THE TOXICITY OF FOSCARNET (PHOSPHONOFORMIC ACID, TRISODIUM SALT, PFA)STUDIED IN CULTURED DOG RENAL TUBULAR CELLS

To investigate the mechanisms of nephrotoxicity of the antiviral drug Foscarnet (phosphonoformic acid), an in vitro model was developed base d on primary cultures of dog renal proximal tubule epithelial cells. T he cells were isolated by the collagenase perfusion technique from kid neys removed post mortem and grown in serum-free conditions. The cell viability was estimated, in confluent cells grown in 'Ca2+-supplemente d medium' (average free Ca2+ concentration, 1 mM), by measuring the re lease of lactate dehydrogenase or by measuring the rate of alpha-methy l glucose uptake. Foscarnet was toxic to the cells at concentrations a bove 1 mM. The toxicity was characterized by a long exposure time befo re any loss of viability was detected. The alpha-methyl glucose uptake was not affected until after 2 days of exposure. In actively dividing cells, Foscarnet displayed a concentration-dependent inhibition of th ymidine incorporation after only 6 hr of exposure. The toxic effects o f Foscarnet may be due to its ability to form complexes with divalent cations. We conclude that we have established an in vitro model system that uses proximal tubular epithelial cells from dogs and in which Fo scarnet is toxic. Our model is therefore well suited for mechanistic s tudies of the nephrotoxicity of Foscarnet.