Statin Induced Proteinuria Clinical Trial
Official title:
The Effect of Statins on the Urinary Proteome
This study aims to investigate whether statines (rosuva- and pravastatin) induce tubular proteinuria.
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.
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Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Crossover Assignment, Masking: Double-Blind, Primary Purpose: Diagnostic