Exposure to an Extended-Interval, High-Dose Gentamicin Regimen in the Neonatal Period Is Not Associated With Long-Term Nephrotoxicity

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.

Keywords: chronic kidney disease; gentamicin exposure; neonates; subclinical nephrotoxicity; urine biomarkers.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Rypdal, Jørandli, Hemmingsen, Solbu and Klingenberg.

Figures

Figure 1

Flow chart of the participants in the study from the original cohort to the present follow-up study.

Figure 2

Scatter plots of cumulative dose gentamicin against each of the four assessed urine biomarkers presented in a log-log graph. The red curves are the results from non-parametric kernel regression for the relationship between the cumulative dose of gentamicin and the urine biomarkers. The y-axis shows the cumulative dose of gentamicin in mg/kg with 100 mg/kg between axis ticks in each of the plots. The red vertical lines are the respective cutoff values for abnormal urine biomarker levels. The tick markers for the x-axes are evenly spaced but appear unevenly spaced since the axes are logarithmic. The distance between axes ticks is chosen so that, in each plot, one tick marker coincides with the cutoff value (red vertical line). (A) NAG-Cr (U/mmol) on a logarithm scale, with the distance between the tick markers for the x-axis of 0.2 U/mmol. (B) KIM-1 (ng/ml) on a logarithm scale, with the distance between the tick markers for the x-axis of 0.2 ng/ml. (C) ACR (mg/mmol) on a logarithm scale, with the distance between the tick markers for the x-axis of 1.0 mg/mmol. (D) PCR (mg/mmol) on a logarithm scale, with the distance between the tick markers for the x-axis of 3.0 mg/mmol.

Figure 3

Scatter plots of gentamicin trough plasma concentration (TPC) against each of the four assessed urine biomarkers presented in a log-log graph. The red curves are the results from non-parametric kernel regression for the relationship between the gentamicin TPC and the urine biomarkers. The y-axis shows the gentamicin TPC in mg/L with 0.4 mg/L between axis ticks in each of the plots. The tick markers for the x-axes are evenly spaced but appear unevenly spaced since the axes are logarithmic. The distance between axes ticks is chosen so that, in each plot, one tick marker coincides with the cut-off value (red vertical line). (A) NAG-Cr (U/mmol) on a logarithm scale, with the distance between the tick markers for the x-axis of 0.2 U/mmol. (B) KIM-1 (ng/ml) on a logarithm scale, with the distance between the tick markers for the x-axis of 0.2 ng/ml. (C) ACR (mg/mmol) on a logarithm scale, with the distance between the tick markers for the x-axis of 1.0 mg/mmol. (D) PCR (mg/mmol) on a logarithm scale, with the distance between the tick markers for the x-axis of 3.0 mg/mmol.