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

(2013) CRITICAL CARE. 17(1).
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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. Trial registration: ClinicalTrials.gov number NCT01209169.
Keywords
ANIMAL-MODELS, ACUTE-RENAL-FAILURE, LONG, PATHOPHYSIOLOGY, PROGRESSION, SENESCENCE, MORTALITY, SURGERY, SEPSIS

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MLA
Kashani, Kianoush, Ali Al-Khafaji, Thomas Ardiles, et al. “Discovery and Validation of Cell Cycle Arrest Biomarkers in Human Acute Kidney Injury.” CRITICAL CARE 17.1 (2013): n. pag. Print.
APA
Kashani, K., Al-Khafaji, A., Ardiles, T., Artigas, A., Bagshaw, S. M., Bell, M., Bihorac, A., et al. (2013). Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. CRITICAL CARE, 17(1).
Chicago author-date
Kashani, Kianoush, Ali Al-Khafaji, Thomas Ardiles, Antonio Artigas, Sean M Bagshaw, Max Bell, Azra Bihorac, et al. 2013. “Discovery and Validation of Cell Cycle Arrest Biomarkers in Human Acute Kidney Injury.” Critical Care 17 (1).
Chicago author-date (all authors)
Kashani, Kianoush, Ali Al-Khafaji, Thomas Ardiles, Antonio Artigas, Sean M Bagshaw, Max Bell, Azra Bihorac, Robert Birkhahn, Cynthia M Cely, Lakhmir S Chawla, Danielle L Davison, Thorsten Feldkamp, Lui G Forni, Michelle Ng Gong, Kyle J Gunnerson, Michael Haase, James Hackett, Patrick M Honore, Eric Hoste, Olivier Joannes-Boyau, Michael Joannidis, Patrick Kim, Jay L Koyner, Daniel T Laskowitz, Matthew E Lissauer, Germot Marx, Peter A McCullough, Scott Mullaney, Marlies Ostermann, Thomas Rimmelé, Nathan I Shapiro, Andrew D Shaw, Jing Shi, Amy M Sprague, Jean-Louis Vincent, Christophe Vinsonneau, Ludwig Wagner, Michael G Walker, R Gentry Wilkerson, Kai Zacharowski, and John A Kellum. 2013. “Discovery and Validation of Cell Cycle Arrest Biomarkers in Human Acute Kidney Injury.” Critical Care 17 (1).
Vancouver
1.
Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. CRITICAL CARE. 2013;17(1).
IEEE
[1]
K. Kashani et al., “Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury,” CRITICAL CARE, vol. 17, no. 1, 2013.
@article{3228267,
  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.
Trial registration: ClinicalTrials.gov number NCT01209169.},
  articleno    = {R25},
  author       = {Kashani, Kianoush and Al-Khafaji, Ali and Ardiles, Thomas and Artigas, Antonio and Bagshaw, Sean M and Bell, Max and Bihorac, Azra and Birkhahn, Robert and Cely, Cynthia M and Chawla, Lakhmir S and Davison, Danielle L and Feldkamp, Thorsten and Forni, Lui G and Gong, Michelle Ng and Gunnerson, Kyle J and Haase, Michael and Hackett, James and Honore, Patrick M and Hoste, Eric and Joannes-Boyau, Olivier and Joannidis, Michael and Kim, Patrick and Koyner, Jay L and Laskowitz, Daniel T and Lissauer, Matthew E and Marx, Germot and McCullough, Peter A and Mullaney, Scott and Ostermann, Marlies and Rimmelé, Thomas and Shapiro, Nathan I and Shaw, Andrew D and Shi, Jing and Sprague, Amy M and Vincent, Jean-Louis and Vinsonneau, Christophe and Wagner, Ludwig and Walker, Michael G and Wilkerson, R Gentry and Zacharowski, Kai and Kellum, John A},
  issn         = {1466-609X},
  journal      = {CRITICAL CARE},
  keywords     = {ANIMAL-MODELS,ACUTE-RENAL-FAILURE,LONG,PATHOPHYSIOLOGY,PROGRESSION,SENESCENCE,MORTALITY,SURGERY,SEPSIS},
  language     = {eng},
  number       = {1},
  pages        = {12},
  title        = {Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury},
  url          = {http://dx.doi.org/10.1186/cc12503},
  volume       = {17},
  year         = {2013},
}

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