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: 10096754
• 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/10096754
• 关键词: Acute; Address; Adolescent; Adult; Age; Allografting; Antibodies; 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; 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.

抽象的 几乎所有儿童和青少年 (PYA) 肾移植都会在 10-15 年内失败，从而显着缩短寿命 患有终末期肾病（ESRD）的年轻人的预期。小儿肾移植受者面临的挑战 同种异体移植存活的明显障碍，包括诊断和预后工具不充分且不适合 对于儿童。因此，肾移植损伤经常无法被发现，直到出现严重损害为止。 发生加速同种异体移植失败。监测活检可以更早地发现亚临床损伤 移植功能障碍，但我们已经证明亚临床表型的存在仍然可以预测 移植失败。需要改进检测临床和亚临床肾移植终点的方法 延长患有 ESRD 的青少年的寿命。最近的研究验证了基因表达的模式（例如， 分子生物标志物）在成人肾移植活检中的诊断精度比传统方法更高 组织学。分子生物标志物的类似进展尚未应用于儿童。此举的目的 建议通过识别和验证关键结果的分子生物标志物来解决这一未满足的临床需求 在年轻的肾移植受者中。我们将整合临床特征、传统组织学和分子生物学 生物标记物可创建强大的工具，用于精确诊断和预测定制的长期结果 用于 PYA 肾移植。我们的中心假设是肾活检中独特的基因表达模式 将预测年轻移植受者的临床和亚临床事件，并扩展传统方法的能力 组织学。中心假设是由我们的初步数据制定的，其中我们确定了分子 WNT 通路激活的生物标志物作为肾移植损伤和随后同种异体移植物的新预测因子 失败，即使是具有令人放心的临床特征和正常传统组织学的个体。我们将测试 使用 NanoString 平台询问存档的 PYA 肾移植活检的中心假设 追求三个具体目标。在目标 1 中，我们将确定 PYA 肾脏临床终点的分子生物标志物 移植。我们期望 PYA 特异性分子生物标志物将： a) 具有出色的诊断能力 临床终点的表现，b) 帮助区分传统组织学诊断不确定的病例， c) 在预测青少年长期结果方面优于传统的临床特征和组织学。瞄准目标 2、我们将辨别亚临床分子表型在 PYA 肾移植中的作用。我们期望找到 亚临床终点的独特分子生物标志物在预测方面将优于传统组织学 未来的排斥反应和同种异体移植失败。在目标 3 中，我们将验证临床和分子生物标志物： PYA 肾移植前瞻性生物样本库队列中肾移植结果的预测因子。 总的来说，该项目将从外部验证 PYA 特异性协变量调整分子生物标志物： 全面的临床预测工具，可用于未来 PYA 肾移植的研究。