Am J Perinatol
DOI: 10.1055/a-2330-1244
Review Article

Necrotizing Enterocolitis-Associated Acute Kidney Injury—Transforming the Paradigm

Padma P. Garg
1   Department of Pediatrics Critical Care, University of Mississippi Medical Center, Jackson, Mississippi
Jeffrey Shenberger
2   Department of Pediatrics/Neonatology, Connecticut Children's, Hartford, Connecticut
Andrew M. South
3   Section of Nephrology, Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
4   Division of Public Health Sciences, Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, North Carolina
Parvesh M. Garg
5   Department of Pediatrics/Neonatology, Wake Forest University, Winston-Salem, North Carolina
› Author Affiliations
Funding A.M.S. has funding from the NHBLI K23-HL148394, R01-HL146818, L40-HL148910-2, and R01-HL164434. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.


Necrotizing enterocolitis (NEC) is one of the most common conditions requiring emergency surgery in the neonatal intensive care unit and is associated with a septic shock-like state contributing to multiorgan dysfunction. NEC affects 6 to 10% of very low-birth-weight infants and remains a leading cause of death. The occurrence of severe acute kidney injury (AKI) following surgical NEC is a harbinger of multiple morbidities. This review presents current evidence about the clinical impact of NEC-associated AKI on the clinical outcomes. Studies evaluating nephroprotective strategies to prevent AKI and its consequences are greatly needed to improve the postoperative recovery and clinical outcomes in neonates with NEC. Future observational studies and clinical trials in preterm infants with NEC prioritize measuring short-term (AKI) and longer term (chronic kidney disease) kidney outcomes.

Key Points

  • Severe AKI is common following surgical NEC.

  • Severe AKI following NEC is associated with poor clinical outcomes.

  • Studies evaluating nephroprotective strategies to prevent AKI and its consequences are needed.


  1. Severe AKI (stage 2 and 3) occurs in 32.6% of neonates after NEC diagnosis and in 58.7% following surgical NEC diagnosis.

  2. NEC-associated AKI is associated with severe postoperative course, moderate-to-severe bronchopulmonary dysplasia, surgical complications, brain injury, and longer hospital stay in preterm infants.

  3. Severity of NEC-associated AKI can be utilized by bedside providers for the prognostication of clinical outcomes in preterm infants.

Authors' Contributions

P.M.G. conceptualized the idea. P.P.G., J.S., A.M.S., and P.M.G. wrote the article. All the authors approved the manuscript.

Publication History

Received: 04 April 2024

Accepted: 17 May 2024

Accepted Manuscript online:
20 May 2024

Article published online:
18 June 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

  • References

  • 1 Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011; 364 (03) 255-264
  • 2 Sankaran K, Puckett B, Lee DS. et al; Canadian Neonatal Network. Variations in incidence of necrotizing enterocolitis in Canadian neonatal intensive care units. J Pediatr Gastroenterol Nutr 2004; 39 (04) 366-372
  • 3 Sjoberg Bexelius T, Ahle M, Elfvin A, Björling O, Ludvigsson JF, Andersson RE. Intestinal failure after necrotising enterocolitis: incidence and risk factors in a Swedish population-based longitudinal study. BMJ Paediatr Open 2018; 2 (01) e000316
  • 4 Allin BSR, Long AM, Gupta A, Lakhoo K, Knight M. British Association of Paediatric Surgeons Congenital Anomalies Surveillance System Necrotising Enterocolitis Collaboration. One-year outcomes following surgery for necrotising enterocolitis: a UK-wide cohort study. Arch Dis Child Fetal Neonatal Ed 2018; 103 (05) F461-F466
  • 5 Knell J, Han SM, Jaksic T, Modi BP. Current status of necrotizing enterocolitis. Curr Probl Surg 2019; 56 (01) 11-38
  • 6 Stoll BJ, Hansen NI, Bell EF. et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012. JAMA 2015; 314 (10) 1039-1051
  • 7 Sántulli TV, Schullinger JN, Heird WC. et al. Acute necrotizing enterocolitis in infancy: a review of 64 cases. Pediatrics 1975; 55 (03) 376-387
  • 8 Mowitz ME, Dukhovny D, Zupancic JAF. The cost of necrotizing enterocolitis in premature infants. Semin Fetal Neonatal Med 2018; 23 (06) 416-419
  • 9 Ganapathy V, Hay JW, Kim JH, Lee ML, Rechtman DJ. Long term healthcare costs of infants who survived neonatal necrotizing enterocolitis: a retrospective longitudinal study among infants enrolled in Texas Medicaid. BMC Pediatr 2013; 13: 127
  • 10 Bao YW, Yuan Y, Chen JH, Lin WQ. Kidney disease models: tools to identify mechanisms and potential therapeutic targets. Zool Res 2018; 39 (02) 72-86
  • 11 Garg PM, Tatum R, Ravisankar S, Shekhawat PS, Chen YH. Necrotizing enterocolitis in a mouse model leads to widespread renal inflammation, acute kidney injury, and disruption of renal tight junction proteins. Pediatr Res 2015; 78 (05) 527-532
  • 12 Schwarz CE, Dempsey EM. Management of neonatal hypotension and shock. Semin Fetal Neonatal Med 2020; 25 (05) 101121
  • 13 Jetton JG, Askenazi DJ. Acute kidney injury in the neonate. Clin Perinatol 2014; 41 (03) 487-502
  • 14 Jetton JG, Boohaker LJ, Sethi SK. et al; Neonatal Kidney Collaborative (NKC). Incidence and outcomes of neonatal acute kidney injury (AWAKEN): a multicentre, multinational, observational cohort study. Lancet Child Adolesc Health 2017; 1 (03) 184-194
  • 15 Charlton JR, Boohaker L, Askenazi D. et al; Neonatal Kidney Collaborative. Incidence and risk factors of early onset neonatal AKI. Clin J Am Soc Nephrol 2019; 14 (02) 184-195
  • 16 Shang S, Du L, Geng N. et al. Neurodevelopmental impairment following surgical necrotizing enterocolitis with gestational age ≥ 28 weeks: who is at risk?. Pediatr Surg Int 2024; 40 (01) 41
  • 17 Hu Q, Li SJ, Chen QL, Chen H, Li Q, Wang M. Risk factors for acute kidney injury in critically ill neonates: a systematic review and meta-analysis. Front Pediatr 2021; 9: 666507
  • 18 Garg PM, Britt AB, Ansari MAY. et al. Severe acute kidney injury in neonates with necrotizing enterocolitis: risk factors and outcomes. Pediatr Res 2021; 90 (03) 642-649
  • 19 Selewski DT, Charlton JR, Jetton JG. et al. Neonatal acute kidney injury. Pediatrics 2015; 136 (02) e463-e473
  • 20 Jetton JG, Guillet R, Askenazi DJ. et al; Neonatal Kidney Collaborative. Assessment of worldwide acute kidney injury epidemiology in neonates: design of a retrospective cohort study. Front Pediatr 2016; 4: 68
  • 21 Zappitelli M, Ambalavanan N, Askenazi DJ. et al. Developing a neonatal acute kidney injury research definition: a report from the NIDDK neonatal AKI workshop. Pediatr Res 2017; 82 (04) 569-573
  • 22 Mahgoob MH, Swelam SH. Incidence, risk factors, and outcomes of acute kidney injury in necrotizing enterocolitis: a prospective single-center study. Saudi J Kidney Dis Transpl 2022; 33 (03) 373-379
  • 23 Zozaya C, García González I, Avila-Alvarez A. et al. Incidence, treatment, and outcome trends of necrotizing enterocolitis in preterm infants: a multicenter cohort study. Front Pediatr 2020; 8: 188
  • 24 Garg PM, Paschal JL, Zhang M. et al. Clinical impact of severe acute kidney injury on post-operative and brain injury outcomes in preterm infants following surgical necrotizing enterocolitis. J Matern Fetal Neonatal Med 2022; 35 (25) 10124-10136
  • 25 Garg PM, Pippin M, Zhang M. et al. Clinical correlates of moderate-to-severe bronchopulmonary dysplasia in preterm infants following surgical necrotizing enterocolitis. Am J Perinatol 2022; (e-pub ahead of print) DOI: 10.1055/a-1904-9194.
  • 26 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 2020; 35 (07) 1341-1346
  • 27 Mallory PP, Selewski DT, Askenazi DJ. et al. Acute kidney injury, fluid overload, and outcomes in children supported with extracorporeal membrane oxygenation for a respiratory indication. ASAIO J 2020; 66 (03) 319-326
  • 28 Starr MC, Boohaker L, Eldredge LC. et al; Neonatal Kidney Collaborative. Acute kidney injury and bronchopulmonary dysplasia in premature neonates born less than 32 weeks' gestation. Am J Perinatol 2020; 37 (03) 341-348
  • 29 Stoops C, Boohaker L, Sims B, Griffin R, Selewski DT, Askenazi D. on behalf of the National Kidney Collaborative (NKC). 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 2019; 116 (04) 321-330
  • 30 Criss CN, Selewski DT, Sunkara B. et al. Acute kidney injury in necrotizing enterocolitis predicts mortality. Pediatr Nephrol 2018; 33 (03) 503-510
  • 31 Bakhoum CY, Basalely A, Koppel RI, Sethna CB. Acute kidney injury in preterm infants with necrotizing enterocolitis. J Matern Fetal Neonatal Med 2019; 32 (19) 3185-3190
  • 32 Sánchez C, García MA, Valdés BD. Acute kidney injury in newborns with necrotizing enterocolitis: risk factors and mortality. Bol Méd Hosp Infant México 2019; 76 (05) 210-214
  • 33 Han R, Bonachea EM, Jackson K. et al. Describing patterns in serum creatinine in infants with and without necrotizing enterocolitis. J Perinatol 2023; 43 (01) 86-90
  • 34 Garg PM, Pittman IA, Ansari MAY. et al. Gestational age-specific clinical correlates of acute kidney injury in preterm infants with necrotizing enterocolitis. Pediatr Res 2023; 94 (06) 2016-2025
  • 35 Murphy HJ, Thomas B, Van Wyk B, Tierney SB, Selewski DT, Jetton JG. Nephrotoxic medications and acute kidney injury risk factors in the neonatal intensive care unit: clinical challenges for neonatologists and nephrologists. Pediatr Nephrol 2020; 35 (11) 2077-2088
  • 36 Salerno SN, Liao Y, Jackson W. et al. Association between nephrotoxic drug combinations and acute kidney injury in the neonatal intensive care unit. J Pediatr 2021; 228: 213-219
  • 37 Rhone ET, Carmody JB, Swanson JR, Charlton JR. Nephrotoxic medication exposure in very low birth weight infants. J Matern Fetal Neonatal Med 2014; 27 (14) 1485-1490
  • 38 Martini S, Vitali F, Capelli I. et al. Impact of nephrotoxic drugs on urinary biomarkers of renal function in very preterm infants. Pediatr Res 2022; 91 (07) 1715-1722
  • 39 Aviles-Otero N, Kumar R, Khalsa DD, Green G, Carmody JB. Caffeine exposure and acute kidney injury in premature infants with necrotizing enterocolitis and spontaneous intestinal perforation. Pediatr Nephrol 2019; 34 (04) 729-736
  • 40 Coggins SA, Laskin B, Harris MC. et al. Acute kidney injury associated with late-onset neonatal sepsis: a matched cohort study. J Pediatr 2021; 231: 185-192.e4
  • 41 Seely KA, Holthoff JH, Burns ST. et al. Hemodynamic changes in the kidney in a pediatric rat model of sepsis-induced acute kidney injury. Am J Physiol Renal Physiol 2011; 301 (01) F209-F217
  • 42 Garg PM, Paschal JL, Ansari MAY, Block D, Inagaki K, Weitkamp JH. Clinical impact of NEC-associated sepsis on outcomes in preterm infants. Pediatr Res 2022; 92 (06) 1705-1715