Statins and the Urinary Proteome

Statin Induced Proteinuria Clinical Trial

Official title:

The Effect of Statins on the Urinary Proteome

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00464503
• Other study ID #: STAT-AZ-01
• Status: Completed
• Phase: N/A
• First received: April 20, 2007
• Last updated: April 3, 2008
• Start date: September 2007
• Est. completion date: October 2007

Study information

• Verified date: April 2008
• Source: Universiteit Antwerpen
• Contact: n/a
• Is FDA regulated: No
• Health authority: Belgium: The Federal Public Service (FPS) Health, Food Chain Safety and EnvironmentBelgium: Federal Agency for Medicines and Health Products, FAMHP
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 7
• Est. completion date: October 2007
• Est. primary completion date: October 2007
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 25 Years to 65 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Crossover Assignment, Masking: Double-Blind, Primary Purpose: Diagnostic

Related Conditions & MeSH terms

• Proteinuria
• Statin Induced Proteinuria

Intervention

Drug:
• Rosuvastatin-Crestor

• Pravastatin-Pravasine

Locations

Country	Name	City	State
Belgium	University of Antwerp	Antwerp

Sponsors (1)

Lead Sponsor	Collaborator
Universiteit Antwerpen

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The urinary protein pattern observed by difference gel electrophoresis based proteomics analysis in healthy subjects before and after the administration of rosuvastatin (Crestor®).
Secondary	The urinary protein pattern observed by difference gel electrophoresis based proteomics analysis in healthy subjects before and during the administration of pravastatin (Pravasine®).
Secondary	The urinary protein pattern observed by difference gel electrophoresis based proteomics analysis in healthy subjects during the administration of rosuvastatin (Crestor®) vs pravastatin (Pravasine®).
Secondary	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.
Secondary	The urinary albumin and retinol binding protein concentration before in healthy subjects, during and after administration of rosuvastatin (Crestor®) or pravastatin (Pravasine®).