The significance of this clinical trial lies in its potential to increase the success of
immunosuppression (IS) therapy withdrawal in liver transplant (LT) recipients, thus
decreasing the negative impact of IS on their long-term outcomes. Lifetime immunosuppression
(IS) with standard agents, the calcineurin inhibitors (CNI) cyclosporine and tacrolimus
(TAC), is currently required at clinically recommended doses and trough levels to prevent
allograft rejection. However, this occurs at the significant expense of long-term CNI
toxicity, i.e. chronic kidney disease (CKD), hypertension, hyperlipidemia, diabetes,
infections and malignancy. With improvements in early graft and patient survival, long term
adverse IS effects have become increasingly important in this rapidly expanding patient
population. The strategies to reduce long term CNI toxicity include dose minimization that
still leaves patients on CNI therapy, conversion to non-CNI therapy, or even complete IS
withdrawal. The second approach, conversion to non-CNI IS therapy, is attractive in the
potential to stabilize or improve renal function and other CNI toxicities. One such
non-nephrotoxic IS agent, the mammalian target of rapamycin inhibitor (mTOR-I) SRL, has a
different mechanism of IS action and studies have shown that CNI to SRL conversion can
stabilize renal dysfunction with a low risk of rejection. Yet even with these possible
benefits, patients on SRL are still subject to lifetime IS therapy with side effects and
costs, highlighting the need to investigate the strategies that promote full IS withdrawal
without rejection (3rd approach), also known as 'operational tolerance'.