Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

Kashani, K and Al-Khafaji, A and Ardiles, T and Artigas, A and Bagshaw, SM and Bell, M and Bihorac, A and Birkhahn, R and Cely, CM and Chawla, LS and Davison, DL and Feldkamp, T and Forni, LG and Gong, MN and Gunnerson, KJ and Haase, M and Hackett, J and Honore, PM and Hoste, EAJ and Joannes-Boyau, O and Joannidis, M and Kim, P and Koyner, JL and Laskowitz, DT and Lissauer, ME and Marx, G and McCullough, PA and Mullaney, S and Ostermann, M and Rimmelé, T and Shapiro, NI and Shaw, AD and Shi, J and Sprague, AM and Vincent, JL and Vinsonneau, C and Wagner, L and Walker, MG and Wilkerson, RG and Zacharowski, K and Kellum, JA (2013) Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Critical Care, 17 (1). ISSN 1364-8535

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Abstract

Introduction: Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI. Methods: We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection. Results: Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P < 0.002), none of which achieved an AUC > 0.72. Furthermore, [TIMP- 2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method. Conclusions: Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Kashani, K Al-Khafaji, A aha6@pitt.edu AHA6 0000-0002-3441-3917 Ardiles, T Artigas, A Bagshaw, SM Bell, M Bihorac, A Birkhahn, R Cely, CM Chawla, LS Davison, DL Feldkamp, T Forni, LG Gong, MN Gunnerson, KJ Haase, M Hackett, J Honore, PM Hoste, EAJ Joannes-Boyau, O Joannidis, M Kim, P Koyner, JL Laskowitz, DT Lissauer, ME Marx, G McCullough, PA Mullaney, S Ostermann, M Rimmelé, T Shapiro, NI Shaw, AD Shi, J Sprague, AM Vincent, JL Vinsonneau, C Wagner, L Walker, MG Wilkerson, RG Zacharowski, K Kellum, JA kellum@pitt.edu KELLUM 0000-0003-1995-2653
Date:	6 February 2013
Date Type:	Publication
Journal or Publication Title:	Critical Care
Volume:	17
Number:	1
DOI or Unique Handle:	10.1186/cc12503
Schools and Programs:	School of Medicine > Critical Care Medicine
Refereed:	Yes
ISSN:	1364-8535
Date Deposited:	06 Oct 2016 19:47
Last Modified:	25 Jun 2021 04:55
URI:	http://d-scholarship.pitt.edu/id/eprint/29762

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