Questions: Glomerulonephritis: Immune and Non-Immune Mechanisms

Question 1

A renal biopsy from a patient with rapidly progressive nephritis shows linear IgG deposits along the glomerular basement membrane on immunofluorescence. What does this pattern indicate, and what serologic test confirms it?

• A. Circulating immune complex trapping in granular patches — confirmed by low complement levels
• B. Anti-GBM antibodies uniformly coating the basement membrane (as in Goodpasture syndrome) — confirmed by anti-GBM antibody serology
• C. ANCA-activated neutrophils depositing IgG linearly — confirmed by positive ANCA
• D. IgA mesangial deposits — confirmed by elevated serum IgA

Answer: (B)

Linear immunofluorescence along the GBM is the hallmark of anti-GBM disease (Goodpasture syndrome). Antibodies targeting type IV collagen bind continuously along the GBM, coating it uniformly — explaining the linear rather than granular pattern. The diagnosis is confirmed with anti-GBM antibody serology. This contrasts with immune complex deposition (granular IF) and ANCA-associated disease (pauci-immune, minimal IF deposits). Treatment requires plasma exchange to remove circulating anti-GBM antibodies.

Question 2

A patient presents with gross hematuria. A urine dipstick and microscopy show red blood cells with irregular, fragmented ('dysmorphic') shapes and RBC casts. A nurse suggests this is likely a bladder infection. What does the urinalysis actually indicate?

• A. The nurse is correct — gross hematuria with RBCs is the typical presentation of a lower UTI
• B. Dysmorphic RBCs and RBC casts indicate glomerular injury: RBCs are forced through the damaged filtration barrier and deformed by osmotic changes in tubular fluid; casts form when cells become trapped in tubular protein matrices — neither finding occurs in lower UTI
• C. Gross hematuria is always of glomerular origin; microscopic hematuria comes from the lower tract
• D. RBC casts are a normal finding that does not indicate glomerular disease

Answer: (B)

Dysmorphic RBCs and RBC casts are pathognomonic for glomerular hematuria. Dysmorphic RBCs result from mechanical deformation as RBCs are squeezed through gaps in the damaged glomerular filtration barrier and then undergo osmotic changes in the tubular lumen. RBC casts form when these RBCs become embedded in Tamm-Horsfall protein secreted by tubular cells. Neither finding can result from lower UTI, where bleeding occurs downstream of the nephron. Recognizing this distinction directs investigation toward glomerular rather than urologic causes.

Question 3

In IgA nephropathy, gross hematuria characteristically appears 2–4 weeks after a respiratory or skin infection, reflecting the time required for IgA immune complexes to form and deposit in the mesangium.

• T. True
• F. False

Answer: False

This describes the timing of post-streptococcal GN, not IgA nephropathy. IgA nephropathy produces 'synpharyngitic' hematuria — gross hematuria within 24–72 hours of a mucosal infection. This rapid timing reflects IgA's mucosal origin: IgA production spikes with any mucosal immune response, and poorly glycosylated IgA₁ deposits in the mesangium coincident with that spike. Post-streptococcal GN shows the 2–4 week delay because time is needed for streptococcal antigens to 'plant' in the glomerulus and for the antibody response to mature and form immune complexes.

Question 4

ANCA-associated glomerulonephritis (pauci-immune GN) causes significant glomerular injury despite minimal immunoglobulin or complement deposits on immunofluorescence.

• T. True
• F. False

Answer: True

Pauci-immune GN is defined by the absence of significant immune deposits on immunofluorescence — yet it causes severe, often rapidly progressive nephritis. The mechanism bypasses immune complex deposition: ANCA (anti-neutrophil cytoplasmic antibodies) activate circulating neutrophils, which then degranulate inside glomerular capillaries, releasing proteases and reactive oxygen species that cause direct necrotizing injury. The damage is mediated by activated neutrophils, not by complement-amplified immune complex injury.

Question 5

A clinician uses serum complement levels (C3 and C4) and ANCA serology to classify a patient's glomerulonephritis. Explain what each test tells you and which GN types each pattern points toward.

Model answer: Low complement (C3 and/or C4) indicates activation of the classical complement pathway by immune complexes, which consume complement proteins. This pattern is seen in post-streptococcal GN (low C3), lupus nephritis (low C3 and C4), and membranoproliferative GN. Normal complement with positive ANCA (anti-PR3 or anti-MPO) points to pauci-immune ANCA-associated vasculitis (granulomatosis with polyangiitis or microscopic polyangiitis), where neutrophil-mediated injury occurs without complement activation. Normal complement with negative ANCA but positive anti-GBM antibody indicates Goodpasture syndrome. IgA nephropathy typically shows normal complement with IgA-dominant mesangial deposits on biopsy. Combining serology with immunofluorescence morphology (linear vs. granular vs. absent IgG) allows mechanistic classification that directly determines treatment.

This integrative approach — serology + immunofluorescence — is the core clinical skill in GN classification. A student who can reason from 'low C3 + granular deposits' to 'complement-activating immune complex disease' and from 'normal complement + pauci-immune IF + positive ANCA' to 'ANCA vasculitis requiring immunosuppression' has mastered the diagnostic logic of this topic.