# Membranoproliferative Glomerulonephritis

## Overview & Classification Evolution

MPGN is a *pattern* of glomerular injury characterized by endocapillary proliferation and thickening of the GBM. The 2016 classification fundamentally reorganized MPGN based on **immunofluorescence patterns and pathogenic mechanisms** rather than EM appearance alone.

#### Traditional Classification (Pre-2016)

- **Type I:** Subendothelial deposits
- **Type II (DDD):** Intramembranous "dense" deposits
- **Type III:** Subendothelial + subepithelial deposits

#### Modern Classification (2016+)

**I. Immune-Complex MPGN:** Dominant Ig deposits on IF. Associated with lupus, post-infectious GN, cryoglobulinemia.

**II. Complement-Mediated (C3-Dominant):** C3-dominant/exclusive on IF. Subdivided into DDD and C3-GN.

**📚 Key Point:** Modern MPGN classification prioritizes IF pattern and genetic/molecular mechanism over EM appearance. This shift has enabled targeted therapy for complement-mediated disease.

## Pathophysiology: Complement Dysregulation

### Alternative Pathway Activation (C3-Mediated MPGN)

Results from uncontrolled alternative complement pathway activation:

- **Factor H mutations** (most common; impairs C3 regulation)
- **Factor B mutations** (alternative pathway amplification)
- **C3 mutations** (rare, highly penetrant)
- **CFHR1-CFHR5 mutations** (factor H-related proteins)
- **Acquired:** Anti-FH antibodies, C3 nephritic factors

### Dense Deposit Disease (DDD) Distinctive Features

- Intramembranous "ribbon-like" electron-dense deposits
- Often associated with C3-nephritic factors or complement gene mutations
- More aggressive course: **70% progression to ESRD at 10 years** without treatment

## Clinical Presentation

- **Hematuria:** Microscopic or gross; persistent or recurrent
- **Proteinuria:** Mild to nephrotic (0.5–10 g/day)
- **Hypertension:** Common
- **Edema:** Variable depending on proteinuria severity

## Diagnosis

### Critical Complement Distinction

| Finding | Immune-Complex MPGN | C3-MPGN |
|----|----|----|
| **C3** | Usually low | Low/normal (dominant pattern) |
| **C4** | Low (classical pathway) | Normal |
| **IF Pattern** | Ig-dominant (IgG, IgM, IgA) ± C3 | C3-dominant or C3-exclusive |
| **Serologies** | Often positive (ANA, HCV, cryoglobulins) | Negative |

**📚 Clinical Pearl:** Low C3 + hematuria + proteinuria + seronegative workup is classic for C3-MPGN. Immune-complex MPGN typically has positive serology and may be reversible if the underlying disease is treated.

### Biopsy: LM Hallmarks

- Endocapillary proliferation with membranoproliferative pattern
- GBM duplication ("tram-track" appearance)
- Mesangial expansion
- Leukocyte infiltration (especially immune-complex MPGN)

## Treatment Approaches

### Immune-Complex MPGN: Address the Underlying Cause

- **Post-infectious GN:** Supportive care; often recovers
- **Lupus GN:** MMF + corticosteroids per SLE guidelines
- **Cryoglobulinemia:** Direct-acting antivirals for HCV; rituximab for vasculitis

### C3-Mediated MPGN: Complement-Targeted Therapy

**📚 Key Point:** Complement inhibition has revolutionized C3-MPGN/DDD treatment. Pegcetacoplan and emerging Factor D inhibitors show promise for inducing remission and halting progression.

- **Pegcetacoplan (C3 inhibitor):** FDA-approved for C3-MPGN; can induce remission/slow progression
- **Iptacopan (Factor D inhibitor):** Emerging evidence in C3-MPGN trials
- **Eculizumab (C5 inhibitor):** Limited efficacy in C3-GN alone; may help in some DDD cases

### Supportive Care (All Patients)

- ACE-I/ARB to reduce proteinuria
- BP control (\<120/80 mmHg target)
- Pneumococcal and meningococcal vaccines (especially before complement inhibitors)

## Prognosis

| Subtype | 10-Year Renal Survival | Key Factors |
|----|----|----|
| Post-infectious | 85–95% | Age \<50, preserved GFR |
| Lupus-associated | 70–85% | Lupus activity; nephritis class |
| Cryoglobulinemia-related | 60–75% | HCV viral load; treatment response |
| DDD (untreated) | 30% | 70% progress to ESRD by 10 years |
| C3-GN with mutations | 40–50% | Without complement-targeted therapy |

**⚠️ Post-Transplant Recurrence:** C3-MPGN/DDD has a 50–80% recurrence rate post-transplant. Consider complement-targeted therapy prophylactically; monitor with protocol biopsies.

## Special Considerations

### Monoclonal Immunoglobulin Deposition (MGRS)

Some MPGN cases present with monoclonal IgG/IgM deposits (kappa or lambda restricted). May represent **Monoclonal Gammopathy of Renal Significance (MGRS)**. Requires hematology evaluation and plasma cell-directed therapy.

## Clinical Pearls & Practice Points

1.  **Always interpret complement levels with immunofluorescence together** — C3-dominant staining with low serum C3 raises suspicion for complement-mediated disease, but infection-related GN must be excluded before diagnosing C3 glomerulopathy
2.  **Post-infectious MPGN may resolve spontaneously** — avoid aggressive immunosuppression
3.  **Genetic testing for complement mutations** increasingly recommended in C3-MPGN
4.  **Complement inhibition represents a paradigm shift** for C3-MPGN/DDD
5.  **DDD morphology portends aggressive disease** — early complement-targeted agents recommended

## References

1.  Sethi S, Fervenza FC. MPGN — a new look at an old entity. *NEJM*. 2012;366(12):1119-1131. [PubMed](https://pubmed.ncbi.nlm.nih.gov/22435371/)
2.  Pickering MC, et al. C3 glomerulopathy: consensus report. *Kidney Int*. 2013;84(6):1079-1089. [PubMed](https://pubmed.ncbi.nlm.nih.gov/24172683/)
3.  Bomback AS, et al. Eculizumab for dense deposit disease and C3 glomerulopathy. *CJASN*. 2012;7(5):748-756. [PubMed](https://pubmed.ncbi.nlm.nih.gov/22403278/)
4.  Jokiranta TS. HUS and atypical HUS. *Blood*. 2017;129(21):2847-2856. [PubMed](https://pubmed.ncbi.nlm.nih.gov/28416508/)

© Urine Nephrology Now — Clinical Mastery Series


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