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

项目总结 这项提案的首要目标是调查现有的尿液mRNA和 代谢产物谱可作为成人移植肾早期损伤的诊断和预后指标 在儿童肾移植受者中得到验证。 患有终末期肾病(ESRD)的儿童预期寿命至少比 无肾脏疾病的儿童。大多数患有终末期肾病的儿童在他们的一生中需要几个肾脏 移植可以延长生命周期和提高生活质量。每一次移植都会带来新的手术和免疫风险。 尽管在通过改进免疫抑制改善同种异体移植的短期结果方面取得了实质性进展 按照目前的治疗方案，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及早发现 临床表现出现前的同种异体移植物损伤。早期同种异体移植损伤是由急性细胞或抗体引起的- 介导的排斥反应或病毒的早期出现，主要是导致BK病毒肾病的BK病毒。 该项目的具体目标是：1)验证高度敏感和特异的成人尿液细胞mRNA 诊断和预测儿童受者急性细胞排斥反应(ACR)的标志，2)评估 尿代谢物谱诊断和预测儿童ACR的临床价值 联合检测成人移植肾尿mRNA和代谢物的敏感性和特异性 3)研究尿细胞中BKV-VP-1mRNA水平是否 BK病毒相关性肾病的诊断及尿细胞纤溶酶原激活物抑制物-1水平 信使核糖核酸和血肌酐，预测未来移植失败。这些目标将通过合作实现 美国和加拿大主要儿科肾脏移植项目的努力，得到两个项目的支持 威尔·康奈尔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 通过非侵入性免疫研究儿童肾移植受者早期移植肾损伤的特征 监视系统。通过这样做，我们将创造机会，更好地为临床决策提供信息，改善 实践范例，以促进积极的长期移植成果。

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.