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

  • Author(s): 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
  • et al.
Abstract

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]·[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]·[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 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]).

Conclusions

Urinary [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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