LETTERS
cultured with CsA, but can be partially protected from the toxic effects of the drug by either removing Ca2' from the growth medium or co-treating the cultured cells with calcium channel blockers (7).
A unifying hypothesis is that activation of Na+/K+-ATPase by the Ca2+-regulated phosphatase calcineurin is an important mechanism for regulating intracellular concentrations of Ca2+. Inhibition of calcineurin by CsA would lead to an overall decrease of Na+/K+ pump activity, and thus increase the intracellular concentration of Ca2+, leading to the pathologic activation of calpain, a Ca2+-dependent proteolytic enzyme, which in turn would lead to cell death. Any cell type in joints or bones that had a Na'/K+-ATPase regulated by calcineurin would be affected by CsA. Furthermore, given this potential link between calcium-mediated bone pain and nephrotoxicity, it would be interesting to know whether transplant patients treated with calcium channel blockers have a decreased incidence of nephrotoxicity.
It is fortunate for individuals requiring treatment with CsA that the mechanism-based toxicities involve different roles for calcineurin in non-T cells (Na' /KC-ATPase-dependent Ca2+ regulation) and T cells (calcium-dependent transcription factor regulation). This allows treatment of a toxicity (bone pain) without mitigation of the clinically desirable effect (inhibition of T cell activation). Calcineurin has also been implicated as a factor regulating nitric oxide synthase (8) and dynamin I GTPase in nerve cells (9), and so it might also play a role in the neurotoxicity associated with CsA treatment.