For most end-stage renal disease (ESRD) patients, successful kidney transplantation (KT) provides longer survival and better quality of life than dialysis. Unfortunately, a consistent balance between organ acceptance and discard rates after procurement has been difficult to achieve given a lack of precise tools to assess donor kidney quality and prognosis. Specifically, as recently reported, deceased donor (DD) kidneys retrieved for transplantation are increasingly being discarded, and the most common reason given for discarding kidneys is histological biopsy results. Two recent studies suggest that histological evaluation of procurement biopsies are not predictive of post-transplant outcomes and may lead to dissuade the use of kidneys that are otherwise suitable for transplant. These findings indicate that additional methods are needed when weighing whether to transplant a DD kidney. Evaluation of organ quality at transplantation time, as a predictor of graft performance, is a critical clinical challenge impacting acceptance of an organ, as well as individualization of post-transplant management. Still, clinical scores and histopathology-based assessments at time of KT have been found to be poor predictors of post-KT outcomes. Currently, there are no markers that specifically relate to organ biology that could be included in a donor risk score. A unique matched donor/recipient cohort including 298 DD primary kidney recipients with 4.1 0.8 years of follow-up, graft biopsies at pre-implantation, post-reperfusion and post- KT and associated phenotypic data is available for the proposed studies. Also, a matched donor/recipient cohort of 250 DD primary KT recipients from 3 different institutions is available (approach including training, validation, and replication sets). Hereby, we hypothesize that the addition of biologically-specific screening for molecular biomarkers to evaluate DD organ quality and function is more accurate in predicting kidney graft outcomes than clinical and histopathological-based assessments alone.
The specific aims (SA) include: SA1: Develop a composite score model to evaluate organ quality at kidney transplantation time and predict short-term outcomes; SA2: Develop composite score models to predict long-term kidney transplant outcomes; and SA3: Validate biomarkers predicting short- and long-term outcomes and derive a composite scoring system for clinical application in a point of care test platform. The current approach will evaluate clinical applicability and benefit of adding molecular markers to currently available scoring systems for predicting graft outcomes by (1) accurate assessment of donor organ quality using a systems biology approach, (2) biomarker/score discovery and validation using a multicenter retrospective cohort of prospectively evaluated patients with already available outcomes and mRNA profiles, and (3) independent replication of biomarkers/scores using clinically usable reactions. This study will yield markers and scoring systems for organ quality evaluation that could be tested prospectively in a large study.
Over 16,000 end-stage renal disease (ESRD) patients undergo kidney transplantation (KT) in the US every year. For most ESRD patients, successful KT provides better survival and quality of life than chronic dialysis. Waiting lists and waiting time are both continuously growing in the US. A balance between organ acceptance and discard rates has been difficult to achieve given a lack of precise tools to assess donor kidney quality and predict outcomes. The resulting markers/scores from the proposed studies have the potential to better evaluate organ quality leading to 1) decrease the discard rate of available DD organs for KT, and 2) improve graft outcomes by decreasing the rate of early injury processes that lead to chronic renal allograft dysfunction. The resulting markers/scores will be ready to be tested in prospective clinical trials for assessing their performance when compared with actual scores being used in the clinical setting.
|Bontha, S V; Maluf, D G; Archer, K J et al. (2017) Effects of DNA Methylation on Progression to Interstitial Fibrosis and Tubular Atrophy in Renal Allograft Biopsies: A Multi-Omics Approach. Am J Transplant 17:3060-3075|