Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication

Azra Bihorac, Lakhmir S. Chawla, Andrew D. Shaw, Ali Al-Khafaji, Danielle L. Davison, George E. DeMuth, Robert Fitzgerald, Michelle Ng Gong, Derrel D. Graham, Kyle Gunnerson, Michael Heung, Saeed Jortani, Eric Kleerup, Jay L. Koyner, Kenneth Krell, Jennifer LeTourneau, Matthew Lissauer, James Miner, H. Bryant Nguyen, Luis M. OrtegaWesley H. Self, Richard Sellman, Jing Shi, Joely Straseski, James E. Szalados, Scott T. Wilber, Michael G. Walker, Jason Wilson, Richard Wunderink, Janice Zimmerman, John A. Kellum

Research output: Contribution to journalArticlepeer-review

385 Scopus citations


Rationale: 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. Objectives: We now validate a clinical test for urinary [TIMP-2]d [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]d[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. Measurements and Main Results: Urinary TIMP-2 and IGFBP7 were measured using a clinical immunoassay platform. The primary endpointwas reached in 17%of patients. For a single urinary [TIMP-2]d [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]d[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]d[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]d[IGFBP7]). Conclusions: Urinary [TIMP-2]d[IGFBP7] greater than 0.3 (ng/ml)2/ 1,000 identifies patients at risk for imminent AKI. Clinical trial registered with (NCT 01573962).

Original languageEnglish (US)
Pages (from-to)932-939
Number of pages8
JournalAmerican journal of respiratory and critical care medicine
Issue number8
StatePublished - Apr 15 2014


  • Acute kidney injury
  • Biomarkers
  • Cell-cycle arrest
  • Insulin-like growth factor binding protein 7
  • Tissue inhibitor of metalloproteinases-2

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine


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