Glomerular disease · KIMS Secunderabad
C3 Glomerulopathy — When the Complement System Damages the Kidney Filters
C3 glomerulopathy (C3G) is a recently classified group of glomerular diseases caused by dysregulation of the alternative complement pathway — the branch of the immune system that normally provides a first line of defence against infection. When the alternative complement pathway cannot switch off, C3 (complement component 3) accumulates in the glomerular capillary walls and mesangium, causing inflammation, glomerular damage, proteinuria, haematuria, and progressive CKD. C3G encompasses two histological entities: C3 glomerulonephritis (C3GN) and Dense Deposit Disease (DDD — formerly called MPGN Type 2).
C3G falls within the broader category of membranoproliferative glomerulonephritis (MPGN) — a pattern of glomerular injury on light microscopy characterised by mesangial expansion, thickening of the glomerular capillary walls, and splitting of the glomerular basement membrane. The reclassification of MPGN into immune complex-mediated MPGN (driven by antibody deposition) and complement-mediated MPGN (C3G — driven by complement dysregulation without significant immunoglobulin deposition) is based on immunofluorescence and electron microscopy findings — making the biopsy with IF and EM not just helpful but essential for diagnosis and classification.
The complement pathway and C3 glomerulopathy
The alternative complement pathway (ACP) is continuously active at a low level — spontaneous C3 hydrolysis generates a small amount of C3b, which deposits on surfaces and is either eliminated by complement regulatory proteins or amplified to trigger inflammation against pathogens. The regulatory proteins — Factor H, Factor I, MCP (CD46), Factor H-related proteins — normally prevent uncontrolled C3 activation on the host's own cells and tissues.
In C3G, this regulation fails: mutations or autoantibodies against complement regulatory proteins (most commonly C3 nephritic factor — an autoantibody that stabilises the C3 convertase, preventing its inactivation) cause uncontrolled alternative pathway activation. The result: C3 is continuously cleaved, depositing fragments (C3b, C3d, C3dg) in the glomerular mesangium and capillary walls. These complement deposits trigger inflammation — mesangial and endocapillary proliferation, basement membrane changes, and progressive glomerular scarring.
Who gets C3 glomerulopathy — the underlying abnormalities
C3G affects all age groups — children, adolescents, and adults. Unlike many glomerular diseases, there is no strong sex predilection. The underlying complement abnormality falls into one of three categories, each with different implications for family screening, prognosis, and treatment.
Acquired — C3NeF and other autoantibodies
C3 nephritic factor (C3NeF) autoantibody, anti-Factor H antibody, or anti-Factor B antibody. C3NeF is found in 50 to 70% of DDD and 40 to 50% of C3GN cases — it stabilises the C3 convertase, preventing its decay and driving uncontrolled alternative pathway activation.
Genetic — complement regulatory gene mutations
Mutations in CFH (Factor H), CFI (Factor I), MCP, C3, CFB (Factor B), or CFHR genes (Factor H-related proteins — particularly the CFHR1-CFHR3 deletion and CFHR5 mutations). CFHR5 nephropathy — a specific genetic variant causing familial C3GN — is particularly prevalent in certain populations.
Monoclonal gammopathy-associated
A paraprotein (M-protein from a plasma cell clone, not meeting myeloma criteria) can act as an acquired complement regulatory inhibitor, driving C3G particularly in adults above 50. This is an important association to identify because treating the underlying paraprotein (with antimyeloma-type therapy) can improve kidney outcomes.
Symptoms and clinical presentation
Haematuria — microscopic (most common) or macroscopic. Often the presenting finding, particularly in younger patients.
Proteinuria — from moderate to nephrotic range. Proteinuria alongside haematuria in the same patient should always prompt nephrology evaluation.
Hypertension — develops as glomerular damage accumulates.
Declining eGFR — the rate of progression varies widely. Some patients have stable kidney function for years; others progress to ESRD within 10 years.
Low serum C3 — reduced complement C3 level (with normal C4 — since the alternative pathway uses C3 without requiring C4) is characteristic of complement-mediated C3G. A low C3 with normal C4 in a patient with haematuria and proteinuria should raise suspicion for C3G or dense deposit disease.
Diagnosis — why biopsy with IF and EM is essential
The diagnosis of C3G cannot be made without kidney biopsy. The classification of MPGN pattern into C3G vs immune complex MPGN is entirely based on biopsy findings:
Light microscopy (LM) — the MPGN pattern
Shows the MPGN pattern — mesangial expansion, endocapillary proliferation, thickening and double-contouring (tram-tracking) of the glomerular basement membrane. LM alone cannot distinguish C3G from immune complex MPGN — IF is required for that distinction.
Immunofluorescence (IF) — the diagnostic test
In C3G, IF shows dominant C3 staining (2+ or more) with absent or trace immunoglobulin staining (IgG, IgM, IgA below 2+). This C3-dominant, immunoglobulin-poor pattern distinguishes C3G from immune complex MPGN (where IgG and C3 are co-deposited in equal intensity). IF is performed in-house at KIMS's NABL-accredited laboratory.
Electron microscopy (EM) — distinguishes C3GN from DDD
In C3GN, EM shows mesangial and subendothelial electron-dense deposits without specific structural characteristics. In Dense Deposit Disease (DDD), EM shows the characteristic extremely dense, 'sausage-shaped', intramembranous deposits within the glomerular basement membrane — a unique appearance that distinguishes DDD from all other glomerular diseases. EM is performed in-house at KIMS and is essential for the C3GN vs DDD distinction, which has prognostic and potentially therapeutic implications.
The distinction between C3GN and Dense Deposit Disease is made only on EM. No other test — not clinical features, not blood tests, not LM, not IF — can make this distinction. DDD has a worse prognosis than C3GN on average, and this distinction matters for genetic counselling (DDD has a higher rate of genetic complement mutations) and for research trial eligibility. EM performed in-house at KIMS NABL laboratory — not outsourced.
Complement workup at KIMS
Serum C3 and C4 levels
Low C3 with normal C4 indicates alternative pathway activation. C4 is consumed by the classical and lectin pathways (which activate C4) but not the alternative pathway — so C3 low + C4 normal = alternative pathway dysregulation = C3G pattern.
C3 nephritic factor (C3NeF)
An autoantibody that stabilises C3 convertase, preventing its decay. Detected by functional assay. Positive in 50 to 70% of DDD cases.
Anti-Factor H antibody
An autoantibody against the primary regulatory protein of the alternative pathway. Associated with both C3G and aHUS.
Factor H level
Reduced Factor H (from consumption or reduced production) indicates uncontrolled alternative pathway activation.
Genetic panel (CFH, CFI, MCP, C3, CFB, CFHR1-5)
Identifies hereditary complement regulatory mutations. Important for genetic counselling of family members.
Serum protein electrophoresis and free light chains
Performed to exclude monoclonal gammopathy-associated C3G in adults above 40.
Treatment
C3G treatment is challenging — no specific therapy has been proven in large randomised trials. Current management combines kidney-protective measures with mechanism-targeted immunosuppression, complement-directed therapy in selected patients, and treatment of any identified underlying monoclonal gammopathy.
General kidney protection
ACE inhibitors or ARBs for proteinuria reduction and blood pressure control. Target BP below 130/80. These measures apply to every patient with C3G regardless of the specific complement abnormality.
Mycophenolate mofetil (MMF)
The most commonly used immunosuppressive agent for C3G. Reduces complement-driven inflammation. Retrospective studies suggest benefit in patients with significant proteinuria or declining eGFR. Used at KIMS for patients with active C3G and proteinuria above 1 gram per day.
Steroids
High-dose prednisolone for patients with rapid progression or crescentic disease on biopsy. Typically used alongside MMF in active disease, with dose tapered as response is achieved.
Eculizumab — complement C5 inhibitor
The same agent used for aHUS. Case series and small studies show benefit in some C3G patients. Currently used for refractory cases. The C3G patient population that responds best to eculizumab is not yet clearly defined.
Plasma infusion or plasma exchange
For patients with identified complement regulatory factor deficiency. Provides exogenous Factor H in Factor H-deficient patients — directly replacing the missing regulatory protein.
Treat underlying monoclonal gammopathy
In adults where a paraprotein is identified as the underlying driver of C3G, antimyeloma therapy targeting the plasma cell clone can lead to C3G remission. This is why every adult with C3G has SPEP and serum free light chains performed as part of the workup.
Book a C3 Glomerulopathy Consultation at KIMS — Complement Workup and EM Biopsy Available
Frequently Asked Questions — C3 Glomerulopathy
MPGN (membranoproliferative glomerulonephritis) is a pattern of glomerular injury seen on light microscopy — characterised by mesangial expansion, endocapillary proliferation, and GBM double contouring. It is not a single disease but a histological pattern that has multiple underlying causes. The modern classification divides MPGN into immune complex-mediated MPGN (where both immunoglobulin and C3 are deposited — from infections like hepatitis C, autoimmune disease, or monoclonal gammopathy) and complement-mediated MPGN (C3G — where dominant C3 with little or no immunoglobulin is deposited, from alternative pathway dysregulation). C3G is a subset of MPGN — all C3G shows an MPGN pattern on LM, but not all MPGN is C3G.
In some cases, yes. Mutations in complement regulatory genes (CFH, CFI, MCP, C3, CFB, CFHR genes) are found in a proportion of C3G patients — more commonly in DDD than C3GN. CFHR5 nephropathy — a specific genetic variant caused by duplication of CFHR5 — causes familial C3GN predominantly in families of Cypriot origin but is also described in Indian families. Genetic testing is part of the KIMS C3G workup. If a genetic mutation is found, first-degree family members should be screened. In the majority of C3G cases, however, the underlying cause is an acquired autoantibody (C3NeF or anti-Factor H) rather than a genetic mutation.
This combination of low serum C3 with normal serum C4 indicates selective activation of the alternative complement pathway — the pathway that uses C3 directly without consuming C4. The classical complement pathway (activated by immune complexes and antibodies) consumes both C4 and C3 — so infections like lupus, post-infectious GN, and immune complex MPGN typically show both C3 and C4 reduced. The alternative pathway uses C3 alone — so uncontrolled alternative pathway activation (as in C3G and aHUS) shows C3 reduced with C4 normal. This pattern is an important clinical clue pointing toward C3G in a patient with haematuria and proteinuria.
Yes — C3G has a high rate of recurrence in the transplanted kidney, estimated at 50 to 70% for DDD and 30 to 50% for C3GN. This recurrence risk is driven by the underlying systemic complement dysregulation, which persists after kidney transplant (the transplanted kidney is exposed to the same abnormal complement environment as the failed native kidneys). Recurrence can cause graft loss — the time to graft failure from C3G recurrence varies from months to years. For patients with identified complement mutations or autoantibodies, the KIMS team counsels carefully about this recurrence risk before proceeding with transplant, and post-transplant complement monitoring is arranged.
The rate of progression in C3G varies widely between patients and is not reliably predicted by the clinical presentation alone. Approximately 50% of C3G patients develop ESRD within 10 years of diagnosis. DDD generally has a worse prognosis than C3GN — approximately 50% of DDD patients reach ESRD within 10 years. Prognostic factors for faster progression: crescentic disease on biopsy (a poor sign), high degree of tubular atrophy and interstitial fibrosis on biopsy, persistent heavy proteinuria, and uncontrolled hypertension. The complement profile (specific mutations or autoantibodies) also influences prognosis. Regular 3 to 6 monthly monitoring of eGFR and urine ACR at KIMS tracks progression and triggers treatment escalation when needed.
Both present with haematuria and proteinuria — sometimes with macroscopic haematuria following upper respiratory infection — and both are common causes of glomerulonephritis in young adults. The key distinctions: IgA nephropathy shows dominant IgA deposition (granular, in the mesangium) on immunofluorescence with mesangial electron-dense deposits on EM; C3G shows dominant C3 with absent or minimal immunoglobulin on IF, and the EM findings differ (mesangial and subendothelial in C3GN; intramembranous in DDD). Complement levels are normal in IgA nephropathy but low C3 is characteristic of C3G. The distinction requires kidney biopsy with full IF and EM — a urine test or blood test alone cannot reliably distinguish them.
Dense Deposit Disease (DDD) is the more severe subtype of C3G — characterised on electron microscopy by extremely electron-dense, continuous, ribbon-like ('sausage-shaped') deposits within the glomerular basement membrane itself (intramembranous deposits). These deposits are caused by the same alternative pathway dysregulation as C3GN but produce this distinctive and specific ultrastructural appearance. DDD has a higher prevalence of C3NeF autoantibody, a stronger association with partial lipodystrophy (loss of subcutaneous fat from the face, arms, and trunk — from complement-mediated destruction of adipocytes), and on average a worse renal prognosis than C3GN. The intramembranous deposits of DDD are visible only on EM — making EM essential for the C3GN vs DDD distinction.
KIMS Secunderabad — Dr. Aswini Dutt T (glomerular disease subspecialty), NABL-accredited kidney biopsy with full complement workup (C3, C4, C3NeF, anti-Factor H, Factor H level), IF with C3, IgG, IgM, IgA, C1q staining, and EM performed in-house (the only test that distinguishes C3GN from Dense Deposit Disease). Genetic complement panel coordination. SPEP/sFLC for monoclonal gammopathy-associated C3G. Call 040-4488-5000.