Clinical Trial: Sirolimus In Autosomal Dominant Polycystic Kidney Disease And Severe Renal Insufficiency

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: EFFECTS OF SIROLIMUS ON DISEASE PROGRESSION IN PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE AND SEVERE RENAL INSUFFICIENCY

Brief Summary: The general aim of this study in adult patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) and severe renal insufficiency is to assess the safety and the efficacy of sirolimus (SRL) in slowing renal function decline as compared to conventional therapy.

Detailed Summary:

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary renal disease, responsible for the 8% to 10% of the cases of end-stage renal disease (ESRD) in Western Countries.

ADPKD shows genetic heterogeneity, with at least three different genes implicated: the PKD1 gene (85% of the cases), the PKD2 (15% of the cases), and probably a PDK3 gene not yet identified. Recently, it has been reported that PC1 tail interacts with tuberin, the product of the TSC2 gene. The main function of the tuberin is to inactivate the Ser/Thr kinase mTOR, whose activity has been linked to increased cell growth, proliferation, apoptosis and differentiation. In ADPKD experimental animal models, researchers have shown that cyst lining epithelial cells exhibited very high mTOR activity; thus, they hypothesized that PC1 normally suppresses mTOR activity, and that defects in PC1 (and other proteins) may lead to aberrant mTOR activation. Studies in rat models of ADPKD have shown that short-term treatment with sirolimus (SRL) resulted in the dramatic reduction of the kidney size.

Recently we have documented that in ADPKD patients with normal kidney function or moderate renal dysfunction a short-course of SRL halted cyst growth and increased parenchyma volume. At this effective SRL dose (target trough blood level 5-10 ng/ml) the only relevant adverse effect observed in some patients was the development of aphthous stomatitis, relieved with topical treatment alone using a mouthwash.

Interestingly a retrospective study in a small number of SRL-treated ADPKD transplant patients showed that the treatment significantly reduced native kidney volumes over an average of 24 month follow-up. This reduction was three times higher than that reported in a control group of ADPKD transplant recipi
Sponsor: Mario Negri Institute for Pharmacological Research

Current Primary Outcome:

  • Glomerular Filtration Rate (GFR) [ Time Frame: At baseline. ]
    To compare changes over baseline of GFR (delta GFR) measured by plasma iohexol clearance in SRL and conventional treatment ADPKD patients.
  • Glomerular Filtration Rate (GFR) [ Time Frame: At 12th month . ]
    To compare changes over baseline of GFR (delta GFR) measured by plasma iohexol clearance in SRL and conventional treatment ADPKD patients.
  • Glomerular Filtration Rate (GFR) [ Time Frame: After six months from baseline. ]
    To compare changes over baseline of GFR (delta GFR) measured by plasma iohexol clearance in SRL and conventional treatment ADPKD patients.
  • Glomerular Filtration Rate (GFR) [ Time Frame: Every 12 months. ]
    To compare changes over baseline of GFR (delta GFR) measured by plasma iohexol clearance in SRL and conventional treatment ADPKD patients.


Original Primary Outcome:

  • Glomerular Filtration Rate (GFR) [ Time Frame: At baseline and after six months. ]
    To compare changes over baseline of GFR (delta GFR) measured by plasma iohexol clearance in SRL and conventional treatment ADPKD patients.
  • Glomerular Filtration Rate (GFR) [ Time Frame: From 12th month and every 12 months.. ]
    To compare changes over baseline of GFR (delta GFR) measured by plasma iohexol clearance in SRL and conventional treatment ADPKD patients.


Current Secondary Outcome:

  • Liver volume parameters. [ Time Frame: At baseline. ]
    To compare absolute and relative changes over baseline of liver volume parameters, assessed by contrast-enhanced spiral computed tomography, in SRL and conventional treatment ADPKD patients.
  • Renal volume parameters. [ Time Frame: At baseline. ]
    To compare absolute and relative changes over baseline of renal volume parameters, assessed by contrast-enhanced spiral computed tomography, in SRL and conventional treatment ADPKD patients.
  • Liver volume parameters. [ Time Frame: At 12 month. ]
    To compare absolute and relative changes over baseline of liver volume parameters, assessed by contrast-enhanced spiral computed tomography, in SRL and conventional treatment ADPKD patients.
  • Liver volume parameters. [ Time Frame: At 36 month. ]
    To compare absolute and relative changes over baseline of liver volume parameters, assessed by contrast-enhanced spiral computed tomography, in SRL and conventional treatment ADPKD patients.
  • Renal volume parameters. [ Time Frame: At 12 month. ]
    To compare absolute and relative changes over baseline of renal volume parameters, assessed by contrast-enhanced spiral computed tomography, in SRL and conventional treatment ADPKD patients.
  • Renal volume parameters. [ Time Frame: At 36 month. ]
    To compare absolute and relative changes over baseline of renal volume parameters, assessed by contrast-enhanced spiral computed tomography, in SRL and conventional treatment ADPKD patients.


Original Secondary Outcome: Same as current

Information By: Mario Negri Institute for Pharmacological Research

Dates:
Date Received: October 12, 2010
Date Started: September 2010
Date Completion:
Last Updated: February 22, 2013
Last Verified: February 2013