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« Maladie du dépôt dense »
Dr Vincent Bourquin - service de néphrologie - http://nephrohug.com
CLASSIFICATION
Glomérulonéphrite membranoproliférative (GNMP) de type II, à dépôts denses au sein des
membranes basales ou « maladie du dépôt dense »
0.22 p. 100 des GN primitives
2 à 3 personnes par million (16-24)
Source: Servais et coll. J Med Genet 2007
Microscopie optique
ME
IF-C3-positive
IF-imunoglobulin
Source: Sethi et coll. Kidney International 2012
Microscopie optique GNMP
ME
IF-C3-positive
IF-imunoglobulin
Source: Sethi et coll. Kidney International 2012
Microscopie optique GNMP
ME
IF-C3-positive
IF-imunoglobulin
Intramembranous subendotelialand subepitelial
DDD Type IIIType 1Subendotelial
Source: Sethi et coll. Kidney International 2012
Microscopie optique GNMP
ME
IF-C3-positive
IF-imunoglobulin
Intramembranous subendotelialand subepitelial
DDD Type IIIType 1Subendotelial
Source: Sethi et coll. Kidney International 2012
Microscopie optique GNMP
ME
IF-C3-positive
IF-imunoglobulin
Intramembranous subendotelialand subepitelial
DDD Type III
Positive Negative Positive
Type 1Subendotelial
Source: Sethi et coll. Kidney International 2012
Microscopie optique GNMP
ME
IF-C3-positive
IF-imunoglobulin
Intramembranous subendotelialand subepitelial
DDD Type III
C3G
Positive Negative Positive
Type 1Subendotelial
Source: Sethi et coll. Kidney International 2012
x 7’000
CLINIQUE
50 p. 100 syndrome néphrotique impur et progressif
25 p. 100 syndrome néphritique aigu
15 p. 100 protéinurie sub-néphrotique
Plus rarement GN rapidement progressive
Source: Atlas de Pathologie rénale 2008
MACULAR DEGENERATION
ACQUIRED PARTIAL LIPODYSTROPHY
CLINIQUE
Hypocomplémentie avec taux abaissé de C3
C4 normal
80 p. 100 C3NeF, auto-anticorps dirigé contre C3 convertase
Source: Atlas de Pathologie rénale 2008
Source: Alchi et coll. Pediatr Nephrol 2010
COMPLEMENT-ALTERNATE PATHWAY
C3
COMPLEMENT-ALTERNATE PATHWAY
C3SPONTANEOUS
COMPLEMENT-ALTERNATE PATHWAY
C3
C3a
SPONTANEOUS
COMPLEMENT-ALTERNATE PATHWAY
C3
C3a
C3b
SPONTANEOUS
COMPLEMENT-ALTERNATE PATHWAY
C3
C3a
C3b
SPONTANEOUS
COMPLEMENT-ALTERNATE PATHWAY
C3
C3a
C3b B
SPONTANEOUS
COMPLEMENT-ALTERNATE PATHWAY
C3
C3a
C3b B
C3bBSPONTANEOUS
COMPLEMENT-ALTERNATE PATHWAY
C3
C3a
C3b B
C3bBSPONTANEOUS
COMPLEMENT-ALTERNATE PATHWAY
C3
C3a
C3b B
C3bBSPONTANEOUS
D
COMPLEMENT-ALTERNATE PATHWAY
C3
C3a
C3b B
C3bB
C3bBb
SPONTANEOUS
D
COMPLEMENT-ALTERNATE PATHWAY
C3
C3a
C3b B
C3bB
C3bBb
SPONTANEOUS
D
P
COMPLEMENT-ALTERNATE PATHWAY
C3
C3a
C3b B
C3bB
C3bBb
SPONTANEOUS
DC3 convertase
P
COMPLEMENT-ALTERNATE PATHWAY
C3
C3a
C3b B
C3bB
C3bBb
SPONTANEOUS
DC3 convertase
P
COMPLEMENT-ALTERNATE PATHWAY
C3
C3a
C3b B
C3bB
C3bBb
SPONTANEOUS
DC3 convertase
P
COMPLEMENT-ALTERNATE PATHWAY
C3
C3a
C3b B
C3bB
C3bBb
(C3b)2BbPC5 convertaseSPONTANEOUS
DC3 convertase
P
COMPLEMENT-ALTERNATE PATHWAY
C3
C3a
C3b B
C3bB
C3bBb
(C3b)2BbPC5 convertaseSPONTANEOUS
DC3 convertase
P
COMPLEMENT-ALTERNATE PATHWAY
C3
C3a
C3b B
C3bB
C3bBb
(C3b)2BbPC5 convertase
MEMBRANEATTACK
COMPLEX(MAC)
SPONTANEOUS
DC3 convertase
P
C3
C3a
C3b B
C3bB
C3bBb
(C3b)2BbPC5 convertase
MEMBRANEATTACK
COMPLEX(MAC)
SPONTANEOUS
DC3 convertase
P
C3 Nephritic factor
C3
C3a
C3b B
C3bB
C3bBb
(C3b)2BbPC5 convertase
MEMBRANEATTACK
COMPLEX(MAC)
SPONTANEOUS
DC3 convertase
P Factor H
C3 Nephritic factor
C3
C3a
C3b B
C3bB
C3bBb
(C3b)2BbPC5 convertase
MEMBRANEATTACK
COMPLEX(MAC)
SPONTANEOUS
DC3 convertase
P Factor H
C3Nef
C3 Nephritic factor
C3
C3a
C3b B
C3bB
C3bBb
(C3b)2BbPC5 convertase
MEMBRANEATTACK
COMPLEX(MAC)
SPONTANEOUS
DC3 convertase
P Factor H
C3Nef
C3 Nephritic factor
C3
C3a
C3b B
C3bB
C3bBb
(C3b)2BbPC5 convertase
MEMBRANEATTACK
COMPLEX(MAC)
SPONTANEOUS
DC3 convertase
P Factor H
Anti-factor H autoantibody
C3
C3a
C3b B
C3bB
C3bBb
(C3b)2BbPC5 convertase
MEMBRANEATTACK
COMPLEX(MAC)
SPONTANEOUS
DC3 convertase
P Factor H
Anti-factor Hautoantibody
Anti-factor H autoantibody
C3
C3a
C3b B
C3bB
C3bBb
(C3b)2BbPC5 convertase
MEMBRANEATTACK
COMPLEX(MAC)
SPONTANEOUS
DC3 convertase
P Factor H
Anti-factor Hautoantibody
Anti-factor H autoantibody
C3
C3a
C3b B
C3bB
C3bBb
(C3b)2BbPC5 convertase
MEMBRANEATTACK
COMPLEX(MAC)
SPONTANEOUS
DC3 convertase
P Factor H
Gain of function C3 mutation
C3
C3a
C3b B
C3bB
C3bBb
(C3b)2BbPC5 convertase
MEMBRANEATTACK
COMPLEX(MAC)
SPONTANEOUS
DC3 convertase
P Factor H
Gain of function C3 mutation
C3b
C3
C3a
C3b B
C3bB
C3bBb
(C3b)2BbPC5 convertase
MEMBRANEATTACK
COMPLEX(MAC)
SPONTANEOUS
DC3 convertase
P Factor H
Gain of function C3 mutation
C3b
C3
C3a
C3b B
C3bB
C3bBb
(C3b)2BbPC5 convertase
MEMBRANEATTACK
COMPLEX(MAC)
SPONTANEOUS
DC3 convertase
P Factor H
Genetic deficiency of factor H
C3
C3a
C3b B
C3bB
C3bBb
(C3b)2BbPC5 convertase
MEMBRANEATTACK
COMPLEX(MAC)
SPONTANEOUS
DC3 convertase
P Factor H
Genetic deficiency of factor H
C3
C3a
C3b B
C3bB
C3bBb
(C3b)2BbPC5 convertase
MEMBRANEATTACK
COMPLEX(MAC)
SPONTANEOUS
DC3 convertase
P Factor H
Genetic deficiency of factor H
C3NeF
C3NeF
Source: Sethi et coll. N Engl J Med 2012
EVOLUTION
40 p.100 des GNMP évoluent vers IRT après 10 ans
Mauvais pronostic si SN, atteinte rénale ou HTA persistante au moment du diagnostic
la MDD a le moins bon pronostic des GNMP
Récidive MDD en cas de greffe dans 80-90%
Source: Alchi et coll. Pediatr Nephrol 2010
RECHERCHE
Factor H and factor B levels and activityif abnormalities search for mutations of factor H, factor I
and C3 or auto-antiboides for factor H
Exclusion of monoclonal gammopathy
Source: Alchi et coll. Pediatr Nephrol 2010
TRAITEMENT
« The efficacy of the various therapeutic regimens tried in MPGN is difficult to assess because of the small patient numbers and short-term nature of published controlled trials; the larger trials carried
out to date have been uncontrolled. »
Source: Alchi et coll. Pediatr Nephrol 2010
KDIGOClinical Practice Guidelines for Glomerulonephritis 2012
Treatment of idiopathic MPGN
We suggest that adults or children with presumed idiopathic MPGN accompanied by nephrotic sydnrome AND progressive decline of kidney function receive oral cyclophosphamide
or MMF plus low-dose alternate-day of daily corticosteroid with initial therapy limited to less than 6
months. (2D)
Source: www.kdigo.org
TRAITEMENT spécifique MDD
Echanges plasmatiquessi déficit facteur H ou C3NeF élevé
Source: Alchi et coll. Pediatr Nephrol 2010
Echanges plasmatiquessi déficit facteur H ou C3NeF élevé
Rituximabpour diminuer production C3NeF
Eculizumaben empêchant formation C5a
Source: Smith et coll. J Am Soc Nephrol 2007
Dr Vincent Bourquin - service de néphrologie - http://nephrohug.com
merci de votre attention
MB-LECTINPATHWAY
Mannose-binding lectinbinds mannose onpathogen surfaces
MBL, MASP-1, MASP-2C4C2
C3 convertase
CLASSICALPATHWAY
ALTERNATIVEPATHWAY
C1q, C1r, C1sC4C2
Pathogen surfaces
C3BD
Antigen:antibodycomplexes
(pathogen surface)
C3a, C5a C3b
Binds to complementreceptors on phagocytes
C3 convertase
Peptide mediatorsof inflammation,
phagocyte recruitment
TerminalComplements components
C5bC6C7C8C9
Membrane-attackcomplex, lysis of
certain pathogens and cells
Opsonizationof pathogensRemoval of
immune complexes