Effect of Sirolimus on Disease Progression in Patients with Autosomal Dominant Polycystic Kidney Disease and CKD Stages 3b-4.

Background and objectives The effect of mammalian target of rapamycin (mTOR) inhibitors has never been tested in patients with autosomal dominant polycystic kidney disease (ADPKD) and severe renal insufficiency. Design, setting, participants, & measurements In this academic, prospective, randomized, open label, blinded end point, parallel group trial (ClinicalTrials.gov no. NCT01223755), 41 adults with ADPKD, CKD stage 3b or 4, and proteinuria ≤0.5 g/24 h were randomized between September of 2010 and March of 2012 to sirolimus (3 mg/d; serum target levels of 5–10 ng/ml) added on to conventional therapy ( n =21) or conventional treatment alone ( n =20). Primary outcome was GFR (iohexol plasma clearance) change at 1 and 3 years versus baseline. Results At the 1-year preplanned interim analysis, GFR fell from 26.7±5.8 to 21.3±6.3 ml/min per 1.73 m 2 ( P 2 ( P μ g/min; P =0.02) and proteinuria (0.3±0.2 versus 06±0.4 g/24 h; P de novo proteinuria ( P =0.04), ten versus three patients doubled proteinuria ( P =0.02), 18 versus 11 patients had peripheral edema ( P =0.04), and 14 versus six patients had upper respiratory tract infections ( P =0.03). Three patients on sirolimus had angioedema, 14 patients had aphthous stomatitis, and seven patients had acne ( P P =0.12). On follow-up, 37% and 7% of serum sirolimus levels fell below or exceeded the therapeutic range, respectively. Conclusions Finding that sirolimus was unsafe and ineffective in patients with ADPKD and renal insufficiency suggests that mTOR inhibitor therapy may be contraindicated in this context.