Cyclosporine Toxicity on Cultured Human Renal Proximal Tubular Cells

ABSTRACT

Nephrotoxicity is the most common dose-limiting factor of cyclosporine A (CSA) in clinical usage. But the mechanism of CSA-induced nephrotoxicity still remains unresolved. Many authors insisted that CSA induced renal proximal tubular cell injury is due to the secondary effects following hemodynamic changes or endothelial cell damage, instead of direct toxicity by CSA. To find out that CSA has a direct toxicity to the proximal tubular cells, the author used primary cultures of human proximal tubular cells to eliminate the hemodynamic or endothelial influences that could be produced in in vivo model. In the present study, the viability against CSA was tested by the neutral red assay method with modulation of Ca2+ amount in incubating media and observed electron microscopically. The viability test showed direct toxic effect of CSA on human proximal tubular cells and this was enhanced by Ca2+ depletion in incubating media. Morphologically noted are accumulation of lipid droplets and polyribosomal dispersion, which may be association with inhibition of cellular synthetic activity. These results suggest the toxixity is a direct effect of cyclosporine and that toxic mechanism may be due to inhibition of cellular synthetic activity. And this experiment also showed that primary cultures of human renal proximal tubular cells can be a good in in vivo model for investigating CSA nephrotoxicity.