Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Clinical Research Article
  • Published:

Perinatal risk factors associated with acute kidney injury severity and duration among infants born extremely preterm

Pediatric Research (2024)Cite this article

Abstract

Background

We evaluated time-varying perinatal risk factors associated with early (≤7 post-natal days) and late (>7 post-natal days) severe acute kidney injury (AKI) occurrence and duration.

Methods

A secondary analysis of Preterm Erythropoietin Neuroprotection Trial data. We defined severe AKI (stage 2 or 3) per neonatal modified Kidney Disease: Improving Global Outcomes criteria.

Adjusted Cox proportional hazards models were conducted with exposures occurring at least 72 h before severe AKI. Adjusted negative binomial regression models were completed to evaluate risk factors for severe AKI duration.

Results

Of 923 participants, 2% had early severe AKI. In the adjusted model, gestational diabetes (adjusted HR (aHR) 5.4, 95% CI 1.1–25.8), non-steroidal anti-inflammatory drugs (NSAIDs) (aHR 3.2, 95% CI 1.0–9.8), and vancomycin (aHR 13.9, 95% CI 2.3–45.1) were associated with early severe AKI.

Late severe AKI occurred in 22% of participants. Early severe AKI (aHR 2.5, 95% CI 1.1–5.4), sepsis (aHR 2.5, 95% CI 1.4–4.4), vasopressors (aHR 2.9, 95% CI 1.8–4.6), and diuretics (aHR 2.6, 95% CI 1.9–3.6) were associated with late severe AKI.

Participants who had necrotizing enterocolitis or received NSAIDs had longer severe AKI duration.

Conclusion

We identified major risk factors for severe AKI that can be the focus of future research.

Impact statement

  • Time-dependent risk factors for severe acute kidney injury (AKI) and its duration are not well defined among infants born <28 weeks’ gestation.

  • Over 1 in 5 infants born <28 weeks’ gestation experienced severe AKI, and this study identified several major time-dependent perinatal risk factors occurring within 72 h prior to severe AKI.

  • This study can support efforts to develop risk stratification and clinical decision support to help mitigate modifiable risk factors to reduce severe AKI occurrence and duration.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Consort flow diagram for this secondary analysis of data from extremely preterm-born infants enrolled in the Preterm Erythropoietin Neuroprotection Trial (PENUT) #.
Fig. 2: Negative binomial regression with 95% confidence intervals (CI) for the association between maternal prenatal exposures and severe AKI duration among extremely preterm-born infants.
Fig. 3: Negative binomial regression with 95% confidence intervals (CIs) for the association between infant exposures and severe AKI duration among extremely preterm born infants.

Similar content being viewed by others

Data availability

Data for this secondary analysis was analyzed from the publicly available dataset from the Preterm Erythropoietin Neuroprotection Trial supported per policy by the NIH National Institute of Neurological Disorders and Stroke and National Institute of Diabetes and Digestive and Kidney Diseases. Data can be requested via the NINDS site at: chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.ninds.nih.gov/sites/default/files/migrate-documents/sig_form_revised_508c.pdf.

References

  1. Askenazi, D. J. et al. Prevalence of acute kidney injury (AKI) in extremely low gestational age neonates (ELGAN). Pediatr. Nephrol. (Berl., Ger.). 35, 1737–1748 (2020).

    Article  Google Scholar 

  2. Aziz, K. B., Schles, E. M., Makker, K. & Wynn, J. L. Frequency of acute kidney injury and association with mortality among extremely preterm infants. JAMA Netw. Open. 5, e2246327 (2022). National Institutes of Health during the study but outside the submitted work. No other disclosures were reported.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Charlton, J. R. et al. Incidence and risk factors of early onset neonatal AKI. Clin. J. Am. Soc. Nephrol. : Cjasn. 14, 184–195 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  4. Charlton, J. R. et al. Late onset neonatal acute kidney injury: results from the AWAKEN Study. Pediatr. Res. 85, 339–348 (2019).

    Article  PubMed  Google Scholar 

  5. Hingorani, S. et al. Prevalence and risk factors for kidney disease and elevated BP in 2-year-old children born extremely premature. Clin. J. Am. Soc. Nephrology. 17, 1129–1138 (2022).

    Article  Google Scholar 

  6. Selewski, D. T. et al. Neonatal acute kidney injury. Pediatrics 136, e463–e473 (2015).

    Article  PubMed  Google Scholar 

  7. Bruel, A. et al. Renal outcome in children born preterm with neonatal acute renal failure: IRENEO-a prospective controlled study. Pediatr. Nephrol. (Berl., Ger.). 31, 2365–2373 (2016).

    Article  Google Scholar 

  8. Abitbol, C. L. et al. Long-term follow-up of extremely low birth weight infants with neonatal renal failure. Pediatr. Nephrol. (Berl., Ger.). 18, 887–893 (2003).

    Article  Google Scholar 

  9. Harer, M. W., Pope, C. F., Conaway, M. R. & Charlton, J. R. Follow-up of acute kidney injury in neonates during childhood years (FANCY): a prospective cohort study. Pediatr. Nephrol. (Berl., Ger.). 32, 1067–1076 (2017).

    Article  Google Scholar 

  10. Daga, A., Dapaah-Siakwan, F., Rajbhandari, S., Arevalo, C. & Salvador, A. Diagnosis and risk factors of acute kidney injury in very low birth weight infants. Pediatrics Neonatol. 58, 258–263 (2017).

    Article  Google Scholar 

  11. Sethi, S. K. et al. Risk factors and outcomes of neonates with acute kidney injury needing peritoneal dialysis: Results from the prospective TINKER (The Indian PCRRT-ICONIC Neonatal Kidney Educational Registry) study. Perit. Dialysis Int. 42, 460–469 (2022).

    Article  CAS  Google Scholar 

  12. Uemura, O. et al. Perinatal factors contributing to chronic kidney disease in a cohort of Japanese children with very low birth weight. Pediatr. Nephrol. (Berl., Ger.). 36, 953–960 (2021).

    Article  Google Scholar 

  13. Hidalgo, G. et al. Association of income level with kidney disease severity and progression among children and adolescents with CKD: a report from the Chronic Kidney Disease in Children (CKiD) Study. Am. J. Kidney Dis. 62, 1087–1094 (2013).

    Article  PubMed  Google Scholar 

  14. Rhone, E. T., Carmody, J. B., Swanson, J. R. & Charlton, J. R. Nephrotoxic medication exposure in very low birth weight infants. J. Matern.-fetal Neonatal Med. 27, 1485–1490 (2014).

    Article  CAS  PubMed  Google Scholar 

  15. Khor, C.-S. & Wang, W.-J. The role of acute kidney injury duration in clinical practice. Annals Transl. Med. 7, S88 1–3 (2019).

  16. Han, S. S. et al. Duration of acute kidney injury and mortality in critically ill patients: a retrospective observational study. BMC Nephrol. 14, 1–7 (2013).

    Article  PubMed Central  PubMed  Google Scholar 

  17. Brown, J. R., Kramer, R. S., Coca, S. G. & Parikh, C. R. Duration of acute kidney injury impacts long-term survival after cardiac surgery. Ann. Thorac. Surg. 90, 1142–1148 (2010).

    Article  PubMed  Google Scholar 

  18. Moffett, B. S. & Arikan, A. A. Trajectory of AKI in hospitalized pediatric patients-impact of duration and repeat events. Nephrol. Dialysis Transpl. 37, 1443–1450 (2022). Epub 2021/07/11. PubMed PMID: 34245299.

    Article  CAS  Google Scholar 

  19. Juul, S. E. et al. A randomized trial of erythropoietin for neuroprotection in preterm infants. N. Engl. J. Med. 382, 233–243 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Juul, S. E., Mayock, D. E., Comstock, B. A. & Heagerty, P. J. Neuroprotective potential of erythropoietin in neonates; design of a randomized trial. Matern. Health Neonatol. Perinatol. 1, 1–9 (2015).

    Article  Google Scholar 

  21. Lazarus, B., Davies, M. R. P., Trubiano, J. A. & Pellicano, R. Time to acute kidney injury in β-lactam-induced acute interstitial nephritis. Kidney Int. Rep. 5, 1068–1070 (2020).

    Article  PubMed Central  PubMed  Google Scholar 

  22. Jetton, J. G. et al. Incidence and outcomes of neonatal acute kidney injury (AWAKEN): a multicentre, multinational, observational cohort study. Lancet Child Adolesc. Health 1, 184–194 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  23. Kaddourah, A., Basu, R. K., Bagshaw, S. M. & Goldstein, S. L. Epidemiology of acute kidney injury in critically Ill children and young adults. N. Engl. J. Med. 376, 11–20 (2017).

    Article  PubMed  Google Scholar 

  24. Salerno, S. N. et al. Association between nephrotoxic drug combinations and acute kidney injury in the neonatal intensive care unit. J. Pediatr. 228, 213–219 (2021).

    Article  CAS  PubMed  Google Scholar 

  25. Mohamed, T. H., Klamer B., Mahan J. D., Spencer J. D., & Slaughter, J. L. Diuretic therapy and acute kidney injury in preterm neonates and infants. Pediatric nephrology (Berlin, Germany). 2021. https://doi.org/10.1007/s00467-021-05132-6.

  26. Cerqueira, D. M. et al. In utero exposure to maternal diabetes impairs nephron progenitor differentiation. Am. J. Physiol. Ren. Physiol. 317, F1318–f30 (2019).

    Article  CAS  Google Scholar 

  27. Aliou, Y. et al. Post-weaning high-fat diet accelerates kidney injury, but not hypertension programmed by maternal diabetes. Pediatr. Res. 79, 416–424 (2016).

    Article  CAS  PubMed  Google Scholar 

  28. Callaway, D. A. et al. Prematurity disrupts glomeruli development, whereas prematurity and hyperglycemia lead to altered nephron maturation and increased oxidative stress in newborn baboons. Pediatr. Res. 83, 702–711 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Dyck, R. F. et al. Congenital anomalies of the kidney and urinary tract (CAKUT): An emerging relationship with pregestational diabetes mellitus among first nations and non-first nations people in Saskatchewan-results from the DIP: ORRIIGENSS project. Can. J. Diabetes 45, 346–54.e1 (2021).

    Article  PubMed  Google Scholar 

  30. Venkatesh, K. K. et al. Risk of adverse pregnancy outcomes among pregnant individuals with gestational diabetes by race and ethnicity in the United States, 2014–2020. JAMA 327, 1356–1367 (2022) The National Institutes of Health outside the submitted work. No other disclosures were reported.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Smythe, C. M., Nickel, J. F. & Bradley, S. E. The effect of epinephrine (USP), l-epinephrine, and l-norepinephrine on glomerular filtration rate, renal plasma flow, and the urinary excretion of sodium, potassium, and water in normal man. J. Clin. Invest. 31, 499–506 (1952).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Hoogenberg, K., Smit, A. J. & Girbes, A. R. J. Effects of low-dose dopamine on renal and systemic hemodynamics during incremental norepinephrine infusion in healthy volunteers. Crit. Care Med. 26, 260–265 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Blatt, N. B., Srinivasan, S., Mottes, T., Shanley, M. M. & Shanley, T. P. Biology of sepsis: Its relevance to pediatric nephrology. Pediatr. Nephrol. (Berl., Ger.). 29, 2273–2287 (2014).

    Article  Google Scholar 

  34. Sakr, Y., Dubois, M. J., De Backer, D., Creteur, J. & Vincent, J. L. Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit. Care Med. 32, 1825–1831 (2004).

    Article  PubMed  Google Scholar 

  35. Venkatachalam, M. A. & Weinberg, J. M. The tubule pathology of septic acute kidney injury: A neglected area of research comes of age. Kidney Int. 81, 338–340 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Adegboyega, O. O., Singh, Y., Bhutada, A., Kupferman, J. C. & Rastogi, S. Recurrent acute kidney injury in preterm neonates is common and associated with worse outcomes and higher mortality. Pediatr. Res. 92, 284–290 (2022).

    Article  CAS  PubMed  Google Scholar 

  37. Daraskevicius, J. et al. Phenotypes and baseline risk factors of acute kidney injury in children after allogeneic hematopoietic stem cell transplantation. Front Pediatr. 8, 499 (2020).

    Article  PubMed Central  PubMed  Google Scholar 

  38. Siew, E. D. et al. Predictors of recurrent AKI. J. Am. Soc. Nephrology 27, 1190–1200 (2016).

    Article  CAS  Google Scholar 

  39. DeFreitas M. J. et al. Maternal hypertension disorders and neonatal acute kidney injury: Results from the AWAKEN Study. Am. J. Perinatol. 2022. https://doi.org/10.1055/a-1780-2249.

  40. Garg P. M. et al. Severe acute kidney injury in neonates with necrotizing enterocolitis: Risk factors and outcomes. Pediatric Res. 2021. https://doi.org/10.1038/s41390-020-01320-6.

  41. Criss, C. N. et al. Acute kidney injury in necrotizing enterocolitis predicts mortality. Pediatr. Nephrol. (Berl., Ger.). 33, 503–510 (2018).

    Article  Google Scholar 

  42. Garg P. M. et al. Gestational age-specific clinical correlates of acute kidney injury in preterm infants with necrotizing enterocolitis. Pediatric Res. https://doi.org/10.1038/s41390-023-02736-6. (2023).

  43. Westreich, D. & Greenland, S. The Table 2 fallacy: Presenting and interpreting confounder and modifier coefficients. Am. J. Epidemiol. 177, 292–298 (2013).

    Article  PubMed Central  PubMed  Google Scholar 

  44. Iacobelli, S. & Guignard, J. P. Maturation of glomerular filtration rate in neonates and infants: an overview. Pediatr. Nephrol. (Berl., Ger.). 36, 1439–1446 (2021).

    Article  Google Scholar 

Download references

Acknowledgements

The following individuals served as collaborators and investigators for the ALMOND studies. They collaborated in protocol development and review, data analysis, and participated in drafting or review of the manuscript, and their names should be citable by PubMed.

Funding

The primary author’s research efforts in this publication are supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) under award numbers K23DK131289 and L40DK130155. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This study is part of the Assessing Longitudinal Micropremie Outcomes in Infants at risk for renal Disease (ALMOND) study coordinated by the NKC. Statistical support for this study is provided by Nuwellis. The original study, the Preterm Erythropoietin Neuroprotection Trial, was funded by grants U01 NS077953 and U01 NS077955 from the National Institute of Neurological Disorders and Stroke. Kidney-specific data collection was funded by grant R01 DK103608 from the NIDDK as part of the Recombinant Erythropoietin for Protection of Infant Renal Disease (REPaIReD) Study on behalf of co-author DJA. JRC receives funding from the NIH/NIDDK: R56DK110622, 1R41DK129138, 2P50DK096373, and 1R21DK134104. AMS reports funding from NIH National Heart, Lung, and Blood Institute K23HL148394, L40HL148910-2, R01HL146818, and R01HL164434. MJD reports funding from NIH 5KL2TR002737-04 and the Micah Batchelor Foundation.

Author information

Authors and Affiliations

  1. University of North Carolina Department of Medicine-Nephrology, Chapel Hill, NC, USA

    Keia Sanderson

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

    Russell Griffin & Nekayla Anderson

  3. Department of Pediatrics, Section of Nephrology, Brenner Children’s, Wake Forest University School of Medicine, Winston Salem, NC, USA

    Andrew M. South

  4. Division of Neonatology, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, USA

    Jonathan R. Swanson

  5. Department of Pediatrics, Division of Nephrology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

    Michael Zappitelli

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

    Michael Zappitelli

  7. Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA

    Heidi J. Steflik

  8. Division of Pediatric Nephrology, Department of Pediatrics, University of Miami, Miami, FL, USA

    Marissa J. DeFreitas

  9. University of Virginia, Department of Pediatrics, Division of Nephrology, Charlottesville, VA, USA

    Jennifer Charlton

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

    David Askenazi

  11. Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA

    Mamta Fuloria

  12. University of Kentucky, Lexington, KY, USA

    Mina Hanna

  13. University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Matthew W. Harer

  14. Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Cara Slagle & Meredith P. Schuh

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

    Robert Woroniecki

Authors
  1. Keia Sanderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Russell Griffin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nekayla Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrew M. South
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jonathan R. Swanson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Zappitelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Heidi J. Steflik
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marissa J. DeFreitas
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jennifer Charlton
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David Askenazi
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

Neonatal Kidney Collaborative (NKC) Research Committee

  • Mamta Fuloria
  • , Mina Hanna
  • , Matthew W. Harer
  • , Cara Slagle
  • , Meredith P. Schuh
  •  & Robert Woroniecki

Contributions

KRS and DJA made substantial contributions to the conceptualization of study, research methodology, formal analysis, writing of the initial manuscript, reviewing or editing of the manuscript, and gave final approval for this version to be published. DJA made substantial contributions to the conceptualization of study, research methodology, formal analysis, reviewing or editing of the manuscript, and gave final approval for this version to be published. RG and NA made substantial contributions to the conceptualization of study, formal analysis, reviewing or editing of the manuscript, and gave final approval for this version to be published. AMS, JRS, MZ, HJS, MJD, and JRC made substantial contributions to the conceptualization of study, reviewing, or editing of the manuscript, and gave final approval for this version to be published.

Corresponding author

Correspondence to Keia Sanderson.

Ethics declarations

Competing interests

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: DJA is a consultant for Baxter, Nuwellis, Seastar, and Bioporto. Over the last 24 months, his institution has received funding for education and research that is not related to this project from NIH, Baxter, Nuwellis, Medtronic, Bioporto, Portero, Lediant and Seastar. He has financial interests in patent/innovations in the area of kidney support therapies and urine collection devices. He is the Founder and Chief Scientific Officer for Zorro-Flow Inc. JRC is a consultant for Medtronics, investor in Zorro-Flow, and co-owner of Sindri Technologies, LLC. She serves on the Board of the Neonatal Kidney Collaborative (NKC).

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sanderson, K., Griffin, R., Anderson, N. et al. Perinatal risk factors associated with acute kidney injury severity and duration among infants born extremely preterm. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03102-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41390-024-03102-w

Search

Advanced search

Quick links