TY  - JOUR
A1  - Kashani, Kianoush
A1  - Al-Khafaji, Ali
A1  - Ardiles, Thomas
A1  - Artigas, Antonio
A1  - Bagshaw, Sean M.
A1  - Bell, Max
A1  - Bihorac, Azra
A1  - Birkhahn, Robert
A1  - Cely, Cynthia M.
A1  - Chawla, Lakhmir S.
A1  - Davison, Danielle L.
A1  - Feldkamp, Thorsten
A1  - Forni, Lui G.
A1  - Gong, Michelle Ng
A1  - Gunnerson, Kyle J.
A1  - Haase, Michael
A1  - Hackett, James
A1  - Honore, Patrick M.
A1  - Hoste, Eric A. J.
A1  - Joannes-Boyau, Olivier
A1  - Joannidis, Michael
A1  - Kim, Patrick
A1  - Koyner, Jay L.
A1  - Laskowitz, Daniel T.
A1  - Lissauer, Matthew E.
A1  - Marx, Gernot
A1  - McCullough, Peter A.
A1  - Mullaney, Scott
A1  - Ostermann, Marlies
A1  - Rimmelé, Thomas
A1  - Shapiro, Nathan I.
A1  - Shaw, Andrew D.
A1  - Shi, Jing
A1  - Sprague, Amy M.
A1  - Vincent, Jean-Louis
A1  - Vinsonneau, Christophe
A1  - Wagner, Ludwig
A1  - Walker, Michael G.
A1  - Wilkerson, R. Gentry
A1  - Zacharowski, Kai
A1  - Kellum, John A.
T1  - Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury
T2  - Critical Care
N2  - 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. Trial registration: ClinicalTrials.gov number NCT01209169.
Y1  - 2013
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/28853
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-288533
SN  - 1875-7081
SN  - 1574-4280
N1  - © 2013 Kashani et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
VL  - 17
IS  - R25
PB  - Bohn Stafleu Van Loghum
CY  - Houten
ER  -