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Early postnatal gentamicin and ceftazidime treatment in normal and food restricted neonatal wistar rats: Implications
Ruud R G Bueters1,2,3, Annelies Jeronimus-Klaasen1,2, Roger J M Brüggemann4,5
1Department of Pediatric Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
Insights
Gentamicin at clinical levels did not affect kidney development in rats, but extrauterine growth restriction impaired it. Ceftazidime impacted renin expression, highlighting potential risks in premature neonates.
Area of Science:
- Neonatal development
- Pharmacology
- Nephrology
Background:
- Aminoglycosides like gentamicin are common treatments for infections in premature neonates.
- Potential long-term developmental effects of these treatments are not fully understood.
- Extrauterine growth restriction is a common complication in premature infants.
Purpose of the Study:
- To investigate the impact of gentamicin and ceftazidime on kidney development in rats.
- To evaluate if extrauterine growth restriction modulates drug-induced kidney toxicity.
Main Methods:
- Wistar rats were subjected to normal or food-restricted conditions to simulate growth restriction.
- Neonates received daily intraperitoneal doses of placebo, gentamicin, or ceftazidime from postnatal day 2 to 8.
- Kidney development markers, including gene expression and glomerular number, were assessed on postnatal days 8 and 35.
Main Results:
- Food restriction led to reduced body weight and glomerular number by postnatal day 35.
- Gentamicin administered at human clinical pharmacokinetic levels did not affect kidney development endpoints.
- Ceftazidime treatment resulted in a significant downregulation of renin expression.
Conclusions:
- Gentamicin at clinical doses does not appear to disrupt kidney development in rats.
- Ceftazidime may influence renin expression, suggesting a potential impact on renal development.
- Extrauterine growth restriction impairs kidney development but does not appear to exacerbate drug toxicity in this model.
Background:
Up to two-thirds of premature born neonates are treated for infections with aminoglycosides such as gentamicin. Although acute toxicities are well described, there is uncertainty on developmental changes after treatment of premature born neonates. We studied the effect of gentamicin and ceftazidime on kidney development in the rat. Additionally, we evaluated the modulating effect of extrauterine growth restriction.
Methods:
On postnatal day (PND) 2, Wistar rats were cross-fostered into normal sized litters (12 pups) or large litters (20 pups) to create normal food (NF) or food restricted (FR) litters to simulate growth restriction and dosed daily intraperitoneally with placebo, 4 mg/kg of gentamicin or 50 mg/kg ceftazidime until PND 8. Gentamicin pharmacokinetics were studied in a separate group of animals. Kidneys were weighed. Renal expression of 18 developmental genes was evaluated by quantitative PCR on PND 8. On PND 35, glomerular number was assessed by stereology and glomerular generations were counted.
Results:
Food restricted litters showed 22% less body weight compared with controls by day 35 (p < 0.001), 1.4- to 1.5-fold down regulation of Renin, Oat1, and Agtr1a (p < 0.05) expression and a 12% reduction in glomerular numbers (mean 30841 vs. 35187, p < 0.001), whereas glomerular generation count was unaffected. Gentamicin pharmacokinetic parameters were found to be in a human clinical range (mean maximum concentration in plasma of 4.88 mg/L and mean area under the plasma-concentration time curve up to the last measured concentration after 4 hr of 10.71 mg.h/L for sexes combined) and all endpoints were unaffected. Ceftazidime reduced Renin expression by 1.7-fold (p < 0.01).
Conclusion:
Our experiments showed that gentamicin at clinical levels did not disturb kidney development, ceftazidime can affect Renin expression, and extrauterine growth restriction impairs kidney development, but did not modulate potential drug toxicity. Birth Defects Research 109:1228-1235, 2017. © 2017 Wiley Periodicals, Inc.
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