Despite a growing understanding of bronchopulmonary dysplasia (BPD) and advances in management, BPD rates remain stable. There is mounting evidence that BPD may be due to a systemic insult, such as acute kidney injury (AKI). Our hypothesis was that severe AKI would be associated with BPD.
We conducted a secondary analysis of premature infants [24–27 weeks gestation] in the Recombinant Erythropoietin for Protection of Infant Renal Disease cohort (N = 885). We evaluated the composite outcome of Grade 2/3 BPD or death using generalized estimating equations. In an exploratory analysis, urinary biomarkers of angiogenesis (ANG1, ANG2, EPO, PIGF, TIE2, FGF, and VEGFA/D) were analyzed.
594 (67.1%) of infants had the primary composite outcome of Grade 2/3 BPD or death. Infants with AKI (aOR: 1.69, 95% CI: 1.16–2.46) and severe AKI (aOR: 2.05, 95% CI: 1.19–3.54). had increased risk of the composite outcome after multivariable adjustment Among 106 infants with urinary biomarkers assessed, three biomarkers (VEGFA, VEGFD, and TIE2) had AUC > 0.60 to predict BPD.
Infants with AKI had a higher likelihood of developing BPD/death, with the strongest relationship seen in those with more severe AKI. Three urinary biomarkers of angiogenesis may have potential to predict BPD development.
AKI is associated with lung disease in extremely premature infants, and urinary biomarkers may predict this relationship.
Infants with AKI and severe AKI have higher odds of BPD or death. Three urinary angiogenesis biomarkers are altered in infants that develop BPD.
These findings have the potential to drive future work to better understand the mechanistic pathways of BPD, setting the framework for future interventions to decrease BPD rates.
A better understanding of the mechanisms of BPD development and the role of AKI would have clinical care, cost, and quality of life implications given the long-term effects of BPD.
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The authors would like to thank Samantha Wallace (Department of Pediatrics, Indiana University School of Medicine) for help with technical editing and proofreading of this manuscript. We would like to thank Lynn Dill, RN, and Emily Pao for their assistance in coordinating the REPaIReD study. We would like to thank the investigators, clinicians, research personnel, study teams, and families who participated in the PENUT Trial. This study was supported by grants R01DK103608, U01NS077955, and U01NS077953. Funding sources for this study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
All authors report no real or perceived conflicts of interest that could affect the study design; collection, analysis and interpretation of data; the writing of the report; or the decision to submit the manuscript for publication. For full disclosure, we provide the additional list of authors’ other commitments and funding sources that are not directly related to this study. R.H.S. receives grant funding for studies not related to this project from NHLBI and PCORI. S.L.G. reports personal fees from and a position as a consultant to Nuwellis, Renibus, ExThera, Reata and Medtronic Inc. S.L.G. has an equity interest in MediBeacon, 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 Diagnostics, Inc. S.L.G. serves on a Speaker’s Bureau for Fresenius Medical Corporation. D.J.A. consults for Baxter, Nuwellis, Medtronic, Bioporto and Seastar Medical. He also receives grant funding for studies not related to this project from Baxter, Nuwellis, Medtronic, SeaStar Medical, Bioporto, and National Institutes of Health (R01 FD005092, U34 KD117128). He is founder and Chief Scientific Officer for Zorro-Flow Inc. He has patents pending for urine collection device and System for Continuous Renal Replacement System.
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Starr, M.C., Schmicker, R.H., Halloran, B.A. et al. Premature infants born <28 weeks with acute kidney injury have increased bronchopulmonary dysplasia rates. Pediatr Res (2023). https://doi.org/10.1038/s41390-023-02514-4
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