Transcript PATHOGENESIS OF GLOMERULAR INJURY

PATHOGENESIS
OF GLOMERULAR
INJURY
Dr; B_BASHARDOUST
NOMENCLATURE
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Glomerulonephritis, Glomerulopathy
Focal, Diffuse
Segmental, Global
Proliferative intracapillary or endocapillary
A crescent is a half-moon-shaped collection of
cells in Bowman's space
Membranous
Sclerosis
Acute , Subacute, Chronic
Primary, Secondary
Primary Mechanisms of Glomerular Injury
Mechanism
of Injury
Some Renal Insults/Defects
Glomerular Disease
Immunologic
Immunoglobulin
Immune complex-mediated
glomerulonephritis
Cell-mediated injury
Pauci-immune glomerulonephritis
Cytokine (or other soluble factor)
Primary focal segmental
glomerulosclerosis
Persistent complement activation
Membranoproliferative glomerulonephritis
(type II)
Metabolic
Hyperglycemia
Fabry's disease and sialidosis
Diabetic nephropathy
Focal segmental glomerulosclerosis
Hemodynamic
Systemic hypertension
Intraglomerular hypertension
Hypertensive nephrosclerosis
Secondary focal segmental
glomerulosclerosis
Toxic
E. coli-derived verotoxin
Therapeutic drugs (e.g., NSAIDs)
Recreational drugs (heroin)
Thrombotic microangiopathy
Minimal change disease
Focal segmental glomerulosclerosis
Deposition
Amyloid fibrils
Amyloid nephropathy
Infectious
HIV
Subacute bacterial endocarditis
HIV nephropathy
Immune complex glomerulonephritis
Inherited
Defect in gene for a5 chain of type IV collagen
Alport's syndrome
Abnormally thin basement membrane
Thin basement membrane disease
Correlation between Site of Glomerular Injury and
Clinicopathologic Presentation
Target of Injury
Physiologic Role
Response to Injury
Representative
Glomerular Disease
Endothelial cell
Maintains glomerular
perfusion
Prevents leukocyte adhesion
Prevents platelet aggregation
and clotting
Vasoconstriction
Leukocyte infiltration
Intravascular microthrombi
Acute renal failure
Focal or diffuse proliferative
GN
Thrombotic microangiopathies
Mesangial cell
Controls glomerular filtration
surface area
Proliferation/increased matrix
Mesangioproliferative
GN/glomerulosclerosis
Basement membrane
Prevents filtration of plasma
proteins
Proteinuria
Membranous nephropathy
Visceral epithelial cell
Prevents filtration of plasma
proteins
Proteinuria
Minimal change disease and
FSGS
Parietal epithelial cell
Maintains Bowman's space
Crescent formation
Crescentic GN
IMMUNOLOGIC GLOMERULAR INJURY
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Deposition of antibodies, often autoantibodies, within the
glomerular tuft, indicating dysregulation of humoral
immunity.
Cellular immune mechanisms also contribute to the
pathogenesis of antibody-mediated glomerulonephritis
by modulating antibody production and through antibodydependent cell cytotoxicity
Cellular immune mechanisms probably play a primary
role in the pathophysiology of "pauci-immune"
glomerulonephritides, notable glomerular inflammation in
the absence of immunoglobulin deposition.
ANTIBODY-MEDIATED INJURY
Reactivity of circulating antibodies with auto- or "planted" antigens
within the glomerulus.
Mechanisms
 (1) reactivity of circulating autoantibodies with intrinsic autoantigens
that are components of normal glomerular parenchyma
 (2) in situ formation of immune complexes through interaction of
circulating antibodies with extrinsic antigens that have been planted
within the glomerulus
 (3) intraglomerular trapping of immune complexes that have formed
in the systemic circulation.
 Autoantibodies against neutrophil cytoplasmic antigens in the
circulation may represent an additional mechanism of antibodymediated glomerular injury in patients without discernible immune
complexes in the glomerular parenchyma
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Generation of Nephritogenic
Antibodies
 Exposure of the host to a foreign antigen
Foreign antigens can provoke autoantibody
formation through several mechanisms.
 First, a foreign antigen, whose structure resembles that
of a host glomerular antigen, may stimulate the
production of autoantibodies that cross-react with the
intrinsic glomerular antigen
 Second, the foreign antigen may trigger aberrant
expression of major histocompatibility complex class II
molecules on glomerular cells which present previously
"invisible" autoantigens to T lymphocytes and thereby
generate an autoimmune response.
 Third, the foreign antigen can trigger polyclonal
activation of B lymphocytes, some of which generate
nephritogenic antibodies.