The purpose of this study is to evaluate the safety of a daily single oral dose of sirolimus in patients with advanced autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of renal cystic diseases, affecting all ethnic groups with an incidence of 1 in 400 to 1.000. In Austria an estimated 8.000 to 21.000 people, and an estimated 670.000 to 1.675.000 people worldwide are affected by ADPKD, although statements of up to 6.000.000 affected individuals have been made. ADPKD is responsible for 5 to 10 percent of patients on chronic hemodialysis. Individuals with ADPKD usually present in the 3rd to 4th decade of life, progressing to end-stage renal disease within 5 to 10 years after the onset of renal insufficiency. Usually renal replacement therapy, either by chronic dialysis or renal transplantation, becomes necessary. Currently there is no treatment for ADPKD other than blood pressure control and supportive care.

Thus, novel therapies for ADPKD are of great importance.

The formation of cysts in ADPKD follows a mutation located within either the polycystic kidney disease 1 or -2 gene on chromosomes 16 and 4, which are coding for polycystin 1 (PC1) and -2 (PC2), respectively. PC1 and PC2 are members of the polycystin family of integral membrane proteins. PC1 acts as a G-protein coupled receptor and is suggested to mediate cell-cell and cell-matrix interactions. PC2 acts as a nonselective cation channel and is supposed to act in ion exchange mechanisms. Among other pathways PC1 and 2 are functioning via a mammalian target of rapamycin (mTOR) pathway, which is essential in protein translation, cell proliferation and -growth. Inhibition of the mTOR-pathway has reduced kidney enlargement in rodent polycystic kidney disease models and has shown to reduce the volume of cysts in human polycystic kidney- and polycystic liver disease. Thus, we hypothesize that the mTOR inhibitor sirolimus, an immunosuppressant drug with strong anti-proliferative effects, will delay the progression of renal insufficiency in patients with ADPKD in advanced stages of the disease.

Before conducting a large multicenter randomized controlled trial in this population we will demonstrate that therapy with mTOR-I does not accelerate the decline in renal function (as natural course of the disease), as well as mTOR-I does not aggravate prevalent-, or cause new onset of proteinuria, as expressed by the protein/creatinine ratio, in patients with ADPKD and an eGFR between 20 and 40 mL/min per 1.73sqm, compared to a historic cohort of patients with ADPKD and an eGFR between 20 and 40 mL/min per 1.73sqm, treated at the Department of Medicine III, Division of Nephrology and Dialysis, Medical University Vienna.

Inclusion Criteria:

• ADPKD
• Eighteen years of age, or older.
• Baseline eGFR of 20-40mL/min per 1.73m2.
• Negative serum pregnancy test prior to administration of sirolimus and agreement to use contraception throughout the pilot safety study and three months after. Any participant who is getting pregnant during the pilot safety study period will have to discontinue.
• Written informed consent.

Exclusion Criteria:

• Pregnancy or lactation or plans to become pregnant in the near future or disagreement to use contraception.
• History of life threatening complications of ADPKD.
• Evidence of active systemic- or localized major infection.
• Evidence of infiltrate, cavities or consolidation on chest X-ray.
• Use of any investigational drug or -treatment up to 4 weeks prior to the enrolment and during the pilot safety study.
• Known hypersensitivity to sirolimus and its derivatives.
• Treatment with substances known to interfere with the cytochrome p-450 (CYP) 3A4/3A5 systems.
• Screening/baseline total white blood cell count below or equal to 3000/mm3.
• Screening/baseline platelet count below or equal to 100.000/mm3.
• Screening/baseline fasting triglycerides above or equal to 400 mg/dL.
• Screening/baseline fasting total cholesterol above or equal to 300 mg/dL.
• Concomitant glomerular diseases.
• Psychiatric disorders or any condition that might prevent the full comprehension of the purposes and risks of the pilot safety study.
• History of malignancies with the exception of adequately treated basal- and squamous-cell carcinomas of the skin.
• HIV infection.