The Assessment of Acute Kidney Injury Sub-phenotypes in the Intensive Care Unit

项目摘要/摘要 Pavan Bhatraju，医学博士，理学硕士，计划成为分子流行病学家和内科科学家的职业生涯 重症监护病房(ICU)的急性肾损伤(AKI)。拟议职业发展的目标 该奖项旨在提供必要的研究方法培训，以促进Bhatraju博士向独立 研究。华盛顿大学(UW)肺科和心内科的导师 重症监护医学(PCCM)和肾脏研究所是杰出的。他将继续他的工作 在威斯康星大学的Mark Wurfel博士(PCCM)和Jonathan Himmelfarb博士(肾脏病)的指导下。 他的多学科研究团队的合作者跨越了基因组科学的各个学科(盖尔·贾维克博士) 流行病学和生物统计学(罗尼特·卡茨博士)和翻译研究在急性KI研究中的应用 (希拉克·帕里克博士)为了补充这个研究团队的支持，Bhatraju博士将增加他的硕士学位 在全国著名的威斯康星大学公共卫生学院攻读流行病学科学硕士学位。 AKI在ICU中很常见，与发病率和死亡率有关。目前我们还没有有效的 AKI的药物治疗。药物开发的局限性可能部分地由生物学上的 AKI表型患者的临床异质性。为了解决这些限制，我们的实验室 使用创新的建模方法确定了两个不同的AKI亚型(也称为内型)， 潜类分析。我们发现这两种AKI亚型具有不同的临床特征， 生物标记物模式和短期结果不佳的风险。我们还开发并验证了一个三变量 预测模型用于前瞻性识别AKI亚型。总体而言，这些发现提供了 Bhatraju博士的K23研究提案的基金会。拟议研究的目标包括：1) 在1年内评估AKI亚型与主要不良肾脏事件的相关性；2)确定 与AKI亚型发展相关的遗传风险因素；以及；3)确定特定的 通过靶向尿蛋白分析AKI亚型之间的病理生理学差异。 该奖项将提供基因组科学、生物统计学、高级流行病学方面的基本研究培训。 并将扩大他的板凳实验室技能。这项建议利用了Bhatraju博士对多个 危重病例队列，进入华盛顿大学的研究基础设施，以登记预期的ICU队列收集 尿液、血浆和DNA样本，以及参加威斯康星大学伯克利分校的世界级教学培训计划 公共卫生。他的总体研究目标是利用分子流行病学技术开发一种 基于病理生理的AKI患者分类改进风险预测，发现新的 以遗传风险因素和信息精确度为基础的预防和治疗急性肾功能衰竭的策略 重症监护室。在K23的支持下，Bhatraju博士设计的研究和教育议程将对他有所帮助 实现他成为一名从事AKI研究的独立翻译调查员的长期目标。

Project Summary/Abstract Pavan Bhatraju, MD, MSc plans for a career as a molecular epidemiologist physician scientist in the field of acute kidney injury (AKI) in the intensive care unit (ICU). The objective of the proposed career development award is to provide necessary training in research methods to facilitate Dr. Bhatraju’s transition to independent research. The mentorship available at the University of Washington (UW) in the Division of Pulmonary and Critical Care Medicine (PCCM) and the Kidney Research Institute are outstanding. He will continue his work under the mentorship of Drs. Mark Wurfel (PCCM) and Jonathan Himmelfarb (Nephrology) at the UW. Collaborators on his multi-disciplinary research team span the disciplines of genome sciences (Dr. Gail Jarvik), epidemiology and biostatistics (Dr. Ronit Katz) and the application of translational research to the study of AKI (Dr. Chirag Parik). To complement the support from this research team, Dr. Bhatraju will augment his Masters in Science in Epidemiology with advanced coursework at the nationally-renowned UW School of Public Health. AKI is common in the ICU and is associated with morbidity and mortality. Currently we have no effective pharmacological therapy for AKI. Limitations in drug development may be partly explained by the biological and clinical heterogeneity in patients included in the AKI phenotype. To address these limitations, our lab has identified two distinct AKI sub-phenotypes (also known as endotypes) using an innovative modeling approach, latent class analysis. We found that the two AKI sub-phenotypes had different clinical characteristics, biomarker patterns and risk of poor short-term outcomes. We also developed and validated a 3-variable prediction model to prospectively identify the AKI sub-phenotypes. Overall, these findings provide the foundation for Dr. Bhatraju’s K23 research proposal. The objectives of the proposed research include: 1) evaluate the association of AKI sub-phenotypes with major adverse kidney events by 1 year; 2) determine the genetic risk factors associated with the development of AKI sub-phenotypes, and; 3) identify specific pathophysiologic differences between the AKI sub-phenotypes through a targeted urinary protein analysis. This award will provide essential research training in genome sciences, biostatistics, advanced epidemiology and will broaden his bench lab skillset. This proposal leverages Dr. Bhatraju’s unique access to multiple critically ill cohorts, access to a research infrastructure at the UW to enroll a prospective ICU cohort collecting urine, plasma and DNA samples and access to world-class didactic training program at the UW School of Public Health. His overall research goal is to use techniques of molecular epidemiology to develop a pathophysiologic based classification of patients with AKI to improve risk prognostication, discover novel genetic risk factors and inform precision based strategies to prevent and treat the development of AKI in the ICU. With the support of this K23, the research and education agenda Dr. Bhatraju has devised will assist him in achieving his long-term goal of becoming an independent translational investigator conducting AKI research.