Activation of
mammalian target of rapamycin (mTOR) pathways may contribute to uncontrolled cell proliferation and secondary
cyst growth in patients with
autosomal dominant polycystic kidney disease (
ADPKD). To assess the effects of mTOR inhibition on
disease progression, we performed a randomized, crossover study (The SIRENA Study) comparing a 6-month treatment with
sirolimus or conventional
therapy alone on the growth of kidney volume and its compartments in 21 patients with
ADPKD and GFR>or=40 ml/min per 1.73 m2. In 10 of the 15 patients who completed the study,
aphthous stomatitis complicated
sirolimus treatment but was effectively controlled by topical
therapy. Compared with pretreatment, posttreatment mean total kidney volume increased less on
sirolimus (46+/-81 ml; P=0.047) than on conventional
therapy (70+/-72 ml; P=0.002), but we did not detect a difference between the two treatments (P=0.45).
Cyst volume was stable on
sirolimus and increased by 55+/-75 ml (P=0.013) on conventional
therapy, whereas parenchymal volume increased by 26+/-30 ml (P=0.005) on
sirolimus and was stable on conventional
therapy. Percentage changes in
cyst and parenchyma volumes were significantly different between the two treatment periods.
Sirolimus had no appreciable effects on intermediate volume and GFR.
Albuminuria and
proteinuria marginally but significantly increased during
sirolimus treatment. In summary,
sirolimus halted
cyst growth and increased parenchymal volume in patients with
ADPKD. Whether these effects translate into improved long-term outcomes requires further investigation.