C3 Glomerulopathy

C3 glomerulopathy is a group of glomerular diseases caused by dysregulation of the alternative complement cascade, characterised on immunofluorescence by dominant glomerular C3 deposition (at least two orders of magnitude greater than any other immunoreactant) with little or no immunoglobulin. Its two main forms are dense deposit disease and C3 glomerulonephritis. The incidence is about 1 to 2 cases for each million population, with a peak in children and young adults, but a second peak above age 50 is associated with monoclonal gammopathy.

Pathophysiology. Uncontrolled activation of the alternative C3 convertase through acquired factors (C3 nephritic factor, anti-factor H antibodies, anti-factor B antibodies, paraprotein driven complement activation) or genetic variants (CFH, CFI, CFB, C3, CFHR1 to CFHR5, MCP). Fluid phase C3 breakdown products deposit in the mesangium and along the capillary wall, producing a membranoproliferative, mesangial, endocapillary or crescentic pattern.

Natural history. About 50% of adults progress to kidney failure within 10 years; the rate is lower in children. Recurrence after kidney transplantation is 50 to 80%.

• Haematuria (microscopic or macroscopic, often after an upper respiratory infection), proteinuria with nephrotic syndrome in 30 to 50%, hypertension, oedema.
• Acute nephritic presentation resembling post-infectious glomerulonephritis but persisting beyond 12 weeks.
• Rapid kidney function decline in a minority with crescents.
• Associated: partial lipodystrophy and retinal drusen (dense deposit disease), thrombotic microangiopathy in some.

Red flags

• Rapid loss of kidney function with crescents on biopsy.
• Nephrotic syndrome with eGFR under 60 mL/min/1.73 m².
• Age over 50 with monoclonal gammopathy (clone directed therapy needed).
• Visual loss from macular drusen or choroidal neovascularisation.

• Urinalysis with microscopy, protein:creatinine ratio, 24-hour protein, creatinine and eGFR, albumin, cholesterol.
• Complement: C3 (low in 50 to 80%), C4 (normal), total haemolytic complement, soluble C5b-9, C3 nephritic factor (functional assay), anti-factor H antibody, factor H, factor I and factor B levels, and genetic testing of complement genes in patients with early onset, family history or recurrent disease.
• Screen for monoclonal protein in all adults over 50: serum protein electrophoresis, immunofixation and free light chains; bone marrow if positive.
• Exclude infection (anti-streptolysin O, anti-DNase B, cultures, hepatitis B and C, HIV), autoimmune disease (antinuclear antibodies, anti-dsDNA, cryoglobulins, rheumatoid factor).
• Biopsy: light microscopy with membranoproliferative, mesangial proliferative, endocapillary or crescentic pattern; immunofluorescence with C3 staining at least two orders of magnitude brighter than immunoglobulin; electron microscopy distinguishes dense deposit disease (intramembranous dense ribbon like deposits) from C3 glomerulonephritis (mesangial, subendothelial and subepithelial deposits).

Differential diagnosis

• Post-infectious glomerulonephritis (C3 normalises in 8 to 12 weeks, resolves spontaneously), immune complex membranoproliferative glomerulonephritis (immunoglobulin dominant), lupus nephritis, thrombotic microangiopathy, atypical haemolytic uraemic syndrome, cryoglobulinaemic glomerulonephritis, monoclonal immunoglobulin related glomerulonephritis.

Supportive care for all patients

• Blood pressure below 130/80 mmHg; ACE inhibitor or angiotensin receptor blocker (ramipril 2.5 mg daily increased to 10 mg daily), checking creatinine and potassium at 1 to 2 weeks; accept a creatinine rise up to 30% and stop if potassium exceeds 6.0 mmol/L.
• SGLT2 inhibitor: dapagliflozin 10 mg daily with eGFR at least 25, or empagliflozin 10 mg daily with eGFR at least 20.
• Sodium restriction below 2 g daily; loop diuretic for oedema (furosemide 40 to 80 mg orally once or twice daily); statin for dyslipidaemia; anticoagulation considered if albumin is under 20 g/L with thrombotic risk.
• Vaccinations against Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae type b before any complement inhibitor.

Disease modifying therapy (proteinuria above 1 g daily after 3 months of supportive therapy, declining eGFR, or crescents)

• Mycophenolate mofetil 1 g orally twice daily (up to 1.5 g twice daily) with prednisolone 0.5 to 1 mg/kg daily (maximum 60 mg) reduced over 6 months; continue mycophenolate for at least 12 months if response occurs. Contraindicated in pregnancy.
• Crescentic or rapidly progressive disease: methylprednisolone 500 mg to 1 g intravenously daily for 3 days, then prednisolone 1 mg/kg daily with mycophenolate or cyclophosphamide.
• Complement inhibition for persistent or progressive disease: iptacopan 200 mg orally twice daily (factor B inhibitor), or pegcetacoplan 1080 mg subcutaneously twice weekly (C3 inhibitor), or eculizumab 900 mg intravenously weekly for 4 doses, 1200 mg at week 5, then 1200 mg every 2 weeks. Meningococcal vaccination (conjugate ACWY and group B) at least 2 weeks before starting, with penicillin V 500 mg twice daily prophylaxis if vaccination is delayed.
• Rituximab (375 mg/m² weekly for 4 doses, or 1 g on days 1 and 15) has been used for C3 nephritic factor positive disease with variable results.
• Factor H deficiency: fresh frozen plasma infusion 10 to 15 mL/kg every 2 weeks, or plasma exchange.
• Associated monoclonal gammopathy: clone directed therapy with haematology (bortezomib based regimens).

Monitoring. Creatinine, protein:creatinine ratio, albumin and blood pressure monthly for 3 months then every 3 months; C3 and C5b-9 on treatment; repeat biopsy if response is unclear.

Referral and escalation. All patients to nephrology with access to complement testing; urgent referral for crescents or eGFR decline; transplant centre for early planning (recurrence in 50 to 80%).

Special groups

• Children: supportive care first; mycophenolate mofetil 600 mg/m² twice daily (maximum 1 g twice daily) with prednisolone; eculizumab dosing by weight.
• Pregnancy: stop ACE inhibitors, angiotensin receptor blockers and mycophenolate before conception; relapse risk and pre-eclampsia risk are raised.
• Transplant: screen for genetic and acquired complement defects before living related donation; recurrence treated with complement inhibition.