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

The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell–mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation

Allograft Function as Endpoint for Clinical Trials in Kidney Transplantation

Clinical study endpoints that assess the efficacy of interventions in patients with chronic renal insufficiency can be adopted for use in kidney transplantation trials, given the pathophysiological similarities between both conditions. Kidney dysfunction is reflected in the glomerular filtration rate (GFR), and although a predefined (e.g., 50%) reduction in GFR was recommended as an endpoint by the European Medicines Agency (EMA) in 2016, many other endpoints are also included in clinical trials. End-stage renal disease is strongly associated with a change in estimated (e)GFR, and eGFR trajectories or slopes are increasingly used as endpoints in clinical intervention trials in chronic kidney disease (CKD). Similar approaches could be considered for clinical trials in kidney transplantation, although several factors should be taken into account. The present Consensus Report was developed from documentation produced by the European Society for Organ Transplantation (ESOT) as part of a Broad Scientific Advice request that ESOT submitted to the EMA in 2020. This paper provides a contemporary discussion of primary endpoints used in clinical trials involving CKD, including proteinuria and albuminuria, and evaluates the validity of these concepts as endpoints for clinical trials in kidney transplantation

Allograft Function as Endpoint for Clinical Trials in Kidney Transplantation

Clinical study endpoints that assess the efficacy of interventions in patients with chronic renal insufficiency can be adopted for use in kidney transplantation trials, given the pathophysiological similarities between both conditions. Kidney dysfunction is reflected in the glomerular filtration rate (GFR), and although a predefined (e.g., 50%) reduction in GFR was recommended as an endpoint by the European Medicines Agency (EMA) in 2016, many other endpoints are also included in clinical trials. End-stage renal disease is strongly associated with a change in estimated (e)GFR, and eGFR trajectories or slopes are increasingly used as endpoints in clinical intervention trials in chronic kidney disease (CKD). Similar approaches could be considered for clinical trials in kidney transplantation, although several factors should be taken into account. The present Consensus Report was developed from documentation produced by the European Society for Organ Transplantation (ESOT) as part of a Broad Scientific Advice request that ESOT submitted to the EMA in 2020. This paper provides a contemporary discussion of primary endpoints used in clinical trials involving CKD, including proteinuria and albuminuria, and evaluates the validity of these concepts as endpoints for clinical trials in kidney transplantation

Modeling graft loss in patients with donor-specific antibody at baseline using the Birmingham-Mayo (BirMay) predictor: Implications for clinical trials.

Predicting which renal allografts will fail and the likely cause of failure is important in clinical trial design to either enrich patient populations to be or as surrogate efficacy endpoints for trials aimed at improving long-term graft survival. This study tests our previous Birmingham-Mayo model (termed the BirMay Predictor) developed in a low-risk kidney transplant population in order to predict the outcome of patients with donor specific alloantibody (DSA) at the time of transplantation and identify new factors to improve graft loss prediction in DSA+ patients. We wanted define ways to enrich the population for future therapeutic intervention trials. The discovery set included 147 patients from Mayo Cohort and the validation set included 111 patients from the Paris Cohort-all of whom had DSA at the time of transplantation. The BirMay predictor performed well predicting 5-year outcome well in DSA+ patients (Mayo C statistic = 0.784 and Paris C statistic = 0.860). Developing a new model did not improve on this performance. A high negative predictive value of greater than 90% in both cohorts excluded allografts not destined to fail within 5 years. We conclude that graft-survival models including histology predict graft loss well, both in DSA+ cohorts as well as DSA- patients

Proposed definitions of T cell-mediated rejection and tubulointerstitial inflammation as clinical trial endpoints in kidney transplantation

The diagnosis of acute T cell-mediated rejection (aTCMR) after kidney transplantation has considerable relevance for research purposes. Its definition is primarily based on tubulointerstitial inflammation and has changed little over time; aTCMR is therefore a suitable parameter for longitudinal data comparisons. In addition, because aTCMR is managed with antirejection therapies that carry additional risks, anxieties, and costs, it is a clinically meaningful endpoint for studies. This paper reviews the history and classifications of TCMR and characterizes its potential role in clinical trials: a role that largely depends on the nature of the biopsy taken (indication vs protocol), the level of inflammation observed (e.g., borderline changes vs full TCMR), concomitant chronic lesions (chronic active TCMR), and the therapeutic intervention planned. There is ongoing variability—and ambiguity—in clinical monitoring and management of TCMR. More research, to investigate the clinical relevance of borderline changes (especially in protocol biopsies) and effective therapeutic strategies that improve graft survival rates with minimal patient morbidity, is urgently required. The present paper was developed from documentation produced by the European Society for Organ Transplantation (ESOT) as part of a Broad Scientific Advice request that ESOT submitted to the European Medicines Agency for discussion in 2020. This paper proposes to move toward refined definitions of aTCMR and borderline changes to be included as primary endpoints in clinical trials of kidney transplantation

Challenges in the management of the kidney allograft: from decline to failure: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

In March 2022, Kidney Disease: Improving Global Outcomes (KDIGO) held a virtual Controversies Conference to address the important but rarely examined phase during which the kidney transplant is failing or has failed. In addition to discussing the definition of a failing allograft, 4 broad areas were considered in the context of a declining functioning graft: prognosis and kidney failure trajectory; immunosuppression strategies; management of medical and psychological complications, and patient factors; and choice of kidney replacement therapy or supportive care following graft loss. Identifying and paying special attention to individuals with failing allografts was felt to be important in order to prepare patients psychologically, manage immunosuppression, address complications, prepare for dialysis and/or retransplantation, and transition to supportive care. Accurate prognostication tools, although not yet widely available, were embraced as necessary to define allograft survival trajectories and the likelihood of allograft failure. The decision of whether to withdraw or continue immunosuppression after allograft failure was deemed to be based most appropriately on risk-benefit analysis and likelihood of retransplantation within a few months. Psychological preparation and support was identified as a critical factor in patient adjustment to graft failure, as was early communication. Several models of care were noted that enabled a medically supportive transition back to dialysis or retransplantation. Emphasis was placed on the importance of dialysis-access readiness before initiation of dialysis, in order to avoid use of central venous catheters. The centrality of the patient to all management decisions and discussions was deemed to be paramount. Patient "activation," which can be defined as engaged agency, was seen as the most effective way to achieve success. Unresolved controversies, gaps in knowledge, and areas for research were also stressed in the conference deliberations

The XVth Banff Conference on Allograft Pathology the Banff Workshop Heart Report: Improving the diagnostic yield from endomyocardial biopsies and Quilty effect revisited.

The XVth Banff Conference on Allograft Pathology meeting was held on September 23-27, 2019, in Pittsburgh, Pennsylvania, USA. During this meeting, two main topics in cardiac transplant pathology were addressed: (a) Improvement of endomyocardial biopsy (EMB) accuracy for the diagnosis of rejection and other significant injury patterns, and (b) the orphaned lesion known as Quilty effect or nodular endocardial infiltrates. Molecular technologies have evolved in recent years, deciphering pathophysiology of cardiac rejection. Diagnostically, it is time to integrate the histopathology of EMBs and molecular data. The goal is to incorporate molecular pathology, performed on the same paraffin block as a companion test for histopathology, to yield more accurate and objective EMB interpretation. Application of digital image analysis from hematoxylin and eosin (H&E) stain to multiplex labeling is another means of extracting additional information from EMBs. New concepts have emerged exploring the multifaceted significance of myocardial injury, minimal rejection patterns supported by molecular profiles, and lesions of arteriolitis/vasculitis in the setting of T cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR). The orphaned lesion known as Quilty effect or nodular endocardial infiltrates. A state-of-the-art session with historical aspects and current dilemmas was reviewed, and possible pathogenesis proposed, based on advances in immunology to explain conflicting data. The Quilty effect will be the subject of a multicenter project to explore whether it functions as a tertiary lymphoid organ