Modern Classification of MPGN Subtypes
MPGN is no longer classified by the old electron microscopy-based system (Types I, II, III), but instead by three distinct immunofluorescence patterns that guide diagnosis and treatment: immune complex-mediated, complement-dominant, and immunofluorescence-negative. 1
The Three Primary Subtypes Based on Immunofluorescence
1. Immune Complex-Mediated MPGN (Immunoglobulin-Positive)
This subtype shows immunoglobulin deposits with or without complement on biopsy and is further subdivided based on whether the immunoglobulin shows monoclonal or polyclonal restriction 1:
Monoclonal Restriction Pattern:
- Plasma cell disorders 1
- Monoclonal gammopathy of undetermined significance (MGUS) 1
- Proliferative GN with monoclonal immune deposits (PGNMID) - notably, a clonal process is found in only 30% of these cases 1
- Chronic lymphocytic leukemia (CLL) and lymphoma 1
Polyclonal Immune Complex Deposition:
Infectious causes:
- Hepatitis B and C (including HCV-associated mixed cryoglobulinemia) 1
- Bacterial endocarditis and infected ventriculo-atrial shunts 1
- Chronic microbial infections (fungal, parasitic, protozoal, mycoplasma, mycobacterial) 1
- Visceral abscesses, leprosy, meningococcal meningitis 1
Autoimmune disorders:
- Systemic lupus erythematosus (SLE) 1
- Sjögren syndrome 1
- Rheumatoid arthritis 1
- Mixed connective tissue disease 1
Other causes:
- Castleman disease 1
- Cystic fibrosis, celiac disease 1
- Sickle cell disease, sarcoidosis 1
- α1-Antitrypsin deficiency 1
2. Complement-Dominant MPGN (Immunoglobulin-Negative, Complement-Positive)
This pattern shows complement deposition without immunoglobulins and indicates dysregulation of the alternative complement pathway 1:
C3 Glomerulopathy (C3G):
Pathogenic mechanisms include:
In children:
- Genetic mutations in C3, complement factors H, I, B 1
- CD46 (membrane cofactor protein) mutations 1
- Complement factor H-related proteins (CFHR) 1-5 mutations 1
In adults:
Critical diagnostic caveat: Infection-related GN or post-infectious GN must be ruled out before assigning the diagnosis of C3 glomerulopathy, as infections can trigger underlying complement abnormalities 1
3. Immunofluorescence-Negative MPGN (Immunoglobulin-Negative, Complement-Negative)
This pattern shows neither immunoglobulin nor complement deposits and predominantly reflects vascular diseases 1:
- Thrombotic microangiopathies (TMA) 1
- Thrombotic thrombocytopenic purpura (TTP) 1
- Hemolytic uremic syndrome (HUS) 1
- Sickle cell disease 1
- Scleroderma 1
- Transplant glomerulopathy 1
- Antiphospholipid syndrome 1
- Malignant hypertension 1
Why the Old Classification System Was Abandoned
The historical electron microscopy-based classification (Types I, II, III) lacked specificity for underlying diagnosis and did not help delineate the underlying cause or guide treatment 1. Light microscopy findings of basement membrane duplication ("tram-tracking") and lobular appearance, while characteristic, occur across multiple etiologies 1. The modern immunofluorescence-based system directly correlates with distinct pathogenetic mechanisms and guides appropriate workup and treatment 1.
Essential Workup Based on Subtype
For immune complex-mediated MPGN with monoclonal restriction:
- Serum and urine protein electrophoresis with immunofixation 1
- Serum free light chain analysis 1
- Hematology consultation for evaluation of clonal process 1
For complement-dominant MPGN:
- Comprehensive complement analysis even in the absence of hypocomplementemia 1
- Genetic screening in children for complement mutations 1
- Testing for C3NeF and anti-factor H antibodies in adults 1
For all MPGN patterns:
- Extensive workup for secondary causes before labeling as "idiopathic" 1
- Evaluation for plasma cell dyscrasias 1
True idiopathic MPGN is rare and will likely become even rarer as additional underlying disease mechanisms are identified 1.