Key Points:

• Membranoproliferative Glomerulonephritis (MPGN) = a pattern of injury characterized by chronic deposition of Ig, complement, and/or fibrin along the glomerular capillary wall, leading to cycles of inflammation and repair
  • LM: mesangial and endocapillary hypercellularity, mesangial expansion (often appears lobular), cellular interposition with double contour formation
  • IF: varies depending on the nature of the deposits (see below)
  • EM: mesangial/capillary wall (subendothelial) deposits, cellular interposition and new basement membrane formation leading to double contours.
• The old MPGN classification system (Type I, II, or III) was based on the deposit location by EM. Now, we classify MPGN based on deposit composition by IF .
  • Ig +/- C3 suggests an Ig (including cryoglobulin) mediated process: think dysproteinemia, autoimmune disease, or infection
  • Dominant C3 (staining 2 orders of magnitude greater than any other immune reactant) suggests a complement mediated process: think C3 glomerulopathy, which includes C3 Glomerulonephritis (C3GN) and Dense Deposit Disease (DDD)
• The underlying pathophysiology of C3 glomerulopathy involves dysregulation and overactivation of the alternative pathway of the complement system.
  • E.g. loss of CFH inhibition (mutations in CFH or auto-antibodies to CFH), CFH deregulation (from altered CFHR proteins), autoantibodies that stabilize C3 convertase (C3 nephritic factor), or impaired inactivation of C3b.
  • This results in overactivity of C3 convertase and then C5 convertase, with resulting deposition of complement proteins in the glomerulus.

• In a Mayo clinic cohort of patients with C3 glomerulopathy, three basic triggers were identified: monoclonal Ig (especially in DDD), infections, and autoimmune disease.
  • Monoclongal Igs were more identified more frequently (~65%) in those older than 50. Pathogenic variants in complement protein genes were rare. These patients tended to do worse clinically.
    • The underlying etiology of the monoclonal Ig included MGRS, myeloma, smoldering myeloma, CLL/lymphoma, and cryoglobulinemia.
    • Treatment targeting monoclonal Ig resulted in remission/stabilization of kidney function in some patients. Hematologic remission was associated with renal remission in this patient subgroup.
  • If there was no monoclonal immunoglobulin detected, 60% of patients had a genetic variant identified.
• Mass spectrometry has been used to determine deposit composition in C3GN and DDD.
  • Both C3 GN and DDD are characterized by large amounts of C3. Less C5-C9 was identified in DDD vs. C3 GN, suggesting a greater role for C5 convertase over activity (vs. C3 convertase over activity) in C3GN than in DDD.
  • In both C3GN and DDD, C3dg was the predominant C3 cleavage product detected.
• Among Mayo clinic patients, there has been no significant difference in response to therapy between conservative vs. immunosuppressive (steroids, MMF, eculizumab, tacrolimus, rituximab) therapy. Approximately 50% reach ESRD at 5 years.

References:

https://www.ncbi.nlm.nih.gov/pubmed/17018561

https://www.ncbi.nlm.nih.gov/pubmed/22435371

https://www.ncbi.nlm.nih.gov/pubmed/25447133

https://www.ncbi.nlm.nih.gov/pubmed/26185203

https://www.ncbi.nlm.nih.gov/pubmed/22456601

https://www.ncbi.nlm.nih.gov/pubmed/23623956

https://www.ncbi.nlm.nih.gov/pubmed/24408117