Nephrotoxicity of calcineurin and mTOR inhibitors

Cyclosporine A (CSA) was introduced into clinical practice in the early 80s resulting in a large decrease in the incidence of acute rejection in renal transplantation and increasing solid organ transplant graft and patient survival to unparalleled levels. Subsequently, its use was extended to bone marrow transplant immunosuppression and to the treatment of a variety of autoimmune diseases refractory to conventional therapy, again with noteworthy efficacy [1-6]. The subsequent development of CSA self-emulsifying formulations improved bioavailability, decreased inter- and intra-patient variability and allowed more precise drug dose-tailoring [3, 7]. More recently, generic CSA brands have become available, decreasing treatment costs substantially. The combination of efficacy, accumulated experience and decreasing cost makes CSA still widely used in the clinical practice, and large numbers of patients are currently exposed to this drug.

In 1989 tacrolimus (TAC), a second calcineurin inhibitor was approved for clinical use [8]. Tacrolimus has an immunosuppressive effect approximately 100 times more potent than CSA and early clinical trials demonstrated that TAC was effective in reversing refractory acute rejection in renal, liver and heart transplantation. Subsequently, this drug was shown to be at least as effective as CSA in the primary immunosuppression schedules for solid organ and bone marrow transplantation and, similar to CSA, has proven to be a valuable alternative in the treatment of autoimmune diseases [3, 9-11]. Because the facility of drug monitoring by trough levels, less cosmetic side effects and a putative better profile in preventing acute rejection, TAC use has increased significantly and in fact, it has become the calcineurin inhibitor of choice for the prevention of rejection in solid organ transplantation in the majority of centers.