glomerular injury 20080318

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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


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:


HUMORAL (Contd.)


Recruitment of circulating

macrophages & polymorphs by

chemotaxis and immune

adherence

Sub-endothelial



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IMMUNOLOGIC INJURY:


HUMORAL (Contd.)


Usually no inflammatory response

Non-inflammatory response ±

proteinuria, reduced GFR

Sub-epithelial



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IMMUNOLOGIC INJURY:


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:


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:


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


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


HUMORALCELLULAR



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Crescentic GN in response tofibrin in the Bowman¶s space

COAGULATION FACTORS



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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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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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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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AMYLOIDOSIS

MULTIPLE MYELOMA

DEPOSITION OF ABNORMALPROTEINS IN GLOMERULUS



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ALPORT¶S SYNDROME

THIN MEMBRANE DISEASE

HEREDITARY NEPHROPATHIES

Due to deficiency or abnormal

compositon of basement membrane

glomerular injury 20080318

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