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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.

项目总结/文摘