title: Impact of Early Postnatal NSAID Treatment on Nephrogenesis in Wistar Rats.
abstract: 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.
  
  
  CONCLUSIONS
  A clinical Ibuprofen dose showed potential to inhibit kidney development in neonatal rats. FR did not modulate these effects.
authors.affiliation: Department of Pediatric Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Ruud R G
authors.initials: RR
authors.lastname: Bueters
authors.affiliation: Department of Pediatric Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Annelies
authors.initials: A
authors.lastname: Klaasen
authors.affiliation: Department of Experimental Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Nuria
authors.initials: N
authors.lastname: Maicas
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.affiliation: Department of Pediatric Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Lambertus P
authors.initials: LP
authors.lastname: van den Heuvel
authors.affiliation: Department of Pediatric Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Michiel F
authors.initials: MF
authors.lastname: Schreuder
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000254:growth & development*; D038081:Organogenesis / Q000187:drug effects*; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal
keywords: extrauterine growth retardation; indomethacin; nephrogenesis; pharmaceuticals; postnatal evaluation; safety assessment