Glomerular Injury 20080318

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MECHANISMS OF

GLOMERULAR INJURY

Dr Meshach G Kirubakaran

PATHOGENESIS OF

GLOMERULAR INJURY

IMMUNOLOGIC INJURY

NON-IMMUNOLOGIC INJURY

PATHOGENESIS OF

GLOMERULAR INJURY

IMMUNOLOGIC INJURY

HUMORAL

CELLULAR

IMMUNOLOGIC INJURY

Characterised by Immune Depositsin the glomerulus.

HUMORAL MECHANISMS:

Results in functional and structural

changes

Functional:

- Proteinuria

Structural:

- Hypercellularity

- Sclerosis- Necrosis

- Thrombosis

- Crescent formation

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.):

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)

IMMUNOLOGIC INJURY

The response to IC deposition

HUMORAL (Contd.):

Inflammatory

Response

Non-inflammatory

response

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.)

IMMUNOLOGIC INJURY

The response to IC deposition:

HUMORAL (Contd.):

Inflammatory

Response

Non-inflammatory

response

Non-inflammatory response to ICdeposition:

Increased capillary permeability

± proteinuria and nephrotic

syndrome

IMMUNOLOGIC INJURY: HUMORAL (Contd.)

Increased matrix formation,

sclerosis

Reduced GFR

IMMUNOLOGIC INJURY:

Factors influencing response to IC deposition:

HUMORAL (Contd.)

A. Site of deposition

Mesangial proliferation

Mesangial Matrix expansion

Change in phenotype

Mesangium

IMMUNOLOGIC INJURY:

HUMORAL (Contd.)

Recruitment of circulating

macrophages & polymorphs by

chemotaxis and immune

adherence

Sub-endothelial

IMMUNOLOGIC INJURY:

HUMORAL (Contd.)

Usually no inflammatory response

Non-inflammatory response ±

proteinuria, reduced GFR

Sub-epithelial

IMMUNOLOGIC INJURY:

HUMORAL (Contd.)

B. Biologic properties of

complex the immune

IgG1 and IgG3 ± Complement

fixing immunoglobulins ± hence

more severe inflammation

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

IMMUNOLOGIC INJURY:

HUMORAL (Contd.)

D. The amount of immune

deposit formed

Larger amount of deposits

produce more severe

inflammatory response.

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

PATHOGENESIS OF

GLOMERULAR INJURY IMMUNOLOGIC INJURY

HUMORALCELLULAR

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

IMMUNOLOGIC INJURY

The glomerular response to immune

challenge and development of

glomerulonephritis is probablygenetically determined.

PATHOGENESIS OF

GLOMERULAR INJURY IMMUNOLOGIC INJURY

HUMORALCELLULAR

Crescentic GN in response tofibrin in the Bowman¶s space

COAGULATION FACTORS

Crescentic GN in response tofibrin in the Bowman¶s space

COAGULATION FACTORS

Endothelial damage due tointravascular coagulation -HUS, PET, TTP etc.

Increased permeability of capillary due to reduction in

anionic chargeCollection of macromolecules

in basement membrane

Thickening of BMAltered collagen metabolism

Nodular sclerosis

DIABETIC NEPHROPATHY

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

AMYLOIDOSIS

MULTIPLE MYELOMA

DEPOSITION OF ABNORMALPROTEINS IN GLOMERULUS

ALPORT¶S SYNDROME

THIN MEMBRANE DISEASE

HEREDITARY NEPHROPATHIES

Due to deficiency or abnormal

compositon of basement membrane

Glomerular Injury 20080318

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