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Kidney non-tumor

Primary glomerular diseases

Membranoproliferative glomerulonephritis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 24 February 2014, last major update May 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
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● Also called hypocomplementemic (C3), lobular or mesangiocapillary / mesangiopathic glomerulonephritis
● Pattern of injury with alterations in basement membrane and proliferation of mesangial cells, due to subendothelial and mesangial deposition of immunoglobulins, caused by persistent antigenemia or circulating immune complexes
● Either immunoglobulin mediated or complement mediated (although all types stain for C3)
● Immunoglobulin mediated: due to chronic infections, autoimmune diseases, monoclonal gammopathy/dysproteinemias
● Complement mediated: due to subendothelial and mesangial deposition of complement from dysregulation of alternative pathway; includes dense deposit disease (membranoproliferative glomerulonephritis type 2) and proliferative glomerulonephritis with C3 deposits; due to genetic mutations or development of autoantibodies to complement (Semin Nephrol 2011;31:341)
● Intermittent remissions but overall downhill course
● Diagnosis of MPGN-I or MPGN-II reduces overall primary allograft survival compared with other forms of glomerulonephritis (10 year graft survival drops from 65% to 56%, Am J Kidney Dis 2011;57:291)

Case reports
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● 27 year old man with recurrent episodes of hypokalemic quadriparesis (type not specified, J Assoc Physicians India 2011;59:735)

Micro images
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Type I and Type II (text and images)

Differential diagnosis
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● Cryoglobulinemic glomerulonephritis: may have similar features (Pathol Res Pract 2012;208:254)
● C3 glomerulopathy: all membranoproliferative GN stains for C3, but C3 glomerulopathies are immunoglobulin negative (Kidney Int 2012;81:434)


Type I: Classical

General
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● 5% of cases of glomerulonephritis affecting children and young adults; 2/3 of membranoproliferative glomerulonephritis cases
● Immune complex deposition and activation of classical and alternative complement pathway
● Typically presents with nephrotic syndrome and hypertension in patients 8-16 years old; less commonly nephritis
● Also associated with Staphylococcus epidermidis infection with ventriculoatrial or ventriculojugular shunts
● 2/3 have persistent decrease in serum C3 due to its hypercatabolism; also reduction in total hemolytic complement (CH) 50 levels and borderline / reduced levels of C1q, C4 and properdin
● Secondary disease occurs with chronic immune complex disorders (SLE, hepatitis B/C, HIV, schistosomiasis), alpha-1-antitrypsin deficiency and malignancies
● May cause high rates of non-diabetic end stage renal disease in Navajo Indians in US (Arch Pathol Lab Med 1989;113:158)

Case reports
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● 16 year old girl with refractory disease and dramatic response to eculizumab, a monoclonal antibody to C5 (N Engl J Med 2012;366:1165)

Treatment
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● No established treatment in adults, but plasmapharesis and Rituximab may reduce proteinuria (Clin Nephrol 2012;77:290, Transplant Proc 2011;43:4005)

Micro description
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● Large glomeruli with accentuation of lobules
● Irregular thickening of glomerular basement membrane by interposition of mesangial cells between endothelium and basement membrane
● Causes tram track / double contour appearance (PAS or silver stain), crescents in 20%
● Neutrophils often present
● May have hyaline aggregates of immune complexes in capillary lumina

Micro images
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Series of images including immunofluorescence and EM


With hepatitis B related disease, showing duplication of capillary wall and tram-track appearance (silver stain)


Hypercellular glomeruli with accentuated lobules


Fluorescence microscopy shows deposits corresponding to immune complexes along glomerular basement membrane


IgG in glomerular capillary loops


C3 with mesangial rings on IF


Membranoproliferative lesions on PAS


Membranoproliferative lesions on Silver stain


Mesangioendocapillary proliferation with mesangial nodular sclerosis

Immunofluorescence
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● Lumpy bumpy (granular) for C3, IgG, early complement (C1q, C4); pattern is mesangial and subendothelial

Immunofluorescence images
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Irregularly granular capillary loop and mesangial staining

Electron microscopy description
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● Subendothelial and mesangial electron-dense deposits, increased mesangial matrix, mesangialization of capillary loops and foot process fusion

Electron microscopy images
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Splitting and reduplication of basement membrane


Series of images


Large subendothelial electron-dense deposit along glomerular basement membrane


Subendothelial deposits


Subendothelial deposits with cellular interposition


Type II: Dense deposit

General
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● Essential diagnostic feature is not the membranoproliferative pattern but the presence of electron dense transformation of the glomerular basement membranes
● Occurs in 1/3 of cases of membranoproliferative glomerulonephritis, but some authors believe this entity is actually distinct from membranoproliferative glomerulonephritis (Mod Pathol 2007;20:605)
● Familial or associated with partial lipodystrophy (loss of subcutaneous fat from fat and upper body)
● Associated with uncontrolled activation of alternative complement pathway because of C3 nephritic factor (stabilizes C3 convertase; promotes C3 degradation)
● Tends to present with nephritis more than nephrotic syndrome
● Poorer prognosis than type I; 50% have renal failure in 10 years; 80-100% recur after renal transplant
● Also deposits in basement membranes of spleen, choroid and Bruchís membrane of retina
● Rarely abnormalities in factor H (Hum Pathol 2011;42:1305, Iran J Kidney Dis 2012;6:149)

Micro description
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● Similar to type I, but less prominent cellular proliferation
● Eosinophilic, refractile and ribbon-like thickening of glomerular basement membrane and basement membrane of Bowmanís capsule and tubules
● Strongly PAS+, stains red with trichrome but dense deposits are negative with silver stain

Micro images
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Type II

Mesangioendocapillary proliferation with lobular accentuation

Immunofluorescence
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● Linear or double contoured C3 and properdin staining of glomerular capillary walls and bright nodular or ring-like reaction in mesangium, NOT in dense deposits
● C3 staining also in mesangium, Bowmanís capsule and tubular basement membranes
● Usually no immunoglobulins

Immunofluorescence images
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Fluorescent ribbons of variable thickness seen along glomerular capillary loops (arrows)

Electron microscopy description
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● Dense deposits in lamina densa of glomerular basement membrane, Bowman's capsule; causes long ribbon of hazy material
● Also nodular deposits of similar material in mesangium

Electron microscopy images
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Ribbon-like dense deposits within glomerular basement membrane

Additional references
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Mod Pathol 2002;15:988


Type III: Mixed

General
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● Two rare morphologic subtypes (Burkholder and Anders) that are clinically similar to each other and to type I membranous glomerulonephritis


Type III: Burkholder variant

General
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● Combined features of type I membranoproliferative glomerulonephritis and membranous glomerulonephritis
● Associated with Hepatitis C and HIV coinfection (J Am Soc Nephrol 1999;10:1566)

Micro images
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Series of images including immunofluorescence and EM

Electron microscopy description
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● Subendothelial and subepithelial deposits and mesangial interposition associated with basement membrane spikes


Type III: Anders variant

General
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● Hybrid of type I and II membranoproliferative glomerulonephritis

Electron microscopy description
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● Massive accumulation of deposits within basement membrane with membranous disruption, highlighted by silver stain

End of Kidney non-tumor > Primary glomerular diseases > Membranoproliferative glomerulonephritis

Ref Updated: 5/25/12


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