Clinical Note

Glomerular Diseases

Glomerular diseases are the primary cause of chronic renal failure that often progresses, either rapidly or more typically over 10-20 years or more, to end-stage renal disease (ESRD). ESRD is defined by a sufficient reduction of GFR (usually to <10% of normal) such that dialysis or kidney transplantation is required to maintain life. The glomerular filtration barrier is the site of primary pathology, which is usually often produced or exacerbated by the immune system. Immune damage can be due either to an abnormal reaction against the normal components of the glomerular filtration barrier, so-called autoimmune disease, or to the deposition of immune complexes against exogenous antigens. Because of the rapid rate of blood flow through the glomerular capillaries, the relatively permeable architecture of the endothelial cells, and the high rate of ultrafiltration, glomerular cells and the basement membrane are particularly susceptible to leukocyte infiltration, and the accumulation of immunoglobulins and immune complexes. The hallmark of glomerular damage is the presence of significant amounts of protein in the urine (proteinuria), which indicates failure of the filtration barrier.

Often the pattern of damage is not one of acute inflammation, and there may be histolo-gical evidence only of immunoglobulins trapped in the endothelial and basement membrane layers, with no cell proliferation. Early in such disease, there is often little evidence of glomerular capillary damage. This pattern is typical of the nephrotic syndrome. In some cases, the patient is asymptomatic, and the disease is first revealed only by proteinuria in a routine urine sample. More often, the disease is characterized by marked edema due to the loss of plasma proteins and renal salt retention. However, early in the course of the nephrotic syndrome, RBF and GFR can be normal and there is no uremia.

In contrast, the more prevalent glomerular disease, glomerulonephritis, is characterized by mild to severe proteinuria, with the presence of red and white blood cells, and epithelial cell casts in the urine. These are signs of an active inflammatory process in the glomeruli that is accompanied by proliferation of inflammatory cells among the endothelial, mesangial, and epithelial cells, and often within Bowman's space. Glomerulonephritis may occur acutely, for example, as the result of immune complex deposition after a streptococcal infection, or in a slow and patchy fashion. However, the GFR is usually reduced from the outset because of the closure of glomerular capillary loops by immune cells.

Both the nephrotic and nephritic forms of glomerular disease usually progress with destruction of the glomeruli by fibrotic infiltration, called glomerulosclerosis, resulting in a progressive decline in the number of functioning nephrons and hence in the RBF and GFR.

FIGURE 7 Electron micrograph of the filtration barrier. The blood space of the capillary lumen is separated from the ultrafiltrate in Bowman's space by three layers: the endothelial cell layer of the capillary (En), the glomerular basement membrane (B), and the visceral epithelial layer of Bowman's capsule (Ep). The cells in this epithelial layer (Ep) are characterized by the foot processes (podocytes) that lie against the basement membrane (B). A portion of a red blood cell (RBC) is seen in the lower right-hand corner of the micrograph surrounded by blood plasma (Pl). The plasma contains significant amounts of protein, as indicated by the diffuse, electron-dense, granular regions. In contrast, the ultrafiltrate (FI) seen in Bowman's space contains no electron-dense material. The scale bar is 0.5 mm in length; magnification is 54,000x. (Electron micrograph courtesy of Dr. Dale R. Abrahamson, University of Kansas Medical Center, Kansas City, KS.)

FIGURE 7 Electron micrograph of the filtration barrier. The blood space of the capillary lumen is separated from the ultrafiltrate in Bowman's space by three layers: the endothelial cell layer of the capillary (En), the glomerular basement membrane (B), and the visceral epithelial layer of Bowman's capsule (Ep). The cells in this epithelial layer (Ep) are characterized by the foot processes (podocytes) that lie against the basement membrane (B). A portion of a red blood cell (RBC) is seen in the lower right-hand corner of the micrograph surrounded by blood plasma (Pl). The plasma contains significant amounts of protein, as indicated by the diffuse, electron-dense, granular regions. In contrast, the ultrafiltrate (FI) seen in Bowman's space contains no electron-dense material. The scale bar is 0.5 mm in length; magnification is 54,000x. (Electron micrograph courtesy of Dr. Dale R. Abrahamson, University of Kansas Medical Center, Kansas City, KS.)

glomerular capillaries, much like the liver, has fenestra-tions occupying nearly 10% of its surface area that allow plasma proteins to reach the basement membrane. on the other side of the basement membrane, the plasma membrane of the epithelial cells is folded intricately into so-called foot processes or podocytes (shown in cross section in Fig. 7) where they contact the basement membrane.

Although good evidence suggests that damage to the basement membrane can lead to proteinuria, recent studies of the congenital nephrotic syndrome have provided evidence that the podocyte layer is at least of equal importance. In contrast to the usual forms of glomerular pathology discussed in the Clinical Note on glomerular diseases, the congenital nephrotic syndrome is an autosomal recessive disorder that is characterized by severe proteinuria, which begins at birth with no underlying immune damage. Although this disorder is relatively rare worldwide, in Finland it has an incidence of 1 in 8000, and it is associated the usual morbidity and mortality associated with rapidly progressive glomerulonephritis. Recently, the gene defect responsible for the congenital nephrotic syndrome has been identified. The gene encodes a protein, named nephrin, which is truncated by a mutation in affected individuals. Nephrin is a member of an immunoglobulin family that is involved in cell adhesion and it is found exclusively in the junctional complexes between glomerular epithelial cells in the region of the podocyte layer. Thus, it appears that an abnormality in a single protein results in sufficient disruption of the cell-to-cell contacts in the epithelial layer to allow substantial protein filtration.

The thickness of the glomerular basement membrane (about 50 nm) is considerably more than that of other capillaries, because this basement membrane is formed by a merging of the capillary and epithelial basement membranes during development. Like all basement membranes, the glomerular basement membrane is a gel-like structure formed from collagenous and noncol-lagenous glycoproteins called proteoglycans. Laminin is one of the more important of these proteoglycans in the glomerular basement membrane. The proteoglycans have a net negative charge because of their sialic and dicarboxylic amino acids. Podocyte membranes also have a high density of negative charge due to the presence of other glycoproteins and, together with the basement membrane, they electrostatically repel negatively charged plasma proteins. Therefore, the ability of macromolecules to permeate the filtration barrier is determined by their size and their valence. These two factors have been well demonstrated by experiments in humans and animals in which the excretion of test macromolecules has been measured as shown in Fig. 8. These test substances have included synthetic polymers

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