A major pathway of antibody-initiated glomerular injury involves complement activation and recruitment of leukocytes. Activation of complement via the classical pathway leads to the generation of chemotactic agents (mainly C5a) for neutrophils and monocytes. Neutrophils release proteases, which cause GBM degradation; oxygen-derived free radicals, which cause cell damage; and arachidonic acid metabolites, which contribute to reduction in GFR. In other types of GN in which neutrophils are not prominent, complement-dependent injury may occur through assembly of the C5b-C9 membrane attack complex. There is evidence that the membrane attack complex injures epithelial cells, inducing them to secrete various inflammatory mediators. The alternative and lectin pathways of complement can be activated by cell injury or apoptosis, and also perhaps by deposited IgA.
In addition to neutrophils and monocytes, which are recruited by antibodies and complement, T lymphocytes activated during the immune reaction also have been implicated in glomerular injury. Platelets may aggregate and release mediators, including prostaglandins. Resident glomerular cells (epithelial, mesangial, and endothelial) can be stimulated to secrete mediators such as cytokines (interleukin-1), arachidonic acid metabolites, growth factors, and nitric oxide.
Thus, virtually all of the mediators described in the discussion of inflammation in Chapter 3 may contribute to glomerular injury.
Non-immune Mechanisms of Glomerular Injury
Mechanisms other than inflammation contribute to glomerular abnormalities in certain primary renal disorders. Two that deserve special mention are podocyte injury and nephron loss.
Podocyte injury can be induced by antibodies to podocyte antigens; by toxins; conceivably by certain cytokines; or by still poorly characterized circulating factors, as in some cases of focal segmental glomerulosclerosis (discussed later). Podocyte injury produces morphologic changes including effacement of foot processes, vacuolization, and retraction and detachment of cells from the GBM, and often results in the development of proteinuria. Of these changes, it is the loss of normal slit diaphragms that is most highly associated with proteinuria. Germline mutations in the structural components of slit diaphragms, such as nephrin and podocin, also are associated with functional alterations that lead to rare hereditary forms of the nephrotic syndrome.
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Once renal disease, glomerular or otherwise, destroys sufficient nephrons to reduce the GFR to 30% to 50% of normal, symptoms appear and progression to end-stage renal disease proceeds at varying rates. Affected individuals have proteinuria, and their glomeruli show widespread scarring, called glomerulosclerosis. Such progressive sclerosis is exacerbated by adaptive changes that occur in response to the loss of nephrons. Specifically, intact glomeruli undergo hypertrophy to maintain renal function, an alteration that is associated with hemodynamic changes, including increases in single-nephron GFR, blood flow, and transcapillary pressure (capillary hypertension). These alterations are ultimately “maladaptive” and lead to further endothelial and podocyte injury, increased glomerular permeability to proteins, and accumulation of proteins and lipids in the mesangial matrix. This is followed by capillary obliteration, increased deposition of mesangial matrix and plasma proteins, and finally segmental (affecting a portion) or global (complete) sclerosis of glomeruli. The latter results in further reduction of nephron mass, initiating a vicious cycle of progressive glomerulosclerosis.
Theclinicalmanifestationsofrenaldiseaseincludenephroticsyndrome,nephriticsyndrome,asymptomatichematuria,rapidlyprogressiveglomerulonephritis,acutekidneyinjury,chronickidneydisease,andend-stagerenaldisease.