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：
10651862
负责人：
JOSH LEVITSKY
金额：
$ 182.71万
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/10651862
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 Hypoxia Immune Immune response Immunosuppression Injury to Kidney Intervention Kidney Kidney Transplantation 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 Testing Therapeutic Therapeutic immunosuppression Time Transplant Recipients Transplantation Transplanted Liver Complication Weaning Withdrawal Work biobank biomarker performance biomarker signature biomarker validation 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 response risk stratification sample collection standard of care technology platform 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.

项目摘要/摘要从诊断的角度和能力足够早早预测疾病状态以告知治疗并改变临床结果。在过去的几年中，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接受者。从我们的CTOT-14研究数据中，我们开发了关键的生物标志物，可以尽早检测（拒绝）和过度（慢性肾脏疾病）免疫抑制的迹象，特别是使用标准钙调蛋白抑制剂疗法。但是，随着分子诊断的准确性，随着技术的改善平台不断发展，关于它们在肝脏管理中的价值的两个重要问题浮出水面移植接受者。首先，生物标志物可以告知患者管理并优化个性化的能力免疫抑制治疗？其次，我们可以表征免疫激活和肾脏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标？我们相信这些问题构成生物标志物研究的下一个领域，因此我们已经提出了此建议，以测试一组与这些问题直接相关的假设。首先，在一项前瞻性多中心临床试验中移植接受者，我们将挑战“护理标准”，并检验串行血液生物标志物的假设分析可以识别肝移植后有肾脏损伤风险的患者，也指导去除肾毒性抑制剂抑制剂疗法安全而不会不利地增加急性排斥。实现这一目标目的，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检测早期排斥和肾脏损伤的迹象，以增强主动，安全戒断钙调神经磷酸酶抑制剂偏爱非氯毒性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，还将分层的患者冒险进入需要或不需要这样的患者干预措施。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保护拒绝的东西。我们将通过执行干预期间，大量的血液免疫细胞，抗体，基因组和蛋白质组学分析最好确定导致我们成果的途径。此外，我们将同时执行新颖的肾脏成像生物标志物询问是什么导致肾脏损伤与我们独特的队列中的保护。在一起，临床试验和随附的机械研究将使我们能够跨越生物标志物研究的下一个领域移植，即使用生物标志物监测免疫反应和药物状态的能力毒性为治疗决定提供信息。我们的临床数据和生物银行样本将为社区并促进了新一代的分子诊断，可以转化为临床实践。