Mammalian target of rapamycin (mTOR) is the core component of two complexes,
mTORC1 and
mTORC2.
mTORC1 is inhibited by
rapamycin and analogues.
mTORC2 is impeded only in some cell types by prolonged exposure to these compounds. mTOR activation is linked to tubular cell proliferation in animal models and human
autosomal dominant polycystic kidney disease (
ADPKD).
mTOR inhibitors impede cell proliferation and
cyst growth in
polycystic kidney disease (PKD) models. After
renal transplantation, two small retrospective studies suggested that mTOR was more effective than
calcineurin inhibitor-based immunosuppression in limiting kidney and/or liver enlargement. By inhibiting
vascular remodeling, angiogenesis, and fibrogenesis,
mTOR inhibitors may attenuate nephroangiosclerosis,
cyst growth, and interstitial
fibrosis. Thus, they may benefit
ADPKD at multiple levels. However, mTOR inhibition is not without risks and side effects, mostly dose-dependent. Under certain conditions, mTOR inhibition interferes with adaptive increases in renal proliferation necessary for recovery from injury. They restrict Akt activation,
nitric oxide synthesis, and endothelial cell survival (downstream from
mTORC2) and potentially increase the risk for glomerular and peritubular capillary loss, vasospasm, and
hypertension. They impair podocyte integrity pathways and may predispose to glomerular injury. Administration of
mTOR inhibitors is discontinued because of side effects in up to 40% of transplant recipients. Currently, treatment with
mTOR inhibitors should not be recommended to treat
ADPKD. Results of ongoing studies must be awaited and patients informed accordingly. If effective, lower dosages than those used to prevent rejection would minimize side effects. Combination
therapy with other effective drugs could improve tolerability and results.