Download - 5-3. Atypical HUS. Rosanna Coppo (eng)
![Page 1: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/1.jpg)
Rosanna CoppoAlessandro AmoreTorinoItaly
Atypical HUS:diagnosis, treatment, outcome
![Page 2: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/2.jpg)
Hemolytic uremic syndrome (HUS) a disease of the microvessels
![Page 3: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/3.jpg)
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)
![Page 4: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/4.jpg)
The endothelial cell
is the thrombotic microangiopathy target
Endothelial cells Small arteriola
![Page 5: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/5.jpg)
Thrombotic Microangiopathy :
Change in the endothelium-platelets balance due to an anatomical and functional alteration of endothelium
![Page 6: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/6.jpg)
![Page 7: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/7.jpg)
2011 Orphanet Frameaux-Bacchi
![Page 8: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/8.jpg)
Infection-induced
Athypical HUS
![Page 9: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/9.jpg)
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:
![Page 10: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/10.jpg)
10
VTEC-induced enteropathyIntestinal epithelium
Enteral vessel
Distruction of brush border: diarrhea
cytotoxic damage involving vessels: intestinal hemorrhages
E.Coli
![Page 11: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/11.jpg)
11
Vessels
VTEC
polymorphonucleates
Gb3
plateletsGb3
endothelium
![Page 12: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/12.jpg)
![Page 13: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/13.jpg)
platelets activation
cytokines,prostanoids,chemokines
• platelets recruitment • parietal thrombus incresase• damage amplification loop
progressive vascular occlusion
Shear stress
![Page 14: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/14.jpg)
Shear stress
![Page 15: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/15.jpg)
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)
![Page 16: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/16.jpg)
genetic HUS
![Page 17: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/17.jpg)
![Page 18: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/18.jpg)
![Page 19: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/19.jpg)
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
![Page 20: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/20.jpg)
Complement and endothelial damage
endothelial surfaceInhibitors:
CFHCFI
in plasma
MCP bound to
cell surface
![Page 21: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/21.jpg)
Complement disorders and athypical HUS
![Page 22: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/22.jpg)
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
![Page 23: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/23.jpg)
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.
![Page 24: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/24.jpg)
30%
10%
5%
Diarrhea negative HUS constitute 10-30% of HUS .(genetic mutation of complement components 10-15%)
![Page 25: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/25.jpg)
ADAMTS 13 and thrombotic microangiopathy
![Page 26: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/26.jpg)
![Page 27: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/27.jpg)
![Page 28: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/28.jpg)
![Page 29: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/29.jpg)
![Page 30: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/30.jpg)
![Page 31: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/31.jpg)
![Page 32: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/32.jpg)
![Page 33: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/33.jpg)
![Page 34: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/34.jpg)
![Page 35: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/35.jpg)
![Page 36: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/36.jpg)
Eculizumab anti C5 monoclonal antibody
Eculizumab 20 mg/kg
![Page 37: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/37.jpg)
![Page 38: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/38.jpg)
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
![Page 39: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/39.jpg)
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
![Page 40: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/40.jpg)
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
![Page 41: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/41.jpg)
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
![Page 42: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/42.jpg)
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
![Page 43: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/43.jpg)
• 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
![Page 44: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/44.jpg)
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.
![Page 45: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/45.jpg)
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)
![Page 46: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/46.jpg)
![Page 47: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/47.jpg)
Complement and innate immunity
![Page 48: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/48.jpg)
Treating a child with atypical HUS is still a challenge. We are planning for this child a liver transplantation under the effect of eculizumab
![Page 49: 5-3. Atypical HUS. Rosanna Coppo (eng)](https://reader035.vdocuments.us/reader035/viewer/2022062614/547b38b1b4af9ff50a8b45ed/html5/thumbnails/49.jpg)
• Thank you