Dense Deposit Disease

Dense deposit disease is a form of C3 glomerulopathy defined by electron dense, ribbon like intramembranous deposits within the glomerular basement membrane, with C3-dominant staining on immunofluorescence. It was formerly called type II membranoproliferative glomerulonephritis.

It is caused by uncontrolled fluid phase activation of the alternative complement cascade, most commonly through C3 nephritic factor (present in 80%), factor H autoantibodies, or factor H and related gene variants. It typically presents in children and adolescents aged 5 to 15 years and carries a worse prognosis than C3 glomerulonephritis: about half of patients reach kidney failure within 10 years.

Extrarenal disease. Acquired partial lipodystrophy (loss of fat from the face and upper trunk, linked to C3 nephritic factor) and retinal drusen with macular degeneration, present in most patients, appear years after kidney disease and can threaten sight.

• Haematuria (microscopic, with episodes of macroscopic haematuria after infections), proteinuria (nephrotic syndrome in about 50%), hypertension, oedema.
• Nephritic presentation after an upper respiratory tract infection that does not resolve.
• Slowly declining kidney function; occasional rapid progression with crescents.
• Partial lipodystrophy; visual disturbance (distortion, blurring) from drusen and choroidal neovascularisation.
• Recurrence in a transplanted kidney in 80 to 90% of patients, often within the first year.

Red flags

• Rapid loss of kidney function or crescents on biopsy.
• Visual symptoms: urgent ophthalmology review.
• Thrombosis or anasarca with severe hypoalbuminaemia.
• Fall in C3 with new haemolysis: thrombotic microangiopathy.

• Urine microscopy, protein:creatinine ratio, creatinine, eGFR, albumin, lipids.
• Low C3 with normal C4 (low in about 60 to 80%), soluble C5b-9, C3 nephritic factor (functional haemolytic assay), anti-factor H antibodies, factor H level, complement gene sequencing.
• Screen for paraprotein in adults: serum protein electrophoresis, immunofixation and free light chains.
• Biopsy: light microscopy shows membranoproliferative, mesangial proliferative or crescentic patterns; immunofluorescence has bright C3 with little immunoglobulin; electron microscopy shows dense, ribbon like intramembranous deposits with an irregularly thickened basement membrane (diagnostic).
• Fundoscopy and retinal imaging (optical coherence tomography) for drusen; clinical review of body fat distribution.

Differential diagnosis

• C3 glomerulonephritis (no intramembranous ribbons), post-infectious glomerulonephritis, immune complex membranoproliferative glomerulonephritis, lupus nephritis, thrombotic microangiopathy, hypocomplementaemic urticarial vasculitis.

Supportive care for all patients

• Blood pressure under 130/80 mmHg (age adjusted target in children); ramipril 2.5 mg daily increased to 10 mg daily with creatinine and potassium checked in 1 to 2 weeks; stop if potassium exceeds 6.0 mmol/L.
• Dapagliflozin 10 mg daily with eGFR at least 25, or empagliflozin 10 mg daily with eGFR at least 20.
• Sodium restriction under 2 g daily; furosemide 40 to 80 mg for oedema; statin; vaccination against pneumococcus, meningococcus and Haemophilus influenzae type b.

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

• Prednisolone 0.5 to 1 mg/kg daily (maximum 60 mg) reduced over 6 months, with mycophenolate mofetil 1 g twice daily (up to 1.5 g twice daily) for at least 12 months. Crescentic disease: methylprednisolone 500 mg to 1 g intravenously daily for 3 days first.
• Complement inhibition for persistent disease: iptacopan 200 mg orally twice daily, pegcetacoplan 1080 mg subcutaneously twice weekly, or eculizumab 900 mg intravenously weekly for 4 doses, 1200 mg at week 5, then 1200 mg every 2 weeks (vaccination against Neisseria meningitidis at least 2 weeks before, and penicillin V 500 mg twice daily during therapy if vaccination is delayed).
• C3 nephritic factor positive disease not responding: rituximab 375 mg/m² weekly for 4 doses.
• Factor H deficiency or antibodies: plasma infusion 10 to 15 mL/kg every 2 weeks or plasma exchange.

Eye care. Ophthalmology review annually; anti-vascular endothelial growth factor injections for choroidal neovascularisation.

Kidney failure and transplantation

• Dialysis and transplant planning when eGFR is under 15 mL/min/1.73 m²; recurrence is high, so discuss complement inhibition prophylaxis around the time of transplantation and avoid living related donors with shared genetic variants.

Monitoring. Creatinine, protein:creatinine ratio and C3 every 3 months; visual acuity annually.

Referral and escalation. Specialist nephrology (paediatric if under 18), ophthalmology, and transplant centre.

Special groups

• Children: mycophenolate mofetil 600 mg/m² twice daily (maximum 1 g twice daily); eculizumab by weight; growth monitoring.
• Pregnancy: avoid mycophenolate and ACE inhibitors; high risk of relapse and pre-eclampsia.