immune-complex mediated glomerulonephritides

**Pathophysiology** - Mechanism: type III hypersensitivity. Circulating immune complexes deposit in the glomerulus, or antibodies bind in situ to fixed or planted antigens (e.g., PLA2R in primary membranous nephropathy). Complement activation (C3a, C5a) recruits neutrophils and monocytes, which injure the glomerular basement membrane (GBM), endothelium, and mesangium. - Location of deposits determines the clinical syndrome: - Subendothelial and/or mesangial deposits: nephritic picture (hematuria, RBC casts, HTN, oliguria, azotemia, mild-moderate proteinuria). - Subepithelial deposits (podocyte side): nephrotic picture (>3.5 g/day proteinuria, hypoalbuminemia, edema, hyperlipidemia, lipiduria). - Immunofluorescence: granular ("lumpy-bumpy") pattern of IgG, IgA, IgM, and/or C3. This contrasts with: - Linear IF: anti-GBM disease (Goodpasture), type II hypersensitivity. - Negative or "pauci-immune" IF: ANCA-associated GN (GPA, MPA, EGPA).

**Major entities (high-yield)** 1. **Post-infectious (poststreptococcal) GN** - Occurs 1–3 weeks after group A β-hemolytic strep pharyngitis (nephritogenic strains) or 2–4 weeks after skin infection. - Presents with nephritic syndrome, cola-colored urine, periorbital edema, and HTN. It is most common in children. - Labs: low C3 (normal C4, alternative pathway), elevated ASO/anti-DNase B. - LM: diffuse proliferative, with neutrophils. IF: granular. EM: subepithelial "humps." Usually self-limited in children (supportive care). 2. **IgA nephropathy (Berger disease)** - Most common GN worldwide. Presents with episodic gross hematuria 1–3 days after a mucosal (URI or GI) infection (synpharyngitic), unlike the 1–3 week latency of PSGN. - Pathogenesis: galactose-deficient IgA1 forms immune complexes that deposit in the mesangium. - Normal complement levels. IF: mesangial IgA (with C3). EM: mesangial deposits. - IgA vasculitis (Henoch-Schönlein purpura) is the systemic form: palpable purpura, arthralgias, abdominal pain, and GN. 3. **Lupus nephritis (SLE)** - ISN/RPS classes I–VI. Class IV (diffuse proliferative) is the most common and most severe. - Class V is membranous (nephrotic). - Low C3 and C4, anti-dsDNA, anti-Smith. "Full-house" IF (IgG, IgA, IgM, C3, C1q). EM: subendothelial deposits. LM: "wire-loop" lesions. - Treatment: steroids plus mycophenolate or cyclophosphamide. 4. **Membranous nephropathy** - Leading cause of nephrotic syndrome in adults (Caucasian adults). - Primary: anti-PLA2R antibodies (~70%). Secondary: HBV, HCV, syphilis, SLE (class V), malignancy, drugs (NSAIDs, penicillamine, gold). - LM: diffusely thickened GBM. Silver stain: "spike and dome." EM: subepithelial deposits. IF: granular. - Risk of renal vein thrombosis and other thromboembolic events. 5. **Membranoproliferative GN (MPGN)** - Presents with a mixed nephritic/nephrotic picture. LM: "tram-track" GBM splitting due to mesangial interposition. - Immune-complex type: chronic infections (HBV, HCV), cryoglobulinemia, autoimmune disease. Low C3 and C4 (classical pathway). - C3 glomerulopathy (dense deposit disease, C3GN) is complement-mediated rather than immune-complex mediated (C3 nephritic factor, alternative pathway). 6. **Cryoglobulinemic GN** - Associated with HCV. Presents with MPGN pattern, palpable purpura, arthralgias, and low C4 (± low C3). 7. **Others** - Infection-related GN: endocarditis (S. aureus), shunt nephritis, HBV-associated, HCV-associated. - Fibrillary GN and immunotactoid GN.

**Complement patterns (commonly tested)** - Low C3 only: PSGN (alternative pathway), C3 glomerulopathy. - Low C3 and C4: lupus nephritis, MPGN (immune-complex), cryoglobulinemia, endocarditis-associated GN. - Normal complement: IgA nephropathy, anti-GBM, ANCA vasculitis, membranous nephropathy (typically).

**Clinical approach** - UA with microscopy (dysmorphic RBCs, RBC casts), urine protein quantification, serologies (ANA, anti-dsDNA, complement, ASO, HBV/HCV, cryoglobulins, ANCA, anti-GBM), and renal biopsy (LM, IF, EM). - Treatment is directed at the underlying cause: supportive care (diuretics, BP control, ACEi/ARB for proteinuria), immunosuppression for lupus, severe IgA nephropathy, and primary membranous nephropathy (e.g., rituximab), and antivirals for HBV/HCV.

**Differentiating from non-immune-complex RPGN (crescentic GN)** - Type I: anti-GBM (linear IF). - Type II: immune-complex (granular IF), e.g., PSGN, lupus, IgA nephropathy. - Type III: pauci-immune (ANCA-associated). - Crescents (fibrin and parietal epithelial cells) are seen on LM in all types.