Indomethacin, ibuprofen and gentamicin administered during late stages of glomerulogenesis do not reduce glomerular number at 14 days of age in the neonatal rat

Abstract

Premature neonates are frequently administered indomethacin, ibuprofen and gentamicin during the period of active glomerulogenesis. These drugs are known to have nephrotoxic effects, but the morphological effect of these drugs is unknown. The purpose of this study was to determine whether administration of these drugs during the late stages of glomerulogenesis in the rat has an effect on glomerular endowment. Rat pups were given, intraperitoneally, indomethacin, ibuprofen or indomethacin and gentamicin for the first 5 days of their postnatal life. The pups were killed at 14 days of age at completion of glomerulogenesis. The total number of glomeruli in the left kidney was determined by the physical disector/fractionator stereological technique. There was no difference between treatment groups in total number of glomeruli per kidney (P = 0.45). There were significantly fewer glomeruli per gram of kidney in those rat pups that had received indomethacin or ibuprofen (P < 0.0001). The reduction in the number of glomeruli per gram of kidney may indicate augmented growth of nephron tubules and/or collecting ducts, and/or be a consequence of oedema secondary to drug exposure. Further study is required to determine whether reduced glomerular number is seen in older animals or following exposure to these drugs at different time-points in kidney development.

Effects of ibuprofen treatment on the developing preterm baboon kidney

“…Therefore, it is possible that any adverse effect NSAID exposure has on the kidney may be short-lived and therefore would not significantly influence final nephron endowment. Indeed Kent et al (17), in a stereological assessment of nephron endowment following in vivo NSAID exposure, demonstrated in a neonatal rat model that total nephron endowment was not altered following extended postnatal exposure to NSAIDs. In that study, the NSAIDs were administered over a period equivalent to 24-to 30-wk gestation in humans (17), a much longer time period of exposure than in the current study.…”

“…Indeed Kent et al (17), in a stereological assessment of nephron endowment following in vivo NSAID exposure, demonstrated in a neonatal rat model that total nephron endowment was not altered following extended postnatal exposure to NSAIDs. In that study, the NSAIDs were administered over a period equivalent to 24-to 30-wk gestation in humans (17), a much longer time period of exposure than in the current study. An examination of the baboon kidneys at a later postnatal time point, after the treatments and nephrogenesis have ceased, would be required to fully describe the long-term effects of NSAID exposure on renal development.…”

“…Komhoff et al (19) and Olliges et al (23) recently determined that NSAID exposure led to a significantly reduced cortical mass, reduced glomerular density, and reduced glomerular and tubular volumes in mice models of NSAID exposure during the period of postnatal renal development. Similarly, Kent et al (17,18) observed a significantly reduced glomerular density and also renal injury in neonatal rats with early postnatal NSAID exposure; however, there was no effect on total nephron endowment. Of particular importance, in human infants exposed in utero to NSAIDs, changes in renal morphology have been described (15,33) which are similar to the glomerulocystic changes observed in the preterm baboon kidney.…”

Effect of Drugs on Renal Development

“…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).…”

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

“…Indomethacin is a tocolytic drug, which functions to reduce prostaglandin synthesis; it is thereby highly effective at prolonging pregnancy [104]. Of concern, however, in rodent studies in utero exposure to indomethacin has been reported to reduce nephron endowment and reduce glomerular filtration [105,106].…”