Derivation and validation of cutoffs for clinical use of cell cycle arrest biomarkers

Nephrol Dial Transplant. 2014 Nov;29(11):2054-61. doi: 10.1093/ndt/gfu292. Epub 2014 Sep 18.


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.

Clinical trials registration: # NCT01209169 (Sapphire) and NCT01846884 (Opal).

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).

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / pathology
  • Acute Kidney Injury / urine*
  • Aged
  • Biomarkers / urine
  • Cell Cycle Checkpoints / physiology
  • Female
  • Follow-Up Studies
  • Humans
  • Insulin-Like Growth Factor Binding Proteins / urine*
  • Male
  • Middle Aged
  • Predictive Value of Tests
  • ROC Curve
  • Tissue Inhibitor of Metalloproteinase-2 / urine*


  • Biomarkers
  • Insulin-Like Growth Factor Binding Proteins
  • TIMP2 protein, human
  • insulin-like growth factor binding protein-related protein 1
  • Tissue Inhibitor of Metalloproteinase-2

Associated data