No abstract

The possible correlation between the severity of chronic progressive glomerulonephropathy (CPN) and the incidence of adrenal pheochromocytoma was examined in selected studies of male Fischer 344 (F344) rats at the National Toxicology Program (NTP). The NTP historical control database was first examined in order to determine whether there was association between the severity of CPN and the occurrence of adrenal pheochromocytoma in unexposed animals. Following this analysis, the 125 most recent NTP studies conducted in F344 rats were examined in order to determine how frequently chemicals that cause increased severity of CPN showed an increased incidence of pheochromocytoma. Finally, we examined the association between the incidence of pheochromocytoma and the severity of CPN in those NTP studies with chemically related increased rates of pheochromocytoma. In control male F344 rats surviving beyond 21 mo, the incidence of adrenal pheochromocytoma was consistently higher in animals with more severe CPN. This association was significant ( p < 0.05) both for 900 NTP inhalation study controls and 900 NTP feeding study controls. An association was not consistently observed when dosed groups were considered. Although 22% (28/125) of NTP studies reported a chemically related increased severity of CPN, only 3 of these reported a corresponding significant increase in the incidence of pheochromocytoma. Of 6 NTP studies that reported increased incidence of pheochromocytoma, animals with pheochromocytoma from 5 of those studies had some degree of increased severity of CPN. However, the estimated strength of the correlation with the severity of CPN varied from study to study and was often quite different from that indicated by an analysis of the more extensive NTP control databases. The possible correlation between the severity of CPN and the incidence of pheochromocytoma may influence interpretation of carcinogenic effects observed at this site.

No abstract

Daily intraperitoneal (i.p.) injection of genatmicin at a dose of 70 mg/kg for 11 days produced nephrotoxicity in female Sprague-Dawley rats as evidenced by increased excretion of urinary protein and trypsin inhibitory activity as well as rise in renal individual class and total phospholipid. The observed proteinuria was associated with a significant twofold fall in creatinine clearance and histopathological changes, including the presence of hyaline casts and flattened epithelial cells within the lumen of proximal convoluted tubules. Although pyridoxal-5-phosphate (50 mg/kg) administered i.p. did not significantly alter creatinine clearance, histopathology, proteinuria, and urinary trypsin inhibitory activity, an increase in individual class and total phospholipid was noted in kidney. In rats simultaneously administered gentamicin and pyridoxal-5-phosphate, the observed fall in renal gentamicin content was associated with a return of individual class and total phospholipid to control values. However, the decline in creatinine clearance, enhanced proteinuria, and increase in urinary trypsin inhibitory activity in the simultaneous-treated group was similar or greater than that seen in the gentamicin-only injected rats. Morphological examination of simultaneous-treated rats revealed extensive alterations in proximal tubules including numerous mitotic figures, large vesicular nucleii, and prominent nucleoli in epithelial cells as well as hyaline casts within the lumen. Our data combined with results of previous studies suggest that sex and type of rat strain are important factors in aminoglycoside-induced nephrotoxicity. It is evident that a specific concentration of pyridoxal-5-phosphate may be necessary to provide protection against all manifestations of aminoglycoside-induced renal damage.

In our previous studies, we found increased levels of urinary trypsin inhibitory activity in gentamicin-induced nephrotoxicity in rats. Following administration of the Bowman-Birk trypsin and chymotrypsin inhibitor (BBI), no proteinuria was detected in gentamicin-treated rats, and a decrease in creatinine clearance was noted in only 50% of the injected rats. In the present study, we examined the antimicrobial activity of gentamicin against Escherichia coli in the presence of BBI in gentamicin-induced nephrotoxicity in rats. We found that 50% of rats with E. coli-positive blood cultures died of septicemia. All the rats injected with E. coli plus gentamicin or E. coli plus gentamicin plus BBI survived, the latter showing no proteinuria or deterioration in creatinine clearance. In conclusion, BBI, which is an effective inhibitor of gentamicin-induced nephrotoxicity, does not affect the antimicrobial activity of gentamicin sulfate.