C3 glomerulopathy
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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
- In 1915, William C. Gunn was first to report an association of low circulating complement levels in patients with acute infection and nephritic presentation.
- Based on the William's observations, role of complement system in inflammatory glomerulonephritis was well described.
- In 1962, Jean Berger and Pierre Galle, Nephro-pathologists, was the first to identify dense intramembranous deposits on transmission EM .
- Mathew TH, Kinaid Smith P coined the term dense deposit disease (DDD).

# Classification
- Initially, C3 glomerulopathy was categorized as a variant of MPGN, namely MPGN type 2. 
- 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.
- Dense deposit disease (DDD)
Dense deposition of compliment in linear pattern.
- Dense deposition of compliment in linear pattern.
- C3 Glomerulonephritis (C3GN)
Isolated deposition of C3.
- Isolated deposition of C3.

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

### Physiology
- Spontaneous cleavage of C3 to C3b results in activation of C3 convertase.
- C3 convertase along with factor B and properdin catalyses the cascade of producing C5 convertase.
- C5 convertse cleaves 5 to C5a initiating C5b-9 ( MAC complex)
- Physiologically activation of C5 convertase is directly related to C3 convertase.
- Factors that can influence and control C3 convertase activity include
Serum protein
Factor H (inhibits the C3 convertase)
- Serum protein
- Factor H (inhibits the C3 convertase)

### Pathogenesis
- Any mechanism by which C3 activity is increased leads to activation of alternate pathway activation resulting in complement deposition.
C3 convertase autoantibody C3 nephritic factor
Loss of factor H
- C3 convertase autoantibody C3 nephritic factor
- Loss of factor H

# Causes
Common causes of C3 glomerulopathy include:
- C3 mutations
- Mutation of Factor H  (CHF)
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. 
- 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.
- Type 1 mutations are associated with decreased levels of CFH.
- Type 2 mutations decrease or diminish the functional activity of CHF.
- Autoantibodies against CFH. 
- Mutation of membrane cofactor protein ( MCP)
MCP is a transmembrane protein, expressed by all nucleated cells and located at the cell surfaces.
Together with Complement Factor I (CFI), MCP is required for the inactivation of C3b,
- MCP is a transmembrane protein, expressed by all nucleated cells and located at the cell surfaces.
- Together with Complement Factor I (CFI), MCP is required for the inactivation of C3b,
- Auto antibody against C3 called as nephritic factor (C3bBb antibody).

# Differentiating C3 Glomerulopathy from other Diseases

# Epidemiology and Demographics
- The prevalence of C3 glomerulopathy is approximately 3 per 100,000 individuals worldwide.
- Patients of all age groups may develop C3 glomerulopathy but it commonly affects young adults and children (Dense deposit disease)
- C3 glomerulopathy affects men and women equally.
- There is no racial predilection for C3 glomerulopathy.

# Risk Factors
Common risk factors in the development of C3 glomerulopathy include:
- Family history of C3 glomerulopathy
- H/O  autoimmune disorders

# 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
- Common complications of C3 glomerulopathy include renal failure, atherosclerosis, and vision loss.
- Prognosis of C3 glomerulopathy is generally poor without proper treatment.
- 10 year mortality of patients with C3 glomerulopathy is approximately 36%.

# 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:
- Foamy urine due proteinuria
- Hematuria
- Signs of renal insufficiency like general fatigue or malaise
- Hypertension
- Hypocomplementimia
- Acquired lipodystrophy
- Macular (Drusen) deposits in the retina of the eye

### 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
Sub-epithelial lumps
Abnormal electron-dense material within the GBM
Dense and linear in DDD
Isolated in C3GN
- Sub-epithelial lumps
- Abnormal electron-dense material within the GBM
Dense and linear in DDD
Isolated in C3GN
- 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.
- 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:
- High blood pressure
- Pallor skin
- Edema of extremities
- Periorbital Edema
- Lipodystrophy

### Imaging Findings
- There are no specific imaging findings associated with C3 glomerulopathy.

# Treatment

## Medical Therapy
- The mainstay of treatment for C3 glomerulopathy is pharmacotherapy.
- Pharmacotherpay can be catagorized into:
Supportive therapy
Specific therapy based on disease severity
- 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
- 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
Preferred regimen (1): Plasma exchange
- 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.
- 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
- Preferred regimen (1): Fresh frozen plasma 10-15 mL/ kg body weight infused regularly x 14 days
- Disease due to C3 mutation
Preferred regimen (1): Plasma exchange
- Preferred regimen (1): Plasma exchange
- Severe disease with rapidly progressive worsening renal function:
Preferred regimen (1): Cyclophosphamide
Preferred regimen (2): Mycophenolate mofetil
- Preferred regimen (1): Cyclophosphamide
- Preferred regimen (2): Mycophenolate mofetil

## Surgery
- Surgical intervention is not recommended for the management of C3 glomerulopathy

## Prevention
- There are no primary preventive measures available for C3 glomerulopathy.