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). 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. While the side effect profile of tacrolimus is generally similar to cyclosporine, there is a higher risk of hyperglycemia, a lower risk of hypertension, and occasional hair loss rather than hirsutism.

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