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 0.72. 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.

Patients: One hundred adult cardiac surgical patients. Measurements and Main Results: We measured concentrations of plasma neutrophil gelatinase-associated lipocalin (NGAL), and serum cystatin C, and creatinine and urea at baseline, on arrival in the intensive care unit (ICU) and at 24 hours postoperatively. We assessed such biomarkers in relation to the development of AKI (>50% increase in creatinine from baseline) and to a composite end point (need for renal replacement therapy and in-hospital mortality). We defined an area under the receiver operating characteristic curve of 0.60–0.69 as poor, 0.70–0.79 as fair, 0.80–0.89 as good, and 0.90–1.00 as excellent in terms of predictive value. On arrival in ICU, plasma NGAL and serum cystatin C were of good predictive value, but creatinine and urea were of poor predictive value. After exclusion of patients with preoperative renal impairment (estimated glomerular filtration rate <60 mL/min), the predictive performance for AKI of all renal biomarkers on arrival in ICU remained unchanged except for cystatin C, which was of fair value in such patients. At 24 hours postoperatively, all renal biomarkers were of good predictive value. On arrival in ICU, novel biomarkers were superior to conventional biomarkers (p < 0.05). Plasma NGAL (p = 0.015) and serum cystatin C (p = 0.007) were independent predictors of AKI and of excellent value in the prediction of the composite end point. Conclusions: Early postoperative measurement of plasma NGAL was of good value in identifying patients who developed AKI after adult cardiac surgery. Plasma NGAL and serum cystatin C were superior to conventional biomarkers in the prediction of AKI and were also of prognostic value in this setting....

Background: The early prediction of acute kidney injury (AKI) by current clinical and laboratory methods remains inadequate. Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as a promising non-invasive biomarker of kidney injury. We systematically reviewed the utility of plasma and urine NGAL measurements for the prediction of AKI in humans. Methods: We searched MEDLINE, PubMed and EMBASE for human biomarker studies that included NGAL (January 2005 to October 2013). Studies reporting on the use of NGAL for the early prediction and prognosis of AKI were analysed in three common clinical settings: cardiac surgery, critical illness and kidney transplantation. Results: We identified 58 manuscripts that met our inclusion and exclusion criteria, reporting on more than 16,500 patients. Following cardiac surgery, NGAL measurement in over 7000 patients was predictive of AKI and its severity, with an overall area under the receiver operator characteristic curve (AUC) of 0.82–0.83. Similar results were obtained in over 8500 critically ill patients. In over 1000 patients undergoing kidney transplantation, NGAL measurements predicted delayed graft function with an overall AUC of 0.87. In all three settings, NGAL significantly improved the prediction of AKI risk over the clinical model alone. Conclusions: We identified several studies that collectively strongly support the use of NGAL as a biomarker for the prediction of AKI. However, we noted some limitations, including lack of published studies that adhere to diagnostic study guidelines, heterogeneity in AKI definition, the lack of uniformly applicable cut-off values and variability in the performance of commercially available NGAL assays.