thrombotic microangiopathy: evolving concepts

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Thrombotic microangiopathy: evolving concepts

Fadi Fakhouri

Department of Nephrology and ImmunologyCHU de Nantes, France


Too many names…but does it really matter?

HUS TTP

secondary HUStypical HUS

atypical HUS

HUS/TTP

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TMA



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


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.


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



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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

« 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




Abraham KA, 2003

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VEGF inhibition and renal TMA

Eremina V, NEJM, 2008



Alternative Pathway Activation of Complement by Shiga Toxin Promotes Exuberant C3a Formation That Triggers Microvascular ThrombosisMorigi M J Immunology 2011

«Typical HUS »


E Coli

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Complement Blockade in Severe Shiga-Toxin-Associated HUS.Lapeyraque AL NEJM 2011

E Coli

«Typical HUS »

Complement dysregulation-

associated TMA



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


FH mutation



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


Is genetics the « Holy Grail »??




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A304V

Mutation Polymorphism

« La Balançoire »FragonardXVIII Century




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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

* * *



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



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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



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



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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



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%


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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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

thrombotic microangiopathy: evolving concepts

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