Membranoproliferative glomerulonephritis pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Ali Poyan Mehr, M.D. [2] Associate Editor(s)-in-Chief: Olufunmilola Olubukola M.D.[3],Nazia Fuad M.D.

MPGN membrano proliferative glomerulonephritis, also known as mesangiocapillary glomerulonephritis, is a glomerular injury on light microscopy that is characterized by mesangial hypercellularity, endocapillary proliferation, and double-contour formation along the glomerular capillary walls. “MPGN” includes two characteristic histologic changes:Thickened glomerular basement membrane (GBM) due to deposition of immune complexes and/or complement factors, intrusion of the mesangial cells and other cellular elements between the glomerular basement membrane and the endothelial cells, and new basement membrane formation. Mesangial and endocapillary cellularity is increased resulting in lobular appearance of the glomerular tuft. Proliferation of mesangial cells and circulating monocytes results in increased cellularity.Two mechanisms are involved in the pathogenesis of MPGN,Immune complex deposition leading to activation of complement (immune complex-mediated) and dysregulation and persistent activation of the alternative complement pathway.

• Type I MPGN:^[1][2]
  • It results from presesnce of a persistent antigen in blood.
  • This leads to generation of nephritogenic immune complexes that localize to the subendothelial spaces.
  • Innate immunity to both the generation of antibodies that are deposited as immune complexes and to the local inflammatory responses directed at the glomerular immune deposits plays a role.
  • The immune complexes activate the complement system via the classical pathway.
  • This results in the generation of chemotactic factors (C3a, C5a) that mediate the accumulation of platelets and leukocytes.
  • Activation of complements (C5b-9) directly induce cell injury.
  • Leukocytes release oxidants and proteases that result in capillary wall damage and cause proteinuria.
  • Cytokines and growth factors released by glomerular cells lead to mesangial proliferation and expansion. 

• Type II MPGN:
  • It results from the uncontrolled systemic activation of the alternative pathway of the complement cascade.
  • In most patients, loss of complement regulation is caused by the C3 nephritic factor , an immunoglobulin (Ig)G autoantibody that binds and prevents the inactivation of C3 convertase (C3bBb) of the alternative pathway.
  • This results in the breakdown of C3.
  • Another cause of type II MPGN is due to mutations in the complement regulatory protein, factor H, or to autoantibodies that impede factor H function, highlighting the role of deregulated alternative complement pathway activity in type II MPGN.

• Type III MPGN:
  • It is thought to be due to a slow-acting nephritic factor that stabilizes a properdin dependent C5-convertase, (Cb3)2BbP.
  • (Cb3)2BbP activates the terminal pathway of the complement system.
  • This nephritic factor has not been reported in healthy subjects.unnlike C3NeF.
  • In addition, the deposits present in renal biopsies of patients with type III MPGN are closely associated with the circulating nephritic factor-stabilized convertase and with hypocomplementemia suggesting that NeFt is fundamental to the pathogenesis of type III MPGN.

• Cryoglobulinemic MPGN :
  • A large percentage of patients with chronic HCV infection develop type II cryoglobulins.
  • However, only a minority of such patients with detectible cryoglobulinemia have clinical manifestations of cryoglobulinemic MPGN.
  • It is unclear why some cryoglobulins are more pathogenic than others, or why cryoglobulins deposit in the kidneys.
  • Recognition of the components of cryoprecipitates, which contain HCV core protein, by circulating leukocytes and intrinsic glomerular cells leads to the production of inflammatory mediators that characterize the glomerular injury of cryoglobulinemic MPGN.

• Glomeruli generally are enlarged and hypercellular
• There is increase in mesangial cellularity and matrix.
• Mesangial increase, when generalized throughout the glomeruli, causes an exaggeration of their lobular form.
• This give rise to the alternative name of lobular nephritis.
• Infiltrating neutrophils and monocytes contribute to glomerular hypercellularity.
• The capillary basement membranes are thickened by interposition of mesangial cells and matrix into the capillary wall.
• This gives rise to the double-contoured appearance of the capillary wall, best appreciated with the methenamine silver stain or the periodic acid-Schiff reagent.
• Crescents may be visible in 10% of patient biopsy specimens.
• Interstitial changes, including inflammation, interstitial fibrosis, and tubular atrophy, are observed in patients with progressive decline in GFR.

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