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.

Public Health Relevance

The kidney provides fluid balance and toxin removal essential to human health. The filtering units (glomeruli) and the permeable drains (tubules) that carry and remove fluid from the body can be easily damaged, and such damage (called 'acute kidney injury', or AKI) often leads to prolonged hospitalization and permanent kidney damage among Veterans. However, physicians are currently only able to measure the function of the glomeruli. I plan to study measures of tubular function in the kidney. My goal is to provide an understanding of how AKI happens and to develop clinical tests that can predict risk of AKI. Based on the data generated from the CDA2 award, I intend to apply for an independent research grant from the VA. I envision testing the markers in a variety of clinical settings, for instance, in cancer patients exposed to life-saving but potentially kidney-damaging medications.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Veterans Administration (IK2)
Project #
1IK2BX004986-01A1
Application #
10007293
Study Section
Special Emphasis Panel (ZRD1)
Project Start
2020-07-01
Project End
2025-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
VA San Diego Healthcare System
Department
Type
DUNS #
073358855
City
San Diego
State
CA
Country
United States
Zip Code
92161