C3 Glomerulonephritis

C3 glomerulonephritis is the form of C3 glomerulopathy in which dominant C3 deposition on immunofluorescence is accompanied by mesangial, subendothelial and often subepithelial (hump like) deposits on electron microscopy, without the intramembranous dense ribbons of dense deposit disease.

It results from dysregulation of the alternative complement cascade through C3 nephritic factor, autoantibodies to factor H or factor B, or variants in complement regulatory genes (CFH, CFI, CFHR5, MCP) and C3. It occurs at any age, with onset in later childhood and adulthood, and has a more variable course than dense deposit disease. Roughly 30 to 40% of patients progress to kidney failure within 10 years.

Distinguishing from infection. A post-infectious glomerulonephritis like picture (hypocomplementaemia, humps) that persists beyond 12 weeks, or recurs with each infection, indicates C3 glomerulonephritis.

• Haematuria (microscopic or macroscopic), proteinuria (nephrotic range in about 40%), hypertension, oedema, and nephritic syndrome.
• Often a relapsing course with each upper respiratory infection.
• Rapid progression with crescents in a minority; thrombotic microangiopathy features in some.
• Familial disease (CFHR5 nephropathy, endemic in Cyprus) with episodic macroscopic haematuria.
• Monoclonal gammopathy in older adults (at least 30% of those over 50).

Red flags

• Rapidly rising creatinine, oliguria or crescents.
• Age over 50 with paraprotein: possible monoclonal gammopathy of renal significance.
• Nephrotic syndrome with albumin under 20 g/L (thrombosis risk).
• Haemolysis and thrombocytopenia (thrombotic microangiopathy).

• Urine microscopy, protein:creatinine ratio, creatinine, eGFR, albumin, cholesterol.
• C3 (low in 50 to 60%), normal C4, soluble C5b-9, C3 nephritic factor, factor H autoantibodies, factor H, I and B levels, and complement gene panel (CFH, CFI, CFB, C3, CFHR1 to CFHR5, MCP, THBD).
• Serum protein electrophoresis, immunofixation and free light chains in all adults.
• Infection screen (anti-streptolysin O, anti-DNase B, cultures), hepatitis B and C, HIV, antinuclear antibodies, cryoglobulins.
• Biopsy: immunofluorescence with C3 at least two orders of magnitude brighter than immunoglobulin; electron microscopy with mesangial, subendothelial and subepithelial humps (no continuous intramembranous ribbons); light microscopy with mesangial, endocapillary or membranoproliferative changes and crescents in some.

Differential diagnosis

• Post-infectious glomerulonephritis (spontaneous recovery by 12 weeks), dense deposit disease (EM ribbon deposits), immune complex membranoproliferative glomerulonephritis, IgA nephropathy with C3 dominance, lupus nephritis, thrombotic microangiopathy.

Supportive care

• Blood pressure under 130/80 mmHg; ramipril 2.5 mg daily to 10 mg daily (creatinine and potassium at 1 to 2 weeks; accept a creatinine rise up to 30%; stop if potassium exceeds 6.0 mmol/L).
• Dapagliflozin 10 mg daily (eGFR at least 25) or empagliflozin 10 mg daily (eGFR at least 20).
• Sodium restriction under 2 g daily; furosemide 40 to 80 mg for oedema; statin; vaccinations for pneumococcus, meningococcus and Haemophilus influenzae type b.
• Antibiotic treatment of precipitating infection; penicillin V 500 mg four times daily for 10 days in streptococcal pharyngitis.

Immunosuppression (proteinuria above 1 g daily after 3 months of supportive care, falling eGFR, or crescents)

• Mycophenolate mofetil 1 g 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 12 months or more if responding.
• Crescents: methylprednisolone 500 mg to 1 g intravenously daily for 3 days, then prednisolone 1 mg/kg daily (maximum 60 mg) tapered to 20 mg by week 6, with mycophenolate or cyclophosphamide (intravenous 15 mg/kg every 2 weeks for 3 doses, then every 3 weeks; 12.5 mg/kg at age 60 to 70 and 10 mg/kg over age 70).
• Rituximab 375 mg/m² weekly for 4 doses (or 1 g on days 1 and 15) for refractory disease with autoantibodies.

Complement inhibitors

• Iptacopan 200 mg orally twice daily; pegcetacoplan 1080 mg subcutaneously twice weekly; eculizumab 900 mg intravenously weekly for 4 doses, 1200 mg at week 5, then every 2 weeks. All need meningococcal vaccination at least 2 weeks before the first dose (ACWY and B) and penicillin V 500 mg twice daily while on treatment if vaccination is delayed.

Paraprotein associated disease. Haematology directed clone targeted therapy (bortezomib, cyclophosphamide and dexamethasone, or daratumumab) when a clone is found.

Monitoring. Creatinine, protein:creatinine ratio, albumin and C3 monthly for 3 months then every 3 months; recheck complement results during therapy.

Referral and escalation. Nephrology for all patients; haematology for paraprotein; transplant planning (recurrence 50 to 70%).

Special groups

• Children: prednisolone 1 mg/kg daily (maximum 60 mg) with mycophenolate mofetil 600 mg/m² twice daily (maximum 1 g twice daily).
• Pregnancy: stop ACE inhibitors, angiotensin receptor blockers and mycophenolate before conception; close monitoring for pre-eclampsia.
• Familial CFHR5 disease: counsel relatives; kidney failure risk is high in affected men.