Optimizing maintenance immunosuppressive therapy after liver transplantation

Objective: to justify the rational selection of maintenance immunosuppressive therapy following liver transplantation (LT).

Materials and methods. The study included 42 recipients of deceased donor liver grafts, observed for periods ranging from 1 month to 15 years LT. The mean age at transplantation was 49.4 ± 7.0 years. All patients received everolimus in combination with low-dose extended-release tacrolimus. Indications for everolimus therapy were tacrolimus-induced nephrotoxicity (n = 13), history of hepatocellular carcinoma (HCC, n = 21), and development of de novo malignancies at non-hepatic sites (n = 8). Target trough concentrations were 2–3 ng/mL for tacrolimus and 3–8 ng/mL for everolimus. Adverse events of everolimus and serum cholesterol dynamics were assessed at 12, 36, 60, and 120 months after conversion to this regimen, and compared with data from 20 randomly selected recipients maintained on tacrolimus monotherapy. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI equation at the same time points. Liver stiffness (kPa) was measured by transient elastography once at study completion. In patients with a history of HCC, baseline alpha-fetoprotein (AFP) levels were also taken into account.

Results. Long-term use of everolimus with low-dose extended-release tacrolimus did not impair renal function (baseline GFR: 84.13 ± 16.70 mL/min/1.73 m2; final GFR: 84.99 ± 21.30 mL/min/1.73 m2). However, serum cholesterol levels were consistently higher compared with tacrolimus monotherapy (12 months: 5.7 ± 0.91 vs 4.01 ± 1.21 mmol/L; 120 months: 5.52 ± 1.51 vs 4.58 ± 0.72 mmol/L). Among 21 patients with a history of HCC, recurrence or progression occurred in 6 patients (30%), which was associated with elevated baseline AFP levels prior to LT (429.2 ± 306.9 U/mL; Z = 4.2, p = 0.0001). Liver stiffness, assessed once at the endpoint of the retrospective study, averaged 4.8 ± 1.8 kPa, corresponding to F0–1 by the METAVIR scale.

Conclusion. Long-term maintenance therapy with everolimus combined with low-dose extended-release tacrolimus after LT is safe and helps mitigate calcineurin inhibitor (CNI) nephrotoxicity. Nevertheless, this regimen does not prevent recurrent HCC, which depends on the biological activity of the tumor.

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