Advancing acute kidney injury phenotyping using biological and clinical criteria

项目摘要 这是Kathleen D的新K24应用程序。刘，医学博士，博士，MAS，谁是副教授， 医学在加州大学，旧金山弗朗西斯科，她是一个肾病学家和重症监护医学 一个专家与指导医学生，居民和研究员谁想要训练一个强大的记录 学术医学的职业生涯。在完成奖学金后的10年里，她建立了一个良好的- 资助的独立研究计划主要集中在急性肾损伤（阿基），一种常见的疾病， 除了支持性护理外，没有其他治疗方法的住院患者。刘博士的长期目标之一是 开展随机临床试验，改善阿基危重患者的护理。脓毒症是 重症监护室（ICU）中阿基的主要原因。败血症临床试验失败的主要批评是 患者群体可能过于异质而无法受益。因此，研究的总体主题 在该K24申请中提出的是改进脓毒症相关阿基的表型。在这些研究中，她 将通过利用美国国立卫生研究院的肾和肺损伤早期评估（EARLI）队列来扩展她的研究， 来自2家UCSF附属医院急诊科的ICU患者支持队列。 在目标1中，Liu博士将测试液体超负荷对脓毒症患者阿基确定的影响。血清 用于定义阿基的肌酸酐（sCr）受分布容积的影响（例如，患者的sCr较低 液体超载）。在患有急性呼吸窘迫综合征（ARDS）的患者中，刘医生显示， 液体超负荷影响阿基确定。现在需要进一步的研究来更好地了解这种影响 液体超负荷对脓毒症患者阿基确定的影响，以及生物标志物与 阿基的发展。在目标2中，她将使用“临床不可知论”或无偏见的方法， 阿基亚表型的鉴定。潜在类别分析已被应用于ARDS，以识别亚类。 使用临床和生物学数据的表型。当鉴定出阿基的亚表型时，可以使用 （1）进一步定义这些亚表型的生物学和（2）测试亚表型中的潜在疗法 更有可能从中受益。因此，目标2将使用潜在类别分析方法， 临床标准，以确定更同质的阿基患者组。 该提案将支持使用库存样本进行额外的生物标志物测量， 在EARLI队列中收集数据，为指导新研究者提供一个平台， 翻译研究此外，如具体目标中所述，通过该提案，刘博士将获得 潜在类别分析的新技能，这将使她能够在其他患者队列中测试这种方法，并将 加强她作为导师的作用，以病人为导向的转化研究的初级研究人员。最后，这个奖 将为刘博士提供关键的保护时间，以进一步发展她的指导技能，并致力于 指导致力于以患者为导向的研究事业的学员。

PROJECT ABSTRACT This is a new K24 application for Kathleen D. Liu, MD, PhD, MAS, who is an Associate Professor of Medicine at the University of California, San Francisco where she is a nephrologist and critical care medicine specialist with a strong record of mentoring medical students, residents and fellows who want to train for a career in academic medicine. In the 10 years since completing her fellowship, she has established a well- funded independent research program focused primarily on acute kidney injury (AKI), a common disease of hospitalized patients for which no therapies apart from supportive care exist. One of Dr. Liu's long term goals is to conduct randomized clinical trials that will improve the care of critically ill patients with AKI. Sepsis is the leading cause of AKI in the Intensive Care Unit (ICU). A major criticism of failed sepsis clinical trials has been that the patient population is likely too heterogeneous to benefit. Thus, the overall theme of the research proposed in this K24 application is to refine phenotyping of sepsis-associated AKI. For these studies, she will extend her research by leveraging the Early Assessment of Renal and Lung Injury (EARLI) cohort, a NIH- supported cohort of ICU patients admitted from the Emergency Department at 2 UCSF-affiliated hospitals. In Aim 1, Dr. Liu will test the impact of fluid overload on AKI ascertainment in patients with sepsis. Serum creatinine (sCr), which is used to define AKI, is affected by volume of distribution (e.g., sCr is lower in patients with fluid overload). Among patients with the acute respiratory distress syndrome (ARDS), Dr. Liu has shown that fluid overload impacts AKI ascertainment. Further research is now needed to better understand the impact of fluid overload on AKI ascertainment in patients with sepsis, and on the relationship of biomarkers with the development of AKI. In Aim 2, she will use “clinically agnostic”, or unbiased methods, that may allow for identification of AKI sub-phenotypes. Latent class analysis has been applied to ARDS to identify sub- phenotypes using clinical and biological data. When sub-phenotypes of AKI are identified, these can be used to (1) further define the biology of these sub-phenotypes and (2) test potential therapies in a sub-phenotype that is more likely to benefit. Thus Aim 2 will use latent class analysis methods to incorporate biological and clinical criteria to identify more homogenous patient groups with AKI. This proposal will support additional biomarker measurements using banked samples and further clinical data collection in the EARLI cohort to provide a platform for mentoring new investigators in patient-oriented translational research. Additionally, as detailed in the Specific Aims, through this proposal Dr. Liu will acquire new skills in latent class analysis which will enable her to test this approach in other patient cohorts and will enhance her role as mentor to junior investigators in patient-oriented translational research. Finally, this award will provide Dr. Liu with critical protected time to further develop her mentorship skills and to devote to mentoring trainees committed to careers in patient-oriented research.