Tacrolimus trough concentrations are essential after kidney transplantation but do not describe the dose required to achieve them. The concentration-to-dose (C/D) ratio adds this denominator and provides a low-cost, time-dependent dose-requirement phenotype from routine data. Low C/D identifies recipients with high dose requirements and is associated with impaired kidney function, rejection, BK virus complications, graft failure, and mortality. Large registry data show graded risk as C/D decreases and more favorable outcomes when low C/D normalizes than when it remains low. C/D can therefore support risk stratification and selective AUC-based exposure assessment, but it is not a stand-alone treatment algorithm: interpretation requires valid sampling, assay, timing, formulation, and clinical context, and outcome benefit from C/D-guided intervention remains unproven.

Knowing the fate of patients removed from waiting lists without transplant is critical for evaluating the equity and efficiency of the US transplant system, but transplant centers are not required to report deaths after delisting. Our aim was to evaluate changes in death risk for adult transplant candidates removed for deteriorated condition over 2 decades using data from the Scientific Registry of Transplant Recipients. From 2003 through 2025, there were 93,571 candidates delisted for deteriorated condition. Using all available death data, between 2015 and 2024, recorded 1-year death risk after removal decreased 27%, 31%, and 5% for heart, liver, and lung candidates (P<.001, P<.001, P=.18, respectively). These trends were not explained by risk adjustment for clinical characteristics in the delisted population. In contrast, recorded death risk for delisted kidney candidates remained stable, likely due to federal death data sharing on patients with end-stage renal disease, as did waitlist and posttransplant deaths, likely due to transplant center death reporting. Our findings suggest the national transplant database is overly reliant on incomplete Social Security national death records after delisting and the observed decrease in mortality is artifactual. These findings have implications beyond transplant for all researchers and policymakers using Social Security death data.

BK polyomavirus (BKPyV) continues to threaten kidney transplantation outcomes by directly or indirectly causing premature allograft failure. Insufficient BKPyV-specific immunity underlies the onset and duration of BKPyV-DNAemia and nephropathy. BKPyV-specific T-cells have been correlated with protection and include cytotoxic CD8 T-cells targeting immunodominant 9mer-epitopes encoded in the viral large tumor-antigen (LTag). To develop vaccines increasing LTag-specific T-cells, we reduced the 695 amino acid-long LTag to 143 residues or less, comprising four clusters of immunodominant 9mers presented by 54 HLA-alleles. Prediction algorithms allowed to improve global coverage, AAY-linker placement, proteasomal processing, and solubility. Using a human cell culture vaccination model, transfection of adherent monocytes with LTAG1-mRNA and LTAG2-mRNA demonstrated the expected 13.9kD and 15.2kD immunogens, respectively. LTAG2-mRNA induced higher CD8 T-cell responses than LTAG1-mRNA, with an interferon-γ-positive CD62L-CD45RA-effector memory phenotype and cytotoxicity for BKPyV-replicating primary human renal tubular epithelial cells. We tested three additional candidates (LTAG3-mRNA, LTAG4-mRNA, LTAG5-mRNA) by changing AAY-linkers and extending immunogenic regions. The encoded immunogens were expressed and increased upon proteasome inhibitor treatment. LTag5-expanded T-cells showed BKPyV-specific interferon-γ expression and cytotoxicity. Our results demonstrate novel approaches to design modular mRNA-based vaccine candidates for clinical development of non-secreted antigens using BKPyV as a paradigm of non-enveloped DNA viruses.

Donor-derived Trypanosoma cruzi infection is a recognized complication of solid organ transplantation, but ocular involvement has never been reported. We described a case of necrotizing retinitis due to T. cruzi in a heart transplant recipient. A 62-year-old man developed unexpected donor-derived Chagas disease three months post-transplant and completed a 12-week course of nifurtimox with near-complete clearance of parasitemia. Thirty-eight days after nifurtimox discontinuation, he presented with progressive unilateral vision loss and clinical findings consistent with acute retinal necrosis. Vitreous biopsy with pan-pathogen PCR was negative for viral etiologies but confirmed T. cruzi. Despite systemic benznidazole therapy and clearance of blood parasitemia, intraocular disease progressed, ultimately attempting a salvage adjunctive intravitreal therapy with voriconazole. Ocular inflammation improved, but vision remained limited to light perception. This case underscores the need for continued clinical vigilance for late complications of Chagas disease in transplant recipients. Universal screening for donors with T. cruzi should be considered in future practice, pending the identification of the most appropriate assay, improved accessibility to such assays, and logistical challenges faced by individual organ procurement organizations.

Although Kaposi sarcoma-associated herpesvirus (KSHV)-associated disease (KAD) has long been recognized as a complication of transplantation, in the past five years, the incidence of KAD among solid organ transplant recipients in the United States has increased greater than five-fold, exposing gaps in screening and monitoring protocols. The United States lacks a coordinated framework for KSHV risk assessment and post-transplant monitoring, primarily because serologic and molecular testing is not yet widely available. Current laboratory-developed tests are not standardized across laboratories and analytes, testing capacity is insufficiently available nationwide and most tests are not approved for clinical use. This diagnostic gap limits the ability to define the KSHV status of donors and recipients before transplantation, distinguish graft-mediated transmission from reactivation of pre-existing infection, and interpret KAD risk across organ type and numerous host factors. International experiences and the HOPE in Action cohort in the US provide context, but do not readily translate into U.S. policy. We outline here priorities for a U.S. response, including generation of representative epidemiological data, diagnostic standardization, consensus testing and monitoring strategies, and clinician education to support safe, efficient, evidence-based organ utilization.

Early identification of rejection remains a critical unmet need in kidney transplantation, as conventional tools detect rejection only after irreversible allograft injury. The pre-transplant gut microbiome may provide novel predictive signals by modulating immune homeostasis. Pre-transplant stool samples underwent shotgun metagenomic sequencing. Composition, functional profiles, and networks were compared between rejection and non-rejection (protocol biopsy ≤ 2 weeks). A pre-specified SCFA biosynthetic KO panel was tested with FDR correction. Stepwise Random Forest models were developed with subgroup analyses and tested in a temporal validation cohort. Of 78 recipients, 26 (33.3%) developed biopsy-proven early acute rejection. Three taxa including Phascolarctobacterium faecium were FDR-significantly reduced. At the gene level, mcmB (a key propionate-biosynthetic enzyme) was the only KO reaching FDR significance in the pre-specified SCFA panel (q = 0.018). Network analysis revealed selective microstructural reorganization. AUC improved stepwise (0.565 → 0.681 → 0.765), was preserved across rejection subtypes (TCMR-spectrum 0.74; ABMR 0.85), and reached 0.721 in temporal validation with improved reclassification (NRI 0.11; IDI 0.055) and clinical net benefit at thresholds 0.2-0.5. Pre-transplant gut microbiome signatures were independently associated with early acute rejection. Microbiome-augmented models outperformed clinical-only models and remained robust in temporal validation, supporting microbiome-based pre-transplant risk stratification.

We conducted a population-based cohort study of pediatric liver transplantation (LT) in Ontario, Canada, a universal healthcare setting, to quantify survivorship burden relative to matched general-population controls and assess whether socioeconomic status (SES) modified these differences. First, isolated pediatric LTs (1991-2021) were linked to provincial administrative data and matched 1:5 on sex and birth year to general-population controls. Outcomes were mortality, chronic conditions, de novo cancers, and live births, with prespecified SES interaction analyses. Among 449 LT recipients and 2,245 controls (median age 1.9 years), 20-year survival was 78%. At 10 years, LT recipients had higher cumulative incidence of mood disorders (16.1% vs 8.77%; IRR 3.61, 95% CI 2.9-4.5) and de novo cancer (7.83% vs 0.19%; IRR 25.1, 95% CI 12.1-52.0), with cancer excess concentrated in the first 5 years. In a female-only landmark analysis beginning at age 15, live-birth incidence was similar between groups (IRR 0.75, 95% CI 0.39-1.44), suggesting childhood LT does not necessarily preclude later family-building. Lower neighborhood income predicted higher post-LT mortality (adjusted HR 2.1, 95% CI 1.2-3.7). Despite universal healthcare, socioeconomic disadvantage was associated with worse long-term outcomes; integrating social determinants of health into survivorship care is needed.

There are a growing number of reproductive age solid organ transplant (SOT) recipients, yet comparative data on contraception use across organ types are limited. We performed a retrospective cohort study of women who underwent first-time liver, kidney, heart, or lung transplantation between the ages of 18 and 45 from 2015 and 2025 using TriNetX (n=10,155). Contraception uptake within two years was assessed by organ, including patterns of initial contraceptive choice and subsequent changes in contraception choice, and clinical outcomes, including osteoporosis, thromboembolism, and graft rejection, were compared by contraception type. Among 10,155 eligible SOTR, 19.9% had documented contraception within two years of SOT (heart 27.3%, lung 22.5%, kidney 19.7%, liver 16.8%, p<0.001). Combined oral contraception was the most common initial contraception method, followed by depot medroxyprogesterone acetate (DMPA). However, those who started on DMPA were more likely to switch medications. Compared with no contraception, DMPA was associated with increased osteoporosis, hypertension, thrombosis, and graft rejection, whereas estradiol-containing agents were not. Overall, contraception use after SOT was extremely uncommon with exceedingly low rates of highly effective options, particularly after liver and kidney transplant. Higher switching and adverse associations with DMPA support early, organ-tailored contraceptive counseling and careful method selection post-SOT.

Cytomegalovirus (CMV) infection after lung transplant is associated with chronic rejection, but risk factors besides serology are not well-defined. Utilizing a multicenter, prospective cohort, CMV infection risk factors during and after prophylaxis were analyzed with an extended Cox model occurring either after completion of primary prophylaxis or for a breakthrough CMV episode, while on prophylaxis. The overall cohort included 785 lung transplant recipients, of which 221 developed at least one CMV episode. Of the 362 recipients eligible for the off-prophylaxis analysis, 124 had a CMV episode a median of 57 days post prophylaxis. In adjusted models off-prophylaxis, an increased risk of CMV was noted for CMV D+/R- serostatus, shorter duration of previous CMV prophylaxis, and augmented immunosuppression with either high dose steroids or T cell targeted therapy. In the 586 recipients eligible for the breakthrough CMV analysis, 71 had a CMV episode and in adjusted models while on primary prophylaxis, CMV D+/R- serostatus was the only significant risk factor. While CMV D+/R- serostatus remains an important risk factor for CMV, additional risk factors include prophylaxis duration and augmented immunosuppression, which should be considered in CMV prevention after lung transplant.

Rejection is a barrier to intestinal transplantation (ITx). ITx rejection may be associated with changes in the ileal microbiome. We sought to analyze whether shifts in the microbiome were associated with intestinal transplant rejection. Ileal effluent samples were collected from ITx patients (n = 8) with multiple samples taken from each patient at times of no (n = 83), mild (n = 39), or moderate (n = 3) rejection, Crohn's disease (n = 20), and noninflamed control patients (n = 25). Ileal microbiota were quantified using 16S rRNA gene sequencing. Compared to nontransplant samples (noninflamed control, Crohn's disease), ITx samples had lower alpha diversity (Shannon and Chao1, P < .001) and different beta diversity (Bray-Curtis, P < .005). Beta diversity differed between samples with and without rejection (P = .002). Differential abundance analyses showed enrichment of pathogenic taxa and depletion of commensals in ITx rejection samples. ITx rejection is associated with ileal microbiome dysbiosis, which is a potential target for diagnostic and therapeutic interventions.

We hypothesized that combined blockade of CD28 and interleukin-6 would favor regulatory T cells (Tregs) and prevent rejection in a novel calcineurin inhibitor-free immunosuppression regimen. In CTOT-24, a multicenter, prospective, phase I/II, pilot trial, live donor kidney transplant recipients received lulizumab pegol, a novel anti-CD28 domain antibody, and tocilizumab, an anti-IL-6R antibody, for 3 months followed by belatacept and tocilizumab for 3 months. All subjects received anti-thymocyte globulin, steroids, and mycophenolate mofetil or everolimus. The primary endpoint was the proportion of subjects free of biopsy-proven acute rejection at 6 months post-transplantation. Of eight treated subjects, five discontinued the study therapy prematurely for early acute T cell-mediated rejection (TCMR), severe neutropenia, and subject preference; three completed the regimen without rejection and remained on belatacept, MMF, and prednisone with mean estimated glomerular filtration rate 85.63 ml/min/1.73 m[2] at 2 years post-transplantation. There were no cases of antibody-mediated rejection, death or graft loss. Flow cytometric analyses showed no increase in circulating Tregs under the study regimen and no differences between rejectors and non-rejectors. We conclude that a regimen of combined CD28 and IL-6 blockade prevented rejection in only a minority and that alternative strategies are needed to promote Tregs under CD28 blockade. NCT04066114.