Urinary Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) • Insulin-Like Growth Factor-Binding Protein 7 (IGFBP7) Predicts Adverse Outcome in Pediatric Acute Kidney Injury.

Jens H Westhoff,Johannes Pöschl,Timm H Westhoff,Sina Waldherr,Alexander Fichtner,Burkhard Tönshoff,Ulrike Teufel,Umberto Simeoni

doi:10.1371/journal.pone.0143628

Abstract

BackgroundThe 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.MethodsThe 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).ResultsWhen 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).ConclusionsThis study shows that urinary [TIMP-2]•[IGFBP7] has a good diagnostic performance in predicting adverse outcomes in neonatal and pediatric AKI of heterogeneous etiology.

Highlights

Acute kidney injury (AKI) is a complex disorder that constitutes an independent risk factor for morbidity and mortality in adult and pediatric patients [1, 2]
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”
When analyzed for AKI etiology, highest [tissue inhibitor of metalloproteinase-2 (TIMP-2)][insulin-like growth factor-binding protein 7 (IGFBP7)] values were found in patients with septic shock

Summary

Introduction

Acute kidney injury (AKI) is a complex disorder that constitutes an independent risk factor for morbidity and mortality in adult and pediatric patients [1, 2]. 10% of all children admitted to a pediatric intensive care unit (PICU) develop AKI, and this rate exceeds 80% with increasing severity of illness [3, 4]. The reported mortality from AKI is still as high as 60% [5]. 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). The prognostic value of urinary TIMP-2 and IGFBP7 in neonatal and pediatric AKI for adverse outcome has not been investigated yet

Methods

Results

Conclusion