Influence of Hydrocortisone on Gentamicin-Induced Nephrotoxicity in Rats

Abstract

Many risk factors associated with aminoglycoside nephrotoxicity have been identified in humans and experimental animals. They include an initial high rate of creatinine clearance, high initial peak levels in serum, age, sex, duration of therapy, liver disease, and renal infection. The concomitant administration of steroids has never been investigated. We evaluated the role of hydrocortisone on gentamicin-induced nephroxicity in a model of infused rats. We showed that hydrocortisone given over 3 days after the infusion did not modify the gentamicin half-life in the renal cortex, gentamicin-induced lysosomal phospholipidosis, or histopathology but did reduce significantly the 3H/DNA ratio on day 4 after gentamicin infusion. We concluded that hydrocortisone interferes with the postnecrotic cellular regeneration process, an important step that is responsible for the recovery of normal kidney structure and function following toxic injuries associated with aminoglycoside therapy.Eliminated essentially by glomerular filtration, aminoglycosides are partially reabsorbed by proximal tubular cells through absorptive endocytosis (pinocytosis) into small vesicles that fuse with primary lysosomes (11, 28). These primary lysosomes transfer the aminoglycoside to secondary lysosomes, where storage occurs independently of the duration of treatment (11). These drugs induce a lysosomal phospholipidosis characterized by inhibition of sphingomyelinase and phospholipase A1 activity and by phospholipid accumulation into lysosomes (17). This lysosomal phospholipidosis is accompanied by cellular necrosis and postnecrotic cell regeneration (10,18,20).Many risk factors associated with aminoglycoside nephrotoxicity have been identified in humans. They are an initial high rate of creatinine clearance, high initial peak levels in serum, age, sex, duration of treatment, and liver disease (23,26). In animals, dose and frequency (4), age (21, 22), sex (3,15), concomitant use of vancomycin (32), and renal infections (2) are clearly recognized as risk factors. The role of antiinflammatory agents like hydrocortisone on aminoglycoside nephrotoxicity is unknown. Steroids and nonsteroidal antiinflammatory agents are frequently administered with antibiotics to patients suffering from severe localized infections. In addition to their mineral and glucocorticoid effects, it has been shown that steroids suppress DNA synthesis in the livers of growing rats (6, 14) and in various nonlymphoid tissue of the weanling rats (19) and inhibit mitosis in various cells in tissue cultures (12).The objective of the present study was to evaluate the role of hydrocortisone on the pathophysiology of gentamicin nephrotoxicity. Special attention was focused on the effect of hydrocortisone on renal tubular epithelial cells undergoing renewal and repair. MATERIALS AND METHODSFemale Sprague-Dawley rats (weight, between 200 and 250 g) were used in this study. They were housed singly and had free access to food and water throughout the experiment. Gentamicin was infused over a 1...

Administration-Time Differences in the Pharmacokinetics of Gentamicin Intravenously Delivered to Human Beings

“…The administration-time dependency in human beings and laboratory animals are reversed because the activity pattern of rodents is delayed by 12h according to the clock time (Nakano et al 1990;Lin et al 1994;Prins et al 1997). These plasma concentrations and the side effects of gentamicin also could be modified highly by other factors such as age, feeding qchedule, and concomitant use of other drugs (Beauchamp and Pettigrew 1988;Beauchamp el al. 1989;Tardif et al 1990;Song et al 1993).…”