Renal/Urology · PANCE / PANRE

Membranoproliferative Glomerulonephritis (MPGN)

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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Risk factors

Chronic infections: hepatitis C (with or without cryoglobulinemia), hepatitis B, endocarditis, shunt nephritis, HIV, schistosomiasis
Autoimmune disease: SLE, Sjögren syndrome, rheumatoid arthritis, mixed cryoglobulinemia
Monoclonal gammopathy of renal significance (MGRS) — myeloma, MGUS, lymphoplasmacytic disorders
Complement dysregulation: C3 nephritic factor, factor H autoantibodies, mutations in CFH, CFI, CFB, MCP, C3 (C3 glomerulopathy / dense deposit disease)
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.

Clinical presentation

Symptoms

Mixed nephritic-nephrotic syndrome: hematuria, proteinuria, edema
Hypertension, fatigue, occasional gross hematuria
Extrarenal symptoms when secondary (rash, arthralgia, hepatitis, lipodystrophy)

Signs / physical exam

Hypertension (often moderate to severe)
Peripheral and periorbital edema
Palpable purpura if cryoglobulinemic vasculitis
Loss of fat in upper body / face (partial lipodystrophy with dense deposit disease)

Classic findings

Persistently low complement levels — C3 ± C4. Tram-track double-contour GBM on biopsy.

Differential diagnosis

Post-infectious glomerulonephritis — Recent strep infection, low C3 with normal C4, typically self-limited
Lupus nephritis class III/IV — Full-house IF (IgG, IgA, IgM, C3, C1q), positive ANA/anti-dsDNA, extrarenal SLE
IgA nephropathy — Mesangial IgA, often normal complement, episodic gross hematuria after URI
Cryoglobulinemic vasculitis (especially HCV) — Palpable purpura, arthralgia, neuropathy, low C4 disproportionate to C3, positive cryoglobulins, RF
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)
Cryoglobulins (warmed sample), rheumatoid factor
ANA, anti-dsDNA
SPEP, UPEP, serum free light chains, immunofixation
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 control (<125/75 if proteinuric)
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
Emerging: factor B inhibitor iptacopan (approved for C3 glomerulopathy in 2024-2025)

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) and other complement-targeted therapeutics under investigation for C3 glomerulopathy and immune-complex MPGN

Complications

Progression to ESKD in 40-50% within 10 years (worse in C3 glomerulopathy/dense deposit disease)
Hypertension and accelerated cardiovascular disease
Thromboembolism if nephrotic
Partial lipodystrophy (with dense deposit disease) — Barraquer-Simons syndrome
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.
Low C3 + low C4 = classical pathway → think immune-complex MPGN (cryoglobulinemia, HCV, SLE, MGRS).
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 — Bomback AS et al. Iptacopan in C3 glomerulopathy (NEJM 2024)
MGRS — Leung N et al. The evaluation of monoclonal gammopathy of renal significance (Nat Rev Nephrol 2019;15:45-59)

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