Dose-response studies of gentamicin nephrotoxicity in rats with experimental renal dysfunction: II. Polyvinyl alcohol glomerulopathy

Animal studies involving concurrent pathophysiologic states, including experimental renal dysfunction, are useful for a proper understanding of the mechanisms of gentamicin nephrotoxicity and acute renal failure. This study examined gentamicin nephrotoxicity in a model of glomerular dysfunction in rats. Administration of medium molecular weight polyvinyl alcohol (PVA) produced a glomerulopathy, with characteristic accumulation of macromolecular PVA in the glomerular mesangium without altering glomerular filtration or causing proteinuria. Subsequent daily doses of gentamicin ranging from 0 to 120 mg/kg elicited a dose-response nephrotoxicity in both control and PVA-pretreated rats after 6 or 12 days of drug. Based on statistical analysis of renal clearances of creatinine, urea, sodium, and potassium; serum creatinine and urea nitrogen; urinary N-acetyl-β- d-glucosaminidase excretion (6 days only); in vitro renal cortical transport of tetraethylammonium (TEA) (6 days); and quantified light-microscopic data (12 days), PVA induced an early (6 days) sensitivity to gentamicin nephrotoxicity. By 12 days, there were no differences in the responses of control and PVA rats to gentamicin. Single-dose gentamicin clearance, volume of distribution, and half-life were not altered by PVA and renal concentrations at 6 days were generally lower in these rats. Results of TEA transport studies tend to rule out PVA-induced metabolic lesions in the proximal tubular epithelium as the mechanism for the early sensitivity. This investigation demonstrates altered gentamicin nephrotoxicity in rats with an otherwise benign glomerulopathy and, combined with similar conclusions from a related study in subtotally nephrectomized rats, presents further evidence that the underlying pathophysiologic state of the kidney is an important factor in the renal response to nephrotoxins.