Clinical and Molecular Biomarkers of Endpoints in Pediatric Renal Transplantation

小儿肾移植终点的临床和分子生物标志物

• 批准号: 10264044
• 负责人: Michael Edward Seifert
• 金额: $ 29.7万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10264044
• 关键词: Acute; Address; Adolescent; Adult; Age; Allografting; Archives; Biological Markers; Biopsy; Categories; Characteristics; Child; Childhood; Clinical; Data; Detection; Diagnosis; Diagnostic; Diagnostic Sensitivity; Early Diagnosis; End stage renal failure; Enrollment; Event; Face; Failure; Functional disorder; Future; Gene Expression Profile; Genes; Health; Histologic; Histology; Immune; Immune system; Individual; Inflammatory; Injury; Institution; Isoantibodies; Kidney; Kidney Transplantation; Life Expectancy; Link; Longevity; Measures; Mediating; Methods; Modeling; Molecular; Nephrology; Outcome; Participant; Pathology; Pathway interactions; Pediatric cohort; Performance; Phenotype; Prospective cohort; Quality of life; Residual state; Retrospective cohort; Retrospective cohort study; Role; Specificity; T-Lymphocyte; Technology; Testing; Translating; Transplant Recipients; Transplant-Related Disorder; Transplantation; Uncertainty; Validation; Youth; antibody-mediated rejection; base; biobank; clinical biomarkers; clinical phenotype; clinical predictors; cohort; design; early detection biomarkers; follow-up; genetic epidemiology; improved; kidney biopsy; medication nonadherence; molecular marker; molecular phenotype; nano-string; novel; personalized diagnostics; post-transplant; prognostic performance; prognostic tool; prognostic value; prospective; racial diversity; repository; surveillance study; tool; translational study; young adult

Abstract Nearly all pediatric and young adult (PYA) kidney transplants fail within 10-15 years, significantly reducing life expectancy for young people with end-stage renal disease (ESRD). Pediatric kidney transplant recipients face distinct barriers to allograft survival, including diagnostic and prognostic tools that are inadequate and not tailored for children. Consequently, kidney transplant injury regularly escapes detection until substantial damage has occurred that hastens allograft failure. Surveillance biopsies allow for earlier detection of subclinical injury prior to transplant dysfunction, but we have shown that the presence of subclinical phenotypes are still predictive of transplant failure. Improved methods of detecting clinical and subclinical kidney transplant endpoints are needed to increase longevity of youth with ESRD. Recent studies have validated patterns of gene expression (e.g., molecular biomarkers) in adult kidney transplant biopsies with greater diagnostic precision than conventional histology. Similar advances with molecular biomarkers have not been translated to children. The objective of this proposal is address this unmet clinical need by identifying and validating molecular biomarkers of key outcomes in young kidney transplant recipients. We will integrate clinical features, traditional histology, and molecular biomarkers to create powerful tools for precision diagnosis and prediction of long-term outcomes that are tailored for PYA kidney transplants. Our central hypothesis is that distinctive gene expression patterns in kidney biopsies will predict clinical and subclinical events in young transplant recipients and expand the capabilities of traditional histology. The central hypothesis was formulated by our preliminary data in which we identified molecular biomarkers of WNT pathway activation as novel predictors of kidney transplant injury and subsequent allograft failure, even in individuals with reassuring clinical features and normal traditional histology. We will test the central hypothesis by using the NanoString platform to interrogate archived PYA kidney transplant biopsies in pursuit of three specific aims. In aim 1, we will identify molecular biomarkers of clinical endpoints in PYA kidney transplantation. We expect that PYA-specific molecular biomarkers will: a) have excellent diagnostic performance for clinical endpoints, b) help discriminate cases with diagnostic uncertainty by traditional histology, and c) outperform conventional clinical features and histology for predicting long-term outcomes in youth. In aim 2, we will discern the role of subclinical molecular phenotypes in PYA kidney transplantation. We expect to find unique molecular biomarkers of subclinical endpoints that will outperform conventional histology in predicting future rejection episodes and allograft failure. In aim 3, we will validate clinical and molecular biomarkers as predictors of kidney transplant outcomes in a prospective biorepository cohort of PYA kidney transplants. Collectively, this project will externally validate PYA-specific covariate-adjusted molecular biomarkers as comprehensive clinical prediction tools that are ready for use in future studies of PYA kidney transplants.

摘要