Therapeutic mTOR inhibition in autosomal dominant polycystic kidney disease: What is the appropriate serum level?

American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
G CanaudC Legendre

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease, and sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been shown to significantly retard cyst expansion in animal models. The optimal therapeutic dose of sirolimus is not yet defined. Here, we report the history of a previously unknown ADPKD deceased donor whose kidneys were engrafted in two different recipients. One of the two received an immunosuppressive regimen based on sirolimus for 5 years while the other did not. After transplantation, both patients developed severe transplant cystic disease. Donor DNA sequence identified a new hypomorphic mutation in PKD1. The rate of cyst growth was identical in the two patients regardless of the treatment. While sirolimus treatment reduced the activation of mTOR in peripheral blood mononuclear cells, it failed to prevent mTOR activation in kidney tubular cells, this could account for the inefficiency of treatment on cyst growth. Together, our results suggest that the dose of sirolimus required to inhibit mTOR varies according to the tissue.

References

Dec 1, 1992·Transplantation·B Siegal
Dec 10, 1999·Transplantation·R J HowardJ C Scornik
Feb 7, 2001·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Y S ShanY J Lin
Aug 13, 2003·Kidney International·Arlene B ChapmanUNKNOWN Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease cohort
Jan 9, 2004·The New England Journal of Medicine·Patricia D Wilson
Jun 8, 2004·Nursing·Becky Lien Munson
Jun 18, 2004·The New England Journal of Medicine·Anthony J Bleyer, Thomas C Hart
Nov 26, 2004·Journal of the American Society of Nephrology : JASN·Yunxia TaoCharles L Edelstein
Oct 14, 2005·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Patricia R WahlRudolf P Wüthrich
Feb 14, 2006·Cell·Stephan WullschlegerMichael N Hall
Mar 29, 2006·Proceedings of the National Academy of Sciences of the United States of America·Jonathan M ShillingfordThomas Weimbs
May 19, 2006·The New England Journal of Medicine·Jared J GranthamUNKNOWN CRISP Investigators
Aug 18, 2006·The New England Journal of Medicine·Godela M Brosnahan
Jun 22, 2007·Journal of the American Society of Nephrology : JASN·Sandro RossettiUNKNOWN CRISP Consortium
Aug 21, 2007·Clinical Journal of the American Society of Nephrology : CJASN·Emmanuel LetavernierChristophe Legendre
Dec 21, 2007·The New England Journal of Medicine·Henrik EkbergUNKNOWN ELITE-Symphony Study
Jan 18, 2008·Journal of the American Society of Nephrology : JASN·Qi QianVicente E Torres
Jul 1, 2008·Clinical Journal of the American Society of Nephrology : CJASN·Charles L Edelstein
Oct 25, 2008·Annual Review of Medicine·Peter C Harris, Vicente E Torres
May 13, 2009·BMJ : British Medical Journal·K SchipperGuy A M Widdershoven
May 21, 2009·Kidney International·Vicente E Torres, Peter C Harris
Oct 3, 2009·Pediatrics in Review·Jacques Benun, Carol Lewis
Oct 17, 2009·Journal of the American Society of Nephrology : JASN·Lesley A Stevens, Andrew S Levey
Dec 8, 2009·Nature Medicine·Francisco VerdeguerMarco Pontoglio

❮ Previous
Next ❯

Citations

Dec 15, 2012·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Max Christoph Liebau, Andreas Lucas Serra
Jun 29, 2010·The New England Journal of Medicine·Terry Watnick, Gregory G Germino
Aug 9, 2011·Human Molecular Genetics·Ayumi TakakuraJing Zhou
Dec 12, 2012·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Meg J JardineVlado Perkovic
Dec 3, 2010·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Thomas S LisseMartin Hewison
Feb 22, 2012·Journal of the American Society of Nephrology : JASN·Zlata NovalicDorien J M Peters
Aug 4, 2012·Journal of the American Society of Nephrology : JASN·Jonathan M ShillingfordThomas Weimbs
Jun 4, 2014·The Journal of Clinical Investigation·Peter C Harris, Vicente E Torres
Jul 24, 2014·The New England Journal of Medicine·Guillaume CanaudFabiola Terzi
Aug 5, 2014·Néphrologie & thérapeutique·Emilie Cornec-Le Gall, Yannick Le Meur
Jul 22, 2011·Trends in Molecular Medicine·Oxana Ibraghimov-Beskrovnaya, Thomas A Natoli
Jan 1, 2016·Seminars in Nephrology·Andrew MallettGopala K Rangan
Mar 29, 2014·Expert Opinion on Pharmacotherapy·Rudolf P Wüthrich, Changlin Mei
Dec 2, 2014·Translational Research : the Journal of Laboratory and Clinical Medicine·Wells B LaRiviereVicente E Torres
Jun 18, 2014·Nature Reviews. Nephrology·Nada KanaanYves Pirson
Apr 12, 2014·Clinical Journal of the American Society of Nephrology : CJASN·William E BraunBrian R Herts
May 27, 2016·Nature Reviews. Disease Primers·Elizabeth P HenskeElizabeth A Thiele
Apr 13, 2012·American Journal of Physiology. Renal Physiology·Wilfred Lieberthal, Jerrold S Levine
Feb 25, 2011·American Journal of Physiology. Renal Physiology·Wouter N LeonhardDorien J M Peters
Jan 26, 2018·Transplantation·Maggie K M MaTak Mao Chan
Dec 31, 2010·Current Opinion in Gastroenterology·Tom J G Gevers, Joost P H Drenth
Oct 13, 2017·American Journal of Physiology. Renal Physiology·Wayne R FitzgibbonTakamitsu Saigusa
Sep 7, 2019·Nature Reviews. Nephrology·Luis Fernando Menezes, Gregory G Germino
Mar 31, 2011·Médecine sciences : M/S·Dominique Joly
Feb 27, 2015·The American Journal of Case Reports·Amit LangoteGreg A Knoll
Dec 5, 2018·Oxidative Medicine and Cellular Longevity·Sofia D VianaRui Alves
Oct 27, 2016·Journal of Nephrology·Piergiorgio MessaRoberta Cerutti
Dec 20, 2019·Journal of Nephrology·Francesca Testa, Riccardo Magistroni
May 9, 2018·Current Medicinal Chemistry·Cherie StaynerMichael R Eccles
Aug 28, 2020·International Journal of Molecular Sciences·Sophie HaumannMax C Liebau
Jan 9, 2020·Cellular Signalling·Thomas A NatoliOxana Ibraghimov-Beskrovnaya

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.