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. 2014 Oct 24;9(10):e110865.
doi: 10.1371/journal.pone.0110865. eCollection 2014.

Validation of Cell-Cycle Arrest Biomarkers for Acute Kidney Injury After Pediatric Cardiac Surgery

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Free PMC article

Validation of Cell-Cycle Arrest Biomarkers for Acute Kidney Injury After Pediatric Cardiac Surgery

Melanie Meersch et al. PLoS One. .
Free PMC article

Abstract

Background: The lack of early biomarkers for acute kidney injury (AKI) seriously inhibits the initiation of preventive and therapeutic measures for this syndrome in a timely manner. We tested the hypothesis that insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, function as early biomarkers for AKI after congenital heart surgery with cardiopulmonary bypass (CPB).

Methods: We prospectively studied 51 children undergoing cardiac surgery with CPB. Serial urine samples were analyzed for [TIMP-2]•[IGFBP7]. The primary outcome measure was AKI defined by the pRIFLE criteria within 72 hours after surgery.

Results: 12 children (24%) developed AKI within 1.67 (SE 0.3) days after surgery. Children who developed AKI after cardiac surgery had a significant higher urinary [TIMP-2]•[IGFBP7] as early as 4 h after the procedure, compared to children who did not develop AKI (mean of 1.93 ((ng/ml)²/1000) (SE 0.4) vs 0.47 ((ng/ml)²/1000) (SE 0.1), respectively; p<0.05). Urinary [TIMP-2]•[IGFBP7] 4 hours following surgery demonstrated an area under the receiver-operating characteristic curve of 0.85. Sensitivity was 0.83, and specificity was 0.77 for a cutoff value of 0.70 ((ng/ml)²/1000).

Conclusions: Urinary [TIMP-2]•[IGFBP7] represent sensitive, specific, and highly predictive early biomarkers for AKI after surgery for congenital heart disease.

Trial registration: www.germanctr.de/, DRKS00005062.

Conflict of interest statement

Competing Interests: Alexander Zarbock is a PLOS ONE Editorial Board member. This does not alter the authors' adherence to PLOS ONE Editorial policies and criteria.

Figures

Figure 1
Figure 1. Flow Diagram.
Figure 2
Figure 2. Analysis of urine biomarkers.
(A) Graph shows creatinine concentrations in the plasma at various time points before and after cardiopulmonary bypass. (B and C) Graph shows mean urine [TIMP-2]*[IGFBP7] (B) and neutrophil gelatinase-associated lipocalin (NGAL) (C) concentrations at various time points before and after cardiopulmonary bypass. Error bars are SE. Asterisks (*) denote significant differences (p≤0.05, Mann-Whitney-U test) between groups (AKI, non-AKI) at the respective time point. (D) Graph shows mean urine kidney injury molecule (KIM)-1 concentrations at various time points before and after cardiopulmonary bypass. Error bars are SE. Asterisks (*) denote significant differences (p≤0.05, Mann-Whitney-U test) between groups (AKI, non-AKI) at the respective time point.
Figure 3
Figure 3. Analysis of ROC curves.
(A) This figure displays the receiver operating characteristic (ROC) curves for the 4 h value of [TIMP-2]•[IGFBP7]. (B) Area under the receiver-operating characteristics curve (AUC) for [TIMP-2]•[IGFBP7] and existing biomarkers of acute kidney injury. The AUC for urinary [TIMP-2]•[IGFBP7] is as large as the AUC for urinary NGAL and significantly larger than the AUC for urinary kidney injury marker-1 (KIM-1).# p<0.05 vs KIM-1.

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Grant support

This study was supported by the German Research Foundation (ZA428/6-1 to A.Z.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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