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