title: Derivation and validation of cutoffs for clinical use of cell cycle arrest biomarkers.
abstract: BACKGROUND
  Acute kidney injury (AKI) remains a deadly condition. Tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein (IGFBP)7 are two recently discovered urinary biomarkers for AKI. We now report on the development, and diagnostic accuracy of two clinical cutoffs for a test using these markers.
  
  
  METHODS
  We derived cutoffs based on sensitivity and specificity for prediction of Kidney Disease: Improving Global Outcomes Stages 2-3 AKI within 12 h using data from a previously published multicenter cohort (Sapphire). Next, we verified these cutoffs in a new study (Opal) enrolling 154 critically ill adults from six sites in the USA.
  
  
  RESULTS
  One hundred subjects (14%) in Sapphire and 27 (18%) in Opal met the primary end point. The results of the Opal study replicated those of Sapphire. Relative risk (95% CI) in both studies for subjects testing at ≤0.3 versus >0.3-2 were 4.7 (1.5-16) and 4.4 (2.5-8.7), or 12 (4.2-40) and 18 (10-37) for ≤0.3 versus >2. For the 0.3 cutoff, sensitivity was 89% in both studies, and specificity 50 and 53%. For 2.0, sensitivity was 42 and 44%, and specificity 95 and 90%.
  
  
  CONCLUSIONS
  Urinary [TIMP-2]•[IGFBP7] values of 0.3 or greater identify patients at high risk and those >2 at highest risk for AKI and provide new information to support clinical decision-making.
  
  
  BACKGROUND
  Clintrials.gov # NCT01209169 (Sapphire) and NCT01846884 (Opal).
authors.affiliation: Intensive Care Unit, Ghent University Hospital, Ghent University, and Research Foundation-Flanders (FWO), Belgium.
authors.forename: Eric A J
authors.initials: EA
authors.lastname: Hoste
authors.affiliation: Baylor University Medical Center, Baylor Heart and Vascular Institute, Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, TX The Heart Hospital, Plano, TX.
authors.forename: Peter A
authors.initials: PA
authors.lastname: McCullough
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Kianoush
authors.initials: K
authors.lastname: Kashani
authors.affiliation: Department of Medicine, Division of Intensive Care Medicine, and the Division of Nephrology, Washington, DC, Veterans Affairs Medical Center Department of Anesthesiology and Critical Care Medicine, George Washington University, Washington, DC.
authors.forename: Lakhmir S
authors.initials: LS
authors.lastname: Chawla
authors.affiliation: Department of Internal Medicine, ICU, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Joannidis
authors.affiliation: Department of Anesthesia, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Shaw
authors.affiliation: Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Germany Department of Nephrology and Hypertension, University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Feldkamp
authors.affiliation: Clinical Laboratory Trials, JT Mather Memorial Hospital, Port Jefferson, NY, USA.
authors.forename: Denise L
authors.initials: DL
authors.lastname: Uettwiller-Geiger
authors.affiliation: Critical Care Medicine, R Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: McCarthy
authors.affiliation: Walker Biosciences, Carlsbad, CA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.affiliation: Walker Biosciences, Carlsbad, CA, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Walker
authors.affiliation: Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Kellum
mesh_terms: D058186:Acute Kidney Injury / Q000473:pathology / Q000652:urine*; D000368:Aged; D015415:Biomarkers / Q000652:urine; D059447:Cell Cycle Checkpoints / Q000502:physiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000652:urine*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012372:ROC Curve; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000652:urine*
chemical_list: D015415:Biomarkers; D018969:Insulin-Like Growth Factor Binding Proteins; C560823:TIMP2 protein, human; C102529:insulin-like growth factor binding protein-related protein 1; D019716:Tissue Inhibitor of Metalloproteinase-2
keywords: acute kidney injury; acute renal failure; biomarkers; insulin-like growth factor binding protein (IGFBP)7 and tissue inhibitor of metalloproteinases (TIMP)-2; sensitivity and specificity (MeSH)