**10. Conclusion**

Establishing optimal immunosuppressive regimens involves maintaining a delicate balance between over-immunosuppression which increases infection risk and under-immunosup‐ pression which increases risk of allograft rejection. Use of potent induction agents and main‐ tenance therapies that include CNI has led to dramatic decrease in the incidence of acute rejection episodes in the immediate post transplantation period. However, late allograft loss and long-term graft survival are problems that persist despite better immunosuppression. Chronic CNI toxicity, humoral rejection and the development of chronic alloreactivity to do‐ nor allograft tissue are major contributing factors to late graft loss.

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One challenge with current maintenance regimens is the toxicity related to long term CNI use. Steroid avoidance/withdrawal protocols continue to be evaluated and are being imple‐ mented successfully at some centers. Rapamune has been studied in several trials as a CNI sparing agent, but has not gained wide acceptance due to its side effect profile. The predom‐ inant trend in recent clinical trials is to find a long term alternative agent to replace CNI. Be‐ latacept was recently approved by the FDA for use as maintenance agent and appears to be a promising alternative to long term CNI use. However, the majority of centers lack experi‐ ence with belatacept and long term outcome data is lacking.

Other challenges include the rising percentage of sensitized patients on the transplant wait list. Strategies to offer transplantation to these highly sensitized recipients include transplan‐ tation against a positive cross match donor, paired kidney exchange and aggressive desensi‐ tization to lower alloantibody titers. Immunosuppressive protocols aimed at successfully transplanting sensitized recipients continue to be investigated as these patients present a special immunologic challenge. Sensitized patients are at increased risk of developing anti‐ body mediated rejection and earlier graft loss post-transplant. Several new agents like borte‐ zomib and eculizumab are currently being tested in these patients.

Finally, the optimal immunosuppressive strategy would ideally be one which promotes the development of tolerance to alloantigens such that immunosuppression can be withdrawn successfully. The development of tolerance is certainly possible as the literature supports in‐ cidental cases of operational tolerance, where recipients are on minimal or no immunosup‐ pression without evidence of allograft rejection. Currently, the majority of patients will require life long immunosuppressive therapy. Basic mechanisms promoting tolerance are being investigated with the hope that new medications or tolerogenic protocols may be im‐ plemented in the near future.
