Mesangial and capillary wall thickening with nephritic-nephrotic features; classified by immunofluorescence pattern.
Also known as: MPGN, membranoproliferative glomerulonephritis, mesangiocapillary glomerulonephritis, C3 glomerulopathy, dense deposit disease
Overview
A pattern of glomerular injury defined by mesangial proliferation, GBM thickening with double contours ('tram-track' appearance), and immune complex or complement deposition. Currently classified by immunofluorescence into immune-complex-mediated MPGN (Ig + complement) and C3 glomerulopathy (complement-only, including dense deposit disease).
Epidemiology
Uncommon; accounts for 5-10% of adult glomerular disease in developed countries but is more frequent where chronic infections (hepatitis C, malaria, schistosomiasis) are endemic. C3 glomerulopathy is rare with peak incidence in adolescents and young adults. Mixed nephritic-nephrotic presentation is typical.
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Question 1RenalMedium
A 45-year-old male with chronic kidney disease (CKD) stage 3 (eGFR 32) develops fever, polyarthritis, and a purpuric rash on the lower legs. Urinalysis shows RBC casts and 3+ proteinuria. A refrigerated serum sample forms a precipitate that redissolves on rewarming; C4 is undetectable, C3 is low, and rheumatoid factor is positive. Hepatitis C virus (HCV) antibody is positive with viral load 2.4 million IU/mL. Which of the following is the most likely diagnosis?
AMembranous nephropathy
BIgA vasculitis nephropathy
CLupus nephritis class IV
DPolyarteritis nodosa
ECryoglobulinemic vasculitis
Reveal answer & full explanation
Correct answer: E — Cryoglobulinemic vasculitis
AMembranous nephropathy
BIgA vasculitis nephropathy
CLupus nephritis class IV
DPolyarteritis nodosa
ECryoglobulinemic vasculitis✓
Why Cryoglobulinemic vasculitis is correct
Hepatitis C virus (HCV) accounts for 80–90% of mixed cryoglobulinemic vasculitis, and this patient has a high HCV viral load.
Type II cryoglobulins (monoclonal IgM with rheumatoid factor activity plus polyclonal IgG) are most common.
Classic triad: palpable purpura, arthralgias, and weakness; peripheral neuropathy and membranoproliferative-pattern glomerulonephritis also occur.
Lab hallmarks: low C4 disproportionate to C3, positive rheumatoid factor, and serum cryoglobulins (immunoglobulins that precipitate in refrigerated serum and redissolve on rewarming) — all present here.
Renal involvement produces RBC casts and proteinuria from subendothelial immune-complex deposition.
Why the others are wrong
IgA vasculitis nephropathy — IgA-driven small-vessel vasculitis without an HCV link, cryoglobulins, or the low-C4 pattern (confused-with, shared purpura).
Lupus nephritis class IV — Systemic lupus erythematosus shows anti-dsDNA and lacks serum cryoglobulins or rheumatoid factor positivity (confused-with immune-complex GN).
Membranous nephropathy — Presents with bland nephrotic-range proteinuria, not palpable purpura, arthritis, or an active urine sediment (right-concept-wrong-setting).
Polyarteritis nodosa — the vasculitis classically linked to hepatitis B, so it is tempting in a febrile patient with viral hepatitis and arthritis, but HCV-associated cases are rare, it involves medium-sized arteries and spares the glomeruli (renal infarcts and renovascular hypertension rather than RBC casts), and it does not produce serum cryoglobulins (confused-with the hepatitis-B-associated vasculitis).
Additional high-yield points
Treatment: direct-acting antiviral (DAA) therapy for HCV (sofosbuvir/velpatasvir or elbasvir/grazoprevir); sustained virologic response clears cryoglobulins in over 90% with vasculitis improvement.
Severe disease (rapidly progressive glomerulonephritis, severe neuropathy): rituximab plus glucocorticoids plus plasma exchange before or alongside DAA therapy.
Question 2RenalMedium
A 20-year-old woman has a nephritic-nephrotic picture and a renal biopsy showing a membranoproliferative pattern. Her clinician wants to characterize the process further. Which of the following laboratory findings is most characteristic of membranoproliferative glomerulonephritis?
APersistently depressed serum C3 level
BMarkedly elevated serum IgA level
CElevated anti-glomerular basement membrane titer
DElevated antistreptolysin O titer
EPositive anti-phospholipase A2 receptor antibody
Reveal answer & full explanation
Correct answer: A — Persistently depressed serum C3 level
APersistently depressed serum C3 level✓
BMarkedly elevated serum IgA level
CElevated anti-glomerular basement membrane titer
DElevated antistreptolysin O titer
EPositive anti-phospholipase A2 receptor antibody
Why Persistently depressed serum C3 level is correct
MPGN is a complement-consumption glomerulonephritis, so a persistently low serum C3 is its most characteristic laboratory feature — driven either by immune complexes (classical pathway, often with hepatitis C and cryoglobulins) or by dysregulated alternative-pathway activation in C3 glomerulopathy and dense-deposit disease.
A depressed C3 that fails to normalize helps separate MPGN from most other glomerulonephritides.
Why the others are wrong
Elevated anti-glomerular basement membrane titer — indicates Goodpasture disease with a linear immunofluorescence pattern and pulmonary-renal syndrome, not a tram-track pattern.
Positive anti-phospholipase A2 receptor antibody — is specific for primary membranous nephropathy.
Markedly elevated serum IgA level — is associated with IgA nephropathy, which shows mesangial IgA deposits and normal complement rather than the MPGN pattern.
Elevated antistreptolysin O titer — post-streptococcal GN also lowers C3, but the drop is transient (typically normalizing within about 8 weeks), and an elevated titer documents recent streptococcal infection rather than the persistent complement consumption of MPGN.
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Partial lipodystrophy (associated with dense deposit disease)
Pathophysiology
Immune-complex MPGN: circulating or in situ immune complexes deposit in subendothelial space → activate classical complement pathway → low C3 and C4 → mesangial and endocapillary proliferation. C3 glomerulopathy: persistent activation of alternative complement pathway (often by C3 nephritic factor stabilizing the C3 convertase) → C3 deposition with normal or low C3 and normal C4. Dense deposit disease (a subtype of C3 glomerulopathy) shows characteristic dense intramembranous osmiophilic deposits on EM. All forms produce GBM duplication from mesangial cell interposition.
Anti-GBM disease / ANCA vasculitis — Crescentic GN with linear (anti-GBM) or pauci-immune (ANCA) IF — both lack the MPGN pattern
Diagnostic workup
Diagnostic criteria
Kidney biopsy is required. LM: mesangial and endocapillary proliferation, GBM thickening with double contours. IF distinguishes: (a) immune-complex MPGN — IgG/IgM and C3 deposits; (b) C3 glomerulopathy — dominant C3 with little or no immunoglobulin; (c) dense deposit disease — intramembranous ribbon-like electron-dense deposits on EM. Monoclonal Ig staining on IF should prompt MGRS workup.
Labs
Complement studies — C3, C4, CH50; low C3 with low C4 suggests classical/immune-complex pathway; low C3 with normal C4 suggests alternative pathway (C3 glomerulopathy)
Hepatitis B and C, HIV, RPR, blood cultures (to exclude endocarditis or shunt nephritis)
Complement regulatory studies — C3 nephritic factor (C3NeF), factor H, factor B, anti-factor H antibodies; consider genetic testing for CFH/CFI/CFB/C3/MCP variants if C3 glomerulopathy
BMP, eGFR, UA with microscopy, UPCR or 24-hour protein
Imaging
Renal ultrasound — generally normal kidney size initially; advanced disease shows atrophy
Diagnostic algorithm
Subtype
IF pattern
Complement
Typical cause
Immune-complex MPGN
Ig + C3
Low C3 and C4
HCV/cryo, SLE, endocarditis, MGRS
C3 glomerulopathy (C3GN)
C3 dominant
Low C3, normal C4
C3 nephritic factor, CFH mutations
Dense deposit disease (DDD)
C3 dominant + ribbon deposits on EM
Low C3
Alt pathway dysregulation, partial lipodystrophy
Monoclonal-Ig–mediated MPGN
Monoclonal IgG kappa or lambda
Variable
MGRS — myeloma, MGUS, lymphoma
MPGN subtypes by immunofluorescence — complement pattern often points to the underlying mechanism.
Treatment
First-line
Treat the underlying cause whenever possible — direct-acting antivirals for hepatitis C (sofosbuvir/velpatasvir, glecaprevir/pibrentasvir), antivirals for hepatitis B, antibiotics and surgical management for endocarditis or shunt nephritis
RAAS blockade — ACE inhibitor (lisinopril, ramipril, enalapril) or ARB (losartan, valsartan) for proteinuria
Blood pressure target systolic <120 mmHg by standardized office measurement when tolerated (KDIGO 2021)
Statin therapy, loop diuretics for edema
Treat MGRS-associated MPGN with clone-directed therapy (bortezomib-based, daratumumab) in conjunction with hematology
Immune-complex MPGN with idiopathic nephrotic-range disease
Corticosteroids (prednisone)
Mycophenolate mofetil
Rituximab for cryoglobulinemic vasculitis (especially HCV-associated; combine with antiviral therapy)
C3 glomerulopathy / dense deposit disease
Supportive care and RAAS blockade as foundation
Mycophenolate mofetil with or without corticosteroids in progressive disease
Eculizumab — anti-C5 monoclonal; variable response; reserved for rapidly progressive or post-transplant recurrence
Complement inhibitors (FDA-approved 2025): iptacopan (oral factor B inhibitor, adults) or pegcetacoplan (C3/C3b inhibitor, age ≥12, also approved for primary immune-complex MPGN)
Hepatitis C–associated MPGN with cryoglobulinemia
Direct-acting antivirals are first-line and often curative
Add rituximab and plasmapheresis if severe cryoglobulinemic vasculitis (RPGN, ischemic digits, mesenteric vasculitis)
Second-line / adjunct
Plasmapheresis for rapidly progressive disease or severe cryoglobulinemia
Kidney transplantation for ESKD — high recurrence rate for C3 glomerulopathy and dense deposit disease in the graft
Pegcetacoplan (C3/C3b inhibitor) — FDA-approved 2025 for C3 glomerulopathy and primary immune-complex MPGN (age ≥12) to reduce proteinuria and slow loss of kidney function
Complications
Progression to ESKD in 40-50% within 10 years (worse in C3 glomerulopathy/dense deposit disease)
Hypertension and accelerated cardiovascular disease
High recurrence in renal allografts, especially complement-driven forms
PANCE pearls
MPGN is a histologic pattern, not a single disease — always search for an underlying cause (HCV is the single most common identifiable cause in adults).
Low C3 with normal C4 = alternative pathway → think C3 glomerulopathy or dense deposit disease.
MGRS workup (SPEP/UPEP/free light chains) is mandatory in adults with monoclonal staining on biopsy — these patients need clone-directed therapy.
Iptacopan (factor B inhibitor) has emerged as a targeted therapy for C3 glomerulopathy (APPEAR-C3G trial).
References
KDIGO 2021 — KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases (Kidney Int 2021;100:S1-S276)
C3G consensus — Goodship THJ et al. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a KDIGO Controversies Conference (Kidney Int 2017;91:539-551)
APPEAR-C3G — Kavanagh D et al. Oral iptacopan therapy in patients with C3 glomerulopathy: a randomised, double-blind, parallel group, multicentre, placebo-controlled, phase 3 study (Lancet 2025;406:1587-1598)
MGRS — Leung N et al. The evaluation of monoclonal gammopathy of renal significance (Nat Rev Nephrol 2019;15:45-59)
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