Dense Deposit Disease

Dense Deposit Disease

A. Brad Farris, III, MD

Dense deposit disease (DDD) often presents with an MPGN pattern, shown here in a biopsy from a 13-year-old boy with gross hematuria and proteinuria 3 days after a meningococcal septicemia. Serum C3 was undetectable.

The diagnosis of DDD is made by electron microscopy, which reveals extremely dark, osmiophilic deposits along the GBM image. Deposits are found also in the mesangium, Bowman capsule, and TBM.



  • Dense deposit disease (DDD)


  • Membranoproliferative glomerulonephritis (MPGN), type II


  • C3-related glomerulopathy manifested by broad, linear, extremely electron-dense deposits with C3 within GBM, mesangium, Bowman capsule, and TBM

    • Once classified as variant of MPGN, but MPGN pattern present in < 50%

    • Hyperdense deposits by EM are pathognomonic; therefore, DDD is preferred name

    • Initially reported by Galle and Berger in 1962


Chronic Activation of Alternative Complement Pathway

  • Autoantibodies to complement components

    • C3 nephritic factor (C3NeF): Autoantibody to C3 convertase of alternative pathway (C3bBb) prevents inactivation, resulting in continuous activation of complement alternative pathway

      • C3NeF present in > 80% of patients (˜ 100% children, ˜ 40% adults)

      • C3NeF may also be present in healthy individuals

      • Specificity of antibody affects functional consequences

    • Autoantibodies to CFH, factor B, or C3

  • Mutations in complement component genes

    • Factor H mutations lead to low plasma levels or affect its C3bBb decay function

      • Tyrosine 402 to histidine common

    • C3 mutation resistant to factor H in fluid phase

Deposition of C3 in Lamina Densa of GBM

  • Local activation of complement pathway

    • Recruitment of leukocytes

    • Inflammatory damage of glomerular components

    • Loss of heparan sulfate (principal negative charge barrier)

Precipitating Factors

  • Infection, various (pneumonia, upper respiratory)

    • Group A streptococcal or meningococcal infections

  • Post chemotherapy for breast cancer

  • ˜ 20% of adults with DDD have monoclonal gammopathy including myeloma

  • ˜ 70% of patients have monoclonal gammopathy of undetermined significance

  • Some patients have multiple susceptibility factors

Animal Models

  • CFH mutation in Norwegian Yorkshire pigs

  • Mouse strain with CFH knockout

    • Prevented by combined factor B or factor I knockout

      • Proves necessity of alternative pathway convertase (C3bBb) and factor I-generated degradation products (iC3b, C3c, C3dg)



  • Incidence

    • Rare; estimated at 1-3 cases/million

      • Familial cases even rarer (˜ 6 patients reported)

  • Age

    • Primarily in children 5-15 years old

    • Increasingly appreciated in adults in recent series

      • ˜ 55% are > 16 years old

      • 40% of adults are > 60 years old

  • Gender

    • Female:male = 1.5:2


  • Hematuria (˜ 90%)

    • Macrohematuria (˜ 15%)/nephritic presentation

  • Proteinuria (˜ 95%)

    • Nephrotic range (˜ 60%)

    • Proteinuria may undergo rapid fluctuation

  • Renal insufficiency (˜ 50%)

  • Acquired partial lipodystrophy (APL) (3-5%)

    • Loss of subcutaneous fat in upper 1/2 of body may precede kidney disease onset by several years

    • ˜ 83% of APL patients have low C3 levels and polyclonal C3NeF

    • ˜ 20% go on to develop MPGN after median of 8 years after onset of lipodystrophy

  • Ocular drusen common

    • ˜ 10% develop decreased visual acuity

Laboratory Tests

  • Decreased serum C3 in ˜ 80% of patients

    • More common in children (100%) than adults (40%)

    • Increased C3dg and C3d

  • C3NeF (antibody to C3bBb) present in > 80% of MPGN II patients

    • Persists in > 50% during disease course

    • C3NeF present in ˜ 50% of MPGN, type I or III

  • CFH mutations


  • Drugs

    • Steroids, immunosuppression not effective

    • Complement inhibition with eculizumab (anti-CD5 antibody) under study

    • Heparinoids may be used to protect GBM from complement activation

  • Plasmapheresis and plasma exchange in patients with CFH mutations

    • Recombinant CFH


  • Spontaneous remission rare

  • ˜ 50% develop ESRD within 10-15 years

    • Mean time to ESRD is 5 years in adults, 20 years in children

  • Recurs in almost all renal allografts

    • ˜ 50% of allografts ultimately fail, typically in 1st 3 years


Histologic Features

  • Glomerular patterns

    • Membranoproliferative glomerulonephritis (25-45%)

      • Mesangial proliferation, thickened GBM, duplication sometimes evident

      • Eosinophilic and refractile and stain brightly with PAS; fuchsinophilic on trichrome

      • DDD deposits stain poorly with Jones stain

    • Mild mesangial hypercellularity (30-50%)

      • Normal GBM by light microscopy

    • Crescentic glomerulonephritis (10-20%)

      • Focal crescents in > 50% of cases

    • Acute glomerulonephritis (10-20%)

      • Poly- or mononuclear cells, mesangial hypercellularity, normal thickness of GBM

    • Necrosis uncommon (˜ 15%)

    • Focal, segmental, and global glomerulosclerosis, late

  • Tubules and interstitium

    • Usually not affected early in disease

    • Thickened TBM sometimes evident due to deposits

    • Tubular atrophy and intersitial fibrosis develop late in disease

  • Vessels

    • No specific changes

  • Follow-up biopsies

    • Less acute glomerular inflammation

    • Increased glomerulosclerosis, tubular atrophy, fibrosis

    • Transitions

      • Progression from mesangial proliferative GN to MPGN pattern

      • Resolution of crescentic GN to mesangial proliferative GN

Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Dense Deposit Disease

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