77 for RIFLE Failure but when included in a ‘most efficient clinical model’ NGAL improved the ROC area under curve for RIFLE Failure to 0.96 [42]. OK In this study, specificity was 50% for a plasma NGAL cut-off value of 168 ng/ml. Emergency promotion information room serum NGAL levels >150 ng/ml were highly sensitive for AKI within 72 hours (96%), but specificity was only 51% [43]. NGAL is known to be released by activated neutrophils and appears to be intrinsically elevated in sepsis, which may explain its limitation as a biomarker specific for SSAKI.A variable that may complicate delineation of biomarkers for SSAKI is that the pathophysiology of SSAKI may be different from that of ischemic or nephrotoxic AKI. Although acute tubular necrosis has traditionally been considered the etiology of AKI in sepsis, no conclusive pathologic evidence has demonstrated that this is true [18].

Animal models of SSAKI demonstrate increased, rather than decreased, renal blood flow and a state of hyperdynamic AKI [44]. The mechanisms mediating disease progression are multifactorial, and AKI during sepsis may be a result of acute tubular apoptosis rather than acute tubular necrosis [18]. Nonhemodynamic-dependent mechanisms of injury during sepsis, inflammatory and immunologic, may trigger this apoptotic response. This pathophysiology has probably decreased the utility of traditional tests based on the functionality of proximal tubular filtration [45].Our study demonstrates that microarray-derived gene expression data can provide a tool for discovery of candidate biomarkers for SSAKI.

Outside the neonatal population, we are the first group to attempt to characterize biomarkers specific to SSAKI (and not all-cause AKI) in children. Our data represent the first 24 hours of presentation to medical care, a timeframe that can be considered a therapeutic window for acute intervention. It is important to note that our patients were restricted to having septic shock, an exclusion criterion not previously used in pediatric studies investigating AKI biomarkers. Additionally, our definition of SSAKI identifies patients with GSK-3 severe, persistent kidney injury up to day 7. These candidate biomarkers thus identify patients with resuscitation unresponsive AKI (that is, patients having high serum creatinine levels at admission who subsequently did not normalize with standard resuscitation). The expression patterns of the 21 upregulated gene probes demonstrate excellent sensitivity and good specificity for SSAKI (Figure (Figure1).1). The negative predictive value of nearly 100% carries obvious import to the bedside practitioner, but should be tempered by the fact that the prevalence of AKI in our cohort was relatively low (31/179, 17%).