Basic Glomerular Pathogenesis

Overview
  • The pathogenesis of glomerular diseases can include a very wide gamut processes including hereditary, drug-induced, immune-mediated, infectious, and idiopathic causes. However, immune-mediated mechanisms of injury are especially important and are commonly seen in many glomerular diseases. Immune injury to the glomerulus can occur through several basic pathogenic sequences which are discussed below.
Pathogenic Sequences
  • Overview
    • Immune-mediated injury to the glomerulus typically arises from the deposition of antibodies within the glomerulus, a process which can occur via a variety of distinct mechanisms as described individually below. Whatever the mechanism, the presence of antibodies within the glomerulus results in a final common pathway of immune-mediated injury. Deposition of immunoglobulins activates complement, resulting in deposition of complement proteins. In some cases, deposited complement proteins perform the bulk of the damage, leading to impairment of the glomerular barrier. However, in other cases, activated complement proteins lead to recruitment of macrophages which then initiate damage of glomerular structures and in doing so impair the selectivity of glomerular filtration.
  • Preformed Immune Complex Deposition
    • Preformed, circulating immune complexes composed of particles of antibody bound to antigen can easily become trapped in the glomerulus either within the glomerular basement membrane or the mesangium. In essence, this is a renal manifestation of Type III Hypersensitivity. Immune complexes deposited within the glomerulus generally result in a granular pattern when immunoglobulin proteins are detected by immunofluorescence.
  • In Situ Immune Complex Formation
    • In this scenario, circulating antibodies react with clumps of antigen which were previously present within the Glomerular Basement Membrane (GBM). Therefore, the immune complex is formed 'in situ' (i.e. at its site of deposition) rather than having been preformed in the plasma. The clumps of antigen may be from circulating antigens that become trapped in the GBM; importantly, these antigens may be either from an endogenous source or in many some cases from viral proteins. Alternatively, antigenic clumps may represent proteins normally present in the GBM which possess a naturally clumpy distribution. In situ immune complexes will also result in a granular pattern when immunoglobulins are detected by immunofluorescence.
  • Anti-Glomerular Basement Membrane Antibody Deposition
    • In this scenario, a specific antibody develops that binds to a normal protein component of the GBM, in essence a form of Type II Hypersensitivity. Here, no immune complexes are present and instead the antibody diffusely deposits along the entire length of the GBM. Anti-GBM antibody deposition appears as a ribbon-like, linear band tracking the GBM upon imunofluorescent detection of immunoglobulin proteins. The prototypical disease involving this pathogenesis is Goodpasture Syndrome.