title: Urinary Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) • Insulin-Like Growth Factor-Binding Protein 7 (IGFBP7) Predicts Adverse Outcome in Pediatric Acute Kidney Injury.
abstract: BACKGROUND
  The G1 cell cycle inhibitors tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been identified as promising biomarkers for the prediction of adverse outcomes including renal replacement therapy (RRT) and mortality in critically ill adult patients who develop acute kidney injury (AKI). However, the prognostic value of urinary TIMP-2 and IGFBP7 in neonatal and pediatric AKI for adverse outcome has not been investigated yet.
  
  
  METHODS
  The product of the urinary concentration of TIMP-2 and IGFBP7 ([TIMP-2]•[IGFBP7]) was assessed by a commercially available immunoassay (NephroCheck™) in a prospective cohort study in 133 subjects aged 0-18 years including 46 patients with established AKI according to pRIFLE criteria, 27 patients without AKI (non-AKI group I) and 60 apparently healthy neonates and children (non-AKI group II). AKI etiologies were: dehydration/hypovolemia (n = 7), hemodynamic instability (n = 7), perinatal asphyxia (n = 9), septic shock (n = 7), typical hemolytic-uremic syndrome (HUS; n = 5), interstitial nephritis (n = 5), vasculitis (n = 4), nephrotoxic injury (n = 1) and renal vein thrombosis (n = 1).
  
  
  RESULTS
  When AKI patients were classified into pRIFLE criteria, 6/46 (13%) patients fulfilled the criteria for the category "Risk", 13/46 (28%) for "Injury", 26/46 (57%) for "Failure" and 1/46 (2%) for "Loss". Patients in the "Failure" stage had a median 3.7-fold higher urinary [TIMP-2]•[IGFBP7] compared to non-AKI subjects (P<0.001). When analyzed for AKI etiology, highest [TIMP-2]•[IGFBP7] values were found in patients with septic shock (P<0.001 vs. non-AKI I+II). Receiver operating characteristic (ROC) curve analyses in the AKI group revealed good performance of [TIMP-2]•[IGFBP7] in predicting 30-day (area under the curve (AUC) 0.79; 95% CI, 0.61-0.97) and 3-month mortality (AUC 0.84; 95% CI, 0.67-0.99) and moderate performance in predicting RRT (AUC 0.67; 95% CI, 0.50-0.84).
  
  
  CONCLUSIONS
  This study shows that urinary [TIMP-2]•[IGFBP7] has a good diagnostic performance in predicting adverse outcomes in neonatal and pediatric AKI of heterogeneous etiology.
authors.affiliation: Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany.
authors.forename: Jens H
authors.initials: JH
authors.lastname: Westhoff
authors.affiliation: Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Tönshoff
authors.affiliation: Department of Neonatology, University Children's Hospital, Heidelberg, Germany.
authors.forename: Sina
authors.initials: S
authors.lastname: Waldherr
authors.affiliation: Department of Neonatology, University Children's Hospital, Heidelberg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Pöschl
authors.affiliation: Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Teufel
authors.affiliation: Medizinische Klinik I, Universitätsklinik Marien Hospital Herne, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Timm H
authors.initials: TH
authors.lastname: Westhoff
authors.affiliation: Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Fichtner
mesh_terms: D058186:Acute Kidney Injury / Q000175:diagnosis* / Q000209:etiology / Q000401:mortality / Q000652:urine*; D000293:Adolescent; D000367:Age Factors; D015415:Biomarkers; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018969:Insulin-Like Growth Factor Binding Proteins / Q000652:urine*; D053208:Kaplan-Meier Estimate; D008297:Male; D063868:Patient Outcome Assessment; D011379:Prognosis; D011446:Prospective Studies; D012372:ROC Curve; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000652:urine*
chemical_list: D015415:Biomarkers; D018969:Insulin-Like Growth Factor Binding Proteins; C102529:insulin-like growth factor binding protein-related protein 1; D019716:Tissue Inhibitor of Metalloproteinase-2