Kidney Transplantation Long-Term Management Challenges Long-Term Immunosuppression Management Opportunities and Uncertainties

The long-termmanagement ofmaintenance immunosuppression in kidney transplant recipients remains complex. The vast majority of patients are treated with the calcineurin inhibitor tacrolimus as the primary agent in combinationwithmycophenolate, with or without corticosteroids. A tacrolimus trough target 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 comparedwithcyclosporingenerated initial enthusiasm,bututilizationhasbeenhamperedbyhigh initial rejection rates.Mammalian target of rapamycin inhibitors have yieldedmixed results aswell,with improved kidney function tempered by higher risk of rejection, proteinuria, and adverse effects leading to higher discontinuation rates. Mammalian target of rapamycin inhibitorsmayplay a role in the secondarypreventionof squamouscell skin cancer as conversion froma calcineurin inhibitor to anmammalian 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-term graft survival is chronic alloimmunity, and regardless of agent used,managing the toxicities of immunosuppression against the risk of chronic antibody-mediated rejection remains a fragile balance. CJASN 16: ccc–ccc, 2021. doi: https://doi.org/10.2215/CJN.15040920 Introduction The long-term management of immunosuppression remains a tale of immediate gratification followed by frustrations and occasional disappointment. The introduction of calcineurin inhibitors and mycophenolate as immunosuppressive therapies began an era of improved maintenance immunosuppression efficacy. Short-term acute rejection rates decreased, and 1-year outcomes improved. Despite this short-term success, long-term kidney allograft survival has frustratingly not enjoyed a similar rate of improvement (1). In evaluating this discrepancy of shortversus long-term outcomes, it is apparent that the same maintenance immunosuppression that provides excellent shortterm results may contribute to graft attrition with long-term exposure. In this review, we evaluate the current state of maintenance immunosuppression in kidney transplant recipients and discuss areas of opportunity and uncertainty in their long-term use. Ideal Calcineurin Inhibitor Targets The current standard of care in kidney transplant immunosuppression in the United States has evolved to be a calcineurin inhibitor–based immunosuppression regimen with tacrolimus and mycophenolate. Over 90% of patients in the United States are maintained on these two agents, with or without steroids (2). This is largely attributed to the landmark Symphony trial, which demonstrated superior outcomes in terms of both acute rejection rates and GFR at 1 in 3 years using a tacrolimus-based regimen when compared with cyclosporinor sirolimus-based regimens (3), and historical studies that support mycophenolate over azathioprine due to reductions in early acute rejection rates (4). However, there remains ongoing debate regarding the appropriate dose of tacrolimus and appropriate mycophenolate exposure for optimal immunosuppression in the long term. Importantly, in the Symphony trial, although tacrolimus trough (tacrolimus C0) level goals were protocol specified at 3–7 ng/ml, the actual achieved tacrolimus C0 exposure averaged 6.4 ng/ml at 12 months and 6.5 ng/ml at 36 months. Thus, a more appropriate interpretation of the Symphony trial is that a tacrolimus C0 dose range of 5–8 ng/ml should be considered the standard of care. Regarding mycophenolate exposure, attempts to define appropriate dose/exposure have not been fruitful, with the best attempt at defining optimal dose residing in the OPTICEPT trial in which a concentration-controlled dosing with reduced calcineurin inhibitor exposure was noninferior to standard calcineurin inhibitor/mycophenolate dosing for prevention of acute rejection (5). Compounding this lack of guidance is a paucity of data supporting improvements in graft or patient survival over time with mycophenolate compared with azathioprine (6). No study to date has demonstrated superior outcomes with low-dose tacrolimus exposure ,5 ng/ml Department of Medicine, University of Texas Southwestern