• Azra Bihorac, Lakhmir S Chawla, Andrew D Shaw, Ali Al-Khafaji, Danielle L Davison, George E Demuth, Robert Fitzgerald, Gong Michelle Ng MN, Derrel D Graham, Kyle Gunnerson, Michael Heung, Saeed Jortani, Eric Kleerup, Jay L Koyner, Kenneth Krell, Jennifer Letourneau, Matthew Lissauer, James Miner, Nguyen H Bryant HB, Luis M Ortega, Wesley H Self, Richard Sellman, Jing Shi, Joely Straseski, James E Szalados, Scott T Wilber, Michael G Walker, Jason Wilson, Richard Wunderink, Janice Zimmerman, and John A Kellum.
• 1 Department of Anesthesiology, University of Florida, Gainesville, Florida.
• Am. J. Respir. Crit. Care Med. 2014 Apr 15; 189 (8): 932-9.

RationaleWe 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.ObjectivesWe now validate a clinical test for urinary [TIMP-2]·[IGFBP7] at a high-sensitivity cutoff greater than 0.3 for AKI risk stratification in a diverse population of critically ill patients.MethodsWe conducted a prospective multicenter study of 420 critically ill patients. The primary analysis was the ability of urinary [TIMP-2]·[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 ResultsUrinary TIMP-2 and IGFBP7 were measured using a clinical immunoassay platform. The primary endpoint was reached in 17% of patients. For a single urinary [TIMP-2]·[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]·[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]·[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]·[IGFBP7]).ConclusionsUrinary [TIMP-2]·[IGFBP7] greater than 0.3 (ng/ml)(2)/1,000 identifies patients at risk for imminent AKI. Clinical trial registered with www.clinicaltrials.gov (NCT 01573962).

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