Identification of Non-Invasive Biomarkers and Indices for Diagnosis of Drug-Induced Acute Interstitial Nephritis

药源性急性间质性肾炎非侵入性生物标志物和诊断指标的鉴定

• 批准号: 10226221
• 负责人: Dennis G. Moledina
• 金额: $ 18.4万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-11 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226221
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Animal Model; Antibiotics; Area; Attention; Award; Biological Markers; Biometry; Biopsy; Blood; Cells; Characteristics; Chronic Kidney Failure; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Data; Delayed Hypersensitivity; Diagnosis; Diagnostic; Diagnostic tests; Disease; Doctor of Philosophy; Drug usage; Enrollment; Faculty; Fellowship; Fibrosis; Future; Goals; Helper-Inducer T-Lymphocyte; Hemorrhage; Histologic; Human; Image; Immune; Immunobiology; Immunotherapeutic agent; Inflammation; Inflammation Mediators; Injury; Injury to Kidney; Interferon Type II; Interferons; Interleukin-13; Interleukin-2; Interleukin-4; Interleukin-5; Interleukin-9; Interstitial Nephritis; Intervention; Intervention Trial; Kidney; Kidney Diseases; Laboratories; Leukocytes; Lung; Lymphocytic Infiltrate; Mediating; Mediator of activation protein; Medicine; Mentors; Mentorship; Methods; Nephrology; Organ; Participant; Patient Care; Patient-Focused Outcomes; Patients; Performance; Pharmaceutical Preparations; Phenotype; Physicians; Plasma; Positioning Attribute; Probability; Procedures; Proton Pump Inhibitors; Reaction; Renal function; Research; Research Methodology; Research Training; Risk; Scientist; Sensitivity and Specificity; Severities; Signs and Symptoms; Skin; Symptoms; TNF gene; Testing; Th1 Cells; Th2 Cells; Therapeutic immunosuppression; Time; Training; Translational Research; Tubular formation; United States National Institutes of Health; Urine; Validation; Woman; Work; base; biobank; cancer immunotherapy; clinical care; clinical decision support; clinical decision-making; clinical diagnostics; cohort; diagnostic biomarker; disease diagnosis; eosinophil; high risk population; improved; indexing; interstitial; kidney biopsy; medical schools; noninvasive diagnosis; novel; novel marker; precision medicine; programs; renal damage; skills; translational physician

Candidate: The candidate, Dr. Dennis G. Moledina, is a board-certified nephrologist at the Yale School of Medicine. The proposed research builds on his past work on evaluating novel biomarkers to phenotype human acute kidney injury. After completing a clinical fellowship in nephrology at Yale, he received three additional years of training in methods of clinical translational research. He is a PhD candidate with Yale’s Investigative Medicine Program, which provides research training to aspiring physician-scientists. Through this program, he attended didactic coursework on clinical research methodology, biostatistics, and immunobiology. During this award, the candidate will develop additional skills that are required to achieve his long-term goal of becoming an academic translational physician-scientist studying immune-mediated kidney diseases. These skill areas will be developed through hands-on, mentored research training and advanced didactic coursework. The candidate has strong institutional commitment from Yale including assured transition to a faculty position. He will conduct the proposed research under the mentorship of Dr. Chirag R. Parikh, who is a world-renowned clinical investigator with expertise in biomarker research in acute kidney injury. Additional, he will receive guidance from a highly-qualified mentorship committee at Yale. Project: Drug-induced acute interstitial nephritis (AIN) results from immune-mediated kidney injury, which is triggered by commonly used drugs. Patients with AIN may escape clinical attention because they have a subtle clinical presentation with minimal symptoms and subacute loss of renal function. Moreover, since there is no noninvasive diagnostic test for this disease, its diagnosis requires a kidney biopsy, which carries risks. As a result, many cases of AIN remain undiagnosed, which leads to permanent kidney damage and chronic kidney disease. The overall goal of this proposal is to improve the ability to non-invasively diagnose AIN by identifying biomarkers and developing indices. The candidate hypothesizes that AIN is a delayed hypersensitivity reaction mediated by type 1 and 2 T-helper cells (Th1/Th2), and predicts that the characteristic inflammatory mediators produced by these cells, specifically interferon-γ, tumor necrosis factor-α, and interleukin(IL)-2 (Th1), and IL-4, IL-5, IL-9, and IL-13 (Th2), will be higher in the plasma and/or urine of AIN participants as compared with study participants without AIN. In aim 1, the candidate will identify biomarkers that distinguish AIN from other causes of acute loss of renal function. In aim 2, the candidate will develop two diagnostic indices for AIN; the first will use currently available clinical and laboratory variables and the second will combine currently available variables with novel biomarkers (from aim 1). These indices will provide probability of AIN diagnosis without requiring a kidney biopsy. In aim 3, the candidate will validate the biomarkers and indices from aims 1 and 2 in three, external, biopsy-based cohorts. These findings will improve patient outcomes through timely diagnosis and intervention, and guide biomarker-based enrollment in future clinical trials of intervention(s) for AIN.

候选人：丹尼斯·g·莫莱迪纳博士是耶鲁大学医学院的认证肾病专家