5-3. atypical hus. rosanna coppo (eng)
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Rosanna CoppoAlessandro AmoreTorinoItaly
Atypical HUS:diagnosis, treatment, outcome
Hemolytic uremic syndrome (HUS) a disease of the microvessels
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)
The endothelial cell
is the thrombotic microangiopathy target
Endothelial cells Small arteriola
Thrombotic Microangiopathy :
Change in the endothelium-platelets balance due to an anatomical and functional alteration of endothelium
2011 Orphanet Frameaux-Bacchi
Infection-induced
Athypical HUS
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
Typical HUS in children:
10
VTEC-induced enteropathyIntestinal epithelium
Enteral vessel
Distruction of brush border: diarrhea
cytotoxic damage involving vessels: intestinal hemorrhages
E.Coli
11
Vessels
VTEC
polymorphonucleates
Gb3
plateletsGb3
endothelium
platelets activation
cytokines,prostanoids,chemokines
• platelets recruitment • parietal thrombus incresase• damage amplification loop
progressive vascular occlusion
Shear stress
Shear stress
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)
genetic HUS
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
Complement and endothelial damage
endothelial surfaceInhibitors:
CFHCFI
in plasma
MCP bound to
cell surface
Complement disorders and athypical HUS
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
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 membrane-bound regulator, which cleaves C3b and C4b on host cells, expressed in glomerular endothelium aslo acts as co-factor of FI.
30%
10%
5%
Diarrhea negative HUS constitute 10-30% of HUS .(genetic mutation of complement components 10-15%)
ADAMTS 13 and thrombotic microangiopathy
Eculizumab anti C5 monoclonal antibody
Eculizumab 20 mg/kg
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
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)
He was treated with plasma infusions (9x 10 ml/kg)
HUS
Heterozigous 3645C>T mutation
Resulting in amino acid change S1191Lin the terminal portion SCR20 of the CFH protein
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
5 5
37 35 31 28
0500
10001500200025003000350040004500
04/1
1/2
006
18/1
1/2
006
02/1
2/2
006
16/1
2/2
006
30/1
2/2
006
13/0
1/2
007
27/0
1/2
007
10/0
2/2
007
24/0
2/2
007
10/0
3/2
007
24/0
3/2
007
07/0
4/2
007
21/0
4/2
007
05/0
5/2
007
19/0
5/2
007
LDH (U/L)
1 2 53 4
9 P 17 P 16 P 7 P
PE 6 PE 1 PE 7 PE 2/week, then 1/week, then stop
P 2/week
P PE Plasma infusions 10 ml/Kg Plasma exchange >1. 5 plasma vol
6 P
PE 6
Exit site PD catether staphilococcal infection
P 1/week
FeverFever
SERUM CREATININE (mg/dl)
00.5
11.5
22.5
33.5
44.5
1 13 25 37 49 61 73 85 97 109 121 133 145 157 169 181 193 205
PD 7 days PD 15 days
11/0
6
12/0
6
01/0
7
02/0
7
03/0
7
04/0
7
05/0
7
0
500
1000
1500
2000
2500
01/0
6/2
007
15/0
6/2
007
29/0
6/2
007
13/0
7/2
007
27/0
7/2
007
10/0
8/2
007
24/0
8/2
007
07/0
9/2
007
21/0
9/2
007
05/1
0/2
007
19/1
0/2
007
02/1
1/2
007
16/1
1/2
007
30/1
1/2
007
LDH (U/L)
SERUM CREATININE (mg/dl)
00.5
11.5
22.5
33.5
44.5
1 11 21 31 41 51 61 71 81 91 101 111 121 131 141 151 161 171 181
06/0
7
07/0
7
08/0
7
09/0
7
10/0
7
11/0
7
12/0
7
6 87
P PE Plasma infusions Plasma exchange
5 P
PE 4 PE 1/week
2 P
PE 6 PE 1/week
1sth CVC infectionStaphilococcus
2nd CVC
infection(Rizobium
radiobacter)
3rd CVC infection
G- sepsis
PD
PE 2-3/week
• From the age of 2 years chronic peritoneal dialysis with 2 more HUS relapses Afterwards no more relapses of HUSPE suspendend 5 months laterRepeated 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
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.
0
100
200
300
400
500
600
700
01/0
1/10
01/0
2/10
01/0
3/10
01/0
4/10
01/0
5/10
01/0
6/10
01/0
7/10
01/0
8/10
01/0
9/10
01/1
0/10
01/1
1/10
01/1
2/10
01/0
1/11
01/0
2/11
01/0
3/11
01/0
4/11
01/0
5/11
01/0
6/11
01/0
7/11
01/0
8/11
01/0
9/11
plt x
100
0/ u
l
transplant
Eculizumab 600 mg e.o week BW - 18 kg (before
kidney transplant, 5.08.2011)
Complement and innate immunity
Treating a child with atypical HUS is still a challenge. We are planning for this child a liver transplantation under the effect of eculizumab
• Thank you
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