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 Dennis G. Moledina 博士是耶鲁大学肾病学院委员会认证的肾脏病专家。 医学。拟议的研究建立在他过去评估人类表型的新型生物标志物的工作的基础上。 在完成耶鲁大学肾病学临床研究后，他又接受了三项研究。 他是耶鲁大学研究中心的博士生，接受过多年的临床转化研究方法培训。 医学项目，通过该项目为有抱负的医生科学家提供研究培训。 在此期间参加了临床研究方法、生物统计学和免疫生物学的教学课程。 获奖后，候选人将发展实现其长期目标所需的额外技能 研究免疫介导的肾脏疾病的学术转化医师科学家。 将通过实践、指导研究培训和高级教学课程来开发。 候选人拥有耶鲁大学强有力的制度承诺，包括确保过渡到教职职位。 将在世界知名的 Chirag R. Parikh 博士的指导下进行拟议的研究 此外，他还将获得具有急性肾损伤生物标志物研究专业知识的临床研究员。 来自耶鲁大学高素质导师委员会的指导。 项目：药物诱发的急性间质性肾炎（AIN）是由免疫介导的肾损伤引起的，这是 由常用药物引发的 AIN 患者可能会逃避临床关注，因为他们有一种微妙的症状。 临床表现轻微，且不存在肾功能亚急性丧失。 对于这种疾病的无创诊断测试，其诊断需要进行肾活检，这存在风险。 结果，许多 AIN 病例仍未得到诊断，从而导致永久性肾损伤和慢性肾损伤 该提案的总体目标是通过识别来提高非侵入性诊断 AIN 的能力。 生物标志物的开发和指标表明 AIN 是一种迟发性超敏反应。 由 1 型和 2 型 T 辅助细胞 (Th1/Th2) 介导，并预测特征性炎症介质 由这些细胞产生，特别是干扰素-γ、肿瘤坏死因子-α、白细胞介素 (IL)-2 (Th1) 和 IL-4， 与研究相比，AIN 参与者血浆和/或尿液中的 IL-5、IL-9 和 IL-13 (Th2) 含量更高 没有 AIN 的参与者 在目标 1 中，考生将识别区分 AIN 和其他原因的生物标志物。 在目标 2 中，候选人将制定 AIN 的两个诊断指标； 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变量 具有新型生物标志物的变量（来自目标 1）。这些指数将提供 AIN 诊断的概率，而无需使用。 在目标 3 中，候选人将验证目标 1 和 2 中的生物标志物和指数。 第三，外部的、基于活检的队列这些发现将通过及时诊断改善患者的治疗结果。 和干预，以及基于生物标志物指南的未来 AIN 干预临床试验的入组。

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。

• 发表时间: 2024-05
• 作者: Krishnan, Namrata;Moledina, Dennis G;Perazella, Mark A
• 通讯作者: Perazella, Mark A

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

术前肾脏生物标志物以及心脏手术后死亡、心血管和慢性肾脏疾病事件的风险：TRIBE-AKI 研究。

• 发表时间: 2022-12-25
• 作者: Vasquez;Moledina, Dennis G;Jia, Yaqi;McArthur, Eric;Mansour, Sherry G;Thiessen;Shlipak, Michael G;Koyner, Jay L;Garg, Amit X;Parikh, Chirag R;Coca, Steven G;TRIBE
• 通讯作者: TRIBE

Association of plasma-soluble ST2 and galectin-3 with cardiovascular events and mortality following cardiac surgery.

血浆可溶性 ST2 和半乳糖凝集素 3 与心脏手术后心血管事件和死亡率的关联。

• DOI: 10.1016/j.ahj.2019.11.014
• 发表时间: 2019-12-03
• 期刊: American heart journal
• 影响因子: 4.8
• 作者: Dipal M. Patel;H. Thiessen;Jeremiah R. Brown;E. McArthur;D. Moledina;Sherry G. Mansour;M. Shlipak;J. Koyner;P. Kavsak;R. Whitlock;A. Everett;D. Malenka;A. Garg;S. Coca;C. Parikh
• 通讯作者: C. Parikh