Application of Novel Biomarkers of Renal Health in Cirrhosis Patients to Stratify Risk of Acute Kidney Injury Occurrence and Reversibility

项目摘要/摘要 在美国，肝硬变是成年人发病率和死亡率的主要原因。急性肾损伤 (AKI)是一种常见的、昂贵的、致命的肝硬变并发症。肝硬变患者急性肾功能衰竭的最强预测因子 无论病因如何，患者都是慢性肾脏疾病(CKD)，以估计的肾小球为标准。 滤过率(EGFR)。鉴于AKI和CKD在这一人群中的发病率都在上升，因此 开发临床工具的迫切需求，以便在AKI发展之前识别有AKI风险的肝硬变患者。 这项提案的三个研究目的就是解决这一需求。利用&gt；1000的持续队列 失代偿期肝硬变患者使用2500种生物检验库，这些目标将：(1)建立 肾脏健康生物标记物与AKI的独立相关性及与新发现的鉴别能力的比较 肾健康生物标志物的血肌酐(Scr)预测AKI(目标1)；开发和内部验证 确定最易患AKI的肝硬变患者的临床风险工具(目标2)；探索 肾脏健康生物标记物对AKI可逆性的纵向变化(目标3)。 我是加州大学旧金山分校专门从事肝移植的肝病专家。通过一个 由美国肝病研究协会提供的试点奖项，我们已经产生了 此应用程序所需的初步数据。这些数据，再加上强大的肝病基础和 肾脏学研究(临床研究高级研究硕士，10种出版物)，让我做好了准备 支持这项提议。然而，在我的培训中有几个空白，这是NIDDK K23职业发展 该奖项将涉及(例如，队列发展、高级统计技术)。在…的直接监督下 一个由肾病学(徐，刘)、肝病(LAI)和生物统计学(McCulloch)领导的多学科团队，I 我将执行详细的职业发展计划，以加速我实现以下4个职业目标的道路 建议：(1)建立核心肾病学原理的基础；(2)获得分析技能以验证 生物标志物的使用；(3)学习风险预测的新方法，包括机器学习技术；(4) 扩大队列，应用纵向数据分析方法。作为我五年计划的一部分，我将积极 参与肾病学、生物统计学和跨学科的课程作业和结构化教程 发展和领导力课程。此外，我还将把自己融入到肾脏病的研究中 社区和建立一个肾脏研究人员网络，以便目前和未来的合作。 相关性：确定一个指标，以确定哪些肝硬变患者风险最高，哪些可能性最小 逆转AKI具有重要的临床意义-它将允许实施以下干预措施 防止这一人群死亡的一个主要驱动因素的发生并阻止其发展。

PROJECT SUMMARY/ABSTRACT Cirrhosis is a leading cause of morbidity and mortality among adults in the United States. Acute kidney injury (AKI) is a common, expensive, and lethal complication of cirrhosis. The strongest predictor of AKI in cirrhosis patients, regardless of etiology, is chronic kidney disease (CKD), as measured by estimated glomerular filtration rate (eGFR). Given that there is a rising incidence of both AKI and CKD in this population, there is a developing critical need for clinical tools that identify cirrhosis patients at risk for AKI before its development. This proposal’s three research aims address this need. Leveraging an ongoing cohort with >1000 decompensated cirrhosis patients with >2500 banked biospecimens, these aims will: (1) establish the independent association between renal health biomarkers and AKI and compare the discrimination of novel renal health biomarkers to serum creatinine (sCr) to predict AKI (Aim 1); develop and internally validate a clinical risk tool to identify cirrhosis patients most vulnerable to AKI (Aim 2); explore the association between longitudinal changes in renal health biomarkers on AKI reversibility (Aim 3). I am a hepatologist specializing in liver transplantation at the University of California, San Francisco. Through a pilot award provided by the American Association for the Study of Liver Disease, we have generated the preliminary data needed for this application. These data, coupled with a strong foundation of hepatology and nephrology research (Master of Advanced Studies in Clinical Research, >10 publications), have prepared me for this proposal. However, there are several gaps in my training that this NIDDK K23 Career Development Award will address (e.g., cohort development, advanced statistical techniques). Under the direct supervision of a multidisciplinary team of leaders in nephrology (Hsu, Liu), hepatology (Lai), and biostatistics (McCulloch), I will execute a detailed career development plan to accelerate my path toward 4 career goals outlined in this proposal: (1) to develop a foundation of core nephrological principles; (2) to acquire analytic skills to validate biomarker use; (3) to learn novel methodologies at risk prediction, including machine learning techniques; (4) to expand a cohort and to apply methods of longitudinal data analysis. As part of my 5-year plan, I will actively engage in coursework and structured tutorials in nephrology and biostatistics, and interdisciplinary development and leadership programs. In addition, I will integrate myself into the nephrology research community and establish a network of nephrology researchers for current and future collaboration. RELEVANCE: Identifying a metric that captures which cirrhosis patients are at greatest risk for and least likely to reverse from AKI has important clinical implications—it will allow for the implementation of interventions that prevent the occurrence and halt the progression of a major driver of mortality in this population.