Hypocomplementaemic Glomerulonephritis
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Direct answer
Hypocomplementaemic glomerulonephritis is a group of glomerular diseases in which serum complement, usually C3, stays persistently low because complement is consumed during immune injury. The pattern narrows the cause: low C3 with normal C4 points to alternative pathway activation, while low C3 with low C4 points to classical pathway activation.
What you must remember
- Defining feature: persistently low serum C3 or C4 on repeat testing is a clue to glomerular disease, not a diagnosis by itself.
- Low C3, normal C4: alternative pathway activation, seen in post-infectious GN, infective endocarditis, shunt nephritis and C3 glomerulopathy.
- Low C3 and low C4: classical pathway activation, seen in lupus nephritis and MPGN type I.
- Post-streptococcal GN: C3 usually returns to normal within about 8 weeks, so persistent hypocomplementaemia argues against it.
- C3 nephritic factor: an autoantibody that stabilises the alternative pathway C3 convertase, linked to dense deposit disease and C3 glomerulopathy.
- Cryoglobulinaemic GN: mixed cryoglobulins, most often linked to hepatitis C, cause low C4 and the Meltzer triad of purpura, arthralgia and weakness.
- Biopsy: immunofluorescence and electron microscopy classify the lesion, and MPGN shows a double-contoured or tram-track basement membrane.
Matching the complement pattern to the cause
Complement levels narrow the list of causes of glomerular disease before a biopsy is reviewed. Each pattern points to a short list of diagnoses that can then be confirmed with serology and histology.
| Complement pattern | Typical causes | Confirmatory clue |
|---|---|---|
| Low C3, normal C4 | Post-infectious GN, infective endocarditis, infected ventriculoatrial shunt | Recent streptococcal infection, raised antistreptolysin titres or an infected device |
| Low C3, normal C4, persistent | Dense deposit disease, C3 glomerulopathy | C3 nephritic factor and dense intramembranous deposits on electron microscopy |
| Low C3 and low C4 | Lupus nephritis, MPGN type I | Anti-dsDNA and ANA in lupus, immune deposits with a double-contoured basement membrane |
| Low C4, C3 often normal | Mixed cryoglobulinaemia | Hepatitis C serology, cryoglobulin assay, purpura and arthralgia |
Low C4 points towards classical pathway and immune complex disease, while low C3 with normal C4 suggests the alternative pathway. The final diagnosis still rests on biopsy findings, because complement values alone cannot separate MPGN from lupus.
Where the exam tries to catch you
Most lost marks come from misreading the complement pattern, not from forgetting the disease names.
- Trap: Calling every low C3 lupus nephritis. Correct: Low C3 with normal C4 points to alternative pathway disease, so lupus is the wrong default.
- Trap: Expecting post-streptococcal GN to keep C3 low for months. Correct: C3 normalises within about 8 weeks, so persistence should prompt a search for MPGN or C3 glomerulopathy.
- Trap: Using complement levels to diagnose without a biopsy. Correct: Immunofluorescence and electron microscopy classify the lesion, because serology alone does not stage the disease.
Frequently asked questions
Which complement pattern points to post-streptococcal glomerulonephritis?
Post-streptococcal glomerulonephritis typically shows low C3 with normal C4, consistent with alternative pathway activation. C3 usually normalises within about 8 weeks, and persistence beyond that time suggests an alternative diagnosis such as MPGN.
How does dense deposit disease differ from MPGN type I?
Dense deposit disease usually shows low C3 with normal C4 and dense intramembranous deposits on electron microscopy. MPGN type I usually shows low C3 and low C4, with subendothelial and mesangial deposits and a double-contoured basement membrane.
Which tests evaluate suspected lupus nephritis in a patient with low complement?
Antinuclear antibody and anti-dsDNA testing screen for systemic lupus, alongside serial C3 and C4 levels. A kidney biopsy with immunofluorescence is needed to classify lupus nephritis, because serology alone does not stage the renal disease.
Why is hepatitis C testing important in hypocomplementaemic glomerulonephritis?
Hepatitis C is the most common cause of mixed cryoglobulinaemia, which produces low C4 and cryoglobulinaemic glomerulonephritis. Anti-HCV antibodies and HCV RNA should be tested in any patient with cryoglobulins or unexplained low complement.