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Kinetics of the cell cycle arrest biomarkers (TIMP-2*IGFBP-7) for prediction of acute kidney injury in infants after cardiac surgery

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Abstract

Background

Tissue inhibitor metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP-7) are cell-cycle arrest biomarkers that have been shown to be predictive of acute kidney injury (AKI) in critically ill adults. AKI affects a large proportion (40%) of children following cardiac surgery. The aim of this study was to describe the kinetics of TIMP-2*IGFBP-7 and test its ability to predict AKI in infants following cardiac surgery.

Methods

A multicenter prospective study was performed in infants undergoing cardiac surgery with cardiopulmonary bypass (CPB) from October 2013 to January 2015. Urine samples were obtained at baseline and at 2, 6, 12, 24, 48 and 72 h after CPB initiation. TIMP-2*IGFBP-7 concentration was measured in urine samples using the Astute 140® meter to determine a risk score for AKI. This risk score is the product of TIMP-2 (ng/mL) and IGFBP-7 (ng/mL) divided by 1000.

Results

A total of 94 infants with a mean age of 154.2 ± 85.7 days were enrolled in the study, of whom 31 (33%) subsequently developed AKI. The mean time to AKI diagnosis was 25 ± 7 h after CPB initiation. The concentration of TIMP-2*IGFBP-7 was significantly higher in patients with AKI at 12 h after CPB initiation relative to baseline (p = 0.006). At 12 h after CPB initiation patients with a TIMP-2*IGFBP-7 concentration of ≥0.78 had a threefold higher odds of developing AKI than those with a TIMP-2*IGFBP-7 concentration of < 0.78 (95% confidence interval 1.47–6.11, p = 0.001).

Conclusion

These results demonstration that TIMP-2*IGFBP-7 concentration can be used in infants to predict subsequent serum creatinine-defined AKI following CPB.

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Acknowledgments

Urinary TIMP-2*IGFBP-7 processing was supported by a pilot grant from the Children’s Hospital Colorado Research Institute. Special thanks to the research coordinators at each of the participating sites: Shruti Marwaha and Shalayna Woodly at Cincinnati Children’s Hospital Medical Center; Krissie Hock at Children’s of Alabama; the team of nurses in the pediatric clinical translation research center at Children’s Hospital Colorado at the University of Colorado. Finally, thanks to the Center for Acute Care Nephrology, the Heart Institute Research Core and the Division of Critical Care Medicine at Cincinnati Children’s Hospital Medical Center for their support throughout the study.

Author information

Authors and Affiliations

  1. Children’s Hospital Colorado–The University of Colorado, 13123 E 16th Ave, Aurora, CO, 80045, USA

    Katja M. Gist, Danielle E. Soranno & Jane Duplantis

  2. The Heart Institute, Children’s Hospital Colorado, 13123 E 16th Ave, B100, Aurora, CO, 80045, USA

    Katja M. Gist & Julia Wrona

  3. Center for Acute Care Nephrology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, MLC 7022, Cincinnati, OH, 45229, USA

    Stuart L. Goldstein

  4. Pediatric Critical Care Medicine, Children’s of Alabama–University of Alabama, WIC 1799 6th Ave S, Suite 9100 176 F, Birmingham, AL, 35233, USA

    Jeffrey A. Alten

  5. Pediatric Critical Care Medicine, Center for Acute Care Nephrology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, MLC 2005, Cincinnati, OH, 45229, USA

    Rajit K. Basu

  6. The Heart Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, MLC 2003, Cincinnati, OH, 45229, USA

    David S. Cooper

  7. The Kidney Center, Children’s Hospital Colorado–The University of Colorado, 13123 E 16th Ave, Aurora, CO, 80045, USA

    Danielle E. Soranno & Jane Duplantis

  8. Department of Internal Medicine, Division of Renal Disease and Hypertension, University of Colorado Anschutz Medical Campus, 12700 E 19th Ave, Box C281, Aurora, CO, 80045, USA

    Christopher Altmann & Sarah Faubel

  9. Heart Institute Research Core, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, MLC, Cincinnati, OH, 45229, USA

    Zhiqian Gao

Authors
  1. Katja M. Gist
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  2. Stuart L. Goldstein
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Corresponding author

Correspondence to Katja M. Gist.

Ethics declarations

A multi-center prospective observational study was performed in infants (≤1 year of age) after cardiac surgery with CPB from October 2013 to January 2015 following institutional review board approval. Informed consent was obtained from the parents, or parent, of each child included in the study.

Clinical Trials Information: NCT01966237, October 17, 2013

Conflict of interest

S. Goldstein reports the following disclosures: Baxter/Gambro renal Products (grant support/expert panel/consultant); Akebia (consultant); Bellco (consultant); Otsuka (steering committee for a clinical trial); La Jolla Pharmaceuticals (teering committee for a clinical trial); Astute Medical Inc (consultant); AM Pharma (consultant); Bioporto Inc. (consultant); Reata Medical Inc. (DSMB member for a study). R. Basu is part of the speakers’ bureau for Baxter Renal Solutions and a consultant for Bioporto Diagnostics. None of the other authors have any disclosures to report.

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Gist, K.M., Goldstein, S.L., Wrona, J. et al. Kinetics of the cell cycle arrest biomarkers (TIMP-2*IGFBP-7) for prediction of acute kidney injury in infants after cardiac surgery. Pediatr Nephrol 32, 1611–1619 (2017). https://doi.org/10.1007/s00467-017-3655-y

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  • DOI: https://doi.org/10.1007/s00467-017-3655-y

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