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C3 GLOMERULOPATHY
Dr Kiran Kumar M,
DM Senior Resident,
Dept of Nephrology
Introduction
MPGN- not a diagnosis per se
Rather a histopathologic pattern of injury seek out potential underlying causes of injury
Clinical classification 1. Idiopathic or primary
2. Secondary
Primary MPGN – based on ultrastructural appearance and location of electron-dense deposits
Type I Type II Type III
MPGN Pathology
Mesangial hypercellularityEndocapillary proliferationCapillary wall remodelling with mesangial
interposition Duplication of glomerular basement membranes
Lobular accentuation of the glomerular tufts
Typically a/w peripheral capillary deposition of Igs , complement components, or both
MPGN III
1. Burkholder subtype - subendothelial and subepithelial
2. Strife and Anders subtype - complex intramembranous, subendothelial and subepithelial
DDD was renamed MPGN2 in 1975
Now considered inappropriate to refer to DDD as MPGN2 ○ Pathological pattern of MPGN is absent in the majority of
cases of DDD.
Some cases of MPGN1 - have negative glomerular staining for Igs
Referred to as “MPGN1 with isolated subendothelial deposition of complement C3
a/w complement abnormalitiesPathologically distinct from both idiopathic and
secondary forms
Definition
Glomerular disorders in which dysregulation of the complement system is either
The key pathophysiological factor
The major mediator of glomerular damage
Proposed re-classification
Ig-mediated disease -classical complement pathway activation
Non-Ig mediated disease- alternative complement pathway activation
New classification – led to emergence of a new grouping of diseases called the ‘C3 glomerulopathies’
Complement activity in MPGN
Glomerular inflammation - commonly a/w with the presence of Igs and complement proteins within the glomerulus
Immune complexes- trigger activation of the complement system through the classical pathwayGlomerular immunostaining – Igs + C3
Minority of cases - absence of immunoglobulin
Activation of the alternative pathway of complement is implicated
Alternative complement - constitutively active at a low level
‘Tickover’ –
Basal, physiologic activation of the alternative pathway
Spontaneous hydrolysis of C3 and the production of C3b
C3b binds complement factor B (CFB) to yield a fluid phase C3 convertase (C3bBb)
C3bBb - under tight modulation by soluble or membrane-bound regulating proteins
Complement factor H (CFH)Complement factor I (CFI)Membrane cofactor protein (MCP)
Defect in either the activation or modulation of the C3 convertase could lead to
Transformation from low-grade physiologic activity (‘tickover’) to unrestrained, hyperactivity
Mutations in either the activating proteins and/or the regulatory proteins of the alternative pathway
Hyperactivity of the alternative complement pathway
Principal activating proteins of the alternative complement -
C3 CFB
Key regulatory or inhibitory proteins of the alternative complement pathway
CFHCFIMCPfive factor‑H-related proteins, CFHR1–5
Autoimmune abnormalities
Acquired autoantibodies targeted at either the activating or regulatory components
Unregulated activity of the C3 and/or C5 convertases of the alternative pathway
C3 Nephritic factor (C3Nef) –
Directly stabilizes the C3 activating complex of the alternative pathway
Prevents the inhibitory actions of factor H prolong the t1/2 C3 convertase from a few seconds
to up to 60 minincreased generation of C3 convertase and C5
convertase
C3Nefs - detected in healthy individuals as well as in other glomerular and non-glomerular diseases
Exact degree to which C3Nefs contribute to C3 glomerulopathies unknown
Many of those with C3Nefs will also have a second (or third) abnormality detected on screening
Accompanying genetic abnormality○ Gene encoding Factor H
Additional serologic autoantibodies directed at a complement regulatory protein
○ Autoantibodies to factor H and/or factor I○ Autoantibodies directed at the individual
components of the C3 convertase - factor C3b and/or CFB
Forms of C3 glomerulopathy
Dense deposit disease Characterized by
Glomerular deposits of C3, with no or only scanty glomerular deposits of Igs
Dense osmiophilic deposits in the mesangium, GBM and tubular basement membrane
Dense deposits - reported to be a/w C3 on their surface but not within the deposits themselves
DDD – a/w presence of
Autoantibodies against complement factor H, C3NeF Genetic deficiency of complement factor H
Pathology in DDD
Mesangial proliferative GNCrescentic GNAcute proliferative and exudative GNMembrano-proliferative change
C3 glomerulonephritis
Uncommon condition characterized by the presence of isolated glomerular C3 deposits
Ultrastructural level - sub endothelial & mesangial electron dense deposits
Pathology 75% of pts with C3 GN - MPGN
○ C3 GN with MPGN25% - mesangial and epimembranous C3 deposits
present in the absence of membrano proliferative changes ○ C3 GN without MPGN
CFHR5 nephropathy
Cases of two Cypriot families - Inherited renal disease characterized by
Variable glomerular inflammation Sub endothelial deposits of C3 but not Ig
Mutation in complement factor H related protein 5, which is encoded by CFHR5
Is atypical HUS a C3 glomerulopathy?
Atypical HUS
Rare thrombotic microangiopathy
Disease of unsuppressed activity of the alternative complement cascade ○ Inactivating mutations in genes encoding
complement regulators (factor H, factor I, MCP, and thrombomodulin)
○ Gain-of-function mutations in genes encoding complement activators (C3 and CFB)
Alternative pathway consists of a network of complement proteins in either
the fluid phase, as soluble plasma proteins, or
in the solid phase, as cell membrane proteins
aHUS C3 GN
Pathology Thrombotic microangiopathy No asstd C3 staining on IF No asstd electron-dense
deposits on electron microscopy
Pathophysiology
Endothelial damage Result from dysregulation at
the level of the cell membrane, or in the solid phase
Pathology deposition of complement
fragments in the glomerular basement membrane
Pathophysiology Excessive activation of the
alternative complement pathway in the fluid phase
Management
Predictors of outcome
Renl dysfunction – Sr Cr, GFRProteinuria
DDD- older age at diagnosis an independent predictor of ESRD
C3GN may have a more benign course than patients with DDD
Treatment
Targeted therapies have not proven to be universally beneficial –
Heterogeneity of the C3 glomerulopathies
Control of alternative complement pathway activity
Replacement of factor H viable option
Pts with genetic defects of inhibitory proteins of the alternative complement pathway replacement of factors
Replacement
Plasma exchangePharmaceteucal preparation (not available at present)
Replacement not successful in certain pts
Mutant C3 convertase that is resistant to factor H control
Require specific treatments
That restore C3 convertase control, Impair C3 convertase activity, orRemove C3 breakdown products from the circulation
Pts with an acquired antibody to an inhibitory protein of the alternative pathway
Immunosuppressive therapy
○ Corticosteroids○ mycophenolate mofetil○ rituximab
Eculizumab
Humanized monoclonal antibody to C5 ○ Prevents the generation of the MAC
Several case reports - potential beneficial effects of Eculizumab
C3 GN vs DDD
C3GN have a slightly better prognosis than do pts with DDD
DDD – progression to ESRD25% after 5 years 50% after 10 years from diagnosis
French cohort - C3 glomerulopathy ¼th of adult pts with C3GN progressed to ESRD
over 10 years of f/u
American cohort - C3GN No significant decline in renal function over a
mean follow-up of 26 months
Renal transplantation in C3 GN
Almost universal rate of recurrence in the allograft in those with DDD
Renal transplantation should be considered
C3GN – relatively new diagnostic category Long-term data on transplantation are lackingRecurrences are likely to be at least as high as
those reported with ‘idiopathic’ MPGN type I (up to 65%
Graft survival may be similar to the 50% at 5 years rate reported for DDD
Plasma exchange
Proven efficacious in the treatment of recurrent disease – some case reports
Eculizumab - 4/10 pts with disease recurrence responded