Prospects for mTOR inhibitor use in patients with polycystic kidney disease and hamartomatous diseases

Vicente E. Torres, Alessandra Boletta, Arlene Chapman, Vincent Gattone, York Pei, Qi Qian, Darren P. Wallace, Thomas Weimbs, Rudolf P. Wüthrich

Research output: Contribution to journalArticle

65 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1312-1329
Number of pages18
JournalClinical Journal of the American Society of Nephrology
Volume5
Issue number7
DOIs
Publication statusPublished - Jul 1 2010

Fingerprint

Polycystic Kidney Diseases
Sirolimus
Autosomal Dominant Polycystic Kidney
Cysts
Cell Proliferation
Kidney
Podocytes
Wounds and Injuries
Growth
Kidney Transplantation
Immunosuppression
Cell Survival
Nitric Oxide
Fibrosis
Endothelial Cells
Animal Models
Retrospective Studies
Hypertension

ASJC Scopus subject areas

  • Nephrology
  • Transplantation
  • Epidemiology
  • Critical Care and Intensive Care Medicine
  • Medicine(all)

Cite this

Prospects for mTOR inhibitor use in patients with polycystic kidney disease and hamartomatous diseases. / Torres, Vicente E.; Boletta, Alessandra; Chapman, Arlene; Gattone, Vincent; Pei, York; Qian, Qi; Wallace, Darren P.; Weimbs, Thomas; Wüthrich, Rudolf P.

In: Clinical Journal of the American Society of Nephrology, Vol. 5, No. 7, 01.07.2010, p. 1312-1329.

Research output: Contribution to journalArticle

Torres, Vicente E. ; Boletta, Alessandra ; Chapman, Arlene ; Gattone, Vincent ; Pei, York ; Qian, Qi ; Wallace, Darren P. ; Weimbs, Thomas ; Wüthrich, Rudolf P. / Prospects for mTOR inhibitor use in patients with polycystic kidney disease and hamartomatous diseases. In: Clinical Journal of the American Society of Nephrology. 2010 ; Vol. 5, No. 7. pp. 1312-1329.
@article{1e325eb7cbef4c87a57963d81193e104,
title = "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.",
author = "Torres, {Vicente E.} and Alessandra Boletta and Arlene Chapman and Vincent Gattone and York Pei and Qi Qian and Wallace, {Darren P.} and Thomas Weimbs and W{\"u}thrich, {Rudolf P.}",
year = "2010",
month = "7",
day = "1",
doi = "10.2215/CJN.01360210",
language = "English",
volume = "5",
pages = "1312--1329",
journal = "Clinical journal of the American Society of Nephrology : CJASN",
issn = "1555-9041",
publisher = "by the American Society of Nephrology",
number = "7",

}

TY - JOUR

T1 - Prospects for mTOR inhibitor use in patients with polycystic kidney disease and hamartomatous diseases

AU - Torres, Vicente E.

AU - Boletta, Alessandra

AU - Chapman, Arlene

AU - Gattone, Vincent

AU - Pei, York

AU - Qian, Qi

AU - Wallace, Darren P.

AU - Weimbs, Thomas

AU - Wüthrich, Rudolf P.

PY - 2010/7/1

Y1 - 2010/7/1

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=77954770878&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954770878&partnerID=8YFLogxK

U2 - 10.2215/CJN.01360210

DO - 10.2215/CJN.01360210

M3 - Article

C2 - 20498248

AN - SCOPUS:77954770878

VL - 5

SP - 1312

EP - 1329

JO - Clinical journal of the American Society of Nephrology : CJASN

JF - Clinical journal of the American Society of Nephrology : CJASN

SN - 1555-9041

IS - 7

ER -