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ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS. Chantal Loirat, Hopital Robert Debré, Paris, France. aHUS IN CHILDREN FRENCH PEDIATRIC REGISTRY. 90 children (onset before age 16), 82 pedigrees 46 boys, 44 girls Sporadic HUS 68 (83 %), familial HUS 14 (17 %, 22 children) - PowerPoint PPT Presentation
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ATYPICAL HEMOLYTIC UREMIC SYNDROME :
TREATMENT OPTIONS
Chantal Loirat, Hopital Robert Debré, Paris, France
aHUS IN CHILDRENFRENCH PEDIATRIC REGISTRY
90 children (onset before age 16), 82 pedigrees
46 boys, 44 girls
Sporadic HUS 68 (83 %), familial HUS 14 (17 %, 22 children)
CFH mutation 17 (19 %)
MCP mutation 13 (14 %)
CFI mutation 8 (9 %)
C3 mutation 6 (7 %)
CFB mutation 1 (1 %)
Combined mutations 7 (8 %) (CFI + either CFH, or MCP, or CBF, or
C3(2); MCP + C3 ; CFH + CFH)
Anti-CFH antibodies 10 (11 %)
Complement – HUS 62 (69 %)
Unexplained HUS 28 (31 %)
AGE AT ONSET90 patients (French cohort)
n = 10 (11 %) n = 27 (30 %) n = 22 (24 %) n = 24 (27 %) n = 7 (8 %)CFH
Anti CFH Ab
CFI
MCP
CFB
C3
Combined
Unexplained
3 m 1 y 4 y 12 y 16 y
J358
I + B I + C3 I + H
I + MCP
8 m 3 y 6 m
J3 J12
J1
H + H
52 %
I + C3
Heterozygous Homozygous
J1 J18 J28
MCP + C3
EXTRA-RENAL INVOLVEMENT
90 patients (French cohort)
Central nervous system (seizures, coma, diffuse cerebral ischemia) 16 (18 %)
Multivisceral failure 2
Cardiorespiratory arrest 3
Pancreatitis/hepatitis 5
OVERALL RISK OF DEATH AND EVOLUTION TO END STAGE RENAL DISEASE
90 patients (French cohort)
DEATH 6 (7 %) (4 from CNS involvement, 1 from pulmonary hemorrhage/ CRA,
1 from sepsis)
all during the first year after onset)
ESRD 38 (42 %)
RELAPSING COURSE(from 1 to 9 relapses)
N (%) of patients with
relapses of HUS
CFH homozygous mutation n=4 3 (75 %)
CFH heterozygous mutation n=5 3 (60 %)
not in ESRD
MCP mutation n=13 10 (77%)
CFI mutation n=8 1 (12 %)
C3 mutation n=6 1 (17 %)*
CFB mutation n=1 1
Combined mutations n=7 5 (71 %) *
Anti-CFH antibodies n=10 5 (50 %)
Unexplained HUS n=28 7 (25 %)
* one additional child had chronic hemolysis/thrombocytopenia until bilateral nephrectomy
PROGNOSIS ACCORDING TO COMPLEMENT MUTATION
French cohort
0
,2
,4
,6
,8
1
Sur
vie
Cum
.
0 100 200 300 400 500Temps
Survie Cum. (5)
Survie Cum. (4)
Survie Cum. (3)
Survie Cum. (2)
Kaplan-Meier Graphe de Survie Cum. pour Colonne 21Variable censure : Colonne 22Facteur : c" cfh cfi mcp
MCP
Time (months)
Fre
e of
ES
RD
or
deat
h
CFH
CFI
C3
p=ns
p=ns
p=0.0003
CFH (n=13)C3 (n=6)CFI (n=8)MCP (n=13)
At 1y At 5y
PROGNOSIS OF aHUS WITH COMBINED MUTATIONS
7 patients French cohort
MCP
0
,2
,4
,6
,8
1
Sur
vie
Cum
.
0 20 40 60 80 100 120 140 160Temps
Délais de Survie (6)
Survie Cum. (6)
Délais de Survie (4)
Survie Cum. (4)
Kaplan-Meier Graphe de Survie Cum. pour Colonne 21Variable censure : Colonne 22Facteur : Colonne 20
Time (months)
Fre
e of
ES
RD
or
deat
h
CFH
3CFI
CFHMCP
C3CFB
CFH CFH
MCPC3
> 1mutation
+
PROGNOSIS IN THE « ORPHAN GROUP » COMPARED TO CFH AND MCP GROUPS
French cohort
0
,2
,4
,6
,8
1
Sur
vie
Cum
.
0 100 200 300 400 500Temps
Survie Cum. (4)
Survie Cum. (2)
Survie Cum. (0)
Kaplan-Meier Graphe de Survie Cum. pour Colonne 9Variable censure : Colonne 10Facteur : Rien cfh mcp
No mutationCFH
Time (months)
MCP
Fre
e of
ES
RD
or
deat
h
p=0.02 p=0.04
At 1y
CFH (n=13)MCP (n=13)No mutation (n=28)
At 5y
PLASMATHERAPY IN aHUS WITH CFH MUTATIONreview in Loirat et al, Pediatr Nephrol 2008 + Lapeyraque, Pediatr Nephrol 2008
4 children with homozygous CFH mutation, 6 children + 1 adult with heterozygous CFH mutation benefited from rescue and preventive plasmatherapy
(follow-ups : 7 m to 6 y)
Example from Davin, Pediatr Nephrol 2008
2 monozygotic twin sisters, HUS at 4 and 4.5 yheterozygous S1191L mutation, SCR 20
First twin : PE with FFP, 40 ml/kg/day x 10 days → resolution of hemolysis Screatinine 166 → 137 µmol/l
next 4 months : 5 FFP infusions,10 ml/kg, for each of 3 relapses → ESRD
Second twin : PE with FFP, 40 ml/kg/day x 21 → resolution of hemolysis Screatinine 132 → 61 µmol/l
→ PE tapered to 40 ml/kg every 2 weeks 2 relapses treated successfully by daily PE x 7 days
follow-up 6 years, Screat 66 µmol/l
long-term PE therapy appears to have benefits over FFP infusions alone
HOMOZYGOUS CFH MUTATIONSRESPONSE TO PLASMATHERAPY
4 patients, French pediatric cohort
Year of HUS Plasmatherapy
at the acute phase
Outcome
1994 – 1995 n = 2 (cousins) 1. no
2*. 15 ml/kg weekly
relapse and ESRD at M9successfull transplantation with FFP10 ml/kg twice a month, x 7 y
preserved RF with FFP 15 ml/kg weekly x 4 y plasma-resistant relapse at 4 y → ESRD
2003 and 2006 n = 2
3. FFP 10 ml/kg x 12
4. PE 60 ml/kg x 10
preserved RF with
• FFP 10 ml/kg every 2 to 3 weeks, plasma-
dependent, x 5 y
• FFP 10 ml/kg x 3 times a week, x 2 y
* published by Nathanson 2001, 2006 ; Larakeb 2008
0
50
100
150
200
250
300
350
400
450 2
0 se
pt-0
6
oct-
06
nov-
06
déc-
06
janv
-07
févr
-07
mar
s-07
avr-
07
mai
-07
juin
-07
juil-
07
août
-07
sept
-07
oct-
07
nov-
07
déc-
07
janv
-08
févr
-08
mar
s-08
avr-
08
mai
-08
juin
-08
juil-
08
août
-08
sept
-08
Creatinine (µmol/l)
Hemoglobin (g/l)
Platelets (103/ml)
Hemofiltration
3 times a week FFP infusion 10 ml/kg
Daily PE
Homozygous CFH mutation 3694-3697 del TAGA, SCR20Girl born on Sept 8, 2006
multivisceralfailure
COMPLEMENT DYSREGULATION AS A CAUSE OF VASCULAR COMPLICATION : RESCUE BY PE
Larakeb et al, Pediatr Nephrol 2007
• HUS at 7 m
• preserved renal function from age 4 to 9 y under weekly plasma infusions
• plasma exchange-resistant relapse at age 9 y → ESRD
• after 3 years on dialysis without plasmatherapy, sudden unilateral blindness with
ischemic/hemorrhagic retinal lesions, rescued by daily plasma exchanges (60 mg/kg FFP) x 10 d,
then 3 times a week
→ complete recovery after 4 weeks
One child with homozygous CFH mutation (Y899X, SCR15)
HETEROZYGOUS CFH MUTATIONOUTCOME ACCORDING TO PERIODS AND TREATMENT
MODALITIES
13 patients, French pediatric cohort
Year of HUS Plasmatherapy *
at the acute phase
Outcome
1984-2001 n=10 no 10/10 ESRD or death within < 1 year 9/10
2004-2007 n = 3 yes 3/3
1. FFP 10 ml/kg x 3 weekly
2. PE (FFP) 60 ml/kg daily x 15
3. FFP 10 ml/kg x 3 weekly
no renal sequelae 3/3
FFP 10 ml/kg weekly (plasma-dependent) x 1 y
PE (FFP) 60 ml/kg weekly (plasma-dependent) x 2.9 y
FFP 10 ml/kg monthly (no relapses) x 4 y
* defined as FFP ≥ 10 ml/kg or PE with FFP 30-60 ml/kg, x ≥ 5 days
0
50
100
150
200
250
300d
éc-0
5
jan
v-06
févr
-06
mar
s-06
avr-
06
mai
-06
juin
-06
juil-
06
aoû
t-06
sep
t-06
oct
-06
no
v-06
déc
-06
jan
v-07
févr
-07
mar
s-07
avr-
07
mai
-07
juin
-07
juil-
07
aoû
t-07
sep
t-07
oct
-07
no
v-07
déc
-07
jan
v-08
févr
-08
mar
s-08
avr-
08
mai
-08
juin
-08
juil-
08
Creatinine (µmol/l)
Hemoglobin (g/l)
Platelets (103/ml)
fever fever fever
Weekly PE, 60 ml/kg FFP
Weekly FFP infusion, 10 ml/kg
Daily PE
Girl born on Aug 2005Heterozygous CFH mutation W1189R, SCR20
aHUS WITH MCP MUTATIONEFFECT OF PLASMATHERAPY
Italian Registry*(Caprioli et al, 2006)
14 patients
French pediatric cohort**
13 patients
N episodes Treated
n=23
Untreated
n=12
Treated
n=12
Untreated
n=37
Remission
21
(91 %)
12
(100 %)
11
(92 %)
35
(95 %)
* Italian cohort : FFP 10-20 ml/kg/day and/or PE 30-40 ml/kg, for a total of 2-36 treatments in 2-6 weeks ; hematological normalization with or without renal sequelae
** French cohort : PE 40-60 ml/kg x ≥ 4, hematological normalization and no renal sequelae
UNEXPLAINED HUSOUTCOME ACCORDING TO TREATMENT
28 patients (French cohort)
28 patients
treated*n = 12
not treatedn = 16
Outcome** poor7
(58 %)
favourable5
(42 %)
poor5
(42 %)
favourable8
(50 %)
* FFP 10 ml/kg x ≥ 4 d (n = 4) PE with FFP 30-60 ml/kg x ≥ 4 d (n = 8)** poor : death, ESRD, CRI ; favourable : no sequelae or mild proteinuria
aHUS : PLASMATHERAPY (1)
In practice : what should be done at admission ?
« Guideline for initial therapy », European Pediatric Study Group for HUS
in press, Pediatr Nephrol 2008
(1) When to start ?
- as soon as possible (within 24 h) as soon as the patient’s condition allows it (BP, volemia, hydroelectrolyte
equilibrium, anemia…)
- question : even if serum creatinine not elevated ? yes, because :
* approximately 50 % of HUS with CFH mutation go to ESRD at the 1st episode
* delay in treatment initiation can be deleterious in HUS with anti-CFH antibodies
(2)
(2) Which volume ?- Exchange 1.5 plasma volume (60-75 ml/kg) with FFP for restitution- If PE is impossible, infuse FFP 10-20 ml/kg (if BP and cardiac
function OK)
(3) Which frequency during the first month ?- daily x 5 days- 5/week x 2 weeks- 3/week x 2 weeks
(4) What are the situations which allow not to do PE or to stop early ?- MCP mutation (PE only during relapses ?)
(5) Which frequency after the 1st month ?empirical : try to find the threshold dose (PE or FFP infusion) and interval for each individual patient
aHUS TREATMENTTHE TRIGGERING EFFECT OF INFECTIONS(upper respiratory tract infection, fever, gastroenteritis)
CFH CFI MCP C3 No mutation mutation mutation mutation
Caprioli 2006 18/26 3/5 12/12 46/66 (69 %) (60 %) (100 %) (70 %)
French pediatric cohort 7/17 5/8 9/12 4/5 21/28 (41 %) (62 %) (75 %) (80 %) (75 %)
Eradicate adenoïdal, tonsils, dental infectionsTriggering effect of vaccinations documented in some patients : benefit probably outweighs the risk → perform vaccinations, including influenza Intensify preventive plasmatherapy during infections and vaccinations (at least intensify biological monitoring)In patients with permanent activation of the alternative pathway and very low C3 : preventive antibiotics and vaccination against Neisseria meningitis and Streptococcus pneumoniae
aHUS ASSOCIATED WITH ANTI-CFH ANTIBODIES
10 patients (French pediatric cohort)
Treatment at the acute phase
none 2 (retrospective diagnosis)
FFP infusions only 1
PE 7
+ steroïds 5
+ immunosuppressors 4 (aza 2, MMF 1, rituximab-cyclophosphamide 1)
Relapses (2 to 3) 5
Outcome
ESRD 2 (1 untreated, 1 delayed treatment)
HT/proteinuria/GFR 70-80 5 (1 untreated, 4 treated)
no sequelae 3 (treated)
PROGNOSIS IN PATIENTS WITH ANTI-CFH ANTIBODIES COMPARED TO PATIENTS WITH CFH MUTATION
French Cohort
0
,2
,4
,6
,8
1
Surv
ie C
um
.
0 20 40 60 80 100 120 140Temps
Survie Cum. (7)
Survie Cum. (2)
Kaplan-Meier Graphe de Survie Cum. pour Colonne 15Variable censure : Colonne 16Facteur : cfh ab
Time (months)
Fre
e of
ES
RD
or
deat
h
CFH
Anti CFH Abp=0.01
At 1y
CFH (n=13)
Anti CFH Ab (n=10)
At 5y
PE
An
ti-F
H t
iter
(AU
/ml)
Bef
ore
PE
Aft
er P
E
Onset
D15 M2
Relapse 1
M6 M7
Relapse 2
M13 M15 M17
Relapse 3
M23 M27 M30
3 year-old boy
IvIgCorticotherapy
Dialysis
D-15Diarrhea
Azathioprine
M44 M48 M54
No renal sequelae at M54
H. Nivet, Tours
Onset
FFP
Plasma Exchanges
11 year old boy
An
ti-F
H t
iter
(AU
/ml)
Dialysis
W3 M1M3
Corticosteroid therapy + azathioprine
M2 M6 M7
J.L. André, NancyB. Ranchin, Lyon
RBC transf
3704
360 310600 648 630
450 520
0
500
1000
1500
2000
2500
3000
3500
4000
18/0
4/20
07
03/0
5/20
07
07/0
5/20
07
10/0
5/20
07
14/0
5/20
07
22/0
5/20
07
29/0
5/20
07
05/0
6/20
07
IgG anti-FH (AU)
7 y old girlHUS Apr 12, 2007
18 PEMay 2008Steroïds
Sept 2008MMF
11 RBC transf
Hematological normalization within 2 weeksRenal function normalization within 2 weeks J.L. André, Nancy
D-HUS WITH ANTI-CFH ANTIBODIESPREPARATION TO TRANSPLANTATION
AND POST-TRANSPLANT COURSEKwon T, 2008
0
500
1000
1500
2000
2500
C3anti CFH Ab
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 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48
months
transplantation
prednisone + azathioprineFFPFFP
PEXPEX PEXPEX
mg/lAU/ml
Hemodialysis
rituximabrituximab
prednisone + cyclosporine + mycophenolate mofetil
graft biopsyno TMA
no rejection
Creatinine85 µmol/l
POST-TRANSPLANT RECURRENCE IN aHUS PATIENTS GENOTYPED FOR CFH, CFI AND MCP
Retrospective studiesReview in Loirat and Fremeaux-Bacchi, Pediatr Transplant 2008
Mutation Number of patients
transplanted
Recurrence
(% patients)
Graft failure for recurrence
within year after recurrence
(% of recurrences)
CFH 34 81 %
CFI 8 100 %
MCP 10 1/2
No mutation in
CFH, CFI or MCP 20 83 %
76 %
88 %
20 %
30 %
POST-TRANSPLANT RECURRENCE IN PATIENTS WITH NO MUTATION IN CFH, CFI, MCP, CFB AND C3
AND NO ANTI-CFH ANTIBODIES
French pediatric cohort
7 transplantations in 5 children*
→ 2 graft loss due to thrombosis (1) and rejection (1)
→ no recurrence of HUS
* including one familial form of HUS
PLASMATHERAPY TO PREVENT POST-TRANSPLANT RECURRENCE IN 2 CFH-MUTATED SIBLINGS
EFFICACY OF PLASMA EXCHANGES WITH FFP STARTED BEFORE RENAL TRANSPLANTATION
Olie, AJKD 2005; Davin, Pediatr Nephrol 2008
CFH heterozygous S1191L mutation, SCR 20)
Older sister Tx1
Tx2 Twin 1
Prophylactic PEPE before surgery daily PE X 7weekly PE X 2 monthsthen PE 1 /2 weeks
no yes yes
Relapses day 2no treatment
Screat 80 to 200 µmol/L when PE 1/2w PE 5 days later
M10 and M12(CMV)daily PE then weekly
Outcome graft loss graft loss Screatinine 127µmol/L at 5 y
THE RISK OF RECURRENCE AFTER RENAL TRANSPLANTATION IN ADULT PATIENTS
French adult cohortTransplantations performed after year 2000
Mutation N patients
transplanted
N
grafts
Recurrence
(% grafts)
Trt of recurrence
Graft loss within the year after
recurrence
CFH 17 18
(2 with preventive plasmatherapy)
14 (78 %)
(1 treated preventively)
PE 11/14 10/14 (71 %)
CFI 8 9
(2 with preventive
plasmatherapy)
4 (44 %)
(no prevention)
PE 4/4 0
(follow-up 1 to 4.2 y)
C3 6 8
(1 with preventive plasmatherapy)
5 (62 %)
(no prevention)
PE 5/5 4/5 (80 %)
1 PE-dependent
1 y after recurrence
B 1 1 1 1
INITIAL EXPERIENCE WITHOUT PREOPERATIVE PLASMATHERAPY
(Remuzzi 2002, 2005 ; Cheong 2004)
3 children → 3 deaths (2 with diffuse thrombotic/ischemic liver lesions, 1 PTLD)
SUCCESS OF COMBINED LIVER + KIDNEY TRANSPLANTATION
UNDER PLASMATHERAPY BEFORE AND DURING SURGERY
(Saland 2006 ; Jalanko 2008)
3 children
PE with FFP, 1,25 to 2 plasma volume (50 to 100 ml/kg) just before surgery
FFP infusion (20 to 36 ml/kg) during surgery or PE (70 ml/kg) between
liver and kidney transplantation
+ post operative anticoagulation
→ excellent function of both grafts at 8 m, 15 m and 4 y follow-up
+ 5 children (unpublished) : 4 combined tx → 3 success,1 death (1/7 = 14 %)
1 liver tx → success
(+ 1 adult, combined tx → success )
aHUS WITH CFH MUTATIONLIVER (n = 2) AND LIVER + KIDNEY (n = 10)
TRANSPLANTATIONS
aHUS
INDICATIONS OF COMBINED LIVER + KIDNEY OR LIVER TRANSPLANTATION IN 2008Consensus Conference, Bergamo, Dec 13, 2007
CFH MUTATION
Consensus + : - patient who lost a 1st graft due to recurrence
- patient with a family member with the same mutation who lost a graft due to recurrence
- patient with a mutation reported in the litterature or registries (www.fh-hus.org) as associated with recurrence after transplantation
- in such cases, liver transplantation has to be considered when renal function is preserved by plasmatherapy
CFI MUTATION
Same recommendations as for HUS mutation (debatable for isolated CFI mutations)
CFB OR C3 MUTATION
Too early to give recommendations
PATIENTS FOR WHOM ISOLATED KIDNEY TRANSPLANTATION IS RECOMMENDED
Bergamo Conference (2)
• Patients with MCP mutation
• Patients without identified mutation in CFH, CFI, CFB and C3
• Patients with "low risk" CFH, CFI and C3 mutations : same mutation in a family member, a patient in the litterature or registries, without post-transplant recurrence
• Except for patients with MCP mutations, intensive plasmatherapy (PE) started just before surgery is recommended
aHUS
Treatment for the future
(1) CFH concentrate (LFB Laboratory)
- 1st trials : end of 2009
- 1st candidates : patients with total or partial CFH deficiency
- respective place of PE and CFH concentrate to be evaluated in
the other patients with functionnal CFH deficiency
(2) COMPLEMENT BLOCKERS
- near future : anti-C5 monoclonal antibodies : eculizimab
- other options in development
ECULIZUMAB IN aHUSPreliminary data (with permission of physicians and Alexion)
• J. Nuernberger et al (Essen)
- One adult, aHUS, Y475S CFH mutation
* 1st transplant : loss after recurrence
* 2 nd transplant : recurrence, resistant to 4 PE
→ 1 injection of 600 mg eculizumab → remission, normalization of graft function
follow-up : 5 months
• B. Hurault de Ligny et al (Caen)
- One woman, aHUS with C3 mutation (R570Q)
* 1st transplant : loss after recurrence
* 2nd transplant, Jan 2004 : several recurrences, responsive to PE
May 2008 : recurrence, PE-dependent.
Switch to eculizumab (protocol as for PNH) → remission maintained.
Follow-up : 2 months.
CONCLUSION
Although evidence from therapeutic trials is lacking, early plasmatherapy, best by PE, remains first line treatment to rescue aHUS, especially in patients with CFH mutation or anti-CFH antibodies. Long-term plasmatherapy also appears efficient to prevent relapses in patients with CFH mutation.
Liver transplantation, isolated or combined with kidney transplantation, has to be discussed on a case by case basis for patients with mutations of complement factors synthetized in the liver. The decision remains difficult.
We are at the crossing of roads, as new therapies, such as eculizumab or other complement inhibitors, and CFH concentrate, will soon be evaluated. Hopefully, these new therapeutics will allow that aHUS will no longer end-up in ESRD and the discussion of liver or combined liver + kidney transplantation might become obsolete.
THANKS TO
Veronique FREMEAUX-BACCHI and the group of the Laboratory of Immunology, Hopital Européen Georges Pompidou
Marie-Agnès Dragon-Durey
Jacques Blouin
Lubka Roumenina
Christophe Hue
Arnaud GARNIER, Hopital Robert Debré
The members of the French Society of Pediatric Nephrology
The patients and their families
The Association pour l'Information et la Recherche sur les Maladies Rénales Génétiques (AIRG) and the Programme Hospitalier de Recherche Clinique