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Understanding the Mechanisms of Proteinuria: Therapeutic Implications

DOI: 10.1155/2012/546039

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A large body of evidence indicates that proteinuria is a strong predictor of morbidity, a cause of inflammation, oxidative stress and progression of chronic kidney disease, and development of cardiovascular disease. The processes that lead to proteinuria are complex and involve factors such as glomerular hemodynamic, tubular absorption, and diffusion gradients. Alterations in various different molecular pathways and interactions may lead to the identical clinical end points of proteinuria and chronic kidney disease. Glomerular diseases include a wide range of immune and nonimmune insults that may target and thus damage some components of the glomerular filtration barrier. In many of these conditions, the renal visceral epithelial cell (podocyte) responds to injury along defined pathways, which may explain the resultant clinical and histological changes. The recent discovery of the molecular components of the slit diaphragm, specialized structure of podocyte-podocyte interaction, has been a major breakthrough in understanding the crucial role of the epithelial layer of the glomerular barrier and the pathogenesis of proteinuria. Thispaper provides an overview and update on the structure and function of the glomerular filtration barrier and the pathogenesis of proteinuria, highlighting the role of the podocyte in this setting. In addition, current antiproteinuric therapeutic approaches are briefly commented. 1. Introduction Proteinuria is considered a major healthcare problem that affects several hundred million people worldwide. In addition, proteinuria is a sensitive marker for progressive renal dysfunction and it is considered an independent risk factor for cardiovascular (CV) morbidity and mortality [1]. Furthermore, it is widely accepted that microalbuminuria (albumin urinary excretion of 30?mg–300?mg/day) is the earliest clue about the renal involvement of diabetes, obesity, and the metabolic syndrome. Interestingly, while microalbuminuria is more predictive of reaching CV end points than kidney end points, macroalbuminuria (total protein urinary excretion >500?mg/day) has been demonstrated to be more associated with reaching kidney end points [2]. However, microalbuminuria can often progress to overt proteinuria leading 10–50% of the patients to end-stage kidney disease development, ultimately requiring dialysis or transplantation. Of similar importance is the observation that even levels of albumin under the microalbuminuria threshold (so-called ‘‘high normal’’) are associated with an increased risk for CV outcomes [3]. Therefore, a reduction or


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