37
ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS Chantal Loirat, Hopital Robert Debré, Paris, France

ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

Embed Size (px)

DESCRIPTION

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

Citation preview

Page 1: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

ATYPICAL HEMOLYTIC UREMIC SYNDROME :

TREATMENT OPTIONS

Chantal Loirat, Hopital Robert Debré, Paris, France

Page 2: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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 %)

Page 3: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 4: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 5: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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 %)

Page 6: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 7: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 8: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

+

Page 9: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 10: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 11: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 12: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 13: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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)

Page 14: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 15: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 16: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 17: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 18: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 19: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

(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

Page 20: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 21: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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)

Page 22: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 23: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 24: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 25: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 26: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 27: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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 %

Page 28: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 29: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 30: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 31: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 32: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 33: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 34: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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

Page 35: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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.

Page 36: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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.

Page 37: ATYPICAL HEMOLYTIC UREMIC SYNDROME : TREATMENT OPTIONS

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