This document provides information on membranoproliferative glomerulonephritis (MPGN), including its classification, pathogenesis, clinical presentation, pathology, and treatment. MPGN is classified based on immunofluorescence and electron microscopy findings. It can be immune-mediated via immune complex deposition or complement-mediated via dysregulation of the alternative complement pathway. On pathology, it is characterized by thickened glomerular basement membranes, mesangial hypercellularity, and endocapillary proliferation. Clinical presentation varies from asymptomatic to nephrotic syndrome or renal failure.
2. MPGN
§ Pattern of glomerular injury on renal biopsy
§ Thickening of GBM
§ Mesangial hypercellularity
§ Endocapillary proliferation
§ Double-contour along glomerular capillary walls
§ Lobulation glomerulonephritis
3. MPGN : Epidemiology
§ 2–10% of all cases of GN confirmed by renal
biopsy.
§ Common age group 8-16 yr
§ 5th leading cause of ESRD among primary
glomerular diseases
§ ‘idiopathic’ MPGN is more commonly seen in
pediatric age than older adults.
Nat. Rev. Nephrol. 11, 14–22 (2015)
19. Mixed cryoglobulinemia
§ Acute nephritic syndrome
§ Hematuria
§ Nephritic range proteinuria
§ Renal insufficiency (50%)
§ Hypertension (80%)
§ Low C3, C4, and C1q with reductions
in C4 > C3 level
•Polyclonal IgG and monoclonal IgM kappa
rheumatoid factor directed against the Fc
portion of IgG
•❖ Circulating anti-HCV antibodies
•❖ Polyclonal IgG anti-HCV antibodies
•within the cryoprecipitate
•❖ HCV RNA in the plasma and the
cryoprecipitate
20. Cryoglobulinemic MPGN
§ Amorphous eosinophilic
PAS- positive
intraluminal thrombi
(cryoglobulins)
§ Thickening of the GBM
with double-contoured
GBMs
§ Cellular proliferation,
including massive
exudation of monocytes
21. Immunofluorescence microscopy
§ Both IgM as well as IgG with C3 and frequently C1q in the
distribution of subendothelial and mesangial deposits and the
intracapillary “thrombi
24. Clinical presentation
§ Most commonly presents in childhood but can occur
at any age.
§ Clinical presentation and course are extremely
variable :
§ From benign and slowly to rapidly progressive.
§ Asymptomatic hematuria and proteinuria,AGN,
nephrotic syndrome, CKD or RPGN.
§ Varied clinical presentation is caused by
§ Different pathogenesis
§ Timing of biopsy relative to clinical course.
N Engl J Med 2012;366:1119-31.
25. Clinical presentation
§ In early disease, kidney biopsy shows :
§ Proliferative lesion : nephritic phenotype
§ Crescentic lesion : RPGN
§ In advanced disease, kidney biopsy shows :
§ Both repair and sclerosis : nephrotic phenotype
§ Classic MPGN : both nephritonephrotic phenotype.
N Engl J Med 2012;366:1119-31.
26. Pathogenesis
§ Two primary mechanisms have been described :
§ Immune complex deposition (immune complex-
mediated)
§ Activation of complement via classical pathway
§ Typically : mildly decreased serum C3 and low C4
§ Dysregulation and persistent activation of alternative
pathway (complement-mediated)
§ usually low C3 and normal C4 levels (80% of cases )
§ normal serum C3 is not excluded complement-
mediated MPGN
N Engl J Med 2012;366:1119-31.
28. N Engl J Med 2012;366:1119-31.
Pathogenesis : immune mediated MPGN
29. Pathology
§ Key characteristic histologic changes:
§ Thickened GBM :
§ deposition of IC and/or complement factors
§ interposition of mesangial cell and other cellular
between GBM and the endothelial cell à new
basement membrane formation.
§ Increased mesangial and endocapillary cellularity à
often leading to lobular appearance of glomerular
tuft.
Fundamental of Renal Pathology, Section II, Chapter 2, Page 31,32
31. MPGN type 1 : LM pathology
§ Mesagial proliferation
§ Increased mesangial matrix
§ Endocapillary proliferation
§ Diffuse global capillary wall thickening
§ Mesangial interposition
§ Doubing or replication of GBM
“Lobular glomerulonephritis”
32. MPGN type 1 : LM pathology
§ Mesangial interposition
§ Doubing or replication of GBM
33. MPGN type 1 : IF pathology
§ Segmental, coarsely
granular-to-globular
or elongated
capillary wall IgG
deposits
§ Less granular and
less symmetrical than
MN
34. MPGN type 1 : EM findings
Mesangial interposition
Subendothelial electrondense deposits
Tram track sign
36. § Very small number of children and
young adults
§ Clinical similar MPGN type I
§ low C3 levels and absence of C3
nephritic factor
§ EM: subendothelial and subepithelial
EDD
Brenner&Rector’s: The Kidney 10th Edition
MPGN type III
(Burkholder, And Strife And Anders Variants)
37. Some Key Pathology to differentiate
Primary VS Secondary MPGN
§ IF :
§ HCV
§ IgM, IgG, C3, kappa and lambda
§ IgG may not be present
§ C1q is typically negative
§ Monoclonal gammopathy
§ monotypic kappa or lambda light-chain
§ Autoimmune diseases : "full house" pattern
38. § Tubuloreticular structures in endothelial cells lupus
nephritis
§ Fingerprint pattern associated with cryoprecipitates
is seen in mixed cryoglobulinemia
Some Key Pathology to differentiate
Primary VS Secondary MPGN
40. Novel Classificationof MPGN
IMMUNOFLUORESCENCE FINDING
IgG + C3
± IgM , C1q
C3 alone or dominant
Immune mediated MPGN
Complement mediated MPGN
(C3 Glomerulopathy)
ELECTROMICROSCOPE FINDING
Subendothel
ail +
Mesangail
deposit
Highly EDD
intramembranous
(Lamina densa) and
mesangial ± Bowman c,
MPGN type 1
Subendothelail and
Mesangail deposit
± Subepithelial or
Intramembranous
deposit
MPGN type 3 DDD
EDD subendothelial /
mesangial ±
subepithelium ,
Bowman c,TBM
C3 GN
Burkholder
Variant
Strife
Variant
W/U 2nd cause : Chr
infection , autoimmune ,
monoclonal gammopathy
Familial form C3 GN
Adapted from N Engl J Med 2012;366:1119-31
Kidney International (2016) 89, 278–288.
Nat. Rev. Nephrol. 11, 14–22 (2015)
LM compatible with MPGN pattern
No IgG, No C3
Chronic TMA
APS
Radiation nephritis
Paraproteinemia
(Fibrillary GN)
Transplant
glomerulopathy
PIGN
Collagen III
glomerlulopathy
C1Q nephropathy
C3 Nef
41. § less common than IC-mediated MPGN
§ results from dysregulation of alternative
complement pathway (AP) à persistent activation
§ C3 are usually low and C4 are normal
N Engl J Med 2012;366:1119-31.
Complement mediated MPGN
43. Pathogenesis
§ Important dysregulation of AP :
§ C3 nephritic factors (C3Nefs)
§ absence of circulating factor H
§ presence of a circulating inhibitor of factor H
§ mutation in gene encoding C3 : Lysine 224,
§ Polymorphism :Tyr 402His allele variant
(impaired factor H regulation of C3 convertase)
Brenner&Rector’s: The Kidney 9th Edition
45. Complement-mediated MPGN
§ In many patients, complement abnormalities does not
develop MPGN, suggests that
§ genetic risk factors are not enough to trigger the
disease
§ additional ‘hit(s)’ are required
§ Activate complement and overwhelm the
regulatory mechanism resulting in high levels of
complement factors then deposited in glomeruli.
Nephrol Dial Transplant (2012) 27: 4288–4294
46. Dense deposit disease
§ Clinical Features
§ 1/3 of patients : nephrotic syndrome
§ 1/4 of patients : nephritic syndrome
§ Mild HT
§ > 50% Renal dysfunction
§ more common in adults than in children
§ Onset is preceded by acute URI , with high ASO
titers in 20-40%.
§ 80 - 90% low C3 levels
§ Depressed C4 levels “uncommon”
§ Syndrome of acquired partial lipodystrophy
Brenner&Rector’s: The Kidney 10th Edition
47. Acquired partial lipodystrophy
- loss of fat from face, neck, upper limbs, trunk and anterior thighs.
- accumulation of excess fat in hips and other regions of lower limbs
48. Ocular drusen in DDD
§ Mild visual field
§ Color defects
§ Prolonged dark adaptation
§ mottled retinal pigmentation
(drusen bodies)
§ Indocyanine green
angiography dense deposits in
ciliary basement membrane
and choroidal
neovascularization
Brenner&Rector’s: The Kidney 10th Edition
49. Dense deposit disease
§ Prognosis is worse than type I
§ Clinical remissions <5%
§ Worse in adults than in children
§ 50% turn to ESRD in 10 years from the onset
Brenner&Rector’s: The Kidney 10th Edition
51. Light microscopy
§ Both DDD and C3GN
§ Typical MPGN patern
§ ⬆ mesangial matrix and cell
§ GBM thickening with double contour
§ Glomerular lobulation
§ Some cases infiltration of macrophages or
neutrophils. Similar to postinfectious GN
§ Crescent formation may be present
52. § In a series of 69 patients with DDD, the incidence
of di erent histologic patterns was
§ membranoproliferative (25%)
§ mesangioproliferative (45%)
§ crescentic (18%)
§ acute proliferative and exudative (12%)
Light microscopy
N Engl J Med 2012;366:1119-31.
53. DDD, LM finding
DDD, capillary walls appear rigid, thickened, and with a more intensely PAS,
also observed with trichrome (sometimes fuchsinophilic) (arrows).
In some cases there is slight cellularity increase and in others it can be mesangial
54. C3
§ Negative staining for Ig
§ Capillary wall staining is
linear or bilinear
§ bandlike staining for C3
§ ring-shaped mesangial
deposits that
correspond to dense
deposits in EM
C3DDD: Immunofluorescence
Fundamental of Renal Pathology, Section II, Chapter 2,
55. DDD: Electronmicroscope
§ DDD shows typical osmiophilic , highly densed
electron deposition in glomerular basement
membrane (Ribbon like)
§ EDD can be seen in Mesangium , Bowman capsule
and tubular basement membranes.
Fundamental of Renal Pathology, Section II, Chapter 2
56. Dense ribbon like appearance of subendothelial and inramembranous material
57. Dense Deposit disease : EDD of GBM and mesangial area
Sausage shaped, wavy or Ribbon-like
Deposits are seen in Bowman capsule and TBM
61. C3 Glomerulonephritis
§ 27% nephrotic syndrome
§ 65% microhematuria
§ 30% elevated blood pressure.
§ Rate of progression to ESRD in C3GN patients was
similar to that in patients with DDD.
Comprehensive Clinical Nephrology 5th Edition
62. C3 Glomerulonephritis
§ Has been reported in
§ association with monoclonal gammopathies
§ anti-factor H activity
§ Inherited disease :
§ mutations in CFHR5 gene (CFHR5
nephropathy)
Nat. Rev. Nephrol. 8, 634–642 (2012)
64. C3GN : IF
widespread staining of capillary walls and
focal granular mesangial staining.
C3
65. C3GN : EM
complex pattern of thickening of GBM with intramembranous electron-dense material.
Similar deposits are also seen in the mesangium
66. CFHR5 nephropathy
§ Familial form of C3GN, autosomal dominant
§ Described in Cypriot origin
§ Mutation in gene that encodes complement factor-H-
related protein 5 (CFHR5).
§ compete with factor H on surfaces such as the GBM
and
§ interfere factor H to inhibit alternative pathway
activation
Nat. Rev. Nephrol. 8, 634–642 (2012)
67. CFHR5 nephropathy
§ Clinical :
§ Hematuria (90%)
§ Proteinuria (38%)
§ often episodes of synpharyngitic haematuria
§ Men > Women to develop CKD (80 vs 21%) and
ESRD (78 vs 4 %)
Nat. Rev. Nephrol. 8, 634–642 (2012)
68. Novel Classificationof MPGN
IMMUNOFLUORESCENCE FINDING
IgG + C3
± IgM , C1q
C3 alone or dominant
Immune mediated MPGN
Complement mediated MPGN
(C3 Glomerulopathy)
ELECTROMICROSCOPE FINDING
Subendothel
ail +
Mesangail
deposit
Highly EDD
intramembranous
(Lamina densa) and
mesangial ± Bowman c,
MPGN type 1
Subendothelail and
Mesangail deposit
± Subepithelial or
Intramembranous
deposit
MPGN type 3 DDD
EDD subendothelial /
mesangial ±
subepithelium ,
Bowman c,TBM
C3 GN
Burkholder
Variant
Strife
Variant
W/U 2nd cause : Chr
infection , autoimmune ,
monoclonal gammopathy
Familial form C3 GN
Adapted from N Engl J Med 2012;366:1119-31
Kidney International (2016) 89, 278–288.
Nat. Rev. Nephrol. 11, 14–22 (2015)
LM compatible with MPGN pattern
No IgG, No C3
Chronic TMA
APS
Radiation nephritis
Paraproteinemia
(Fibrillary GN)
Transplant
glomerulopathy
PIGN
Collagen III
glomerlulopathy
C1Q nephropathy
C3 Nef
69. MPGN without immunoglobulin
or complement deposition
§ In TMA resulting from injury to endothelial cells.
§ In the acute phase : endothelial swelling, and
fibrin thrombi in the glomerular capillaries,
mesangiolysis
§ In reparative and chronic phase : remodeling of
glomerular capillary wall à double-contour
formation.
N Engl J Med 2012;366:1119-31.
70. TMA
Nat. Rev. Nephrol. 11, 14–22 (2015)
Early changes : endothelial swelling and lifting from basement membrane,
with relatively electronlucent flocculent material filling the space
Over time : new layers of basement membrane form beneath the endothelium giving rise to the hallmark double contours.
71. Treatment of Primary MPGN
§ Idiopathic MPGN is now an uncommon condition.
§ The few RCTs of treatment of idiopathic MPGN in
children and adults have given inconsistent and
largely inconclusive results .
§ Many of the reported trials have weak experimental
design or are underpowered, and the evidence base
underlying the recommendations for treatment of
§ “idiopathic” MPGN is very weak.
N Engl J Med 2012;366:1119-31.
72. Treatment
§ Evaluate for underlying diseases before considering
a specific treatment regimen (Not Graded).
§ For idiopathic MPGN :
§ If accompanied by nephrotic syndrome AND
progressive decline of kidney function receive
§ oral cyclophosphamide/MMF plus low-dose
alternate-day/daily corticosteroids with initial
therapy limited to less than 6 months. (2D)
74. Corticosteroid
§ No systematic evaluation of glucocorticoid therapy
for idiopathic MPGN in adults.
§ Retrospective studies showed no clear benefit.
75.
76.
77.
78. Cyclophosphamide
• RCT (n=59)
• Compare
•Combination
•Cyclophosphamide 1.5-2.0 mg/dl
•Coumadin keep PT 2-2.5 times
•Dipyridamole start 25 mg qid full dose 100 mg qid
•No specific therapy
83. Eculizumab
§ anti-C5 monoclonal antibody à inhibits C5
activation
§ MPGN due to a genetic mutation in complement-
regulating proteins may benefit that inhibit
formation of MAC.
§ elevated serum levels of MAC more likely to
response with eculizumab.
N Engl J Med 2012;366:1119-31.