The toxicity of Foscarnet (phosphonoformic acid, trisodium salt; PFA) studied in cultured dog renal Tubular Cells

Abstract To investigate the mechanisms of nephrotoxicity of the antiviral drug Foscarnet (phosphonoformic acid), an in vitro model was developed based on primary cultures of dog renal proximal tubule epithelial cells. The cells were isolated by the collagenase perfusion technique from kidneys removed post mortem and grown in serum-free conditions. The cell viability was estimated, in confluent cells grown in ‘Ca 2+ -supplemented medium’ (average free Ca 2+ concentration, 1 mM), by measuring the release of lactate dehydrogenase or by measuring the rate of α-methyl glucose uptake. Foscarnet was toxic to the cells at concentrations above 1 mM. The toxicity was characterized by a long exposure time before any loss of viability was detected. The α-methyl glucose uptake was not affected until after 2 days of exposure. In actively dividing cells, Foscarnet displayed a concentration-dependent inhibition of thymidine incorporation after only 6 hr of exposure. The toxic effects of 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 Foscarnet is toxic. Our model is therefore well suited for mechanistic studies of the nephrotoxicity of Foscarnet.