L2. Glomerular Injury Flashcards
What special feauture of the endothelium contributes to selectivity of capillary wall
Negatively charge glycocalyx –> selective barrier in filtration
What compose the glomerular capillary wall
- endothelium
- GBM
- Podocytes = epithelium
What kind of molecules (charge/size) move more effectively across the glomerular capillary wall
Smaller cations
What are the mechanisms of glomerular injury
- Podocyte injury
- Immune complex mediated subepithelial
- Immune complex mediated Subendothelial and mesangial
- Anti-GBM antibody mediated
- Progressive glomerulosclerosis
Podocyte injury is the etiologic factor of which disease(s)?
- Minimal change disease
- FSGS
Sequence of podocyte morphologic changes
Foot process effacement
Disruption of slit diaphragms
Vacuolization
Detachment from GBM
Protein leakage
FSGS Pathogenesis
Loss of nephrons –> compensatory hyperthropy of remaining glomeruli –> increased glomerular blood flow, filtration and glomerular hypertension –> endothelial cell and podocyte injury + increased glomerular permeability + mesangial cell proliferation and ECM production
Subepithelial deposits –> why is the glomerulus normocellular?
Immune complexes and activated complements are on the subepithelial side of the GBM = not in contact with circulating leukocytes and where resident glomerular cells usually do not proliferate
Why there is no acute inflammatory cellular response in subepithelila immune deposits
Because the subepithelial area is not in contact with circulating leukocytes = no inflammatory response, no cell proliferation/infiltration
Why subepithelial immune deposits lead to CHRONIC podocyte and GBM damage
Subepithelial immune deposits are away from circulation and thiusdeposits cannot be cleared effectively
What is the major targte antigen in membranous glomerulopathy
Phospholipase A2 receptor (PLA2R)
Explain the two mechanisms that exist in subendothelial/mesangial immune complexes deposition
(1) in situ mechanism where a circulating, often endogenous antigen, such as nucleosomes or IgA, becomes planted in subendothelial or mesangial regions (because of size or charge) and reacts with auto-antibodies.
(2) preformed circulating Ag-Ab complexes cannot pass thru GBM and localize in subendothelial or mesangial regions. These mechansims are not mutually exclusive.
Subendothelila deposits - Why is the glomerulus hypercellular?
The subendothelial (and mesangial) immune complexes have access to the circulation (no GBM barrier). Complement activation products C3a and C5a attract neutrophils and monocytes, which in turn, release cytokines which stimulate endothelial and mesangial cell proliferation.
Describe the pathogenesis of Anti-GBM antibody mediated injury
Auto-antibodies are directed against an intrinsic, fixed antigen in the GBM.
Since the antigen molecule (a3 chain of type IV collagen) is an integral component throughout the GBM, IF shows a linear pattern deposition of IgG.
Complement is activated and an intense inflammatory reaction leads to severe glomerular capillary wall damage
Why is there crescent formation in anti-GBM Ab injury?
The Ag-Ab immune complex formation within the GBM
activates complement and stimulates a cellular inflammatory response leading to severe capillary wall damage. Blood and fibrin spill into Bowman’s space and cause parietal epithelial cell proliferation and monocyte infiltration.
