Abstract
Objectives: To assess the association between gentamicin exposure and subclinical signs of nephrotoxicity in school children who were exposed to a high-dose gentamicin regimen in the neonatal period.Methods: Children receiving three or more doses (6 mg/kg) of gentamicin as neonates were invited to a follow-up in school age. We evaluated potential signs of subclinical nephrotoxicity with four validated urine biomarkers: protein-creatinine ratio (PCR), albumin-creatinine ratio (ACR), kidney injury molecule-1 (KIM-1), and N-acetyl-beta-D-glucosaminidase (NAG) normalized for urine creatinine (NAG-Cr). In addition, blood pressure was measured. The measures of gentamicin exposure were cumulative dose (mg/kg) and highest trough plasma concentration (TPC) in mg/L. We used logistic and linear regression and non-parametric kernel regression to analyze the relationship between gentamicin exposure and the urine biomarkers.Results: A total of 222 gentamicin exposed children were included. As neonates, the children were exposed to a median (interquartile range-IQR) cumulative gentamicin dose of 36 (26–42) mg/kg and the median (IQR) TPC was 1.0 (0.7–1.3) mg/L. At follow-up, 15 children (6.8%) had either one abnormal urine biomarker value (13 children) or two abnormal urine biomarker values (2 children). These 17 biomarker values were all marginally above the suggested upper cutoff, and included the following markers; KIM-1 (n = 2), NAC-Cr (n = 5), ACR (n = 6), and PCR (n = 4). All other 207 children had normal sets of all four urine biomarkers. One child had hypertension. There were no differences in gentamicin exposure, gestational age (GA) at birth or birth weight between the group of 15 children with one or two abnormal urine biomarker values compared to the other 207 children who had normal biomarker values. Using different regression analyses, we did not find any association between gentamicin exposure (cumulative dose and/or TPC) and the urine biomarker values.Conclusions: Exposure to an extended-interval, high-dose gentamicin regimen in the neonatal period was not associated with signs of subclinical nephrotoxicity in schoolchildren. We therefore suggest that the gentamicin treatment regimen evaluated in this study is safe in terms of long-term nephrotoxicity.Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT03253614.
Highlights
Gentamicin is widely used for treatment of neonatal sepsis [1, 2]
There are conflicting results regarding nephrotoxicity among neonates treated with gentamicin
When we compared the original cohort of neonates to the children included in the follow-up study there were no significant differences in birth weight, the proportion of infants with a birth weight 2.0 mg/L between the two cohorts (Table 2)
Summary
Gentamicin is widely used for treatment of neonatal sepsis [1, 2]. Some experts suggest that each dose should be as high as 7.5 mg/kg due to the large distribution volume in neonates [3], there is still uncertainty regarding the optimal dosage regimen [4, 5]. There are conflicting results regarding nephrotoxicity among neonates treated with gentamicin. Several studies report no obvious nephrotoxicity, while others report rates up to 27% [4, 6]. The central aspect of gentamicin-induced nephrotoxicity is proximal tubular damage [7]. Gentamicin may in rare cases cause tubulointerstitial fibrosis and mesangial contraction leading to acute kidney injury (AKI) with reduced glomerular filtration rate (GFR) [8]
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