Incidence, risk and risk factors for acute kidney injury associated with the use of intravenous indomethacin in neonatal patent ductus arteriosus: A 16-year retrospective cohort study

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Keywords

Acute Kidney Injury, Cohort Studies, Indomethacin, Infant, Ductus Arteriosus, Patent, Renal Insufficiency

Abstract

Background: Intravenous indomethacin has been used in infants for many years as the pharmacological closure of ductus arteriosus, but the incidence, risk, and risk factors of acute kidney injury (AKI) among infants treated with indomethacin, were still scarce. Objectives: To determine the incidence, risk, and risk factors of AKI among infants treated with indomethacin (exposed group) for patent ductus arteriosus (PDA) closure compared with the matched non-exposed infants. Methods: A matched retrospective cohort study of infants admitted to the neonatal intensive care unit of Songklanagarind Hospital from January 2003 to December 2018 was performed. All data were collected from computerized medical records. A non-exposed infant was matched (1:1) by gestational age and birth weight to each exposed infant. AKI, the outcome of interest, was diagnosed according to neonatal AKI definitions. The incidence (95% CI) of AKI was estimated for each group. Conditional logistic regression was used to estimate the odds ratio (OR) of developing AKI among those who received indomethacin compared with those who did not, adjusted for potential confounders (concomitantly used nephrotoxic potential medications including aminoglycosides, amphotericin B, vancomycin, furosemide, systemic corticosteroids, and systemic vasopressors and inotropes). Kaplan-Meier estimate was performed to examine probability of recovery from AKI after AKI events. Results: The matching resulted in 193 pairs of exposed and non-exposed infants. The incidences [95% CI] of AKI in the exposed and the non-exposed group, were 33.7% [27.0%:40.4%] and 15.5% [10.4%:20.7%], respectively. Indomethacin statistically increased the risk for developing AKI, crude OR 2.94[95%CI 1.77:4.90], McNemar’s chi square p<0.001, and adjusted OR 2.73 [95%CI 1.55:4.80], p=0.001. The risk of AKI associated with potentially nephrotoxic medications were inconclusive. Time to recovery from AKI was relatively rapid, median recovery time was 3 days in both groups and all infants who developed AKI recovered within 6 days. Conclusions: The incidence of AKI among infants treated with indomethacin for PDA closure were doubled that in the indomethacin-nonexposed infants. Indomethacin significantly increased the risk of AKI, while the risk associated with other concomitant nephrotoxic medications were inconclusive. Transient nephrotoxicity associated with indomethacin should be balanced with the risk associated with delayed PDA closure. All infants receiving indomethacin should be routinely monitored for serum creatinine and/or urine output, throughout the treatment and one to two weeks after treatment cessation. Alternatives with better renal safety profiles should be considered in the population with higher risk of AKI.

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References

1. Hermes-De Santis ER, Clyman RI. Patent ductus arteriosus: pathophysiology and management. J Perinatol. 2006;26(S1):S14-S18. https://doi.org/10.1038/sj.jp.7211465
2. Dani C, Mosca F, Cresi F, et al. Patent ductus arteriosus in preterm infants born at 23–24 weeks’ gestation: Should we pay more attention? Early Hum Dev. 2019;135:16-22. https://doi.org/10.1016/j.earlhumdev.2019.06.002
3. Davidson JM, Ferguson J, Ivey E, et al. A randomized trial of intravenous acetaminophen versus indomethacin for treatment of hemodynamically significant PDAs in VLBW infants. J Perinatol. 2021;41(1):93-99. https://doi.org/10.1038/s41372-020-0694-1
4. Lin YJ, Chen CM, Rehan VK, et al. Randomized trial to compare renal function and ductal response between indomethacin and ibuprofen treatment in extremely low birth weight infants. Neonatology. 2017;111(3):195-202. https://doi.org/10.1159/000450822
5. Pacifici GM. Clinical pharmacology of indomethacin in preterm infants: implications in patent ductus arteriosus closure. Pediatr Drugs. 2013;15(5):363-376. https://doi.org/10.1007/s40272-013-0031-7
6. Shaffer CL, Gal P, Ransom JL, et al. Effect of age and birth weight on indomethacin pharmacodynamics in neonates treated for patent ductus arteriosus: Crit Care Med. 2002;30(2):343-348. https://doi.org/10.1097/00003246-200202000-00013
7. Akima S, Kent A, Reynolds GJ, et al. Indomethacin and renal impairment in neonates. Pediatr Nephrol. 2004;19(5):490-493. https://doi.org/10.1007/s00467-003-1402-z
8. Constance JE, Reith D, Ward RM, et al. Risk of nonsteroidal anti-inflammatory drug-associated renal dysfunction among neonates diagnosed with patent ductus arteriosus and treated with gentamicin. J Perinatol. 2017;37(10):1093-1102. https://doi.org/10.1038/jp.2017.80
9. Vachvanichsanong P, McNeil E, Dissaneevate S, et al. Neonatal acute kidney injury in a tertiary center in a developing country. Nephrol Dial Transplant. 2012;27(3):973-977. https://doi.org/10.1093/ndt/gfr477
10. Kumar R, Yu V. Prolonged low-dose indomethacin therapy for patent ductus arteriosus in very low birthweight infants. J Paediatr Child Health. 1997;33(1):38-41. https://doi.org/10.1111/j.1440-1754.1997.tb00988.x
11. Askenazi DJ, Feig DI, Graham NM, et al. 3-5 year longitudinal follow-up of pediatric patients after acute renal failure. Kidney Int. 2006;69(1):184-189. https://doi.org/10.1038/sj.ki.5000032
12. Mammen C, Al Abbas A, Skippen P, et al. Long-term risk of CKD in children surviving episodes of acute kidney injury in the intensive care unit: a prospective cohort study. Am J Kidney Dis. 2012;59(4):523-530. https://doi.org/10.1053/j.ajkd.2011.10.048
13. Adamska E, Helwich E, Rutkowska M, et al. Comparison of the efficacy of ibuprofen and indomethacin in the treatment of patent ductus arteriosus in prematurely born infants. Med Wieku Rozwoj. 2005;9(3 Pt 1):335-354.
14. Leonhardt A, Strehl R, Barth H, et al. High efficacy and minor renal effects of indomethacin treatment during individualized fluid intake in premature infants with patent ductus arteriosus. Acta Paediatr Oslo Nor 1992. 2004;93(2):233-240.
15. Fanos V, Benini D, Verlato G, et al. Efficacy and renal tolerability of ibuprofen vs. indomethacin in preterm infants with patent ductus arteriosus. Fundam Clin Pharmacol. 2005;19(2):187-193. https://doi.org/10.1111/j.1472-8206.2004.00314.x
16. Selewski DT, Charlton JR, Jetton JG, et al. Neonatal acute kidney injury. Pediatrics. 2015;136(2):e463-473. https://doi.org/10.1542/peds.2014-3819
17. Saban JA, Pizzi M, Caldwell J, et al. Previous aminoglycoside use and acute kidney injury risk in non-critically ill children. Pediatr Nephrol. 2017;32(1):173-179. https://doi.org/10.1007/s00467-016-3471-9
18. Carmody JB, Swanson JR, Rhone ET, Charlton JR. Recognition and Reporting of AKI in Very Low Birth Weight Infants. Clin J Am Soc Nephrol. 2014;9(12):2036-2043. https://doi:10.2215/CJN.05190514 375
19. Askenazi DJ, Heagerty PJ, Schmicker RH, Griffin R, Brophy P, Juul SE, Mayock DE, Goldstein SL, Hingorani S, on behalf of the PENUT Trial Consortium. Prevalence of acute kidney injury (AKI) in extremely low gestational age neonates (ELGAN). Pediatr Nephrol. 2020;35(9):1737-1748. https://doi:10.1007/s00467-020-04563-x
20. Gynecologists OA. Definition of term pregnancy. Committee opinion No. 579. Obstet Gynecol. 2013;122(5):1139-1140. https://doi.org/10.1097/01.AOG.0000437385.88715.4a
21. Martin JA, Hamilton BE, Ventura SJ, et al. Births: final data for 2011. Natl Vital Stat Rep Cent Dis Control Prev Natl Cent Health Stat Natl Vital Stat Syst. 2013;62(1):1-69, 72.
22. 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(4):569-573. https://doi.org/10.1038/pr.2017.136
23. Hinchliffe SA, Sargent PH, Howard CV, et al. Human intrauterine renal growth expressed in absolute number of glomeruli assessed by the disector method and Cavalieri principle. Lab Investig J Tech Methods Pathol. 1991;64(6):777-784.
24. Bhat R, Vidyasagar D, Fisher E, et al. Pharmacokinetics of oral and intravenous indomethacin in preterm infants. Dev Pharmacol Ther. 1980;1(2-3):101-110.
25. Romagnoli C, Zecca E, Papacci P, et al. Furosemide does not prevent indomethacin-induced renal side effects in preterm infants. Clin Pharmacol Ther. 1997;62(2):181-186. https://doi.org/10.1016/S0009-9236(97)90066-7
26. Lee BS, Byun SY, Chung ML, et al. Effect of furosemide on ductal closure and renal function in indomethacin-treated preterm infants during the early neonatal period. Neonatology. 2010;98(2):191-199. https://doi.org/10.1159/000289206
27. Pandey V, Kumar D, Vijayaraghavan P, et al. Non-dialytic management of acute kidney injury in newborns. J Ren Inj Prev. 2016;6(1):1-11. https://doi.org/10.15171/jrip.2017.01
28. Mian AN, Askenazi DJ, Mhanna MJ. Therapeutic options for neonatal acute kidney injury (AKI). Curr Treat Options Pediatr. 2016;2(2):69-81. https://doi.org/10.1007/s40746-016-0048-6
29. Cristea S, Allegaert K, Falcao AC, et al. Larger dose reductions of vancomycin required in neonates with patent ductus arteriosus receiving indomethacin versus ibuprofen. Antimicrob Agents Chemother. 2019;63(8):e00853-19, /aac/63/8/AAC.00853-19.atom. https://doi.org/10.1128/AAC.00853-19
30. Evans P, O’Reilly D, Flyer JN, et al. Indomethacin for symptomatic patent ductus arteriosus in preterm infants. Cochrane Neonatal Group, ed. Cochrane Database Syst Rev. Published online January 15, 2021. https://doi.org/10.1002/14651858.CD013133.pub2
31. El-Mashad AE-R, El-Mahdy H, El Amrousy D, et al. Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates. Eur J Pediatr. 2017;176(2):233-240. https://doi.org/10.1007/s00431-016-2830-7
32. Joy SDS. Using diaper weight to measure urine output: AJN Am J Nurs. 2009;109(2):37-38. https://doi.org/10.1097/01.NAJ.0000345431.52981.47