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Ruud R G Bueters1, Annelies Klaasen1, Nuria Maicas2
1Department of Pediatric Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
Insights
Clinical ibuprofen doses may impede kidney development in neonatal rats, even without growth restriction. Ibuprofen
Area of Science:
- Neonatal medicine
- Pediatric nephrology
- Pharmacology
Background:
- Premature infants with patent ductus arteriosus receive ibuprofen or indomethacin.
- These drugs may negatively impact kidney development.
- The study investigated these effects with and without extrauterine growth retardation.
Purpose of the Study:
- To determine if clinical doses of ibuprofen or indomethacin affect kidney development and function in neonatal rats.
- To assess the influence of food restriction on these drug-induced effects.
Main Methods:
- Wistar rats were assigned to normal or food-restricted litters.
- Neonates received saline, indomethacin, or ibuprofen via intraperitoneal injection.
- Kidneys were analyzed for apoptosis, proliferation, gene expression, and nephron number; clinical pathology and blood pressure were also assessed.
Main Results:
- Ibuprofen administration was associated with decreased kidney proliferation/apoptosis ratios and a trend towards reduced nephron numbers.
- Food restriction did not alter the effects of ibuprofen on kidney development.
- No significant differences were observed in clinical pathology markers or blood pressure.
Conclusions:
- A clinical dose of ibuprofen demonstrated potential to inhibit kidney development in neonatal rats.
- Extrauterine growth retardation did not modify the impact of ibuprofen on kidney development.
Background:
Prematurely born children with patent ductus arteriosus are treated with ibuprofen or indomethacin, which may inhibit kidney development. We determined whether clinical doses affected kidney development and function, with or without extrauterine growth retardation.
Methods:
Wistar rats were cross-fostered in normal food (NF) or food restricted (FR) litters at postnatal day (PND) 2. On PND 3 to 4, three doses of 0.9% NaCl, 0.1 mg/kg indomethacin, or 10 mg/kg ibuprofen were administered via intraperitoneal injection with 12-hr intervals. Kidneys were evaluated for apoptosis, proliferation, and gene expression at PND 8; stereological assessment of nephron number at PND 35; and clinical pathology and neutrophil gelatinase-associated lipocalin at 4 and 9 months. Blood pressure was measured at the ages of 4, 6, and 9 months.
Results:
NF and FR bodyweight differed from PND 3 onwards, ranging from 16.5 g at weaning (p < 0.001) to 39 g at necropsy (p = 0.019). Kidney proliferation/apoptosis ratios were 7:1 and 3:1 (p = 0.001), respectively and different expression of Wnt4 (0.7x), Oat1 (1.3x), Nphs1 (1.7x), and Aqp4 (1.3x) was noted (but its biological relevance doubted). Nephron numbers were decreased by 12% (p = 0.109) in the ibuprofen-NF group and 7.5% (p = 0.237) in FR groups. This coincided with a tendency to increased neutrophil gelatinase-associated lipocalin at 9 months. No differences were noted in electrolytes, creatinine, or urea clearance. No valid blood pressure results could be obtained.
Conclusion:
A clinical Ibuprofen dose showed potential to inhibit kidney development in neonatal rats. FR did not modulate these effects.
