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  • Clinical Research Article
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Caffeine and kidney function at two years in former extremely low gestational age neonates

Pediatric Research volume 95, pages 257–266 (2024)Cite this article

Abstract

Background

Extremely low gestational age neonates (ELGANs) are at risk for chronic kidney disease. The long-term kidney effects of neonatal caffeine are unknown. We hypothesize that prolonged caffeine exposure will improve kidney function at 22–26 months.

Methods

Secondary analysis of the Preterm Erythropoietin Neuroprotection Trial of neonates <28 weeks’ gestation. Participants included if any kidney outcomes were collected at 22–26 months corrected age. Exposure was post-menstrual age of caffeine discontinuation. Primary outcomes: ‘reduced eGFR’ <90 ml/min/1.73 m2, ‘albuminuria’ (>30 mg albumin/g creatinine), or ‘elevated blood pressure’ (BP) >95th %tile. A general estimating equation logistic regression model stratified by bronchopulmonary dysplasia (BPD) status was used.

Results

598 participants had at least one kidney metric at follow up. Within the whole cohort, postmenstrual age of caffeine discontinuation was not associated with any abnormal measures of kidney function at 2 years. In the stratified analysis, for each additional week of caffeine, the no BPD group had a 21% decreased adjusted odds of eGFR <90 ml/min/1.73m2 (aOR 0.78; CI 0.62–0.99) and the BPD group had a 15% increased adjusted odds of elevated BP (aOR 1.15; CI: 1.05–1.25).

Conclusions

Longer caffeine exposure during the neonatal period is associated with differential kidney outcomes at 22–26 months dependent on BPD status.

Impact

  • In participants born <28 weeks’ gestation, discontinuation of caffeine at a later post menstrual age was not associated with abnormal kidney outcomes at 22–26 months corrected age.

  • When assessed at 2 years of age, later discontinuation of caffeine in children born <28 weeks’ gestation was associated with a greater risk of reduced eGFR in those without a history of BPD and an increased odds of hypertension in those with a history of BPD.

  • More work is necessary to understand the long-term impact of caffeine on the developing kidney.

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Fig. 1: Consort diagram.
Fig. 2: 22–26 month corrected gestational age kidney outcomes.
Fig. 3: Last caffeine administration by post menstrual age.
Fig. 4: Post menstrual age at caffeine discontinuation stratified by bronchopulmonary dysplasia status and follow-up at 22–26 months corrected gestational age.

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Data availability

The datasets analyzed during the current study can be requested from the NINDS at the following website: https://www.ninds.nih.gov/current-research/research-funded-ninds/clinical-research/archived-clinical-research-datasets.

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Funding

The study is coordinated by the Neonatal Kidney Collaborative Research Committee. Statistical support for this study is provided by Nuwellis. The original study, the Preterm Erythropoietin Neuroprotection Trial (PENUT trial) was funded by the NIH-NINDS (U01 NS077953, U01 NS077955). Kidney-specific data collection was funded by the NIH-NIDDK as part of the Recombinant Erythropoietin for Protection of Infant Renal Disease (REPaIReD) Study (NIH NIDDK (R01 DK103608).

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Matthew W. Harer

  2. Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA

    Russell Griffin & David J. Askenazi

  3. Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA

    Mamta Fuloria

  4. Department of Pediatrics, University of Rochester, Rochester, NY, USA

    Ronnie Guillet

  5. Department of Pediatrics, University of Kentucky, Lexington, KY, USA

    Mina Hanna

  6. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Meredith P. Schuh, Cara Slagle & Katja M. Gist

  7. Department of Pediatrics, Stony Brook University, Stony Brook, NY, USA

    Robert Woroniecki

  8. Department of Pediatrics, University of Virginia, Charlottesville, VA, USA

    Jennifer R. Charlton

  9. Department of Pediatrics, University of Miami, Miami, FL, USA

    Marissa DeFreitas

  10. Department of Pediatrics, University of Washington, Seattle, WA, USA

    Shina Menon

  11. Department of Pediatrics, St. Johns Medical College Hospital, Bangalore, Karnataka, India

    Saudamini Nesargi

  12. Akron Children’s Hospital, Akron, OH, USA

    Rupesh Raina

  13. Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USA

    Keia Sanderson

  14. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA

    Jeffrey L. Segar

  15. Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA

    David T. Selewski & Heidi J. Steflik

  16. Department of Pediatrics, Wake Forest School of Medicine, Winston Salem, NC, USA

    Andrew M. South

  17. Department of Pediatrics, Indiana University, Indianapolis, IN, USA

    Michelle C. Starr

  18. University of Virginia Children’s Hospital, Charlottesville, Virginia, USA

    Jonathan R. Swanson

  19. McGill University Health Centre, Montreal, QC, Canada

    Michael Zappitelli

Authors
  1. Matthew W. Harer
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  2. Russell Griffin
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  6. Mina Hanna
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  8. Cara Slagle
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Consortia

Neonatal Kidney Collaborative Research Committee

  • Marissa DeFreitas
  • , Katja M. Gist
  • , Shina Menon
  • , Saudamini Nesargi
  • , Rupesh Raina
  • , Keia Sanderson
  • , Jeffrey L. Segar
  • , David T. Selewski
  • , Andrew M. South
  • , Heidi J. Steflik
  • , Michelle C. Starr
  • , Jonathan R. Swanson
  •  & Michael Zappitelli

Contributions

M.W.H. made significant contributions to the design and conception, data analysis and interpretation, drafting the manuscript, critical revision of the manuscript and final approval. R.Griffin made significant contributions to the statistical analysis and interpretation, drafting the manuscript, and final approval. D.A. made significant contributions to the design, data interpretation, critical revision of the manuscript and final approval. M.F. made contributions to the design of the study, revision of the manuscript and final approval. R.Guillet made significant contributions to the design and conception, data interpretation, critical revision of the manuscript and final approval. M.H. made contributions to the design of the study, revision of the manuscript and final approval. M.S. made contributions to the design of the study, revision of the manuscript and final approval. C.S. made significant contributions to the design of the study, revision of the manuscript and final approval. R.W. made significant contributions to the design, data interpretation, critical revision of the manuscript and final approval. J.R.C. made significant contributions to the design and conception, data analysis and interpretation, critical revision of the manuscript and final approval.

Corresponding author

Correspondence to Matthew W. Harer.

Ethics declarations

Competing interests

All authors declare no real or perceived conflicts of interest that could affect the study design, collection, analysis, 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 author’s commitments and funding sources that are not directly related to this study: M.W.H. receives research funding unrelated to this project from the NIH, Wisconsin Partnership Program, and Meriter Foundation. D.J.A. is a consultant for Baxter, Nuwellis, Medtronic Bioporto, and Seastar. His institution receives grant funding for education and research that is not related to this project from NIH, Baxter, Nuwellis, Medtronic, Bioporto, and Seastar. He has patents pending on inventions to improve the kidney care of neonates. He is the Founder and Chief Scientific Officer for Zorro-Flow. J.R.C. is a consultant for Medtronics and investor in Zorro-Flow. She receives funding for research not related to this project from the NIH. She is Vice-President of the Neonatal Kidney Collaborative. R.Guillet is a consultant for NEMA Research. She receives funding for research not related to this project from NIH. C.S. is a consultant for AM Pharma which is unrelated to the content in this manuscript. Meredith Schuh receives research funding unrelated to this project from NIH and Otsuka

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Harer, M.W., Griffin, R., Askenazi, D.J. et al. Caffeine and kidney function at two years in former extremely low gestational age neonates. Pediatr Res 95, 257–266 (2024). https://doi.org/10.1038/s41390-023-02792-y

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