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  • Clinical Research Article
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Gestational age-specific clinical correlates of acute kidney injury in preterm infants with necrotizing enterocolitis

Pediatric Research volume 94, pages 2016–2025 (2023)Cite this article

Abstract

Background

To study the gestational age-specific risk factors and outcomes of severe acute kidney injury (AKI) in neonates with necrotizing enterocolitis (NEC).

Methods

Retrospective cohort study comparing gestational age (GA)-specific clinical data between infants without severe AKI (stage 0/1 AKI) and those with severe AKI (stages 2 and 3 AKI) stratified by GA ≤27 and >27 weeks.

Results

Infants with GA ≤27 weeks had double the rate of severe AKI (46.3% vs. 20%). In infants with GA >27 weeks, male sex, outborn, and nephrotoxic medication exposure were associated with severe AKI. On multivariable logistic regression, in infants with GA ≤27 weeks, surgical NEC (OR 35.08 (CI 5.05, 243.73), p < 0.001) and ostomy (OR 6.2(CI 1.29, 29.73), p = 0.027) were associated with significantly higher odds of severe AKI. Surgical NEC infants with GA >27 weeks and severe AKI were significantly more likely to be outborn, have later NEC onset, need dopamine, and have longer hospitalization (158 days [110; 220] vs.75.5 days [38.8; 105]; p = 0.007 than those with non-severe AKI.

Conclusion

In neonates with NEC, surgical intervention was associated with moderate-to-severe AKI in infants with GA ≤27 weeks and with longer hospitalization in infants with GA >27 weeks.

Impact

  • In both cohorts need for surgery, stoma, cholestasis, and mechanical ventilation were associated with severe AKI; however, the infants with GA <27 weeks had twice the risk of severe AKI than GA >27 weeks group.

  • The longer exposure to nephrotoxic medication and referral need were significant risk factors for AKI in GA >27 weeks group.

  • GA-specific kidney protective and monitoring strategies to prevent AKI and its consequences are needed to improve the clinical outcomes in neonates with NEC. Understanding the risk factors and short- and long-term outcomes unique to different GA groups will help inform those strategies.

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Fig. 1
Fig. 2: Trend of serum creatinine and urine output parameters at different time points before and after NEC onset among NEC preterm infants by GA with and without severe AKI.
Fig. 3: Trend of serum sodium and weight change parameters at different time points before and after NEC onset among NEC preterm infants by GA with and without severe AKI.

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Data availability

All data generated and analyzed during this study are included in this article and its supplementary information files.

References

  1. Neu, J. & Walker, W. A. Necrotizing enterocolitis. N. Engl. J. Med. 364, 255–264 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sankaran, K. et al. Variations in incidence of necrotizing enterocolitis in Canadian neonatal intensive care units. J. Pediatr. Gastroenterol. Nutr. 39, 366–372 (2004).

    Article  PubMed  Google Scholar 

  3. 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  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  5. Wu, Y., Hua, X., Yang, G., Xiang, B. & Jiang, X. Incidence, risk factors, and outcomes of acute kidney injury in neonates after surgical procedures. Pediatr Nephrol. 35, 1341–1346 (2020).

  6. Mallory, P. P. et al. Acute kidney injury, fluid overload, and outcomes in children supported with extracorporeal membrane oxygenation for a respiratory indication. ASAIO J. 66, 319–326 (2020).

    Article  PubMed  Google Scholar 

  7. Starr, M. C. et al. Acute kidney injury and bronchopulmonary dysplasia in premature neonates born less than 32 weeks' gestation. Am. J. Perinatol. 37, 341–348 (2020).

    Article  PubMed  Google Scholar 

  8. Stoops, C. et al. The Association of Intraventricular Hemorrhage and Acute Kidney Injury in Premature Infants from the Assessment of the Worldwide Acute Kidney Injury Epidemiology in Neonates (AWAKEN) Study. Neonatology 116, 321–330 (2019).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  10. Bakhoum, C. Y., Basalely, A., Koppel, R. I. & Sethna, C. B. Acute kidney injury in preterm infants with necrotizing enterocolitis. J. Matern Fetal Neonatal Med. 32, 3185–3190 (2019).

    Article  PubMed  Google Scholar 

  11. Garg, P. M., Tatum, R., Ravisankar, S., Shekhawat, P. S. & Chen, Y. H. Necrotizing enterocolitis in a mouse model leads to widespread renal inflammation, acute kidney injury, and disruption of renal tight junction proteins. Pediatr. Res. 78, 527–532 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sanchez, C., Garcia, M. A. & Valdes, B. D. Acute kidney injury in newborns with necrotizing enterocolitis: risk factors and mortality. Bol. Med. Hosp. Infant Mex. 76, 210–214 (2019).

    PubMed  Google Scholar 

  13. Garg, P. M. et al. Severe acute kidney injury in neonates with necrotizing enterocolitis: risk factors and outcomes. Pediatr. Res. 90, 642–649 (2021).

  14. Bell, M. J. et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann. Surg. 187, 1–7 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jetton, J. G. & Askenazi, D. J. Acute kidney injury in the neonate. Clin. Perinatol. 41, 487–502 (2014).

    Article  PubMed  Google Scholar 

  16. Zappitelli, M. et al. Developing a neonatal acute kidney injury research definition: a report from the NIDDK neonatal AKI workshop. Pediatr. Res. 82, 569–573 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Basu, R. K. et al. Assessment of Worldwide Acute Kidney Injury, Renal Angina and Epidemiology in Critically Ill Children (AWARE): a prospective study to improve diagnostic precision. J Clin Trials 5, 222 (2015).

  18. Garg, P. M. et al. Hematological predictors of mortality in neonates with fulminant necrotizing enterocolitis. J. Perinatol. 41, 1110–1121 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hashem, R. H., Mansi, Y. A., Almasah, N. S. & Abdelghaffar, S. Doppler ultrasound assessment of the splanchnic circulation in preterms with neonatal sepsis at risk for necrotizing enterocolitis. J. Ultrasound 20, 59–67 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Murphy, H. J. et al. Nephrotoxic medications and acute kidney injury risk factors in the neonatal intensive care unit: clinical challenges for neonatologists and nephrologists. Pediatr. Nephrol. 35, 2077–2088 (2020).

    Article  PubMed  Google Scholar 

  21. 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 

  22. 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 

  23. Martini, S. et al. Impact of nephrotoxic drugs on urinary biomarkers of renal function in very preterm infants. Pediatr. Res. 91, 1715–1722 (2022).

    Article  CAS  PubMed  Google Scholar 

  24. Garg, P. M. et al. Clinical impact of NEC-associated sepsis on outcomes in preterm infants. Pediatr. Res. 92, 1705–1715 (2022).

  25. Coggins, S. A. et al. Acute kidney injury associated with late-onset neonatal sepsis: a matched cohort study. J. Pediatr. 231, 185–192.e184 (2021).

    Article  PubMed  Google Scholar 

  26. Seely, K. A. et al. Hemodynamic changes in the kidney in a pediatric rat model of sepsis-induced acute kidney injury. Am. J. Physiol. Ren. Physiol. 301, F209–F217 (2011).

    Article  CAS  Google Scholar 

  27. Geier, A., Fickert, P. & Trauner, M. Mechanisms of disease: mechanisms and clinical implications of cholestasis in sepsis. Nat. Clin. Pract. Gastroenterol. Hepatol. 3, 574–585 (2006).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The Mississippi Center for Clinical and Translational Research for supporting NEC research.

Funding

P.M.G. and W.B.H. are partially supported by the NIGMS of the NIH under Award Number 5U54GM115428. A.M.S. has funding from the NHBLI K23-HL148394, R01-HL146818, L40-HL148910-2, and R56-HL164434. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pediatrics/Neonatology, Atrium Health Wake Forest Baptist Hospital, Wake Forest University School of Medicine, Winston Salem, NC, USA

    Parvesh Mohan Garg

  2. Department of Pediatrics/Neonatology, University of Mississippi Medical Center, Jackson, MS, USA

    Parvesh Mohan Garg, Isabella A. Pittman, Chin Wen Yen & Robbin Riddick

  3. Department of Data Sciences, University of Mississippi Medical Center, Jackson, MS, USA

    Md Abu Yusuf Ansari & William B. Hillegass

  4. Section of Pediatric Nephrology, Medical College of Wisconsin, Milwaukee, WI, USA

    Jennifer G. Jetton

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

    Andrew M. South

  6. Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA

    William B. Hillegass

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Contributions

P.M.G. designed the study. P.M.G., I.A.P., R.R., M.A.Y.A., C.W.Y., J.G.J., A.M.S., and W.B.H. collected, analyzed the data and wrote the manuscript. All authors contributed to and approved the manuscript.

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Correspondence to Parvesh Mohan Garg.

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Garg, P.M., Pittman, I.A., Ansari, M.A.Y. et al. Gestational age-specific clinical correlates of acute kidney injury in preterm infants with necrotizing enterocolitis. Pediatr Res 94, 2016–2025 (2023). https://doi.org/10.1038/s41390-023-02736-6

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