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

VIRTUUS 儿童研究：利用儿童尿液特征验证肾移植损伤

基本信息

批准号：
9290052
负责人：
Sandra Amaral
金额：
$ 80.07万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-10 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9290052
关键词：
Acute Adolescent Adult Allografting Antibodies Area Analyses Area Under Curve BK Virus Biological Markers Biopsy CXCL10 gene Canada Caring Cells Child Childhood Childhood Injury Clinical Clinical Trials Cohort Studies Core Biopsy Creatinine Development Diagnosis Diagnostic End stage renal failure Enrollment Failure Future Gene Expression Genes Gold Half-Life Health Hemorrhage Hospitalization Immune response Immunity Immunologic Surveillance Immunologics Immunosuppressive Agents Incidence Individual Injury Kidney Diseases Kidney Transplantation Life Expectancy Measures Mediating Medicine Messenger RNA Modeling Operative Surgical Procedures Organ Transplantation Outcome Plasminogen Activator Inhibitor 1 Prognostic Marker Prospective Studies Public Health Quality of life RNA Receiver Operating Characteristics Regimen Research Research Design Ribosomal RNA Risk Sampling Sampling Errors Sedation procedure Sensitivity and Specificity Serum Specificity Time Transplant Recipients Transplantation Tubular formation United States United States National Institutes of Health Urine Virus Virus Diseases base clinical decision-making clinical efficacy clinical practice diagnosis standard diagnostic biomarker genetic signature graft failure improved individualized medicine kidney allograft member metabolomics minimally invasive noninvasive diagnosis predictive modeling prognostic programs urinary xanthosine

Acute Adolescent Adult Allografting Antibodies Area Analyses Area Under Curve BK Virus Biological Markers Biopsy CXCL10 gene Canada Caring Cells Child Childhood Childhood Injury Clinical Clinical Trials Cohort Studies Core Biopsy Creatinine Development Diagnosis Diagnostic End stage renal failure Enrollment Failure Future Gene Expression Genes Gold Half-Life Health Hemorrhage Hospitalization Immune response Immunity Immunologic Surveillance Immunologics Immunosuppressive Agents Incidence Individual Injury Kidney Diseases Kidney Transplantation Life Expectancy Measures Mediating Medicine Messenger RNA Modeling Operative Surgical Procedures Organ Transplantation Outcome Plasminogen Activator Inhibitor 1 Prognostic Marker Prospective Studies Public Health Quality of life RNA Receiver Operating Characteristics Regimen Research Research Design Ribosomal RNA Risk Sampling Sampling Errors Sedation procedure Sensitivity and Specificity Serum Specificity Time Transplant Recipients Transplantation Tubular formation United States United States National Institutes of Health Urine Virus Virus Diseases base clinical decision-making clinical efficacy clinical practice diagnosis standard diagnostic biomarker genetic signature graft failure improved individualized medicine kidney allograft member metabolomics minimally invasive noninvasive diagnosis predictive modeling prognostic programs urinary xanthosine

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项目摘要

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.

项目摘要该提案的总体目标是调查现有的尿mRNA和代谢物剖面是成年人早期肾脏同种异体损伤的诊断和预后，可以是在小儿肾脏移植受者中得到验证。末期肾病（ESRD）的儿童的预期寿命至少比没有肾脏疾病的儿童。在他们的一生中，大多数ESRD的孩子都需要几个Kidsney 移植以延长持续时间和质量。每种移植都会造成新的外科手术和免疫学风险。尽管通过改进的免疫抑制作用改善了短期同种异体后果的增长巨大方案是肾脏移植的半衰期仍然只有10 - 12年。那是迫切需要延长的同种异体移植生存。推进长期结果的主要障碍是无法可靠地检测到临床表现之前出现同种异体移植损伤。急性细胞或抗体 - 早期同种异体损伤 - 介导的排斥反应或早期出现病毒，原发性BK病毒，导致BK病毒肾病。该项目的具体目的是：1）验证高度敏感和特定的成年尿细胞mRNA 诊断和预测小儿接受者急性细胞排斥（ACR）的签名，2）评估尿液代谢物分析的临床效率，以诊断和预后ACR在儿科接受者中和验证组合成人肾脏同类尿mRNA和代谢物的敏感性和特异性儿科接受者ACR的签名和3）研究尿细胞中BKV-VP-1 mRNA水平是否是 BK病毒相关肾病的诊断，以及纤溶酶原激活剂抑制剂1的尿细胞水平 mRNA和血清肌酐预测未来的移植失败。这些目标将通过协作实现在美国和加拿大的主要小儿肾脏移植计划的努力，由两个 Weill Cornell Medicine和Stanford的杰出实验室。这项研究的结果将提高识别能力并通过非侵入性免疫来表征小儿肾脏同种异体移植者的早期同种异体损伤监视。通过这样做，我们将创造机会更好地为临床决策提供信息，并改善实践范式来促进积极的长期移植结果。