Clinical Research Article | Published:

Urinary acute kidney injury biomarkers in very low-birth-weight infants on indomethacin for patent ductus arteriosus

Pediatric Research (2019) | Download Citation




Serum creatinine (SCr)- or urine output-based definitions of acute kidney injury (AKI) have important limitations in neonates. This study evaluates the diagnostic value of urinary biomarkers in very low-birth-weight (VLBW) infants receiving indomethacin for closure of a patent ductus arteriosus (PDA).


Prospective cohort study in 14 indomethacin-treated VLBW infants and 18 VLBW infants without indomethacin as controls. Urinary biomarkers were measured before, during, and after indomethacin administration.


Indomethacin therapy was associated with significantly higher SCr concentrations at 36, 84, and 120 h compared to controls. At 36 h, three indomethacin-treated patients met the criteria for neonatal modified Kidney Disease: Improving Global Outcomes (KDIGO) AKI. The product of urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 ([TIMP-2]•[IGFBP7]) was significantly elevated in the AKI subgroup at 12 h (P < 0.05), hence 24 h earlier than the increase in SCr. Urinary neutrophil gelatinase-associated lipocalin (NGAL) and calprotectin were significantly increased in the indomethacin group at 12 h (P < 0.05), irrespective of fulfillment of the AKI criteria. Urinary kidney injury molecule-1 (KIM-1) was not significantly altered.


While urinary [TIMP-2]•[IGFBP7] proves valuable for the early diagnosis of neonatal modified KDIGO-defined AKI, elevated urinary NGAL and calprotectin concentrations in indomethacin-treated VLBW infants not fulfilling the AKI criteria may indicate subclinical kidney injury.

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We thank all nurses of the NICU for their diligence in collecting samples. We also thank Simone Voigt for her indefatigable efforts in this study. We are indebted to all parents of our tiny patients who gave their consent to have their children participate in this study. The study was funded by the German Research Foundation (Research Unit FOR1368). NephroCheck® Test Kits and the Astute 140® Meter were kindly provided by Astute Medical (San Diego, CA, USA). ARCHITECT® Urine NGAL assays were kindly provided by Abbott Diagnostics (Abbott Laboratories, Abbott Park, IL, USA).

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Author notes

  1. These authors contributed equally: Sina Waldherr, Alexander Fichtner


  1. Department of Neonatology, University Children’s Hospital, Heidelberg, Germany

    • Sina Waldherr
    • , Bernd Beedgen
    •  & Johannes Pöschl
  2. Department of Pediatrics I, University Children’s Hospital, Heidelberg, Germany

    • Alexander Fichtner
    • , Franz Schaefer
    • , Burkhard Tönshoff
    •  & Jens H. Westhoff
  3. Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany

    • Thomas Bruckner
  4. Medical Department I, Marien Hospital Herne, University Hospital of the Ruhr-University of Bochum, Herne, Germany

    • Timm H. Westhoff


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A.F., S.W., and J.H.W. conceived and designed the experiments. S.W., A.F., B.B., T.H.W., and J.H.W. performed the experiments. S.W., A.F., T.B., F.S., B.T., J.P., T.H.W., and J.H.W. analyzed the data or interpreted the results. J.H.W. wrote the draft of the article. A.F., S.W., B.T., and T.H.W. edited the manuscript. All other authors approved the manuscript to be published.

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The authors declare no competing interests.

Corresponding author

Correspondence to Jens H. Westhoff.

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