--- GLOMERULAR DISEASES --- Section 1: Classification & Histologic Patterns --- Classification of Glomerular Diseases Glomerular diseases are broadly divided in
--- GLOMERULAR DISEASES --- Section 1: Classification & Histologic Patterns --- Classification of Glomerular Diseases Glomerular diseases are broadly divided into three groups: 1. Primary Glomerulopathies — kidney is the principal organ involved - Acute proliferative glomerulonephritis (postinfectious and other) - Rapidly progressive (crescentic) glomerulonephritis - Membranous nephropathy - Minimal change disease - Focal segmental glomerulosclerosis (FSGS) - Membranoproliferative glomerulonephritis (MPGN) - Dense deposit disease - IgA nephropathy 2. Systemic Diseases with Glomerular Involvement - Systemic lupus erythematosus (SLE) - Diabetes mellitus - Amyloidosis - Goodpasture syndrome - Microscopic polyangiitis / Granulomatosis with polyangiitis - Henoch-Schönlein purpura 3. Hereditary Disorders - Alport syndrome - Thin basement membrane nephropathy - Fabry disease --- Histologic Distribution — Key Terms When a biopsy is reported, changes are described by their distribution: Term Meaning --- --- Diffuse All glomeruli in the kidney are involved Global The entire individual glomerulus is involved Focal Only a fraction of glomeruli are involved Segmental Only part of an individual glomerulus is affected Mesangial Changes predominantly in the mesangium Capillary loop Changes predominantly in the capillary loops Example: In focal segmental glomerulosclerosis — only some glomeruli are affected (focal), and within those, only part of the tuft is sclerosed (segmental). --- Four Basic Pathologic Responses to Glomerular Injury These are the fundamental tissue reactions seen across all glomerular diseases. 1. Hypercellularity An increase in cell number within the glomerular tuft. Occurs via: - Proliferation of mesangial or endothelial cells - Leukocyte infiltration — neutrophils, monocytes, lymphocytes - Endocapillary proliferation — combined leukocyte infiltration + swelling and proliferation of mesangial and/or endothelial cells - Crescent formation — the most severe form Crescents — important: - Composed of proliferating parietal glomerular epithelial cells + infiltrating leukocytes - Form in the urinary (Bowman's) space - Triggered by immune/inflammatory injury to capillary walls - Plasma proteins leak → tissue factor exposure → fibrin deposition → thrombin activation → crescent formation - Multiple proinflammatory cytokines recruit leukocytes into crescents - Hallmark of rapidly progressive GN (RPGN) 2. Basement Membrane Thickening Seen as thickened capillary walls on light microscopy — best visualized with PAS stain. Three mechanisms on electron microscopy: - Deposition of electron-dense material (immune complexes, fibrin, amyloid, cryoglobulins) on the endothelial or epithelial side, or within the GBM itself - Increased synthesis of basement membrane proteins — as in diabetic glomerulosclerosis - Duplication or additional layers of basement membrane matrix in subendothelial locations — as in MPGN 3. Hyalinosis - Accumulation of homogeneous, eosinophilic, extracellular material (hyalin) seen on light microscopy - Hyalin = plasma proteins that have leaked from the circulation into glomerular structures - When extensive, obliterates capillary lumens - Consequence of endothelial or capillary wall injury - Represents the end result of various forms of glomerular damage 4. Sclerosis - Deposition of extracellular collagenous matrix - May be confined to mesangial areas (e.g., diabetic glomerulosclerosis), involve capillary loops, or both - Can obliterate capillary lumens in affected glomeruli - Represents irreversible damage — the final common pathway of glomerular injury --- Clinical Syndromes — Overview Syndrome Key Manifestations --- --- Nephritic syndrome Haematuria, red cell casts, subnephrotic proteinuria, oliguria, oedema, hypertension, azotemia Rapidly progressive GN Acute nephritis + rapid loss of renal function over days to weeks Nephrotic syndrome Proteinuria 3.5 g/day, hypoalbuminemia, oedema, hyperlipidaemia, lipiduria Chronic kidney disease Azotemia progressing to uraemia over months to years Isolated urinary abnormalities Asymptomatic haematuria and/or subnephrotic proteinuria --- Progression of Glomerular Disease - Podocyte injury is a common final pathway across many glomerular diseases - Injury triggers a cycle: glomerular loss → compensatory hypertrophy of remaining nephrons → further injury → glomerulosclerosis → ESRD - Progressive glomerular injury is almost always accompanied by tubulointerstitial fibrosis --- Section 2: Pathogenesis of Glomerular Injury --- Overview Immune mechanisms underlie most primary glomerulopathies and many secondary glomerular disorders. The three main pathways are: 1. Antibody-mediated injury 2. Cell-mediated immune injury 3. Activation of the alternative complement pathway Cell-mediated immune reactions usually occur in concert with antibody-mediated events, not in isolation. --- A. In Situ Immune Complex Formation Antibodies react directly with antigens already present in or deposited within the glomerulus. 1. Fixed Intrinsic Tissue Antigens — normally part of the glomerulus - NC1 domain of type IV collagen — target in anti-GBM nephritis (Goodpasture syndrome) - PLA2R (phospholipase A2 receptor) on podocytes — main target in primary membranous nephropathy (~75% of cases) - THSD7A (thrombospondin type 1 domain containing 7A) — less common target in membranous nephropathy - Mesangial antigens 2. Planted Antigens — foreign antigens lodge in the glomerulus first, then antibodies form against them - Cationic molecules binding to anionic components of the GBM - DNA, nucleosomes, nuclear proteins (seen in SLE) - Bacterial products - Large aggregated proteins e.g. aggregated immunoglobulins - Exogenous antigens: infectious agents, drugs Immunofluorescence pattern: Granular — reflecting the localized, discrete nature of antigen-antibody interactions --- B. Circulating Immune Complex Deposition - Antigen-antibody complexes form in the circulation and are then trapped in the glomerulus - Antibodies have no immunologic specificity for glomerular constituents - Localization depends on physicochemical properties of the complexes and haemodynamic factors peculiar to the glomerulus Antigens involved: Endogenous: - DNA, nuclear antigens (SLE) - Tumour antigens - IgA (IgA nephropathy) Exogenous (infectious): - Streptococcal proteins - Hepatitis B surface antigen - Hepatitis C virus antigens - Treponema pallidum, Plasmodium falciparum - Various other viruses Important: A single agent can cause more than one pattern. Hepatitis B and C can cause either membranous GN (subepithelial in situ deposition) or MPGN (subendothelial/circulating complex deposition) depending on where the antigen-antibody interaction predominantly occurs. --- Anti-GBM Antibody Disease — Special Case - Antibodies target the NC1 domain of type IV collagen, uniformly distributed along the entire GBM - Immunofluorescence pattern: Linear — distinguishes it from all immune complex diseases - Accounts for less than 5% of human glomerulonephritis - Causes severe necrotizing and crescentic glomerular damage - Clinical presentation: RPGN - When combined with pulmonary haemorrhage: Goodpasture syndrome --- C. Cell-Mediated Immunity - T lymphocytes and macrophages cause glomerular injury independent of antibodies - Usually occurs alongside antibody-mediated events - Relevant in diseases where immune complex deposition alone cannot fully explain the injury — e.g., minimal change disease, some forms of FSGS --- D. Activation of the Alternative Complement Pathway - Occurs in dense deposit disease and C3 glomerulopathies - Characterized by: - Decreased serum C3 - Normal C1 and C4 (classical pathway not activated) - Decreased Factor B and properdin - Glomerular deposits of C3 and properdin but not IgG - Often driven by C3 nephritic factor (C3NeF) — an autoantibody that stabilizes the alternative pathway C3 convertase, causing uncontrolled C3 consumption (high-yield, frequ