VIRTUUS Children's Study: Validating Injury to the Renal Transplant Using Urinary Signatures in Children

项目摘要 这项提案的总体目标是调查现有的尿mRNA和 代谢物谱，这是诊断和预后的早期肾移植损伤的成人，可以是 在儿童肾移植受者中得到验证。 患有终末期肾病（ESRD）的儿童的预期寿命至少比正常儿童短20年。 没有肾病的孩子在他们的一生中，大多数患有ESRD的儿童将需要几个肾脏。 移植以延长寿命和生活质量。每次移植都会带来新的手术和免疫风险。 尽管通过改善免疫抑制剂在改善移植物短期预后方面取得了实质性进展， 虽然目前的治疗方案中，肾移植的半衰期仍然只有10-12年。因此，迫切需要延长 同种异体移植物存活率。推进长期结果的一个主要障碍是无法可靠地早期检测 在临床表现出现之前，移植物损伤。早期同种异体移植物损伤由急性细胞或抗体引起- 介导的排斥或病毒的早期出现，主要是导致BK病毒肾病的BK病毒。 本项目的具体目标是：1）验证高度敏感和特异的成人尿细胞mRNA 诊断和预测儿科受者的急性细胞排斥反应（ACR）的特征，2）评估 尿代谢物谱分析对儿童受者ACR诊断和预测的临床疗效， 验证成人移植肾尿mRNA和代谢产物联合检测的敏感性和特异性 3）研究尿细胞中的BKV-VP-1 mRNA水平是否与 BK病毒相关性肾病的诊断，以及纤溶酶原激活物抑制剂-1的尿细胞水平 mRNA和血清肌酐，预测未来的移植失败。这些目标将通过合作来实现。 在美国和加拿大的关键儿科肾移植计划的努力，由两个 威尔康奈尔大学医学院和斯坦福大学的杰出实验室。这项研究的结果将提高识别 并通过非侵入性免疫来表征儿童肾移植受者的早期移植物损伤 监视通过这样做，我们将创造机会，更好地为临床决策提供信息， 实践范例，以促进积极的长期移植结果。

PROJECT SUMMARY The overarching objectives of this proposal are to investigate whether existing urinary mRNA and metabolite profiles, which are diagnostic and prognostic for early renal allograft injury in adults, can be validated in pediatric kidney transplant recipients. Children with end-stage renal disease (ESRD) have a life expectancy at least 20 years shorter than children without renal disease. During their lifetime, most children with ESRD will require several kidney transplants to prolong duration and quality of life. Each transplant incurs new surgical and immunological risk. Despite substantial gains in improving short-term allograft outcomes through improved immunosuppressive regimens, the half-life of a kidney transplant is still only 10-12 years. Thus, there is a critical need to prolong allograft survival. A major hindrance to advancing long-term outcomes is the inability to reliably detect early allograft injury before clinical manifestations arise. Early allograft injury results from acute cellular or antibody- mediated rejection or early emergence of viruses, primarily BK virus which leads to BK virus nephropathy. This project’s specific aims are: 1) to validate highly sensitive and specific adult urinary cell mRNA signatures to diagnose and predict acute cellular rejection (ACR) in pediatric recipients, 2) to evaluate the clinical efficacy of urine metabolite profiling to diagnose and prognosticate ACR in pediatric recipients and to validate the sensitivity and specificity of a combined adult kidney allograft urinary mRNA and metabolite signature for ACR in pediatric recipients and 3) to investigate if BKV-VP-1 mRNA levels in urinary cells are diagnostic of BK virus associated nephropathy, and if urinary cell levels of Plasminogen Activator Inhibitor-1 mRNA and serum creatinine, predict future graft failure. These aims will be achieved through the collaborative effort of key pediatric kidney transplant programs across the United States and Canada, supported by two outstanding labs at Weill Cornell Medicine and Stanford. This study’s results will advance the ability to identify and characterize early allograft injury in pediatric kidney allograft recipients through non-invasive immune surveillance. By doing so, we will create opportunities to better inform clinical decision-making, improving practice paradigms to promote positive long-term graft outcomes.