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 +/- 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.

Figure 1.

(A) Average changes in the liver volume in autosomal dominant polycystic kidney disease (ADPKD) patients with or without receiving sirolimus. (B) Reduction in total liver volume plotted as a function of the duration of sirolimus treatment.

Figure 2.

Total liver volume in each individual patient at the first and second imaging studies. Each circle or square represents a single subject.

Figure 3.

Representative series of transaxial computed tomography sections obtained from an ADPKD patient at the mid-level of the liver before (left column) and after (right column) 15.5 mo of the sirolimus-containing immunosuppressant shows a reduction in the size and number of liver cysts. The top cuts of the two computed tomography series are aligned at the center of a partially calcified cyst.

Figure 4.

The changes of the native polycystic kidneys at the first and second imaging studies. A and C show average changes, mean and SEM, of right and left kidney volumes in patients with or without receiving the sirolimus-containing immunosuppression. B and D show the total right and left kidney volumes in each patient at the time of the first and second imaging studies.

Figure 5.

Phospho-mammalian target of rapamycin (mTOR) expression is elevated in polycystic liver disease (PLD) cyst-lining epithelia. Liver sections from two normal subjects (A and B) and two PLD patients (C to F) were immunostained with antibody against Ser2448 phospho-mTOR. PLD cyst-lining epithelial cells from both ADPKD patients showed intense staining for phospho-mTOR (C and D, enlarged views in G to I). The phospho-mTOR was nondetectable in the biliary epithelia from normal controls (A and B) and almost nondetectable in the noncystic biliary epithelia at portal triads (E and F) of the same PLD sections as in C and D.

Figure 6.

The expression of effectors of phospho-mTOR, phospho-S6 ribosomal protein and phospho-AKT are elevated in PLD cyst-lining epithelia. Liver sections from a normal subject were immunostained with antibodies that specifically recognize mTOR downstream effector, p-S6rp (A) and p-AKT (B). Consecutive PLD sections from an ADPKD patient (C, E, G, and I) were immunostained with antibodies against Ser2448 p-mTOR (C), Ser240/244 p-S6rp (E), Ser473 p-AKT (G), and Thr202/Tyr204 p-ERK (I). D, F, H, and J are enlarged views of C, E, G, and I, respectively. PLD cyst-lining epithelia show a high level of staining for activated mTOR, S6rp, AKT, and ERK, whereas the normal biliary epithelia show nondetectable p-S6rp (A) and p-AKT (B).