Patogenesi della PTT e della SEU

Elena BresinIRCCS - Istituto Mario Negri, Bergamo

Convegno Microangiopatie Trombotiche UCSC 2016Roma, 19 Febbraio 2016

THROMBOTIC THROMBOCYTOPENIC PURPURA

TTP is a thrombotic microangiopathy characterized by

thrombocytopenia, microangiopathic hemolytic anemia, central

nervous system involvement and/or renal impairment.

In the majority of patients deficiency of ADAMTS13, the von Willebrand

factor-cleaving protease, is associated with autoantibodies to

ADAMTS13.

These cases are at high risk of disease relapse when there is a

persistence of anti-ADAMTS13 autoantibodies.

Congenital deficiency of ADAMTS13 cause Hereditary

THROMBOTIC THROMBOCYTOPENIC PURPURA

Hereditary TTP is very rare (< 10% of all TTP cases) and usually

manifests in the postnatal period or during infancy, although in some

cases (especially women) the onset is later at 20-30 years.

Hereditary TTP is caused by homozygous or double heterozygous

mutations of ADAMTS13 gene that determine congenital deficiency of

ADAMTS13, the von Willebrand Factor (VWF)-cleaving protease.

Patients with hereditary TTP tipically exhibit a relapsing course and need

regular plasma infusions to prevent relapses.

Family A

10

5

4

7

8

7

5

3

2

7

5

3

10

5

4

7

8

7

5

3

2

7

5

3

10

5

4

7

8

7

6

5

/

7

6

7

1

5

/

7

7

7

5

3

2

7

5

3

5

3

2

7

5

3

10

5

4

7

8

7

731 78679 8277

< 6%

1580

6

5

5

7

6

/

1

5

3

7

7

7

108% 62% < 6% 67%< 6%

ADAMTS13 antigen (ng/mL)

ADAMTS13 activity (%)

ADAMTS13 activity (%) < 6%

6

5

3

6

5

4

Family B

ADAMTS13 antigen (ng/mL) < 62.5

Family C

< 6% < 6%

6

5

1

5

6

6

6

5

1

5

6

6

6

5

1

5

6

6

6

5

1

5

6

6

< 62.5 < 62.5

Val88Met(metalloprotease)

Gly1239Val (CUB1)

Heterozygous

6

5

3

6

5

4

Arg1123Cys (TSP8) Arg1219Trp (CUB1)

ADAMTS13 MUTATIONS IN TTP CAUSE SEVERELY REDUCED

PLASMA ADAMTS13 CONCENTRATION

Homozygous Homozygous

43% 47% 45%

REDUCED ADAMTS13 ACTIVITY IN HEALTH AND DISEASE

Mannucci et al., Blood, 2001

- elderly

- newborns

- third trimester of pregnancy

- uremia

- after major surgery

- inflammatory states

- liver cirrhosis

DIFFERENTIAL DIAGNOSIS BETWEEN TTP ASSOCIATED WITH

GENETIC OR IMMUNE-MEDIATED ADAMTS13 DEFICIENCY IS

IMPORTANT TO GUIDE SPECIFIC TREATMENTS

Genetic ADAMTS13 deficiency:

- replacement with plasma of the defective activity

Immuno-mediated ADAMTS13 deficiency:

- plasma exchange to remove anti-ADAMTS13 autoantibodies

and to replace the metalloprotease

- inhibition of the autoantibodies production through treatment

with glucocorticoids, immunosuppressive agents, or rituximab

A multisystem disease with predominant

renal involvement, characterized by a

triad of symptoms:

- microangiopathic hemolytic anemia,

- thrombocytopenia,

- formation of platelet-rich thrombi in the

microcirculation

Definition

Hemolytic Uremic SyndromeTHROMBOTIC MICROANGIOPATHY

Classification of the different forms of Hemolytic Uremic Syndrome

Typical HUS

Infections by E. coli producing Shiga-like toxin/verotoxin and causing hemorrhagic colitis

Typical HUS manifests expecially in children with diarrhea often bloody

Typical HUS usually has a favorable outcome: only 10% of patients progress to ESRD

Atypical HUS

Atypical HUS is rare: 10% of all HUS cases

Atypical HUS may be familial or sporadic and may manifest at all ages.

Atypical HUS has a poor outcome: 50 to 60% of patients reach ESRD at the 1st episode

Atypical HUS

In the last 15 years, extensive research

has established a clear link between

aHUS and defects in regulation of the

alternative complement pathway

resulting in uncontrolled activation of

the complement system

10

COMPLEMENT ACTIVATION PATHWAYS

CR1

Factor I

DAF

MCP

AP dysregulation on endothelial cells resulting in endothelial injury and loss of anti-thrombogenic properties.

C5a

C5b-9

Lectin pathwayClassical pathway

Mannose

residues

IgM, IgG

Immune complexes

C1q,C1r,C1s

C4,C2

C4bC2a

C3 convertase

C3

C3b

C3a

C4bC2aC3b

C5 convertase

MBL, MASP

C1-est inhib

C4bp

C5

Factor H

Alternative pathway

bacteria, bacterial toxin,

LPS, tick-over

C3

C3b

C3a

C3bBb

C3 convertase

C3

C3b

C3a

(C3b)2Bb

C5 convertase

Factor B

Bergamo

Trento

Padova

Treviso

Vicenza

ParmaGenova

Torino

Pavia

Milano

Varese

MonzaBrescia

Firenze

Roma

Foggia

BariSalerno

Reggio Calabria

Palermo

Cagliari

Sassari

UK9 cases

USA58 cases

Argentina23 cases

Belgium

1 case

Israel14 cases

Portugal11 cases

Canada4 cases

Switzerland22 cases

South Africa2 cases

Germany19 cases

Denmark3 cases

Saudi Arabia4 cases

Czech R.11 cases

Esthonia1 case

Serbia5 cases

Italy765 cases

Greece4 cases

Australia14 cases

Malaysia2 cases

Turkey

8 cases

IRAN49 cases

Spain5 cases

Poland13 cases

Russia

6 cases

UAE

1 caseIndia

5 cases

Japan

2 cases

Chile3 cases

Participating Centers

HUS/TTP patients

Italian cases

Foreign cases

180

1160

780

380

INTERNATIONAL REGISTRY OF

HUS/TTP

09/2015

http://www.marionegri.it

Brazil2 cases

Croatia2 cases

FIMAC SRCR LRDR-1 LRDR-2 S-S SP

H Chain L Chain

C43FT72SP50A

P230E

A240G

G243fs46X

C247G

G261D

G349R

W399R

I416L

G424D

A431T

I433V

K441R

W456L

D519N

W546X

MG2 MG3 MG4 MG5

MG

6β

LNK

β-chain α-chain

α’NT

MG

6α

MG7

CU

B g

TED MG8AN

A

CU

B f

Anchor

C345C

R592WR592Q

R1042WK1051MS1063RA1094VI1095SD1115NI1157TC1158W

T1383NH1461D

1 2 3

SCRslinker

Ba Bb

R138W

1 2 3

SCRslinker

VWA SP

S298Lfs2X

R317W

c.884-7T>C

T162RT162KR161W

Q185E

Regulatory

domain

C3b

Recognition

domain

C3bproteoglycansproteoglycans C3b proteoglycans

E847V

C853T

C864SK474Nfs6X

N516K

Q950H

T956M

I970V

P968Lfs7X

G1011Vfs4X

D1119G

D1119N

Q1137L

Y1142C

C1163W

P166L

E1172X

R1182S

W1183L

W1183R

W1183X

T1184A

T1184R

K1188del

L1189F

L1189R

S1191L

S1191W

G1194D

V1197A

E1198A

F1199A

V1200L

R1210C

R1215Q

R1215G

C1218R

c.3546_3581dup

c.3675-3699del

R53CR78GQ81PT30Nfs10X

11 12 13 145 6 7 8 9 10 17 1815 162 3 41 2019

F242C

Y248X

T267Nfs4X

c.745_751del

c.800_820del

SCRs

STP

TM

CT

2

3

4

1

C35X

C35Y

R59X

K65DfsX39

c.286+1G>C

c.286+2T>G

A353V

C99R

R103Q

R103W

G130V

c.287-2A>G

c.390-11G>C

MG1

R478L

CFH 25%

MCP 7%

CFI 6%

C3 5%

CFB 1%

Anti-CFH Ab 8%

COMPLEMENT ABNORMALITIES IN aHUS PATIENTS (Noris et al CJASN 2010; Bresin et al 2013)

A43TD53GV81L

D486YP495SP501L

CT

Lectin-Like

domain

TME1

TME2

TME3

TME4

TME5

TME6

ST-rich

peptide

TM

TM 5%

R735WV762I

Y854X V1658A

I340T

I357M

L484Vfs3X

Y459S

D524V

c.1429+1G>C

T538X

P553S

E554V

G119R

W145X

N177I

H118R

H183R

N151S

F286LK323EV455I

Y534F

E179Q

D185N

Y189D

G196R

G240R

S206P

P165S

I208Y

C210F

c.902-2A>G

c.1027+2T>C

Q1076E

S890I

H893R

Y899D

Y899X

W920R

Q925X

c.2686_2700del

E762X

N767Kfs7X

K768Kfs7X

G786fs871X

C673YC569XK584XC623S

G397R

Q400K

S411T

C431Y

V111EW134Rc.351delG

A161S

G218E

R341H

13

1 2 3 4 20

19

18

17

16

15

14

13

12

11

10

98765

Dragon-Durey et al, JASN, 2005

Jozsi et al., Blood, 2007

HUS associated factor H autoantibodies (described in 10% of aHUS

cases, mainly in children) mimic the effect of C-terminal factor H

mutations, as they inhibit the regulatory function of factor H at cell

surfaces by blocking its C-terminal recognition region

FACTOR H AUTOANTIBODIES IN aHUS

14

Blanc C. et al. J Immunol, 2012

RECOGNITION SITES OF THE ANTI-FH AUTOANTIBODIES

TO CFHR1 AND FH IN aHUS

Factor H

1 2 3 4 98765 10 11 12 13 14 15 16 17 18 19 20

(94%)

(94%)

(100%)

1 2 3 4 5

CFHR1

(80%)

Among 104 aHUS patients tested both for the CFHR1

deletion and anti-CFH autoantibodies, 23 out of 27

patients with autoantibodies (85%) were also homozygous

for the CFHR1 deletion.

15

Valoti et al. Immunobiology 2012

The Hom ∆CFHR1 is a strong predisposing factor for the

generation of anti-CFH autoantibodies.

Blanc C. et al. J Immunol 2012

1616

The formation of hybrid genes is a recently described

mechanism for CFH abnormalities in HUS

High degree of sequence identity between the gene for factor H (CFH)

and the genes for the five factor H-related proteins (CFHR1-5)

CFH consists of 20 SCR and CFHR1 of 5 SCR. CFH SCR20 and

CFHL1 SCR 5 differ at only 2 aminoacids

17

ATYPICAL HEMOLYTIC UREMIC SYNDROME ASSOCIATED WITH A

HYBRID COMPLEMENT GENE

Affected individuals carry a heterozygous CFH/CFHL1 hybrid protein in

which SCR 1-18 are derived from CFH and SCR 19/20 from SCR 4/5 of

CFHR1 by non allelic homologous recombination

The protein product of the hybrid gene is a protein that lacks any

complement regulatory activity on endothelial cell surface

4

Venables et al., PLoS Med, 2006

Noris et al., CJASN, 2010

CFH mutations: 48%

MCP mutations: 53%

CFI mutations: 50%

C3 mutations: 56%

INCOMPLETE PENETRANCE OF aHUS IN CARRIERS OF COMPLEMENT

GENE MUTATION

#01 HUS

I

II

III

2

F34

4yr, dialysis

F82F35F70

F83*

*

*

•3 subjects in the III generation developed aHUS in infancy: 2 died and 1 reached ESRD

•father F35 never developed aHUS

•grandfather F83, carrier of the R1215Q/CFH mutation, developed aHUS and died at 82 years of age

Noris et al., CJASN 2010

Incomplete penetrance of aHUS indicates that

additional genetic and/or environmental hits are

necessary for disease manifestation

T30Nfs10X

G1194D

G1194D

R1210C

R1210C

R1210C

R1215Q

N767Kfs7X

P968fs947X

S1191L

V1197A

R341H

R1210C

R1210C19

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

S

I

I

F

I

I

S

F

S

I

I

F

F

F

S

S

S

I

S

S

UK

F

F

F

F

I

H183R

I340T

E554V

P50A

H118R

N151S

N151S

C247G

L484V+Q485G+

W486X

T538X

T538X

P553S

D524V

Y459S

P553S

I357M

G1094R

R161W

H1464V

P1114L

V455I

Cohort CFH MCP CFI C3 CFB#

I208Y

F242C

F242C

Y29X

C35Y and R59X

C35Y and R59X

R103Q

R103W

IVS2+2

R103W

R103W+c.800-820del

C210F

(96-129)del+

G130I+Y131I+Y132T+L133X

P165S

P165S

A353V

A353V

Y29X

IVS2+2 Bresin et al, JASN 2013

20

Combined complement gene mutations were found in 3% of aHUS patients, more

frequently in those with MCP or CFI mutation than in patients with CFH or C3 or CFB

mutations.

8.7% 8.2% 10%

22.6% 27%

Bresin et al, JASN 2013

COMBINED complement gene MUTATIONS in aHUS

21Caprioli et al., Hum Mol Gen, 2003

-257T Promoter

2089G/SCR11, 2881T/SCR16

Promoter + SCR16

Genotypes Odds Ratios (95 % C.I.) P value

1 2 3 4 5 6 8 97

High risk

0.0015

< 0.0001

< 0.0001

Risk haplotype CFH-tgt

22

A specific SNP haplotype block, spanning the MCP gene in the regulators of

complement activation gene cluster, which is over-represented in aHUS patients and

strongly associates with the severity of the disease.

IMPACT of presence of CFH and MCP RISK HAPLOTYPES on aHUS PENETRANCE

Overall

0-1 risk haplotype

2 risk haplotype

0

20

40

60

80

100P

en

etr

an

ce (

%)

Two mutations Three mutations

55.2

35.7

73.3

100

Risk haplotypes

CFH-tgt:

c.1-332C>T (rs3753394) and c.2808G>T, p.E936D (rs1065489)

MCPggaac:

c.*897T>C (rs7144)

*

*P<0.05 vs 0-1 risk haplotype

The concomitant presence of CFH

and MCP risk haplotypes

increased aHUS penetrance in

carriers of combined mutations

Bresin et al, JASN 2013

Abnormalities of complement

regulators in aHUS: how do they

impact clinical phenotype and

management of patients?

AGE AT ONSET%

of

pati

en

ts

% o

f p

ati

en

ts

% o

f p

ati

en

ts

MCPCFI

CFH

05

101520253035404550

0 - 2 3 - 10 11 - 16 17 - 34 35 - 54

05

101520253035404550

0 - 2 3 - 10 11 - 16 17 - 34 35 - 54 >55

05

101520253035404550

0 - 2 3 - 10 11 - 16 17 - 34 35 - 54 >55

% o

f p

ati

en

ts

C3

0

5

10

15

20

25

30

35

40

45

50

0 - 2 3 - 10 11 - 16 17- 34 35 - 54

*

% o

f p

ati

en

ts THBD

0

5

10

15

20

25

30

35

40

50

60

0 - 2 3 - 10 11 - 16 17 - 34 35 - 54 >55

45

% o

f p

ati

en

ts

Non mut

0

5

10

15

20

25

30

35

40

45

50

0 - 2 3 - 10 11 - 16 17 - 34 35 - 54 >55

>55

>55

- aHUS manifested during infancy in most patients

- The earliest onset was in subjects with CFH or THBD mutations

- A second pick was at 20-30 years of age, often in association with post-partum

Years of age Years of age

Noris et al CJASN 2010

TRIGGERING /UNDERLYING CONDITION%

of

HU

S p

ati

en

ts

CFH MCP CFI

40

30

20

0

No mutation

10

C3

Upper respiratory

tract infection

Diarrhea

Post-partum

Noris et al, CJASN 2010

OUTCOME OF THE FIRST EPISODE

Noris et al CJASN 2010

*P<0.05 vs MCP

0

10

20

30

40

50

60

70

80

no mut CFH CFI C3

% o

f even

ts

(ES

RF

or

death

)

THBD

**

**

*

MCP

Overall population

Children (40%)

Adults (60%)

2828

LONG TERM OUTCOME OF aHUS PATIENTS

CFH mutation

Patients

fre

e o

f events

Death

or

ES

RD

(%

)

100

80

60

40

20

0

0 2 4 6 8 10 12

CFI mutation

C3 mutation

Follow up (years)

MCP mutation

Noris et al CJASN 2010

TM mutation

Mutations in CFH, CFI, C3 and THBD were associated with a worse long-term outcome than mutations in MCP.

Patients with:

- CFH mutations 60/76 49/76 (64%) 40 out 49 (82%)

- CFI mutations 23/26 19/26 (73%) 18 out 19 (95%)

- C3 mutations 18/30 16/30 (53%) 12 out 16 (75%)

- CFB mutations 3/4 4/4 (100%) 4 out 4 (100%)

Noris & Remuzzi, Am J Transplant 2010

Zuber Jet al. Nat Rev Nephrol 2011

Le Quintrec M et al. Am J Tranpl 2013

RENAL TRANSPLANTATION OUTCOMES

graft failure for

aHUS recurrence

In patients with alterations in circulating complement proteins, the risk of graft failure

for aHUS recurrence is high since the altered protein is produced by the liver and

persists in the circulation after kidney transplantation.

recurrences

(% grafts)patients/grafts

SURVIVAL TIME OF THE KIDNEY GRAFT IN PATIENTS

WITH SINGLE MCP MUTATIONS

Noris and Remuzzi, Am J Transplant 2010

Follow up (years)

100

80

60

40

20

00 105

Surv

ival (%

)MCP

No HUS recurrence in 10 out of 12 kidney grafts.

MCP is a membrane-bound protein highly expressed in the kidney.

A dysfunction in MCP can be corrected by transplanting a normal kidney.

OUTCOME OF KIDNEY TRANSPLANTATION OF COMBINED AND

SINGLE MUTATED PATIENTS FROM 4 COHORTS OF aHUS PATIENTS

Kid

ne

yg

raft

los

tfo

rre

cu

rre

nc

e(%

)

Single mutated patients

Combined mutated patients

Single mutated patients considered overall

Combined mutated patients considered overall

77 14 37 8 13 12 Number of transplanted

kidney for each group

Bresin et al, JASN 2013

Recurrence of HUS after live-related renal transplantation

associated with subsequent de novo disease in the donor

Proband: a 4 month-old female with ESRD following an episode of

aHUS and no familial history of the disease

Living-related renal transplant from the father with graft loss in 7 weeks

for HUS

The donor developed HUS 10 months after donation and subsequently

progressed to ESRD

Genetic screening revealed that both the proband and her donor father

carried a heterozygous S1191L mutation in CFH

Donne et al., Am J Kidney Dis, 2002

In the case of CFH associated HUS, living related kidney transplant is

risky not only for the recipient, but also for the donor

SCR 1

Paziente

c.286+2T>G

SCR 1

Madre

c.286+2T>G

c.286+2T>G

c.286+2T>G

Patiente con mutazione MCP e

recidiva di SEU post-trapianto

La paziente aveva ricevuto il rene

dalla madre, portatrice dello stessa

mutazione MCP.

Il rene trapiantato produceva la

stessa proteina MCP disfunzionale

come il rene nativo e non era

abbastanza protetto dalla

iperattivazione del complemento.

Alberti M. et al. Am J Transpl 2013

La SEU tipica ha un basso tasso di recidiva post-trapianto (0-5%)

Caso

Una giovane donna con IRT dopo

grave episodio di SEU tipica aveva

ricevuto un trapianto di rene da

cadavere che era fallito dopo 1

anno, per ricorrenza della SEU.

Lo screening genetico eseguito

prima di pianificare 2° trapianto

rivelava una mutazione di CFI.

Alberti M. et al. Am J Transpl 2013

Questo caso indica che lo screening dei geni associati alla SEU si dovrebbe eseguire anche

in pazienti in dialisi a seguito di gravi episodi di SEU tipica.

Ci possono essere casi non diagnosticati di SEU atipica, innescati da infezione da

Escherichia Coli che hanno una predisposizione genetica.

Light

Chain

Val412Met

FIMAC SRCR LRDR-1 LRDR-2 S-S Serine Protease

Heavy Chain

3535

C3b

C3

C3b CFB

C3b

Bb

C3C3

convertase

C3b

C5

C3b

Bb

C5b

C5b-9

formation

EculizumabA humanized monoclonal antibody

that binds to C5

Endothelial cell

C5a

Eculizumab was safe and well tolerated in patients with Paroxistic Nocturnal Hemoglobinuria

(PNH).

This antibody against terminal complement protein 5 reduced intravascular hemolysis,

hemoglobinuria, and the need for transfusion, with an associated improvement in the quality of life.

TRIALS OF ECULIZUMAB IN ATYPICAL HUS (62 weeks data)

Patients resistant to plasma therapy

-Platelet normalization

-TMA event-free status

-Change in renal function

One-stage improvement

>25% creatinine reduction

Patients on chronic plasma therapy

-TMA event-free status

-Hematological normalization

-One-stage renal function improvement

Licht et al., J Am Soc Nephrol (Abstract), 2011

Greenbaum et al., J Am Soc Nephrol (Abstract), 2011

Nester CM and Brophy PD, Curr Opin Pediatr, 2013

Legendre CM et al., NEJM, 2013

15/17 patients

15/17 patients

11/17 patients

13/17 patients

17/20 patients

18/20 patients

9/20 patients

Ten patients had no identified genetic abnormalities or anti-CFH antibodies

Managing and preventing aHUS recurrence after kidney tx

Patients with aHUS recurrence in the kidney graft (n=13)

Mutation Response to plasma Response to Ecu Loss

CFH 2/8 6/8 *1/8

C3 2(partial)/2 2/2 0/2

not identified 0/3 *1/3 2/3

Patients with post-transplant Eculizumab prophylaxis (n=10)

Mutation Plasma therapy Recurrence Loss

-CFH 4/9 0/9 1/9

-C3 0/1 0/1 0/1

Two pts received PEX just before tx and were switched to eculizumab at day 5 and 10 post-tx.

In 3 pts eculizumab was started 1 week or more before tx, preceded (in 2 pts) by PEX.

The more common strategy was based on eculizumab alone, started immediately before tx.

Only one patient lost the graft for immediated arterial thrombosis at day 1 post-tx.

*Single dose of Eculizumab

Two patients were plasma-dependent whereas the other had plasma-resistant forms.

A single-dose eculizumab and eculizumab discontinuation after several months were associated with

subsequent relapses and graft loss in 3 patients despite re-initiation of eculizumab.

Congenital TTP and eculizumab

A 12-year-old Italian boy was admitted to the Hospital with hemolytic

anemia, thrombocytopenia, acute renal failure requiring hemodialysis

and generalized seizures, preceded by an upper respiratory tract

infection

Absence of prodromal diarrhoea and negative results (by stool culture

and sierology) for Shiga-like toxin-producing E.coli

Elevated plasma levels of the terminal complement complex sC5b-9

(520 ng/ml, n.v.<400 ng/ml)

Diagnosis of complement-mediated atypical hemolytic uremic syndrome

(aHUS)

38

Pla

tele

t count

(10

3/m

icro

lite

r)

days

Lower limit of

normal range

EculizumabHD

Relapse

900 mg

1200 mg

Pecoraro C, Remuzzi G, 2015

renal function

normalized

in 3 days

0

6000

12000

18000°

* *

pre-

Ecu

3 days

post-

Ecu

C5

b-9

fo

rme

d(p

ixe

l2/f

ield

)

15 days

post-

Ecu

normal range

Serum-induced C5b-9 deposits on HMEC-1 ex-vivo normalized after Eculizumab

40

No mutations in CFH, MCP, CFI, C3, CFB, THBD, and no anti-CFH antibodies.

Undetectable plasma ADAMTS13 activity (<6% by CBA, without inhibitory

antibodies).

Two compound heterozygous ADAMTS13 mutations:

CUB1 CUB2TSP-1

1Metalloprotease Disintegrin Cys Spacer TSP-1

3

TSP-1

4

TSP-1

5

TSP-1

6

TSP-1

7

TSP-1

2TSP-1

8

c.3251G>A

p.C1084Y

N-term C-term

vWF binding

c.4049delC

p.E1351STOP

Vessel wall

Shear

Folded vWF

Vessel wall

Platelet rolling Platelet adhesion

Platelet

Platelet

Shear Unfolded vWF

Vessel wall

Platelet adhesion and

aggregation

Platel

et

ADAMTS13

Platelet

Unfolded vWF

TTP

Pecoraro C, Remuzzi G, 2015

41

The clinical evolution of this patient and the

intense C5b-9 deposits suggested a role of

complement activation in the pathogenesis of

TTP and opens a perspective for the treatment of

this disease

42

Disease presentation before the age of 1 year, with multiple relapsing

episodes, often progressing to CKD by the second decade of life.

Mutations in DGKE encoding diacylglycerol kinase ɛ. Recessive

inheritance. Explained 27% of aHUS cases in the first year of life.

No evidence linking DGKE deficiency to complement cascade.

One of 7 patients with DGKE mutation on maintenance Eculizumab

therapy had an HUS relapse.

Renal transplantation can be efficacious in patients with DGKE

mutations. No aHUS recurrence after transplantation in 3/3 subjects.

Lemaire M et al, Nature Genet 2013

RECESSIVE MUTATIONS IN DGKE CAUSE

ATYPICAL HEMOLYTIC-UREMIC SYNDROME

Conclusioni

• La PTT è causata da deficienza acquisita o congenita di ADAMTS13 ed è

importante definire la causa per scegliere la terapia appropriata.

• Importante lo screening di mutazioni del complemento nella SEU atipica,

e nelle forme severe di SEU tipica.

• Elevato rischio di recidiva post-tx in pazienti con mutazioni in geni che

codificano per proteine del complemento circolanti (CFH, CFI, C3, CFB).

• Pazienti con mutazioni in MCP e DGKE hanno una prognosi favorevole e mostrano buon esito del trapianto.

Laboratory

ClinicalMarina Noris

Roberta Donadelli

Elisabetta Valoti

Rossela Piras

Caterina Mele

Marta Alberti

Matteo Breno

Serena Bettoni

Giuseppe Remuzzi

Erica Daina

Piero Ruggenenti

Sara Gamba

Paraskevas Iatropoulos

Manuela Curreri

Collaborations

Santiago Rodriguez DeCordoba

Veronique Fremeaux-Bacchi

Tim Goodship

Peter Zipfel