title: Acute kidney injury subphenotypes based on creatinine trajectory identifies patients at increased risk of death.
abstract: Acute kidney injury (AKI) is common among intensive care unit (ICU) patients. AKI is highly heterogeneous, with variable links to poor outcomes. Current approaches to classify AKI severity and identify patients at highest risk for poor outcomes focus on the maximum change in serum creatinine (SCr) values. However, these scores are hampered by the need for a reliable baseline SCr value and the absence of a component differentiating transient from persistent rises in SCr. We hypothesized that identification of resolving or nonresolving AKI subphenotypes based on the early trajectory of SCr values in the ICU would better differentiate patients at risk of hospital mortality.
  
  
  
  We performed a secondary analysis of two prospective studies of ICU patients admitted to a trauma ICU (group 1; n = 1914) or general medical-surgical ICUs (group 2; n = 1867). In group 1, we tested definitions for resolving and nonresolving AKI subphenotypes and selected the definitions resulting in subphenotypes with the greatest separation in risk of death relative to non-AKI controls. We applied this definition to group 2 and tested whether the subphenotypes were independently associated with hospital mortality after adjustment for AKI severity.
  
  
  
  AKI occurred in 46% and 69% of patients in groups 1 and 2, respectively. In group 1, a resolving AKI subphenotype (defined as a decrease in SCr of 0.3 mg/dl or 25% from maximum in the first 72 h of study enrollment) was associated with a low risk of death. A nonresolving AKI subphenotype (defined as all AKI cases not meeting the "resolving" definition) was associated with a high risk of death. In group 2, the resolving AKI subphenotype was not associated with increased mortality (relative risk [RR] 0.86, 95% CI 0.63-1.17), whereas the nonresolving AKI subphenotype was associated with higher mortality (RR 1.68, 95% CI 1.15-2.44) even after adjustment for AKI severity stage.
  
  
  
  The trajectory of SCr levels identifies AKI subphenotypes with different risks for death, even among AKI cases of similar severity. These AKI subphenotypes might better define the patients at risk for poor outcomes who might benefit from novel interventions.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Washington, Harborview Medical Center, 325 9th Avenue, Seattle, WA, 98104, USA. bhatraju@uw.edu.
authors.forename: Pavan K
authors.initials: PK
authors.lastname: Bhatraju
authors.affiliation: Kidney Research Institute, University of Washington, Seattle, WA, USA.|Division of Nephrology, University of Washington, Seattle, WA, USA.
authors.forename: Paramita
authors.initials: P
authors.lastname: Mukherjee
authors.affiliation: Kidney Research Institute, University of Washington, Seattle, WA, USA.|Division of Nephrology, University of Washington, Seattle, WA, USA.
authors.forename: Cassianne
authors.initials: C
authors.lastname: Robinson-Cohen
authors.affiliation: Department of Surgery, University of Washington, Seattle, WA, USA.
authors.forename: Grant E
authors.initials: GE
authors.lastname: O'Keefe
authors.affiliation: Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.|Division of Pulmonary and Critical Care Division, Department of Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Frank
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Christie
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Nuala J
authors.initials: NJ
authors.lastname: Meyer
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.|Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.|Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.|Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.|Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.|Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.|Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
authors.forename: Carolyn S
authors.initials: CS
authors.lastname: Calfee
authors.affiliation: Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.|Division of Pulmonary and Critical Care Division, Department of Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
authors.affiliation: Kidney Research Institute, University of Washington, Seattle, WA, USA.|Division of Nephrology, University of Washington, Seattle, WA, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Himmelfarb
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Washington, Harborview Medical Center, 325 9th Avenue, Seattle, WA, 98104, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Wurfel
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood* / Q000175:diagnosis / Q000401:mortality*; D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D015331:Cohort Studies; D003404:Creatinine / Q000097:blood*; D005260:Female; D017052:Hospital Mortality / Q000639:trends*; D006801:Humans; D007362:Intensive Care Units / Q000639:trends*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011446:Prospective Studies; D012307:Risk Factors; D055815:Young Adult
chemical_list: D015415:Biomarkers; D003404:Creatinine
keywords: Acute kidney injury; Critical care; Intensive care unit; Mortality; Subphenotypes; Trajectory