Assessment of the Utility of Kidney Histology as a Basis for Discarding Organs in the United States: A Comparison of International Transplant Practices and Outcomes.

peer reviewedBACKGROUND: Many kidneys donated for transplant in the United States are discarded because of abnormal histology. Whether histology adds incremental value beyond usual donor attributes in assessing allograft quality is unknown. METHODS: This population-based study included patients who received a deceased donor kidney that had been biopsied before implantation according to a prespecified protocol in France and Belgium, where preimplantation biopsy findings are generally not used for decision making in the allocation process. We also studied kidneys that had been acquired from deceased United States donors for transplantation that were biopsied during allocation and discarded because of low organ quality. Using donor and recipient characteristics, we fit multivariable Cox models for death-censored graft failure and examined whether predictive accuracy (C index) improved after adding donor histology. We matched the discarded United States kidneys to similar kidneys transplanted in Europe and calculated predicted allograft survival. RESULTS: In the development cohort of 1629 kidney recipients at two French centers, adding donor histology to the model did not significantly improve prediction of long-term allograft failure. Analyses using an external validation cohort from two Belgian centers confirmed the lack of improved accuracy from adding histology. About 45% of 1103 United States kidneys discarded because of histologic findings could be accurately matched to very similar kidneys that had been transplanted in France; these discarded kidneys would be expected to have allograft survival of 93.1% at 1 year, 80.7% at 5 years, and 68.9% at 10 years. CONCLUSIONS: In this multicenter study, donor kidney histology assessment during allocation did not provide substantial incremental value in ascertaining organ quality. Many kidneys discarded on the basis of biopsy findings would likely benefit United States patients who are wait listed

Race-Free Estimated Glomerular Filtration Rate Equation in Kidney Transplant Recipients: Development and Validation Study

OBJECTIVE: To compare the performance of a newly developed race-free kidney recipient specific glomerular filtration rate (GFR) equation with the three current main equations for measuring GFR in kidney transplant recipients. DESIGN: Development and validation study SETTING: 17 cohorts in Europe, the United States, and Australia (14 transplant centres, three clinical trials). PARTICIPANTS: 15 489 adults (3622 in development cohort (Necker, Saint Louis, and Toulouse hospitals, France), 11 867 in multiple external validation cohorts) who received kidney transplants between 1 January 2000 and 1 January 2021. MAIN OUTCOME MEASURE: The main outcome measure was GFR, measured according to local practice. Performance of the GFR equations was assessed using P RESULTS: The study included 15 489 participants, with 50 464 mGFR and eGFR values. The mean GFR was 53.18 mL/min/1.73m2 (SD 17.23) in the development cohort and 55.90 mL/min/1.73m2 (19.69) in the external validation cohorts. Among the current GFR equations, the race-free CKD-EPI 2021 equation showed the lowest performance compared with the MDRD and CKD-EPI 2009 equations. When race was included in the kidney recipient specific GFR equation, performance did not increase. The race-free kidney recipient specific GFR equation showed significantly improved performance compared with the race-free CKD-EPI 2021 equation and performed well in the external validation cohorts (P30 ranging from 73.0% to 91.3%). The race-free kidney recipient specific GFR equation performed well in several subpopulations of kidney transplant recipients stratified by race (P30 73.0-91.3%), sex (72.7-91.4%), age (70.3-92.0%), body mass index (64.5-100%), donor type (58.5-92.9%), donor age (68.3-94.3%), treatment (78.5-85.2%), creatinine level (72.8-91.3%), GFR measurement method (73.0-91.3%), and timing of GFR measurement post-transplant (72.9-95.5%). An online application was developed that estimates GFR based on recipient’s creatinine level, age, and sex (https://transplant-prediction-system.shinyapps.io/eGFR_equation_KTX/). CONCLUSION: A new race-free kidney recipient specific GFR equation was developed and validated using multiple, large, international cohorts of kidney transplant recipients. The equation showed high accuracy and outperformed the race-free CKD-EPI 2021 equation that was developed in individuals with native kidneys

Race-free estimated glomerular filtration rate equation in kidney transplant recipients:development and validation study

OBJECTIVE: To compare the performance of a newly developed race-free kidney recipient specific glomerular filtration rate (GFR) equation with the three current main equations for measuring GFR in kidney transplant recipients.DESIGN: Development and validation study SETTING: 17 cohorts in Europe, the United States, and Australia (14 transplant centres, three clinical trials).PARTICIPANTS: 15 489 adults (3622 in development cohort (Necker, Saint Louis, and Toulouse hospitals, France), 11 867 in multiple external validation cohorts) who received kidney transplants between 1 January 2000 and 1 January 2021.MAIN OUTCOME MEASURE: The main outcome measure was GFR, measured according to local practice. Performance of the GFR equations was assessed using P 30 (proportion of estimated GFR (eGFR) within 30% of measured GFR (mGFR)) and correct classification (agreement between eGFR and mGFR according to GFR stages). The race-free equation, based on creatinine level, age, and sex, was developed using additive and multiplicative linear regressions, and its performance was compared with the three current main GFR equations: Modification of Diet in Renal Disease (MDRD) equation, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation, and race-free CKD-EPI 2021 equation. RESULTS: The study included 15 489 participants, with 50 464 mGFR and eGFR values. The mean GFR was 53.18 mL/min/1.73m 2 (SD 17.23) in the development cohort and 55.90 mL/min/1.73m 2 (19.69) in the external validation cohorts. Among the current GFR equations, the race-free CKD-EPI 2021 equation showed the lowest performance compared with the MDRD and CKD-EPI 2009 equations. When race was included in the kidney recipient specific GFR equation, performance did not increase. The race-free kidney recipient specific GFR equation showed significantly improved performance compared with the race-free CKD-EPI 2021 equation and performed well in the external validation cohorts (P 30 ranging from 73.0% to 91.3%). The race-free kidney recipient specific GFR equation performed well in several subpopulations of kidney transplant recipients stratified by race (P 30 73.0-91.3%), sex (72.7-91.4%), age (70.3-92.0%), body mass index (64.5-100%), donor type (58.5-92.9%), donor age (68.3-94.3%), treatment (78.5-85.2%), creatinine level (72.8-91.3%), GFR measurement method (73.0-91.3%), and timing of GFR measurement post-transplant (72.9-95.5%). An online application was developed that estimates GFR based on recipient's creatinine level, age, and sex (https://transplant-prediction-system.shinyapps.io/eGFR_equation_KTX/). CONCLUSION: A new race-free kidney recipient specific GFR equation was developed and validated using multiple, large, international cohorts of kidney transplant recipients. The equation showed high accuracy and outperformed the race-free CKD-EPI 2021 equation that was developed in individuals with native kidneys.TRIAL REGISTRATION: ClinicalTrials.gov NCT05229939.</p

Validation et application d’un système de scores pronostiques multidimensionnels de la survie du greffon comme critère de jugement principal des essais thérapeutiques en transplantation rénale

Abstract: the development of pharmaceutical agents in transplantation is currently limited by long waits for hard endpoints. We sought to validate and use a risk stratification system as a surrogate endpoint in randomized controlled trial in kidney transplantation.Methods: a post-hoc analysis of three randomized controlled trials was performed to validate an integrative risk score system named iBox as a surrogate endpoint in randomized controlled trials. Allograft survival predicted by the iBox system was compared with the observed allograft survival. We also applied the iBox system as a surrogate endpoint using the validated data from the TRANSFORM trial measured at 12 months after randomization (primary end point timeline) and projected patient's individual long-term allograft survival. Results: The immunological, functional and histological parameters were entered into the iBox risk prediction system, which translated to an overall patient graft survival at 4, 6, 8 and 11 years after randomization of 90.92 % vs 92.12 %, of 87.9% vs 86.24%, of 87.6 % vs 88.7 %, and 79.98% vs 82.45% in the everolimus and MPA arms respectively (below the non-inferiority margin of 10%). These results were confirmed in the subset of patient with immunological and histological data available.Conclusion: the iBox system confirms the non-inferiority of everolimus vs mycophenolic acid 11 years after patient’s randomization in the RCT. Given the unmet need for surrogate end point for clinical trials, this study shows the potential of a clinical trial simulation tool to fast track the development and approval of pharmaceutical agents.Résumé : l'arrivée de nouvelles molécules en transplantation rénale est actuellement limitée par la difficulté de construire des essais thérapeutiques avec un critère de jugement de substitution permettant de prédire précocement la survie à long terme du greffon. Un outil de stratification du risque de perte du greffon a été validé puis utilisé comme critère de jugement dans quatre essais thérapeutiques en transplantation rénale.Méthodes : une analyse post-hoc de trois essais thérapeutiques a été réalisée afin d’évaluer les performances du système iBox comme critère de jugement en transplantation en comparant la survie prédite lors de l’évaluation du critère de jugement principal à la survie observée.Le système iBox a été utilisé comme critère de jugement principal dans l’essai randomisé de non-infériorité Transform en utilisant les données collectées à 12 mois de la randomisation (critère d’évaluation principal) afin de projeter la survie individuelle à long terme de la population en intention de traiter.Résultats : les paramètres fonctionnels, immunologiques et histologiques ont été intégrés dans le système iBox, la survie moyenne prédite à 10 ans après évaluation était non-inférieure entre les 2 groupes de traitement en respectant la marge de non-infériorité de 10 % avec une survie moyenne projetée à 10 ans de 79,98% dans le groupe everolimus vs 82,45% dans le groupe contrôle.Conclusion : le système iBox utilisé comme critère de jugement confirme la non-infériorité à long terme du traitement par everolimus versus l’association contrôle. Cette application montre le potentiel de cet outil de prédiction pour aider le développement de nouvelles molécules en transplantation rénale

Validation et application d’un système de scores pronostiques multidimensionnels de la survie du greffon comme critère de jugement principal des essais thérapeutiques en transplantation rénale

Abstract: the development of pharmaceutical agents in transplantation is currently limited by long waits for hard endpoints. We sought to validate and use a risk stratification system as a surrogate endpoint in randomized controlled trial in kidney transplantation.Methods: a post-hoc analysis of three randomized controlled trials was performed to validate an integrative risk score system named iBox as a surrogate endpoint in randomized controlled trials. Allograft survival predicted by the iBox system was compared with the observed allograft survival. We also applied the iBox system as a surrogate endpoint using the validated data from the TRANSFORM trial measured at 12 months after randomization (primary end point timeline) and projected patient's individual long-term allograft survival. Results: The immunological, functional and histological parameters were entered into the iBox risk prediction system, which translated to an overall patient graft survival at 4, 6, 8 and 11 years after randomization of 90.92 % vs 92.12 %, of 87.9% vs 86.24%, of 87.6 % vs 88.7 %, and 79.98% vs 82.45% in the everolimus and MPA arms respectively (below the non-inferiority margin of 10%). These results were confirmed in the subset of patient with immunological and histological data available.Conclusion: the iBox system confirms the non-inferiority of everolimus vs mycophenolic acid 11 years after patient’s randomization in the RCT. Given the unmet need for surrogate end point for clinical trials, this study shows the potential of a clinical trial simulation tool to fast track the development and approval of pharmaceutical agents.Résumé : l'arrivée de nouvelles molécules en transplantation rénale est actuellement limitée par la difficulté de construire des essais thérapeutiques avec un critère de jugement de substitution permettant de prédire précocement la survie à long terme du greffon. Un outil de stratification du risque de perte du greffon a été validé puis utilisé comme critère de jugement dans quatre essais thérapeutiques en transplantation rénale.Méthodes : une analyse post-hoc de trois essais thérapeutiques a été réalisée afin d’évaluer les performances du système iBox comme critère de jugement en transplantation en comparant la survie prédite lors de l’évaluation du critère de jugement principal à la survie observée.Le système iBox a été utilisé comme critère de jugement principal dans l’essai randomisé de non-infériorité Transform en utilisant les données collectées à 12 mois de la randomisation (critère d’évaluation principal) afin de projeter la survie individuelle à long terme de la population en intention de traiter.Résultats : les paramètres fonctionnels, immunologiques et histologiques ont été intégrés dans le système iBox, la survie moyenne prédite à 10 ans après évaluation était non-inférieure entre les 2 groupes de traitement en respectant la marge de non-infériorité de 10 % avec une survie moyenne projetée à 10 ans de 79,98% dans le groupe everolimus vs 82,45% dans le groupe contrôle.Conclusion : le système iBox utilisé comme critère de jugement confirme la non-infériorité à long terme du traitement par everolimus versus l’association contrôle. Cette application montre le potentiel de cet outil de prédiction pour aider le développement de nouvelles molécules en transplantation rénale

Validation et application dans différents contexte d'utilisation d'un modèle pronostique multidimensionnel comme critère de substitution dans les essais cliniques en transplantation rénale

Actuellement, l'amélioration des résultats à long terme de la transplantation rénale est un défi. La principale limite est l'absence de nouvelle molécule en raison de la difficulté à construire des essais cliniques lié à une longue attente pour les critères durs comme la perte du greffon et l'absence de critères de substitution précoces fiables. Notre objectif était de valider et appliquer un modèle pronostique multidimensionnel comme critère de substitution permettant une prédiction précoce et fiable de la perte du greffon à long terme dans différents contextes d'utilisation pour les essais cliniques en transplantation rénale. Nous avons rassemblé les données de huit essais internationaux contrôlés randomisés et de deux cohortes observationnelles multicentriques basées sur la population de transplantés rénaux adultes et pédiatriques d'Europe et d'Amérique du Nord. Plusieurs paramètres actuellement qualifiés par les agences du médicament ou candidats à une qualification incluant le débit de filtration glomérulaire estimé, la protéinurie, le rejet aigu histologiquement prouvé et un modèle pronostique multidimensionnel (le système iBox), ont été investigués comme substituts de la perte du greffon à long terme en comparant la survie prédite au moment de l'évaluation du critère de jugement principal à la survie observée en utilisant la discrimination (indice c de concordance) et la calibration pour évaluer les performances des prédictions. Ces critères de substitution ont été comparés dans cinq contextes différents d'utilisation pour les essais cliniques : transplantation rénale de novo, rejet médié par les anticorps, rejet cellulaire, stratégies sans inhibiteurs de la calcineurine et receveurs pédiatriques. Des analyses supplémentaires ont été effectuées pour démontrer l'utilisation potentielle du critère de substitution ayant les meilleures performances : 1) démontrer sa valeur ajoutée par rapport à l'évaluation humaine, 2) application du critère de substitution dans un grand essai contrôlé randomisé et 3) utiliser ce critère de substitution pour simuler un essai clinique en vie réelle pour les patients convertis au belatacept après transplantation. Au total, 11131 transplantés rénaux ont été inclus, dont 4322 patients provenant de neuf essais multicentriques contrôlés randomisés et 6809 patients provenant de cohortes adultes et pédiatriques d'Europe et d'Amérique du Nord. Parmi les critères de substitution de la perte du greffon à long terme étudiés, le système iBox a montré les meilleures performances de prédiction basées sur la discrimination et la calibration dans les cinq contextes d'utilisation pour les essais cliniques. Nous avons ensuite démontré que le système iBox avait de meilleures performances que les médecins pour prédire la perte du greffon à long terme à un an après la transplantation chez 400 patients, avec une discrimination de 0,79 alors que les médecins avaient tendance à surestimer le risque. En outre, une première application du système iBox dans l'essai de non-infériorité contrôlé randomisé Transform en utilisant les données recueillies à 12 mois de la randomisation, confirmant la non-infériorité à 10 ans après l'évaluation avec une survie moyenne projetée à 10 ans de 79,98 % pour le groupe everolimus contre 82,45 % pour le groupe contrôle. Enfin, nous avons réalisé une application du système iBox dans un essai clinique simulé en vie réelle afin de garantir la comparabilité des patients appariés avant intervention. Dans cette étude, nous avons observé que la survie greffon était significativement améliorée après la conversion au belatacept par rapport aux patients appariés maintenus avec une immunosuppression à base d’anticalcineurines (p<0,0001). Ces travaux confirment les performances prédictives et l’applicabilité du système iBox comme paramètre de substitution de la perte du greffon à long terme dans différents contextes d’utilisation dans les essais cliniques en transplantation rénale.Background: Currently, the improvement of long-term outcomes in kidney transplantation is a challenge. The main limitation is the lack a new molecule due to difficulty of constructing clinical trials because of the long wait for hard outcomes and the absence of reliable early surrogate endpoints. Our goal was to validate a multidimensional prognostic model as a surrogate endpoint that allows early and robust prediction of long-term allograft failure in different contexts of use for clinical trials. Methods: We curated the data of eight international randomized controlled trials and two observational population-based cohort of adult and pediatric kidney transplant recipients from Europe and North America. Several currently qualified and candidates’ endpoints including eGFR, proteinuria, biopsy proven acute rejection (BPAR) and a multidimensional prognostic model (the iBox system) were investigated for surrogacy of long-term allograft failure by comparing predicted survival at time of the primary endpoint assessment to observed survival using discrimination (concordance c-index) and calibration to assess predictions performances. These surrogate endpoints were compared in five different contexts of use for clinical trials: de novo kidney transplant recipient, antibody mediated rejection, T-cell mediated rejection, calcineurin inhibitor (CNI) avoidance strategies, and pediatric kidney transplant recipients. Additional analyses to demonstrate the potential use of the surrogate endpoint with the best performances were performed: 1) To demonstrate it added value compared with human assessment, 2) To perform a proof-of-concept study of its application in a large randomized controlled trial and 3) To use this surrogate endpoint to simulate a real-world evidence clinical trial for patients converted to belatacept after transplantation. Results: Overall, 11131 kidney transplant recipients were included of whom 4322 patients were from nine international multicentric randomized controlled trials and 6809 patients were from adult and pediatric population-based observational cohort from Europe and north America. Several candidate surrogate endpoints for allograft failure in kidney transplant clinical trials were investigated and the iBox system showed the best predictions performances using discrimination and calibration in the five contexts of use for clinical trials. We then demonstrated that the iBox system outperforms physicians to predict long-term kidney graft failure based on data available at one-year post-transplant in 400 patients, with a discrimination of 0.79 while physicians tended to overestimate the risk of allograft failure. In addition, we performed a proof-of-concept study of the first application of the iBox system as the primary endpoint that confirmed the non-inferiority at 10 years post-evaluation with a mean projected survival at 10 years of 79.98% for the everolimus group versus 82.45% for the control group in the Transform randomized non-inferiority trial using data collected at 12 months from randomization (primary endpoint). Last, we performed an application of the iBox system in a real-world evidence clinical trial to ensure the comparability of matched patients before intervention regarding the primary endpoint of allograft failure. In this study, we found that allograft survival is significantly improved after conversion to belatacept compared with the matched patients maintained with a CNI based immunosuppression (p<0.0001). Conclusion: This work confirms the robustness and potential application of the iBox system to be used as a surrogate endpoint of long-term allograft failure in different context of use in adult and pediatric kidney transplant clinical trials

Renal biopsies should be performed whenever treatment strategies depend on renal involvement

International audienc

High-sensitivity cardiac troponin T is a biomarker for atherosclerosis in systemic lupus erythematous patients: a cross-sectional controlled study

Abstract Background Cardiovascular disease (CVD) is the main cause of death in systemic lupus erythematous (SLE) patients. The Framingham score underestimates the risk for CVD in this population. Our study aimed to determine whether serum high-sensitivity cardiac troponin T (HS-cTnT) might help to identify SLE patients at risk for CVD. Methods The presence of carotid plaques was prospectively assessed by ultrasound in 63 consecutive SLE patients asymptomatic for CVD and 18 controls. Serum HS-cTnT concentration was measured using the electrochemiluminescence method. Factors associated with carotid plaques were identified and multivariate analysis was performed. Results Framingham score was low in both SLE patients (median 1 (range 1–18%)) and controls (1 (1–13%)). Nevertheless, 23 (36.5%) SLE patients, but only 2 (11.1%) controls (p = 0.039), had carotid plaque detected by vascular ultrasound. In the multivariate analysis, only age (p = 0.006) and SLE status (p = 0.017) were independently associated with carotid plaques. Serum HS-cTnT concentration was detectable (i.e. >3 ng/L) in 37 (58.7%) SLE patients and 6 (33.3%) controls (p = 0.057). Interestingly, 87% of SLE patients with carotid plaques, but only 42.5% of SLE patients without plaques (p < 0.001), had detectable HS-cTnT. Conversely, 54.5% of SLE patients with detectable HS-cTnT, but only 11.5% with undetectable HS-cTnT (p < 0.001), had a carotid plaque. In the multivariate analysis, only body mass index (p = 0.006) and HS-cTnT (p = 0.033) were statistically associated with carotid plaques in SLE patients. Overall, the risk of having a carotid plaque was increased by 9 (odds ratio 9.26, 95% confidence interval 1.55–90.07) in SLE patients in whom HS-cTnT was detectable in serum. Conclusion Serum HS-cTnT level is high and associated with carotid plaques in SLE patients who are at an apparently low risk for CVD according to the Framingham score. HS-cTnT may be a useful biomarker for SLE-associated atherosclerosis

An automated histological classification system for precision diagnostics of kidney allografts

For three decades, the international Banff classification has been the gold standard for kidney allograft rejection diagnosis, but this system has become complex over time with the integration of multimodal data and rules, leading to misclassifications that can have deleterious therapeutic consequences for patients. To improve diagnosis, we developed a decision-support system, based on an algorithm covering all classification rules and diagnostic scenarios, that automatically assigns kidney allograft diagnoses. We then tested its ability to reclassify rejection diagnoses for adult and pediatric kidney transplant recipients in three international multicentric cohorts and two large prospective clinical trials, including 4,409 biopsies from 3,054 patients (62.05% male and 37.95% female) followed in 20 transplant referral centers in Europe and North America. In the adult kidney transplant population, the Banff Automation System reclassified 83 out of 279 (29.75%) antibody-mediated rejection cases and 57 out of 105 (54.29%) T cell-mediated rejection cases, whereas 237 out of 3,239 (7.32%) biopsies diagnosed as non-rejection by pathologists were reclassified as rejection. In the pediatric population, the reclassification rates were 8 out of 26 (30.77%) for antibody-mediated rejection and 12 out of 39 (30.77%) for T cell-mediated rejection. Finally, we found that reclassification of the initial diagnoses by the Banff Automation System was associated with an improved risk stratification of long-term allograft outcomes. This study demonstrates the potential of an automated histological classification to improve transplant patient care by correcting diagnostic errors and standardizing allograft rejection diagnoses.ClinicalTrials.gov registration: NCT05306795

Prognostic Biomarkers in Kidney Transplantation: a Systematic Review and Critical Appraisal.

peer reviewed[en] BACKGROUND: Despite the increasing number of biomarker studies published in the transplant literature over the past 20 years, demonstrations of their clinical benefit and their implementation in routine clinical practice are lacking. We hypothesized that suboptimal design, data, methodology and reporting might contribute to this phenomenon. METHODS: A systematic literature search was performed in PubMed, Embase, Scopus, Web of Science, and Cochrane Library between 1 January 2005 and 12 November 2022 (PROSPERO ID: CRD42020154747). All English language, original studies investigating the association between a biomarker and kidney-allograft outcome were included. The final set of publications was assessed by expert reviewers. After data collection, two independent reviewers randomly evaluated the inconsistencies for 30% of the references for each reviewer. If more than 5% of inconsistencies were observed for one given reviewer, a re-evaluation was conducted for all the references of the reviewer. The biomarkers were categorized according to their type and the biological milieu from which they were measured. The study characteristics related to the design, methods, results, and their interpretation were assessed, as well as reproducible research practices and transparency indicators. RESULTS: A total of 7372 publications were screened and 804 studies met the inclusion criteria. A total of 1143 biomarkers were assessed among the included studies from blood (n=821, 71.8%), intragraft (n=169, 14.8%), or urine (n=81, 7.1%) compartments. The number of studies significantly increased, with a median, yearly number of 31.5 studies (IQR: 23.8-35.5) between 2005 and 2012, and 57.5 (IQR: 53.3-59.8) between 2013 and 2022 (p<0.001). A total of 655 studies (81.5%) were retrospective, while 595 (74.0%) used data from a single center. The median number of patients included was 232 (IQR: 96-629) with a median follow-up posttransplant of 4.8 years (IQR: 3.0-6.2). Only 4.7% of studies were externally validated. A total of 346 studies (43.0%) did not adjust their biomarker for key prognostic factors while only 3.1% of studies adjusted the biomarker for standard-of-care patient monitoring factors. Data sharing, code sharing, and registration occurred in 8.8%, 1.1%, and 4.6% of studies, respectively. A total of 158 studies (20.0%) emphasized the clinical relevance of the biomarker despite the reported nonsignificant association of the biomarker with the outcome measure. A total of 288 studies assessed rejection as an outcome. We showed that these rejection studies shared the same characteristics as other studies. CONCLUSIONS: and Relevance Biomarker studies in kidney transplantation lack validation, rigorous design, methods and interpretation, and transparency. Higher standards in biomarker research may improve the clinical utility and clinical use