What are the clinical presentation, laboratory findings, biopsy characteristics, and recommended management (including ACE inhibitor/angiotensin‑converting enzyme inhibitor, ARB/angiotensin receptor blocker, eculizumab, plasma exchange, corticosteroids, and immunosuppressants) for dense deposit disease?

Dense Deposit Disease: Clinical Overview and Management

Diagnostic Characteristics

Dense deposit disease (DDD) is definitively diagnosed by the pathognomonic finding of highly osmiophilic, intramembranous, continuous electron-dense deposits along large segments of the glomerular basement membrane on electron microscopy, appearing less discrete and more confluent than typical immune-complex deposits. 1

Clinical Presentation

• Nephrotic syndrome is the most common presentation, with edema and nephrotic-range proteinuria 2, 3
• Nephritic syndrome with hematuria (microscopic or gross), hypertension, and acute kidney injury 4
• Acute kidney injury with rapidly progressive glomerulonephritis, sometimes with crescentic features 2
• Recurrent gross hematuria may occur with intercurrent infections, particularly streptococcal infections 4
• Partial lipodystrophy is an associated finding in some patients 2

Laboratory Findings

The hallmark laboratory abnormality is persistently low serum C3 levels with normal C4, indicating alternative complement pathway dysregulation. 2, 4

• C3 nephritic factor (C3NeF) is positive in many patients, representing an autoantibody that stabilizes the C3 convertase 2, 4, 5
• Anti-factor B autoantibodies may be present even when C3NeF is negative 5
• Complement factor H (CFH) polymorphisms or decreased CFH levels are frequently detected 2, 4
• Nephrotic-range proteinuria (>3.5 g/day or UPCR >3.5 g/g) 2
• Hypoalbuminemia in nephrotic presentations 2
• Normal or elevated C4 distinguishes DDD from immune-complex disease 6

Renal Biopsy Characteristics

Light microscopy typically shows:

• Membranoproliferative pattern with mesangial proliferation and capillary wall thickening 1
• Crescents may be present in aggressive cases 2
• Endocapillary proliferation in some cases 4

Immunofluorescence microscopy shows:

• Dominant or isolated C3 staining along glomerular capillary walls and mesangium (C3 glomerulopathy pattern) 1
• Minimal or absent immunoglobulin staining, distinguishing it from immune-complex disease 1
• Rare cases may show C4d staining (C4 DDD variant) 6

Electron microscopy (diagnostic gold standard):

• Highly osmiophilic, ribbon-like intramembranous deposits within the glomerular basement membrane 1
• Deposits appear as continuous, confluent, ill-defined segments rather than discrete deposits 1
• Mesangial deposits may also be present 1

Management Strategy

Supportive Care (First-Line for All Patients)

Initiate ACE inhibitor or ARB immediately and uptitrate to maximum tolerated dose, targeting systolic blood pressure <120 mmHg using standardized office measurements. 1, 7

• Blood pressure control: Target SBP <120 mmHg with ACE inhibitor or ARB as first-line therapy 1, 7
• Proteinuria reduction: Uptitrate RAS blockade to maximum FDA-approved dose 1, 7
• Dietary sodium restriction: Limit to <2.0 g/day (<90 mmol/day) to enhance antiproteinuric effect 1, 7
• Diuretics: Add potassium-wasting diuretics for volume management and to allow continued RAS blockade despite hyperkalemia 1, 7
• Potassium management: Use potassium-binding agents if needed to maintain normal potassium and continue RAS blockade 1, 7
• Lipid management: Consider statin therapy for persistent hyperlipidemia, especially with cardiovascular risk factors 1

Immunosuppressive Therapy

Traditional immunosuppression (corticosteroids, cyclophosphamide, mycophenolate) has limited efficacy in DDD and should generally be avoided unless crescentic disease is present. 1, 2

• Corticosteroids: May be attempted in crescentic DDD with rapidly progressive renal deterioration, but efficacy is limited 2
• Cyclophosphamide: Consider only for crescentic DDD with >50% crescents and rapidly progressive kidney injury, using protocols similar to ANCA vasculitis 1, 8, 2
• Avoid routine immunosuppression: Standard immunosuppressive regimens used for other glomerulonephritides are generally ineffective 2, 3

Plasma Exchange

Plasma exchange may provide temporary benefit but does not achieve sustained remission as monotherapy. 2, 3

• Consider for acute severe presentations with rapidly declining kidney function 2, 3
• Typically requires multiple sessions but effects are transient 2, 3
• Should not be used as sole therapy; consider as bridge to complement-targeted therapy 2, 3

Eculizumab (Complement C5 Inhibitor)

Eculizumab represents the most promising targeted therapy for DDD, particularly in patients with preserved kidney function or post-transplant recurrence, by blocking terminal complement activation. 2, 3

Indications for eculizumab:

• Failure of corticosteroids and/or plasmapheresis to control proteinuria 2
• Persistent low C3 levels despite supportive care 2
• Crescentic DDD with preserved renal function (eGFR >30 mL/min/1.73m²) 2
• Post-transplant recurrence of DDD 3
• Positive C3NeF or anti-factor B autoantibodies with progressive disease 2, 5

Dosing and monitoring:

• Standard dosing: 900 mg weekly × 4 weeks, then 1200 mg at week 5, then 1200 mg every 2 weeks 2, 3
• Mandatory meningococcal vaccination at least 2 weeks before starting therapy 2, 3
• Monitor for complement inhibition, proteinuria reduction, and preservation of renal function 2, 3
• Duration: Typically requires long-term therapy (≥18-30 months based on reported cases) 3

Expected outcomes with eculizumab:

• Marked reduction or remission of proteinuria within 3-6 months 2, 3
• Stabilization or improvement in kidney function 2, 3
• Normalization or improvement in C3 levels 2
• Prevention of histological progression on repeat biopsy 3

Special Considerations

Post-transplant management:

• DDD recurs in approximately 50% of transplanted kidneys, often within 3 months 3
• Early recurrence warrants immediate eculizumab therapy 3
• Prophylactic eculizumab may be considered in high-risk patients (positive C3NeF, CFH mutations) 3

Infection triggers:

• Streptococcal infections may trigger disease onset or exacerbations in genetically predisposed individuals 4
• Treat intercurrent infections promptly and consider antibiotic prophylaxis during high-risk periods 4

Genetic testing:

• Screen for CFH polymorphisms and other complement regulatory gene mutations 2, 4
• Positive findings support use of complement-targeted therapy and inform transplant risk 2, 4

Prognosis and Monitoring

Approximately 50% of patients progress to end-stage kidney disease within 10 years despite treatment, with high recurrence rates post-transplant. 3, 4

• Monitor proteinuria and eGFR every 3 months 1
• Target proteinuria reduction of ≥50% by 6 months 7
• Check C3 levels every 3-6 months to assess disease activity 2, 4
• Consider repeat biopsy if clinical deterioration occurs despite therapy 3

Critical counseling points:

• Counsel patients to hold ACE inhibitor/ARB during intercurrent illnesses to prevent acute kidney injury 1, 7
• Emphasize medication adherence, particularly for eculizumab if prescribed 2, 3
• Discuss high risk of post-transplant recurrence when planning for kidney transplantation 3