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

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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.