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 Ϫ1 ·dose Ϫ1 indomethacin; 10 mg·kg Ϫ1 ·dose Ϫ1 ibuprofen) or postnatally intraperitoneally from day 1 to 3 or day 1 to 5 (0.2 mg·kg Ϫ1 ·dose Ϫ1 indomethacin; 10 mg·kg Ϫ1 ·dose Ϫ1 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 ϭ 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. kidney; glomerular number; indomethacin; ibuprofen; premature neonate; fetus INDOMETHACIN MAY BE ADMINISTERED to a pregnant woman as a tocolytic to prevent preterm delivery. Adverse effects of indomethacin on the fetus and neonate have been described including oligohydramnios, persistent renal insufficiency, gastrointestinal bleeding and perforation, and persistent pulmonary hypertension (8,11,21,54,58). It has not been determined whether there is any long-term effect on fetal glomerular development or glomerular endowment following exposure to intrauterine indomethacin.Indomethacin and ibuprofen have been shown to close a patent ductus arteriosus (PDA). The timing of administration of these medications is during a time of active glomerulogenesis (15,16,41,59). Indomethacin is known to be nephrotoxic causing acute renal failure in 25% of premature neonates treated for a PDA (2). Ibuprofen is felt to be less renal toxic than indomethacin, but it is as efficacious as indomethacin at closing the patent ductus (45). Two animal studies have shown an effect on glomerulogenesis (induction of new nephrons and glomeruli) in the rat and mouse with ibuprofen and a cyclooxygenase-2 (COX-2)-selective inhibitor. In both studies, the number and size of glomeruli were decreased (3, 34). Administration of indomet...

Incidence and Risk Factors of Early Onset Neonatal AKI

“…NSAIDs are vasoconstrictive agents used to prevent intraventricular hemorrhage and treat patent ductus arteriosus. Previous clinical studies have shown an association between NSAID exposure and AKI (48,49) and animal models have shown that NSAIDs given to neonatal rodents reduce nephron number (50). Within the 22-28-week group, 36% received some NSAID in the first week after birth and NSAID exposure was associated with lower odds of AKI.…”

Animal models of bronchopulmonary dysplasia. The preterm baboon models

“…More importantly, this model first demonstrated the neurological impact of mechanical ventilation on the preterm brain and the relative sparing effect of early noninvasive respiratory support (43,63,85). Other studies have demonstrated that this model also mimics the preterm human condition related to the occurrence of functional adrenal insufficiency and to adverse end-organ effects on the kidney and liver (33,40,41,73,93). Additionally, the 125-day baboon model is relatively unique among most animal models in that persistent patency of the ductus arteriosus is a common finding, similar to very preterm humans.…”

Mapping vascular and glomerular pathology in a rabbit model of neonatal acute kidney injury using MRI

“…The highly vascularized kidney is particularly vulnerable to the effects of preterm birth with 60% of glomerular development occurring in the third trimester (Hinchliffe, Sargent, Howard, Chan, & van Velzen, 1991). During this period of active nephrogenesis, fluctuations in tissue oxygenation (Hemker, Sims-Lucas, & Ho, 2016), renal perfusion, and exposures to medications (Kent et al, 2014;Kent, Brown, Broom, Broomfield, & Dahlstrom, 2012) can lead to a reduced glomerular number. In children, radiologic evaluations of the vasculature are limited due radiation exposure and sedation effects.…”

“…Neonates who received these drugs had a greater risk of developing AKI. Several studies in animals have also demonstrated nephron malformation or loss following exposure to gentamicin or indomethacin (Gilbert, Lelievre-Pegorier, & Merlet-Benichou, 1991;Kent et al, 2014). However, little data exists on the structural changes in the vessels in response to these nephrotoxic medications, because reconstruction of the whole vasculature using histology is challenging.…”