFα donor plasma, demonstrated TNFR1 signaling driven injury profiles, a response that was ameliorated by infliximab. Our data provide evidence that monitoring plasma inflammation levels during donor management offers a window of opportunity to intervene and improve optimisation and quality of deceased donor organs.

Cytomegalovirus (CMV) disease in solid organ transplant recipients (SOTr) can be prevented by antiviral prophylaxis or preemptive therapy (PET). The optimal CMV monitoring frequency remains unclear and it is debated whether CMV surveillance after prophylaxis (SAP) is needed. CMV IgG donor (D)+/recipient (R)- or R+ SOTr in Zürich, Lausanne, and Copenhagen (2008-2021) were followed for six months after stop of CMV prophylaxis or transplantation if no prophylaxis was given. Associations between monitoring intervals and CMV disease were analyzed by Cox regression. Numbers needed to test (NNT) with monitoring intervals of ≤7 vs >7 days were calculated. Among 3,411 SOTr, CMV monitoring interval of 8-14 or >14 days vs ≤7 days were associated with higher risk of CMV disease (adjusted hazard ratio (95%-CI), 4.74 (2.17-10.36), and 3.98 (1.92-8.26), respectively). The increased risk of CMV disease associated with monitoring intervals >7 days was consistent across subgroups. The first three months of PET/SAP, NNT (95%-CI) was 11 (8-19) for D+/R- vs 71 (35-218) for R+ SOTr, and did not differ between PET and SAP. Our findings support weekly CMV monitoring during first three months at risk, regardless of CMV preventative strategy. Close monitoring is more efficient in D+/R- SOTr, reflected by lower NNTs.

The role of gut microbiota in acute cellular rejection (ACR) after intestinal transplantation (ITx) remains poorly defined. This study investigated whether ileal microbial dysbiosis precedes ACR and is associated with barrier injury. We conducted a longitudinal and cross-sectional analysis of 16 ITx recipients. Ileal effluents were profiled via 16S rRNA gene sequencing, short-chain fatty acid (SCFA) quantification, complemented by graft histopathology and assessment of systemic biomarkers of barrier dysfunction. Eight recipients (50.0 %) developed biopsy-proven ACR (median 25.5 days post-ITx). Recipients who developed ACR exhibited early and sustained microbial divergence, characterized by Enterobacteriaceae dominance and loss of diversity. Samples collected at a median of 7.0 days before ACR diagnosis revealed a pre-rejection dysbiotic state marked by reduced microbial diversity, diminished SCFA levels, enrichment of Enterobacteriaceae, and depletion of Enterococcaceae and Bacteroidaceae. Functional profiling indicated pre-ACR upregulation of bacterial motility, flagellar assembly, and lipopolysaccharide biosynthesis pathways. These microbial shifts correlated with mucosal injury (mucus thinning, goblet cell loss, and bacterial adherence) and elevated systemic barrier dysfunction biomarkers. Collectively, ileal microbial and metabolic dysbiosis precede clinical ACR and correlate with barrier injury, nominating the ileal microbiota as a predictive biomarker source and therapeutic target in ITx.

It is now appreciated that CD154 and CD40 may be differentially effective as therapeutic targets in transplantation owing to the ability of CD154 to bind to a second receptor, CD11b. We previously reported that the combination of anti-CD40 and a specific CD154:CD11b blocker enhanced allograft survival compared to anti-CD40 alone. In the current study, we have utilized a novel nanoparticle-based approach to more effectively deliver CD154:CD11b blockade during transplantation. Recipients of allogeneic skin grafts were treated with either CTLA-4Ig or the combination of CTLA-4Ig plus a hyaluronic acid nanoparticle-conjugated CD154:CD11b peptide inhibitor (iPepHANP). Results indicated that iPepHANP synergized with CTLA-4Ig in prolonging allograft survival and inhibiting donor-reactive CD4⁺ and CD8⁺ T cell responses. Specifically, frequencies of donor-reactive CD4⁺ and CD8⁺ T cells in the spleen were significantly reduced in iPepHANP+CTLA-4Ig-treated animals as compared to CTLA-4Ig alone. Moreover, iPepHANP+CTLA-4Ig administration significantly reduced donor-reactive CD4⁺ T cell and activated CD8⁺ T cell infiltration into skin allografts compared to CTLA-4Ig alone. Notably, mice treated for 100 days with the CD154:CD11b blocking nanoparticle demonstrated sustained transplantation tolerance following secondary graft rechallenge in the absence of any further immunosuppression. Taken together, these data highlight the potential of CD154:CD11b-blocking nanoparticles as a therapeutic strategy in transplantation.