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

作者：Kianoush Kashani, Ali Al‐Khafaji, Thomas Ardiles, Antonio Artigas, Sean M. Bagshaw, Max Bell, Azra Bihorac, Robert Birkhahn, Cynthia Cely, Lakhmir S. Chawla, Danielle Davison, Thorsten Feldkamp, Lui G. Forni, Michelle N. Gong, Kyle J. Gunnerson, Michael Haase, James Hackett, Patrick M. Honoré, Eric A. J. Hoste, Olivier Joannès-Boyau, Michael Joannidis, Patrick Kim, Jay L. Koyner, Daniel T. Laskowitz, Matthew Lissauer, Gernot Marx, Peter A. McCullough, Scott Mullaney, Marlies Ostermann, Thomas Rimmelé, Nathan I. Shapiro, Andrew D Shaw, Jing Shi, Amy Sprague, Jean‐Louis Vincent, Christophe Vinsonneau, Ludwig Wagner, Michael G. Walker, R. Gentry Wilkerson, Kai Zacharowski, John A. Kellum · 发表于：Critical Care · 年份：2013 · DOI：10.1186/cc12503 · 被引用次数：1402 · 研究领域：Acute Kidney Injury Research、Trauma, Hemostasis, Coagulopathy, Resuscitation、Chronic Kidney Disease and Diabetes

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 AU...