Pathogenic Mechanisms - Mechanism of Injury



In most glomerular diseases, in which the kid­ney is the primary focus of the disease process,injury is believed to occur through immunological processes. The primary indicator of this associa­tion comes from the regular finding by immuno-fluorescent staining of immune reactants (IgG, IgM, IgA, C3, or C4) within the glomeruli .

Complement can be activated through the bind­ing of antigen by specific antibody (IgG or IgM). Three modes of antigen-antibody interaction have been described for the activation of complement within the glomerulus. Circulating immune com­plexes (CIC) form within the circulation and may be trapped in the glomerular capillary wall during ultrafiltration. In situ immune complex formation takes place when circulating free antigen lodges within the glomerulus and antibody subsequently binds to the trapped antigen. Finally, antirenal antibody (specifically, anti-glomerular basement membrane antibody) may form, bind to an ele­ment of the glomerulus, and activate injury path­ways.

Complement activation via the classic pathway is inferred from the presence of IgG or IgM plus C4 and C3 within glomeruli. The presence of C3, sometimes with properdin, but the absence of C4 and IgG or IgM indicates alternate pathway com­plement activation within glomeruli.

Attraction of polymorphonuclear leukocytes (PMN’s) appears to be the most direct conse­quence of immune complex complement activa­tion. However, injury does occur in a number of glomerular diseases associated with immune de­posits in which PMN infiltration is minimal or absent. Moreover, in some common human glo­merulopathies, immune reactants are absent. The mode of glomerular injury and/or dysfunction in these instances is uncertain. Glomerular injury in diseases such as diabetes mellitus and amyloi­dosis likely proceeds from a metabolic etiology. Finally, hemodynamic insults to the glomerular capillary bed may lead to glomerular necrosis, as in the case of severe hypertension, or sclerosis, as with sustained glomerular hyperfiltration.