**5. Advances in immunosuppression – Future trends**

Maintenance immunosuppressive therapy over the past decade has become more diversified. Until the mid-1990s, CsA and azathioprine were the cornerstones in maintenance immuno‐ suppressive therapy. Today, these agents have been largely replaced by the newer agents TRL and MMF. Triple immunosuppression continues to be the standard, and corticosteroids are still part of most widely used immunosuppressive protocols. More effective immunosuppres‐ sion has reduced the incidence of acute rejection without a reduction in patient survival [125]. Calcineurin inhibitors are still the cornerstone of current immunosuppressive therapy, but have important cardiovascular and oncogenic side effects and nephrotoxicity effects that contributes to the multifactorial process called "chronic allograft dysfunction", the leading cause of chronic allograft failure among kidney transplant recipients. New drugs, with a different mechanism of action, are being developed focusing on a better balance between drug efficacy and toxicity. These novel compounds interfere with either T-cell mediated or antibodymediated rejection [126].

**Author details**

go State, Mexico

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Ana Luisa Robles Piedras\*

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\*Address all correspondence to: roblesa@uaeh.edu.mx

, Minarda De la O Arciniega and Josefina Reynoso Vázquez

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A number of novel drugs are currently under investigation in Phase I, II, or III clinical trials primarily to replace the nephrotoxic but highly effective calcineurin inhibitors. ISA247 (voclosporine) is a CsA analog with reduced nephrotoxicity in Phase III study. AEB071 (sotrastaurin), a protein kinase C inhibitor, and CP-690550, a JAK3 inhibitor, are small molecules in Phase II studies EVL is derived from the mTOR inhibitor SRL and is in Phase III study. Belatacept is a humanized antibody that inhibits T-cell costimulation and has shown encouraging results in multiple Phase II and III trials. Alefacept and Efaluzimab are humanized antibodies that inhibit T-cell adhesion and are in Phase I and II clinical trials [127]. Finally, the exciting field of tissue engineering and stem cell biology with the repopulation of decellular‐ ized organs is ushering in a new paradigm for transplantation. The era of simplified immu‐ nosuppression regimens devoid of toxicities is upon us with the promise of dramatic improvement in long term survival [128].

#### **6. Conclusions**

Monitored drug therapy has undergone a tremendous change over the past quarter of a century with the increasing availability of advanced techniques like liquid chromatography with tandem mass spectrometry detection and immunoassays. Currently, the possibility of accurately and specifically measuring almost any drug in any biological fluid is a reality, and while TDM has become a standard of care for most immunosuppressive drugs, TDM practices will continue to evolve with the field of transplantation. New immunosuppressives, such as sotrastaurin, exhibit pharmacokinetic variability comparable to that seen with currently used immunosuppressive drugs and may benefit from monitoring therapy [129]. Although TDM of biologic drugs such as belatacept have not been reported in clinical trials to date, potentially useful pharmacodynamic assays that can be performed on blood specimens have been described [51,130]. The information gained through further study in these complex regimens should provide innovative strategies and new immunosuppressive agents that will serve to extend the functional life of allografts without toxicity or infection.
