Utility of Biomarkers of Rejection and Kidney Injury in Tailoring Liver Transplant Immunosuppression

排斥和肾损伤生物标志物在调整肝移植免疫抑制中的效用

基本信息

批准号：
10482420
负责人：
JOSH LEVITSKY
金额：
$ 179.15万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-06 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10482420
关键词：
Acute Antibodies Benefits and Risks Biological Markers Blood Calcineurin inhibitor Cells Cellular Assay Chronic Kidney Failure Clinical Clinical Data Clinical Trials Communities Complication Data Decision Making Deterioration Diagnostic Dialysis procedure Disease Drug toxicity Early Diagnosis Equilibrium Excision FRAP1 gene Fibrosis Future Gene Expression Generations Genomics Glomerular Filtration Rate Graft Survival Immune Immune response Immunosuppression Injury to Kidney Intervention Kidney Kidney Transplantation Lead Liver Magnetic Resonance Imaging Modeling Monitor Multi-Institutional Clinical Trial Multicenter Trials Outcome Pathway interactions Patient Selection Patients Pharmaceutical Preparations Phenotype Physiological Plasma Proteins Property Proteomics Randomized Regimen Regulatory T-Lymphocyte Renal function Research Resources Risk Role SDZ RAD Sampling Science Surface T-Lymphocyte Tacrolimus Technology Testing Therapeutic Therapeutic immunosuppression Time Transplant Recipients Transplantation Transplanted Liver Complication Weaning Withdrawal Work biomarker performance biomarker signature clinical practice cohort effector T cell exhaustion frontier high risk imaging biomarker immune activation improved inhibitor inhibitor therapy insight kidney imaging kidney preservation liver transplantation loss of function mTOR Inhibitor molecular diagnostics molecular marker nephrotoxicity new therapeutic target novel patient stratification pre-clinical predictive marker preservation prevent primary endpoint primary outcome prospective proteogenomics renal ischemia/hypoxia response risk stratification sample collection standard of care treatment strategy validation studies

项目摘要

Project Summary/Abstract The advent of molecular biomarkers holds great promise, both from a diagnostic perspective as well as the ability to predict a disease state early enough to inform therapy and change clinical outcomes. In the last several years, studies have suggested a role for biomarker profiling in the management of immunosuppression in liver transplant recipients. From our CTOT-14 study data, we have developed key biomarkers that can detect early signs of under- (rejection) and over- (chronic kidney disease) immunosuppression, particularly with use of standard calcineurin-inhibitor therapy. But as the accuracy of molecular diagnostics improves, and as technology platforms evolve, two important questions have surfaced regarding their value in the management of liver transplant recipients. First, can biomarkers inform patient management and optimize the ability to personalize immunosuppressive therapy? Second, can we characterize key pathways of immune activation and kidney injury to further optimize the use of biomarkers and identify new therapeutic targets? We believe that these questions comprise the next frontier in biomarker research, and we have therefore formulated this proposal to test a set of hypotheses that relate directly to these questions. First, in a prospective multi-center clinical trial of liver transplant recipients, we will challenge the `standard of care' and test the hypothesis that serial blood biomarker profiling can identify patients at risk of kidney injury after liver transplantation and also guide the removal of nephrotoxic calcineurin-inhibitor therapy safely without adversely increasing acute rejection. To achieve this objective, we will leverage these immune and kidney biomarkers developed in our CTOT-14 validation study to detect early signs of rejection and kidney injury to enhance proactive, safe withdrawal of calcineurin-inhibitors in favor of non-nephrotoxic mTOR-inhibitors. This biomarker-guided interventional approach will be tested against current standard management and also risk-stratify patients into those needing or not needing such interventions. Second, we will leverage the clinical trial sample collections to gain deeper understanding of what leads to rejection or alternatively what is protective of rejection. We will accomplish this by performing an extensive battery of blood immune cell, antibody, genomic and proteomic profiling during the interventions to best identify the pathways leading to our outcomes. In addition, we will simultaneously perform novel kidney imaging biomarkers to ask what leads to kidney injury vs. protection in our unique cohorts. Together, the clinical trial and accompanying mechanistic studies will allow us to cross the next frontier in biomarker research in transplantation, namely the ability to use biomarkers to monitor the state of immune responsiveness and drug toxicity to inform therapeutic decisions. Our clinical data and bio-banked samples will create a new resource for the community and facilitate a new generation of molecular diagnostics translatable into clinical practice.

项目概要/摘要分子生物标志物的出现无论是从诊断角度还是从能力上都带来了巨大的希望。尽早预测疾病状态，为治疗提供信息并改变临床结果。在过去的几年里，研究表明生物标志物分析在肝脏免疫抑制管理中的作用移植受者。根据我们的 CTOT-14 研究数据，我们开发了可以早期检测的关键生物标志物免疫抑制不足（排斥）和过度（慢性肾病）的迹象，特别是使用标准钙调神经磷酸酶抑制剂治疗。但随着分子诊断准确性的提高以及技术的进步随着平台的发展，关于其在肝脏管理中的价值的两个重要问题已经浮出水面移植受者。首先，生物标志物能否为患者管理提供信息并优化个性化能力免疫抑制治疗？其次，我们能否描述免疫激活和肾损伤的关键途径进一步优化生物标志物的使用并确定新的治疗靶点？我们相信这些问题构成生物标志物研究的下一个前沿，因此我们制定了此提案来测试一组与这些问题直接相关的假设。首先，在肝脏的前瞻性多中心临床试验中对于移植受者来说，我们将挑战“护理标准”并测试一系列血液生物标志物的假设分析可以识别肝移植后有肾损伤风险的患者，并指导切除肾毒性钙调神经磷酸酶抑制剂治疗安全，不会增加急性排斥反应。为了实现这一目标目标，我们将利用 CTOT-14 验证研究中开发的这些免疫和肾脏生物标志物来检测排斥和肾损伤的早期迹象，以增强钙调神经磷酸酶抑制剂的主动、安全撤药作用有利于非肾毒性 mTOR 抑制剂。这种生物标志物引导的介入方法将进行测试当前的标准管理，并将患者风险分层为需要或不需要的患者干预措施。其次，我们将利用临床试验样本收集来更深入地了解什么导致拒绝，或者导致拒绝的保护措施。我们将通过执行在干预期间进行广泛的血液免疫细胞、抗体、基因组和蛋白质组分析最好地确定导致我们结果的途径。此外，我们还将同步进行新型肾对生物标志物进行成像，以了解在我们独特的队列中是什么导致了肾损伤与保护。一起，临床试验和伴随的机制研究将使我们能够跨越生物标志物研究的下一个前沿移植，即使用生物标志物监测免疫反应和药物状态的能力毒性以指导治疗决策。我们的临床数据和生物库样本将为社区并促进新一代分子诊断转化为临床实践。