Long-term Outcome of Conversion to Sirolimus Monotherapy After Liver Transplant

Abstract

Objectives: This study sought to assess the longterm efficacy and safety of conversion from a calcineurin inhibitor-based immunosuppressive regimen to sirolimus monotherapy in liver transplant recipients with renal dysfunction. Materials and Methods: Twenty-five liver transplant recipients with calcineurin inhibitor-based immunosuppression were included in this singlecenter, prospective study. Indications were renal dysfunction, avoidance of tumor recurrence, combination renal dysfunction and avoidance of tumor recurrence, and calcineurin inhibitor-related adverse effects. Results: Mean interval between liver transplant and initiation of sirolimus monotherapy was 51.7 months. The mean follow-up was 75.6 months. The mean ± SD sirolimus whole-blood trough level was 9.0 ± 2.8 ng/mL after 6 months and 6.0 ± 1.8 ng/mL after 18 months. No rejection episode occurred. There was an improvement of the mean creatinine level: 156.1 ± 54.9 µmol/L before conversion versus 129.1 ± 34.7 µmol/L approximately 3 years after conversion (P < .05). The glomerular filtration rate, measured by technetium Tc-99m-diethylenetriamine penta acetic aerosol scintigraphy, improved from 27.4 ± 6.8 mL/min/1.73 m 2 before conversion to 43.3 ± 6.3 mL/min/1.73 m 2 at final follow-up. Proteinuria increased after conversion to sirolimus after 6 months (P < .05) and at last follow-up. The systolic blood pressure decreased from 151.5 ± 20.2 to 132.1 ± 19.4 mm Hg, and the diastolic from 89.7 ± 11.2 to 82.1 ± 9.1 mm Hg at last followup. Serum cholesterol and serum triglyceride levels were nearly unchanged. However, 50% of the patients were treated with lipid-lowering agents. Four patients had sirolimus-induced adverse effects (thrombocytopenia, gingival hyperplasia, oral ulceration). Conclusions: Conversion from calcineurin inhibitors to sirolimus monotherapy after liver transplant results in stabilization of renal function in 75% to 85% of cases and of blood pressure, without increased risk of rejection. The spectrum of adverse effects is low.

The Role of mTOR Inhibitors in Liver Transplantation: Reviewing the Evidence

“…From our literature search, proteinuria was observed in six liver transplant studies of variable quality involving sirolimus use (Table 3(d)) [67, 72, 73, 75, 77, 86]. In one of these, a small, prospective, randomized study, the rate of proteinuria during the 1-year followup was similar to that observed in controls receiving mycophenolate mofetil (MMF) [73].…”

“…Three prospective and four retrospective studies (a mixture of low- and medium quality) demonstrated improvements in renal function in recipients converting to sirolimus [77, 78, 81, 83–86]. Two of these studies (one prospective, one retrospective) demonstrated long periods of improved GFR after conversion in sirolimus conversion groups at 27.5 months [81] and up to 60 months after conversion [77]. Two small prospective studies (one low quality, single-arm and one medium quality, randomized) showed only numerical improvements at 6 [82] and 12 [76] months after conversion.…”

“…The development of oral ulcers has been reported in 9.5–42.0% of patients receiving sirolimus (Table 4(b)) [45, 48, 67, 73, 75, 77, 78, 80, 83] across a mixture of quality and trial designs. Mouth ulcers have been reported as occurring at a significantly higher rate in patients receiving sirolimus as compared to those receiving MMF [73] or CNI [45, 48], although it should be noted that two of these studies used high loading doses (≥10 mg) [45, 73].…”

“…Our search identified six studies (all conversion) that measured hypertension in liver transplant recipients receiving mTOR inhibitors (Table 5) [50, 75, 77, 78, 87, 99]. Of these six, one single-center prospective, single-arm, medium quality study demonstrated improvements in both diastolic and systolic blood pressure in 12 liver transplant recipients who had hypertension and had converted from CNI treatment to sirolimus.…”

Nonstandard Drugs and Feasible New Interventions for Autoimmune Hepatitis: Part I

“…The diverse actions of rapamycin on the immune response justify its candidacy as a treatment for autoimmune hepatitis, and limited experiences after liver transplantation have supported its further study in this disease [210][211][212][213][214]. The use of rapamycin has not been reported in patients with autoimmune hepatitis outside of liver transplantation, and this experience has been meager but promising.…”