title: Indomethacin administered early in the postnatal period results in reduced glomerular number in the adult rat.
abstract: Indomethacin and ibuprofen are administered to close a patent ductus arteriosus (PDA) during active glomerulogenesis. Light and electron microscopic glomerular changes with no change in glomerular number were seen following indomethacin and ibuprofen treatment during glomerulogenesis at 14 days after birth in a neonatal rat model. This present study aimed to determine whether longstanding renal structural changes are present at 30 days and 6 mo (equivalent to human adulthood). Rat pups were administered indomethacin or ibuprofen antenatally on days 18-20 (0.5 mg·kg(-1)·dose(-1) indomethacin; 10 mg·kg(-1)·dose(-1) ibuprofen) or postnatally intraperitoneally from day 1 to 3 or day 1 to 5 (0.2 mg·kg(-1)·dose(-1) indomethacin; 10 mg·kg(-1)·dose(-1) ibuprofen). Control groups received no treatment or normal saline intraperitoneally. Pups were killed at 30 days of age and 6 mo of age. Tissue blocks from right kidneys were prepared for light and electron microscopic examination, while total glomerular number was determined in left kidneys using unbiased stereology. Eight pups were included in each group from 14 maternal rats. At 30 days and 6 mo, there were persistent electron microscopy abnormalities of the glomerular basement membrane in those receiving postnatal indomethacin and ibuprofen. There were no significant light microscopy findings at 30 days or 6 mo. At 6 mo, there were significantly fewer glomeruli in those receiving postnatal indomethacin but not ibuprofen (P = 0.003). In conclusion, indomethacin administered during glomerulogenesis appears to reduce the number of glomeruli in adulthood. Alternative options for closing a PDA should be considered including ibuprofen as well as emerging therapies such as paracetamol.
authors.affiliation: Department of Neonatology, Canberra Hospital, Woden, ACT, Australia; Australian National University Medical School, Canberra, ACT, Australia alison.kent@act.gov.au.
authors.forename: A L
authors.initials: AL
authors.lastname: Kent
authors.affiliation: Department of Anatomical Pathology, Canberra Hospital, Woden, ACT, Australia;
authors.forename: M E
authors.initials: ME
authors.lastname: Koina
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia; and.
authors.forename: L
authors.initials: L
authors.lastname: Gubhaju
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia; and.
authors.forename: L A
authors.initials: LA
authors.lastname: Cullen-McEwen
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia; and.
authors.forename: J F
authors.initials: JF
authors.lastname: Bertram
authors.affiliation: Department of Anatomical Pathology, Canberra Hospital, Woden, ACT, Australia;
authors.forename: J
authors.initials: J
authors.lastname: Lynnhtun
authors.affiliation: Clinical Epidemiology Unit, Canberra Hospital, Woden, ACT, Australia; Australian National University Medical School, Canberra, ACT, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Shadbolt
authors.affiliation: Department of Renal Medicine, Canberra Hospital, Woden, ACT, Australia; Australian National University Medical School, Canberra, ACT, Australia.
authors.forename: M C
authors.initials: MC
authors.lastname: Falk
authors.affiliation: Department of Anatomical Pathology, Canberra Hospital, Woden, ACT, Australia; Australian National University Medical School, Canberra, ACT, Australia.
authors.forename: J E
authors.initials: JE
authors.lastname: Dahlstrom
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects*; D005260:Female; D007052:Ibuprofen / Q000009:adverse effects*; D007213:Indomethacin / Q000009:adverse effects*; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000196:embryology / Q000648:ultrastructure; D011247:Pregnancy; D017207:Rats, Sprague-Dawley; D015149:Tocolytic Agents / Q000009:adverse effects*
chemical_list: D016861:Cyclooxygenase Inhibitors; D015149:Tocolytic Agents; D007052:Ibuprofen; D007213:Indomethacin
keywords: fetus; glomerular number; ibuprofen; indomethacin; kidney; premature neonate