Kidney Tubule Cell Function and Future Risk of Acute Kidney Injury

这是亚历山大布伦医学博士在Dena的指导下第二次提交CDA 2申请 里夫金说，他是圣地亚哥退伍军人医疗中心的研究员。这份提案将使布伦博士成为一名 独立的临床研究者，并将严格评估肾小管功能障碍的标志物是如何 与急性肾损伤的发生、进展和恢复相关。 候选人：Bullen博士的职业目标是：1）提高对肾小管间关系的理解， 功能障碍和阿基; 2）精通新的生物标志物方法学并将其翻译给患者， 导向研究; 3）获得生物标志物分析的先进统计方法的专业知识; 4） 建立独立的研究计划。为了实现这些目标，他组建了一个多学科的 导师团队由主要导师Dena Rifkin组成，Dena Rifkin是一位获得优异奖的领先VA研究员 资金和在肾脏疾病研究设计方面的丰富经验，以及以下额外的共同导师 和顾问：Joachim IX，肾脏疾病管状方面的专家， 临床试验的实施以及对收缩压干预试验（SPRINT）的见解 用于目标1和REGARDS用于目标2; Edward Siew，医学博士，临床研究专家， 阿基中的生物标志物，具有验证急性肺损伤诊断生物标志物（VALID）的专业知识， Aim 3和Ronit Katz博士，一位在肾脏研究方面具有专业经验的统计学家， 与Bullen、Rifkin和IX博士的合作，以及利用SPRINT和REGARDS数据的经验。 研究：阿基在CKD的非线性进展中发挥着重要作用。当患者 是健康的，倾向于未来的阿基风险，可能会提供的见解，不仅阿基的风险，而且CKD。 博士Bullen的总体假设是，肾小管细胞功能障碍的测量不仅可以提供临床意义， 未来阿基风险评估的实用性，但也可能为导致阿基的机制提供重要见解 严重，并恢复。在目标1中，他将扩展在试点中评估的小管功能障碍的标志物， 数据并检查标记物的纵向变化，以确定肾小管功能恶化的轨迹 预测阿基高于或超过单个基线值。他之前在SPRINT的工作评估了肾小管功能， 稳定的门诊患者和继发于脱水/低血压的后续阿基的风险。在目标2中，他将扩大 他的研究调查了阿基的其他原因，评估了肾小管细胞功能障碍与AKI的关系， 由于感染，退伍军人中AKI的常见原因，导致AKI的健康时间和未来风险。最后，在Aim 3，他将在VALID队列入住ICU时检查肾小管功能，并确定 功能标志物是否可预测阿基的短期风险，并确定肾小管功能障碍标志物 阿基发作期间的变化。

This is a second submission of a CDA2 application by Alexander Bullen MD, under the mentorship of Dena Rifkin, a researcher at VA Medical Center in San Diego. This proposal will establish Dr. Bullen as an independent clinical investigator and will rigorously evaluate how markers of tubular dysfunction are associated with development, progression, and recovery of acute kidney injury. Candidate: Dr. Bullen’s career goals are: 1) to improve understanding on associations between tubular dysfunction and AKI; 2) to become proficient at novel biomarkers methodology and translation to patient- oriented research; 3) to gain expertise in advanced statistical methods for biomarker analyses; and 4) to develop an independent research program. To accomplish these goals, he has assembled a multidisciplinary mentorship team comprised of a primary mentor, Dena Rifkin, a leading VA researcher with Merit Award funding and extensive experience in research design in kidney disease and the following additional co-mentors and advisors: Joachim Ix, an established expert on tubular aspect of kidney disease in design and implementation of clinical trials as well as insight to the Systolic Blood Pressure Intervention Trial (SPRINT) utilized for Aim 1 and REGARDS utilized for Aim 2; Edward Siew, MD, an expert in clinical research and biomarkers in AKI with expertise in the Validating Acute Lung Injury Biomarkers for Diagnosis (VALID) used for Aim 3, and Ronit Katz PhD, a statistician with expertise experience in kidney research, collaborative history with Drs. Bullen, Rifkin, and Ix, and experience in utilizing the SPRINT and REGARDS data. Research: AKI plays an important role in the non-linear progression of CKD. Factors at the time when patients are healthy that predispose to future AKI risk are likely to give insights not only to risk of AKI but also to CKD. Dr. Bullen’s overall hypothesis is that measurement of tubular cell dysfunction may not only provide clinical utility for future AKI risk assessment but may also provide important insights to mechanisms leading to AKI acutely, and to its recovery. In Aim 1, he will expand upon the markers of tubule dysfunction evaluated in pilot data and examine longitudinal changes in markers to determine if trajectories of worsening tubule function predict AKI above and beyond a single baseline value. His prior work in SPRINT evaluates tubule function in stable outpatients and risk for subsequent AKI secondary to dehydration/hypotension. In Aim 2, he will expand his research to investigate other causes of AKI, evaluating the association between tubule cell dysfunction at times of health and future risk of AKI due to infection, a common cause of AKI among Veterans. Finally, in Aim 3, he will examine tubule function at the time of ICU admission among the VALID cohort and determine whether the function markers predict short-term risk of AKI and determine how tubule dysfunction markers change during episodes of AKI.