PPT-SHU démarche diagnostic Dr Moglie Le Quintrec CRC « Complement and diseases » Service de Néphrologie Hôpital Foch Thrombotic microangiopathy Anemia, fragmentation erythrocytes Low haptoglobin,High LDH level Thrombocytopenia Acute renal failure Organ damage (brain,liver ..) Arteriolar and glomerular capillary thrombi Mesangiolysis 2 Thrombotic microangiopathy TTP HUS typical HUS secondary HUS atypical HUS Thrombotic microangiopathy 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 ADAMTS13-deficiency in TTP Normal Cleaved unusually large multimers of von Willebrand factor TTP Adhesion and aggregation of platelets Uncleaved unusually large multimers of von Willebrand factor ADAMTS 13 Binding site ADAMTS 13 Binding site Endothelial cell Secretion of multimers from Weibel-Palade body Endothelial cell Secretion of multimers from Weibel-Palade body Adapted from Moake, NEJM, 2002. 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) 6 Thrombotic microangiopathy TTP HUS typical HUS secondary HUS atypical HUS 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 8 Thrombotic microangiopathy TTP HUS typical HUS secondary HUS atypical HUS Complement System Classical pathways Alterna,ve pathways Lec,n Pathway Low permanent Activation C1q MBL C4, C2 C3b‐like ou C3(H2O) C3 FB FD Alterna,ve C3 convertase C3bBb Classical C3 convertase C4bC2a C3b Rôle : protection des cellules de l’hôte Activation permanente à bas bruit de la voie alterne C3 C3b Agents pathogènes Cellules du soi C3b C3b ‐ ‐ C3b ‐ Amplification de la boucle Bb C3b Protéines Régulatrices du complément ‐ Elimination de l’agent pathogène ‐ C3b ‐ ‐ Préven,on de l’ac,va,on Alternative pathways regulation Fluide phase B C3H2O C3 FH B C3b C3b B Bb Bb C3b C3b C3b C3b D D FH FH C3b FI iC3b La voie alterne : régula,on Phase fluide B FH B C3b C3b C3H2O C3 FH B Bb Bb C3b C3b C3b C3b D D FH FH FH C3b C3b FI FI Fonctions du FH FH FH Compé,,on de liaison au C3b avec le FB Dissocia,on de la C3 convertase alterne Cofacteur du FI iC3b iC3b La voie alterne : régulation Membranes cellulaires Phase fluide FI !! C3b #$"% #$*+,! C3 FH B "! #$! B !! Bb !"! C3b #$"% C3b #$"% D )% #$! FH #$! #$! #$"% C3b FH C3b MCP iC3b FI iC3b &#$"% FI '(% #$! iC3b C3b FH + THBM FI C3b iC3biC3biC3b FH, MCP, THBD/FH Cofacteur du FI Modèle physiopathologique proposé SHUa Maladie Tissulaire FI C3b C3b C3b Bb C3bC3b C 5 C6 C8 C5b C7 C9 Défaut de protec,on des membranes chargées néga,vement avec des acides sialiques, GAGs SHU atypique Prognosis of aHUS French cohort, 214 patients Pediatric onset, n=89 Overall renal survival (%) 100 P<0,0001 Adult onset, n=125 80 60 40 20 0 5 10 Years 15 20 Number of aHUS patients at risk Pediatric onset 89 34 17 13 6 125 18 7 2 0 Adult onset 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) N 214 89 125 CFH 27,5 21.3 (19) 32 (40) MCP 9.3 13.5 (12) 6.4 (8) C3 8.8 7.8 (7) 10 (12) ns CFI 8.8 6.7 (6) 10 (13) ns CFB 2.4 2 (2) 2.4 (3) ns Combinated 4.2 3.4 (3) 4 (6) ns 6.5 11 (10) 3.2 (4) 0.03 32.7 33 (30) 31 (39) ns 0.005 aFHG None/Incomplete p ns aHUS : many risks factors Mutation in one of the six genes (CFH,CFI,MCP,C3,CFB) • • The term of Mutation is reserved to rare pathogenic sequence changes The Identification of the effects that each mutation causes on function is mandatory. + Commun polymorphisms (CFH; MCP; CFHR1) (Esparza-Gordillo et al, 2005; Fremeaux-Bacchi et al,2005; Abarrategui-Garrido et al, 2009 ) + Trigger events • • 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 (Review in Noris et al, 2010 ) Thrombotic microangiopathy TTP HUS typical HUS secondary HUS atypical HUS Secondary Thrombotic microangiopathy • 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 Italian Registry n=273 (13%) Noris CJASN 2010 Thrombotic microangiopathy : evolving concepts Too many names… but does it really matter? Secondary TMA / TMA-like disorders Kidney-transplantation related TMA « CFH or CFI gene mutations found in 7/24 patients (29%) » Le Quintrec M, AJT 2008 Thrombotic microangiopathy : evolving concepts Too many names… but does it really matter? Secondary TMA / TMA-like disorders Pregnancy-associated TMA Complement dysregulation-TMA in the French aHUS cohort P-associated TMA due to ADAMTS13 deficiency « complement abnormalities found in 18 of the 21 patients with pregnancy-related aHUS» F Fakhouri, JASN 2010 First episode of TMA Medical History (malignancies, systemic disease, pregnancy, medications) Physical examination Serologies HIV, APL, DNA 23 First episode of TMA ADAMTS13 v/s C3 convertase Coppo P PlosOne 2010 ADAMTS13 v/s C3 convertase Coppo P PlosOne 2010 ADAMTS13 v/s C3 convertase French aHUS Registry Plts < 30 G/L Cr < 200 μmol/l Critères 1+2 7% 10% 2% ? ? ? Merci pour votre attention
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