Introduction:Although genetic testing is increasingly used in evaluating living kidney donor (LKD) candidates and recipients, objective data on genetic testing practices are limited. This study aimed to describe current genetic testing practices in LKD evaluation using data from the international living donor genetic registry. Methods:A research electronic data capture (REDCap) registry was developed to collect cross-sectional, deidentified information on LKD candidates and genetic test results. Participating centers registered candidates meeting at least 1 of the following criteria: (i) underwent genetic testing; (ii) family history of genetic kidney disease; and/or (iii) were evaluated to donate to a biologically related recipient with kidney disease of unknown etiology. Data were collected between June 1, 2023 and November 10, 2025. Results:Among 1259 LKD evaluations from 24 centers (10 US, 14 international), genetic testing was performed in 295 (23.4%). US donor candidates were younger (median 39 vs. 48 years, P < 0.001). Testing strategies differed by region as follows: international centers predominantly used recipient-first testing (92.1%), whereas US centers more often performed direct LKD testing (61.5%; P < 0.001). These differences persisted after excluding apolipoprotein L-1 (APOL1) testing, with direct LKD candidate testing remaining more common in US (34.0% vs. 7.9%; P < 0.001). Among tested LKD candidates, 20.7% (61/295) were not approved for donation, with 7.8% (23/295) attributed to genetic findings. In multivariable analysis, younger donor age was independently associated with LKD nonacceptance (adjusted odds ratio [OR]: 0.89 per-year; 95% confidence interval [CI]: 0.83-0.95; P < 0.001). Conclusion:Genetic testing practices vary substantially across regions, with US centers favoring direct LKD testing and international centers using recipient-first approaches. Younger donor candidate age was independently associated with nonacceptance.

The Sensitization in Transplantation: Assessment of Risk initiative aimed to translate human leukocyte antibody (HLA) laboratory data into clinical practice and identify key knowledge gaps to guide future research. The Sensitization in Transplantation: Assessment of Risk working group has held 3 consensus meetings and published reports that have influenced clinical care. In 2025, the group focused on 5 evolving areas: donor-derived cell-free DNA tests, innate immunity in allograft rejection, immunogenicity and antigenicity, HLA antibody quantification, and non-HLA antibodies. Three years of work culminated in 2 webinars and a February 2025 community meeting, which are summarized in this report. The group outlined considerations for integrating donor-derived cell-free DNA tests into practice, proposed a definition for genetic prediction of natural killer-cell missing self, and discussed monocyte activation via the Signal-regulatory protein alpha - cluster of differentiation 47 (SIRPα-CD47) pathway. They reviewed molecular mismatch approaches, limitations, and immune-recognition complexities. Finally, they provided updates on HLA antibody quantification, non-HLA antibodies, and ongoing studies addressing critical knowledge gaps.

BACKGROUND:Immunosuppression is a major, known risk factor for cutaneous squamous cell carcinoma (CSCC). Immunosuppressed patients with CSCC are at significantly increased risk of recurrence and death compared to their non-immunosuppressed counterparts. To date, this high-risk population has been excluded from most clinical trials. METHODS:The National Cancer Institute Head and Neck Cancer Steering Committee (NCI-HNSC) commissioned a Clinical Trials Planning Meeting (CTPM) specifically for immunosuppressed patients with high-risk/advanced CSCC. The CTPM was designed to bring together key scientific and pharmaceutical stakeholders, as well as multi-disciplinary physician sub-specialists who manage these high-risk, complex patients with the goal of developing clinical trial concepts that could be readily conducted through the NCI Clinical Trial Network (NCTN) groups. RESULTS:With extensive virtual pre-planning and a 2-day in-person summary meeting, the CTPM was structured as two multi-disciplinary breakout groups focused on immunosuppressed populations with either: 1) high risk resectable CSCC; or 2) advanced/metastatic CSCC. Five clinical trial concepts were designed specifically for immunosuppressed patients and suitable to conduct via NCTN groups. CONCLUSIONS:A CTPM was successfully conducted for immunosuppressed patients with CSCC, a historically underserved population with poor clinical outcomes.

Importance Accurate understanding of long-term risks after living kidney donation is critical to inform evidence-based policies for donor candidate evaluation and selection. Objective To determine whether apolipoprotein L1 gene ( APOL1 ) polymorphisms were associated with worse kidney function after living kidney donation. Design, Setting, and Participants This retrospective cohort study included all living US kidney donors who donated from January 2000 to December 2008, whose contact information was obtained from the Scientific Registry of Transplant Recipients. After using online search tools to update addresses and telephone numbers, Black and White US living kidney donors who donated during this period were invited to participate. Enrolled study participants had home-based research visits conducted by a subcontract agency between March 2020 and March 2024. Final data analysis was conducted from April 2024 until February 2026. Exposures APOL1 polymorphisms and race. Main Outcomes and Measures The primary outcome was an estimated glomerular filtration rate (eGFR) of less than 45 mL/min/1.73 m 2 by serum creatinine at the time of home-based research visits. Additional outcomes were an eGFR of less than 60 mL/min/1.73 m 2 , urinary albumin-creatinine levels of 30 or greater or 300 or greater mg/g, and hypertension. Results A total of 445 Black kidney donors (295 female individuals [66%]; mean [SD] age, 38 [10] years) and 208 White kidney donors (141 female individuals [68%]; mean [SD] age, 44 [10] years) were enrolled. Sixty-eight Black donors (15.3%) had APOL1 high-risk genotypes (G1/G1, G2/G2, or G1/G2). Home-based research study visits occurred a median (IQR) of 18.5 (16.9-20.5) years after donation. Forty-six of all participants (7.0%) were noted to have an eGFR of less than 45 mL/min/1.73 m 2 . Black kidney donors with APOL1 high-risk genotypes had a higher risk of developing an eGFR of less than 45 mL/min/1.73 m 2 than Black kidney donors without APOL1 high-risk genotypes (relative risk, 2.31; 95% CI, 1.16-4.61; P = .02) (after adjustment for predonation eGFR: relative risk, 1.91; 95% CI, 0.90-4.03; P = .09). Conclusions and Relevance The study found that the APOL1 genotype is a risk factor for reduced kidney function postdonation. These results suggest that all Black individuals who are living donor candidates in the US should undergo APOL1 genotyping for better risk stratification.

The purpose of this white paper is to recommend essential reporting standards for pathologic characterization of kidney and heart xenografts in humans. This proposal is based on the current classifications for human kidney and heart allografts, with additions and caveats relevant to xenografts, primarily derived from nonhuman primate studies and a limited number of organ xenografts in decedent and living humans. Such recommendations should not be regarded as diagnostic criteria, given that many pathologic patterns and mechanisms remain to be fully characterized. While xenograft transplantation continues to evolve, this report serves as groundwork and an initial step toward defining international standards in xenograft histopathology assessment and reporting.

The XVIIth Banff meeting for transplant pathology was held in Paris, France, from September 16, 2024 to September 20, 2024, hosted by the Paris Institute for Transplantation & Organ Regeneration. The Banff 2024 meeting resulted in no changes to the Banff kidney classification. Important outputs of the meeting were a reaffirmation of the clinical usefulness of the clinical reasoning framework and flowchart for cases with microvascular inflammation/antibody-mediated rejection introduced at the Banff 2022 meeting and the introduction of a similar flowchart for tubulointerstitial inflammation and intimal arteritis (v lesion). The meeting highlighted the complexity of the immunologic processes (alloimmune and others) that lead to allograft inflammation and the need to strengthen the Banff system for differential diagnostic reasoning. Guidance is put in place for cases with incomplete/mixed phenotypes, which acknowledges the limits of our understanding. A proposal for potential future implementation of activity and chronicity indices was discussed, as well as digital and biopsy-based molecular tools that have the potential to help transform the classification into a probabilistic tool reflective of the underlying immunologic processes. Finally, guidelines for reporting of glomerular disease in the posttransplant setting were developed.

Chronic active antibody-mediated rejection (caAMR) is a leading cause of kidney allograft loss; there are no approved therapies. Clazakizumab binds interleukin-6 and was associated with reduced donor-specific antibodies and stabilized estimated glomerular filtration rate (eGFR) in kidney transplantation (KTx) recipients with caAMR in a phase 2 study. We report the final analysis from the phase 3 Interleukin-6 Blockade Modifying Antibody-mediated Graft Injury and Estimated Glomerular Filtration Rate Decline (IMAGINE) trial, the largest placebo-controlled study in KTx recipients with caAMR. KTx recipients were randomized 1:1 to clazakizumab (12.5 mg subcutaneous every 4 weeks) or placebo. One-year interim analysis of eGFR (N = 115) indicated that the trial was unlikely to meet the primary outcome (time to all-cause allograft loss or irreversible loss of allograft function), resulting in early termination. In the final analysis (N = 191), least-squares mean eGFR change from baseline to week 52 (95% confidence interval) for clazakizumab was -8.0 mL/min/1.73 m2 (-10.2, -5.8) vs -5.2 mL/min/1.73 m2 (-7.4, -3.1) for placebo (P = .959). Allograft loss or irreversible loss of allograft function was experienced by 28.3% and 22.2% of patients treated with clazakizumab and placebo, respectively. Reduced C-reactive protein was observed with treatment. No safety concerns were noted. In conclusion, interleukin-6 blockade with clazakizumab did not translate into improvement in eGFR in KTx recipients with caAMR.

KEY POINTS:Pretransplant early acute rejection risk stratification offers a novel approach to personalized immunosuppression management in patients who received a kidney transplant. Stratifying immunologic risk independent of donor characteristics may help guide immunosuppression management in patients who received a kidney transplant. The pretransplant risk assessment gene set reflects metabolic and immune pathways involved in T-cell- and antibody-mediated mechanisms of transplant rejection. BACKGROUND:Although donor and recipient characteristics are used to estimate graft failure risk, they remain limited in predicting early acute rejection (EAR). We developed and validated a next-generation sequencing assay targeting the pretransplant immunologic profile to predict EAR following kidney transplantation. METHODS:This prospective, international study enrolled 321 kidney transplant participants across 13 sites, forming discovery and validation cohorts. Peripheral blood was collected before transplant and at 1, 3, 6, 12, and 24 months post-transplant, with protocol biopsies performed at 3 and 12 months, as well as any indication biopsies. Biopsies were assessed by a blinded central pathologist according to the 2019 Banff criteria. The pretransplant risk assessment (PTRA) test to evaluate RNA expression of a 29-gene signature algorithm designed to predict EAR risk was clinically validated using 122 deceased donor kidney transplant recipients. RESULTS:PTRA classified 31 of 122 participants (25%) as high risk and 91 (75%) as low risk. There were nine EAR events in the first 60 days post-transplant: 6/31 (19%) in the high-risk group and 3/91 (3%) in the low-risk group. PTRA discrimination for EAR at 60 days post-transplant yielded an area under the curve of 0.78 (95% confidence interval [CI], 64.4 to 91.5), P < 0.001. A cutoff of ≤45 was defined as low risk and >45 as high risk for EAR within 60 days post-transplant. Sensitivity was 0.67 (95% CI, 0.36 to 0.97), specificity 0.78 (95% CI, 0.70 to 0.86), positive predictive value 0.19 (95% CI, 0.05 to 0.33), and negative predictive value 0.97 (95% CI, 0.93 to 1.00). The odds ratio comparing patients identified as high versus low risk by PTRA was 7.04 (95% CI, 1.64 to 30.2), P = 0.009. CONCLUSIONS:This study validates the ability of PTRA to stratify kidney transplant recipients as high or low risk for EAR using a pretransplant transcriptomic profile, with implications for graft health and personalized treatment management.

American Journal of Transplantation (AJT) has showcased research and clinical innovations during its first 25 years. A review of its contents during these years has reflected the tremendous progress in transplantation during this time. This article highlights the evolution of immunosuppression, rejection, posttransplant complications, allocation, and policy during this period. We endeavored to highlight key developments and acknowledge that our review cannot include all of the important contributions to the science of transplantation published in AJT.

Purpose: Canadian researchers have made significant contributions to the advancement of organ transplantation globally. The COVID-19 pandemic made transparent the importance of reflecting on our accomplishments and the current and future challenges that limit the lives of our patients and to celebrate individual and collective achievement. Sources of Information/Methods: On October 6, 2025, thought leaders in the field of organ transplantation assembled in Vancouver to recognize the contributions of Paul Keown, a clinician scientist and translational researcher, whose work has directly impacted thousands of transplant recipients worldwide. Key Findings: This article summarizes the invited speaker presentations and represents a unique opportunity to celebrate the past and to focus on current challenges and future opportunities to advance the field of organ transplantation.

Background: The iBox is a validated prognostication system that predicts long-term death-censored graft loss in kidney transplant recipients, but its performance in the specific population of African American recipients has not been fully studied. Methods: We conducted a multicenter study including 3,866 kidney transplant recipients from North America, of whom 1,040 (27%) were African American, to assess the impact of race on the iBox’s performance in predicting graft loss. Discrimination, calibration, overall fit and clinical utility were evaluated in the whole cohort and in African American and non-African American recipients. Results: Performance metrics for the prediction of graft loss were similar in both subgroups in terms of discrimination (c-index 0.80 [95% CI: 0.77-0.83] in African American recipients and 0.83 [95% CI: 0.81-0.85] in non-African American recipients, p=0.07), and observed/expected ratios (1.08 [95% CI: 0.95-1.23] and 0.99 [95% CI: 0.88-1.10], respectively, p=0.28). No significant interaction between iBox score values and race was found in multivariable analysis stratified by transplant center (p=0.29 for the interaction term). Results were consistent between subgroups regardless of the equation used to estimate glomerular filtration rate (Kidney Recipient Specific [KRS], CKD-EPI, or MDRD), with small variations in calibration across equations. Conclusions: The iBox prognostication system showed accurate discrimination, overall fit, and clinical utility up to 7 years post-risk evaluation in African American and non-African American kidney transplant recipients, supporting its robustness in this population.

Randomized controlled trials remain the gold standard for evaluating the benefits and risks of new interventions, yet they face persistent challenges including high costs constraining sample sizes, complex eligibility criteria, recruitment difficulties, prolonged follow-up periods to capture hard end points, and the growing prevalence of poorly designed studies that create noise in literature. This Review proposes an artificial intelligence (AI)-enabled clinical trial engineering framework, applicable across medical specialties. This framework builds on four stages: assembling and harmonizing multimodal data to develop and validate tools for enabling trials; matching fit-for-purpose tools to the research question and target outcome; AI-supported trial conduct, including patient-to-trial matching, surrogate end points, externally matched comparator arms, digital twins, and automated data collection and curation; and faster, evidence-based go/no-go decisions that flag non-promising drugs early. Three overarching principles operate throughout: fit-for-purpose validation, continuous regulatory engagement and human oversight. This Review illustrates the framework through representative case studies, with the iBox surrogate in transplantation, the annualized relapse rate in multiple sclerosis, heart digital twins for ventricular tachycardia, AI-assisted histology (AIM-MASH) in hepatology and a large language model for patient-to-trial matching. It further maps the evolving regulatory landscape for AI-enabled clinical trials (EMA, FDA and the EU AI Act). Applied judiciously, AI-enabled clinical trials could shorten timelines, reduce costs and accelerate both the identification of effective therapies and the earlier elimination of futile ones. Artificial intelligence is poised to reshape clinical trials, addressing challenges in design, recruitment, monitoring and conduct. This Review outlines a framework built on deeply phenotyped cohorts, validated surrogate end points, digital twins and agentic AI systems that could shorten timelines and support the trial life cycle, highlighting opportunities to accelerate drug development while maintaining rigorous regulatory and benefit–risk assessment.

Background: Recent studies indicate that up to 36% of pediatric and adult kidney transplant recipients with stable serum creatinine levels will have acute rejection detected on surveillance biopsy. The purpose of this study was to develop and validate a risk algorithm for identifying low- and high-risk patients using a novel automated platform that simultaneously measures urinary CCL2, CXCL9, CXCL10 and VEGF-A with high precision. Methods: We designed a multicenter observational study to evaluate the performance of urinary CCL2, CXCL9, CXCL10 and VEGF-A in a training set of 517 banked samples collected at the time of surveillance or indication kidney biopsies from both adult and pediatric recipients. Risk algorithms combining all four analytes were developed in the training set, and subsequently validated in three laboratory sites in two additional pediatric cohorts (N=174). Results: The automated platform had remarkably high throughput, generating reproducible results in 60-70 minutes. Analysis was initially performed in the training set (N=517), which included biopsies read as normal (N=330), acute rejection (N=92) or borderline rejection (N=95). We found that each biomarker independently discriminated normal biopsies vs. those with acute rejection ( P < 10 -5 ). A risk algorithm utilizing all four biomarkers (score4) had excellent diagnostic performance for acute rejection in both for-cause and surveillance biopsies performed on patients with stable GFRs, outperforming any individual biomarker as well as estimated GFR assessments. Validation assays performed in the two additional pediatric cohorts in three laboratory sites demonstrated a robust correlation of results; score4 retained excellent diagnostic performance (75% specificity and 92% negative predictive value). Conclusions: Automated measurements of urine CCL2, CXCL9, CXCL10 and VEGF-A can distinguish kidney transplant recipients at low- vs. high-risk for rejection. We suggest that this assay can advantage clinical decision-making in routine post-transplant monitoring due to its low cost, rapid throughput, and operator independence.

A working group under the Sensitization in Transplantation: Assessment of Risk initiative was established in 2023 to develop guidelines for analytical and clinical validity of lab-based testing for donor-derived cell-free DNA (dd-cfDNA). Measurement of dd-cfDNA as a minimally invasive marker of allograft injury has become more widely used over the last few years. To date, various technical and quantitation methods have hindered the standardization and interpretation of the results, leading to variability in understanding how to best utilize cell-free DNA in transplantation. Kits are being formulated for local laboratory testing, but we lack an organized framework for laboratory quality assurance. Further, threshold values and methods of measurement have changed over time, indicating that assay sensitivity and clinical relevance are still being refined. Harmonization and reproducibility will be critical as the field moves forward to local laboratory-based testing. The goal of this work group was to review and analyze technical and biological variables and clinical settings that could contribute to disparities in results, which will ultimately influence clinical validity and utility. High-quality, standardized decentralized dd-cfDNA testing is the essential prerequisite for conducting real-world evidence-generating multicenter studies to establish the appropriate context of use for this promising assay.