Immunosuppression minimization: current and future trends in transplant immunosuppression.

The past decade has witnessed unprecedented advances in renal transplantation propelled by novel and effective immunosuppression drugs. The introduction of mycophenolate mofetil (MMF), tacrolimus, cyclosporine microemulsion, sirolimus, a new generation of monoclonal antibodies (the anti–interleukin-2 receptor blockers, daclizumab and basiliximab), and the depleting polyclonal biologic Thymoglobulin has provided transplant physicians with a wide choice in selecting effective immunosuppression regimens (1–5). The intensification of immunosuppression, however, results in overimmunosuppression–associated complications such as opportunistic infections and malignancies. This is exemplified by the emergence of a previously rare infection, BK virus nephropathy, which may account for irreversible graft loss in 3 to 5% of renal transplant recipients (6). The threat of malignancy is yet another risk confronting patients on long-term immunosuppression, reported to occur in up to 40% of patients by 20 yr after transplantation (7). Another factor limiting improvement in long-term outcome is the occurrence of cardiovascular disease, a major cause of death in renal transplant recipients (8,9). Many of the current immunosuppression drugs are associated with one or more risk factors that predispose to atherosclerotic cardiovascular disease. Of the current immunosuppressive agents in use, corticosteroids and calcineurin inhibitors (CNI) are the most pro-atherogenic drugs (9). The cardiovascular risk of sirolimus is unclear: it can induce hyperlipidemia, but it has also been shown to inhibit intimal and smooth muscle cell proliferation (10). The prospect for approval by the Food and Drug Administration of newer and more specific immunosuppressive drugs that lack nephrotoxicity and cardiovascular toxicities is several years away (4). No new drug or biologic agent is currently in phase III trial; it is thus unlikely that novel therapy for renal or solid organ transplantation will be approved before the latter part of the decade (4). In the interim, drug minimization regimens in select patient populations are being explored to improve the safety of immunosuppression regimens while preserving their efficacy. The two main classes of drugs that are targeted for drug minimization are corticosteroid and CNI. Drug minimization strategies are not safe for all patients, and patient selection is as important as the choice of the minimization protocol (11). This review will summarize current and emerging drug minimization strategies.