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Neonatal nephrotoxic medication exposure and early acute kidney injury: results from the AWAKEN study

Journal of Perinatology volume 43, pages 1029–1037 (2023)Cite this article

Subjects

Abstract

Background

We aimed to describe nephrotoxic medication exposure and investigate associations between exposure and acute kidney injury (AKI) in the neonatal intensive care unit during the first postnatal week.

Design/methods

Secondary analysis of the AWAKEN cohort. We evaluated nephrotoxic medication exposure during the first postnatal week and associations with AKI using time-varying Cox proportional hazard regressions models. Nephrotoxic medication exposure categories were defined as: no nephrotoxic medication, nephrotoxic medications excluding aminoglycosides, aminoglycoside alone, and aminoglycoside and another nephrotoxic medication.

Results

Of 2162 neonates, 1616 (74.7%) received ≥1 nephrotoxic medication. Aminoglycoside receipt was most common (72%). AKI developed in 211(9.8%) neonates and was associated with a nephrotoxic medication exposure (p < 0.01). Nephrotoxic medication exposures including a nephrotoxic medication excluding aminoglycoside (aHR 3.14, 95% CI 1.31–7.55) and aminoglycoside and  another nephrotoxic medication (aHR 4.79, 95% CI 2.19–10.50) were independently associated with AKI and severe AKI (stage 2/3), respectively.

Conclusions

Nephrotoxic medication exposure in critically ill infants is common during the first postnatal week. Specific nephrotoxic medication exposure, principally aminoglycosides with another nephrotoxic medication, are independently associated with early AKI.

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Fig. 1: Study flow diagram.
Fig. 2: Heat map of nephrotoxic medication exposure by gestational age and postnatal day.

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Acknowledgements

We acknowledge the outstanding work of the following clinical research personnel and colleagues for their involvement in the AWAKEN study: 1. Ariana Aimani, Samantha Kronish, Ana Palijan, MD, and Michael Pizzi (Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada). 2. Laila Ajour, BS, and Julia Wrona, BS (University of Colorado, Children’s Hospital Colorado, Aurora, CO, USA). 3. Melissa Bowman, RN (Golisano Children’s Hospital, University of Rochester, Rochester, NY, USA). 4. Teresa Cano, RN, Marta G. Galarza, MD, Wendy Glaberson, MD, Aura Arenas Morales, MD, and Denisse Cristina Pareja Valarezo, MD (Holtz Children’s Hospital, University of Miami, Miami, FL, USA). 5. Sarah Cashman, BS, and Madeleine Stead, BS (University of Iowa Children’s Hospital, Iowa City, IA, USA). 6. Jonathan Davis, MD, and Julie Nicoletta, MD (Floating Hospital for Children at Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts). 7. Alanna DeMello (British Columbia Children’s Hospital, Vancouver, Canada). 8. Lynn Dill, RN, and Emma Perez-Costas, PhD (The University of Alabama at Birmingham). 9. Ellen Guthrie, RN (MetroHealth Medical Center, CaseWestern Reserve University, Cleveland, Ohio). 10. Nicholas L. Harris, BS, and Susan M. Hieber, MSQM (C.S. Mott Children’s Hospital, University of Michigan, Ann Arbor). 11. Katherine Huang and Rosa Waters (University of Virginia Children’s Hospital, Charlottesville). 12. Judd Jacobs, Ryan Knox, BS, Hilary Pitner,MS, and Tara Terrell (Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio). 13. Nilima Jawale,MD (Maimonides Medical Center, Brooklyn, New York). 14. Emily Kane (Australian National University, Canberra). 15. Vijay Kher, DM, and Puneet Sodhi, MBBS (Medanta Kidney Institute, Medanta the Medicity, Gurgaon, Haryana, India). 16. Grace Mele (New York College of Osteopathic Medicine, Westbury). 17. Patricia Mele, DNP (Stony Brook Children’s Hospital, Stony Brook, New York). 18. Charity Njoku, Tennille Paulsen, and Sadia Zubair (Texas Children’s Hospital, Baylor College of Medicine, Houston). 19. Emily Pao (University of Washington, Seattle Children’s Hospital, Seattle). 20. Becky Selman, RN, and Michele Spear, CCRC (University of New Mexico Health Sciences Center, Albuquerque). 21. Melissa Vega, PA-C (The Children’s Hospital at Montefiore, Bronx, New York). 22. Leslie Walther, RN (Washington University in St Louis, Missouri).

Funding

Cincinnati Children’s Hospital Center for Acute Care Nephrology provided funding to create and maintain the Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates (AWAKEN) study Medidata Rave electronic database. The Pediatric and Infant Center for Acute Nephrology (PICAN) at the University of Alabama at Birmingham (UAB) provided support for web meetings and for the NKC steering committee annual meeting at UAB as well as support for some of the AWAKEN study investigators at UAB (DA, LBJRG) through support from the UAB Department of Pediatrics at Children’s of Alabama, UAB School of Medicine, and UAB’s Center for Clinical and Translational Sciences (National Institutes of Health grant UL1TR001417). The AWAKEN study at The University of New Mexico was supported by the Clinical and Translational Science Center at The University of New Mexico (National Institutes of Health grant UL1TR001449) and by The University of Iowa Institute for Clinical and Translational Science (grant U54TR001356). The AWAKEN study investigators at the Canberra Hospital at the Australian National University Medical School were supported by the Canberra Hospital Private Practice Fund, and investigators at University of Virginia Children’s Hospital were supported by a 100 Women Who Care Grant from the 100 Women Charitable Foundation. The funding sources for this study had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Author information

Authors and Affiliations

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

    Heidi J. Steflik & David T. Selewski

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

    Jennifer R. Charlton, Jonathan R. Swanson & Patricio E. Ray

  3. Department of Pediatrics, Vanderbilt University, Nashville, TN, USA

    Meagan Briley

  4. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Katja M. Gist, Stuart L. Goldstein & Amy T. Nathan

  5. University of Kentucky, Lexington, KY, USA

    Mina H. Hanna & Aftab S. Chishti

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

    David Askenazi & Namasivayam Ambalavanan

  7. Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA

    Russell Griffin

  8. CS Mott Children’s Hospital, University of Michigan, Ann Arbor, MI, USA

    Subrata Sarkar

  9. Centenary Hospital for Women and Children, Canberra Hospital, Australian National University Medical School, Canberra, ACT, Australia

    Alison Kent & Jeffery Fletcher

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

    Alison Kent, Ronnie Guillet, Carl D’Angio, Ayesa Mian, Erin Rademacher & Patrick D. Brophy

  11. Holtz Children’s Hospital, University of Miami, Miami, FL, USA

    Carolyn L. Abitbol, Marissa DeFreitas & Shahnaz Duara

  12. MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA

    Maroun J. Mhanna, Rupesh Raina & Deepak Kumar

  13. Ochsner/Louisiana State University Health, Shreveport, LA, USA

    Maroun J. Mhanna

  14. Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA

    Ayse Akcan Arikan & Christopher J. Rhee

  15. Maimonides Medical Center, Brooklyn, NY, USA

    Juan C. Kupferman, Alok Bhutada & Shantanu Rastogi

  16. Nationwide Children’s Hospital, Columbus, OH, USA

    Elizabeth Bonachea, Susan Ingraham, John Mahan & Arwa Nada

  17. Kapi’olani Medical Center for Women & Children, Honolulu, HI, USA

    Susan Ingraham

  18. LeBonheur’s Children’s Hospital/University of Tennessee, Memphis, TN, USA

    Arwa Nada

  19. University of Iowa Children’s Hospital, Iowa City, IA, USA

    Jennifer Jetton, Patrick D. Brophy, Tarah T. Colaizy & Jonathan M. Klein

  20. Washington University, St Louis, MO, USA

    F. Sessions Cole & T. Keefe Davis

  21. University of Saskatchewan, Saskatoon, SK, Canada

    T. Keefe Davis

  22. Tufts University School of Medicine, Boston, MA, USA

    Joshua Dower, Lawrence Milner & Alexandra Smith

  23. The Children’s Hospital at Montefiore, Bronx, NY, USA

    Mamta Fuloria, Kimberly Reidy & Frederick J. Kaskel

  24. University of Colorado, Children’s Hospital Colorado, Aurora, CO, USA

    Danielle E. Soranno & Jason Gien

  25. University of Indiana, Indianapolis, IN, USA

    Danielle E. Soranno & Michelle Starr

  26. University of Washington, Seattle Children’s Hospital, Seattle, WA, USA

    Sangeeta Hingorani, Sandra Juul & Michelle Starr

  27. University of New Mexico Health Sciences Center, Albuquerque, NM, USA

    Craig S. Wong, Catherine Joseph, Tara DuPont, Robin Ohls & Amy Staples

  28. University of Utah, Salt Lake City, UT, USA

    Robin Ohls

  29. Kidney and Urology Institute Medanta—The Medicity, Gurgaon, India

    Smriti Rohatgi & Sidharth K. Sethi

  30. Cloudnine Hospital, Gurgaon, Haryana, India

    Sanjay Wazir

  31. Apollo Cradle, Gurgaon, Haryana, India

    Surender Khokhar

  32. Children’s National Medical Center, George Washington University School of Medicine and the Health Sciences, Washington, DC, USA

    Sofia Perazzo, Patricio E. Ray & Mary Revenis

  33. British Columbia Children’s Hospital, Vancouver, BC, Canada

    Cherry Mammen & Anne Synnes

  34. Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada

    Pia Wintermark & Michael Zappitelli

  35. The Hospital for Sick Children, Toronto, ON, Canada

    Michael Zappitelli

  36. Stony Brook School of Medicine, Stony Brook, NY, USA

    Robert Woroniecki & Shanthy Sridhar

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  1. Heidi J. Steflik
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  2. Jennifer R. Charlton
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  3. Meagan Briley
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  4. David T. Selewski
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  5. Katja M. Gist
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  6. Mina H. Hanna
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  7. David Askenazi
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  8. Russell Griffin
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Consortia

Neonatal Kidney Collaborative

  • Subrata Sarkar
  • , Alison Kent
  • , Jeffery Fletcher
  • , Carolyn L. Abitbol
  • , Marissa DeFreitas
  • , Shahnaz Duara
  • , Jonathan R. Swanson
  • , Ronnie Guillet
  • , Carl D’Angio
  • , Ayesa Mian
  • , Erin Rademacher
  • , Maroun J. Mhanna
  • , Rupesh Raina
  • , Deepak Kumar
  • , Namasivayam Ambalavanan
  • , Ayse Akcan Arikan
  • , Christopher J. Rhee
  • , Stuart L. Goldstein
  • , Amy T. Nathan
  • , Juan C. Kupferman
  • , Alok Bhutada
  • , Shantanu Rastogi
  • , Elizabeth Bonachea
  • , Susan Ingraham
  • , John Mahan
  • , Arwa Nada
  • , Jennifer Jetton
  • , Patrick D. Brophy
  • , Tarah T. Colaizy
  • , Jonathan M. Klein
  • , F. Sessions Cole
  • , T. Keefe Davis
  • , Joshua Dower
  • , Lawrence Milner
  • , Alexandra Smith
  • , Mamta Fuloria
  • , Kimberly Reidy
  • , Frederick J. Kaskel
  • , Danielle E. Soranno
  • , Jason Gien
  • , Aftab S. Chishti
  • , Sangeeta Hingorani
  • , Sandra Juul
  • , Michelle Starr
  • , Craig S. Wong
  • , Catherine Joseph
  • , Tara DuPont
  • , Robin Ohls
  • , Amy Staples
  • , Smriti Rohatgi
  • , Sidharth K. Sethi
  • , Sanjay Wazir
  • , Surender Khokhar
  • , Sofia Perazzo
  • , Patricio E. Ray
  • , Mary Revenis
  • , Cherry Mammen
  • , Anne Synnes
  • , Pia Wintermark
  • , Michael Zappitelli
  • , Robert Woroniecki
  •  & Shanthy Sridhar

Contributions

HJS contributed to the design of the work, the interpretation of data, drafting and revision of the manuscript and provides final approval of this version. JC, DTS, DA, and RG all contributed to the conception and design of this work, the acquisition, analysis, and interpretation of data, drafting and revision of the manuscript and provide final approval of this version. MB contributed to the conception and design of this work, interpretation of the data, the revision of the manuscript, and provides final approval of this version. KM and MHH contributed to the interpretation of data, the revision of the manuscript, and provides final approval of this version. All authors agree to be accountable for all aspects of this work.

Corresponding author

Correspondence to Heidi J. Steflik.

Ethics declarations

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 funding sources that are not directly related to this study. DJA is a consultant for Baxter, Nuwellis, 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, Portero, 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 Inc. HJS received research grants with Baxter. No other disclosures were reported. KG is a consultant for Bioporto and Potrero Medical. JRC is on the Executive Board for the Neonatal Kidney Collaborative, a consultant for Medtronics, and an investor in Zorro-Flow.

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Steflik, H.J., Charlton, J.R., Briley, M. et al. Neonatal nephrotoxic medication exposure and early acute kidney injury: results from the AWAKEN study. J Perinatol 43, 1029–1037 (2023). https://doi.org/10.1038/s41372-023-01684-7

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