Renal Glomeruli and Tubular Injury Following Indomethacin, Ibuprofen, and Gentamicin Exposure in a Neonatal Rat Model

Abstract

Indomethacin, ibuprofen, and gentamicin are commonly administered to neonates between 24 and 28 wk gestation when glomerulogenesis is still occurring. Indomethacin is known to cause renal failure in up to 25% of infants treated. Possible morphologic effects of these drugs are largely unknown. The purpose of this study was to determine the type of renal changes found on light (LM) and electron microscopy (EM) following administration of indomethacin, ibuprofen, and gentamicin in a neonatal rat model. Rat pups were exposed to indomethacin or ibuprofen and/or gentamicin antenatally for 5 d before birth or postnatally for 5 d from d 1 of life. Pups were killed at 14 d of age. LM examination in all indomethacin-and ibuprofen-treated pups both antenatally and postnatally showed vacuolization of the epithelial proximal tubules, interstitial edema, intratubular protein deposition but no significant glomerular changes. EM examination showed pleomorphic mitochondria and loss of microvilli in the tubules. The glomeruli showed extensive foot process effacement and irregularities of the glomerular basement membrane. EM changes were most marked in pups treated antenatally with ibuprofen, and indomethacin with gentamicin postnatally. Indomethacin, ibuprofen, and gentamicin cause significant change in glomerular and tubular structure in the neonatal rat model. U p to 5% of infants are delivered between 24 and 28 wk gestation, at a time when glomerulogenesis is occurring. Indomethacin and ibuprofen are commonly used in extremely premature neonates to close a patent ductus arteriosus at this time (1,2). Both of these drugs are successful in closing the ductus (3,4), but the morphologic effects these drugs may have on the developing kidney are unknown. Both drugs are known to be nephrotoxic, with indomethacin causing acute renal failure in 25% of premature neonates treated (5). Ibuprofen is considered to have less renal toxicity than indomethacin, but is as efficacious as indomethacin at closing the patent ductus (6). Two animal studies have shown an effect on glomerulogenesis by ibuprofen and a COX-2 selective inhibitor. In both studies, the number and size of glomeruli was decreased (7,8).Gentamicin is frequently administered at the same time as indomethacin or ibuprofen. Gentamicin has been shown in in vitro studies to affect nephron development (9). The combination of nonsteroidal anti-inflammatory drugs (NSAID) and gentamicin on glomerular development is unknown. The renal effect of indomethacin has not been examined in a neonatal animal model, nor has the combination of both indomethacin or ibuprofen and gentamicin.In the human, glomerulogenesis is complete at 36 wk gestation. The metanephron develops at 5 wk gestation, with vesicular glomeruli development occurring at 18 wk gestation. Glomerular tubular development occurs from 24 wk gestation and is complete at 36 wk (10 -12). In the rat model, glomerulogenesis continues after birth until 14 d of life (13). At birth the neonatal rat kidney is similar to that of a ...

Effect of Drugs on Renal Development

“…Treating neonatal rats with aminoglycosides during this postnatal nephrogenesis has also been shown to lead to a reduced nephron endowment (19) and tubular damage (21). However, these drugs are still commonly used in premature neonates for the treatment of (suspected) infections and a large proportion of premature infants receive aminoglycosides during active nephrogenesis.…”

“…These drugs inhibit the (renal) cyclooxygenase system, and a well known side effect of treatment in premature neonates is anuria or oliguria during the course of treatment, which occurs less often during treatment with ibuprofen (25). Because a normalfunctioning cyclooxygenase system is essential for nephrogenesis, it can be expected that these drugs not only influence short-term renal function, but also impair nephron formation (21,26,27). Indeed, harmful renal effects have been shown of acetylsalicyclic acid, another prostaglandin synthetase inhibitor (28).…”

Developmental Origins of Renal Disease

“…The NICU environment uses standard pharmacologic interventions, many developed before our awareness of the potential for postnatal nephrogenesis. Some of those interventions (e.g., nonsteroidal anti-inflammatory drugs, gentamycin) involve known nephrotoxins and impair nephron number in neonatal rodents (26). In the premature babies studied by Rodriquez (25), postnatal nephrogenesis was less sustained in babies experiencing renal failure.…”

Preterm Birth and/or Factors that Lead to Preterm Delivery: Effects on the Neonatal Kidney

“…Importantly, in this regard, antibiotics such as the aminoglycosides can readily cross the placenta [98] and there have been a number of experimental studies linking antibiotics with impairment of nephrogenesis [99][100][101][102]. For instance, it has been shown that incubation of metanephroi in culture with gentamicin leads to decreased branching morphogenesis of the ureteric tree and thus reduced nephron formation [99].…”