Cyclosporine: from renal transplantation to autoimmune diseases.

Over the last 20 years, cyclosporine (CsA) has been the mainstay of immunosuppression in renal transplantation. Initially, CsA was administered at high doses, which enhanced its potential nephrotoxicity. Better handling of the drug was obtained by lowering the dose, monitoring CsA concentration and renal function, and using graft biopsy in difficult cases. In the early 1990s, a new microemulsion showed better pharmacokinetics and efficacy than did the previous formulation. A few years later, evidence showed that checking blood levels 2 hours after administration was a more reliable indicator of CsA exposure than were trough blood levels. The combination with newer immunosuppressive drugs allowed further reduction in the doses of CsA to maintain stable renal allograft function and to improve long-term graft survival. CsA has largely been used in autoimmune diseases. There is concern about its nephrotoxicity, however, as in some studies control renal biopsies showed that CsA-treated patients developed progressive interstitial fibrosis. The risk of nephrotoxicity was related to the initial doses of CsA and to the increase in serum creatinine. Avoiding CsA in patients with creatinine clearance <60 mL/min and in those with uncontrolled hypertension, starting with CsA microemulsion at doses not higher than 4 mg/kg, and reducing the doses whenever serum creatinine increases to 30% or more over baseline may prevent deterioration of renal function. If these guidelines are followed, CsA may be safely used in autoimmune diseases.