Sirolimus Reduces Polycystic Liver Volume in ADPKD Patients
Open Access
- 1 March 2008
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 19 (3), 631-638
- https://doi.org/10.1681/asn.2007050626
Abstract
The immunosuppressive agent sirolimus exerts an antiproliferative effect by inhibiting mammalian target of rapamycin (mTOR). Because excessive proliferation of the biliary epithelium is a prominent feature of the polycystic liver that accompanies autosomal dominant polycystic kidney disease (ADPKD), we hypothesized that sirolimus may benefit patients with this disorder. We retrospectively measured the volumes of polycystic livers and kidneys in ADPKD patients who had received kidney transplants and had participated in a prospective randomized trial that compared a sirolimus-containing immunosuppression regimen to a tacrolimus-containing regimen. Sixteen subjects (seven with sirolimus, nine with tacrolimus) had received abdominal imaging studies within 11 mo before and at least 7 mo after transplantation, making them suitable for our analysis. Treatment with the sirolimus regimen for an average of 19.4 mo was associated with an 11.9 ± 0.03% reduction in polycystic liver volume, whereas treatment with tacrolimus for a comparable duration was associated with a 14.1 ± 0.09% increase. A trend toward a greater reduction in native kidney volume was also noted in the sirolimus group compared with the nonsirolimus group. Regarding mechanism, the epithelium that lines hepatic cysts exhibited markedly higher levels of phospho-AKT, phospho-ERK, phospho-mTOR, and the downstream effector phospho-S6rp compared with control biliary epithelium. In summary, treatment with sirolimus was associated with decreased polycystic liver volume, perhaps by preventing aberrant activation of mTOR in epithelial cells lining the cysts.Keywords
This publication has 45 references indexed in Scilit:
- Phase II Trial of Single-Agent Temsirolimus (CCI-779) for Relapsed Mantle Cell LymphomaJournal of Clinical Oncology, 2005
- Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR ComplexScience, 2005
- Quantitative Assessment of Angiographic Restenosis After Sirolimus-Eluting Stent Implantation in Native Coronary ArteriesCirculation, 2004
- Secretion of cytokines and growth factors into autosomal dominant polycystic kidney disease liver cyst fluidHepatology, 2004
- Sirolimus-Eluting Stents versus Standard Stents in Patients with Stenosis in a Native Coronary ArteryThe New England Journal of Medicine, 2003
- United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signallingBiochemical Society Transactions, 2003
- Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneysKidney International, 2003
- mTOR Interacts with Raptor to Form a Nutrient-Sensitive Complex that Signals to the Cell Growth MachineryCell, 2002
- cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathwayKidney International, 2000
- Association of cyclosporin A with acquired cystic kidney disease of the native kidneys in renal transplant recipientKidney International, 1993