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2016-02-22
1
TMA = pathological feature
Thrombotic microangiopathy
by courtesy of Dr Anne Moreau, Nantes, France
aHUS TTP
Thrombotic microangiopathy
Complement alternative pathway dysregulation
ADAMTS13 deficiency
2016-02-22
2
u C3 convertase
C5 convertase
sMAC
iC3b
C3
C5b
C5
C6,7,8,9
C3b
Complement system
Thrombotic microangiopathy
CAP dysregulation in aHUS
Noris M, NEJM 2009
2016-02-22
3
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
2016-02-22
4
Complement genetics
Mutation Polymorphism(s) aHUSPrecipitating
event+ +
aHUS: the genetics
2016-02-22
5
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
2016-02-22
6
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)
French aHUS registry: A new clinical picture of aHUS
Adults (n=125)
Triggering event 33%
Diarrhoea 15%
Upper respiratory tract infection 1%
Pregnancy (post-partum) 19% of female patients
Frémeaux-Bacchi V, F Fakhouri et al. Clin J Am Soc Nephrol 2013
2016-02-22
7
French aHUS registry: A new clinical picture of aHUS
Adults (n=125)
Triggering event 33%
Diarrhoea 15%
Upper respiratory tract infection 1%
Pregnancy (post-partum) 19% of female patients
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%
Frémeaux-Bacchi V, F Fakhouri et al. Clin J Am Soc Nephrol 2013
French aHUS registry: A new clinical picture of aHUS
Adults (n=125)
Triggering event 33%
Diarrhoea 15%
Upper respiratory tract infection 1%
Pregnancy (post-partum) 19% of female patients
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%
Frémeaux-Bacchi V, F Fakhouri et al. Clin J Am Soc Nephrol 2013
2016-02-22
8
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
2016-02-22
9
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
2016-02-22
10
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 )
2016-02-22
11
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
2016-02-22
12
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
2016-02-22
13
n = 57 aHUS pts + 71 RT
Le Quintrec M, AJT 2013
Complement Genes Strongly Predict Recurrence and Graft Outcome in Adult Renal Transplant Recipients with aHUS
Graft SurvivalRecurrence hazard ratio
n = 57 aHUS pts + 71 RT
Le Quintrec M, AJT 2013
Complement Genes Strongly Predict Recurrence and Graft Outcome in Adult Renal Transplant Recipients with aHUS
Graft Survival
2016-02-22
14
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
2016-02-22
15
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)
F. Fakhouri, ASN 2013
2016-02-22
16
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
Trial 4: the largest prospective study with eculizumab in aHUS (adults)
F. Fakhouri, ASN 2013
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
Trial 4: the largest prospective study with eculizumab in aHUS (adults)
F. Fakhouri, ASN 2013
2016-02-22
17
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
2016-02-22
18
Platelets >150 G/LComplete triad
16%83%
Recommendations for managingadult patients with aHUS
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
First-line PE therapy
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
Recommendations for managingadult patients with 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
First-line PE therapy
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
First-line PE therapy
You do not need complement tests/genetics to diagnose aHUS or start treatment
2016-02-22
19
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
20
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
21
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
2016-02-22
22
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
2016-02-22
23
Renal Arteriolar C4d Deposition: A Novel Characteristic of
Hematopoietic Stem Cell Transplantation-Associated Thrombotic
Microangiopathy.
Laskin, Transplantation, 2013
2016-02-22
24
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
2016-02-22
25
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