Síndrome Hemolítico Urémico atípico

Síndrome Hemolítico
Urémico atípico
JM.Campistol, Departamente de Nefrología y Trasplante Renal
Hospital Clínic, Universidad de Barcelona,
Barcelona, España
jmcampis@clinic.ub.es
Síndrome Hemolítico
Urémico atípico
Estructura
!  Microangiopatía trombótica (MAT)
!  SHUa – Entidad
Patogenia
Diagnóstico diferencial
Tratamiento
Microangiopatía trombótica (MAT)
La microangiopatía trombótica (MAT) es un trastorno
caracterizado por un síndrome agudo de anemia
hemolítica microangiopática, trombocitopenia, y
signos variables de las lesiones de órganos (riñón)
debido a la trombosis plaquetar en la microcirculación.
Tsai HM et al. Kid Int 2006; 70:16-23
Benz K et al. Curr Opin Nephrol Hypertens 2010;19:242-47
Activación del complemento NO controlada
produce daño de los órganos diana
Clinical
Consequences:
Uncontrolled
complement
activation on cells
Platelets:
•  Activation
•  Aggregation
Endothelial cells:
•  Activation
•  Swelling and disruption
Red cells:
•  Hemolysis
Leukocytes:
•  Activation
Blood clotting
Platelet consumption
Mechanical hemolysis
Vessel occlusion
Inflammation
Ischemia
Systemic organ
complications
Modified by Zipfel and Jokiranta from Desch et al. JASN 2007;18:2457–6240; Licht C et al. Blood 2009 114:4538–4545;
Noris M et al. NEJM 2009;361:1676–687; Stahl A et al. Blood 2008;111:5307–5315; Morigi et al. J Immunol 2011
MAT Causa complicaciones clínicas sistémicas
potencialmente mortales
Cardiovascular2,3,4,6
•  Myocardial infarction
•  Thromboembolism
•  Cardiomyopathy
•  Diffuse vasculopathy
Renal7,8,9,11,12
•  Elevated creatinine
•  Edema, malignant
hypertension
•  Renal failure
•  Dialysis, transplant
Pulmonary1
•  Dyspnea
•  Pulmonary edema
•  PE
Chronic Uncontrolled
Complement Activation
Systemic
Thrombosis,
Inflammation,
Occlusion of
Small Vessels
Blood11
•  Hemolysis
•  Thrombocytopenia
•  Fatigue
•  Transfusions
CNS1,2,3,4,5
•  Confusion
•  Seizures
•  Stroke
•  Encephalopathy
Gastrointestinal2,3,5,10,11,12
•  Liver necrosis
•  Pancreatitis
•  Colitis, Diarrhea
•  Nausea/vomiting
•  Abdominal pain
Impaired Quality of Life1
•  Fatigue
•  Pain/Anxiety
•  Reduced mobility
1. George et al. Blood. 2010;116(20):4060-69. 2. Hosler et al. Arch Pathol Lab Med. 2003;127(7):834-39. 3. Noris M, et al. CJASN. 2010;10(5)1844-59. 4. Neuhaus et al. Arch Dis Chilid.
1997;76(6)518-21. 5. Vesely et al Blood. 2003;102(1):60-8. 6. Sallee et al. Nephron Dial Trans. 2010; 25(6)2028-32. 7. Kose et al. Semin Thromb Hemost. 2010;36(6)669-72. 8. Davin et al. Am
J Kid Dis. 2010;55(4):708-77. 9. Caprioli et al. Blood. 2006;108(4)1267-7. 10. Dragon-Durey et al. J Am Soc Nephrol. 2010;21(12)2180-87. 11. Loirat et al. Pediatr Nephrol. 2008;23(11)1957-72.
12. Stahl et al. Blood. 2008;111(11)5307-15.
Patología de la microangiopatia
trombótica (MAT)
!  Lesión patológica
!  Trombo (coágulo) en la
formación de la microvasculatura
(vasos pequeños)
!  Múltiples coágulos conducen a la
isquemia (deficiencia de flujo
sanguíneo a un órgano o tejido)
y disfunción de órganos
!  La hemólisis microangiopática
–  Presencia de esquistocitos
Benz K et al Curr Opin Nephrol Hypertens. 2010 May;19(3):242-7.
Nester C et al Clin J Am Soc Nephrol 6: 1488–1494, 2011
Enfermedades potencialmente
asociadas a MAT
!  Typical -Hemolytic uremic syndrome (HUS), also known as STEC-HUS
!  Atypical -HUS
!  Thrombotic thrombocytopenic purpura (TTP)
!  Post renal transplant HUS
!  Malignancy-related HUS
!  Systemic lupus erythematosus (SLE)
!  HELLP syndrome (a hypertensive complication of late pregnancy)
!  Catastrophic antiphospholipid antibody syndrome
!  Allogeneic stem cell transplantation
!  Drug induced nephrotoxicity
!  Malignant Arterial Hypertension
!  Disseminated intravascular coagulation (DIC)
!  Paroxysmal nocturnal hemoglobinuria (PNH)
Adapted from Tsai HM et al. Kid Int 2006; 70:16-23 Benz K et al. Curr Opin Nephrol Hypertens 2010;19:242-47
Taylor CM et al Br J Haem. 2010;148:37-47 Besbas N et al Kid Int 2006;70:423-431. Mosby䇻 Medical Dictionary, 2006
Causas del MAT
aHUS
STEC-HUS
TTP
Genetic defect in complement regulation
Shiga toxin
Severe deficiency of ADAMTS13 activity
Chronic uncontrolled complement activation
!  Direct complement activation
!  Interferes with Complement regulation
!  Endothelial damage
Uncleaved
Long VWF Multimeric Strings
Platelet, white blood cell
and endothelial cell activation
SYSTEMIC THROMBOTIC MICROANGIOPATHY:
Multiple thromboses and inflammation throughout the body
Platelets
Cell surface and fluid phase complement inhibitors
Uncleaved long VWF multimeric strings
Adapted from Zipfel PF et al. Current Opinions in Nephrology and Hypertension 2009, 19:372-378
MAT: Patogénesis
Loss of Natural Inhibitors Leads to Chronic
Uncontrolled Complement Activation
SECONDARY
TMA
aHUS
STEC-HUS
ENVIROMENTAL FACTORS
GENETIC PREDISPOSITION
Mutations - SNPs
(FH, FHRP, FI, C3, MCP)
Síndrome Hemolítico
Urémico atípico
Estructura
!  Microangiopatía trombótica (MAT)
!  SHUa – Entidad
Patogenia
Diagnóstico diferencial
Tratamiento
SHUa
Epidemiología
"  Enfermedad ultra-rara - MAT
"  INCIDENCIA: USA ~1-2 casos/millón hab./año
Europa: 0,11 casos/millón hab (0-18 años)
"  El SHUa afecta mayoritariamente a niños y adultos jóvenes,
aunque puede aparecer en cualquier edad de la vida.
"  El inicio de la enfermedad es más frecuente antes de los 18
años (60 vs. 40 %), siendo la distribución por sexos similar
"  SHUa forma de MAT secundaria a la activación crónica NO
controlada del complemento por vía alternativa.
Complemento
Activation
Complement has evolved
to fight infection, to remove
injured self tissue and to
amplify/modulate adaptive
immunity.
Amplification
Inflammation
lysis
Opsonization
Regulación del complemento
ACTIVATORS
REGULATORS
Al iniciarse, la activación
del complemento sólo
procede si la regulación
vence
Regulación – Alternativa Via C
C’ Desregulación = SHUa
!"#$%&'(#)*#+,#-."#$/0)"#12!3#!242564#7899:;#
Características clínicas de los pacientes con
SHUa según alteración del complemento
Gene or
subgroup
Frequency
in aHUS,
%
Minimal age at onset
Children
Adults
Risk of death or
ESRD at 1st episode
or within <1 y, %
Risk of
relapses,
%
Risk of recurrence
after renal
transplantation, %
Plasma
therapy
indicated
CFH
20–30
Birth
Any age
50–70
50
75–90
Yes
CFI
4–10
Birth
Any age
50
10–30
45–80
Yes
MCP
C3
5–15
>1 y
age
0–6
70–90
Questionable
Cannot
beAnyidentified
in 30!40%
of<20patients
2–10
7m
Any age
60
50
40–70
Yes
CFB
1–4
1m
Any age
50
3/3 not in
ESRD
100
Yes
THBD
3–5
6m
Rare
50
30
1 patient
Yes
30–40
40–60
Yes if high Ab titre
Yes (+ IS)
Anti-CFH
Ab
6
Mostly 7–11 y
Ab, antibodies; CFB, complement factor B; CFH, complement factor H;
CFI, complement factor I; ESRD, end-stage renal disease:
IS, immunosuppressive treatment; THBD, thrombomodulin
Loirat C, Frémeaux-Bacchi V, Orphanet J Rare Dis 2011;6;60
Factores de riesgo SHUa
Sialic acid
C3b
C3b
Hep
Hep
C3b
anti fH autoantibodies
RGD
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Cofactor activity
Decay accelerating activity
aHUS patients have a specific
dysfuntion in the protection of cellular
surfaces from complement activation.
Mutations in factor I and MCP, as well
as functional characterization of anti
fH antibodies, support defective
regulation on self-tissue
Noris et al. 2003; Richards et al. 2003; Fremeaux-Bacchi et al.
2004
Goicoechea de Jorge et al. 2007; Fremeaux-Bacchi et al. 2007
Dragon-Durey et al. 2005; Sellier-Leclerc et al. 2007).
16
17
18
19
20
Surface binding
Cell surface regulation
Plasma
Factor H
Factor I
C3b
b
iC3
MCP
C3
b
1
Cell
aHUS: sistémica, mediada por el complemento.
MAT afecta a múltiples órganos y tejidos vitales
Renal
>50% of patients progress to ESRD1
! Elevated creatinine2
! Proteinuria3
! Oedema,4 malignant hypertension5
! Decreased eGFR6
CNS
"48% of patients experience
neurological symptoms3
• 
• 
• 
• 
Confusion7
Stroke7
Encephalopathy5
Seizure3
Blood
•  Thrombocytopenia1
•  Decreased haptoglobin1
•  Elevated LDH1
•  Decreased haemoglobin1
•  Schistocytes1
Cardiovascular
"43% of patients experience
cardiovascular symptoms3
• 
• 
• 
• 
Myocardial infarction8
Hypertension9
Diffuse vasculopathy6
Peripheral gangrene10
Gastrointestinal
"30% of patients present with diarrhoea11
• 
• 
• 
• 
• 
• 
Colitis7
Nausea / vomiting12
Pancreatitis12
Abdominal pain7
Gastroenteritis3
Liver necrosis3
Pulmonary
•  Dyspnoea8
•  Pulmonary haemorrhage13
•  Pulmonary oedema8
Visual
•  Ocular occlusion14
eGFR, estimated glomerular filtration rate;
ESRD, end-stage renal disease;
LDH, lactate dehydrogenase
1. Caprioli J et al. Blood 2006;108:1267-79; 2. Ariceta G et al. Pediatr Nephrol 2009;24:687-96;
3. Neuhaus TJ et al. Arch Dis Child 1997;76:518-21; 4. Ståhl AL et al. Blood 2008;111:5307-15;
5. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844-59; 6. Loirat C et al. Pediatr Nephrol 2008;23:1957-72;
7. Ohanian M et al. Clin Pharmacol 2011;3:5-12; 8. Sallée M et al. Nephrol Dial Transplant 2010;25:2028-32;
9. Kavanagh D et al. Br Med Bull 2006;77-78:5-22; 10. Malina M et al. Pediatr Nephrol 2013;131:e331-5;
11. Zuber J et al. Nat Rev Nephrol 2011;7:23-35; 12. Dragon-Durey MA et al. J Am Soc Nephrol 2010;21:2180-7;
13. Sellier-Leclerc AL et al. J Am Soc Nephrol 2007;18:2392-400; 14. Larakeb A et al. Pediatr Nephrol 2007;22:1967-70
Diagnóstico Diferencial TMA:
SHUa, PTT y STEC-HUS
Microangiopathic Hemolysis2,3
Thrombocytopenia1,2
Schistocytes2,3 and/or
AND
Elevated LDH2 and/or
Platelet count <150,000 Or
Decreased haptoglobin2 and/or
>25% Decrease from baseline1
Decreased hemoglobin2
Plus One or More of the Following:
Neurological Symptoms4-7
Renal Impairment2,9,10
Gastrointestinal Symptoms
Confusion4,5 and/or
Seizures6,8 and/or
Other cerebral abnormalities5
Elevated sCr and/or
Decreased eGFR and/or
Elevated BP pressure and/or
Abnormal urinalysis
Diarrhea + blood and/or
Nausea/vomiting and/or
Abdominal pain and/or
Gastroenteritis
Evaluate ADAMTS13 Activity and Shiga-toxin/EHEC* Test
While waiting for ADAMTS13 results, a platelet count >30,000 mm3 or serum creatinine >150-200 #mol/L
(>1.7-2.3 mg/dL) almost eliminates a diagnosis of severe ADAMTS13 deficiency (TTP)16
"5% ADAMTS13 Activity8,13,14
>5% ADAMTS13 Activity12
Shiga-toxin/EHEC Positive14
TTP
aHUS
STEC-HUS
This pathway is intended as educational information for healthcare providers. It does not replace a healthcare professional䇻s judgment or clinical
diagnosis.
* Shiga-toxin/EHEC test is warranted with history/presence of GI symptoms.
1. Data on file. Alexion Pharmaceuticals, Inc.; 2. Caprioli et al. Blood 2006;108:1267-7; 3. Noris M et al. NEJM 2009;361:1676–1687; 4. Neuhaus et al. Arch Dis Chilid
1997;76:518–521; 5. Noris M et al. JASN 2005;16:1177–1183; 6. Dragon-Durey et al. J Am Soc Nephrol 2010;21:2180–2187; 7. Davin et al. Am J Kid Dis 2010;55:708–777;
8. Bianchi et al. Blood 2002;110:710–713; 9. Al-Akash et al. Pediatr Nephrol 2011;26:613–619; 10. Sellier-Leclerc AL. JASN 2007;18:2392–2400; 11. Benz et al. Curr Opin
Nephrol Hypertens 2010;19:242–247; 12. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844–1859; 13. Tsai H-M. Int J Hematol 2010;91:1–19; 14. Barbot et al. Br J Haematol
2001;113:649; 15. Bitzan M. Semin Thromb Hemost 2010;36:594–610; 16. Zuber J et al. Nat Rev Nephrol 2012 Nov;8:643–657.
Síndrome Hemolítico
Urémico atípico
Estructura
!  Microangiopatía trombótica (MAT)
!  SHUa –
Entidad
Patogenia
Diagnóstico diferencial
Tratamiento
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Síndrome urémico hemolítico atípico (SHUa): Una
enfermedad devastadora y potencialmente mortals
!  Sudden death and vital
organ damage1
!  Chronic progressive course
with premature mortality2-4
!  65% of all patients die,
require dialysis, or have
permanent renal damage
within 1 year after
diagnosis despite plasma
exchange or plasma
infusion2
Cumulative fraction of patients
free of events
!  33-40% of patients die or
progress to end-stage renal
disease (ESRD) with the
first clinical manifestation2,3
1.00
Up to 70% of
patients (with the
most common
mutation, CFH)
die, require
dialysis, or have
permanent renal
damage within
1 year2
0.75
0.50
0.25
0.00
0
3
6
12.5
25
Follow-up (months)
Modified from Caprioli J et al. 2006. CFH mutation
depicted.
1. Sallee M et al. Nephrol Dial Transplant 2010;25:2028–2032; 2. Caprioli J et al. Blood
2006;108:1267–1272; 3. Noris M et al. CJASN 2010;10:1844–1859;
4. Noris M et al. N Engl J Med 2009;361:1676–1687.
Eculizumab bloquea la formación
del complejo de ataque del complemento
Terminal
Proximal
Complement cascade1
C3
C3a
!  Eculizumab binds with high
affinity to C51,2
C3b
C5
Eculizumab
!  Terminal complement activity
is blocked1
!  Proximal functions of
complement remain intact1
C5a
–  Weak anaphylatoxin
C5b
C5b-9
–  Immune complex clearance
–  Microbial opsonisation
1. Rother RP et al. Nat Biotechnol 2007;25:1256-64;
2. Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012
F&%L&-G-#O+#O+(-&&%..%#O+#/B<.'R<G-P##
#+C#STU-#789!!N8981;##
Prospective1 (26 weeks)
Study C08-003
Adult/adolescent
(N=20)
Study C08-002
Adult/adolescent
(N=17)
!99#>-E+C,(#'C#,%,-.##
'C#>&%(>+BE=+#B.'C'B-.#,&'-.(#
Prospective (26 weeks)
Long-term extension studies5,6
86% (32/37) of patients continued
chronic eculizumab treatment in
extension studies
Study C10-0032
Paediatrics (N=22)
Study C10-0043
Adults (N=41)
Retrospective4
Study C09-001
Patients <12 years
(N=15)
Long-term follow-up study
C11-0037: 5 years
(Mar 2012–Dec 2017)
All aHUS
patients
aHUS registry M11-0018:
treated and not treated
(Apr 2012–Dec 2023)
1. Legendre CM et al. N Engl J Med 2013;368:2169–81; 2. Greenbaum L, et al., Presented at ASN; Nov 5-10 2013 Atlanta USA, abstract
5579; 3. Fakhouri F, et al. Presented at ASN; Nov 5-10 2013 Atlanta USA, abstract 5593; 4. Eculizumab Summary of Product
Characteristics. Alexion Europe SAS, 2014; 5. Licht C et al. ASH; Atlanta, USA; 8–11 Dec 2012. Poster 985; 6. Greenbaum L et al. ASH;
Atlanta, USA; 8–11 Dec 2012. Poster 2084; 7. http://clinicaltrials.gov/show/NCT01522170; 8. Licht C, et al., Presented at ASN; Nov 5-10
2013 Atlanta USA, abstract 5184
Estudios prospectivos:
Dosis de Eculizumab*
Pretreatment
!2 weeks
before induction
Neisseria
meningitidis
vaccination/
antibiotics
Induction Phase
Week
"
Eculizumab
dose, mg
"
Maintenance Phase
1
2
3
4
5
6
7
8
9 and
every
2 weeks
thereafter
900
900
900
900
1200
X
1200
X
1200
! 
Administration: IV infusion over 35 minutes every 7 days during induction and every 14 days
during maintenance
–  Dose adjustment to every 12 days permitted
! 
Meningococcal prophylaxis: patients received meningococcal vaccination prior to receipt of eculizumab
or received prophylactic treatment with antibiotics until 2 weeks after vaccination
! 
Severe TMA complications observed in aHUS patients deviating from recommended dosing schedule
# 
5/18 patients experienced TMA complications following missed dose
# 
Eculizumab was reinitiated in 4/5 patients
*For patients <18 years of age, administration of eculizumab is based on body weight.
1. Eculizumab Summary of Product Characteristics. Alexion Europe SAS, 2014
F%P.-B'VC#B%C#STU-"#/C(-M%(#B.WC'B%(3#
B&',+&'%(#O+#'CB.<('VC#
Baseline
characteristics
Patients with long duration
of aHUS and CKD
(C08-003)1
Patients with aHUS and
progressing TMA
(C08-002)1
Patients with aHUS
(C10-004)2
20
17
41
$12 years
$12 years
$18 years
No decrease in platelet count
>25%
Platelet count decreased >25%
1 week prior
Platelet count <150 x 109/L
Haemoglobin $ LLN
LDH %1.5 x ULN
Serum creatinine %ULN
Ongoing long-term
(%1 every 2 weeks, but
$3 per week for %8 weeks)
%4 PE/PI sessions in the week
before screening
No specification for PE/PI
prior to enrolment
>5%
>5%
>5%
No
No
No
Not required
Not required
Not required
n
Patient age
Inclusion criteria
PE/PI prior to enrolment
ADAMTS13 activity
Evidence of STEC-HUS
or Shiga toxin
Genetic mutations,
polymorphism or
autoantibody
GQ&R)1)0F#)&)%&(+H&S)P&-01+&T&A)F"'"0)&UVBC&
!Q&!(W/D9#"&)%&(+H&?7S&UVBC&
Población con SHUa. Ensayos clínicos
Patients with long duration
of aHUS and CKD
(C08-003; n=20)1
Patients with aHUS
and progressing TMA
(C08-002; n=17)1
Patients with aHUS
(C10-004; n=41)2
Median duration from aHUS
diagnosis to screening,
months (range)
48.3 (0.7–285.8)
9.7 (0.3–235.9)
0.79 (0.03–311.3)
Median duration of current
TMA, months to screening,
months (range)
8.6 (1.2–45.0)
0.8 (0.2–3.7)
0.5 (0.0–19.2)
PE/PI prior to eculizumab
Median duration: 10.1 months
Median no. 1 week
prior: 6 (0–7)
Median no. 1 week
prior: 3 (0–8)
Platelet count
Median & 109/L (range)
<150 & 109/L, no. (%)
218 (105–421)
3 (15)
118 (62–161)
15 (88)
125 (16–332)
27 (66)
50% of patients with CKD
Stage 4–5;
2 (10%) patients on chronic
dialysis
70% of patients with CKD
Stage 4–5;
5 (29%) patients on dialysis
80% of patients with CKD
Stage 4–5;
24 (59%) patients on
dialysis
30% of patients had none
identified
24% of patients had none
identified
49% of patients had none
identified
Baseline
characteristics
Renal damage
Genetic mutations or
autoantibody
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!Q&!(W/D9#"&)%&(+H&?7S&UVBC&
Normalización hematológica a los
2 años de Eculizumab
Patients Achieving Hematologic Normalization
Hematologic normalization =
Normal platelet (%150&109/L) and
LDH levels, %2 consecutive
measurements, %4 weeks apart
!  Patients achieved hematologic
normalization regardless of the
identification of a genetic
complement mutation*
Median 26
Weeks*
Median 62
Weeks*
! 
83% of pts with no known
complement mutation
! 
93% of pts positive for
complement mutation
Median 114
Weeks*
1. Goodship T, et al. Eculizumab (ECU) Is Effective in Patients (pts) with Atypical Hemolytic Uremic Syndrome (aHUS) Regardless of
Underlying Genetic Mutations or Complement Factor H (CFH) Auto-Antibodies. Presented at the 2012 Meeting of the American Society of
Nephrology, November 1, 2012; San Diego, CA. Poster TH-PO442.
*At
C08-003
data cutoff
Estatus libre de TMA a los 2 años con
Eculizumab
88%
88%
Patients (%) Achieving
TMA-Event–Free Status
88%
*At
1. 
C08-002
TMA-event–free status:
Achieved by 88% of patients
For 12 consecutive weeks, no
decrease in platelet count >25%
from baseline, and no PE/PI,
and no new dialysis
!  Median TMA intervention rate per
patient: 0.88 pretreatment, 0.00
baseline through data cut off
(P<0.0001)
!  TMA-event-free status achieved
regardless of the identification of a
genetic complement mutation1
15/17
15/17
15/17
Median 26
Weeks*
Median 64
Weeks*
Median 100
Weeks*
•  12/13 (92%) with mutation
•  3/4 (75%) without mutation
data cutoff
Goodship T, et al. Eculizumab (ECU) Is Effective in Patients (pts) with Atypical Hemolytic Uremic Syndrome (aHUS) Regardless of Underlying Genetic Mutations or Complement Factor H (CFH)
Auto-Antibodies. Presented at the 2012 Meeting of the American Society of Nephrology, November 1, 2012; San Diego, CA. Poster TH-PO442.
Eculizumab reduce la necesidad de PE/PI y diálisis
C08-002
P<.0001
Median (Range)
TMA Intervention Rate
0.88
(0.04–1.59)
TMA intervention rate:
number of PE/PI or new dialysis
per patient per day
!  Reduction from median 6 interventions
per patient per week prior to eculizumab
to median 0 intervention during
eculizumab treatment
!  4/5 (80%) eliminated the need for
dialysis and remained dialysis
free through week 100
0
(0 – 0.31)
Baseline
(N=17)
$ At median 100 weeks, only 2*/17
patients (12%) on dialysis.
Week 100
(N=17)
- Dialysis duration prior to eculizumab: 6 to 26 days (23 days in the patient not free of dialysis).
- *One patient started dialysis at wk 64 (baseline eGFR 19 ml/min/1.73m2 )
- One patient received 5 PE/PI without interruption of eculizumab and one received PE/PI after treatment discontinuation (protocol
violation)
Mejoría del eGFR en pacientes aHUS con
larga duración de la enfermedad (C08-003)
Slope
1 2 3
Patients
! 
20 20
Week 26
+6.1 (95% CI, 3.3 to 8.8)
p=0.0001
20
20
20
19
17
18
2-year update
+7.2 (95% CI, 0.76 to 13.6)
p<0.05
17
18
18
13
17
17
15
Mean eGFR change from baseline (mL/min/1.73 m2) with continuous eculizumab treatment from
baseline to 2-year update (median treatment duration = 114 weeks)
Rápida mejoría del eGFR en pacientes con
progresión aHUS TMA (C08-002)
Week 26
+32.0 (95% CI, 14.5 to 49.4)
p=0.001
2-year update
+35.2 (95% CI, 17.3 to 53.1)
p=0.0005
Slope
1 2 3
Patients 55556617
1717
17
1615
1515
1515
1515
15
15
15
13
15
Patients
16
15
15 15
13
15
! 
15 14
14 13
13 12
12 11
11 12
12 11
11 13
13 12
12 13
1313
13 12
12 99 12
12 12
12 10
10 99 99 99
15
Mean eGFR change from baseline (mL/min/1.73 m2) with continuous eculizumab treatment from
baseline to 2-year data cut-off (median duration = 100 weeks)
C08-003
Effects of Early Intervention
Mean eGFR Change (SE) from Baseline
to Median of Week 62 (mL/min/1.73 m2)
Intervención precoz con Eculizumab
mejora el eGFR
!  Earlier eculizumab treatment was a significant
predictor of improved eGFR through week 62,
(ANOVA with clinical disease manifestation as
covariate, P=0.008)
20
10
0
Correlation = -0.60; P=0.0066
-10
0
10
20
30
40
Duration from Clinical Manifestation to TMA Screening (Months)
Licht C et al. Presented at ASH; December 10–12, 2011; San Diego, CA. 3033.
Intervención más precoz con Eculizumab conduce a
una mejoría significativa de la función renal
GQ&R)1)0F#)&)%&(+H&S)P&-01+&T&A)F"'"0)&UVBC&
C08-003
Eculizumab mejora la calidad
de vida 2 años
Change in EQ-5D Score from Baseline Through 114 Weeks of Eculizumab
Extension Treatment
26-Week Treatment
‡‡ †
* * †
†
* ‡ *‡
*
*
*
*
†
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
Clinically meaningful threshold = 0.06
*P<0.0001
†P<0.001
‡P<0.05
Patients
20 19
17
16 18
5
17
3
19 17
19
18
Clinically meaningful threshold %0.6. Bars represent 95% CI.
EQ-5D=5-dimension EuroQol questionnaire.
19 18
17
16 18
17 18 17
16 15
/B<.'R<G-P#P<+C-#,%.+&-CB'-#5#8#-X%(#
C08-002 (n=17)
C08-003 (n=20)
Event#
Patients (%)# Worst severity#
Event
Patients (%)#
Worst severity
Serious AEs#
Serious AEs
Peritonitis&
1 (5)&
Severe&
Hypertension
1 (6)
Severe
Influenza&
1 (5)&
Severe&
Accelerated hypertension
2 (12)
Moderate
Venous sclerosis at infusion site&
2 (10)&
Severe&
Asymptomatic bacteriuria
1 (6)
Mild
AEs#
AEs
Headache&
3 (15)&
Moderate (1 pt)&
Leukopenia
2 (12)
Mild
Lymphopenia&
2 (10)&
Moderate (1 pt)&
Nausea
2 (12)
Mild
Leukopenia&
2 (10)&
Mild&
Vomiting
3 (18)
Mild
Cough or productive cough&
2 (10)&
Mild&
Asthenia
1 (6)
Moderate
Abnormal blood clotting&
1 (5)&
Mild&
Dermatitis
1 (6)
Mild
Anaemia&
1 (5)&
Moderate&
Diarrhoea
1 (6)
Mild
Deafness bilateral&
1 (5)&
Moderate&
Erythema
!  AE rates remained steady
or declined
with longer
duration eculizumab1 (6)
treatmentModerate
Extravasation&
1 (5)&
Moderate&
Fatigue
1 (6)
Moderate
Chest
discomfort&
Mild&
Mild
!  One
death at 1.9 years1 (5)&
deemed unrelated
toHeadache
eculizumab treatment 1 (6)
BK infection &
1 (5)&
Mild&
Haematocrit decreased
1 (6)
Mild
Nasopharyngitis&
1 (5)&
Mild&
Haematuria
1 (6)
Mild
Nasal congestion&
1 (5)&
Mild&
Haemoglobin decreased
1 (6)
Mild
Rhinorrhoea&
1 (5)&
Moderate&
Herpes zoster
1 (6)
Mild
Pharyngolaryngeal pain&
1 (5)&
Moderate&
Impetigo
1 (6)
Moderate
Alopecia&
1 (5)&
Mild&
Pyrexia
1 (6)
Mild
Pruritus&
1 (5)&
Mild&
Tremor
1 (6)
Moderate
Hypotension&
1 (5)&
Moderate&
Urinary tract infection
1 (6)
Mild
Q fever&
1 (5)&
Moderate&
Vertigo
1 (6)
Mild
Menorrhagia&
1 (5)&
Mild&
Eculizumab – Ensayos Clínicos (2 años)
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Base de datos demográficos y características de la
enfermedad: pacientes con SHUa (C10-004)
Baseline demographics and disease characteristics (N=41)
Median (range) age at first infusion, years
35 (18, 80)
Female gender, n (%)
28 (68)
Patient-reported family history of aHUS, n (%)
6 (15)
Identified complement regulatory protein mutation or autoantibody, n
(%)
20 (49)
CFHR 1/3 polymorphism, n (%)
Median time from aHUS diagnosis until screening, months (range)
Median duration of current clinical manifestation, months (range)
PE/PI duration
None
<2 months
%2 months
1 (2)
0.8 (0.03–311.3)
0.5 (0.0–19.2)
6
30
5
Dialysis at baseline, n (%)
24 (59)
Prior renal transplant, n (%)
9 (22)
!Q&!(W/D9#"&)%&(+H&?7S&UVBC&
Consecución de los objetivos primario y
secundarios con Eculizumab
98%
88%
73%
(95% CI: 87.1–99.9)
(95% CI: 73.8–95.9)
(95% CI: 57.1–85.8)
Median days
to endpoint
(range)
!Q&!(W/D9#"&)%&(+H&?7S&UVBC&
30/41
36/41
40/41
56 (2–147)
55 (2–146)
8 (0–84)
)+j%&W-#O+.#+`ab#
29.3 mL/min/1.73m2: Mean change from baseline in eGFR at Week 26
35
*
*
eGFR change from baseline
(mL/min/1.73m2)
30
*
*
*
25
20
*
#
15
Dialysis could be discontinued
10
5
†
! 
20/24 (83%) of patients on dialysis at
baseline could discontinue dialysis
! 
15/17 (88%) patients not on dialysis at
baseline were dialysis-free at 26 weeks
0
0
1
!Q&!(W/D9#"&)%&(+H&?7S&UVBC&
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
Study week
AE hallazgos fueron consistentes con
otros estudios de Eculizumab
C10-004 (n=41) AEs occurring
in $15%
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)
!  Most AEs were mild or
moderate
!  Two patients had
meningococcal infection
–  One patient recovered and
discontinued from the study due
to meningococcal infection
–  The second patient recovered,
and stayed on eculizumab
treatment
!  No new safety concerns
!  No deaths
!Q&!(W/D9#"&)%&(+H&?7S&UVBC&
C10-004
aHUS - Consenso francés
Nat Rev Nephrol. 2012 Nov;8(11):643-57.
Conclusiones
• SHUa es una forma de MAT ultra-rara, sistémica y agresiva,
secundaria a un trastorno genético en la regulación del
complemento (vía alternativa), con predominio clínico de
afectación renal.
• El diagnóstico diferencial del SHUa es esencial para su
correcto tratamiento, especialmente entre SHU-STEC y PTT.
El análisis genético NO es imprescindible para su
diagnóstico, ni para el inicio del tratamiento.
• El tratamiento con Eculizumab (bloqueo C5) ha cambiado la
historia natural del SHUa. El inicio precoz del tratamiento
garantiza la recuperación hematológica y renal asociado al
SHUa.
GRACIAS !!!!!