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: 10457945
• 负责人: Dennis G. Moledina
• 金额: $ 18.31万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457945
• 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：候选人，丹尼斯·G·莫莱迪纳（Dennis G. 药品。拟议的研究是基于他过去的评估新型生物标志物对人类表型的工作的基础 急性肾脏受伤。在耶鲁大学完成了肾脏科学临床研究金之后，他又获得了三个 临床转化研究方法的多年培训。他是耶鲁大学调查的博士候选人 医学计划，为有抱负的身体科学家提供研究培训。通过这个程序，他 参加了有关临床研究方法，生物统计学和免疫生物学的教学课程。在此期间 奖项，候选人将发展其他技能，以实现他的长期目标 研究免疫介导的肾脏疾病的学术翻译身体科学家。这些技能领域 将通过动手，讨论研究培训和高级教学课程开发。 候选人从耶鲁大学拥有强大的机构承诺，包括假定过渡到教师职位。他 将根据Chirag R. Parikh博士的心态进行拟议的研究，他是一个世界知名的 具有急性肾脏损伤生物标志物研究专业知识的临床研究者。另外，他会收到 耶鲁大学高度合格的精通委员会的指导。 项目：药物诱导的急性间质性肾炎（AIN）是由免疫介导的肾损伤引起的，即 由常用药物触发。 AIN患者可能会引起临床注意力，因为他们有微妙 临床表现，具有最小的症状和亚急性的肾功能丧失。而且，由于没有 该疾病的无创诊断测试，其诊断需要进行肾脏活检，这会带来风险。作为 结果，许多AIN病例仍未诊断，从而导致永久性肾脏损伤和慢性肾脏 疾病。该提案的总体目标是通过识别非侵入性诊断AIN的能力 生物标志物和开发指数。候选人假设AIN是延迟的超敏反应 由1型和2型T助焊剂细胞（TH1/TH2）介导，并预测特征性炎症介质 由这些细胞，特异性干扰素-γ，肿瘤坏死因子-α和白介素（IL）-2（Th1）和IL-4，，， 与研究相比 没有AIN的参与者。在AIM 1中，候选人将确定将AIN与其他原因区分开的生物标志物 肾功能的急性丧失。在AIM 2中，候选人将为AIN开发两个诊断指数。第一个意愿 使用当前可用的临床和实验室变量，第二个将结合当前可用的 具有新型生物标志物的变量（来自AIM 1）。这些指数将提供AIN诊断的可能性 需要肾脏活检。在AIM 3中，候选人将验证AIM 1和2的生物标志物和指数 三，基于活检的同类。这些发现将通过及时的诊断来改善患者的结果 和干预措施，并指导基于生物标志物的AIN干预临床试验的注册。

项目成果

Toxic Nephropathies of the Tubulointerstitium: Core Curriculum 2024.

肾小管间质中毒性肾病：2024 年核心课程。

• DOI: 10.1053/j.ajkd.2023.09.017
• 发表时间: 2024
• 期刊: American journal of kidney diseases : the official journal of the National Kidney Foundation
• 作者: Krishnan,Namrata;Moledina,DennisG;Perazella,MarkA
• 通讯作者: Perazella,MarkA

Pre-operative kidney biomarkers and risks for death, cardiovascular and chronic kidney disease events after cardiac surgery: the TRIBE-AKI study.

• DOI: 10.1186/s13019-022-02066-4
• 发表时间: 2022-12-25
• 期刊: JOURNAL OF CARDIOTHORACIC SURGERY
• 影响因子: 1.6
• 作者: Vasquez-Rios, George;Moledina, Dennis G.;Jia, Yaqi;McArthur, Eric;Mansour, Sherry G.;Thiessen-Philbrook, Heather;Shlipak, Michael G.;Koyner, Jay L.;Garg, Amit X.;Parikh, Chirag R.;Coca, Steven G.
• 通讯作者: Coca, Steven G.