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

• Type of Material: Article
• Authors: Vincente E. Torres, Mayo Clinic College of Medicine; Alessandra Boletta, San Raffaele Scientific Institute; Arlene Chapman, Emory University; Vincent Gattone, Indiana University School of Medicine; York Pei, Toronto General Hospital; Qi Qian, Mayo Clinic College of Medicine; Darren P. Wallace, University of Kansas Medical Center; Thomas Weimbs, University of California Santa Barbara; Rudolf P. Wuthrich, University Hospital Zurich
• Language: English
• Date: 2010-07-01
• Publisher: American Society of Nephrology
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 by the American Society of Nephrology
• Final Published Version (URL): http://dx.doi.org/10.2215/CJN.01360210
• Title of Journal or Parent Work: Clinical Journal of the American Society of Nephrology
• ISSN: 1555-9041
• Volume: 5
• Issue: 7
• Start Page: 1312
• End Page: 1329
• Grant/Funding Information: The meeting was funded by Wyeth Pharmaceuticals [makers of Rapamune (sirolimus)], which was acquired by Pfizer, Inc., in October 2009.; MediMedia Educational Group, LLC, provided support for the meeting.
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Anatomy

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.