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Urine acute kidney injury biomarkers in extremely low gestational age neonates: a nested case control study of 21 candidate urine biomarkers

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Abstract

Background

Acute kidney injury (AKI) is common and is associated with poor clinical outcomes in premature neonates. Urine biomarkers hold the promise to improve our understanding and care of patients with kidney disease. Because kidney maturation and gender can impact urine biomarker values in extremely low gestational age neonates (ELGANs), careful control of gestational age (GA) and time is critical to any urine biomarker studies in neonates.

Methods

To improve our understanding of the potential use of urine biomarkers to detect AKI during the first postnatal weeks, we performed a nested case–control study to evaluate 21 candidate urine AKI biomarkers. Cases include 20 ELGANs with severe AKI. Each case was matched with 2 controls for the same GA week (rounded down to the nearest week), gender, and birth weight (BW) (± 50 g).

Results

Urine cystatin C, creatinine, ghrelin, fibroblast growth factor-23 (FGF23), tissue metalloproteinase 2 (TIMP2) and vascular endothelial growth factor A (VEGFa) concentrations were higher in ELGANs with early severe AKI compared to matched control subjects without AKI. Urine epidermal growth factor (EGF) and uromodulin (UMOD) concentrations are lower in cases than controls. Interleukin (IL)-15 was lower on day 1, but higher on day 8 in cases than controls; while VEGFa was lower on day 1, but higher on day 5 in cases than controls.

Conclusion

Urine biomarkers hold the promise to improve our ability to reliably detect kidney injury. Interventional studies are needed to determine the biomarkers’ ability to predict outcomes, enhance AKI phenotypes, and improve timely interventions which can prevent the sequalae of AKI in ELGANs.

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Funding

The Recombinant Erythropoietin for Protection of Infant Renal Disease (REPaIReD) Study is an NIH NIDDK funded (R01 DK103608) ancillary study designed to look at kidney outcome in patients enrolled in the Preterm Erythropoietin Neuroprotection Trial (PENUT trial) which is an NIH NINDS funded (U01 NS077953, U01 NS077955) trial. Urine creatinine was run at the UAB AKI O’Brien Center core (NIH P30-DK079337). The clinicaltrials.gov identifier is NCT01378273.

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Authors and Affiliations

  1. Department of Pediatrics, University of Alabama at Birmingham, 1600 5th Avenue South, Birmingham, AL, 35233, USA

    David J. Askenazi & Brian A. Halloran

  2. Department of Biostatistics, University of Washington, Seattle, WA, USA

    Patrick J. Heagerty & Robert H. Schmicker

  3. Department of Pediatrics, University of Washington/Seattle Children’s Hospital, Seattle, WA, USA

    Sandra E. Juul & Sangeeta Hingorani

  4. Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Stuart L. Goldstein

Authors
  1. David J. Askenazi
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  2. Brian A. Halloran
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  3. Patrick J. Heagerty
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  4. Robert H. Schmicker
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  5. Sandra E. Juul
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  6. Sangeeta Hingorani
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  7. Stuart L. Goldstein
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Consortia

the PENUT Trial Consortium

Contributions

DA contributed to the conceptualization and design of the study, data analysis, and drafted the initial manuscript. BH, RS, PH, SJ, SH, and SG contributed to the conceptualization and design of the study, data analysis and assisted in the manuscript preparation. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to David J. Askenazi.

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Disclaimer

Funding sources for this study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Consent statement

Parental/guardian consent was required for participation.

Conflict of interest

All authors declare no real or perceived conflicts of interest that could affect the study design, collection, analyses, and interpretation of data, writing of the report, or the decision to submit for publication. For full disclosure, we provide here an additional list of authors’ commitments and funding sources that are not directly related to this study:

Dr. Askenazi is a consultant for Baxter, Nuwellis. Medtronic, BioPorto, and SeaStar. His institution receives external education and research funding not related to this project from Baxter, Nuwellis, Medtronic, Seastar, and Bioporto. He has patents pending for inventions in the neonatal nephology field. He is Chief Scientific Officer of Zorro-Flow Inc.

Dr. Goldstein reports personal fees from and a position and as a consultant to Nuwellis, Renibus, ExThera, Reata, and Medtronic Inc. Dr. Goldstein receives grant funding from and serves as a consultant and on a Speaker’s Bureau for Baxter Healthcare, Inc. Dr. Goldstein receives grant funding and serves as a consultant for BioPorto, Inc. Dr. Goldstein serves on a Speaker’s Bureau for Fresenius Medical Corporation. Dr. Juul receives grant funding from NINDS and NICHD for studies not related to this project. Dr. Heagerty and Mr. Schmicker receive grant funding from NIH and PCORI for studies not related to this project.

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Some data presented in this study were previously presented as an e-poster abstract presentation at the 2021 American Society of Nephrology meeting.

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Askenazi, D.J., Halloran, B.A., Heagerty, P.J. et al. Urine acute kidney injury biomarkers in extremely low gestational age neonates: a nested case control study of 21 candidate urine biomarkers. Pediatr Nephrol 38, 1329–1342 (2023). https://doi.org/10.1007/s00467-022-05688-x

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  • DOI: https://doi.org/10.1007/s00467-022-05688-x

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