Polycystic Kidney Clinical Trial
— SIRENAOfficial title:
Sirolimus Treatment in Patients With ADPKD
Autosomal-Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary renal
disease, characterized by the progressive development of fluid-filled cysts in the kidney
leading to progressive loss of renal function and eventually to renal failure. It is
responsible for 8% to 10% of the cases of end stage renal disease (ESRD) in Western
countries. ADPKD progression is largely dependent on the development and growth of the cysts
and secondary disruption of the normal tissue. Renoprotective interventions in ADPKD - in
addition to achieve maximal reduction of arterial blood pressure and proteinuria and to
limit the effects of additional potential promoters of disease progression such as
dyslipidemia, chronic hyperglycemia or smoking - should also be specifically aimed to
correct the dysregulation of epithelial cell growth, secretion, and matrix interactions
characteristic of the disease. Genetically in the ADPKD three different genes are implicated
(PKD1 85% of the cases, PKD2 15% and probably PDK3 not yet identified). PKD1 gene encodes a
protein named polycystin-1 (PC1). Defect in PC1 lead to aberrant activation of the enzyme
mTOR in the epithelial cells of the renal tubules which eventually leads to abnormal
proliferation of these cells and cysts generation.
Sirolimus (Rapamycin) is an immunosuppressant mostly used for the management of kidney
transplant recipients. This drug by very specifically and effectively inhibiting mTOR,
exerts antiproliferative and growth inhibiting effects and could be extremely important for
the inhibition of cyst progression in ADPKD. Animal models of ADPKD have shown that
short-term treatment with sirolimus resulted in dramatic reduction of kidney size, prevented
the loss of kidney function, and lowered cyst volume density. Similarly, retrospective
observations from kidney transplant recipients have documented that sirolimus treatment
reduced kidney volumes by 25%, whereas there was no effect in patients not given the drug.
Overall, these findings provide the basis for designing a prospective study in ADPKD
patients aimed to document the efficacy of sirolimus treatment in preventing further
increase or even reducing the total kidney volume and the renal volume taken up by small
cysts, eventually halting kidney disease progression. It is a 6 month treatment with
sirolimus compared to conventional therapy in adult patients with ADPKD and normal renal
function or mild to moderate renal insufficiency.
Status | Completed |
Enrollment | 22 |
Est. completion date | August 2009 |
Est. primary completion date | July 2009 |
Accepts healthy volunteers | No |
Gender | Both |
Age group | 18 Years to 80 Years |
Eligibility |
Inclusion Criteria: - Age >18 years - Clinical and ultrasound diagnosis of ADPKD - GFR >40 ml/min/1.73 m2 (estimated by the 4 variable MDRD equation) - Urinary protein excretion rate = 0.5 g/ 24 hrs - Written informed consent Exclusion Criteria: - Diabetes - Urinary protein excretion rate >0.5 g/ 24 hrs or abnormal urinalysis suggestive of concomitant, clinically significant glomerular disease - Urinary tract lithiasis, infection or obstruction - Cancer - Psychiatric disorders and any condition that might prevent full comprehension of the purposes and risks of the study - Pregnancy, lactation or child bearing potential and ineffective contraception (estrogen therapy in post menopausal women should not be stopped) |
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment
Country | Name | City | State |
---|---|---|---|
Italy | Hospital "Azienda Ospedaliera Ospedali Riuniti di Bergamo" Unit of Neprology and Dialysis | Bergamo |
Lead Sponsor | Collaborator |
---|---|
Mario Negri Institute for Pharmacological Research |
Italy,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Total kidney volume (estimated by computed tomography, CT) in sirolimus and conventional treatment ADPKD groups during 6 month follow-up. | At 0,6 and 12 months. | Yes | |
Secondary | Renal cyst volume, renal parenchymal volume and renal intermediate volume. | At 0,6 and 12 months. | Yes |
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