Post on 21-Jul-2020
C3 Glomerulopathy: A clinical approach.
Fadi Fakhouri
ITUN, Department of nephrology and Immunology,
CHU de Nantes.
INSERM UMR S-1064
« Membranoproliferative » is a pathological feature
Mesangial expansion « Doubles contours »
Immune deposits
MPGN I
MPGN : classification
MPGN II/DDD
MPGN : classification
MPGN II/DDD
MPGN : classification
C9
C3
MPGN II/DDD
MPGN : classification
MPGN III
MPGN : classification
SLE HCV/Cryoglobulinemia
MPGN secondary to monoclonal gammapathy
Secondary MPGN
MPGN : classification
TMA Chronic infections
Some MPGN do not have a « MPGN » pattern
Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients. Nasr S, CJASN 2009; 4: 22-32.
n=32 DDD cases
MPGN 44% Mesangial GN 28%
EndoC Proliferation 19% Crescentic GN 9%
Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients. Nasr S, CJASN 2009; 4: 22-32.
n=27 DDD cases
Outcome of DDD patients n=27 Mean follow-up: 5 years Complete response to TRT CKD ESRD Death
Is it «DDD versus the rest of MPGN »?
26% 48% 25% 11%
Acquired and genetic complement abnormalities play a critical role in dense deposit
disease and other C3 glomerulopathies. A Servais, VFB. KI 2012; 82: 454-64.
Do MPGN types differ?
Do MPGN types differ?
Acquired and genetic complement abnormalities play a critical role in dense deposit
disease and other C3 glomerulopathies. A Servais, VFB. KI 2012; 82: 454-64.
Do MPGN types differ?
Acquired and genetic complement abnormalities play a critical role in dense deposit
disease and other C3 glomerulopathies. A Servais, VFB. KI 2012; 82: 454-64.
Is it «DDD versus the rest of MPGN »?
Little MA, KI 2006.
Severity of primary MPGN, rather than MPGN type, determines renal survival and post-transplantation recurrence risk.
AS, VFB KI 2012
Do MPGN types differ?
AS, VFB KI 2012
Do MPGN types differ?
Do MPGN types differ?
C3Nef
58% 53% 86% 45%
Do MPGN types differ?
C3Nef
58% 53% 86% 45%
Isolated C3 deposits glomerulonephritis:
a new entity.
MPGN I
DDD
C3GN
IF C3 deposits Ig deposits
+ +
+ -
+ -
EM Dense deposits
-
+
-
Reclassifying MPGN: a mission impossible?
MPGN I
DDD
C3GN
IF C3 deposits Ig deposits
+ +
+ -
+ -
EM Dense deposits
-
+
-
Reclassifying MPGN: a mission impossible?
2010
Noris, NEJM, 2010
Is C3 the culprit in MPGN?
Complement-dysregulation associated nephropathies
Complement-dysregulation associated nephropathies
aHUS
C3 Glomerulopathy
F Fakhouri Nature Rev Nephrology, 2010
Complement-dysregulation associated nephropathies
aHUS
C3 Glomerulopathy
DDD
C3G
F Fakhouri Nature Rev Nephrology, 2010
MPGN I
DDD
C3GN IF
C3 deposits
+
+
+
Reclassifying MPGN: a mission impossible?
Complement-dysregulation associated nephropathies
aHUS
C3 Glomerulopathy
DDD
C3G
MPGN pattern
F Fakhouri Nature Rev Nephrology, 2010
Complement-dysregulation associated nephropathies
aHUS
C3 Glomerulopathy
DDD
C3G
MPGN pattern
Primary
MPGN I
Secondary
MPGN
F Fakhouri Nature Rev Nephrology, 2010
10/23 patients had different IF patterns on repeat kidney biopsy
u C 3 c o n v e r t a s e
C 5 c o n v e r t a s e
s M A C
i C 3 b
C 3
C 5 b
C 5
C 6 , 7 , 8 , 9
C 3 b
Complement system
Anti C3/C3b Ab
Eculizumab
FH FH/CR1
Anti-MASP Ab
rhC1INH
Eculizumab
6/10 improved
C3c C3d C3c C3d
C5b9 C5b9
Eculizumab for rapidly progressing C3G: case 1
C3c C3d C3c C3d
C5b9 C5b9
Eculizumab for rapidly progressing C3G: case 1
C. Kandel et K. Renaudin
C3c C3d C3c C3d
C5b9 C5b9
Eculizumab for rapidly progressing C3G: case 1
C. Kandel et K. Renaudin
C3c C3d C3c C3d
C5b9 C5b9
Eculizumab for rapidly progressing C3G: case 1
C. Kandel et K. Renaudin
C3d
A personal view of the management of C3G/MPGN
A personal view of the management of C3G/MPGN
Complement tests 1
C3Nef
C3, FB, sC5b-9 (urinary?), C5b-9 staining in KB
Anti-FH Ab, Monoclonal gammapathy
Sheep erythrocyte lysis assay.
J Immunol 2015
CJASN 2011
N= 6
5 MGRS + 1 smouldering M (kappa 4/6)
Light chain Puria 5
Low C3 and/or FB: 4/6
Anti-FH IgG 1/6
No complement gnes variants 4/4
No C3 nef 6/6
ESRD 5/6 (chemotherapy 4)
Study of Ig L chain restriction of anti-FH recognition by ELISA. The binding of anti-FH IgG was revealed using an anti-κ or anti-λ
human Ig L chain.
J Immunol 2015
JI 1999
Conversion of C3 by alternative C3 convertase
Binding of LC to FH
A personal view of the management of C3G/MPGN
Complement tests 1
C3Nef: pathogenic relevance?
C3, FB, sC5b-9 (urinary?), C5b-9 staining in KB
Anti-FH Ab, Monoclonal gammapathy
KB 2 Cellular proliferation
Inflammatory cells infiltration
Fibrosis
EM
A personal view of the management of C3G/MPGN
Complement tests 1
C3Nef: pathogenic relevance?
C3, FB, sC5b-9 (urinary?), C5b-9 staining in KB
Anti-FH Ab, Monoclonal gammapathy
KB 2 Cellular proliferation
Inflammatory cells infiltration
Fibrosis
EM
Not all C3G/MPGN are to be (agressively) treated 3
A personal view of the management of C3G/MPGN
Complement tests 1
C3Nef: pathogenic relevance?
C3, FB, sC5b-9 (urinary?), C5b-9 staining in KB
Anti-FH Ab, Monoclonal gammapathy
KB 2 Cellular proliferation
Inflammatory cells infiltration
Fibrosis
EM
Not all C3G/MPGN are to be (agressively) treated 3
1st-line treatment: Cs + MMF
FFP/PE: FH deficiency 4
KI, 2015
KI, 2015
KI, 2015
3pts/60 (5%) had complement genes variants: two pathogenic variants (cfh, c3) and at-risk mcp polymorphism.
KI, 2015
KI, 2015
KI, 2015
A personal view of the management of C3G/MPGN
Complement tests 1
C3Nef: pathogenic relevance?
C3, FB, sC5b-9 (urinary?), C5b-9 staining in KB
Anti-FH Ab, Monoclonal gammapathy
KB 2 Cellular proliferation
Inflammatory cells infiltration
Fibrosis
EM
Not all C3G/MPGN are to be (agressively) treated 3
1st-line treatment: Cs + MMF
FFP/PE: FH deficiency 4
2nd-line treatment: Eculizumab 5 RPGN
Elevated sC5b-9
Inflammatory changes in KB
C3G: two parts of the disease.
Anti C3/C3b Ab
Eculizumab
FH FH/CR1 sCR1
Three concepts
1. « MPGN » is a pathological feature
« C3GN » relates to pathogenesis
2. Treatment of C3G should target AP dysregulation.
3. Eculzimab (and cie) are potential therapies