Sirolimus Reduces Polycystic Liver Volume in ADPKD Patients

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 Ϯ 0.03% reduction in polycystic liver volume, whereas treatment with tacrolimus for a comparable duration was associated with a 14.1 Ϯ 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 phosphoS6rp 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.

Dose-Dependent Effects of Sirolimus on mTOR Signaling and Polycystic Kidney Disease

“…Supporting the latter, patients receiving mTOR inhibitors after transplantation in retrospective studies have shown decreasing renal and liver cystic volumes. 10,32 The effect of mTOR inhibition on cyst volume regression may be caused by increased apoptosis and/or by a potential effect on fluid reabsorption as suggested for fetal lung epithelia. 30,33 Nonetheless, our results support the concept of cyst regression by mTOR inhibitors when used at high enough concentrations.…”

Medical and surgical treatment options for polycystic liver disease1

“…17,18 Additionally, markedly higher levels of phospho-ERK, phospho-AKT, phospho-mammalian target of rapamycin (mTOR), and its downstream effector phospho-S6 ribosomal protein (S6rp) are found in hepatic cysts. 19 Finally, the second messenger 3 0 -5 0 -cyclic adenosine monophosphate (cAMP) regulates cholangiocyte proliferation and fluid secretion. 20 There are higher cAMP levels in cholangiocytes of ADPKD rodent models, which is associated with cholangiocyte hyperproliferation and cyst expansion.…”

“…55 liver volume by 11.9% when given for an average of 19.4 months, whereas tacrolimus caused an increase of 14.2%. 19 There are still many outstanding questions. It is unknown why some patients respond well, whereas others do not, but it appears that larger livers respond better to treatment than smaller livers.…”

A General Overview to the Treatment of Cystic Renal Diseases and Innovations in the Treatment: Review

“…54 Böbrek nakli yapılan ODPBH olan hastalarda yapılan iki retrospektif çalışmada, mTOR inhibitörlerinin diğer grup immünsupresif-lere göre hem böbrek hem de karaciğer volümle-rinde azalmaya yol açtığı gözlemlenmiştir. 52,55 mTOR kinazın kist oluşumunu indüklediği ve hastalığın progresyonuna neden olduğu hipotezinden yola çıkılarak, 214 erişkin hastaya çift-kör randomize plasebo kontrollü bir çalışma ile everolimus verilmiştir. 56 Birinci ve ikinci yılın sonunda total böbrek volümünde azalma everolimus grubunda daha belirgin olmuştur (sırasıyla p=0,02; p=0,06).…”