title: Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury.
abstract: BACKGROUND
  Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.
  
  
  METHODS
  We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.
  
  
  RESULTS
  Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.
  
  
  CONCLUSIONS
  Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI.
  
  
  BACKGROUND
  ClinicalTrials.gov number NCT01209169.
authors: Kianoush
authors: K
authors: Kashani
authors: Ali
authors: A
authors: Al-Khafaji
authors: Thomas
authors: T
authors: Ardiles
authors: Antonio
authors: A
authors: Artigas
authors: Sean M
authors: SM
authors: Bagshaw
authors: Max
authors: M
authors: Bell
authors: Azra
authors: A
authors: Bihorac
authors: Robert
authors: R
authors: Birkhahn
authors: Cynthia M
authors: CM
authors: Cely
authors: Lakhmir S
authors: LS
authors: Chawla
authors: Danielle L
authors: DL
authors: Davison
authors: Thorsten
authors: T
authors: Feldkamp
authors: Lui G
authors: LG
authors: Forni
authors: Michelle Ng
authors: MN
authors: Gong
authors: Kyle J
authors: KJ
authors: Gunnerson
authors: Michael
authors: M
authors: Haase
authors: James
authors: J
authors: Hackett
authors: Patrick M
authors: PM
authors: Honore
authors: Eric A J
authors: EA
authors: Hoste
authors: Olivier
authors: O
authors: Joannes-Boyau
authors: Michael
authors: M
authors: Joannidis
authors: Patrick
authors: P
authors: Kim
authors: Jay L
authors: JL
authors: Koyner
authors: Daniel T
authors: DT
authors: Laskowitz
authors: Matthew E
authors: ME
authors: Lissauer
authors: Gernot
authors: G
authors: Marx
authors: Peter A
authors: PA
authors: McCullough
authors: Scott
authors: S
authors: Mullaney
authors: Marlies
authors: M
authors: Ostermann
authors: Thomas
authors: T
authors: Rimmelé
authors: Nathan I
authors: NI
authors: Shapiro
authors: Andrew D
authors: AD
authors: Shaw
authors: Jing
authors: J
authors: Shi
authors: Amy M
authors: AM
authors: Sprague
authors: Jean-Louis
authors: JL
authors: Vincent
authors: Christophe
authors: C
authors: Vinsonneau
authors: Ludwig
authors: L
authors: Wagner
authors: Michael G
authors: MG
authors: Walker
authors: R Gentry
authors: RG
authors: Wilkerson
authors: Kai
authors: K
authors: Zacharowski
authors: John A
authors: JA
authors: Kellum
mesh_terms: D058186:Acute Kidney Injury / Q000175:diagnosis* / Q000652:urine*; D000368:Aged; D015415:Biomarkers / Q000652:urine; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000652:urine*; D008297:Male; D008875:Middle Aged; 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
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