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.