This document discusses atypical hemolytic uremic syndrome (aHUS), a rare genetic disorder caused by uncontrolled activation of the complement system leading to damage of endothelial cells. The case of an Italian child diagnosed with aHUS at 6 months of age is presented, who was found to have a mutation in the complement factor H gene. He experienced multiple relapses requiring plasma therapy and dialysis. At age 5 prior to kidney transplantation, treatment with the monoclonal antibody eculizumab was started, which successfully prevented relapse. The child's kidney function recovered after transplantation while on eculizumab and transplant. Future treatment with liver transplantation under eculizumab is being considered.

1. Rosanna Coppo
Alessandro Amore
Torino
Italy
Atypical HUS:
diagnosis, treatment, outcome

2. Hemolytic uremic syndrome (HUS)
a disease of the microvessels

3. Thrombotic
microangiopathy
• Thrombocytopenia
• Fragmented red
cells, schistocytes
• Intravascular
haemolysis
• Renal failure of
various severity
Moschowitz’s
Thrombotic
Thrombocytopenic
Purpura (TTP)
(neurological symptoms,
limited renal damage)
Gasser’s
Hemolytic-Uremic
Syndrome (HUS)
(renal damage, few
neurological symptoms)

4. The endothelial cell
is the thrombotic microangiopathy target
Endothelial cells
Small arteriola

5. Thrombotic Microangiopathy :
Change in the endothelium-platelets balance due to an
anatomical and functional alteration of endothelium

7. 2011 Orphanet
Frameaux-Bacchi

8. Athypical HUS
Infection-induced

9. Typical HUS in children:
Verotoxin induced Thrombotic Microangiopathy
 E. Coli O157-H7: verotoxin
(shiga-like toxin VTEC) found in 50%
of sporadic HUS and in 90% of
epidemic HUS
 50 serotypes of E. Coli
( O111: H neg; O26: H11)
 Shigella, Salmonella, Streptococcus,
etc

10. Intestinal
epithelium
VTEC-induced enteropathy
E.Coli
Distruction of brush border: diarrhea
Enteral vessel
cytotoxic damage involving vessels:
intestinal hemorrhages
10

11. Vessels
VTEC
Gb3
polymorphonucleates
Gb3
platelets
endothelium
11

13. platelets activation
cytokines,
prostanoids,
chemokines
• platelets recruitment
• parietal thrombus incresase
• damage amplification loop
progressive
vascular occlusion
Shear
stress

14. Shear stress

15. shear stress due to parietal thrombus induces
intravascular mechanical hemolysis with
skystocytis formation
Parietal thrombus.
red blood cell fragmentation
Skystocytes
low platelet count, hemolytic anemia (negative Coomb’s test)

16. genetic HUS

19. Complemet pathway is continously activated at subliminar level
C3b circulates in the blood stream and
can bind to endothelial cell receptors
Abnormalities in complement cascade can induce endothelial cell damage

20. Complement and endothelial damage
endothelial surface
Inhibitors:
CFH
CFI
in plasma
MCP
bound to
cell surface

21. Complement disorders and athypical HUS

22. Genetic HUS
Defective H factor (CFH). This plasma protein
binds to host cell surfaces and prevents formation
of C3bBb , the C3 convertase, by factor B.
the result is uncontrolled C3 activation and
endothelial damage (gene on chromosome 1q).
Early in life, sometimes low C3 , hypertension, high
risk of relapse, poor prognosis in 50%.
80% risk of recurrence and graft loss

23. Genetic HUS
Defective FI (a co-factor for FH) cleaves C3b
interrupting the cascade before C5a
FI circulates in plasma using FH, MCP or CR1 as
co-factors. Heterozigous patients have low FI
levels.
MCP (membrane cofactor protein), a membranebound regulator, which cleaves C3b and C4b on
host cells, expressed in glomerular endothelium
aslo acts as co-factor of FI.

24. Diarrhea negative HUS constitute 10-30% of HUS .
(genetic mutation of complement components 10-15%)
5%
10%
30%

25. ADAMTS 13 and thrombotic microangiopathy

36. Eculizumab anti C5 monoclonal antibody
Eculizumab 20 mg/kg

38. Family history
• Both parents and 2 older twin brothers in good
health
• The child’s aunt (mother’s sister)
-
-
At 26 years of age, june 1998: normal routine lab. data.
September 1998: Cr 2-4 mg/dl - hypertension
Hb 5 g/dl - Plts 150.000/mm3
 Diagnosis of HUS
26 PE : Cr 4-2 mg/dl - Plts 250.000/mm3
ESRF in March 2000  start HD
No recurrence of hemolysis
(stable Plts 300,000, stable LDH 300 U/L)
HT controlled, now normotensive
No mutations detected.
No inclusion in transplant list

39. AD at the age of 6 months: after febrile URT infection,
gross hematuria and paleness
•Diarrhea negative
•Plts 50.000/mm3
•Severe anemia (Hb 6.6 g/dl)
•Fragmented erythrocytes 20%
•LDH 9.000 U/L
•C3 95 mg/dl ; C4 22mg/dl
•Serum creatinine 1.0 mg/dl (eGFR 30 ml/min/1.73m2)
HUS
He was treated with plasma infusions (9x 10 ml/kg)

40. Genetic analysis was then performed
(Bresin E, Bergamo):
A complement factor H mutation was found in the child, his
mother, his aunt and his grand-mother
Heterozigous
3645C>T mutation
Resulting in amino acid
change S1191L
in the terminal
portion SCR20
of the CFH protein
37
5
5
35
31
28

41. PE
Plasma infusions 10 ml/Kg
2
3
4
17 P
7P
PE 1
PE 7
P 2/week
6P
PE 2/week,
then 1/week, then stop
PE 6
85
97
109 121
133 145 157
21/04/2007
07/04/2007
24/03/2007
10/03/2007
24/02/2007
10/02/2007
27/01/2007
13/01/2007
73
169 181
04/07
61
03/07
49
02/07
37
PD 15 days
01/07
25
30/12/2006
16/12/2006
PD 7 days
12/06
11/06
02/12/2006
18/11/2006
04/11/2006
13
SERUM CREATININE (m g/dl)
19/05/2007
Exit site PD
catether
staphilococcal
infection
Fever
1
P 1/week
LDH (U/L)
Fever
4500
4000
3500
3000
2500
2000
1500
1000
500
0
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
16 P
PE 6
9P
5
193 205
05/07
1
Plasma exchange >1. 5 plasma vol
05/05/2007
P

42. P
PE
Plasma infusions
6
7
5P
2P
PE 4
PE 1/week
2000
8
PE 6
LDH (U/L)
1sth CVC
infection
2500
Plasma exchange
PE 1/week
PE 2-3/week
2nd CVC
3rd CVC infection
infection
Staphilococcus
G- sepsis
(Rizobium
1500
radiobacter)
1000
81
91
101
111
121
131
141
151
161
171
12/07
71
11/07
61
10/07
51
PD
16/11/2007
02/11/2007
19/10/2007
05/10/2007
21/09/2007
07/09/2007
24/08/2007
10/08/2007
27/07/2007
13/07/2007
41
09/07
31
SERUM CREATININE (m g/dl)
08/07
21
29/06/2007
15/06/2007
11
07/07
1
06/07
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
01/06/2007
0
30/11/2007
500
181

43. • From the age of 2 years chronic peritoneal
dialysis with 2 more HUS relapses
Afterwards no more relapses of HUS
PE suspendend 5 months later
Repeated peritoneal catheter infections
• From the age of 3 years switched to
haemodialysis following fungual peritonitis
• No more relapses of HUS
• No signs of haemolisis
• Repeated CVC infection

44. On August 5 2011 immediately before kidney
transplant when he was 5-year-old he was treated
with 600 mg of eculizumab (body weight 18 Kg)
Then we infused eculizumab on post-transplant day 1
(300 mg) and 7 (600 mg), and every other week
thereafter (300 mg).
He was induced with low-dose thymoglobulin and
basiliximab, and maintained on steroid, cyclosporine
and mycophenolate mofetil.
His renal function promptly recovered to normal
range.

45. 01/09/11
01/08/11
01/07/11
01/06/11
600
01/05/11
01/04/11
01/03/11
01/02/11
01/01/11
01/12/10
01/11/10
01/10/10
01/09/10
01/08/10
01/07/10
01/06/10
01/05/10
01/04/10
01/03/10
01/02/10
01/01/10
plt x 1000/ ul
700
Eculizumab 600 mg e.o
week BW - 18 kg (before
kidney transplant,
5.08.2011)
transplant
500
400
300
200
100
0

47. Complement and innate immunity

48. Treating a child with atypical HUS is still
a challenge.
We are planning for this child a
liver transplantation under the effect of eculizumab

49. • Thank you