Kianoush Kashani 1 , Ali Al-Khafaji 2 , Thomas Ardiles 3 , Antonio Artigas 4 , Sean M Bagshaw 5 , Max Bell 6 , Azra Bihorac 7 , Robert Birkhahn 8 , Cynthia M Cely 9 , Lakhmir S Chawla 10 , Danielle L Davison 10 , Thorsten Feldkamp 11 , Lui G Forni 12 , Michelle Ng Gong 13 , Kyle J Gunnerson 14 , Michael Haase 15 , James Hackett 16 , Patrick M Honore 17 , Eric AJ Hoste 18 , Olivier Joannes-Boyau 19 , Michael Joannidis 20 , Patrick Kim 21 , Jay L Koyner 22 , Daniel T Laskowitz 23 , Matthew E Lissauer 24 , Gernot Marx 25 , Peter A McCullough 26 , Scott Mullaney 27 , Marlies Ostermann 28 , Thomas Rimmelé 29 , Nathan I Shapiro 30 , Andrew D Shaw 31 , Jing Shi 32 , Amy M Sprague 33 , Jean-Louis Vincent 34 , Christophe Vinsonneau 35 , Ludwig Wagner 36 , Michael G Walker 32 , R Gentry Wilkerson 37 , Kai Zacharowski 38 , John A Kellum , 39
6 February 2013
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.
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.
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.
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.
ClinicalTrials.gov number NCT01209169.