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).