Maintenance immunosuppressive therapy usually consists of a three-drug regimen, with each drug targeted at a different stage in the immune response. The calcineurin inhibitors cyclosporine and tacrolimus are the cornerstones of immunosuppressive therapy. The most potent of orally available agents, calcineurin inhibitors have vastly improved short-term graft survival. Side effects of cyclosporine include hypertension, hyperkalemia, resting tremor, hirsutism, gingival hypertrophy, hyperlipidemia, hyperuricemia and gout, and a slowly progressive loss of renal function with characteristic histopathologic patterns (also seen in exposed recipients of heart and liver transplants). Tacrolimus (previously called FK506) is a fungal macrolide that has the same mode of action as cyclosporine as well as a similar side-effect profile; it does not, however, produce hirsutism or gingival hyperplasia. De novo diabetes mellitus is more common with tacrolimus. Recently, the U.S. Food and Drug Administration (FDA) approved a new costimulatory blocking antibody, belatacept, as a new strategy to prevent long-term calcineurin inhibitor toxicity.

Prednisone is frequently used in conjunction with cyclosporine, at least for the first several months following successful graft function. Side effects of prednisone include hypertension, glucose intolerance, cushingoid features, osteoporosis, hyperlipidemia, acne, and depression and other mood disturbances. Some centers have adopted “steroid-free” immunosuppressive regimens to avoid prednisone-associated side effects.

Mycophenolate mofetil has proved more effective than azathioprine in combination therapy with calcineurin inhibitors and prednisone. The major side effects of mycophenolate mofetil are gastrointestinal (diarrhea is most common); leukopenia (and thrombocytopenia to a lesser extent) develops in a fraction of pts.

Sirolimus is an alternative immunosuppressive agent often used in combination with other drugs, particularly when calcineurin inhibitors are reduced or eliminated. Side effects include hyperlipidemia and oral ulcers.