Clinical and Molecular Biomarkers of Endpoints in Pediatric Renal Transplantation

摘要 几乎所有的儿童和年轻成人（PYA）肾移植在10-15年内失败，显着减少了生命 终末期肾病（ESRD）患者的预期寿命。儿童肾移植受者面临 同种异体移植物存活的明显障碍，包括诊断和预后工具不足和不适合 是为了带孩子因此，肾移植损伤经常逃避检测，直到实质性损害已经发生。 会加速同种异体移植失败。监测活检允许早期检测亚临床损伤， 移植功能障碍，但我们已经表明，亚临床表型的存在仍然是预测 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ESRD患者的寿命。最近的研究已经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高于常规 组织学分子生物标志物的类似进展尚未转化为儿童。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 年轻的肾移植受者。我们将整合临床特征、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制的长期结果创造强大的工具 进行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， 组织学中心假设是由我们的初步数据，其中我们确定了分子 WNT通路活化的生物标志物作为肾移植损伤和随后的同种异体移植物的新预测因子 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体中。我们将测试 中心假设，使用NanoString平台询问存档的PYA肾移植活检， 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）具有良好的诊断性， 临床终点的性能，B）帮助区分具有传统组织学诊断不确定性的病例， 和c）在预测青年的长期结果方面优于常规的临床特征和组织学。在aim中 2、明确亚临床分子表型在PYA肾移植中的作用。我们希望能找到 亚临床终点的独特分子生物标志物，在预测 将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肾移植前瞻性生物库队列中肾移植结局的预测因素。 总的来说，该项目将外部验证PYA特异性协变量调整的分子生物标志物， 这是一个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.