Glomerulonephritis: Immune and Non-Immune Mechanisms

Core Idea

Glomerulonephritis involves immune-mediated glomerular injury via in situ complex deposition, circulating immune complex trapping, or anti-glomerular basement membrane antibodies. Non-immune forms include hemolytic uremic syndrome and thrombotic microangiopathy.

How It's Best Learned

Classify by serology and morphology: ANCA-associated (pauci-immune), post-streptococcal (subepithelial bumps), lupus (multiple patterns), IgA disease. Use immunofluorescence findings to distinguish pathways.

Common Misconceptions

Hematuria with dysmorphic RBCs and casts indicates glomerular injury, not lower UTI. Nephritic versus nephrotic presentation reflects glomerular permeability and inflammation severity, not necessarily different diseases.

Explainer

The glomerulus is a specialized capillary tuft that filters roughly 180 liters of plasma per day while retaining proteins and cells. From your study of GFR, you understand that this remarkable barrier depends on three layers — fenestrated endothelium, glomerular basement membrane (GBM), and podocyte foot processes — whose integrity requires the immune system to tolerate rather than attack them. Glomerulonephritis occurs when this tolerance breaks down and immune mechanisms target the glomerular capillary wall, disrupting filtration and allowing proteins and red blood cells to enter the urine.

The immune mechanisms fall into three distinct patterns, each identifiable by immunofluorescence and electron microscopy of a renal biopsy. The first is in situ immune complex formation: circulating antibodies bind directly to antigens in or on the GBM itself. The clearest example is Goodpasture syndrome, where antibodies target type IV collagen in the GBM, producing a *linear* immunofluorescence pattern (antibodies coating the entire GBM uniformly) and triggering complement activation that causes rapidly progressive nephritis — often with simultaneous pulmonary hemorrhage, since type IV collagen also lines alveolar basement membranes. The second pattern is circulating immune complex trapping: preformed antigen-antibody complexes circulating in the blood deposit in the glomerular mesangium or subendothelial/subepithelial space, producing a *granular* immunofluorescence pattern (lumpy deposits at irregular intervals). Post-streptococcal glomerulonephritis is the prototype — streptococcal antigens "planted" in the subepithelial space trigger antibody formation 2–4 weeks after infection, and the resulting complexes activate complement, producing hematuria and the characteristic electron-dense "humps" on biopsy. Lupus nephritis uses the same mechanism with multiple deposit patterns depending on disease activity. The third pattern is pauci-immune: little or no immunoglobulin or complement is deposited, but ANCA (anti-neutrophil cytoplasmic antibodies) activate circulating neutrophils, which degranulate inside glomerular capillaries causing direct necrotizing injury without complement-mediated amplification.

IgA nephropathy, the most common GN worldwide, occupies a distinct mechanistic niche. Poorly glycosylated IgA₁ deposits in the mesangium, activating mesangial cells and alternative complement pathway, producing mesangial proliferation. The hallmark timing — gross hematuria appearing within 24–72 hours of a mucosal infection ("synpharyngitic hematuria") — reflects IgA's mucosal origin: IgA production spikes with mucosal immune responses, and poorly glycosylated IgA₁ deposits before it can be cleared. This contrasts sharply with post-streptococcal GN, where hematuria appears weeks after infection (the time required for immune complex formation and deposit accumulation).

Integrating serology with biopsy findings is the core clinical skill in GN classification. Complement levels (C3, C4) fall when the classical complement pathway is activated by immune complexes — in post-streptococcal GN, lupus, and membranoproliferative GN — but remain normal in ANCA-associated and IgA disease where complement is not the primary driver. ANCA testing (anti-PR3 for granulomatosis with polyangiitis; anti-MPO for microscopic polyangiitis) identifies the pauci-immune vasculitides. Anti-GBM antibodies identify Goodpasture syndrome. Learning to combine these serologic patterns with immunofluorescence morphology — linear vs. granular IgG, presence or absence of complement, IgA-dominant vs. IgG-dominant deposits — allows classification that directly determines treatment: plasma exchange for anti-GBM disease, high-dose steroids plus cyclophosphamide for ANCA vasculitis, hydroxychloroquine and steroids for lupus nephritis.