PATHOGENESIS OF GLOMERULAR DISEASES---Practical

PATHOGENESIS OF GLOMERULAR DISEASES
Immune mechanisms (antibody-associated & cellular) underlie most primary and many secondary glomerular diseases.
Circulating Immune Complex-mediated Nephritis (type III hypersensitivity reactions) With circulating immune complex-mediated disease.
The antigen in these complexes may be::
1-Endogenous, as in SLE
2-Exogenous, as in bacterial (streptococcal), viral (hepatitis B), parasitic (Plasmodium falciparum malaria), and spirochetal (Treponema pallidum) infections.
3. Unknown as often the case in membranous nephropathy.
The antigen-antibody complexes are trapped in the glomeruli, where they produce injury, mainly through the activation of complement and the recruitment of leukocytes.
Electron microscopy reveals the immune complexes as electron-dense deposits or clumps that are:
1. Mesangial
.2 Subendothelial i.e. between the endothelial cells and the GBM.
3. Subepithelial i.e. at the outer surface of the GBM and the podocytes.
The presence of immunoglobulins and complement in these deposits can be demonstrated by immunofluorescence microscopy. When fluoresceinated antiimmunoglobulin or anti-complement antibodies are used, the immune complexes are seen as granular deposits in the glomerulus .
Cell-Mediated Immune Glomerulonephritis
T cell-mediated injury may account for some cases of glomerulonephritis (GN) in which either there are no deposits of antibodies or immune complexes, or the deposits do not correlate with the severity of damage.
Mediators of Immune Injury::
A major pathway of antibody-initiated injury is activation of the complement that leads to the generation of chemotactic agents (mainly C5a) and thus recruitment of neutrophils and monocytes.Neutrophils in turn release:
1. . Proteases, which cause GBM degradation
2. . Oxygen-derived free radicals, which cause cell damage
3. Arachidonic acid metabolites, which contribute to reduction in GFR.
In some cases, complement-dependent ,injury occurs through the effect of the C5-C9 lytic component (membrane attack complex) of complement, which causes:
1-Epithelial cell detachment .
2- Stimulation of mesangial and epithelial cells to secrete various mediators of cell injury.
3-Up-regulation of transforming growth factor-? (TGF-?) receptors on podocytes .
TGF-? stimulates synthesis of extracellular matrix, thus giving rise to altered GBM composition and thickening.
deposit in the mesangium because of their size. Most of these planted antigens induce a granular pattern of immunoglobulin deposition as seen by immunofluorescence microscopy.
Acute postinfectious (Poststreptococcal) GN
Its typically associated with streptococcal infection, other infectious agents may be responsible.
pneumococcal and staphylococcal infections , some common viral diseases such as mumps, measles, chickenpox, and hepatitis B and C. The classical case of poststreptococcal GN develops in a child 1 to 4 weeks after recovery from "nephritogenic" strains of ?-emolytic, group A streptococcal infection, usually of the pharynx or skin. Immune complex deposition is involved in the pathogenesis. The relevant antigens are probably streptococcal proteins. Serum complement levels are low and serum anti-streptolysin O antibody titers are elevated.
Morphology
• Its shows a uniformly increased cellularity of the glomerular tufts that affects nearly all glomeruli .
• This increased cellularity is caused both by proliferation and swelling of both endothelial and mesangial cells as well as by a neutrophilic and
• monocytic infiltrate. Electron microscopy shows subepithelial "humps".
Immunofluorescence
displays these immune complexes as scattered granular deposits of IgG and complement within the capillary walls. Recovery occurs in most children. But up to 50% of adults develop end-stage renal disease.
CHRONIC GLOMERULONEPHRITIS
Its one of the outcomes of the various glomerular diseases. It is an important cause of end-stage renal disease. Among all individuals who require chronic hemodialysis or renal transplantation, 30% to 50% have the diagnosis of chronic GN.
the glomerular changes are so advanced that it is difficult to detect the nature of the original lesion.
Classically, the kidneys are symmetrically contracted with red-brown surface.
Microscopically, The glomerular histology depends on the stage of the disease. In early cases, the glomeruli may still show evidence of the primary disease (e.g., membranous glomerulopathy or MPGN).
However, there eventually ensues hyaline obliteration of glomeruli, transforming them into acellular eosinophilic masses.
the feature common to all cases is advanced scarring of the glomeruli, reach the point of complete sclerosis .then progression to uremia and death.
The hyalin represents a combination of trapped plasma proteins, increased mesangial matrix, basement membrane-like material, and collagen) . Because hypertension is an accompaniment of chronic glomerulonephritis, arterial and arteriolar sclerosis may be evident, Marked atrophy of associated tubules,
irregular interstitial fibrosis, and mononuclear leukocytic infiltration of the interstitium also occur.