Safety and immunologic benefits of conversion to sirolimus in kidney transplant recipients with long-term exposure to calcineurin inhibitors

Abstract

Background/Aims:Sirolimus (SRL) is a promising immunosuppressant replacingcalcineurin inhibitors (CNIs). This study was performed to evaluate the safetyand immunologic benefits of conversion to SRL in stable kidney transplant (KT)recipients exposed to CNIs for long periods.Methods:Fourteen CNI-treated KT recipients with stable renal function for morethan 10 years were included. Either 2 or 3 mg per day of SRL was administeredwhile CNIs were reduced by half starting on day 1, and then stopped 2 weeks afterSRL introduction. The safety of SRL conversion was assessed considering thegraft function, acute rejection, and graft loss. Immunologic alterations were measuredvia serial changes of T cell and B cell subsets after SRL conversion. Adverseeffects of SRL conversion were also evaluated.Results:Conversion to SRL was successful in nine patients (64.2%). Conversionto SRL preserved graft function as compared to the baseline value (p = 0.115). Noacute rejection or allograft loss was observed during the follow-up period. Immunemonitoring of T and B cells revealed a regulatory T cells increase after SRL conversion (p = 0.028). Most adverse events developed within 6 weeks after SRLconversion, and oral mucositis was the main cause of SRL withdrawal.Conclusions:Conversion to SRL can be safe and has immunologic benefits in KTrecipients with long-term CNI exposure. Close monitoring of mucocutaneous adverseevents is, however, required in the early period after SRL conversion.

Treatment of Lymphatic Malformations with the mTOR Inhibitor Sirolimus: A Systematic Review

“…Main and most common adverse effects of sirolimus treatment are anemia, thrombocytopenia, leukopenia, and increases in triglyceride and cholesterol levels. 37 Due to the intrinsic immunosuppressive potential of sirolimus, which is the reason for its use in transplant medicine, there is a high risk for infections. 38 Other adverse effects associated with sirolimus include hemodynamic (e.g., hypertension), dermatologic (e.g., rash, mucositis), renal (e.g., proteinuria), and hormonal problems.…”

Regulatory B cells and advances in transplantation

“…Given that immunosuppressive drugs are routinely used to treat transplant recipients and Bregs are immunosuppressive in transplantation, it is interesting to discuss the effects of routine drugs administered to kidney transplant recipients, such as calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors, on Bregs …”

“…However, only mTOR inhibitor‐treated patients rather than CNI‐treated patients exhibit expanded CD4 + CD25 + FOXP3 + Tregs, implying that an increase in Tregs compensates for a reduction in Bregs . The compensation mechanism probably explains the clinical observation that conversion to mTOR inhibition increases Treg numbers and then improves renal function after CNI discontinuation in renal transplantation patients …”

“…Given that immunosuppressive drugs are routinely used to treat transplant recipients and Bregs are immunosuppressive in transplantation, it is interesting to discuss the effects of routine drugs administered to kidney transplant recipients, such as calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors, on Bregs. [122][123][124] CNIs and mTOR inhibitors are known to exert immunosuppression mainly by inhibiting T cell proliferation and their effects on B cells have not been extensively studied. 122,123,125 Lower numbers of IL-10-producing B cells and CD19 + CD24 hi CD38 hi transitional B cells are detected in CNI-and mTOR inhibitor-treated patients than in untreated healthy individuals.…”

“…126 The compensation mechanism probably explains the clinical observation that conversion to mTOR inhibition increases Treg numbers and then improves renal function after CNI discontinuation in renal transplantation patients. 124,125…”