PMID- 20498248 OWN - NLM STAT- MEDLINE DCOM- 20101026 LR - 20211203 IS - 1555-905X (Electronic) IS - 1555-9041 (Print) IS - 1555-9041 (Linking) VI - 5 IP - 7 DP - 2010 Jul TI - Prospects for mTOR inhibitor use in patients with polycystic kidney disease and hamartomatous diseases. PG - 1312-29 LID - 10.2215/CJN.01360210 [doi] AB - 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. FAU - Torres, Vicente E AU - Torres VE AD - Division of Nephrology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905, USA. torres.vicente@mayo.edu FAU - Boletta, Alessandra AU - Boletta A FAU - Chapman, Arlene AU - Chapman A FAU - Gattone, Vincent AU - Gattone V FAU - Pei, York AU - Pei Y FAU - Qian, Qi AU - Qian Q FAU - Wallace, Darren P AU - Wallace DP FAU - Weimbs, Thomas AU - Weimbs T FAU - Wuthrich, Rudolf P AU - Wuthrich RP LA - eng GR - R01 DK044863/DK/NIDDK NIH HHS/United States GR - R01 DK062338/DK/NIDDK NIH HHS/United States GR - R01 DK078043/DK/NIDDK NIH HHS/United States GR - TCR07005/TI_/Telethon/Italy PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20100524 PL - United States TA - Clin J Am Soc Nephrol JT - Clinical journal of the American Society of Nephrology : CJASN JID - 101271570 RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Protein Kinase Inhibitors) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Disease Models, Animal MH - Hamartoma/*drug therapy/enzymology MH - Humans MH - Intracellular Signaling Peptides and Proteins/*antagonists & inhibitors/metabolism MH - Polycystic Kidney Diseases/*drug therapy/enzymology MH - Protein Kinase Inhibitors/adverse effects/*therapeutic use MH - Protein Serine-Threonine Kinases/*antagonists & inhibitors/metabolism MH - Risk Assessment MH - Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases MH - Treatment Outcome PMC - PMC5619657 MID - NIHMS906658 EDAT- 2010/05/26 06:00 MHDA- 2010/10/27 06:00 PMCR- 2017/09/28 CRDT- 2010/05/26 06:00 PHST- 2010/05/26 06:00 [entrez] PHST- 2010/05/26 06:00 [pubmed] PHST- 2010/10/27 06:00 [medline] PHST- 2017/09/28 00:00 [pmc-release] AID - CJN.01360210 [pii] AID - 10.2215/CJN.01360210 [doi] PST - ppublish SO - Clin J Am Soc Nephrol. 2010 Jul;5(7):1312-29. doi: 10.2215/CJN.01360210. Epub 2010 May 24.