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

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 eti...

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Vydáno v:	Critical care (London, England) Ročník 17; číslo 1; s. R25
Hlavní autoři:	Kashani, Kianoush, Al-Khafaji, Ali, Ardiles, Thomas, Artigas, Antonio, Bagshaw, Sean M, Bell, Max, Bihorac, Azra, Birkhahn, Robert, Cely, Cynthia M, Chawla, Lakhmir S, Davison, Danielle L, Feldkamp, Thorsten, Forni, Lui G, Gong, Michelle Ng, Gunnerson, Kyle J, Haase, Michael, Hackett, James, Honore, Patrick M, Hoste, Eric AJ, Joannes-Boyau, Olivier, Joannidis, Michael, Kim, Patrick, Koyner, Jay L, Laskowitz, Daniel T, Lissauer, Matthew E, Marx, Gernot, McCullough, Peter A, Mullaney, Scott, Ostermann, Marlies, Rimmelé, Thomas, Shapiro, Nathan I, Shaw, Andrew D, Shi, Jing, Sprague, Amy M, Vincent, Jean-Louis, Vinsonneau, Christophe, Wagner, Ludwig, Walker, Michael G, Wilkerson, R Gentry, Zacharowski, Kai, Kellum, John A
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London BioMed Central 06.02.2013 BioMed Central Ltd
Témata:	Acute Kidney Injury - diagnosis Acute Kidney Injury - urine Acute renal failure Aged Biological markers Biomarkers - urine Cell cycle Cell Cycle Checkpoints - physiology Cohort Studies Comparative analysis Critical Care Medicine Emergency Medicine Female Humans Insulin-Like Growth Factor Binding Proteins - urine Intensive Male Medical research Medicine Medicine & Public Health Medicine, Experimental Middle Aged Pharmaceutical industry Physiological aspects Protein binding Tissue Inhibitor of Metalloproteinase-2 - urine United States Integrate Discrimination Improvement Acute Kidney Injury Renal Replacement Therapy Persistent Renal Dysfunction Plasma NGAL
ISSN:	1364-8535, 1466-609X, 1364-8535, 1466-609X
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Shrnutí:	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 G 1 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 .
Bibliografie:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Undefined-3
ISSN:	1364-8535 1466-609X 1364-8535 1466-609X
DOI:	10.1186/cc12503