American Journal of Transplantation最新文献

This study aimed to identify the parenchymal structural features by both computed tomography (CT) and histology that are associated with death-censored graft failure in recipients of living donor kidneys. We analyzed kidney recipients of ABO-compatible living donor kidneys from 2000-2020 with follow-up through 2023. Cortical volume and thickness, individual medullary pyramid volume and count, glomerular volume, nephrosclerosis, and nephron number were assessed by deep learning models applied to the predonation CT and by morphometric histology analysis from the biopsy at the time of transplantation. There were 3098 recipients followed for a median of 5 years with 346 graft failure events. In adjusted analyses, the only structural measures associated with graft failure were fewer medullary pyramids on CT and a higher fraction of interstitial fibrosis and tubular atrophy on histology. Having ≤15 pyramids donated occurred in 9% and was associated with a graft failure incidence of 2.5 per 100 person-years compared to 1.6 per 100 person-years in the 17% with ≥26 pyramids donated. Fewer medullary pyramids were associated with a lower 1-year estimated glomerular filtration rate, which mediated the subsequent risk of graft failure. Interstitial fibrosis and tubular atrophy >1% is also associated with graft failure. Medullary pyramid count is a potentially useful predonation prognostic biomarker for graft failure in transplant recipients.

The lung continuous distribution system was modified on September 27, 2023, with the goal of increasing transplant access for blood-type-O candidates after an error was discovered in the simulation used to support the development of the initial allocation policy. This retrospective observational study compares national waitlist outcomes (transplant rate, waitlist mortality) under continuous distribution before (3/10/23-9/26/23; premodification) and after (9/27/23-4/14/24; postmodification) the blood-type score modification. We fit adjusted Poisson regression models of the transplant rate and mortality rate. The transplant rate was lowest for type-O candidates in both eras, but significantly increased after the score modification, from a premodification adjusted rate ratio (95% CI) of 0.40 (0.36, 0.45) to postmodification 0.52 (0.45, 0.59), relative to premodification type-A candidates. The adjusted mortality incidence (95% CI) decreased in type-O candidates from 3.6% (3.0%, 4.3%) premodification to 3.2% (2.6%, 3.8%) postmodification. In an exploratory analysis, we estimated there would have been the same number of waitlist deaths (approximately 105) if the modified score had been adopted at the start of continuous distribution; however, transplants would have shifted towards type-O candidates (57.8 [95% CI: 35.1, 80.9] additional transplants) and deaths would have shifted away from type-O candidates (4.6 [95% CI: 2.7, 6.8] fewer deaths).

Universal cytomegalovirus (CMV) prophylaxis is recommended for at-risk lung transplant recipients. Valganciclovir (VGCV) is currently the preferred first-line agent. VGCV-related myelosuppression, however, can lead to drug discontinuation or reduction in antimetabolite immunosuppression. Variable VGCV pharmacokinetics in the setting of renal injury are also associated with development of resistant CMV. Letermovir, a newer anti-CMV agent, is an attractive alternative for first-line prophylaxis in many lung transplant recipients. Initially investigated in bone marrow transplant, there are now multiple retrospective studies of lung transplant recipients who were switched from VGCV to letermovir because of tolerability, dosing, or resistance. These studies have reaffirmed the safety and efficacy of letermovir in the lung transplant population. Despite this, letermovir continues to be recommended as second-line prophylaxis with use limited to those who fail VGCV. We argue that there are now sufficient data to support letermovir use in lung transplant recipients at high risk of VGCV toxicity. This includes patients with renal insufficiency, of advanced age, and with cytolytic immunosuppression, high risk of rejection, and telomere biology disorders, among other conditions. First-line letermovir would reduce the risk of VGCV-related myelosuppression and attendant reduction in immunosuppression, as well as development of CMV resistance due to variable renal function and VGCV pharmacokinetics.

Posttransplant lymphoproliferative disorder (PTLD) poses a serious challenge in kidney transplant recipients. Epstein-Barr virus (EBV)-seronegative recipients have a significantly increased risk of PTLD, but few studies have investigated risk factors for PTLD in EBV-seronegative recipients in the current era of immunosuppression. This cohort study from Norway and western Denmark included first-time kidney transplant recipients between 2007 and 2021 and estimated the cumulative incidence, risk, and prognosis of PTLD. In total, 80 of 5084 recipients developed biopsy-proven PTLD (median follow-up of 6.8 years). Two-year cumulative incidence of PTLD was 7.3% in EBV-seronegative adults and 14.1% in EBV-seronegative children. The age-adjusted hazard ratio (HR) for PTLD was 30.7 (95% CI, 13.9-67.9) in EBV-seronegative vs EBV-seropositive adults and 5.4 (95% CI, 1.1-26.9) in children. Recipients receiving induction therapy with antithymocyte globulin had an increased risk of PTLD (HR, 4.4; 95% CI, 1.8-10.6), while rituximab induction was associated with a lower risk of PTLD (HR, 0.20; 95% CI, 0.03-1.49). The age-adjusted mortality rate was higher in EBV-seronegative recipients with vs without PTLD (HR, 3.3; 95% CI, 1.3-8.3). In conclusion, the risk of PTLD in EBV-seronegative kidney transplant recipients is high in the contemporary era of immunosuppression. Induction therapy should be carefully considered in this high-risk population.

Chronic allograft rejection is mainly mediated by indirect recognition. Dendritic cells (DCs), as the major antigen-presenting cells in indirect recognition, exhibit an enhanced antigen-presenting ability in chronic rejection, but the specific mechanism is still unclear. Here, we found that pretreatment with high mobility group box-1 protein (HMGB1) in vivo can induce trained immunity in DCs. These trained DCs demonstrated an enhanced ability to present alloantigen, accelerating allograft rejection in a CTLA4-Ig-induced chronic rejection model by upregulating the expression of major histocompatibility complex (MHC)-II and class II major histocompatibility complex transactivator (CIITA) molecules. Mechanistically, we found that HMGB1 promoted the formation of superenhancers (SEs) of CIITA, epigenetically reprogramming DCs and promoting trained immunity. The SE inhibitor JQ1 reduced the expression of CIITA and MHC-II in DCs, thereby delaying the occurrence of chronic rejection. Interestingly, we identified HMGB1 as a specific inducer of SE formation in a newly named SEa region of CIITA. Targeted knockout of the CIITA's SEa region inhibited HMGB1-induced trained immunity in DCs. Taken together, our data confirm that HMGB1 can induce the formation of the SEs of CIITA, promote trained immunity in DCs, and accelerate allograft rejection, thus offering a new potential target for the treatment of chronic rejection.

We created and validated the Neuro-Score, a specific scale to detect and monitor cognitive impairment, including mild stages, in kidney or liver transplant recipients. A qualitative study was conducted to define a preliminary set of 62 items. Item reduction was performed using exploratory factor analysis. Confirmatory factor analysis assessed the adequacy of the factorial solution. The total scores of the Neuro-Score and Mini-Mental State Examination (MMSE) were compared. Responsiveness to change was evaluated from visit 1 (baseline) to 2A (18 months later) and temporal stability from visit 2A to 2B (1-2 weeks later). Factor analysis showed 11 factors with an eigenvalue >1. Confirmatory factor analysis yielded a logical solution with one factor and 11 items that explained 27.9% of the variance. The final model showed satisfactory internal consistency (Cronbach's alpha=0.82). A weak negative correlation was found between Neuro-Score and MMSE total scores (Pearson's r=-0.12; p=0.0095). The Neuro-Score responsiveness to change was demonstrated (p=0.022). No significant differences in the total score were observed between visits 2A and 2B, supporting the Neuro-Score temporal stability. The Neuro-Score scale is a simple, reliable, self-administered, easy to interpret and consistent 11-item scale to detect and monitor cognitive impairment in kidney and liver transplant recipients.

There is substantial variation in access to transplantation across the United States that is not entirely explained by the availability of donor organs. Barriers to transplantation and variation in care among patients with end-stage organ disease exist prior to patients' placement on a transplant waiting list as well as following waitlist placement. However, there are currently no national data available to examine rates and variations in key care processes related to prelisting, including transplant referral, evaluation, or candidate selection. In February of 2024, the Health Resources and Services Administration released a directive and, in November 2024, released for public comment the proposed expansion of the Organ Procurement and Transplantation Network data collection to include pre-waitlist data for all solid organ transplant patients to promote transparency across the transplant continuum. Although data elements and details have not been finalized, the purpose of this article is to detail the rationale and anticipated details for pre-waitlisting data collection to inform the transplant community. These data aim to examine care processes and barriers to care for patients with end-stage organ disease in the United States.

Hepatitis C virus (HCV) infection is increasing in prevalence due to the growing opioid epidemic; however, its impact on pediatric kidney transplantation is unknown. This study compared kidney transplant outcomes between HCV-positive and propensity score-weighted HCV-negative pediatric recipients. It also examined HCV-positive kidney utilization for pediatric transplantation in the United States. We used the Scientific Registry of Transplant Recipients to identify pediatric kidney transplants (aged < 18 years) performed between April 1, 1994 and December 1, 2022. We used propensity score weighting to create a group of HCV-negative recipients with characteristics similar to HCV-positive recipients. Odds ratios for delayed graft function and hazard ratio (HR) for patient and graft survival were estimated using logistic and Cox regression models. We found similar delayed graft function rates (13.9% vs 10.3%, P = .14) and no difference in the graft (HR: 1.04, 95% CI: 0.83-1.31, P = .71; 10-year survival 54.9% vs 54.5%) or patient survival (HR: 1.06, 95% CI: 0.58-1.95, P = .84; 10-year survival 93.9% vs 92.0%) between the groups. Four HCV-positive (2.5%), 3 HCV-negative children (0.02%), and 1 (0.05%) child with unknown HCV status received HCV-positive kidneys. We observed no increased risk of graft loss or death in children with HCV infection. The use of HCV-positive donors for pediatric kidney transplantation is rare.

Bariatric surgery has been shown to be safe in chronic kidney disease and improves access of patients to transplantation. Whether bariatric surgery after kidney transplantation is associated with improved graft or patient survival has not been examined nationally. We included adults with obesity who received a first kidney transplant according to the US Renal Data System between 2003-2019. We matched 4 controls to each case of bariatric surgery based on age at transplantation, sex, donor type, diabetes, and body mass index at transplantation. We examined the association between bariatric surgery and graft failure or death using multivariable Cox proportional hazards models and Fine-Gray models accounting for death as a competing risk. We included 770 patients, of whom 155 (20%) received bariatric surgery. Median age was 45 years and 56% were women. Receipt of bariatric surgery was associated with improved graft survival (hazard ratio [HR], 0.57; 95% CI, 0.34-0.98) in fully adjusted models, although findings did not consistently maintain statistical significance in competing risk analyses (subHR, 0.60; 95% CI, 0.35-1.02). Receipt of bariatric surgery was associated with lower risk of death (HR, 0.45; 95% CI, 0.26-0.76). In conclusion, bariatric surgery is associated with improved patient survival and potentially graft survival after kidney transplantation.