Thrombotic microangiopathy - CUEN · Thrombotic microangiopathy: evolving concepts Complement dysregulation-associated TMA ADAMTS13 deficiency-associated TMA Post infection TMA Pneumococcal

2016-02-22

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TMA = pathological feature

Thrombotic microangiopathy

by courtesy of Dr Anne Moreau, Nantes, France

aHUS TTP


Complement alternative pathway dysregulation

ADAMTS13 deficiency

2016-02-22

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u C3 convertase

C5 convertase

sMAC

iC3b

C3

C5b

C5

C6,7,8,9

C3b

Complement system


CAP dysregulation in aHUS

Noris M, NEJM 2009

2016-02-22

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Alternative pathwayC3 convertase

Inactivating mutations in inhibitory factors

Activating mutations in C3convertase components

Of the importance of a tight regulation of the AP C3 convertase

FHFIMCP

C3 FB

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Complement genetics

Mutation Polymorphism(s) aHUSPrecipitating

event+ +

aHUS: the genetics

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Thrombotic microangiopathy: evolving concepts

Complement dysregulation-associated

TMA

ADAMTS13 deficiency-associated TMA

Post infection TMAPneumococcal

HIV

Drug-mediated TMACNI, anti VEGF

VitB12 metabolism mediated TMA

Adapted from Fakhouri, Nature Rev Nephrology, 2009

aHUS

BMT-TMACoagulation mediated-TMA

DGKεεεε

TTP

ST-HUS

TMA of unknown mechanism

French aHUS registry: A new clinical picture of aHUS

Adults (n=125)

Frémeaux-Bacchi V, F Fakhouri et al. Clin J Am Soc Nephrol 2013

58% of cohort were adults

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0 10 20 30 40 50 60

100

80

60

40

20

0P

rob

abil

ity

of

on

set

of

the

dis

eas

e(%

)

Age (years)Number at risk

214 137 110 67 32 10 2

aHUS is not a predominantly pediatric disease

65% of adults start the disease between 20-40 y

Fremeaux-Bacchi et al, CJASN 2013

French cohort, 125 adultsAge at onset: 18 to 87 yearsAdult Onset (F/M:3/1)


Adults (n=125)

Triggering event 33%

Diarrhoea 15%

Upper respiratory tract infection 1%

Pregnancy (post-partum) 19% of female patients


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Adults (n=125)


Diarrhoea 15%



Complete triad (microangiopathic haemolysis, thrombocytopenia and renal dysfunction)

83%

Platelets >150 G/L 16%

Haemoglobin >10 g/L 11%

CNS involvement 8%

Dialysis required 81%



Adults (n=125)


Diarrhoea 15%



Complete triad (microangiopathic haemolysis, thrombocytopenia and renal dysfunction)

83%

Platelets >150 G/L 16%

Haemoglobin >10 g/L 11%

CNS involvement 8%

Dialysis required 81%

ESRF following first presentation: 46% in adultsESRF at 5-year follow-up: 64% in adultsDeath: <2%


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65% of patients were treated with plasma exchange / plasma infusion

French aHUS registry (adults):effect of mutational status on survival

Time from diagnosis (months)

Ove

rall

ren

al s

urv

ival

(%

)

CFH

CFI

C3

MCP

No identified mutation

0 10 20 40 6030 50

100

80

60

40

20

0

Recommendations for managingadult patients with aHUS

1st episode of TMA in adult

ADAMTS13 deficiencySuspected HIVNeoplasia, DrugsSystemic disease-related HUS

First TMA manifestationin an adultFirst TMA

manifestation in an adult

Medical history (malignancies, systemic diseases, pregnancy, medications)Stools: culture, free Shiga toxin or Shiga toxin genes ±±±± LPS serologyADAMTS13HIV serologyANA, anti-DNA Ab, APL

Who should be treated with eculizumab?

Any patient with a clinical presentation of aHUS should be considered as a candidate

The spectrum of indications encompasses aHUS involving either native or transplanted kidneys as well as aHUS with incomplete clinical presentation

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Plts < 30 G/L 7%Cr < 200 10%1+2 2%

French aHUS Registry

Severe ADAMTS13 deficiency vs Complement mediated TMA

Coppo P PlosOne 2010

Severe ADAMTS13 deficiency vs Complement mediated TMA

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Complement assays

Normal serum complement levels do not rule out aHUS

aHUS phase

Overall Mutations anti-CFH Ab

No mutations

Reduced serum C3 Acute 10/18 5/9 5/9

Increased serum C5a Acute 9/19 3/10 6/9

Increased sC5b-9 Acute 10/19 4/10 6/9

Absence of complement genes mutations does not exclude aHUS

C3

cfi mut

C9

c3 mut

C9cfh mut

C9no mut

C3 C3

cfh mut cfi mut

C9

cfh mut

C9

ct

Adapted from Noris et al., Blood, 2014

10000

8000

6000

4000

2000

0

ComplementBlockade

CFH CFI C3 CFB antiCFH Ab

Nomutation

- + - + - + - + - + - +

C5b

-9 d

epo

siti

on

on

act

ivat

ed

end

oth

elia

l cel

l in

pat

ien

ts w

ith

aH

US

wit

ho

ut o

vert

TM

A(p

ixel

2 )

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Blood, 2015

Threshold for aHUS onset

C genes mut+at-risk C genespolymorphisms

at-risk C genespolymorphisms

no mutno poylmorphisms

Co

mp

lem

en

t in

du

ced

en

do

the

lia

l da

ma

ge

A hypothesis…

InfectionPregnancy

Precipitating factors

Complement activation and aHUS

Individual variability

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aHUS: risk of relapse

All CFH CFI MCP C3 No Mut

(n=66) (n=20) (n=8) (n=6) (n=7) (n=21)

F -up (M) 52 55 58 11 50 42

> 1R 35% 30% 38% 33% 71% 33%

1 st R < 1y 29% 30% 38% 33% 43% 25%

1st R > 1y 6% 0 0 0 28% 5%

R > 1y 20% 19% 25% 33% 20% 20%

Relapse pattern in adult aHUS patients

Le Quintrec M, AJT 2013

n = 57 aHUS pts + 71 RT

Complement Genes Strongly Predict Recurrence and Graft Outcome in Adult Renal Transplant Recipients with aHUS

Graft Survival

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Graft SurvivalRecurrence hazard ratio




Graft Survival

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Hinge

CH

3C

H2

Human IgG4 heavy chain constant regions 2 and 3(eliminates complement

activation)

Complementarity determining regions

(murine origin)

Human framework regions• No mutations• Germline

Human IgG2 heavy chain constant region 1 and hinge

(eliminates Fc receptor binding)

Eculizumab: humanised anti-C5 antibody

C5

C5b

C5a

MACC3b C3b

Bb

Overview of observation period and treatment period in prospective trials

The infusion schedule was designed to ensure immediate and sustained complete terminal complement inhibition

Patients received meningococcal vaccination prior to receipt of eculizumab or received prophylactic treatment with antibiotics until 2 weeks after vaccination

Wk5Wk1

900mg/wk900mg/wk900mg/wk900mg/wk

1200 mg every 2 weeks through 26 weeks1200 mg every 2 weeks through 26 weeks1200 mg every 2 weeks through 26 weeks1200 mg every 2 weeks through 26 weeksC08-003:8-week observation period

C08-002:No observation period

PE/PI Removed

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Trial 4: the largest prospective study with eculizumab in aHUS (adults)

F. Fakhouri, ASN 2013

n= 41

≥18 years

Inclusion criteria

Plts <150 × 109/L

Hb ≤ LLN

LDH ≥1.5 × ULN

SCr ≥ ULN

No specification for PE / PI prior to enrolment

ADAMTS13 activity > 5%

No evidence of STEC-HUS

Identification of C genes mutations / polymorphisms or autoAbs, not required.

Trial 4: primary and secondary end points.

Primary outcome:

- Platelet ≥150 × 109/L

- LDH ≤ ULN

- <25% increase in SCr from baseline

Secondary outcomes included:

− Modified complete TMA response

- Plts + LDH normalisation

- ≥25% decrease in SCr from baseline

− Haematological normalisation (Pltsand LDH normalisation)

− Change from baseline in eGFR

n=41

Identified complement genes mutation or autoantibody, n (%) 20 (49)

Median duration of current clinical manifestation, months (range) 0.5 (0.0–19.2)

Mean SCr, µmol/L (SD) 411.0 (264.6)

Mean eGFR, mL/min/1.73 m2 (SD) 17.3 (12.1)

Dialysis at baseline, n (%) 24 (59)

Prior renal transplant, n (%) 9 (22)


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Adverse events

(n=41)n (%)

Headache 15 (37)

Diarrhoea 13 (32)

Oedema (peripheral) 9 (22)

Cough 8 (20)

Pyrexia 7 (17)

Nasopharyngitis 7 (17)

Urinary tract infection 7 (17)

Arthralgia 7 (17)

Anaemia 7 (17)

2 patients had meningococcal infection (no antibioprohylaxis)

Uncertainties regarding:

-the efficacy of anti-meningococcal vaccine in AKI/RT/CKD patients.

- the protective effect of anti-meningococcal Abs in the setting of complement inhibition.

Antibioprophylaxis during all duration of Ecu treatment (France, UK, etc.)

Most AEs were mild or moderate / No deaths



0

5

10

15

20

25

30

35

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

†

#

*

** *

**

20 / 24 (83%) of patients on dialysis at baseline could discontinue dialysis

eGF

R c

hang

e fr

om b

asel

inea

(mL/

min

/1.7

3 m

2 )

Study week†p<0.05#p<0.001*p<0.0001vs baseline

29.3 mL/min/1.73 m2



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Issues in the treatment of aHUS

Eculizumab inhibits complement activation and EC damage and improves renal function.(prospective non-controlled trials)

Adults

French cohort: Fremeaux-Bacchi et al, CJASN 2013

ESRD (% patients)

Follow-upFrench cohort

N= 125

Trial 1N=17

Trial 2N=20

Trial 4N=41

First episode

46%

6 months 6% 10% 15%

1 year 56% 6% 10% 12%

2 years 12% 10%

5 years 64%

C. Loirat

Ped Nephrol, 2015

C5

C3b C3b

Bb

Eculizumab

Issues in the treatment of aHUS

Eculizumab inhibits complement activation and EC damage and improves renal function.

(retrospective studies)

(2004-2008)

Fakhouri F et al. Am J Kidney Dis 2014

C5

C3b C3b

Bb

Eculizumab

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Platelets >150 G/LComplete triad

16%83%


1st episode of TMA in adult

ADAMTS13 deficiencySuspected HIVNeoplasia, DrugsSystemic disease-related HUS

First TMA manifestationin an adult

First-line PE therapy

Switch to eculizumab therapy?

Uncertain diagnosisof primary aHUS

Complement factors (C3, C4, CFH, CFI, CFB)MCP expression, anti-CFH Ab


Plasma resistance after 5 PE Dependence on plasma

Absence of one of:Normal plateletsNormal LDHDecrease in SCr >25%

First TMAmanifestation in an adult

First-lineeculizumab

Unequivocaldiagnosis of aHUS

Medical history (malignancies, systemic diseases, pregnancy, medications)Stools: culture, free Shiga toxin or Shiga toxin genes ±±±± LPS serologyADAMTS13HIV serologyANA, anti-DNA Ab, APL

Who should be treated with eculizumab?

Any patient with a clinical presentation of aHUS should be considered as a candidate

The spectrum of indications encompasses aHUS involving either native or transplanted kidneys as well as aHUS with incomplete clinical presentation

Post-transplantation recurrence of aHUS or the nth aHUS relapse

involving native kidneys

First TMAmanifestation in an adult

First-lineeculizumab

Unequivocaldiagnosis of aHUS


• Medical history (malignancies, systemic diseases, pregnancy, medications)• Physical examination• Stools: culture, free Shiga toxin or Shiga toxin genes ± LPS serology•± ADAMTS13• HIV serology• ANA, anti-DNA Ab, APL

• ADAMTS13 deficiencySuspected HIV, neoplasia, drug, systemic disease-related HUS

Switch to eculizumab therapy

Uncertain diagnosisof primary aHUS


Plasma resistance after 5 PE Dependence on plasma therapy

Complement factors (C3, C4, CFH, CFI, CFB)MCP expression, anti-CFH Ab

Do complement investigations impact on therapeutic decisions?

• Eculizumab should be considered for all patients with aHUS without waiting for results from complement investigations, although screening for anti-CFH antibodies should be done rapidly as positive drug results would indicate a switch to PE and immunosuppressive drugs

• Screening for genetic complement abnormalities is needed for individualised management


You do not need complement tests/genetics to diagnose aHUS or start treatment

2016-02-22

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Early Ecu intiation = Better renal outcome

eGFR >60 mL/min

eGFR <60 mL/min

Dialysis

0 10 20 30 40 50 60 90

Time after aHUS onset (days)

Pt 2

Pt 3

Pt 10

Pt 12

Pt 1

Pt 15

Pt 11

Pt 18

Pt 19

Pt 9

Pt 4

Pt 7

Pt 14

Pt 8

Pt 5

Pt 16

Pt 13

Pt 17

Pt 6

*

*

*

-

+

+

+

+

+

-

+

+

+

-

+

+

+

+

+

+

+

+

Eculizumab ongoing at 3m

Insights from use in clinical practice of eculizumab in adult patients with aHUS affecting the native kidneys: an analysis of 19

cases

Fakhouri F et al. Am J Kidney Dis 2014;63:40-48

F. Fakhouri, AJKD

Insights from the use in clinical practice of eculizumab in adult patients with aHUS affecting the native kidneys: an analysis of 19 cases.

2016-02-22

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Thrombotic microangiopathy: evolving concepts

Complement dysregulation-associated

TMA

ADAMTS13 deficiency-associated TMA

Post infection TMAPneumococcal

HIV

Drug-mediated TMACNI, anti VEGF

VitB12 metabolism mediated TMA

Adapted from Fakhouri, Nature Rev Nephrology, 2009

aHUS

BMT-TMACoagulation mediated-TMA

DGKεεεε

TTP

ST-HUS

TMA of unknown mechanism

2016-02-22

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Postpartum

4 8 12 16 20 24 28 32 36 D 4 8 12 160

TMA in pregnancy

Fakhouri F, JASN, 2010

F, 34 y2nd uneventful pregnancy3 weeks PPSCr 650 mmol/lPlts 110 G/LLDH 2.5 ULNHb 10 g/dlHaptoglobin undetectableSchizocytes negPuria 2 g/l

1 woman/5 had aHUS during pregnancy79% of cases occurred during the post partum

Complement dysregulation-related TMA in pregnancy

Age at aHUS onset (years) 26 ± 5 33 ± 12 p < 0.05

Nb of pregnancies 2 ± 0.8 2.3 ± 1.5 NS

Nb of patients reaching ESRD < 6 months after aHUS

11 (52%) 20 (57%) NS

Number of patients reaching ESRD at last follow-up

16 (76%) 26 (74%) NS

Number of patients with complement abnormality

18 (86%) 26 (74%) NS

CFH10 (48%) 14 (40%) NS

CFI3 (14%) 6 (17%) NS

MCP1 (5%) 3 (8.5%) NS

C32 (9.5%) 1 (3%) NS

FB0 (0%) 2 (5.5%) NS

Patients with P-associated aHUS

(n=21)

Patients with aHUS non related to pregnancy

(n=35)

More than one mutation 2 (9.5%) 1 (3%) NS

Fakhouri F, JASN, 2010

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Pregnancy-associated TMA

P-associated TMA due to ADAMTS13 deficiency

P-associated TMA due to complement dysregulation-TMA in the French aHUS cohort

Post-Partum HUS = aHUS precipitated by pregnancy

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Renal Arteriolar C4d Deposition: A Novel Characteristic of

Hematopoietic Stem Cell Transplantation-Associated Thrombotic

Microangiopathy.

Laskin, Transplantation, 2013

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Renal Arteriolar C4d Deposition: A Novel Characteristic ofHematopoietic Stem Cell Transplantation-Associated ThromboticMicroangiopathy.Laskin, Transplantation, 2013

Eculizumab therapy in children with severe hematopoietic stem cell transplantation-associated thrombotic microangiopathy.Jodele S, Biol Blood Marrow Transplant, 2014

Successful use of eculizumab in a patient with post-transplant thrombotic microangiopathy.Peffault de Latour R, Br J Haematol 2013

APSBakhtar O Transplantation, 2014 Gemcitabine

Starck M, BJH, 2013Al Ustwani, JGO, 2014

Mitomycin CFaguer S, CKJ 2013

Cancer-associated TMA Favre G, BJH, 2014

Complement as an amplifying process in secondary HUS.

HELLP syndromeFakhouri F, Blood 2010

SLEEl-Husseini, AJKD 2015

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Conclusions

1) aHUS is a devastating TMA disease.

2) Urgent treatment is crucial.

3) Eculizumab has tranformed the clinical picture of aHUS.

Questions: STEC-HUS? Secondary HUS? Duration?

Conclusions

1) aHUS is a devastating TMA disease.

2) Urgent treatment is crucial.

3) Eculizumab has tranformed the clinical picture of aHUS.

Questions: STEC-HUS? Secondary HUS? Duration?

STOPECU

Documents

Thrombotic microangiopathy - CUEN · Thrombotic microangiopathy: evolving concepts Complement dysregulation-associated TMA ADAMTS13 deficiency-associated TMA Post infection TMA Pneumococcal