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

基本信息

批准号：
10670946
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
项目类别：
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/10670946
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 Epidemiology Event Exclusion Face Failure Functional disorder Future Gene Expression Profile Genes Genetic 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 Persons 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 biobank clinical biomarkers clinical phenotype clinical predictors cohort design detection method diagnostic tool early detection biomarkers follow-up improved kidney biopsy medication nonadherence molecular marker molecular phenotype nano-string novel participant enrollment personalized diagnostics post-transplant predictive tools prognostic performance prognostic tool prognostic value prospective racial diversity repository surveillance study tool translational study validation studies vascular injury young adult

项目摘要

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.

抽象的几乎所有的儿科和年轻人（PYA）肾脏移植失败了10 - 15年，大大降低了生活终末期肾脏疾病（ESRD）的年轻人的期望。小儿肾脏移植接受者面对同种异体生存的独特障碍，包括不足而不是量身定制的诊断和预后工具适合儿童。因此，肾脏移植损伤定期逃脱检测，直到实质性损害已发生了加速同种异体失败的情况。监视活检允许早期检测到亚临床损伤事先对于移植功能障碍，我们已经表明，亚临床表型的存在仍然可以预测移植失败。需要改进的检测临床和亚临床肾移植终点的方法用ESRD来增加青年的寿命。最近的研究验证了基因表达的模式（例如，成人肾脏移植活检中的分子生物标志物）比常规的诊断精度更高组织学。分子生物标志物的类似进展尚未转化为儿童。这个目的建议是通过识别和验证关键结果的分子生物标志物来解决这种未满足的临床需求在年轻的肾脏移植接受者中。我们将整合临床特征，传统组织学和分子生物标志物创建强大的工具，以精确诊断和预测长期量身定制的长期结果用于PYA肾脏移植。我们的中心假设是肾脏活检中独特的基因表达模式将预测年轻移植接受者的临床和亚临床事件，并扩大传统的能力组织学。中央假设是由我们的初步数据提出的，我们在其中确定了分子 Wnt途径激活的生物标志物是肾移植损伤的新预测指标和随后的同种异体移植物失败，即使在具有令人放心的临床特征和正常传统组织学的个体中。我们将测试中央假设通过使用纳米弦平台询问存档的PYA肾脏移植活检追求三个特定目标。在AIM 1中，我们将确定PYA肾脏中临床终点的分子生物标志物移植。我们希望PYA特异性分子生物标志物将：a）具有出色的诊断临床终点的性能，b）有助于区分传统组织学的诊断不确定性病例， c）优于常规临床特征和组织学，以预测青年长期结局。目标 2，我们将辨别亚临床分子表型在PYA肾移植中的作用。我们希望找到亚临床终点的独特分子生物标志物，在预测方面将胜过常规的组织学未来的拒绝发作和同种异体移植失败。在AIM 3中，我们将验证临床和分子生物标志物为肾脏移植肾脏肾移植的前瞻性生物疗法队列中肾脏移植预后的预测因子。总体而言，该项目将在外部验证PYA特异性协变量调整的分子生物标志物为综合的临床预测工具，可以在未来对PYA肾脏移植的研究中使用。