학술논문
Validation of Cell-Cycle Arrest Biomarkers for Acute Kidney Injury Using Clinical Adjudication
Document Type
article
Author
Bihorac, Azra; Chawla, Lakhmir S; Shaw, Andrew D; Al-Khafaji, Ali; Davison, Danielle L; DeMuth, George E; Fitzgerald, Robert; Gong, Michelle Ng; Graham, Derrel D; Gunnerson, Kyle; Heung, Michael; Jortani, Saeed; Kleerup, Eric; Koyner, Jay L; Krell, Kenneth; LeTourneau, Jennifer; Lissauer, Matthew; Miner, James; Nguyen, H Bryant; Ortega, Luis M; Self, Wesley H; Sellman, Richard; Shi, Jing; Straseski, Joely; Szalados, James E; Wilber, Scott T; Walker, Michael G; Wilson, Jason; Wunderink, Richard; Zimmerman, Janice; Kellum, John A
Source
American Journal of Respiratory and Critical Care Medicine. 189(8)
Subject
Language
Abstract
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).