« 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