Membranoproliferative Glomerulonephritis: Understanding the Evolving Classification and Pathogenic Mechanisms

Membranoproliferative glomerulonephritis (MPGN) has long been a challenging diagnosis for nephrologists due to its complex pathology and diverse underlying causes. Historically, MPGN was classified into three subtypes—Type I, Type II, and Type III—based primarily on electron microscopy findings. These classifications helped guide initial treatment approaches but failed to fully capture the disease's immunological and molecular diversity.

The Shift from Morphology-Based to Mechanism-Based Classification

In recent years, advances in immunology and complement system research have led to a paradigm shift in how MPGN is understood and categorized. Rather than relying solely on structural appearance under the microscope, clinicians and pathologists now classify MPGN based on its underlying pathogenic mechanisms. This updated framework divides MPGN into three main mechanistic categories: immune complex-mediated, complement-mediated (due to dysregulation of the alternative pathway), and a rare form that involves neither immune complexes nor complement deposition.

Immune Complex-Mediated MPGN: When Trapped Antigens Trigger Inflammation

Immune complex-mediated MPGN occurs when antigen-antibody complexes deposit in the glomerular basement membrane, activating the complement cascade and attracting inflammatory cells. This leads to thickening of the basement membrane and proliferation of mesangial cells—hallmarks of MPGN. This subtype is often secondary to conditions such as chronic infections (e.g., hepatitis B or C), autoimmune disorders like systemic lupus erythematosus (SLE), or monoclonal gammopathies including multiple myeloma.

Diagnosis typically involves immunofluorescence testing showing deposits of immunoglobulins (such as IgG or IgM) and complement components like C3. Identifying and treating the underlying cause is crucial in managing this form effectively, as resolution of the primary condition can sometimes lead to remission of kidney disease.

Complement-Mediated MPGN: Dysregulation of the Alternative Pathway

A major breakthrough in nephrology has been the recognition of complement-mediated MPGN, where abnormal regulation of the alternative complement pathway results in continuous activation and damage to the glomeruli—despite the absence of immune complexes. In these cases, only complement components, particularly C3, are found deposited in the kidneys.

This category is further subdivided into C3 glomerulopathy and, less commonly, C4 glomerulopathy, depending on which complement protein dominates the deposits. Genetic mutations in regulators such as Factor H, Factor I, or CD46, as well as autoantibodies like C3 nephritic factor, are frequently implicated. These discoveries have opened doors to targeted therapies, including eculizumab and other complement inhibitors, offering new hope for patients with previously refractory disease.

Rare Forms: Non-Immune, Non-Complement MPGN

The third and rarest category includes cases where neither immune complexes nor complement proteins are significantly deposited. The exact mechanism remains poorly understood, and diagnosis often requires exclusion of other known causes. These forms may represent novel disease pathways or unusual presentations of other systemic conditions affecting the kidneys.

Clinical Implications and Future Directions

The transition from a purely histological classification to a mechanism-driven model has transformed the approach to diagnosing and treating MPGN. Accurate subtyping now requires a combination of light microscopy, immunofluorescence, electron microscopy, and increasingly, genetic and serological testing for complement abnormalities.

For clinicians, this means a more personalized treatment strategy—whether it's antiviral therapy for infection-related cases, immunosuppression for autoimmune forms, or complement-targeted drugs for those with pathway dysregulation. Ongoing research continues to refine our understanding, promising even more precise diagnostics and effective interventions in the near future.