Frontiers in transplantation最新文献

Introduction: Vascularized composite allotransplantation (VCA) has achieved significant clinical success, but lifelong immunosuppression remains essential to prevent rejection. Despite potent regimens, including tacrolimus, mycophenolate mofetil, and steroids, rejection episodes frequently occur within the first postoperative year. The side effects of immunosuppressive drugs must be carefully balanced against the risks of insufficient therapy. This review specifically aims to evaluate current immunosuppressive regimens and infection prophylaxis in VCA to identify evidence based approaches that attempt to mitigate rejection, prevent infections, and improve long-term graft survival.

Methods: A systematic review was conducted across PubMed/MEDLINE, EMBASE, and Web of Science databases, adhering to PRISMA 2020 guidelines. Inclusion criteria focused on studies reporting immunosuppressive regimens, dosages, and infection prophylaxis in VCA surgery. Non-VCA, animal, feasibility studies, and non-English publications were excluded.

Results: Of 1,150 screened articles, 42 met inclusion criteria. Upper extremity and facial VCAs represented 50% and 29% of cases, respectively, with traumatic amputation as the primary indication (37%). Antithymocyte globulin was the most common induction drug, while tacrolimus, mycophenolate mofetil, and steroids were predominant for maintenance therapy in 33% and 11% of cases, respectively. Infection prophylaxis was used in 31% of cases. Drug dosages varied widely, and no standardized immunosuppressive protocols were identified.

Conclusion: Current immunosuppressive strategies in VCA lack standardization, leading to variability in outcomes and increased risks. Infection prophylaxis remains underutilized despite recipient vulnerability. There is a critical need for standardized and tailored guidelines to optimize immunosuppressive therapy and infection control, ensuring graft survival and improved patient outcomes.

Recent changes to allocation systems have increased the geographic distribution of pancreas offers, often originating from outside a transplant center's donor service area or region. The impact of this wider sharing on outcomes remains uncertain. This study analyzed outcomes of primary pancreas transplants (2000-2018) at a large transplant center, stratified retrospectively on the nautical miles distance from the donor hospital. Primary endpoints were death-censored graft survival (DC-GS), patient survival, and graft thrombosis at different time points. No significant differences were found in DC-GS or patient survival for recipients of simultaneous pancreas-kidney (SPK), pancreas after kidney (PAK), or pancreas transplant alone (PTA), regardless of the distance from the donor hospital to the transplant center. Thrombosis rates were comparable across groups. Imported pancreata were from younger donors with lower BMI compared to locally recovered grafts. These findings support the notion that importing pancreata for transplantation is a feasible and safe practice that benefits patients, increases organ utilization, while benefiting transplant center volume data and reducing waiting times for patients. Encouraging wider importation may reduce waiting times and improve access to pancreas transplantation.

Introduction: BK polyomavirus (BKPyV) and JC polyomavirus (JCPyV) are thought to establish persistent, low-grade infections in the kidney. However, their specific intrarenal reservoirs remain unclear. To explore their localization and potential presence prior to transplantation, we analyzed different kidney regions from deceased donors.

Method: Donor kidneys discarded for donation and subsequently designated for research purposes between November 2023 and October 2024 were included. For each kidney, cortex, medulla, pelvis, and ureter were sampled. These samples were analyzed using qPCR for the presence of JCPyV and BKPyV.

Results: In total, 10 kidneys were analyzed with a total 72 samples taken from the cortex: n = 22, medulla: n = 22, renal pelvis: n = 14, and ureter: n = 14. All samples tested negative for BKPyV. JCPyV DNA was detected in 4 out of 10 kidneys. When analyzed by tissue type, positive samples were found in 6/22(27.3%) cortex, 6/22(27.3%) medulla, 4/14(28.6%) renal pelvis, and 4/14(28.6%) ureter samples. The cycle threshold (Ct) values did not show significant differences among the various regions within the kidney. Notably, JCPyV distribution within individual kidneys was markedly heterogeneous, with substantial variation in Ct-values within the same kidney.

Conclusion: JCPyV DNA was detected in 40% of kidneys from deceased donors, with comparable detection rates across cortex, medulla, pelvis, and ureter, suggesting no clear tissue preference. However, within individual kidneys, the distribution and Ct-values varied considerably. BKPyV DNA was not detected in any sample. These findings support the hypothesis that JCPyV may be present prior to transplantation and potentially donor-derived. The potential role of JCPyV in kidney transplant recipients and its relationship with BKPyV warrant further investigation.

Introduction: We have recently shown that the DNA hypomethylating agent decitabine (DAC) rescues lung allografts from acute rejection. This involves a mechanism that is dependent on host CD4+ FoxP3+ T cells for maximal benefit. DAC treatment also reduces host T-cell IFN-γ production. We therefore hypothesized that DAC may also reduce host macrophage activation. Our objective was to determine if an effect on macrophages contributes to the beneficial effects of DAC in transplantation.

Methods: In murine orthotopic lung transplant, hosts were treated on post-op day 3-8 with Clodronate (n = 5), DAC (n = 9), or DMSO (n = 11).

Results: Partial macrophage depletion (clodronate) improves allograft gross and histologic integrity. DAC-mediated allograft rescue was associated with reduced host macrophage recruitment into allograft airways, reduced activation of recruited macrophages, and regeneration of donor resident alveolar macrophages.

Discussion: These findings suggest that infiltrating host macrophages promote allograft rejection. They also suggest that donor alveolar health is indicative and/or promoting of allograft tolerance.

Introduction: Donor-recipient compatibility remains a central determinant of transplant success, yet conventional antigen-level human leukocyte antigen (HLA) matching provides limited resolution for predicting alloimmune risk. Molecular matching at the eplet level, which quantifies structural motifs on HLA molecules recognized by B- and T-cells, has emerged as a promising strategy to refine immunologic risk assessment.

Methods: We conducted a scoping review of 98 studies encompassing 286,101 solid organ transplant (SOT) recipients across kidney, heart, lung, liver, pancreas, and combined grafts. Data on HLA typing approaches, eplet mismatch (epMM) algorithms, thresholds, and associations with clinical outcomes were systematically extracted and synthesized.

Results: The majority of studies were retrospective kidney transplant cohorts, though evidence from heart, lung, and liver transplantation is expanding. Across organs, higher class II epMM burden-particularly at HLA-DQ and HLA-DR-was consistently associated with de novo donor-specific antibodies, antibody mediated rejection, and graft dysfunction. Reported epMM thresholds varied but were most robust for class II loci, while findings for class I loci were less consistent. Observed differences in epMM thresholds and effect sizes reflected both organ-specific immunobiology and methodological heterogeneity, including variation in typing resolution, mismatch algorithms, immunosuppression exposure, and study design.

Conclusion: Eplet matching demonstrates significant potential to improve risk stratification and long-term graft outcomes across SOT. However, clinical translation is limited by inconsistent methods, equity concerns, and the absence of standardized epMM thresholds. Prospective studies, harmonized molecular typing, and integration with allocation frameworks are needed to establish the clinical utility and policy implications of molecular-level HLA matching.

Tacrolimus is a widely used immunosuppressive therapy in transplant recipients, but its narrow therapeutic index necessitates accurate monitoring. Tacrolimus levels can be quantified using immunoassays (IAs) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), however, differences between these methods may influence clinical decision-making. In this study, we compared two IAs, i.e., chemiluminescent (CMIA) and electrochemiluminescent (ECLIA), with three LC-MS/MS assays in 181 clinical specimens. When compared with the overall mean concentration, all five assays showed strong correlations, though with variability across methods: three LC-MS/MS assays demonstrated correlation coefficients of 0.9927, 0.9612, and 0.9920, while two immunoassays yielded coefficients of 0.9938 and 0.9857. Deming regression analysis revealed slopes of 0.96, 0.94, and 0.93 for the three LC-MS/MS, while the immunoassays showed higher slopes of 1.032 (ECLIA) and 1.21 (CMIA). Bland-Altman analysis indicated systematic underestimation by the LC-MS/MS methods (-7.5%, -18.7%, and -8%) and overestimation by the immunoassays (ECLIA +9.7%, CMIA +18.4%), relative to the overall mean. The two immunoassays showed only moderate agreement with each other (slope = 0.85, intercept = 0.49), and even the LC-MS/MS assays were not fully concordant. Among 47 patients within 3 months post-transplantation and 134 patients beyond 3 months, clinically relevant discrepancies (≥2 ng/ml) between LC-MS/MS and immunoassay results were observed in 13 patients (28%) and 49 patients (37%), respectively. These findings underscore the substantial impact of assay-dependent variability on tacrolimus monitoring and emphasize the need for standardized laboratory practices as well as assay-specific therapeutic ranges to prevent underexposure with rejection or overexposure with toxicity.

As the "Father of Modern Transplantation", Dr. Starzl pioneered every aspect of organ transplantation: immunosuppression, organ procurement and preservation, tissue matching, surgical transplant technology, and the operational management of the transplant team. His work paved the way for heart, lung, pancreas, intestinal, liver, and kidney transplantation and opened doors to understanding immune regulation of a number of acquired and inherited disorders. Dr. Starzl's contributions to the scientific literature, in a span of 60 years, are nothing short of remarkable-2,872 publications placing him at the top of scientific citations according to the Institute of Scientific Information. Dr. Starzl was a man of unique vision, enthusiasm, and persistence; many of his ideas were considered revolutionary and radical-stimulating opposition and criticism. He called upon an inner strength, likely entrenched from his small-town upbringing, to persist in spite of adversity and promote social and medical acceptance of transplantation. Through his tireless efforts he educated scientists, other professionals, and the public. He was involved in all of the controversies of organ donation, from the use of non-heart beating donors, to living donors, to brain dead donor and to xenotransplantation (animal-to-human transplantation).

Introduction: Ischemia-reperfusion injury causes endothelial damage, partly through degradation of the glycocalyx. This study aimed to evaluate glycocalyx degradation from graft procurement to reperfusion and assess its potential as a biomarker of early graft function (early allograft dysfunction, EAD).

Methods: This single-center observational prospective study was conducted at Paul Brousse Hospital from April 2022 to April 2023. All primary liver transplantation (LT) recipients were included. Glycocalyx degradation was assessed at procurement, at the end of cold ischemia, and during LT in liver graft caval effluent and correlated with liver histological injury. The primary endpoint was EAD, defined as a Model for Early Allograft Function score ≥9. We quantified glycocalyx components [Syndecan-1 (Synd-1), heparan sulfate, angiopoietin-1, and angiopoietin-2], inflammation (TNF-alpha), and cell death markers.

Results: Thirty-one patients were included; 12 (39%) developed EAD. Synd-1 plasma levels at procurement (donor Synd-1 level = d-Synd-1) were significantly higher in patients with EAD [12,173 pg/mL (10,538-17,570) vs. 6,282 pg/mL (4,604-10,002), p = 0.004]. A plasma d-Synd-1 cutoff of 9,419.7 pg/mL predicted EAD [AUC = 0.81, 95% confidence interval (95% CI) (0.65-0.97); sensitivity 83%; specificity 74%, positive predictive value = 67%, negative predictive value = 88%, p < 0.05]. d-Synd-1 ≥9,419.7 pg/mL was associated with severe post-LT complications (p = 0.007).

Conclusions: d-Synd-1 levels in graft effluent during procurement may serve as a predictor of early allograft dysfunction. Strategies aimed at protecting the endothelial during procurement could improve graft outcomes.

Background: While ABO-incompatible kidney transplantation (ABOiKT) has demonstrated favorable short-term outcomes, data on its long-term effects remain limited. This study evaluated the short- and long-term clinical outcomes of ABOiKT across various ABO-incompatible donor-recipient combinations.

Methods: We included patients who underwent ABOiKT at our institution in 2007-2024. The outcomes assessed included 15-year data on graft, patient survival, and early AMR rates.

Results: Of 239 ABOiKT cases, AMR occurred in 9.2% and was linked to longer hospitalization and higher graft failure. AMR was most frequent in B-O (20.3%) and A1-O (13.3%) transplants but no cases of AMR were observed in the recipients of kidneys from A2 donors. B to O mismatch significantly increased the risk of AMR-related graft loss. Patient survival was 99.1% at 1 year and 86.2% at 15 years and Graft survival was 92.7% and 87.5% respectively.

Conclusions: Our study showed favorable outcomes of ABOiKT across different mismatch types. As the largest ABOiKT study in the Middle East with extended follow-up, our study provides important regional insights and contribute significantly to the global understanding of ABOiKT outcomes.

Background: Cytomegalovirus (CMV) causes significant morbidity and mortality following kidney transplantation. Late CMV infection (≥2 years post-transplant) is uncommon, and its risk factors and outcomes may differ from earlier infection.

Methods: We conducted a single-centre retrospective study of kidney transplant recipients between 2009 and 2019. Patients were grouped by CMV status: no infection, early infection (<2 years post-transplant), and late infection (≥2 years post-transplant). Clinical characteristics and outcomes were compared.

Results: Donor-positive/recipient-negative (D+/R-) serostatus was observed in 105/710 (14.8%) patients without CMV, 28/42 (66.7%) with early CMV, and 2/28 (7.1%) with late CMV (p < 0.001). Prior rejection occurred in 5.9%, 16.7%, and 10.7% respectively (p = 0.017). Median serum creatinine was 113.0, 127.5, and 219.5 µmol/L respectively (p < 0.001). CMV serostatus was significantly associated with early infection (p < 0.001), while only serum creatinine was associated with late infection (p = 0.003). Trends were seen toward better one-year patient survival (97.6% vs. 85.7%, p = 0.051) and graft survival (88.1% vs. 71.4%, p = 0.073) after early vs. late infection.

Conclusions: Risk factors for CMV infection differ by timing post-transplant. Renal dysfunction may be a key predictor of late infection. identifying at-risk patients may support targeted surveillance and improve long-term outcomes.