Membranoproliferative Glomerulonephritis
Pattern of glomerular injury characterised by mesangial cell proliferation, GBM thickening with double contour formation, and lobular appearance. Now reclassified by immunopathogenesis into immune complex-mediated and complement-mediated (C3 glomerulopathy) forms.
Key Facts
MPGN is a histological pattern reclassified into immune complex-mediated (Ig-positive) and complement-mediated (C3 glomerulopathy) (Ig-negative) Classic biopsy finding: tram-track/double-contour GBM on silver stain, lobular glomeruli, mesangial proliferation Immune complex-mediated MPGN: associated with hepatitis C (most common), cryoglobulinaemia, SLE, monoclonal gammopathy C3 glomerulopathy (C3GN, dense deposit disease): caused by dysregulation of alternative complement pathway (C3 nephritic factor, Factor H deficiency) Low serum C3 is characteristic; C4 may be low (immune complex) or normal (complement-mediated) Treatment: treat underlying cause (HCV, SLE); immunosuppression for progressive disease; eculizumab for refractory C3 glomerulopathy 50% progress to ESRD within 10 years; recurrence in transplant ~30-65%
Overview
Key Facts
MPGN represents a pattern of glomerular injury with shared morphological features but distinct pathogenic mechanisms. Modern classification focuses on immunopathogenesis rather than ultrastructural appearance.
Epidemiology
- Rare; <5% of primary glomerulonephritis
- Most common in young adults and adolescents
- Incidence declining in Western countries due to HCV treatment
Aetiology
Immune complex-mediated:
- Hepatitis C with cryoglobulinaemia (most common cause overall)
- Hepatitis B, SLE, monoclonal gammopathy (MGRS)
- Bacterial endocarditis, shunt nephritis
Complement-mediated (C3 glomerulopathy):
- C3 nephritic factor (autoantibody stabilising C3 convertase)
- Factor H deficiency or antibodies
- Genetic complement mutations
Pathophysiology
- Immune complex deposition or complement dysregulation activates complement cascade within glomeruli
- Mesangial and endocapillary proliferation
- Mesangial cell interposition between endothelium and GBM → double-contour (tram-track) GBM
- Progressive glomerulosclerosis
Clinical Presentation
Presentation
- Nephrotic syndrome (40-50%) or nephritic-nephrotic overlap
- Nephritic syndrome (20-30%): haematuria, proteinuria, hypertension, renal impairment
- Asymptomatic urinary abnormalities: microscopic haematuria and proteinuria
- Acute nephritis: rare, can mimic post-infectious GN
Associated Features
- Hepatitis C: arthralgia, purpura, neuropathy (cryoglobulinaemia)
- SLE: rash, arthritis, serositis
- Lipodystrophy: associated with C3 glomerulopathy
- Drusen (retinal deposits): dense deposit disease
Red Flags
- Low C3 in older adult → screen for monoclonal gammopathy
- Cryoglobulinaemia → test for hepatitis C
- Rapidly declining GFR → urgent biopsy
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| Post-infectious GN | Recent infection, low C3 (normalises in 8 weeks) | ASO titre, C3 serial |
| Lupus nephritis | ANA, dsDNA, low C3/C4 | Immunology, biopsy |
| IgA nephropathy | Mesangial IgA, normal complement | Renal biopsy |
| Cryoglobulinaemic vasculitis | Purpura, neuropathy, hepatitis C | Cryoglobulins, HCV |
| Monoclonal gammopathy | Paraprotein, bone marrow disease | SPEP, bone marrow |
Diagnosis / Investigation
Bloods
- C3: low in both forms; C4: low in immune complex-mediated, normal in C3 glomerulopathy
- Hepatitis B/C serology: mandatory
- Cryoglobulins: if HCV positive or vasculitis suspected
- ANA, dsDNA: exclude SLE
- Serum protein electrophoresis and free light chains: exclude monoclonal gammopathy
- C3 nephritic factor, Factor H/I levels: if C3 glomerulopathy suspected
- FBC, U&Es, albumin, lipids: standard workup
Imaging
- Renal USS: normal kidney size initially
Special Tests
- Renal biopsy (essential):
- LM: lobular glomeruli, mesangial proliferation, GBM double contours
- IF: distinguishes immune complex (IgG/IgM + C3) from C3 glomerulopathy (C3 dominant, Ig negative)
- EM: subendothelial deposits (type I), intramembranous dense deposits (dense deposit disease/type II), subepithelial/subendothelial (type III)
- Complement genetics: if C3 glomerulopathy confirmed
Management
Non-pharmacological
- Treat underlying cause: antiviral therapy for HCV (direct-acting antivirals), treat SLE, treat monoclonal gammopathy
- Supportive care: RAAS blockade, sodium restriction
Pharmacological
Immune complex-mediated:
- Treat underlying disease (HCV: sofosbuvir-based DAAs; SLE: immunosuppression; MGRS: haematological treatment)
- Rituximab: for cryoglobulinaemic MPGN refractory to antiviral therapy
C3 glomerulopathy:
- Mycophenolate mofetil 1-2g/day: first-line for progressive disease
- Eculizumab (anti-C5 monoclonal): for refractory cases with evidence of terminal complement activation
- Plasma exchange: for Factor H antibodies
Supportive (all):
- ACEi/ARB for proteinuria
- Statins, anticoagulation if nephrotic
Referral Criteria
- All cases → nephrology
- C3 glomerulopathy → tertiary centre with complement expertise
Prognosis
- 50% progress to ESRD within 10 years
- Immune complex-mediated: prognosis depends on treating underlying cause; HCV cure can induce remission
- C3 glomerulopathy: generally poorer prognosis; dense deposit disease worst
- Transplant recurrence: 30-65% (higher for C3 glomerulopathy)
- C3GN post-transplant: ~50% graft loss from recurrence at 10 years
Other Relevant Information
Modern Classification of MPGN
| Category | IF Pattern | Key Associations |
|---|---|---|
| Immune complex-mediated | IgG/IgM + C3 | HCV, SLE, MGRS |
| C3 glomerulonephritis | C3 dominant (Ig-negative) | C3 nephritic factor, complement mutations |
| Dense deposit disease | C3 dominant (Ig-negative) | Factor H deficiency, C3 nephritic factor |
Complement Profile in GN
| Disease | C3 | C4 |
|---|---|---|
| MPGN (immune complex) | Low | Low |
| C3 glomerulopathy | Low | Normal |
| Post-infectious GN | Low | Normal |
| SLE nephritis | Low | Low |
| IgA nephropathy | Normal | Normal |