Acute kidney injury (AKI) in the intensive care unit is common and highly associated with morbidity and mortality. AKI is an abrupt decline in renal function due to glomerular or tubular dysfunction. The current, most widely accepted definition of AKI from the Kidney Disease Improving Global Outcomes (KDIGO) group, classifies patients based on a maximum creatinine or a minimum urine output throughout their hospital stay from stage 0 (no AKI) to stage 3 AKI. However AKI is a heterogeneous disease with differing risk factors, pathophysiology and clinical outcomes. This heterogeneity may reflect our incomplete understanding of the biology of AKI and likely contributes to the poor track record of novel therapies for patients with AKI. In other heterogeneous diseases, such as lung cancer, acute respiratory distress syndrome (ARDS), or asthma, identification of sub-phenotypes has led to improved understanding of pathogenesis and has had implications for individualized care. Unlike other diseases in AKI there has been few studies identifying sub-phenotypes. The overall study objective is to categorize novel sub-phenotypes of AKI in the ICU, determine the association of sub-phenotypes with short and long-term clinical outcomes and identify molecular pathways associated with AKI sub-phenotypes. This project accomplishes the overall study objective by pursuing the following two specific aims: 1) Compare sub-phenotypes of AKI either defined by the latent class analysis (LCA) or by a trajectory based approach in terms of their relation to short and long-term outcomes; 2) Identify plasma biomarkers that differentiate AKI sub-phenotypes from a panel of biomarkers reflecting endothelial dysfunction (angiopoietin 1, 2 and vascular endothelial growth factor) and inflammation (interleukin 6, 8 and TNF alpha, TNFR-1). Refining the classification of patients with AKI in the ICU is foundationally essential to further research in this heterogeneous disease. Expected results will allow identification of patients at risk of poor outcomes, allow for inclusion of homogeneous populations in future clinical trials, characterize biological pathways to target with novel therapies and support future research to evaluate genetic risk factors associated with the development of AKI.

Public Health Relevance

Acute kidney injury (AKI) affects millions in the intensive care unit and is highly associated with morbidity and mortality. Even though AKI is a heterogeneous disease, our current clinical practice does not differentiate AKI sub-phenotypes. Identification of AKI sub-phenotypes will allow inclusion of homogeneous populations in future clinical studies, support evaluation of mechanistic pathways, and provide a foundation for genetic research.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDK1)
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Rankin, Tracy L
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Bhatraju, Pavan K; Zelnick, Leila R; Shlipak, Michael et al. (2018) Association of Soluble TNFR-1 Concentrations with Long-Term Decline in Kidney Function: The Multi-Ethnic Study of Atherosclerosis. J Am Soc Nephrol 29:2713-2721
Esposito, Anthony J; Bhatraju, Pavan K; Stapleton, Renee D et al. (2017) Hyaluronic acid is associated with organ dysfunction in acute respiratory distress syndrome. Crit Care 21:304
Bhatraju, Pavan K; Robinson-Cohen, Cassianne; Mikacenic, Carmen et al. (2017) Circulating levels of soluble Fas (sCD95) are associated with risk for development of a nonresolving acute kidney injury subphenotype. Crit Care 21:217
Bhatraju, Pavan K; Mukherjee, Paramita; Robinson-Cohen, Cassianne et al. (2016) Acute kidney injury subphenotypes based on creatinine trajectory identifies patients at increased risk of death. Crit Care 20:372