Validation of cell-cycle arrest biomarkers for acute kidney injury after pediatric cardiac surgery

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


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:, DRKS00005062.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / etiology*
  • Acute Kidney Injury / urine
  • Biomarkers / urine*
  • Cardiac Surgical Procedures / adverse effects*
  • Cell Cycle Checkpoints*
  • Child
  • Female
  • Humans
  • Insulin-Like Growth Factor Binding Proteins / urine
  • Male
  • Pediatrics
  • Proportional Hazards Models
  • ROC Curve
  • Tissue Inhibitor of Metalloproteinase-2 / urine


  • Biomarkers
  • Insulin-Like Growth Factor Binding Proteins
  • insulin-like growth factor binding protein-related protein 1
  • Tissue Inhibitor of Metalloproteinase-2

Associated data

  • DRKS/DRKS00005062

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.