Normally, the glomerular filtration system is highly permeable to water and small solutes and almost completely impermeable to molecules of the size and molecular charge of albumin (a 70,000-kDa protein). This selective permeability discriminates among protein molecules according to size (the larger, the less permeable), charge (the more cationic, the more permeable), and shape. Podocyte slit diaphragms are important diffusion barriers for plasma proteins, and podocytes are also largely responsible for synthesis of GBM components. Nephrin, a transmembrane glycoprotein, is the major component of the slit diaphragms between adjacent foot processes. The intracellular part of nephrin interacts with several cytoskeletal and signaling proteins (see
Fig. 14.1 ). Nephrin and its associated proteins, including podocin, have a crucial role in maintaining the selective permeability of the glomerular filtration barrier. This is dramatically illustrated by rare hereditary diseases in which mutations of nephrin or its partner proteins lead to abnormal leakage of plasma proteins into the urine and the nephrotic syndrome. As might be expected, acquired defects in podocytes and slit diaphragms, which are seen in a number of renal diseases, also are associated with proteinuria of varying severity.
Glomeruli may be injured by diverse mechanisms in the course of a number of systemic diseases (
Table 14.1 ). These are termed secondary glomerular diseases to differentiate them from those in which the kidney is the only or predominant organ involved. The latter constitute the various types of primary glomerular diseases, which are discussed later in this section. The glomerular alterations in systemic diseases are discussed elsewhere.
Immune mechanisms underlie most types of primary glomerular diseases and many of the secondary glomerular diseases. Under experimental conditions, GN can be readily induced by antibodies, and glomerular deposits of immunoglobulins, often with various components of complement, are found frequently in patients with GN. Two mechanisms of antibody deposition in the glomerulus have been established: (1) deposition of circulating antigen-antibody complexes in the glomerular capillary wall or mesangium, and (2) antibodies reacting in situ within the glomerulus, either with fixed (intrinsic) glomerular antigens or with extrinsic molecules that are planted in the glomerulus (
Fig. 14.3 ). These pathways are not mutually exclusive, and in humans all may contribute to injury. Abnormal activation and glomerular deposition of complement may be the sole culprit in some forms of GN. Cell-mediated immune mechanisms also may play a role in certain glomerular diseases.
Deposition of circulating immune complexes in the glomerulus initiates complement (and/or Fc receptor) mediated leukocyte activation, resulting in glomerular injury.
The pathogenesis of immune complex diseases is discussed in detail in Chapter 5. Presented here is a brief review of the salient features that relate to glomerular injury in GN.
In circulating immune complex–mediated diseases, the complexes may be formed with endogenous antigens, as in the GN associated with systemic lupus erythematosus, or the antigens may be exogenous, as is probable in the GN that follows certain bacterial (streptococcal), viral (hepatitis B), parasitic (Plasmodium falciparum malaria), and spirochetal (Treponema pallidum) infections. Often the inciting
Table 14.1 Glomerular Diseases
Glomerulopathies Secondary to Systemic Diseases
IgA, ImmunoglobulinA.
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