title: Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication.
abstract: BACKGROUND
  We recently reported two novel biomarkers for acute kidney injury (AKI), tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7), both related to G1 cell cycle arrest.
  
  
  OBJECTIVE
  We now validate a clinical test for urinary [TIMP-2]·[IGFBP7] at a high-sensitivity cutoff greater than 0.3 for AKI risk stratification in a diverse population of critically ill patients.
  
  
  METHODS
  We conducted a prospective multicenter study of 420 critically ill patients. The primary analysis was the ability of urinary [TIMP-2]·[IGFBP7] to predict moderate to severe AKI within 12 hours. AKI was adjudicated by a committee of three independent expert nephrologists who were masked to the results of the test.
  
  
  RESULTS
  Urinary TIMP-2 and IGFBP7 were measured using a clinical immunoassay platform. The primary endpoint was reached in 17% of patients. For a single urinary [TIMP-2]·[IGFBP7] test, sensitivity at the prespecified high-sensitivity cutoff of 0.3 (ng/ml)(2)/1,000 was 92% (95% confidence interval [CI], 85-98%) with a negative likelihood ratio of 0.18 (95% CI, 0.06-0.33). Critically ill patients with urinary [TIMP-2]·[IGFBP7] greater than 0.3 had seven times the risk for AKI (95% CI, 4-22) compared with critically ill patients with a test result below 0.3. In a multivariate model including clinical information, urinary [TIMP-2]·[IGFBP7] remained statistically significant and a strong predictor of AKI (area under the curve, 0.70, 95% CI, 0.63-0.76 for clinical variables alone, vs. area under the curve, 0.86, 95% CI, 0.80-0.90 for clinical variables plus [TIMP-2]·[IGFBP7]).
  
  
  CONCLUSIONS
  Urinary [TIMP-2]·[IGFBP7] greater than 0.3 (ng/ml)(2)/1,000 identifies patients at risk for imminent AKI. Clinical trial registered with www.clinicaltrials.gov (NCT 01573962).
authors.affiliation: 1 Department of Anesthesiology, University of Florida, Gainesville, Florida.
authors.forename: Azra
authors.initials: A
authors.lastname: Bihorac
authors.forename: Lakhmir S
authors.initials: LS
authors.lastname: Chawla
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Shaw
authors.forename: Ali
authors.initials: A
authors.lastname: Al-Khafaji
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Davison
authors.forename: George E
authors.initials: GE
authors.lastname: Demuth
authors.forename: Robert
authors.initials: R
authors.lastname: Fitzgerald
authors.forename: Michelle Ng
authors.initials: MN
authors.lastname: Gong
authors.forename: Derrel D
authors.initials: DD
authors.lastname: Graham
authors.forename: Kyle
authors.initials: K
authors.lastname: Gunnerson
authors.forename: Michael
authors.initials: M
authors.lastname: Heung
authors.forename: Saeed
authors.initials: S
authors.lastname: Jortani
authors.forename: Eric
authors.initials: E
authors.lastname: Kleerup
authors.forename: Jay L
authors.initials: JL
authors.lastname: Koyner
authors.forename: Kenneth
authors.initials: K
authors.lastname: Krell
authors.forename: Jennifer
authors.initials: J
authors.lastname: Letourneau
authors.forename: Matthew
authors.initials: M
authors.lastname: Lissauer
authors.forename: James
authors.initials: J
authors.lastname: Miner
authors.forename: H Bryant
authors.initials: HB
authors.lastname: Nguyen
authors.forename: Luis M
authors.initials: LM
authors.lastname: Ortega
authors.forename: Wesley H
authors.initials: WH
authors.lastname: Self
authors.forename: Richard
authors.initials: R
authors.lastname: Sellman
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.forename: Joely
authors.initials: J
authors.lastname: Straseski
authors.forename: James E
authors.initials: JE
authors.lastname: Szalados
authors.forename: Scott T
authors.initials: ST
authors.lastname: Wilber
authors.forename: Michael G
authors.initials: MG
authors.lastname: Walker
authors.forename: Jason
authors.initials: J
authors.lastname: Wilson
authors.forename: Richard
authors.initials: R
authors.lastname: Wunderink
authors.forename: Janice
authors.initials: J
authors.lastname: Zimmerman
authors.forename: John A
authors.initials: JA
authors.lastname: Kellum
mesh_terms: D058186:Acute Kidney Injury / Q000175:diagnosis* / Q000652:urine*; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000652:urine; D016923:Cell Death; D015331:Cohort Studies; D016638:Critical Illness; D005260:Female; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000652:urine*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D011480:Protease Inhibitors / Q000652:urine*; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D013997:Time Factors; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000652:urine*; D014481:United States
chemical_list: D015415:Biomarkers; D018969:Insulin-Like Growth Factor Binding Proteins; D011480:Protease Inhibitors; C560823:TIMP2 protein, human; C102529:insulin-like growth factor binding protein-related protein 1; D019716:Tissue Inhibitor of Metalloproteinase-2