glomerular injury 20080318
TRANSCRIPT
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MECHANISMS OF
GLOMERULAR INJURY
Dr Meshach G Kirubakaran
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PATHOGENESIS OF
GLOMERULAR INJURY
IMMUNOLOGIC INJURY
NON-IMMUNOLOGIC INJURY
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PATHOGENESIS OF
GLOMERULAR INJURY
IMMUNOLOGIC INJURY
NON-IMMUNOLOGIC INJURY
HUMORAL
CELLULAR
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IMMUNOLOGIC INJURY
Characterised by Immune Depositsin the glomerulus.
HUMORAL MECHANISMS:
Results in functional and structural
changes
Functional:
- Proteinuria
- GFR
Structural:
- Hypercellularity
- Sclerosis- Necrosis
- Thrombosis
- Crescent formation
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IMMUNOLOGIC INJURY
Most GN are due to humoral
mechanism (immune deposits)
PSGNIgA Nephropathy
Anti-GBM antibody GN
Lupus Nephritis
Membranous Nephropathy
Membranoproliferative GN
HUMORAL (Contd.):
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IMMUNOLOGIC INJURY
The antibodies involved are often against:
HUMORAL (Contd.):
-Normal Glomerular constituents ±
IC formed in situ (eg Anti-GBM Ab¶s)
- Non-renal autoantigens ± IC¶s lodge in the
glomeruli because of the ± ve charge (eg SLE)
- Exogenous antigens which gets lodged in theglomeruli by passive trapping or local
precipitation (eg. Rheumatoid factor)
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IMMUNOLOGIC INJURY
The response to IC deposition
HUMORAL (Contd.):
Inflammatory
Response
Non-inflammatory
response
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Inflammatory response to IC deposition:
Complement Activation
Release of Cytokines
Chemo-attractants Release
Migration of inflammatory cells
(polymorphs, macrophages)
Proliferation of resident cells
Increased Matrix production
IMMUNOLOGIC INJURY: HUMORAL (Contd.)
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IMMUNOLOGIC INJURY
The response to IC deposition:
HUMORAL (Contd.):
Inflammatory
Response
Non-inflammatory
response
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Non-inflammatory response to ICdeposition:
Increased capillary permeability
± proteinuria and nephrotic
syndrome
IMMUNOLOGIC INJURY: HUMORAL (Contd.)
Increased matrix formation,
sclerosis
Reduced GFR
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IMMUNOLOGIC INJURY:
Factors influencing response to IC deposition:
HUMORAL (Contd.)
A. Site of deposition
Mesangial proliferation
Mesangial Matrix expansion
Change in phenotype
Mesangium
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IMMUNOLOGIC INJURY:
Factors influencing response to IC deposition:
HUMORAL (Contd.)
A. Site of deposition
Recruitment of circulating
macrophages & polymorphs by
chemotaxis and immune
adherence
Sub-endothelial
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IMMUNOLOGIC INJURY:
Factors influencing response to IC deposition:
HUMORAL (Contd.)
A. Site of deposition
Usually no inflammatory response
Non-inflammatory response ±
proteinuria, reduced GFR
Sub-epithelial
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IMMUNOLOGIC INJURY:
Factors influencing response to IC deposition:
HUMORAL (Contd.)
B. Biologic properties of
complex the immune
IgG1 and IgG3 ± Complement
fixing immunoglobulins ± hence
more severe inflammation
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IMMUNOLOGIC INJURY:
Factors influencing response to IC deposition:
HUMORAL (Contd.)
C. Mechanism of formation of
deposits
Locally formed IC¶s (as in anti-
GBM Ab) are more nephritogenic
than trapped IC¶s
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IMMUNOLOGIC INJURY:
Factors influencing response to IC deposition:
HUMORAL (Contd.)
D. The amount of immune
deposit formed
Larger amount of deposits
produce more severe
inflammatory response.
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IMMUNOLOGIC INJURY:
The injury is rarely due to theIC themselves
HUMORAL (Contd.)
It is mainly due to activation and
release of various inflammatorymediators such as:
Complement activation
Oxidants, proteasesreleased by the cells
Cytokines, growth factors
Vasoactive substances
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PATHOGENESIS OF
GLOMERULAR INJURY IMMUNOLOGIC INJURY
NON-IMMUNOLOGIC INJURY
HUMORALCELLULAR
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IMMUNOLOGIC INJURY
CELLULAR IMMUNE MECHANISMS
Related to T Cell activity
Circulating factors produced by T-
Cells account for the injury
Usually affect the podocytes
resulting in increased
permeability - Proteinuria,Nephrotic syndrome
Result in Minimal Change Disease,
Focal Segmental Sclerosis
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IMMUNOLOGIC INJURY
The glomerular response to immune
challenge and development of
glomerulonephritis is probablygenetically determined.
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PATHOGENESIS OF
GLOMERULAR INJURY IMMUNOLOGIC INJURY
NON-IMMUNOLOGIC INJURY
HUMORALCELLULAR
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NON-IMMUNOLOGIC INJURY
Crescentic GN in response tofibrin in the Bowman¶s space
COAGULATION FACTORS
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NON-IMMUNOLOGIC INJURY
Crescentic GN in response tofibrin in the Bowman¶s space
COAGULATION FACTORS
Endothelial damage due tointravascular coagulation -HUS, PET, TTP etc.
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NON-IMMUNOLOGIC INJURY
Increased permeability of capillary due to reduction in
anionic chargeCollection of macromolecules
in basement membrane
Thickening of BMAltered collagen metabolism
Nodular sclerosis
DIABETIC NEPHROPATHY
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NON-IMMUNOLOGIC INJURY
Hypertension, Atherosclerosis
Results in progressivesclerosis of the glomeruli
Role of Angiotensin II
Hypertrophy, Hyperplasia of intrinsic cells
Extracellular matrix production,
deposition and degradation
ISCHEAMIC GLOMERULOPATHY
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NON-IMMUNOLOGIC INJURY
AMYLOIDOSIS
MULTIPLE MYELOMA
DEPOSITION OF ABNORMALPROTEINS IN GLOMERULUS
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NON-IMMUNOLOGIC INJURY
ALPORT¶S SYNDROME
THIN MEMBRANE DISEASE
HEREDITARY NEPHROPATHIES
Due to deficiency or abnormal
compositon of basement membrane
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