Caffeine exposure and acute kidney injury in premature infants with necrotizing enterocolitis and spontaneous intestinal perforation

  • Noelia Aviles-Otero
  • Reeti Kumar
  • Dev Darshan Khalsa
  • Glen Green
  • J. Bryan Carmody
Original Article



Acute kidney injury (AKI) is common in preterm infants, but specific therapies remain scarce. Recent studies have demonstrated an association between caffeine exposure and less frequent AKI in the first 7–10 days after birth. We hypothesized that patients with necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) would provide a better natural model of AKI to evaluate this association.


We reviewed all premature patients diagnosed with NEC or SIP at our institution from 2008 to 2014. AKI was defined by change in serum creatinine using the neonatal Kidney Disease: Improving Global Outcomes definition. Caffeine was prescribed for apnea of prematurity and caffeine exposure was determined by chart review.


A total of 146 patients with NEC/SIP were reviewed. Of these, 119 (81.5%) received caffeine, and 91 (62.3%) developed AKI. AKI occurred less frequently in patients who received caffeine than in those who did not (55.5% vs. 92.6%; odds ratio (OR) 0.10; 95% confidence interval (CI) 0.02–0.44). This association persisted in multivariable models after adjustment for potential confounders (adjusted OR 0.08; 95% CI 0.01–0.42; number needed to be exposed to caffeine to prevent one case of AKI = 2.6). Although baseline serum creatinine did not differ by caffeine exposure, patients receiving caffeine had lower peak creatinine (median 1.0 mg/dl vs. 1.5 mg/dl; p = 0.008) and absolute creatinine change (median 0.42 mg/dl vs. 0.68 mg/dl; p = 0.003) than those who did not.


Caffeine exposure in preterm infants with NEC/SIP is associated with decreased incidence and severity of AKI.


Acute kidney injury Caffeine Infant Intestinal perforation Low birth weight Necrotizing enterocolitis Premature 


Compliance with ethical standards

The Institutional Review Board at Eastern Virginia Medical School approved the study protocol and waived the need for consent.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Selewski DT, Charlton JR, Jetton JG, Guillet R, Mhanna MJ, Askenazi DJ, Kent AL (2015) Neonatal acute kidney injury. Pediatrics 136:e463–e473. CrossRefPubMedGoogle Scholar
  2. 2.
    Zappitelli M, Ambalavanan N, Askenazi DJ, Moxey-Mims MM, Kimmel PL, Star RA, Abitbol CL, Brophy PD, Hidalgo G, Hanna M, Morgan CM, Raju TNK, Ray P, Reyes-Bou Z, Roushdi A, Goldstein SL (2017) Developing a neonatal acute kidney research definition: a report from the NIDDK neonatal AKI workshop. Pediatr Res 82:569–573. CrossRefPubMedGoogle Scholar
  3. 3.
    Koralkar R, Ambalavanan N, Levitan EB, McGwin G, Goldstein S, Askenazi D (2011) Acute kidney injury reduces survival in very low birth weight infants. Pediatr Res 69:354–358. CrossRefPubMedGoogle Scholar
  4. 4.
    Arcinue R, Kantak A, Elkhwad M (2015) Acute kidney injury in ELBW infants (<  750 grams) and its associated risk factors. J Neonatal-Perinatal Med 8:349–357. CrossRefPubMedGoogle Scholar
  5. 5.
    Jetton JG, Boohaker LJ, Sethi SK, Wazir S, Rohatgi S, Soranno DE, Chishti AS, Woroniecki R, Mammen C, Swanson JR, Sridhar S, Wong CS, Kupferman JC, Griffin RL, Askenazi DJ (2017) Incidence and outcomes of neonatal acute kidney injury (AWAKEN): a multicentre, multinational observational cohort study. Lancet Child Adolesc Health 1:184–194. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Shalaby MA, Sawan ZA, Nawawi E, Alsaedi S, Al-Wassia H, Kari JA (2018) Incidence, risk factors, and outcome of neonatal acute kidney injury: a prospective cohort study. Pediatr Nephrol. CrossRefGoogle Scholar
  7. 7.
    Jenik AG, Ceriani Cernadas JM, Gorenstein A, Ramirez JA, Vain N, Armadans M, Ferraris JR (2000) A randomized, double-blind, placebo-controlled trial of the effects of prophylactic theophylline on renal function in term neonates with perinatal asphyxia. Pediatrics 105:e45CrossRefGoogle Scholar
  8. 8.
    Bhat MA, Shah ZA, Makhdoomi MS, Mufti MH (2006) Theophylline for renal function in term neonates with perinatal asphyxia: a randomized, placebo-controlled trial. J Pediatr 149:180–184. CrossRefPubMedGoogle Scholar
  9. 9.
    Bakr AF (2005) Prophylactic theophylline to prevent renal dysfunction in newborns exposed to perinatal asphyxia – a study in a developing country. Pediatr Nephrol 20:1249–1252. CrossRefPubMedGoogle Scholar
  10. 10.
    Cattarelli D, Spandrio M, Gasparoni A, Bottino R, Offer C, Chirico G (2006) A randomised, double blind, placebo controlled trial of the effect of theophylline in prevention of vasomotor nephropathy in very preterm neonates with respiratory distress syndrome. Arch Dis Child Fetal Neonatal Ed 91:F80–F84. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Raina A, Pandita A, Harish R, Yachha M, Jamwal A (2016) Treating perinatal asphyxia with theophylline at birth helps to reduce the severity of renal dysfunction in term neonates. Acta Paediatr 105:e448–e451. CrossRefPubMedGoogle Scholar
  12. 12.
    Kidney Disease: Improving Global Outcomes (KDIGO) Work Group (2012) KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2:2. CrossRefGoogle Scholar
  13. 13.
    Aydin M, Hakan N, Zenciroglu A, Okumus N (2014) Is the use of prophylactic theophylline safe for the prevention of severe renal dysfunction in term and post-term neonates with perinatal asphyxia? J Perinatol 34:82. CrossRefPubMedGoogle Scholar
  14. 14.
    Lowry JA, Jarrett RV, Wasserman G, Pettett G, Kauffman RE (2001) Theophylline toxicokinetics in premature newborns. Arch Pediatr Adolesc Med 155:934–939CrossRefGoogle Scholar
  15. 15.
    Dobson NR, Patel RM, Smith PB, Kuehn DR, Clark J, Vyas-Read S, Herring A, Laughon MM, Carlton D, Hunt CE (2014) Trends in caffeine use and association between clinical outcomes and timing of therapy in very low birth weight infants. J Pediatr 164:992–998.e3. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Carmody JB, Harer MW, Denotti AR, Swanson JR, Charlton JR (2016) Caffeine exposure and risk of acute kidney injury in a retrospective cohort of very low birth weight neonates. J Pediatr 172:63–68. CrossRefPubMedGoogle Scholar
  17. 17.
    Harer MW, Askenazi DJ, Boohaker LJ, Carmody JB, Griffin RL, Guillet R, Selewski DT, Swanson JR, Charlton JR, Neonatal Kidney Collaborative (2018) Association between early caffeine citrate administration and risk of acute kidney injury in preterm neonates: results from the AWAKEN study. JAMA Pediatr 172:e180322. CrossRefPubMedGoogle Scholar
  18. 18.
    Parry G, Tucker J, Tarnow-Mordi W, UK Neonatal Staffing Study Collaborative Group (2003) CRIB II: an update of the clinical risk index for babies score. Lancet 361:1789–1791. CrossRefPubMedGoogle Scholar
  19. 19.
    Kyriacou DN, Lewis RJ (2016) Confounding by indication in clinical research. JAMA 316:1818–1819. CrossRefPubMedGoogle Scholar
  20. 20.
    Lee JS, Polin RA (2003) Treatment and prevention of necrotizing enterocolitis. Semin Neonatol 8:449–459. CrossRefPubMedGoogle Scholar
  21. 21.
    Okuyama H, Kubota A, Oue T, Kuroda S, Ikegami R, Kamiyama M (2002) A comparison of the clinical presentation and outcome of focal intestinal perforation and necrotizing enterocolitis in very-low-birth-weight neonates. Pediatr Surg Int 18:704–706. CrossRefPubMedGoogle Scholar
  22. 22.
    Jetton JG, Askenazi DJ (2012) Update on acute kidney injury in the neonate. Curr Opin Pediatr 24:191–196. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Charles BG, Townsend SR, Steer PA, Flenady VJ, Gray PH, Shearman A (2008) Caffeine citrate treatment for extremely premature infants with apnea: population pharmacokinetics, absolute bioavailability, and implications for therapeutic drug monitoring. Ther Drug Monit 30:709–716. CrossRefPubMedGoogle Scholar
  24. 24.
    Bender R, Blettner M (2002) Calculating the “number needed to be exposed” with adjustment for confounding variables in epidemiologic studies. J Clin Epidemiol 55:525–530CrossRefGoogle Scholar
  25. 25.
    Ostilie DJ, Spilde TL, St Peter SD, Sexton N, Miller KA, Sharp RJ, Gittes GK, Snyder CL (2003) Necrotizing enterocolitis in full-term infants. J Pediatr Surg 38:1039–1042CrossRefGoogle Scholar
  26. 26.
    Gordon PV, Attridge JT (2009) Understanding clinical literature relevant to spontaneous intestinal perforation. Am J Perinatol 26:309–316. CrossRefPubMedGoogle Scholar
  27. 27.
    Osswald H, Muhlbauer B, Schenk F (1991) Adenosine mediates tubuloglomerular feedback response: an element of metabolic control of kidney function. Kidney Int Suppl 32:S128–S131PubMedGoogle Scholar
  28. 28.
    Thomson S, Bao D, Deng A, Vallon V (2000) Adenosine formed by 5′-nucleotidase mediates tubuloglomerular feedback. J Clin Invest 106:289–298CrossRefGoogle Scholar
  29. 29.
    Osswald H, Schnermann J (2011) Methylxanthines and the kidney. Handb Exp Pharmacol 200:391–412. CrossRefGoogle Scholar
  30. 30.
    Alabbas A, Campbell A, Skippen P, Human D, Matsell D, Mammen C (2013) Epidemiology of cardiac surgery-associated acute kidney injury in neonates: a retrospective study. Pediatr Nephrol 28:1127–1134. CrossRefPubMedGoogle Scholar
  31. 31.
    Selewski DT, Jordan BK, Askenazi DJ, Dechert RE, Sarkar S (2013) Acute kidney injury in asphyxiated newborns treated with therapeutic hypothermia. J Pediatr 162:725–729. CrossRefPubMedGoogle Scholar
  32. 32.
    Gadepalli SK, Selewski DT, Drongowski RA, Mychaliska GB (2011) Acute kidney injury in congenital diaphragmatic hernia requiring extracorporeal life support: an insidious problem. J Pediatr Surg 46:630–635. CrossRefPubMedGoogle Scholar
  33. 33.
    Carmody JB, Swanson JR, Rhone ET, Charlton JR (2014) Recognition and reporting of AKI in very low birth weight infants. Clin J Am Soc Nephrol 9:2036–2043. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Bakhoum CY, Basalely A, Koppel RI, Sethna CB (2018) Acute kidney injury in preterm infants with necrotizing enterocolitis. J Matern Fetal Neonatal Med 9:1–6. CrossRefGoogle Scholar
  35. 35.
    Criss CN, Selewski DT, Sunkara B, Gish JS, Hsieh L, Mcleod JS, Robertson JO, Matusko N, Gadepalli SK (2018) Acute kidney injury in necrotizing enterocolitis predicts mortality. Pediatr Nephrol 33:503–510. CrossRefPubMedGoogle Scholar
  36. 36.
    Abu Jawdeh EG, O’Riordan M, Limrungsikul A, Bandyopadhyay A, Argus BM, Nakad PE, Supapannachart S, Yunis KA, Davis PG, Martin RJ (2013) Methylxanthine use for apnea of prematurity among an international cohort of neonatologists. J Neonatal-Perinatal Med 6:251–256. CrossRefPubMedGoogle Scholar
  37. 37.
    Basu RK, Andrews A, Krawczeski C, Manning P, Wheeler DS, Goldstein SL (2013) Acute kidney injury based on corrected serum creatinine is associated with increased morbidity in children following the arterial switch operation. Pediatr Crit Care Med 14:e218–e224. CrossRefPubMedGoogle Scholar
  38. 38.
    Allegaert K, Kuppens M, Mekahli D, Levtchenko E, Vanstapel F, Vanhole C, van den Anker JN (2012) Creatinine reference values in ELBW infants: impact of quantification by Jaffe or enzymatic method. J Matern Fetal Neonatal Med 25:1678–1681. CrossRefPubMedGoogle Scholar
  39. 39.
    Pumberger W, Mayr M, Kohlhauser C (2002) Spontaneous localized intestinal perforation in very-low-birth-weight infants: a distinct clinical entity different from necrotizing enterocolitis. J Am Coll Surg 195:796–803. CrossRefPubMedGoogle Scholar
  40. 40.
    Gordon PV, Swanson JR, Attridge JT, Clark R (2007) Emerging trends in acquired neonatal intestinal disease: is it time to abandon Bell’s criteria? J Perinatol 27:661–671. CrossRefPubMedGoogle Scholar
  41. 41.
    Cox C, Hashem N, Tebbs J, Bookstaver PB, Iskersky V (2015) Evaluation of caffeine and the development of necrotizing enterocolitis. J Neonatal-Perinatal Med 8:339–347. CrossRefPubMedGoogle Scholar
  42. 42.
    Vongbhavit K, Underwood MA (2017) Intestinal perforation in the premature infant. J Neonatal-Perinatal Med 10:281–289. CrossRefPubMedGoogle Scholar
  43. 43.
    Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W (2006) Caffeine therapy for apnea of prematurity. N Engl J Med 354:2112–2121. CrossRefPubMedGoogle Scholar

Copyright information

© IPNA 2018

Authors and Affiliations

  1. 1.Department of Pediatrics, Division of NeonatologyUniversity of VirginiaCharlottesvilleUSA
  2. 2.Department of Pediatrics, Division of NephrologyNationwide Children’s HospitalColumbusUSA
  3. 3.Department of PediatricsCohen Children’s Medical CenterNew Hyde ParkUSA
  4. 4.Department of Pediatrics, Division of NeonatologyEastern Virginia Medical SchoolNorfolkUSA
  5. 5.Department of Pediatrics, Division of NephrologyEastern Virginia Medical SchoolNorfolkUSA

Personalised recommendations