Thrombotic microangiopathy and nephrotic syndrome risk on if nbeta mhra sept 2014
Thrombotic microangiopathy: evolving concepts
Transcript of Thrombotic microangiopathy: evolving concepts
08/03/2012
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Thrombotic microangiopathy: evolving concepts
Fadi Fakhouri
Department of Nephrology and ImmunologyCHU de Nantes, France
Thrombotic microangiopathy: evolving concepts
Too many names…but does it really matter?
HUS TTP
secondary HUStypical HUS
atypical HUS
HUS/TTP
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TMA
Thrombotic microangiopathy: evolving concepts
Too many names…but does it really matter?
by courtesy of Dr Anne Moreau, Nantes, France
HUS TTP
Thrombotic microangiopathy: evolving concepts Too many names…but does it really matter?
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
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Complement alternative pathway dysregulation
ADAMTS13 deficiency
Thrombotic microangiopathy: evolving concepts Too many names…but does it really matter?
HUS TTP
Thrombotic microangiopathy
CAP dysregulation in aHUS
Noris M, NEJM 2009
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Endothelial cell
Adhesion andaggregationof platelets
ADAMTS 13
Bindingsite
Uncleaved unusuallylarge multimers of
von Willebrand factor
Cleaved unusuallylarge multimers of
von Willebrand factor
Secretion of multimers from Weibel-Palade body
Endothelial cell
Bindingsite
Secretion of multimers from Weibel-Palade body
ADAMTS 13
Normal TTP
Adapted from Moake, NEJM, 2002.
Thrombotic microangiopathy
ADAMTS13-deficiency in TTP
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?
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Pregnancy-associated TMA
« complement abnormalities found in 18 of the 21 patients with pregnancy-related aHUS»F Fakhouri, JASN 2010
Secondary TMA / TMA-like disorders
Thrombotic microangiopathy: evolving concepts
Too many names…but does it really matter?
P-associated TMA due to ADAMTS13 deficiency
Complement dysregulation-TMA in the French aHUS cohort
« 4/11 patients had a mutation in one of the genes coding for proteins involved in the regulation of the CAP »F Fakhouri, Blood 2008
HELLP syndrome
Secondary TMA / TMA-like disorders
Thrombotic microangiopathy: evolving concepts
Too many names…but does it really matter?
Abraham KA, 2003
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VEGF inhibition and renal TMA
Eremina V, NEJM, 2008
Secondary TMA / TMA-like disorders
Thrombotic microangiopathy: evolving concepts Too many names…but does it really matter?
Alternative Pathway Activation of Complement by Shiga Toxin Promotes Exuberant C3a Formation That Triggers Microvascular ThrombosisMorigi M J Immunology 2011
«Typical HUS »
Thrombotic microangiopathy: evolving concepts Too many names…but does it really matter?
E Coli
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Thrombotic microangiopathy: evolving concepts Too many names…but does it really matter?
Complement Blockade in Severe Shiga-Toxin-Associated HUS.Lapeyraque AL NEJM 2011
E Coli
«Typical HUS »
Complement dysregulation-
associated TMA
Thrombotic microangiopathy: evolving concepts
Too many names…but does it really matter?
ADAMTS13 deficiency-associated
TMA
F Fakhouri, Nature Rev Nephrology, 2009
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CFH mutation in familial TTP with ADAMTS13 deficiency and renal involvement M Noris JASN 2005
CRF+
CRF-
Thrombotic microangiopathy: evolving concepts 1
Too many names…but does it really matter?
FH mutation
Thrombotic microangiopathy: evolving concepts
Too many names…but does it really matter?
Complement dysregulation-
associated TMA
ADAMTS13 deficiency-associated
TMA
E ColiAnti-VEGF
TMA of unknown mechanism
F Fakhouri, Nature Rev Nephrology, 2009
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We have no definitive proof of the pathogenicity of some complement genes mutations
Thrombotic microangiopathy
Is genetics the « Holy Grail »??
Thrombotic microangiopathy
Is genetics the « Holy Grail »??
We have no definitive proof of the pathogenicity of some complement genes mutations
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Thrombotic microangiopathy
Is genetics the « Holy Grail »??
We have no definitive proof of the pathogenicity of some complement genes mutations
A304V
Mutation Polymorphism
« La Balançoire »FragonardXVIII Century
Thrombotic microangiopathy
Is genetics the « Holy Grail »??
We have no definitive proof of the pathogenicity of some complement genes mutations
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CFI G243D
R. Salomon, Paris E. Bérard, Nice G. Deschênes , Paris
aHUS 8M aHUS D3
C Loirat, V Frémeaux-Bacchi
aHUS 8M aHUS 3MaHUS 3YaHUS 5M
No mutation CFHA161SNo mutation CFI C453RNo mutation
* * *
Thrombotic microangiopathy
Is genetics the « Holy Grail »??
Childhood-onset aHUS
Adulthood-onset aHUS
Renal su
rvival (%
)
0 2 4 6 8 10
100
60
20
0 2 4 6 8 10
Years
MCP
CFH
0 2 4 6 8 10
100
80
60
40
20
C3
0 2 4 6 8 10
Years
Undetermined80
40
Renal su
rvival (%
)
Long-term outcome of aHUSFrench aHUS registry F Fakhouri, C Loirat, V Frémeaux-Bacchi
Thrombotic microangiopathy
Is genetics the « Holy Grail »??
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Complement genetics as a predictive tool before renal transplantation
Complement genetics as a therapeutic tool
TMA/HUS/TTP
PEFFPCS
IVIgCYPVINAZARTXSPL
Complement-dysregulation TMA
ADAMTS13-deficiency TMA
Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient TTP.
Fakhouri F, Blood. 2005
Thrombotic microangiopathy
Is genetics the « Holy Grail »??
Should we screen for complement genes mutations in aHUS patients’ relatives?
No…uncertainities of geneticsincomplete penetrance of mutationsunpredictable precipitating factors
but…..
pregnancy and renal transplantation are predictable precipitating factors
Thrombotic microangiopathy
Is genetics the « Holy Grail »??
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1/5 women in the aHUS French cohort experienced aHUS during a pregnancyF Fakhouri, JASN 2010
P-associated TMA due to ADAMTS13 deficiency
Complement dysregulation-TMA in the French aHUS cohort
Thrombotic microangiopathy
Is genetics the « Holy Grail »??
Relapse pattern in the French aHUS registryF Fakhouri, C Loirat, Véronique Frémeaux-Bacchi
Percentage of patients with at least one aHUS relapse
Early onset Late onset
CFH 31% 16%
CFI 31% 11%
MCP 77% 33%
C3 33% 29%
anti-FH Ab 71% /
Unexplained 27% 19%
Thrombotic microangiopathy
Is atypical HUS a relapsing disease?
In late onset aHUS 81% of relapses occur during the1st year of follow-up (63% in early onset aHUS)
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Thrombotic microangiopathy
Eculizumab and aHUS
Murine IgG m5G1.1
Humanised murine IgG
Eculizumab
Humanised murine IgG(Soliris)
Half-life 272h
DV: vascular spaceSteady state 150 days
Concentration > 35 mg/mL achieve
total in vivo inhibition of hamelotytic activity
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Noris M, NEJM 2009
Eculizumab
Paroxymal nocturnal haemoglobinuria
Decay of C3 and C5 convertases
Stem cells clonal expansion
Somatic mutations of PIGA gene
Glycosyl transferase deficiency
Parker C, Lancet. 2009
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Parker C, Lancet. 2009
Paroxymal nocturnal haemoglobinuria
Thrombotic microangiopathyEculizumab and aHUS
Open Label Controlled Trial of Eculizumab in Adult Patients With Plasma-Resistant aHUS
Open Label Controlled Trial of Eculizumab in Adult Patients With Plasma-Dependent aHUS
Open Label Controlled Trial of Eculizumab in Adult Patients With aHUS
Nurnberger et al. NEJM 2009
Female 37 yRT / CFH missense mutations
Gruppo el al. NEJM 2009
M 18MNo mutations
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Platelets increased by 96 G/L compared to baseline, starting day 7.
TMA-free for at least 12 consecutive weeks in 88% of patients.
Phase 2 study of eculizumab in patients with aHUS who were resistant or intolerant to plasma therapy.
17 adolescent and adult patients.Eculizumab therapy for 26 w
No cases of meningococcal infection
Primary endpoint : change in platelets count from baseline at 26 w.
Improvement of at least one stage in CKD in 65% of patients
Among 7 patients on dialysis before the study, 5 became dialysis-free.
Eculizumab and aHUS
Eculizumab is most probably an optimal first-line treatment for aHUS
But, it costs 300 000 euros/year !!
Then, eculizumab is most probably an optimal second-line treatmentfor plasma-resistant aHUS
But, what is a « plasma-resistant aHUS»?
aHUS is plasma-resistant if: platelets < 150 G/land/or LDH > 2Nand/or increase or absence of 25% decrease in SCrdespite 3-5 daily PE
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Don’t wait for genetics to start eculizumab
900 mg/w 1200 mg/2w
Eculizumab and aHUS
« Chronic HPN regimen »
In acute aHUS, higher and/or more frequent doses may be required
Optimal complement blockade = CH50 < 20%
1 year?
When do we stop eculizumab?
Anti-FH aHUSADAMTS13-TMA
ImmunosuprressorsEculizumab in acute anti-FH aHUS
Age/Precipitating factor/Genetic defect
Recombinant/purified FH New complement modulators
Anti-meningococcal vaccine
Methylpenicillin 2MU/day
In Conclusion….three concepts1. A tremendous shift
Name(s)TMAHUSTTP
Mechanism(s)Complement dysregulation
2. An achievement
The rediscovery of complement
Nephrologists
« Le Conseil de l’Ordre », Verlinde, XX°°°° century
3. Breakthrough We have the tools to modulate complement activation….… we still need to learn how to use them