Statins and the Urinary Proteome

This study has been completed.
Sponsor:
Information provided by:
Universiteit Antwerpen
ClinicalTrials.gov Identifier:
NCT00464503
First received: April 20, 2007
Last updated: April 3, 2008
Last verified: April 2008
  Purpose

This study aims to investigate whether statines (rosuva- and pravastatin) induce tubular proteinuria.


Condition Intervention
Statin Induced Proteinuria
Drug: Rosuvastatin-Crestor
Drug: Pravastatin-Pravasine

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Crossover Assignment
Masking: Double-Blind
Primary Purpose: Diagnostic
Official Title: The Effect of Statins on the Urinary Proteome

Resource links provided by NLM:


Further study details as provided by Universiteit Antwerpen:

Primary Outcome Measures:
  • The urinary protein pattern observed by difference gel electrophoresis based proteomics analysis in healthy subjects before and after the administration of rosuvastatin (Crestor®).

Secondary Outcome Measures:
  • The urinary protein pattern observed by difference gel electrophoresis based proteomics analysis in healthy subjects before and during the administration of pravastatin (Pravasine®).
  • The urinary protein pattern observed by difference gel electrophoresis based proteomics analysis in healthy subjects during the administration of rosuvastatin (Crestor®) vs pravastatin (Pravasine®).
  • The urinary protein pattern observed by difference gel electrophoresis based proteomics analysis in healthy subjects during the administration of rosuvastatin (Crestor®) or pravastatin (Pravasine®) and after wash-out of these compounds.
  • The urinary albumin and retinol binding protein concentration before in healthy subjects, during and after administration of rosuvastatin (Crestor®) or pravastatin (Pravasine®).

Enrollment: 7
Study Start Date: September 2007
Study Completion Date: October 2007
Primary Completion Date: October 2007 (Final data collection date for primary outcome measure)
Detailed Description:

The proximal tubular cells of the kidney are responsible for reabsorption of proteins from the tubular lumen. In a study using Opossum kidney (OK) cells, receptor-mediated protein endocytosis was reduced by statins, inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, which are widely used for therapeutic reduction of plasma cholesterol levels (1). In a subsequent in vitro study protein endocytosis in human mixed proximal/distal kidney tubular cells was investigated in the presence and absence of statins to explore the possible clinical relevance of the observations in OK cells (2). The uptake of FITC-labeled albumin in these cultures occurred selectively into proximal tubular cells while it was absent in distal tubular/collecting duct cells. Three statins (simvastatin, pravastatin, and rosuvastatin) significantly inhibited the uptake of protein in a concentration-dependent way. This inhibitory effect of statins could be prevented by the co-addition of mevalonate, the product of HMG-CoA reductase. This effect was not the result of a statin-induced cytotoxicity since cell-viability was unaffected.

These data suggest that statins have the potential to inhibit albumin uptake by the human proximal nephron as a result of inhibition of HMG-CoA reductase in the proximal tubule cells. A reduced prenylation of some proteins critically involved in endocytosis has been put forward as the underlying mechanism.

Knowing these data it has been suggested that the occurrence of proteinuria in some patients treated with high statin doses is the result of a reduced tubular reabsorption/endocytosis of normally filtered proteins. To further explore the clinical relevance of such a mechanism, the composition of the urinary proteome under statin treatment will be investigated in normal healthy volunteers by two-dimensional gel electrophoresis based proteomics analysis.

  Eligibility

Ages Eligible for Study:   25 Years to 65 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Male, age range: 25 - 65 years
  • Non-smoker
  • Proteinuria: < 60 mg/24 hours
  • Dipstick negative hematuria
  • Bloodpressure: < 135 mm systolic, < 85 mm dyastolic
  • Waist circumference: < 94 cm

Exclusion Criteria:

  • Treatment with lipid-lowering drugs <1 year prior to the study
  • Known history of diabetes or fasting glucose level: < 110 mg/dl
  • Anti-hypertensive medication
  • Life-expectancy < 1 year
  • Pharmacological treatment with inotropes
  • Acute or chronic inflammatory process, use if anti-inflammatory drugs or immunosuppression
  • Clinically active malignant disease
  • Administration of any investigational drug within 30 days preceding study start and during the study
  • Known intolerance to rosuvastatin or other statins
  • Acute or chronic liver disease or ALAT>2.0 x upper limit of normal (ULN) at enrolment visit.
  • Chronic muscle disease such as dermatomyositis or polymyositis or unexplained creatinine kinase (CK) above 3 x ULN at enrolment.
  • Uncontrolled hypothyroidism as indicated by a thyroid stimulating hormone (TSH) > 2 x ULN at enrolment.
  • Renal insufficiency: creatinine > 2.0mg/dl
  • Known or suspect alcohol or drug abuse.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00464503

Locations
Belgium
University of Antwerp
Antwerp, Belgium, 2610
Sponsors and Collaborators
Universiteit Antwerpen
Investigators
Study Director: Patrick C D'Haese, Prof Universiteit Antwerpen
  More Information

No publications provided

ClinicalTrials.gov Identifier: NCT00464503     History of Changes
Other Study ID Numbers: STAT-AZ-01
Study First Received: April 20, 2007
Last Updated: April 3, 2008
Health Authority: Belgium: The Federal Public Service (FPS) Health, Food Chain Safety and Environment
Belgium: Federal Agency for Medicines and Health Products, FAMHP

Keywords provided by Universiteit Antwerpen:
statins
proteinuria
proteomic analysis
healthy volunteers

Additional relevant MeSH terms:
Proteinuria
Urination Disorders
Urologic Diseases
Urological Manifestations
Signs and Symptoms
Rosuvastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Enzyme Inhibitors
Lipid Regulating Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 18, 2014