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PPT-SHU démarche diagnostic
Dr Moglie Le Quintrec
CRC « Complement and diseases »
Service de Néphrologie Hôpital Foch
Thrombotic microangiopathy
2
Anemia, fragmentation erythrocytes Low haptoglobin,High LDH level Thrombocytopenia Acute renal failure Organ damage (brain,liver ..)
Arteriolar and glomerular capillary thrombi Mesangiolysis
Thrombotic microangiopathy
HUS TTP
secondary HUS typical HUS
atypical HUS
TTP HUS
10% TTP patients have ARF, Hovinga Blood 2010
In autopsy studies, the most affected organ in TTP patients is the kidney, Hosler GA Arch Pathol Lab Med 2003
Thrombotic microangiopathy
Endothelial cell
Adhesion and aggregation of platelets
ADAMTS 13
Binding site
Uncleaved unusually large multimers of
von Willebrand factor
Cleaved unusually large multimers of
von Willebrand factor
Secretion of multimers from Weibel-Palade body
Endothelial cell
Binding site
Secretion of multimers from Weibel-Palade body
ADAMTS 13
Normal TTP
Adapted from Moake, NEJM, 2002.
ADAMTS13-deficiency in TTP Thrombotic microangiopathy
6
Purpura thrombotique thrombocytopénique
Atteinte neurologique et défaillance multi-viscérale Activité ADAMTS 13 < 10% Anticorps anti-nucléaires positifs Forme acquise (95% des cas) : IgG anti-ADAMTS 13 Deficit congénital (5% des cas): Mutation homozygote d’ADAMTS 13 (syndrome de Upshaw-Schulman)
Thrombotic microangiopathy
HUS TTP
secondary HUS typical HUS
atypical HUS
8
SHU Typique
SHU typique : 90% des SHU de l’enfant (pic de fréquence avant 3 ans) Epidémie saisonnière Diarrhées : 97% des cas avec un début 6 jours avant Facteurs de risque : viande hachée peu cuite, fromage lait cru, contact animaux, baignade Diarrhée dans l’entourage (20%) E coli producteur de shiga-toxine (sérotype O157:H7, épidémie allemande O104:H4 ) Plus rare, pyélonéphrite bactériémie à E Coli-shiga-toxine + et SHU secondaire Moins de 10% IRCT
Thrombotic microangiopathy
HUS TTP
secondary HUS typical HUS
atypical HUS
FB FD
Alterna,ve pathways
C3b‐like ou C3(H2O)
Alterna,ve C3 convertase C3bBb
Classical pathways
Lec,n Pathway
C4, C2
Classical C3 convertase C4bC2a
C1q MBL
C3b
C3
Low permanent Activation
Complement System
Protéines Régulatrices du complément
Préven,on de l’ac,va,on
Agents pathogènes
Amplification de la boucle
Rôle : protection des cellules de l’hôte
‐ ‐ ‐ ‐
Cellules du soi
‐ ‐ ‐
C3b
C3
C3b
Elimination de l’agent pathogène
C3b
Activation permanente à bas bruit de la voie alterne
C3b
C3b
C3b Bb
Alternative pathways regulation
Fluide phase
iC3b
FI
C3b
FHFHBbC3b C3b
B
BC3b
D
C3 C3b
B C3b C3b
Bb
D
C3H2O
B
FH
La voie alterne : régula,on
Phase fluide
Compé,,on de liaison au C3b avec le FB Dissocia,on de la C3 convertase alterne Cofacteur du FI
Fonctions du FH
iC3b
FI
C3b
FHFHBbC3b C3b
B
BC3b
D
C3
B Bb
C3b iC3b
FI
FH
FH
FH
FH
FH
C3b
B C3b C3b
Bb
D
C3H2O
B
C3b iC3b iC3b
iC3b
iC3b
iC3b
MCP
FH
FH + THBM
FI
FI
FI
Membranes cellulaires
La voie alterne : régulation
Phase fluide
FH, MCP, THBD/FH Cofacteur du FI
iC3b
FI
C3b
FHFHBbC3b C3b
B
BC3b
D
C3
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C3b
C3b
Défaut de protec,on des membranes chargées néga,vement avec des acides sialiques, GAGs
C3b Bb
C3b
C3b C3b C3b
Modèle physiopathologique proposé SHUa Maladie Tissulaire
C6 C7
C8 FI
SHU atypique
C5b C9 C5
Number of aHUS patients at risk
Pediatric onset 89 34 17 13 6
Adult onset 125 18 7 2 0
100
60
20
Years
Ove
rall
rena
l su
rvival (%)
0 5 10 15 20
Pediatric onset, n=89 Adult onset, n=125 P<0,0001
80
40
Prognosis of aHUS French cohort, 214 patients
Mortality: 8% in children, 2% in adults ESRF at first episode: 16% in children, 46% in adults
ESRF at 5 years follow-up: 36% in children, 64% in adults
Fremeaux-Bacchi et al, CJASN 2013
Thrombotic microangiopathy
Genetics
(%) all Early (n) Late (n) p
N 214 89 125CFH 27,5 21.3 (19) 32 (40) nsMCP 9.3 13.5 (12) 6.4 (8)C3 8.8 7.8 (7) 10 (12) nsCFI 8.8 6.7 (6) 10 (13) nsCFB 2.4 2 (2) 2.4 (3) nsCombinated 4.2 3.4 (3) 4 (6) ns aFHG 6.5 11 (10) 3.2 (4) 0.03None/Incomplete 32.7 33 (30) 31 (39) 0.005ns
aHUS : many risks factors
Trigger events
Commun polymorphisms (CFH; MCP; CFHR1)
Mutation in one of the six genes (CFH,CFI,MCP,C3,CFB)
+
(Esparza-Gordillo et al, 2005; Fremeaux-Bacchi et al,2005; Abarrategui-Garrido et al, 2009 )
(Review in Noris et al, 2010 )
• Diarrhea and upper respiratory tract infections were frequent in children • Pregnancy is the trigger event in 20% adult female patients with aHUS mainly in the
post partum period
• The term of Mutation is reserved to rare pathogenic sequence changes • The Identification of the effects that each mutation causes on function is mandatory.
+
Thrombotic microangiopathy
HUS TTP
secondary HUS typical HUS
atypical HUS
• Infections (pneumococal, HIV) • Hematopoietic stem cell Trx • Cancer • Auto immune diseases (lupus, APS) • Drugs : anti VEGF, chemotherapy (cycA, FK, Sirolimus, quinine, ticlopidine, mitomycine C)
• Malignant hypertension • De novo TMA after kidney Trx
Secondary Thrombotic microangiopathy
Italian Registry n=273 (13%)
Noris CJASN 2010
Secondary TMA / TMA-like disorders
Kidney-transplantation related TMA
« CFH or CFI gene mutations found in 7/24 patients (29%) »
Thrombotic microangiopathy : evolving concepts
Too many names… but does it really matter?
Le Quintrec M, AJT 2008
Pregnancy-associated TMA
« complement abnormalities found in 18 of the 21 patients with pregnancy-related aHUS» F Fakhouri, JASN 2010
P-associated TMA due to ADAMTS13 deficiency
Complement dysregulation-TMA in the French aHUS cohort
Thrombotic microangiopathy : evolving concepts
Secondary TMA / TMA-like disorders
Too many names… but does it really matter?
First episode of TMA
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Medical History (malignancies, systemic disease, pregnancy, medications) Physical examination
Serologies HIV, APL, DNA
First episode of TMA
Coppo P PlosOne 2010
ADAMTS13 v/s C3 convertase
Coppo P PlosOne 2010
ADAMTS13 v/s C3 convertase
Plts < 30 G/L 7% Cr < 200 μmol/l 10% Critères 1+2 2%
French aHUS Registry
ADAMTS13 v/s C3 convertase
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Merci pour votre attention