Glomerular disease

Glomerular disease

The glomerulus is an intricate structure, the function of which depends on all its constituent parts being intact (see Fig. 6.7).

1.     Blood reaches the glomerular capillary system via the afferent arteriole. On the vascular side of the barrier between the blood and the filtrate is endothe-lium, fused to the glomerular basement membrane (GBM). On the filtrate side is an epithelium composed of podocytes, attached to the GBM by foot processes. The connective tissue, which supports the capillary network, is called ‘mesangium’.

2.     The pressure in the glomerular capillaries is higher than that in the urinary lumen, so that constituents of the blood are filtered into the urinary lumen. This ‘ultrafiltrate’ is almost an exact mirror of plasma except for proteins because the GBM is relatively impermeable to high molecular weight proteins such as albumin. It is also less permeable to negatively charged molecules.

There are three main types of glomerular disease:

·        Glomerulonephritis describes a variety of conditions characterised by inflammation of glomeruli in both kidneys, which have an immunological basis.

·        Vasculitis which can mimic glomerulonephritis, by damage to the glomerular vessels.

·        Glomerular damage may also occur due to infiltration by abnormal material, such as by amyloid.

The type of damage caused to the structure of the glomerulus determines the pathological appearance, has a broad relationship to the effect on renal function and hence the clinical presentation. The disease process may be diffuse affecting all the glomeruli, or focal affecting only some of the glomeruli. Affected glomeruli may be completely damaged (global), or only a part may be damaged (segmental). Most glomerular diseases are either diffuse global or focal segmental.

Within the glomerulus itself, there are different appearances:

·        Proliferation of endothelial cells and mesangial cells is common in diseases that cause nephritic syndrome (see Fig. 6.8). Endothelial cell proliferation leads to occlusion of the capillary lumen, reduced blood flow, oliguria and acute renal failure. Mesangial cell proliferation, which is usually associated with increased production of mesangial matrix, can lead to scarring (sclerosis) of all or part of the glomerulus. Increased matrix can lead to reduced blood flow and/or proteinuria.

·        GBM thickening, which can be due to a number of mechanisms, tends to cause nephrotic syndrome, and can be due to a number of mechanisms (often coexistent) including deposition of immune complexes, oversynthesis of basement membrane material and ingrowth of mesangium.

·        More severe patterns may occur when the glomerular capillary walls are acutely and severely damaged.

·        Fibrinoid necrosis, where fibrin is deposited in the necrotic vessel walls. Crescents are formed when necrotic vessel walls leak blood and fibrin, so that macrophages and proliferating epithelial cells invade the Bowman’s space, crushing the glomerulus. If there are crescents in most of the glomeruli, the term rapidly progressive glomerulonephritis is used, as severe rapid onset acute renal failure usually results.

·        Almost all forms of glomerulonephritis have a cellular or humoral immunological basis:

·        Humoral response: Immune deposits (antibodies or antibody–antigen complexes) in the glomerulus fix and activate complement and a variety of other inflammatory mediators such as antioxidants, proteases and cytokines. The sites, number and type of deposits determine the type and extent of damage caused. Mesangial deposits cause mesangial cell proliferation and increased mesangial matrix. Subendothelial deposits are close to the glomerular capillary lumen, so excite marked inflammation which can lead to rapidly progressive glomerular nephritis, whereas subepithelial deposits excite less of an inflammatory response, because the glomerular basement membrane prevents the influx of cells from the capillaries. Circulating immune complexes filtered by the kidney tend to cause less injury than complexes formed de novo in the glomerulus.

·        Cellular response: Some glomerular diseases (such as minimal change nephropathy and focal segmental  glomerulosclerosis) show little or no antibody deposition. It appears that lymphocytes, in particular T cells play a role in causing the functional changes.

·        Macrophages: These may be involved in both humoral and cellular pathways.

Immunofluorescence and electron microscopy: The diagnosis of glomerular disease may not be possible with light microscopy only. Immunofluorescence is used to look for immune complex and C₃ and C₄ deposits and electron microscopy is also used.