Aminoglycoside antibiotics remain important life-saving drugs despite their intrinsic nephrotoxicity. Extensive studies in rats indicate differences in the nephrotoxic potential of individual aminoglycosides, but these differences are difficult to assess in seriously ill patients. Data obtained in rats on pathogenic mechanisms and toxicity inhibitors also suffer from this lack of confirmation of rats as valid human surrogates. A similar lack of validation also applies to various human and animal-derived renal tissue culture systems. The integration of two recent developments may help evaluate the human relevance of in vivo rat data as well as data obtained in several in vitro systems. Utilizing brush border membranes (BBM) isolated from the primary nephrotoxic site, proximal tubule cells (PTC), two polyamino acids were identified which block the binding of aminoglycosides to BBM of rats. Subsequent in vivo studies with these polymers revealed the complete elimination of the nephrotoxicity of co-administered aminoglycosides in rats. The second development was the serial propagation of human PTC in tissue culture for the first time. Since both capabilities are now located at this institution, we propose to investigate the binding kinetics and characteristics of aminoglycosides to BBM obtained from fresh human and rat kidneys and from PTC cultures of both species. In addition, the ability of the polyamino acids to block aminoglycoside binding to BBM and to eliminate the toxicity to tissue cultures will be examined. Results of these integrated studies will further define the appropriateness of in vivo studies in rats and the usefulness of in vitro studies in tissue cultures as well as appraise the potential human utility of the nephrotoxicity inhibitors.
