2.3.2 mTOR inhibitors
Regarding mTOR inhibitors-related edema, incidence is higher in kidney than in liver transplant recipients and approximately 5-fold higher with sirolimus compared to matched everolimus-treated patients (Gharbi et al., 2014). Sirolimus (Huber et al., 2007; Wang et al., 2019) directly impairs lymphatic drainage trough VEGF-C/VEGFR-3 signaling, leading to stasis of extravasated tissue fluid and macromolecules (Gharbi et al., 2014). To such an extent that sirolimus is used to treat lymphatic malformations related to PI3K/AKT/mTOR upregulation (Fereydooni, Dardik, & Nassiri, 2019). In a review of 26 cases, the time from sirolimus initiation to lymphedema onset ranged from 1 to 30 months (Rashid-Farokhi & Afshar, 2017). Sirolimus-induced lymphedema is usually unilateral or asymmetrical especially when located in upper extremities (Rashid-Farokhi & Afshar, 2017). Diuretics are ineffective and it may progress to permanent scleroderma-like lesions (E. Mahé et al., 2005) when the dosage is not reduced or drug is not interrupted early (Gharbi et al., 2014). In most patients with mTOR inhibitor-related lymphedema, early withdrawal of the medication leads to partial or complete resolution of edema after several months (Rashid-Farokhi & Afshar, 2017).