Mechanisms of Proteinuria

Introduction The current understanding of why protein appears in the urine in patients with renal diseases is based upon knowledge collected from observations dating back to past centuries, and up until our modern times of advanced scientific technology. The concepts which dominated during certain periods of time were built upon the current knowledge about renal physiology and the available experimental evidence, and because it was only indirect, also upon logical theoretical elaborations. From the evolution of these concepts we can see how technical advances can bring down established scientific theories and how inaccurate speculations about the cause for what has been observed can swing the whole scientific thinking into a wrong direction. We can also see how careful one should be when making such speculations. A critical review of the controversial evolution of human understanding of what today is termed “nephrotic syndrome” by Cameron and Hicks (1) emphasizes how young is the scientific concept that the kidneys are the diseased organs which lose endogenous protein by leaking it into the urine, thus causing a hypoproteinemic edematous state. It all started with Richard Bright’s (1789-1858) definition of the kidney as the cause of proteinuria and dropsy (generalized edema) who extended the idea of William Wells (1757-1817) that albumin in the urine was arising from blood plasma. Yet, even until the first quarter of the 20-th century it was believed that “’pure nephrosis’ was a systemic disorder which arose from a disturbance of protein synthesis”, while the abnormal protein was lost in the urine (“dyscratic proteinuria”) (1). The first experimental evidence that under normal conditions protein-free urine forms out of the glomeruli into the tubular lumen was demonstrated using micropuncture methods by Wearn and Richards in 1924 (1, 2) and soon after that confirmed by White and Schmitt (3). Further studies using this technique directly pointed at the glomerulus as the site of origin of albuminuria and thus finally it was understood that albuminuria was a result of disturbed function of the glomerular capillary wall, which normally acts as a filter rejecting albumin. Where exactly and how exactly the glomerular capillary filter rejects macromolecules is still a mystery today, with all the advances of modern science. It is now clear that the glomerular capillary wall is composed of three distinct layers: endothelium, basement membrane and epithelium. While the endothelium and the basement membrane can be found everywhere throughout the microvascular system, the epithelium is located only at the urinary aspect of glomerular capillary walls in the kidney. Role of the glomerular epithelium The glomerular epithelium consists of a single layer of specialized cells, podocytes, which connect to each other through interdigitations (foot processes). At the site of connection there is a highly organized structure, the slit diaphragm, which was first observed under electron microscopy by Rodewald and Karnovski (4). It is now known to be composed of several distinct proteins among which nephrin was isolated, its coding DNA sequenced and shown to be mutated in a hereditary disease of massive albuminuria, the Finnish type nephrotic syndrome (5). Since the pores of the slit diaphragm are about the size of an albumin molecule and since when the slit diaphragm is defective there is massive albuminuria, it is now assumed that the slit diaphragm is the site of rejection of macromolecules (6). Such assumption, however, can be made only if we ignore another possibility: that a defective slit diaphragm could just decrease the mechanical support at the urinary aspect of the glomerular capillary wall and thus render the basement membrane more prone to stretching, ruptures and protein leaking. The latter possibility, however, is not discussed by proponents of the slit diaphragm theory.