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

候选人：候选人丹尼斯·G·莫莱迪纳博士是耶鲁大学医学院的一名经过董事会认证的肾病学家 医学。这项拟议的研究建立在他过去评估人类表型的新生物标记物的工作基础上 急性肾损伤。在耶鲁大学完成了肾病学的临床研究后，他获得了另外三个 多年的临床转化研究方法培训。他是耶鲁大学《调查》的博士生 医学计划，为有抱负的内科科学家提供研究培训。通过这个节目，他 参加临床研究方法学、生物统计学和免疫生物学的教学课程。在此期间 获奖后，候选人将发展其他技能，这些技能是实现他成为 一位研究免疫介导的肾脏疾病的学术翻译内科医生兼科学家。这些技能领域 将通过实际操作、有指导的研究培训和高级教学课程进行开发。这个 这位候选人有耶鲁大学坚定的机构承诺，包括确保过渡到教员职位。他 将在希拉格·R·帕里克博士的指导下进行拟议的研究，希拉格·R·帕里克博士是世界著名的 在急性肾损伤的生物标志物研究方面具有专业知识的临床研究员。另外，他将收到 来自耶鲁一个非常合格的导师委员会的指导。 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，这是 是由常用药物引发的。AIN患者可能会逃脱临床注意，因为他们有一种微妙的 临床表现为轻微症状和亚急性肾功能丧失。此外，由于没有 对于这种疾病的非侵入性诊断测试，其诊断需要进行肾脏活检，这是有风险的。作为一名 结果许多AIN患者仍未得到诊断，导致永久性肾损害和慢性肾脏损害。 疾病。这项建议的总体目标是通过识别 生物标志物和发育指数。候选人假设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、白介素2(IL)-2和IL-4， 与研究相比，AIN参与者的血浆和/或尿液中的IL-5、IL-9和IL-13(Th2)水平将更高 参与者没有AIN。在目标1中，候选人将确定区分AIN和其他原因的生物标记物 急性肾功能丧失。在目标2中，候选人将为AIN制定两个诊断指数；第一个将 使用当前可用的临床和实验室变量，第二个变量将结合当前可用的变量 具有新生物标志物的变量(来自目标1)。这些指标将提供AIN诊断的概率而不是 需要做肾脏活检。在目标3中，候选人将验证目标1和目标2中的生物标志物和指数 三是外部的、以活检为基础的队列。这些发现将通过及时的诊断改善患者的预后。 和干预，并指导AIN未来干预临床试验中基于生物标记物的登记(S)。

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.