Safety and tolerability of sirolimus treatment in patients with autosomal dominant polycystic kidney disease

Abstract

Background. We initiated a randomized controlled clinical trial to assess the effect of sirolimus on disease progression in patients affected by autosomal dominant polycystic kidney disease (ADPKD). Here we report the preliminary safety results of the first 6 months of treatment.Method. A total of 25 patients were randomized to sirolimus 2 mgday and 25 patients to no treatment except standard care. Treatment adherence was monitored electronically. At baseline and at Month 6, laboratory parameters were analysed and the urinary protein profile in 24-h urine collections was determined.Results. Both treatment groups were well balanced for age, sex and renal function. In 94.1 ± 11.4 of the study days, patients in the sirolimus group were exposed to the drug when assuming a therapeutic efficacy duration of 30 h. At Month 6, the mean sirolimus dose and trough level were 1.28 ± 0.71 mgday and 3.8 ± 1.9 μgl, respectively. Glomerular (albumin, transferrin, IgG) and tubular (retinol-binding protein, α1-microglobulin) protein excretion remained unchanged. Glomerular filtration rate also did not change significantly. Haematological parameters were similar in both groups, except for a mild reduction of the mean corpuscular volume of erythrocytes in patients receiving sirolimus. Lipid levels were similar in both groups. Adverse events were transient and mild, and no grade 3 or 4 events occurred. The incidence of infections was similar in the sirolimus group (80) and the standard group (88). The most common gastrointestinal adverse events were mucositis (72 in the sirolimus group versus 16 in the standard group, P = 0.0001) and diarrhoea (36 in the sirolimus versus 20 in the standard group, P = 0.345).Conclusion. Treatment of ADPKD patients with sirolimus with a dose of 1-2 mg/day is safe and does not cause proteinuria or impairment of GFR. Treatment adherence was excellent.