title: Clinical adjudication in acute kidney injury studies: findings from the pivotal TIMP-2*IGFBP7 biomarker study.
abstract: The NEPROCHECK test (Astute Medical, San Diego, CA, USA) combines urinary tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) to identify patients at high risk for acute kidney injury (AKI). In a US Food and Drug Administration registration trial (NCT01573962), AKI was determined by a three-member clinical adjudication committee. The objectives were to examine agreement among adjudicators as well as between adjudicators and consensus criteria for AKI and to determine the relationship of biomarker concentrations and adjudicator agreement.
  
  
  
  Subjects were classified as AKI 3/3, 2/3, 1/3 or 0/3 according to the proportion of adjudicators classifying the case as AKI. Subjects were classified as Kidney Disease: Improving Global Outcomes (KDIGO) AKI(+) when stage 2 or 3 AKI criteria were met.
  
  
  
  Concordance between adjudicators and between adjudicators and KDIGO criteria were lower for AKI than non-AKI subjects [78.9 versus 97.3% (P < 0.001) and 91.5 versus 97.9% (P = 0.01)]. Subjects who were AKI 3/3 or 2/3 but KDIGO AKI(-) had higher median [TIMP-2]•[IGFBP7] compared with those who were AKI-1/3 or 0/3 but KDIGO AKI(+) {2.78 [interquartile range (IQR) 2.33-3.56] versus 0.52 [IQR 0.26-1.64]; P = 0.008}. [TIMP-2]•[IGFBP7] levels were highest in patients with AKI 3/3 and lowest in AKI 0/3, whereas AKI 2/3 and 1/3 exhibited intermediate values.
  
  
  
  In this analysis, urine [TIMP-2]•[IGFBP7] levels correlated to clinically adjudicated AKI better than to KDIGO criteria. Furthermore, in difficult cases where adjudicators overruled KDIGO criteria, the biomarker test discriminated well. This study highlights the importance of clinical adjudication of AKI for biomarker studies and lends further support for the value of urine [TIMP-2]•[IGFBP7].
authors.affiliation: Division of Nephrology, Department of Medicine and Division of Critical Care Medicine, Department of Anesthesia, University of California, San Francisco, CA, USA.
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Liu
authors.affiliation: Division of Nephrology, Department of Medicine, Washington University, St Louis, MO, USA.
authors.forename: Anitha
authors.initials: A
authors.lastname: Vijayan
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, VA, USA.
authors.forename: Mitchell H
authors.initials: MH
authors.lastname: Rosner
authors.affiliation: Statistics, Walker Bioscience, Carlsbad, CA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Medicine, Divisions of Intensive Care Medicine and Nephrology, Veterans Affairs Medical Center, Washington, DC, USA.
authors.forename: Lakhmir S
authors.initials: LS
authors.lastname: Chawla
authors.affiliation: Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Kellum
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000145:classification / Q000175:diagnosis* / Q000652:urine; D000328:Adult; D015415:Biomarkers / Q000097:blood* / Q000652:urine*; D005260:Female; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000032:analysis*; D008297:Male; D011379:Prognosis; D011446:Prospective Studies; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis*
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; biomarkers; diagnosis; insulin-like growth factor binding protein 7; tissue inhibitor of metalloproteinases-2