Development of a clinical protocol for personalized minimization of immunosuppression in liver recipients in the long-term period after transplantation

Background. Long-term immunosuppression in standard regimens, though preventing a rejection, simultaneously increases morbidity and mortality in liver transplant recipients. Minimization or discontinuation of immunosuppressive drugs may reduce this burden; however, the permissible limits, safety, tolerability, clinical outcomes, and long-term results of this strategy remain undefined and require thorough study and clarification.

Objective. To develop a clinical protocol and investigate the feasibility and clinical safety of personalized immunosuppression minimization in the long-term period after liver transplantation.

Material and methods. Forty stable liver recipients, at 74±7.21 months (range: 6–182 months) post-transplantation, were included in a retrospective single-center study on tacrolimus minimization/discontinuation. Mean age at enrollment was 56.3±1.4 years. Twenty-two (55%) patients were on tacrolimus monotherapy, and 18 (45%) on a combination tacrolimuseverolimus therapy. Tacrolimus dose was gradually reduced over 8 (4;11) months.

Results. Graft dysfunction developed in 32.5% of cases (n=13) with dose reductions of 25–95%. Rejection was diagnosed in 7 (17.5%) patients based on laboratory and morphological data, 3–9 months after starting minimization. All dysfunction episodes were reversible. The median duration of subsequent dysfunction-free graft period in all intolerant patients was 28 (26;33) months. Twenty-seven (67.5%) patients tolerated minimization: 15 (37.5%) completely discontinued tacrolimus, and 12 (30%) achieved a 40–87.5% dose reduction (mean 62.7%). Median follow-up for tolerant patients after completing the minimization was 26 (20;30) months. Control biopsies performed 1–33 months (median 15 months) after completing the minimization showed no negative dynamics in histological patterns. Comparison between the everolimus group and the monotherapy group revealed significant differences: tolerant patients to immunosuppression minimization accounted for 83% vs. 55% (p=0.053); tacrolimus discontinuation was achieved in 72.2% vs. 9.1% (p<0.001); the dose reduction extent was 100 (90.3;100) % vs. 56 (42.5;78.8) % (p<0.001). In the whole cohort, the estimated GFR increased from the baseline of 62 (50;70) mL/min/1.73 m² to 66.5 (54;80) mL/min/1.73 m² by the end of the follow-up (p=0.011).

Conclusion. Controlled immunosuppression minimization in the long-term post-transplant period is successful in a significant proportion of carefully selected recipients. The procedure being safe with strict protocol adherence. A maximal tacrolimus dose reduction is achieved more frequently and with lower rejection risk in patients on everolimus. A positive effect of minimization on kidney function has been confirmed.

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