Plasma Neutrophil Gelatinase-Associated Lipocalin for Detection of Ibuprofen-Induced Acute Kidney Injury in Preterm Infants with Symptomatic Patent Ductus Arteriosus

Presenter: B. M. Choi (e-mail: [e-mail])

Introduction: Ibuprofen is as effective as indomethacin in closing the ductus arteriosus in preterm infants with symptomatic patent ductus arteriosus (sPDA) and seems to be the first choice due to its higher safety profile, as it is associated with fewer risk of transient renal insufficiency than indomethacin. Nevertheless, drug-induced acute kidney injury (AKI) is most frequently related to exposure to ibuprofen and is associated with adverse outcomes in critically ill neonates. Neutrophil gelatinase-associated lipocalin (NGAL) is released from tubular epithelial cells following damage in AKI. Plasma NGAL is a proven early and sensitive indicator of AKI and also has been proposed as a useful diagnostic biomarker of drug-induced AKI in the clinical setting. We investigated the effect of ibuprofen on plasma NGAL levels as a marker for drug-induced AKI in preterm infants with sPDA, during the 1st course of ibuprofen treatment.

Materials and Methods: This observational study was conducted in the 3rd level NICU of the Korea University Ansan Hospital from January 2012 to October 2015. Preterm infants who required respiratory support received initial screening echocardiography within 24 hours of birth and were monitored for clinical symptoms of PDA. Individualized intravenous pharmacological treatment was used after confirming the diagnosis of sPDA, starting with the 1st dose (10 mg/kg) of ibuprofen and withholding additional doses (5 mg/kg) of ibuprofen at 24-hour intervals, if the BNP concentration was < 600 pg/mL and clinical symptoms of PDA were improved before the next scheduled dose of ibuprofen. Plasma NGAL levels were measured using a commercial kit (Alere Triage NGAL test; Alere Inc., San Diego, CA) by competitive immunoassay at the bedside before the initiation of ibuprofen treatment and at 24 hours after the administration of ibuprofen. Forty-two infants were enrolled and divided into two groups based on the plasma NGAL level before the initiation of ibuprofen treatment. High NGAL group (20 infants), was suspected as infants with preexisting AKI, who have various factors to affect the high NGAL levels, was defined as level ≥ 70 ng/mL. Low NGAL group (22 infants), as control infants without preexisting AKI, was defined as level < 70 ng/mL.

Results: Plasma NGAL levels significantly correlated with serum creatinine levels. In the low NGAL group, plasma NGAL levels were significantly increased at 24 hours after the initial loading dose (N = 22, 42.3 ± 16.4 vs. 57.8 ± 32.0 ng/mL, p = 0.016), but were unchanged at 24 hours after the 2nd dose (N = 14, 40.8 ± 16.5 vs. 49.1 ± 17.9 ng/mL, p = 0.148) and the 3rd dose of ibuprofen (N = 8, 49.1 ± 15.8 vs. 56.3 ± 15.7 ng/mL, p = 0.277). In the high NGAL group, plasma NGAL levels were significantly decreased at 24 hours after the 1st dose (N = 20, 138.5 [93.0–242.3] vs. 134.5 [86.0–166.8] ng/mL, p = 0.007), the 2nd dose (N = 13, 188.0 [128.5–311.0] vs. 113.0 [88.0–183.5] ng/mL, p = 0.005), and the 3rd dose of ibuprofen (N = 8, 202.0 [124.8–322.0] vs. 109.5 [83.8–125.5] ng/mL, p = 0.080).

Conclusion: Administration of initial loading dose (10 mg/kg) of ibuprofen resulted in increased plasma NGAL levels at 24 hours after the administration of ibuprofen in preterm infants with sPDA. However, such effect was not detected after 2nd and 3rd maintenance dose of ibuprofen. Moreover, this feature was not detectable in those infants with suspected pre-existing AKI, who have various confounding factors that may affect the high NGAL levels. When considering plasma NGAL levels as a surrogate marker of AKI, ibuprofen-induced AKI was transient only after the initial loading dose and was not serious during the 1st course of ibuprofen treatment in preterm infants with sPDA, even in the case of infants with preexisting AKI.

Keywords: ibuprofen, acute kidney injury, neutrophil gelatinase-associated lipocalin, symptomatic patent ductus arteriosus, preterm infant