Prospects for mTOR Inhibitor Use in Patients with Polycystic Kidney Disease and Hamartomatous Diseases

Abstract

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.

Folate-Conjugated Rapamycin Slows Progression of Polycystic Kidney Disease

“…Although mTOR inhibitors have probably been the most robust and effective therapeutics in preclinical trials using PKD rodent models, 33 recent results from clinical trials have been disappointing. The mTOR inhibitor rapamycin is an exquisitely specific drug that does not appear to affect molecular targets other than mTOR.…”

Tumor cell metabolism

“…The disruption of the mTORC2 assembly is observed only in certain cell types after prolonged exposure to these compounds. 93 mTORC1 is activated by growth factor signaling through PI3K activation of AKT 94 and regulates cell mass by increasing protein synthesis.…”

Sirolimus-induced Pneumonitis Complicated by Pentamidine-induced Phospholipidosis in a Renal Transplant Recipient: A Case Report

“…1999, and the PSIs are now also being used to treat metastatic cancer, hamartomatous diseases, polycystic kidney disease (2), and to prevent restenosis of coronary artery stents.…”