immune-complex mediated glomerulonephritis

**Pathophysiology** - Type III hypersensitivity: circulating antigen-antibody complexes deposit in glomeruli (or antibody binds an in situ/planted antigen). The complexes activate the classical complement pathway (C3a, C5a, MAC), recruit neutrophils and monocytes, and cause endothelial, mesangial, and podocyte injury. - The location of deposits determines the clinical syndrome: - **Subendothelial and mesangial** deposits are close to the blood, so they produce a **nephritic** picture (hematuria, RBC casts, HTN, oliguria, azotemia) with proliferation and inflammation. - **Subepithelial** deposits are on the podocyte side of the GBM. Large deposits (PSGN) produce a nephritic picture. Deposits with little inflammatory cell access (membranous) produce a **nephrotic** picture (proteinuria >3.5 g/day, hypoalbuminemia, edema, hyperlipidemia, lipiduria). - Diagnosis: renal biopsy shows **granular ("lumpy-bumpy") immunofluorescence** (IgG, IgM, IgA, C3). This contrasts with linear IF in anti-GBM disease (type II hypersensitivity) and with negative or "pauci-immune" IF in ANCA vasculitis.

**Key entities (high-yield)** - **Post-streptococcal GN (PSGN):** Occurs 1–3 weeks after group A β-hemolytic strep pharyngitis (nephritogenic strains, e.g., M12) or 3–6 weeks after skin infection (impetigo). It affects children and causes cola-colored urine, periorbital edema, HTN, and **low C3** (normal C4, alternative pathway activation). ASO and anti-DNase B titers are elevated. LM shows diffuse proliferative GN. EM shows **subepithelial "humps"**. IF shows granular IgG/C3. Treatment is supportive, and most children recover fully. - **Lupus nephritis:** Anti-dsDNA immune complexes cause **low C3 and C4**. The most severe form is class IV (diffuse proliferative), which shows **"wire-loop" lesions** (subendothelial deposits) and a **"full-house"** IF pattern (IgG, IgA, IgM, C3, C1q). Class V is membranous and presents as nephrotic syndrome. - **IgA nephropathy (Berger disease):** The most common GN worldwide. Gross hematuria occurs **1–3 days** after a mucosal (URI/GI) infection. IF shows mesangial IgA deposits. Complement is normal. It is related to Henoch-Schönlein purpura (IgA vasculitis). - **Membranous nephropathy:** The most common cause of nephrotic syndrome in white adults. It is primary (anti-**PLA2R**, anti-THSD7A) or secondary (HBV, HCV, SLE, solid tumors, NSAIDs, penicillamine, gold). LM shows diffuse GBM thickening. EM shows subepithelial deposits with a **"spike and dome"** appearance (silver stain). It carries a risk of **renal vein thrombosis**. - **MPGN (membranoproliferative GN):** Presents as mixed nephritic and nephrotic disease. EM shows **"tram-track"** GBM splitting. Type I is subendothelial and associated with **HCV, cryoglobulinemia**, and chronic infections. Complement-mediated (C3 glomerulopathy) forms, including dense deposit disease with C3 nephritic factor, involve the alternative pathway. Complement is low. - **Cryoglobulinemic GN:** Associated with HCV. Presents with palpable purpura, arthralgias, and low C4. - **Infection-associated GN:** Includes endocarditis, shunt nephritis, and hepatitis B (PAN or membranous).

**Clinical pearls** - **Low complement** with GN suggests: PSGN (low C3), lupus (low C3 and C4), MPGN/C3 glomerulopathy, cryoglobulinemia, and endocarditis-associated GN. **Normal complement** suggests: IgA nephropathy, anti-GBM, ANCA vasculitis. - Treatment depends on the cause: supportive care for PSGN; steroids plus cyclophosphamide, mycophenolate, or other immunosuppression for lupus class III/IV; ACE inhibitors/ARBs and BP control for proteinuria; and antiviral therapy for HCV/HBV-related disease. - Compare with other mechanisms: **anti-GBM (Goodpasture)** is type II hypersensitivity with linear IF and anti-α3 chain of type IV collagen. **Pauci-immune** GN (GPA, MPA, EGPA) is ANCA-associated with minimal immune deposits.