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

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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