Post-infectious & C3 Glomerulopathy

The contract between this chapter and the reader.

1. 1. Recognise these as the complement-driven, low-complement nephritic diseases.
2. 2. Describe the MPGN histologic pattern.
3. 3. Apply the modern reclassification (immune-complex vs complement-mediated).
4. 4. Recognise post-infectious / post-streptococcal GN.
5. 5. Diagnose and manage post-infectious GN.
6. 6. Define C3 glomerulopathy and the alternative-pathway dysregulation.
7. 7. Work up and treat C3 glomerulopathy.
8. 8. Use the complement pattern (C3/C4) to point to the mechanism.
9. 9. Distinguish the three entities.

A sixty-second reading. Each bullet stands alone.

• These are the complement-driven, low-complement nephritic glomerular diseases.
• MPGN is a histologic pattern — mesangial proliferation and basement-membrane double contours — not a single disease.
• It is reclassified by immunofluorescence into immune-complex-mediated and complement-mediated forms.
• Immune-complex MPGN shows immunoglobulin and complement and comes from infection, autoimmunity, or a monoclonal gammopathy.
• Complement-mediated MPGN is C3 glomerulopathy, with C3-dominant deposits and alternative-pathway dysregulation.
• Post-infectious GN is an acute nephritic syndrome one to three weeks after infection, with transient low complement.
• It is usually self-limiting in children and treated supportively.
• C3 glomerulopathy arises from alternative complement pathway dysregulation (C3 nephritic factor, complement variants).
• It causes a persistently low C3 and is often progressive.
• C3 glomerulopathy is treated supportively, by addressing any driver, and increasingly with complement inhibitors.
• A low C3 with a normal C4 points to the alternative pathway (C3 glomerulopathy).
• A low C3 with a low C4 points to the classical pathway (immune-complex disease).
• The complement pattern helps distinguish these diseases.

The medical core. An expert should agree these complement-driven nephritides are fully covered here.

Why it matters at the bedside

Alow complement on the blood panel is one of nephrology's most useful clues, and it points here — to a family of nephritic diseases bound together by complement. Learn to read the complement pattern and the immunofluorescence, and a confusing group — post-infectious GN, the MPGN pattern, C3 glomerulopathy — resolves into a logic of pathways consumed and proteins deposited.

The unifying theme: complement and low complement

• What ties this chapter together is complement. These are the low-complement nephritic diseases flagged by the approach chapter, and they are understood through the complement system — which pathway is activated, what is consumed, and what is deposited. The same low complement that narrows the differential at the bedside organises the diseases mechanistically.

The MPGN pattern

• Membranoproliferative glomerulonephritis (MPGN) is a histologic pattern, not a disease: mesangial proliferation with basement-membrane double contours (‘tram-tracking’), produced by subendothelial deposits and cellular interposition, giving a nephritic (sometimes nephritic-nephrotic) picture with low complement. Recognising the pattern is only the first step — the immunofluorescence then tells you which disease it is.

The modern reclassification

• MPGN is now classified by immunofluorescence and pathogenesis, not by the old electron-microscopy types. Immune-complex-mediated MPGN shows both immunoglobulin and complement, and arises from a definable cause — chronic infection (hepatitis C, endocarditis), autoimmunity (lupus, cryoglobulinemia), or a monoclonal gammopathy. Complement-mediated MPGN shows C3 with little or no immunoglobulin and is C3 glomerulopathy. This split — immunoglobulin-plus-complement versus complement-alone — is the key diagnostic fork.

Post-infectious / post-streptococcal GN

• Post-infectious glomerulonephritis is the classic acute nephritic syndrome — haematuria, oedema, hypertension — appearing one to three weeks after an infection, typically streptococcal. It is immune-complex-mediated, with subepithelial ‘humps’ on electron microscopy and granular C3/IgG, and the complement is low but transiently so, normalising over weeks. It is predominantly a childhood disease.

Managing post-infectious GN

• In children, post-streptococcal GN is usually self-limiting, so management is supportive — controlling fluid overload and hypertension while the disease resolves and complement normalises. The important caveats: in adults, especially with comorbidity (infection-related GN), the course can be worse; and a ‘post-infectious’ nephritis whose low complement does not resolve should prompt reconsideration of C3 glomerulopathy.

C3 glomerulopathy: the mechanism

• C3 glomerulopathy is the disease of alternative-complement-pathway dysregulation. Drivers — a C3 nephritic factor (an autoantibody that stabilises the C3 convertase, driving persistent activation), complement gene variants, or a monoclonal gammopathy acting on complement — cause unchecked alternative-pathway activity, depositing C3 in the glomerulus and producing the MPGN pattern. Its two subtypes are C3 glomerulonephritis and dense deposit disease (with characteristic intramembranous dense deposits).

Working up and treating C3 glomerulopathy

• The workup is a complement workup: a persistently low C3 (with a typically normal C4), a search for a C3 nephritic factor and complement gene variants, and — importantly — screening for a monoclonal gammopathy, which can drive it. Treatment is supportive (RAAS blockade), addressing any driver (treating a monoclonal gammopathy), and — increasingly — complement inhibition, an evolving area; the disease is often progressive and recurs after transplantation.

The complement framework

• The C3/C4 pattern is the framework that distinguishes the pathways. A low C3 with a normal C4 indicates isolated alternative-pathway activation — C3 glomerulopathy. A low C3 with a low C4 indicates classical-pathway activation — immune-complex disease (lupus, cryoglobulinemia, endocarditis-associated, and some post-infectious GN). Reading the two complement components together points directly at the mechanism.

Distinguishing the three entities

• In practice the three are separated thus: post-infectious GN — a recent infection, transiently low complement, a self-limiting course, subepithelial humps; immune-complex MPGN — immunoglobulin and C3, with a findable underlying cause (hepatitis C, lupus, monoclonal); and C3 glomerulopathy — C3-dominant deposits, a persistently low C3, alternative-pathway dysregulation. The history, the complement pattern, and the immunofluorescence together assign the diagnosis.

Five fully-built tables.

Table A — The complement-driven nephritides

Table B — The MPGN reclassification

Table C — Post-infectious GN

Table D — C3 glomerulopathy

Table E — The complement pattern

Visualise & Map

Causal chains, each ending in a named action.

Chain 1 — The post-infectious wave

Infection → immune complexes → subepithelial ‘humps’ and transient complement consumption → acute post-infectious nephritis → ACTION: treat supportively (usually self-limiting).

Chain 2 — The unchecked alternative pathway

C3 nephritic factor / complement variants → persistent alternative-pathway activation → C3-dominant glomerular deposits → C3 glomerulopathy → ACTION: complement workup and complement-directed treatment.

Chain 3 — The C3/C4 read-out

Low C3 with normal C4 → isolated alternative-pathway activation → C3 glomerulopathy → ACTION: pursue the complement workup.

Chain 4 — The classical signature

Low C3 with low C4 → classical-pathway activation → immune-complex disease (lupus, cryoglobulinemia, endocarditis) → ACTION: find and treat the underlying cause.

Chain 5 — Immunoglobulin plus complement

Immunoglobulin and C3 on immunofluorescence → immune-complex MPGN → a definable driver (hepatitis C, lupus, monoclonal gammopathy) → ACTION: identify and treat the underlying cause.

Numbered rules. These numbers are the cross-reference handle for the cases and flowcharts.

Clinical Reasoning

Five cases. Each stops you at a decision before it answers it.

Every mechanism from Level 3 earns a bedside consequence and an action.

Exhaustive. Every rule in the chapter is here.

Safety & Evidence

Panel A — Red flags

Panel B — NEVER DO

Anti-patterns clinicians fall into. Each becomes a Level 22 distractor.

The grade reflects strength of evidence, not importance.

Patient Decisions

Outcomes as natural frequencies. Figures are representative; the direction of effect is given where precise numbers are uncertain.

Apply & Test

Copy-paste chart notes that map to the real decisions in this chapter.

Template 1 — Low-complement nephritis workup note

• Presentation: nephritic syndrome; recent infection; timing ___.
• Complement pattern: C3 ___; C4 ___ (alternative vs classical pathway).
• Persistence of low complement (transient vs persistent): ___.
• Causes screened: hepatitis C, lupus, cryoglobulins, endocarditis, monoclonal gammopathy ___.
• Provisional entity: post-infectious / immune-complex MPGN / C3 glomerulopathy ___.

Template 2 — MPGN classification / C3G note

• Biopsy: MPGN pattern; immunofluorescence (Ig + C3 vs C3-dominant) ___.
• If C3 glomerulopathy: C3 nephritic factor; complement gene variants; subtype (C3GN vs DDD) ___.
• Driver identified (monoclonal gammopathy, etc.): ___.
• Treatment: supportive (RAAS); cause-directed; complement inhibitors ___.
• Transplant note (C3G recurrence risk): ___.

Pre-rounds compression. Rules only.

Active recall. At least one card per objective.

Micro-teaching for rounds. Two scenarios, five steps each.

Nine items, each anchored in this chapter. At least one per objective.