Statins and the Urinary Proteome

Universiteit Antwerpen

Status

Completed

Conditions

Statin Induced Proteinuria

Treatments

Drug: Pravastatin-Pravasine

Drug: Rosuvastatin-Crestor

Study type

Interventional

Funder types

Other

Identifiers

NCT00464503

STAT-AZ-01

Details and patient eligibility

About

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

Full 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.

Enrollment

7 patients

Sex

Male

Ages

25 to 65 years old

Volunteers

Accepts Healthy Volunteers

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.