Long-term immunosuppression management opportunities and uncertainties

The long-term management of maintenance immunosuppression in kidney transplant recipients remains complex. The vastmajority of patients are treatedwith the calcineurin inhibitor tacrolimus as the primary agent in combinationwithmycophenolate, with orwithout corticosteroids.Atacrolimus troughtarget 5–8 ng/ml seems to be optimal for rejection prophylaxis, but long-term tacrolimus-related side effects and nephrotoxicity support the ongoing evaluation of noncalcineurin inhibitor–based regimens. Current alternatives include belatacept or mammalian target of rapamycin inhibitors. For the former, superior kidney function at 7 years post-transplant compared with cyclosporin generated initial enthusiasm, but utilization has been hampered by high initial rejection rates.Mammalian target of rapamycin inhibitors have yielded mixed results as well, with improved kidney function tempered by higher risk of rejection, proteinuria, and adverse effects leading to higher discontinuation rates.Mammalian target of rapamycin inhibitorsmay play a role in the secondary prevention of squamous cell skin cancer as conversion from a calcineurin inhibitor to an mammalian target of rapamycin inhibitor resulted in a reduction of new lesion development. Early withdrawal of corticosteroids remains an attractive strategy but also is associated with a higher risk of rejection despite no difference in 5-year patient or graft survival. Amajor barrier to long-termgraft survival is chronic alloimmunity, and regardless of agent used, managing the toxicities ofimmunosuppressionagainst the risk of chronic antibody-mediated rejectionremains a fragile balance.