Abstract
Background
Our understanding of the normative concentrations of urine biomarkers in premature neonates is limited.
Methods
We evaluated urine from 750 extremely low gestational age (GA) neonates without severe acute kidney injury (AKI) to determine how GA affects ten different urine biomarkers at birth and over the first 30 postnatal days. Then, we investigated if the urine biomarkers changed over time at 27, 30, and 34 weeks postmenstrual age (PMA). Next, we evaluated the impact of sex on urine biomarker concentrations at birth and over time. Finally, we evaluated if urine biomarkers were impacted by treatment with erythropoietin (Epo).
Results
We found that all ten biomarker concentrations differ at birth by GA and that some urine biomarker concentrations increase, while others decrease over time. At 27 weeks PMA, 7/10 urine biomarkers differed by GA. By 30 weeks PMA, 5/10 differed, and by 34 weeks PMA, only osteopontin differed by GA. About half of the biomarker concentrations differed by sex, and 4/10 showed different rates of change over time between males vs. females. We found no differences in urine biomarkers by treatment group.
Conclusions
The temporal patterns, GA, and sex differences need to be considered in urine AKI biomarker analyses.
Impact
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Urine biomarker concentrations differ by GA at birth.
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Some urine biomarkers increase, while others decrease, over the first 30 postnatal days.
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Most urine biomarkers differ by GA at 27 weeks PMA, but are similar by 34 weeks PMA.
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Some urine biomarkers vary by sex in premature neonates.
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Urine biomarkers did not differ between neonates randomized to placebo vs. Epo.
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Change history
13 December 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41390-021-01898-5
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Acknowledgements
We would like to thank Lynn Dill, RN and Emily Pao for their assistance in coordinating the REPaIReD study, and to Dana Pass for the preparation of the manuscript. We would like to thank the additional primary investigators, co-investigators, clinicians, research personnel, study team, and families who participated in the PENUT study. Some data presented in this study were previously presented as an e-poster abstract presentation at the 2020 American Society of Nephrology meeting.
Funding
Recombinant Erythropoietin for Protection of Infant Renal Disease (REPaIReD) Study is a NIHNIDDK-funded (R01 DK103608) ancillary study designed to look at kidney outcome in patients enrolled in the Preterm Erythropoietin Neuroprotection Trial (PENUT trial), which is a NIHNINDS-funded (U01 NS077953, U01 NS077955) trial. Urine creatinine was run at the UAB AKIO’Brien Center core (NIH P30-DK079337). The clinicaltrials.gov identifier is NCT01378273. Funding sources for this study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
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D.J.A. contributed to the conceptualization and design of the study, data analysis, and drafted the initial manuscript. B.A.H., R.H.S., P.J.H., P.B., S.E.J., S.L.G., and S.H. 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.
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Competing interests
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 other authors’ commitments and funding sources that are not directly related to this study: D.J.A. is a consultant for Baxter, Nuwellis, Medtronic, Bioporto, AKI foundation, and SeaStar. He also receives external education and research funding not related to this project from Baxter, Nuwelis, and Medtronic. S.L.G. reports personal fees from and a position as a consultant to Nuwellis, Renibus, ExThera, Reata, and Medtronic Inc. S.L.G. receives grant funding from and serves as a consultant and on a Speaker’s Bureau for Baxter Healthcare, Inc. S.L.G. receives grant funding and serves as a consultant for BioPorto, Inc. S.L.G. serves on a Speaker’s Bureau for Fresenius Medical Corporation. S.E.J. receives grant funding from NINDS and NICHD for studies not related to this project. P.J.H. and R.H.S. receive grant funding from NHLBI and PCORI for studies not related to this project.
Ethics committee approval
The University of Washington Institutional Review Board (IRB) approved this collaborative study, and each center received approval from its respective IRBs.
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Parental/guardian consent was required for participation.
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The original online version of this article was revised: The list of authors has been corrected and Brian Halloran has been added to the PDF.
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Askenazi, D.J., Halloran, B.A., Heagerty, P.J. et al. Gestational age, sex, and time affect urine biomarker concentrations in extremely low gestational age neonates. Pediatr Res 92, 151–167 (2022). https://doi.org/10.1038/s41390-021-01814-x
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DOI: https://doi.org/10.1038/s41390-021-01814-x
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