The safety of calcineurin inhibitors for kidney-transplant patients.
BACKGROUND
Cyclosporine-A and tacrolimus are the cornerstones in modern immunosuppression after organ transplantation. They are potent inhibitors of calcineurin, that is, so-called calcineurin-inhibitors (CNIs). However, because these drugs have narrow therapeutic windows, they are associated with many side-effects, with some being dose related.


METHODS
The most frequent side-effect of CNIs is nephrotoxicity, which in the long term can contribute, to allograft deterioration. Other frequent side-effects include metabolic disorders (new onset of diabetes, dyslipidemia), neurotoxicity, or promoting of de novo cancers.


CONCLUSIONS
In kidney transplantation, many strategies have been developed to minimize nephrotoxicity while maintaining efficacy of immunosuppression: for example, the minimization of CNI in addition to either full-dose mycophenolic acid or low doses of m-TOR inhibitors, mainly everolimus (EVR). Attempts made to eliminate CNIs by replacing them with m-TOR inhibitors have been unsuccessful because of occurrence of de novo donor-specific alloantibodies in a substantial number of patients, associated with antibody-mediated rejection. Conversely, CNI-avoidance by replacing them by Belatacept is feasible with very good renal function in the long term despite a significant increase in acute cellular rejections within the first-year posttransplantation. Other side-effects of CNIs, such as neurologic disorders, diabetes, dyslipidemia, viral infections, and cancer, seem to be less frequent in low-dose or CNI-free immunosuppressive regimens. Thus, although CNIs remain the major immunosuppressive treatment, their dosage should be minimized by using them with either full-dose MPA or reduced-dose EVR.
a 1 Clinique Universitaire de Néphrologie, CHU Grenoble , Grenoble, France.
Paolo
P
Malvezzi
b 2 Department of Nephrology and Organ Transplantation, CHU Rangueil , TSA 50032, 31059 Toulouse Cedex 9, France +33 5 61 32 23 35 ; +33 5 61 32 39 89 ; rostaing.l@chu-toulouse.fr.|c 3 INSERM U563, IFR-BMT, CHU Purpan , Toulouse, France.|d 4 Université Paul Sabatier , Toulouse, France.
Lionel
L
Rostaing
D065095:Calcineurin Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D000068338:Everolimus / Q000008:administration & dosage; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control / Q000601:surgery; D016030:Kidney Transplantation / Q000379:methods*; D009173:Mycophenolic Acid / Q000008:administration & dosage; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D009173:Mycophenolic Acid; D016559:Tacrolimus
calcineurin inhibitors; cyclosporine; diabetes; nephrotoxicity; neurotoxicity; safety; tacrolimus