Membranoproliferative Glomerulonephritis &
C3 Glomerulopathy
DR SCIENTHIA SANJEEVANI
SEMINAR
MODERATOR DR SAHIL BAGAI

COMPLEMENT PATHWAY

DEFINITION
 Pattern of glomerular injury on renal biopsy with characteristic light microscopy
changes.
-lobular appearance of glomerular tuft-due to mesangial hypercellularity and
endocapillary proliferation
-Duplication of glomerular basement membranes –due to deposition of immune
complex and /or complement factors
 Also K/a mesangiocapillary glomerulonephritis

Pathogenesis
2 primary mechanism
 IMMUNE COMPLEX DEPOSITION
 DYSREGULATION AND PERSISTENT ACTIVATION OF ALTERNATE PATHWAY

CLASSIFICATION BY LIGHT MICROSCOPY
 Classical
 Lobular
 Crescentic
 Focal.
ONLY HISTORICAL IMPORTANCE

CLASSIFICATION BY EM

TYPE 1 MPGN

TYPE 2 MPGN
 dark electron dense deposits within the basement membrane often coalesce to
form a ribbon-like mass of deposits

TYPE 3 MPGN

Type 3 MPGN- C3 GN or PIGN??
Cases which are Ig negative but complement positive by IF , subepithelial humps on
EM BUT absence of recent infection---
Can be
 PIGN
 C3GN (bright staining of c3 and lack of significant ig staining )

Limitation of classification by EM
 Overlap of type 1 and 3
 Many cases of MPGN type 1 and 3 show strong c3 staining without Ig staining
 Many cases show depressed c3 levels with normal c4/c1 q alternate pathway
activation
 C3 convertase stabilising antibody called c3 nephritic factor in approximately 80
% patients with DDD , but also identified in type 1 and 3

Classification by IF
Mainly on pathogenesis
 Mediated by immune complex
 complement dysregulation
 Not involving IC or complement, e.g. endothelial injury

IMMUNE COMPLEX MEDIATED MPGN
EM
 subendothelial and mesangial deposits
 In autoimmune –may show subepithelial deposits (e.g. diffuse proliferative lupus
nephritis)

INFECTION
 Usually Hep C, Hep B. also chronic bacterial (e.g. endocarditis, shunt nephritis,
abscesses), fungal, parasitic (schistosomiasis, echinococcosis)
 HCV related MPGN usually associated with mixed cryoglobinemia
 Granular deposition of IgM , C3, both kappa and lambda light chains,typically
negative ,± IgG

MONOCLONAL GAMMOPATHY
 In 2/3 cases monoclonal Ig cannot be detected in serum or urine with normal
bone marrow biopsy
 Deposition of monotypic kappa or lambda light chain but not both
 Those a/w heavy chain deposition disease may show immunoglobuin
(heavy chan isotype ) in absence of either light chain
 High rate of recurrence after kidney transplant -70%(occur EARLY, AGGRESSIVE
and HIGH RISK OF GRAFT FAILURE)

AUTOIMMUNE DISEASE
 SLE (usually in chronic phase of lupus nephritis), less common in RA , Sjogren’s
 IF-Typically “FULL HOUSE “ pattern of Ig deposition including IgG,IgM,IgA,C1q,
, kappa , lambda light chain

MPGN WITH MASKED DEPOSITS
 Low grade lymphoma , plasma cell dyscrasia
 May present with isolated C3 deposits with no staining of immunoglobulin by
standard IF -OFTEN MISDIAGNOSED AS C3 GLOMEROPATHY
 IF on formalin fixed paraffin embedded tissue after pronase digestion may
MASKED MONOCLONAL IMMUNOGLOBULINS
 Another method- positive staining for C4d (by product of classic and lectin
complement pathway)

RARE CAUSES
 NHL, RCC, melanoma
 snake venom
 splenorenal shunt surgery for portal hypertension
 alpha 1 antitrypsin deficiency
 cryoglobulinemic GN
 idiopathic-diagnosis of exclusion

COMPLEMENT MEDIATED MPGN
 Less common than IC mediated
 Can be divided into C3 and C4 glomeropathy
 Each can be further divided into C3 or C4 dense deposit
disease and C3 or C4 glomerulonephritis

C3 GLOMERULOPATHY
CLINICAL MANIFESTATION
 Usually young but if in older population usually a/w monoclonal gammopathies
 Proteinuria (variable , may be nephrotic range) ± hematuria
 Can have
 acute nephritic syndrome 16-38%
 Isolated macroscopic hematuria 21-36%
 Nephrotic syndrome 21-36%
 Microscopic hematuria with subnephrotic range proteinuria 15%
 Isolated proteinuria 15-41%
 Sterile pyuria
 Renal dysfunction , HTN

DIAGNOSIS
 RENAL BIOPSY
 L/M-not specific
 IF - C3 deposits along glomerular, tubular, bowmans capsule basement
membrane. Ig typically absent
 EM
DDD-
 abnormal INTRAMEMBRANNOUS electron dense deposit within GBM which
replaces and widens lamina densa
 ± subepithilial humps
C3GN
 Subendothelial, mesangial ± subepithilial humps

 SPECIAL DIAGNOSTIC TESTS
 C3NEF
 Serum factor H
 complement factor H related protein gene mutation(CFHR5 mutation )
 SPEP, IF, Se free light chain
 Se factor B , I and MCP
 soluble membrane attack complex (C5-9)

C3 DENSE DEPOSIT DISEASE
 May be preceded with URTI infection , usually strep
 Primarily children
 C3 NEPHRITIC FACTOR –present in circulation in 80% patients
Extra renal involvement-
 drusen (macular deposits ) in Bruch membrane in retina- correlation between
drusens and renal activity
 may have acquired partial lipodystrophy (DUNNIGAN –KOBBERLING
SYNDROME )- loss of sub cut fat in upper part of body

C3 GLOMERULONEPHRITIS
 Glomerular inflammation with C3 deposition, without significant immunoglobulin deposition,
and in the absence of dense transformation of the basement membrane
 affects mostly young adulthood
 Rare, probably accounting for < 10% of proliferative GN
 C3NeF is seen in approximately 40% of cases
 mutations of the complement regulators CFH, complement factor I, and membrane cofactor
protein (MCP) have also been described in sporadic cases

Familial forms of C3GN
CFHR5 NEPHROPATHY
 mutations and rearrangements of the CFHR genes
 highly penetrant monogenic disease with autosomal dominant inheritance
 endemic in Cyprus with an allele frequency of 1:6000 in this population.
 Features which are distinct from those of C3GN due to other causes
 microscopic haematuria (present in > 90% of mutation carriers
 episodes of macroscopic haematuria occur at times of upper respiratory tract or other infections.
 may also be acute kidney injury during these episodes
 clinical resemblance to IgA nephropathy is striking.
 Proteinuria is usually only seen after the development of established chronic renal impairment and is
usually low grade (i.e. < 1 g/day).

MPGN WITHOUT Ig OR COMPLEMENT
DEPOSITION

CLASSIFICATION

CBC, peripheral smear
Urinanalysis
Urine PCR
Viral markers
Fundus

MANAGEMENT
 Depends on underlying cause
 Predictors of poor renal prognosis
 Nephrotic range proteinuria
 High creatiine
 Hypetension
 Renal biopsy- crescents, tubulointerstitial disease (IFTA)

Idiopathic MPGN in Adult
 Non-nephrotic, normal renal function:
follow with 3-month visits
 Nephrotic or impaired renal function:
6-month course of corticosteroid with/without cyclophosphamide,
cyclosporine,tacrolimus, or mycophenolate (MMF)
 Rapidly progressive renal failure with diffuse crescents:
Pulse steroid & cyclophosphamide +/- plasmapheresis

Idiopathic MPGN in children
 Non-nephrotic proteinuria, normal renal function: follow with 3-month visits
 Normal renal function and moderate proteinuria (>3 g/day): prednisone 40
mg/m2 on alternate days for 3 months
 Nephrotic or impaired renal function: prednisone 40 mg/m2 on alternate days
(maximum 80 mg) for 2 years, tapering to 20 mg on alternate days for 3-10 years

Hep C related MPGN

INTERFERON FREE REGIMEN IN Egfr< 30
-glecaprevir-pibrentasvir (pangenotypic)
-

C3 GLOMERULOPATHIES
GENERAL MEASURES
 HTN and/or proteinuria- ACE inhibitor or ARB
 Treat dyslipidemia if present

Mild disease
 Hematuria , mild proteinuria (<500 mg/d), normal RFT
 General measures, routine follow up

Moderately severe disease
 proteinuria> 500 mg/day,nephrotic syndrome and /or azotemia (BUT NOT RAPIDLY
PROGRESSIVE DISEASE)
IDENTIFY UNDERLYING ETIOLOGY
 DUE TO AUTO ANTIBODY (C3NeF, anti factor H antibody)
-Plasma exchange
-combined immunosuppression
-rituximab
-eculizumab (elevated levels of soluble membrane attack complex)
 DUE TO GENETIC DEFICIENCY (inherited factor H deficiency)
-periodic infusion of FFP
 DUE TO GENETIC ACTIVATING MUTATION OF C3
-Plasma exchange
WHEN UNDERLYING ETIOOGY NOT IDENTIFED
 GIVE TRIAL OF PLASMA EXCHANGE

rapidly progressive disease
 Crescentric glomerulonephritis
 Glucocorticoids + cyclophosphamide /mycophenolatemofetil
 Can give trial of plasma exchange also
 If factor deficiency documented periodic FFP tranfusion after remission
 i/V methylprednisolone f/b tapering dose oral predni plus either
cyclophosphamide or MMF

Tx in DDD/C3GN
 RECURRENCE HIGH 20-48%
 Treatment should be initiated prior to tx to correct identifiable defects and specific
treatment for factor H deficiency or C3NeF should be continued post Tx

PROGNOSIS in DDD/C3GN
DDD
 Poor
 ESRD detected in over 70% affected indiviuals with median onset of 9 yrs after
diagnosis
C3GN
 VARIABLE
 Persistently low grade proteinuria but maintain renal function for long time

PLASMA EXCHANGE
 only case reports
 every 14 days for 6-12 weeks
 follow up with se creatinine and proteinuria
 if response present>continue indefinitely
 Plasma exchange with albumin stabilize ds progression in some patients with
C3NeF
 In patients with monoclonal gammopathy , they may have acquired factor H
deficiency in that case PLEX with FFP might help

Eculizumab
 High affinity to C5 which prevents cleavage of C5
 Severe deteriorating renal function

Immunonsuppressive therapy
 Glucocorticoids cyclophosphamide, CNI
 Rabasco et al in 2015 (Effectiveness of mycophenolate mofetil in C3
glomerulonephritis)-immunosuppressive treatments, particularly corticosteroids
plus mycophenolate mofetil, can be beneficial in C3 glomerulonephritis.

RITUXIMAB
 Decrease C3NeF
 Indicated in those posiive for C3NeF , not responding to plasma exchange ,
actively progressing disease