The Effects of Early Postnatal Diuretics Treatment on Kidney Development and Long-Term Kidney Function in Wistar Rats

Abstract

Background: Diuretics are administered to neonates to control fluid balance. We studied whether clinical doses affected kidney development and function and whether extrauterine growth retardation (EUGR) could be a modulator. Methods: Wistar rats were cross-fostered in normal food or food restricted litters at postnatal day (PND) 2 and treated daily with 0.9% NaCl, 5 mg/kg furosemide or 5 mg/kg hydrochlorothiazide (HCTZ) up to PND 8. Kidneys were evaluated on proliferation, apoptosis and a set of mRNA target genes at PND 8, glomerular- and glomerular generation count at PND 35, clinical pathology parameters at 3- and 9 months, neutrophil gelatinase-associated lipocalin at PND 8, 3 and 6 months, monthly blood pressure from 3 months onward and histopathology at study end. Results: Treatment with furosemide or HCTZ did not have relevant effects on measured parameters. EUGR resulted in lower body weight from day 3 onwards (-29% at weaning; p < 0.001, -10% at necropsy; p < 0.001), less glomerular generations (4.4 ± 0.32 vs. 5.0 ± 0.423; p = 0.025, males only), decreased glomerular numbers (27,861 ± 3,468 vs. 30,527 ± 4,096; p = 0.026), higher creatinine clearance (0.84 ± 0.1 vs. 0.77 ± 0.09 ml/min/kg; p = 0.047) at 3 months and lower plasma creatinine (25.7 ± 1.8 vs. 27.5 ± 2.8 µmol/l; p = 0.043) at 9 months. Conclusion: Furosemide and HCTZ did not influence kidney development or function when administered in a clinically relevant dose to rat pups at a stage of ongoing nephrogenesis. EUGR led to impaired kidney development but did not modify furosemide or HCTZ findings.

Salt supplementation ameliorates developmental kidney defects in COX-2−/− mice

“…Although torsemide-induced PGE 2 would increase renin activity (9) and thereby ANG II and aldosterone, we assume that continuous blockade of NKCC2 by torsemide promotes electrolyte loss in the neonates and provokes developmental damages. In contrast to our study, no effect of early postnatal diuretic treatment on kidney development was observed in rats in a recent study (5). However, differences in the experimental design may explain this discrepancy, because the loop diuretic furosemide was used in this study at a dosage of 5 mg•kg Ϫ1 •day Ϫ1 by single daily intraperitoneal injection.…”

Early postnatal gentamicin and ceftazidime treatment in normal and food restricted neonatal wistar rats: Implications for kidney development

“…Our second aim was to evaluate whether extrauterine growth restriction could modulate the potential toxicity of drug treatment. Using the rat model of litter enlargement, we have previously shown that extrauterine growth restriction results in a reduction in nephron numbers (Bueters et al, , ). From the changes noted in body weight, it is clear that a state of extrauterine growth restriction was induced, even though body weights were slightly different from the start of the study.…”