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

Pediatric Nephrology volume 34, pages 729–736 (2019)Cite this article

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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

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References

  1. Selewski DT, Charlton JR, Jetton JG, Guillet R, Mhanna MJ, Askenazi DJ, Kent AL (2015) Neonatal acute kidney injury. Pediatrics 136:e463–e473. https://doi.org/10.1542/peds.2014-3819

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1038/pr.2017.136

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1203/PDR.0b013e31820b95ca

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.3233/NPM-15915022

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1016/S2352-4642(17)30069-X

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1007/s00467-018-3966-7

  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:e45

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.jpeds.2006.03.053

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1007/s00467-005-1980-z

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1136/adc.2005.073650

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1111/apa.13469

    Article  PubMed  CAS  Google Scholar 

  12. Kidney Disease: Improving Global Outcomes (KDIGO) Work Group (2012) KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2:2. https://doi.org/10.1038/kisup.2012.2

    Article  Google Scholar 

  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. https://doi.org/10.1038/jp.2013.123

    Article  PubMed  CAS  Google Scholar 

  14. Lowry JA, Jarrett RV, Wasserman G, Pettett G, Kauffman RE (2001) Theophylline toxicokinetics in premature newborns. Arch Pediatr Adolesc Med 155:934–939

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.jpeds.2013.12.025

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.jpeds.2016.01.051

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1001/jamapediatrics.2018.0322

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/S0140-6736(03)13397-1

    Article  PubMed  Google Scholar 

  19. Kyriacou DN, Lewis RJ (2016) Confounding by indication in clinical research. JAMA 316:1818–1819. https://doi.org/10.1001/jama.2016.16435

    Article  PubMed  Google Scholar 

  20. Lee JS, Polin RA (2003) Treatment and prevention of necrotizing enterocolitis. Semin Neonatol 8:449–459. https://doi.org/10.1016/S1084-2756(03)00123-4

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s00383-002-0839-7

    PubMed  Article  Google Scholar 

  22. Jetton JG, Askenazi DJ (2012) Update on acute kidney injury in the neonate. Curr Opin Pediatr 24:191–196. https://doi.org/10.1097/MOP.0b013e32834f62d5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. https://doi.org/10.1097/FTD.0b013e3181898b6f

    Article  PubMed  CAS  Google Scholar 

  24. Bender R, Blettner M (2002) Calculating the “number needed to be exposed” with adjustment for confounding variables in epidemiologic studies. J Clin Epidemiol 55:525–530

    Article  PubMed  Google Scholar 

  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 38:1039–1042

    Article  Google Scholar 

  26. Gordon PV, Attridge JT (2009) Understanding clinical literature relevant to spontaneous intestinal perforation. Am J Perinatol 26:309–316. https://doi.org/10.1055/s-0028-1103514

    Article  PubMed  Google Scholar 

  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–S131

    PubMed  CAS  Google Scholar 

  28. Thomson S, Bao D, Deng A, Vallon V (2000) Adenosine formed by 5′-nucleotidase mediates tubuloglomerular feedback. J Clin Invest 106:289–298

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Osswald H, Schnermann J (2011) Methylxanthines and the kidney. Handb Exp Pharmacol 200:391–412. https://doi.org/10.1007/978-3-642-13443-2_15

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1007/s00467-013-2454-3

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.jpeds.2012.10.002

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.jpedsurg.2010.11.031

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.2215/CJN.05190514

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1080/14767058.2018.1459553

    Article  Google Scholar 

  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. https://doi.org/10.1007/s00467-017-3809-y

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.3233/NPM-1371013

    PubMed  CAS  Article  Google Scholar 

  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. https://doi.org/10.1097/PCC.0b013e3182772f61

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.3109/14767058.2012.657277

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1016/S1072-7515(02)01344-3

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1038/sj.jp.7211782

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.3233/NPM-15814059

    Article  PubMed  CAS  Google Scholar 

  42. Vongbhavit K, Underwood MA (2017) Intestinal perforation in the premature infant. J Neonatal-Perinatal Med 10:281–289. https://doi.org/10.3233/NPM-16148

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1056/NEJMoa054065

    Article  PubMed  CAS  Google Scholar 

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Author information

Affiliations

  1. Department of Pediatrics, Division of Neonatology, University of Virginia, Charlottesville, VA, USA

    Noelia Aviles-Otero

  2. Department of Pediatrics, Division of Nephrology, Nationwide Children’s Hospital, Columbus, OH, USA

    Reeti Kumar

  3. Department of Pediatrics, Cohen Children’s Medical Center, New Hyde Park, NY, USA

    Dev Darshan Khalsa

  4. Department of Pediatrics, Division of Neonatology, Eastern Virginia Medical School, Norfolk, VA, USA

    Glen Green

  5. Department of Pediatrics, Division of Nephrology, Eastern Virginia Medical School, 601 Children’s Lane, Norfolk, VA, 23507, USA

    J. Bryan Carmody

Authors
  1. Noelia Aviles-Otero
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  2. Reeti Kumar
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  3. Dev Darshan Khalsa
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  4. Glen Green
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  5. J. Bryan Carmody
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Corresponding author

Correspondence to J. Bryan Carmody.

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

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The authors declare that they have no conflict of interest.

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Cite this article

Aviles-Otero, N., Kumar, R., Khalsa, D.D. et al. Caffeine exposure and acute kidney injury in premature infants with necrotizing enterocolitis and spontaneous intestinal perforation. Pediatr Nephrol 34, 729–736 (2019). https://doi.org/10.1007/s00467-018-4140-y

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  • DOI: https://doi.org/10.1007/s00467-018-4140-y

Keywords

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