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

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.