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  • Clinical Research Article
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Premature infants born <28 weeks with acute kidney injury have increased bronchopulmonary dysplasia rates

Pediatric Research volume 94, pages 676–682 (2023)Cite this article

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Impact

  • 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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Fig. 1: Consort diagram of infants in the study.
Fig. 2: Urinary biomarkers in infants.

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Data availability

De‐identified individual participant data are available through the NINDS Data Archive: https://www.ninds.nih.gov/Current‐Research/Research‐ Funded‐NINDS/Clinical‐Research/Archived‐Clinical‐ Research‐Datasets. The data will be de‐identified and a limited access data is available through a request form on that page. Data dictionaries, in addition to study protocol, the statistical analysis plan, and the informed consent form are included. The data will be made available to researchers who provide a methodologically sound proposal for use in achieving the goals of the approved proposal.

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Acknowledgements

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.

Author information

Author notes

  1. These authors contributed equally: Sangeeta Hingorani7, David J. Askenazi.

  2. A full list of members and their affiliations appears in the Supplementary Information.

Authors and Affiliations

  1. Division of Pediatric Nephrology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA

    Michelle C. Starr

  2. Center for Pediatric and Adolescent Comparative Effectiveness Research, Indiana University, Indianapolis, IN, USA

    Michelle C. Starr

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

    Robert H. Schmicker & Patrick Heagerty

  4. Division of Pediatric Nephrology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA

    Brian A. Halloran & David J. Askenazi

  5. University of Rochester and Golisano Children’s Hospital, Rochester, NY, USA

    Patrick Brophy

  6. Pediatric Nephrology & Hypertension, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Stuart L. Goldstein

  7. Department of Pediatrics, Seattle Children’s Hospital and University of Washington, Seattle, WA, USA

    Sandra E. Juul & Sangeeta Hingorani

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Consortia

for the PENUT Trial Consortium

Contributions

Dr. Starr conceptualized and designed this study, assisted with biomarker performance and data analysis, drafted the initial manuscript, and reviewed and revised the manuscript. Mr. Schmicker and Halloran performed biomarker and data analysis and critically revised the manuscript. Drs. Heagerty, Brophy, Goldstein, and Juul made substantial contributions to the conception of this project and reviewed and revised the manuscript. Drs. Hingorani and Askenazi provided oversight and made substantial contributions to the design of this study and acquisition of data, reviewed, and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Michelle C. Starr.

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Competing interests

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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Caregiver consent was required for participation in primary (PENUT) study.

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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 94, 676–682 (2023). https://doi.org/10.1038/s41390-023-02514-4

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