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. Ortega & 11 others Wesley 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 journalArticle

215 Citations (Scopus)

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]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 www.clinicaltrials.gov (NCT 01573962).

Original languageEnglish (US)
Pages (from-to)932-939
Number of pages8
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume189
Issue number8
DOIs
StatePublished - Apr 15 2014

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Tissue Inhibitor of Metalloproteinase-2
Cell Cycle Checkpoints
Acute Kidney Injury
Biomarkers
Critical Illness
Confidence Intervals
Area Under Curve
G1 Phase Cell Cycle Checkpoints
insulin-like growth factor binding protein-related protein 1
Immunoassay
Multicenter Studies
Clinical Trials
Prospective Studies

Keywords

  • 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

Cite this

Bihorac, A., Chawla, L. S., Shaw, A. D., Al-Khafaji, A., Davison, D. L., DeMuth, G. E., ... Kellum, J. A. (2014). Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication. American Journal of Respiratory and Critical Care Medicine, 189(8), 932-939. https://doi.org/10.1164/rccm.201401-0077OC

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

In: American Journal of Respiratory and Critical Care Medicine, Vol. 189, No. 8, 15.04.2014, p. 932-939.

Research output: Contribution to journalArticle

Bihorac, A, Chawla, LS, Shaw, AD, Al-Khafaji, A, Davison, DL, DeMuth, GE, Fitzgerald, R, Gong, MN, Graham, DD, Gunnerson, K, Heung, M, Jortani, S, Kleerup, E, Koyner, JL, Krell, K, LeTourneau, J, Lissauer, M, Miner, J, Nguyen, HB, Ortega, LM, Self, WH, Sellman, R, Shi, J, Straseski, J, Szalados, JE, Wilber, ST, Walker, MG, Wilson, J, Wunderink, R, Zimmerman, J & Kellum, JA 2014, 'Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication', American Journal of Respiratory and Critical Care Medicine, vol. 189, no. 8, pp. 932-939. https://doi.org/10.1164/rccm.201401-0077OC
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. / Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication. In: American Journal of Respiratory and Critical Care Medicine. 2014 ; Vol. 189, No. 8. pp. 932-939.
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author = "Azra Bihorac and Chawla, {Lakhmir S.} and Shaw, {Andrew D.} and Ali Al-Khafaji and Davison, {Danielle L.} and DeMuth, {George E.} and Robert Fitzgerald and Gong, {Michelle Ng} and Graham, {Derrel D.} and Kyle Gunnerson and Michael Heung and Saeed Jortani and Eric Kleerup and Koyner, {Jay L.} and Kenneth Krell and Jennifer LeTourneau and Matthew Lissauer and James Miner and Nguyen, {H. Bryant} and Ortega, {Luis M.} and Self, {Wesley H.} and Richard Sellman and Jing Shi and Joely Straseski and Szalados, {James E.} and Wilber, {Scott T.} and Walker, {Michael G.} and Jason Wilson and Richard Wunderink and Janice Zimmerman and Kellum, {John A.}",
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T1 - Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication

AU - Bihorac, Azra

AU - Chawla, Lakhmir S.

AU - Shaw, Andrew D.

AU - Al-Khafaji, Ali

AU - Davison, Danielle L.

AU - DeMuth, George E.

AU - Fitzgerald, Robert

AU - Gong, Michelle Ng

AU - Graham, Derrel D.

AU - Gunnerson, Kyle

AU - Heung, Michael

AU - Jortani, Saeed

AU - Kleerup, Eric

AU - Koyner, Jay L.

AU - Krell, Kenneth

AU - LeTourneau, Jennifer

AU - Lissauer, Matthew

AU - Miner, James

AU - Nguyen, H. Bryant

AU - Ortega, Luis M.

AU - Self, Wesley H.

AU - Sellman, Richard

AU - Shi, Jing

AU - Straseski, Joely

AU - Szalados, James E.

AU - Wilber, Scott T.

AU - Walker, Michael G.

AU - Wilson, Jason

AU - Wunderink, Richard

AU - Zimmerman, Janice

AU - Kellum, John A.

PY - 2014/4/15

Y1 - 2014/4/15

N2 - 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 www.clinicaltrials.gov (NCT 01573962).

AB - 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 www.clinicaltrials.gov (NCT 01573962).

KW - Acute kidney injury

KW - Biomarkers

KW - Cell-cycle arrest

KW - Insulin-like growth factor binding protein 7

KW - Tissue inhibitor of metalloproteinases-2

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