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Use of Cell Cycle Arrest Biomarkers in Conjunction With Classical Markers of Acute Kidney Injury

Joannidis, Michael, Forni, Lui G., Haase, Michael, Koyner, Jay, Shi, Jing, Kashani, Kianoush, Chawla, Lakhmir S. and Kellum, John A. (2019) Use of Cell Cycle Arrest Biomarkers in Conjunction With Classical Markers of Acute Kidney Injury Critical Care Medicine, 47 (10). e820-e826.

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Decreased urine output and/or increased serum creatinine may herald the development of acute kidney injury or reflect normal physiology. In this secondary analysis of the Sapphire study, we examined biomarkers of cell cycle arrest in the settings of oliguria and/or azotemia to improve risk assessment when used with conventional indices in predicting severe acute kidney injury (Kidney Disease: Improving Global Outcomes 3 defined by the need for renal replacement therapy or changes in urine output, serum creatinine or both) or death.

Design: Prospective, international, Sapphire study.

Setting: Academic Medical Center.

Patients: Patients without acute kidney injury Kidney Disease: Improving Global Outcomes stage 2 or 3.

Interventions: None.

Measurements and Main Results:

The primary endpoint being development of severe acute kidney injury or death within 1 week. Secondary analysis examined the relationship between tissue inhibitor of metalloproteinases-2 ([TIMP-2]) and insulin growth factor binding protein 7 ([IGFBP7]) and 9-month death or dialysis conditioned on progression to stage 2–3 acute kidney injury within 1 week. Seventy-nine patients reached the primary endpoint and were more likely to be surgical, with higher nonrenal Acute Physiology and Chronic Health Evaluation III scores and more chronic kidney disease. Stage 1 urine output, serum creatinine, and urinary [TIMP-2]•[IGFBP7] greater than 2.0 were all predictive of progression to the primary endpoint independent from nonrenal Acute Physiology and Chronic Health Evaluation III score. Combinations of predictors increased the hazard ratios considerably (from 2.17 to 4.14 to 10.05, respectively). In the presence of acute kidney injury (stage 1), [TIMP-2]•[IGFBP7] greater than 2.0 leads to an increased risk of death or dialysis at 9 months even in the absence of progression of acute kidney injury (stage 2–3) within 7 days.


Cell cycle arrest biomarkers, TIMP-2 and IGFBP7, improve risk stratification for severe outcomes in patients with stage 1 acute kidney injury by urine output, serum creatinine or both, with risk increasing with each acute kidney injury indicator. Longer term outcomes demonstrate that the associated risks of a [TIMP-2]•[IGFBP7] greater than 2.0 is equivalent to acute kidney injury progression even where no progression from stage 1 acute kidney injury is observed.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
Joannidis, Michael
Forni, Lui
Haase, Michael
Koyner, Jay
Shi, Jing
Kashani, Kianoush
Chawla, Lakhmir S.
Kellum, John A.
Date : October 2019
DOI : 10.1097/CCM.0000000000003907
Copyright Disclaimer : Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Uncontrolled Keywords : Acute kidney injury; Biomarkers; Cell cycle arrest; Oliguria
Depositing User : Diane Maxfield
Date Deposited : 29 Oct 2019 10:16
Last Modified : 29 Oct 2019 10:16

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