1. PATHOGENESIS OF GLOMERULAR INJURY Dr; B_BASHARDOUST

2. NOMENCLATURE 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

3. Primary Mechanisms of Glomerular Injury Mechanism of Injury Some Renal Insults/DefectsGlomerular Disease ImmunologicImmunoglobulinImmune complex-mediated glomerulonephritis Cell-mediated injuryPauci-immune glomerulonephritis Cytokine (or other soluble factor)Primary focal segmental glomerulosclerosis Persistent complement activationMembranoproliferative glomerulonephritis (type II) MetabolicHyperglycemia Fabry's disease and sialidosis Diabetic nephropathy Focal segmental glomerulosclerosis HemodynamicSystemic hypertension Intraglomerular hypertension Hypertensive nephrosclerosis Secondary focal segmental glomerulosclerosis ToxicE. coli-derived verotoxin Therapeutic drugs (e.g., NSAIDs) Recreational drugs (heroin) Thrombotic microangiopathy Minimal change disease Focal segmental glomerulosclerosis DepositionAmyloid fibrilsAmyloid nephropathy InfectiousHIV Subacute bacterial endocarditis HIV nephropathy Immune complex glomerulonephritis InheritedDefect in gene for a5 chain of type IV collagenAlport's syndrome Abnormally thin basement membraneThin basement membrane disease

4. Correlation between Site of Glomerular Injury and Clinicopathologic Presentation Target of InjuryPhysiologic RoleResponse to InjuryRepresentative Glomerular Disease Endothelial cellMaintains 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 cellControls glomerular filtration surface area Proliferation/increased matrixMesangioproliferative GN/glomerulosclerosis Basement membranePrevents filtration of plasma proteins ProteinuriaMembranous nephropathy Visceral epithelial cellPrevents filtration of plasma proteins ProteinuriaMinimal change disease and FSGS Parietal epithelial cellMaintains Bowman's spaceCrescent formationCrescentic GN

5. IMMUNOLOGIC GLOMERULAR INJURY 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 antibody- dependent 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.

6. 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 antibody- mediated glomerular injury in patients without discernible immune complexes in the glomerular parenchyma

8. 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.