Differential diagnosis of MPGN and C3G 

Current overview of MPGN and C3 Glomerulopathy

Once secondary causes have been excluded, an abnormality of complement dysregulation should be considered in MPGN and C3G. In these overlapping conditions, C3 deposition is usually present. MPGN is shown in dashed circle and includes IC-MPGN (Ig and C3 deposition – Green) and C3G (Dominant C3 deposition). C3G is shown in large circle (pink) any can associate with an MPGN pattern of glomerular injury. Specific forms of C3G include C3GN, DDD and CFHR5 nephropathy.

Cases of MPGN that do not fulfil the criteria of C3G should be termed immune-complex MPGN. Disorders of complement dysregulation have been identified in cases of immune-complex MPGN and should be sought once secondary causes of MPGN have been excluded. This overlap of MPGN and C3G in which a disorder of complement dysregulation could be considered is summarised in the figure below.   

Diseases associated with C3G

Drusen, age-related macular degeneration and acquired partial lipodystrophy have been reported in association with C3G and should be considered.

Familial history has been reported in cases of C3G.

In particular, large pedigrees of C3G have been identified with Cypriot ancestry with CFHR5 nephropathy. 



Membranoproliferative Glomerulonephritis

Membranoproliferative glomerulonephritis (MPGN) is a pattern of glomerular injury defined by mesangial expansion, cellular proliferation and double contouring of glomerular basement membrane. It was historically classified according to the relationship of electron dense deposits to the glomerular basement membrane (type 1 – sub-endothelial, 2 – intramembranous and 3 – sub-endothelial and sub-epithelial). 

An MPGN pattern of glomerular injury (usually type 1 or type 3) is associated with a number of secondary causes. These usually have a pattern of C3 and immunoglobulin staining on IF and are best classified as immune-complex MPGN. MPGN has also been historically associated with C3 dominant staining on IF, (a pattern now better recognised as C3G). Secondary causes of MPGN (usually immune-complex MPGN) include infective diseases, auto-immune conditions and haematological disorders. A list of possible causes that could be considered are listed below. Drusen, age-related macular degeneration and acquired partial lipodystrophy have been reported in association with MPGN. Familial history has been reported in cases of MPGN. 

A pattern of C3 dominant staining on IF was previously recognised in all types of MPGN that prompted the possibility of a disorder of complement regulation. These have now been reclassified as C3G (with MPGN). 

Secondary causes of MPGN:

Autoimmune diseases 

  • Systemic lupus 
  • Sjogren’s syndrome 
  • Rheumatoid arthritis 
  • Mixed connective tissue disease 


  • Hepatitis B 
  • Hepatitis C 
  • Epstein-Barr virus 
  • Human immunodeficiency virus 
  • Endocarditis 
  • Shunt infections 
  • Visceral abscesses 
  • Leprosy 
  • Malaria 
  • Schistosomiasis 
  • Mycoplasma 
  • Brucellosis 


  • Monoclonal gammopathy of undetermined significance 
  • Plasma Cell dyscrasia 
  • Waldenstrom macroglobulinaemia 
  • Chronic lymphocytic leukaemia 
  • Low-grade B-cell lymphoma 
  • Cryoglobulinaemia type 1 and 2 
  • Immunotactoid glomerulopathy 
  • Monoclonal Ig deposition disease 
  • Fibrillary glomerulopathy 
  • Carcinomas, Wilms’ tumour, malignant melanoma 

Chronic liver disease 

  • Chronic active hepatitis (B,C) 
  • Cirrhosis 
  • Alpha-1 antitrypsin deficiency 


  • Thrombotic microangiopathy 
  • Sickle cell disease 
  • Transplant glomerulopathy 
  • Niemann-Pick disease (Type C) 

More Information

Pathophysiology of C3G

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Diagnosis of C3G

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