C3 glomerulopathy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2] Aditya Ganti M.B.B.S. [3]

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Synonyms and keywords: Glomerulonephritis; C3 glomerulonephritis; dense deposit disease

Overview

C3 glomerulopathy is a complement system dysregulatory disorder resulting in abnormal activation of the alternative pathway. C3 glomerulopathy includes C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). Both, C3GN and dense deposit disease are characterized by marked by C3 deposition along the capillary loop, the basement membrane, and the mesangium. Identification of C3 deposits without any concomitant immunoglobulin deposition is characteristic for diagnosing C3 glomerulopathy. The activation of the alternative pathway of the complement system can be either due to inherited, or acquired defects of the complement system. Gene mutations are the most common inherited causes while autoimmune disorders are responsible for acquired glomerulopathy.

Historical Perspective

Classification

  • Initially, C3 glomerulopathy was categorized as a variant of MPGN, namely MPGN type 2. [5][6]
  • However in 2007, Servais A. et al described C3GN as an separate entity.
  • C3 Glomerulopathy may be classified into 2 main subtypes based on the appearance of complement deposition in the glomerular basement membrane on EM:
    • Dense deposit disease (DDD)
      • Dense deposition of compliment in linear pattern.
    • C3 Glomerulonephritis (C3GN)
      • Isolated deposition of C3.

Pathophysiology

  • Excessive activation of the alternative complement pathway is the inciting event in the pathogenesis of C3 glomerulopathy.[7]
  • Activation of alternative pathway results in excessive deposition of complement along the glomerular basement membrane.
  • Pattern of compliment deposition is regulated by:[8]
    • Leukocytic chemotaxis
    • Cytolytic effects of C5b-9

Physiology

Pathogenesis

  • Any mechanism by which C3 activity is increased leads to activation of alternate pathway activation resulting in complement deposition.[10][11]
    • C3 convertase autoantibody C3 nephritic factor
    • Loss of factor H

Causes

Common causes of C3 glomerulopathy include:[12]

  • C3 mutations
  • Mutation of Factor H (CHF)[13]
    • CFH is a small glycoprotein which is produced in the liver, and circulates freely in the blood plasma .
    • Primary role of factor H is to inhibit C3 convertase and thus not activating alternative complement pathway.
    • Two types of mutations are of important significance
      • Type 1 mutations are associated with decreased levels of CFH.
      • Type 2 mutations decrease or diminish the functional activity of CHF.
    • Autoantibodies against CFH. [14]
  • Auto antibody against C3 called as nephritic factor (C3bBb antibody).[15]

Differentiating C3 Glomerulopathy from other Diseases

Medical condition Differentiating features
C3 glomerulopathy
  • Persistent glomerulonephritis over prolonged period
  • Decreased C3 levels persist
  • Immunofluorescence microscopy shows intense C3 staining without immunoglobulin staining.
Lupus nephritis
  • Anti C1q autoantibodies
  • Immune complex glomerulonephritis
  • Glomerular deposits of IgG, IgM, IgA, C3 and C1q
Poststreptococcal glomerulonephritis
  • Glomeruonephritis in most cases resolves after infection subsides
  • Decreased levels of C3 is transient
  • Immunoflouroescence microscopy shows immunoglobulin deposition in poststreptococcal infection
Staphylococcal associated glomerulonephritis
  • Glomerulonephritis resolves after infection subsides
  • Decreased C3 is transient
  • Immunofluorescence microscopy shows immunoglobulin deposition in staphylococcal associated glomerulonephritis.

Epidemiology and Demographics

Risk Factors

Common risk factors in the development of C3 glomerulopathy include:

Screening

  • There is insufficient evidence to recommend routine screening for C3 glomerulopathy. However, screening is indicated for family members of affected individuals using genetic testing.

Natural History, Complications and Prognosis

Diagnosis

Diagnostic test of choice

Kidney biopsy is the gold standard test for the diagnosis of C3 glomerulopathy.

Symptoms

Common symptoms of C3 glomerulopathy may include:[18][19]

Characterstics DDD C3GN
Mean age 14 24
ESRD 50% in 10 years 10% in 2.5 years
Associated conditions -
C3 convertase dysregulation ↑↑
C5 convertase dysregulation ↑↑
C3NF +++ +
MAC ↑↑↑

Laboratory Findings

  • C3 glomerulopathy is diagnosed using immunofluorescence microscopy and electron microscopy.
  • There are no specific findings for C3 glomerulopathy on light microscopic.
  • Findings on electron microscopy include[20][21]
    • Sub-epithelial lumps
    • Abnormal electron-dense material within the GBM
      • Dense and linear in DDD
      • Isolated in C3GN
  • Findings on immunofluorescence microscopy include:
    • C3 deposits along the Bowman's capsule of glomerular and tubular basement membranes.

Other Diagnostic tests

Other diagnostic tests that can help in diagnosing C3 glomerulopathy include:

  • Measurement of complement C3, C3 Nef, serum factor H, CFHR ( Complement factor H-related protein)
  • Serum protein electrophoresis, immunofixation and serum free light chains
  • sMAC level activity

Physical Examination

Common physical examination findings of patients with C3 glomerulopathy include:

Imaging Findings

Treatment

Medical Therapy

  • The mainstay of treatment for C3 glomerulopathy is pharmacotherapy.[22][23]
  • Pharmacotherpay can be catagorized into:
    • Supportive therapy
    • Specific therapy based on disease severity

Supportive Therapy

Supportive therapy include antihypertensive medications and lipid lowering

  • Indicated in C3 glomerulopathy patients associated with HTN and proteinuria.
  • Preferred regimen (1): ACE-inhibitors
  • Preferred regimen (2): Angiotensin-11 receptor blockers

Specific therapy based on disease severity

  • Mild disease
    • Supportive therapy
    • Regular follow up
  • Moderate disease
    • Disease due to auto-antibody
      • Preferred regimen (1): Plasma exchange
      • Alternative regimen (1): Rituximab
      • Alternative regimen (2): Eculizumab 900 mg IV/week for 4-5 weeks followed by 1200 mg every 2 weeks for approximately one year.
    • Disease due to factor H deficiency
      • Preferred regimen (1): Fresh frozen plasma 10-15 mL/ kg body weight infused regularly x 14 days
    • Disease due to C3 mutation
  • Severe disease with rapidly progressive worsening renal function:

Surgery

  • Surgical intervention is not recommended for the management of C3 glomerulopathy

Prevention

References

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