title: Urine Interleukin 18 and Lipocalin 2 Are Biomarkers of Acute Tubular Necrosis in Patients With Cirrhosis: A Systematic Review and Meta-analysis.
abstract: OBJECTIVE
  Acute kidney injury (AKI) is a common complication in patients with cirrhosis that increases mortality. The most common causes of AKI in these patients are prerenal azotemia, acute tubular necrosis (ATN), and hepatorenal syndrome; it is important to determine the etiology of AKI to select the proper treatment and predict patient outcome. Urine biomarkers could be used to differentiate between patients with ATN and functional causes of AKI. We performed a systematic review and meta-analysis of published studies to determine whether urine levels of interleukin (IL)18 and lipocalin 2 or neutrophil gelatinase-associated lipocalin (NGAL) are associated with the development of ATN in patients with cirrhosis.
  
  
  METHODS
  We searched MEDLINE, Scopus, ISI Web of Knowledge, and conference abstracts through December 31, 2015, for studies that assessed urine biomarkers for detection of acute kidney injury in patients with cirrhosis or reported an association between urine biomarkers and all-cause mortality in these patients. We included only biomarkers assessed in 3 or more independent studies, searching for terms that included urine biomarkers, cirrhosis, NGAL, and IL18. We calculated the pooled sensitivities and specificities for detection and calculated the area under the receiver operating characteristic curve (AUC) values using a bivariate logistic mixed-effects model. We used the χ2test to assess heterogeneity among studies.
  
  
  RESULTS
  We analyzed data from 8 prospective studies, comprising 1129 patients with cirrhosis. We found urine levels of the markers discriminated between patients with ATN and other types of kidney impairments, with AUC values of 0.88 for IL18 (95% confidence interval [CI], 0.79-0.97) and 0.89 for NGAL (95% CI, 0.84-0.94). Urine levels of IL18 identified patients who would die in the hospital or within 90 days (short-term mortality) with an AUC value of 0.76 (95% CI, 0.68-0.85); NGAL identified these patients with the same AUC (0.76; 95% CI, 0.71-0.82).
  
  
  CONCLUSIONS
  In a systematic review and meta-analysis, we found that urine levels of IL18 and NGAL from patients with cirrhosis discriminate between those with ATN and other types of kidney impairments, with AUC values of 0.88 and 0.89, respectively. Urine levels of IL18 and NGAL identified patients with short-term mortality with an AUC value of 0.76. These biomarkers might be used to determine prognosis and select treatments for patients with cirrhosis.
authors.affiliation: Program of Applied Translational Research, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Puthumana
authors.affiliation: Clínic de Barcelona, Universitat de Barcelona, University of Barcelona, Institut d'Investigacions Biomèdiques August-Pi-Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Ariza
authors.affiliation: Program of Applied Translational Research, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut; Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Belcher
authors.affiliation: Clínic de Barcelona, Universitat de Barcelona, University of Barcelona, Institut d'Investigacions Biomèdiques August-Pi-Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Graupera
authors.affiliation: Clínic de Barcelona, Universitat de Barcelona, University of Barcelona, Institut d'Investigacions Biomèdiques August-Pi-Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Ginès
authors.affiliation: Program of Applied Translational Research, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut; Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut; Veterans Affairs Connecticut Healthcare System, New Haven, Connecticut. Electronic address: chirag.parikh@yale.edu.
authors.forename: Chirag R
authors.initials: CR
authors.lastname: Parikh
mesh_terms: D015415:Biomarkers / Q000652:urine*; D006801:Humans; D020382:Interleukin-18 / Q000652:urine*; D007683:Kidney Tubular Necrosis, Acute / Q000175:diagnosis* / Q000473:pathology; D000071068:Lipocalin-2 / Q000652:urine*; D008103:Liver Cirrhosis / Q000150:complications*
chemical_list: D015415:Biomarkers; C000589760:IL18 protein, human; D020382:Interleukin-18; C489506:LCN2 protein, human; D000071068:Lipocalin-2
keywords: Cytokine; Prediction; Prognostic Factor; Survival