Clinical and Molecular Biomarkers of Endpoints in Pediatric Renal Transplantation

摘要 几乎所有的儿童和青壮年(PYA)肾移植都会在10-15年内失败，从而显著缩短生命。 终末期肾病(ESRD)年轻人的预期。儿童肾移植受者面对 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和没有量身定做 为儿童准备的。因此，肾移植损伤通常不会被发现，直到出现实质性损害。 会加速同种异体移植物的失败。监测活组织检查可以更早地发现亚临床损伤 移植功能障碍，但我们已经表明，亚临床表型的存在仍然可以预测 移植失败。需要改进检测临床和亚临床肾移植终点的方法 目的：延长ESRD青年的寿命。最近的研究已经证实了基因表达的模式(例如， 分子生物标志物)在成人肾移植活检中的诊断准确性高于常规 组织学。分子生物标记物方面的类似进展尚未转化为儿童。这样做的目的是 建议是通过识别和验证关键结果分子生物标记物来解决这一未得到满足的临床需求 在年轻的肾移植受者身上。我们将结合临床特征、传统组织学和分子生物学 生物标志物，为精确诊断和预测量身定做的长期结果创造强大的工具 用于PYA肾移植。我们的中心假设是肾脏活检组织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，并扩展传统的 组织学。中心假设是通过我们的初步数据提出的，在这些数据中，我们发现了分子 WNT途径激活的生物标志物作为肾移植损伤和随后移植肾的新预测指标 失败，即使在具有令人放心的临床特征和正常的传统组织学的个人。我们将测试 中心假设通过使用纳米串平台询问存档的PYA肾移植活检组织 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记物 移植。我们期望PYA特异的分子生物标志物将：a)具有很好的诊断能力 临床终点的表现，b)通过传统组织学帮助区分具有诊断不确定性的病例， 以及c)优于传统的临床特征和组织学来预测青年的长期结果。在AIM 2、了解亚临床分子表型在PYA肾移植中的作用。我们希望能找到 独特的亚临床终点分子生物标记物，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记物为 在PYA肾移植的前瞻性生物信息库队列中预测肾移植结果的因素。 总的来说，该项目将外部验证PYA特定的协变量调整的分子生物标记物 全面的临床预测工具，可用于未来的PYA肾移植研究。

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.