Gestational age, sex, and time affect urine biomarker concentrations in extremely low gestational age neonates

David J Askenazi, Brian A Halloran, Patrick J Heagerty, Robert H Schmicker, Patrick Brophy, Sandra E Juul, Sangeeta Hingorani, Stuart L Goldstein, PENUT Trial Consortium, Sandra E Juul, Bryan A Comstock, Rajan Wadhawan, Dennis E Mayock, Sherry E Courtney, Tonya Robinson, Kaashif A Ahmad, Ellen Bendel-Stenzel, Mariana Baserga, Edmund F LaGamma, L Corbin Downey, Raghavendra Rao, Nancy Fahim, Andrea Lampland, Ivan D Frantz 3rd, Janine Y Khan, Michael Weiss, Maureen M Gilmore, Robin Ohls, Nishant Srinivasan, Jorge E Perez, Victor McKay, Phuong T Vu, Patrick J Heagerty, David J Askenazi, Brian A Halloran, Patrick J Heagerty, Robert H Schmicker, Patrick Brophy, Sandra E Juul, Sangeeta Hingorani, Stuart L Goldstein, PENUT Trial Consortium, Sandra E Juul, Bryan A Comstock, Rajan Wadhawan, Dennis E Mayock, Sherry E Courtney, Tonya Robinson, Kaashif A Ahmad, Ellen Bendel-Stenzel, Mariana Baserga, Edmund F LaGamma, L Corbin Downey, Raghavendra Rao, Nancy Fahim, Andrea Lampland, Ivan D Frantz 3rd, Janine Y Khan, Michael Weiss, Maureen M Gilmore, Robin Ohls, Nishant Srinivasan, Jorge E Perez, Victor McKay, Phuong T Vu, Patrick J Heagerty

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: Urine biomarker concentrations differ by GA at birth. Some urine biomarkers increase, while others decrease, over the first 30 postnatal days. Most urine biomarkers differ by GA at 27 weeks PMA, but are similar by 34 weeks PMA. Some urine biomarkers vary by sex in premature neonates. Urine biomarkers did not differ between neonates randomized to placebo vs. Epo.

Trial registration: ClinicalTrials.gov NCT01378273.

Conflict of interest statement

Disclosures

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:

Dr. Askenazi 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.

Dr. Goldstein reports personal fees from and a position 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 NHLBI and PCORI for studies not related to this project.

© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.

Figures

Figure 1:
Figure 1:
Consort diagram showing the reasons for exclusion for this analysis from the 940 enrolled into the PENUT trial.
Figure 2:
Figure 2:
Mean log-10 urine biomarker concentrations over postnatal days by GA groups (24, 25, 26, 27 weeks GA) using a 7-day rolling mean.
Figure 3:
Figure 3:
Median (IQR) log !0 urine biomarker concentrations by GA groups at 27, 30 and 34 weeks post-menstrual age (PMA) by groups (24, 25, 26, 27 weeks GA).
Figure 4:
Figure 4:
Mean log-10 urine biomarker concentrations over postnatal days for males vs. females using a 7-day rolling mean.
Figure 5:
Figure 5:
Correlation between the 10 biomarkers and one another

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Source: PubMed

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