title: Incorporation of biomarkers with the renal angina index for prediction of severe AKI in critically ill children.
abstract: OBJECTIVE
  Novel AKI biomarkers carry variable performance for prediction of AKI in patients with heterogeneous illness. Until utility is demonstrated in critically ill patients outside of the cardiopulmonary bypass population, AKI biomarkers are unlikely to gain widespread implementation. Operationalization of an AKI risk stratification methodology, termed renal angina, was recently reported to enhance prediction at the time of intensive care unit admission for persistent severe AKI. The renal angina index (RAI) was developed to provide the clinical context to direct AKI biomarker testing. This study tested the hypothesis that incorporation of AKI biomarkers in patients fulfilling renal angina improves the prediction of persistent severe AKI.
  
  
  METHODS
  In a multicenter study of 214 patients admitted to the pediatric intensive care unit with sepsis, the discrimination of plasma neutrophil gelatinase-associated lipocalin (NGAL), matrix metalloproteinase-8 (MMP-8), and neutrophil elastase-2 (Ela-2) were determined individually and in combination with the RAI for severe AKI. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were calculated.
  
  
  RESULTS
  Individual biomarkers demonstrated marginal discrimination for severe AKI (area under curve [AUC]: NGAL, 0.72; MMP-8, 0.68; Ela-2, 0.72), inferior to prediction by the clinical model of the RAI (AUC=0.80). Incorporation of each biomarker significantly added to the renal angina model AKI prediction (AUC=0.80, increased to 0.84-0.88; P<0.05 for each). The inclusion of each biomarker with the RAI demonstrated NRI (0.512, 0.428, and 0.545 for NGAL, MMP-8, and Ela-2, respectively; all P<0.03) and IDI (0.075 for Ela-2). The inclusion of both Ela-2 and NGAL with RAI demonstrated an NRI of 0.871 (P<0.001) and an IDI of 0.1 (P=0.01).
  
  
  CONCLUSIONS
  This study shows that incorporation of AKI biomarkers into the RAI improves discrimination for severe AKI. The RAI optimizes the utility of AKI biomarkers in a heterogeneous, critically ill patient population.
authors.affiliation: Center for Acute Care Nephrology,, Divisions of ‡Critical Care and, §Biostatistics and Epidemiology, and, ¶The Heart Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;, †Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, ‖Division of Anesthesiology and Critical Care Medicine, George Washington University, Washington, DC.
authors.forename: Rajit K
authors.initials: RK
authors.lastname: Basu
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Hector R
authors.initials: HR
authors.lastname: Wong
authors.forename: Lakhmir S
authors.initials: LS
authors.lastname: Chawla
authors.forename: Derek S
authors.initials: DS
authors.lastname: Wheeler
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Goldstein
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000175:diagnosis* / Q000209:etiology; D000209:Acute-Phase Proteins; D000367:Age Factors; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D002648:Child; D002675:Child, Preschool; D004796:Clinical Enzyme Tests; D016638:Critical Illness; D016002:Discriminant Analysis; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015278:Intensive Care Units, Pediatric; D019272:Leukocyte Elastase / Q000097:blood*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000097:blood*; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000097:blood*; D011237:Predictive Value of Tests; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000097:blood*; D012372:ROC Curve; D018570:Risk Assessment; D012307:Risk Factors; D018805:Sepsis / Q000150:complications* / Q000175:diagnosis; D012720:Severity of Illness Index; D014481:United States
chemical_list: D000209:Acute-Phase Proteins; D015415:Biomarkers; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D019272:Leukocyte Elastase; C488762:MMP8 protein, human; D020784:Matrix Metalloproteinase 8