Rosanna Coppo
Alessandro Amore
Torino
Italy

Atypical HUS:
diagnosis, treatment, outcome
Hemolytic uremic syndrome (HUS)
a disease of the microvessels
Thrombotic
microangiopathy
• Thrombocytopenia
• Fragmented red
cells, schistocytes
• Intravascular
haemolysis
• Renal fail...
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...
2011 Orphanet
Frameaux-Bacchi
Athypical HUS

Infection-induced
Typical HUS in children:
Verotoxin induced Thrombotic Microangiopathy

 E. Coli O157-H7: verotoxin
(shiga-like toxin VTEC...
Intestinal
epithelium

VTEC-induced enteropathy
E.Coli

Distruction of brush border: diarrhea
Enteral vessel
cytotoxic dam...
Vessels
VTEC

Gb3

polymorphonucleates

Gb3

platelets

endothelium
11
platelets activation

cytokines,
prostanoids,
chemokines

• platelets recruitment
• parietal thrombus incresase
• damage a...
Shear stress
shear stress due to parietal thrombus induces
intravascular mechanical hemolysis with
skystocytis formation

Parietal thro...
genetic HUS
Complemet pathway is continously activated at subliminar level
C3b circulates in the blood stream and
can bind to endothel...
Complement and endothelial damage

endothelial surface
Inhibitors:
CFH
CFI
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 , th...
Genetic HUS
Defective FI (a co-factor for FH) cleaves C3b
interrupting the cascade before C5a

FI circulates in plasma usi...
Diarrhea negative HUS constitute 10-30% of HUS .
(genetic mutation of complement components 10-15%)

5%

10%

30%
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 ye...
AD at the age of 6 months: after febrile URT infection,
gross hematuria and paleness
•Diarrhea negative
•Plts 50.000/mm3
•...
Genetic analysis was then performed
(Bresin E, Bergamo):

A complement factor H mutation was found in the child, his
mothe...
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

9...
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 exchang...
• From the age of 2 years chronic peritoneal
dialysis with 2 more HUS relapses
Afterwards no more relapses of HUS
PE suspe...
On August 5 2011 immediately before kidney
transplant when he was 5-year-old he was treated
with 600 mg of eculizumab (bod...
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

01/10/1...
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 ...
• Thank you
5-3. Atypical HUS. Rosanna Coppo (eng)
5-3. Atypical HUS. Rosanna Coppo (eng)
5-3. Atypical HUS. Rosanna Coppo (eng)
5-3. Atypical HUS. Rosanna Coppo (eng)
5-3. Atypical HUS. Rosanna Coppo (eng)
5-3. Atypical HUS. Rosanna Coppo (eng)
5-3. Atypical HUS. Rosanna Coppo (eng)
5-3. Atypical HUS. Rosanna Coppo (eng)
5-3. Atypical HUS. Rosanna Coppo (eng)
5-3. Atypical HUS. Rosanna Coppo (eng)
5-3. Atypical HUS. Rosanna Coppo (eng)
5-3. Atypical HUS. Rosanna Coppo (eng)
5-3. Atypical HUS. Rosanna Coppo (eng)
5-3. Atypical HUS. Rosanna Coppo (eng)
5-3. Atypical HUS. Rosanna Coppo (eng)
5-3. Atypical HUS. Rosanna Coppo (eng)
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5-3. Atypical HUS. Rosanna Coppo (eng)

  1. 1. Rosanna Coppo Alessandro Amore Torino Italy Atypical HUS: diagnosis, treatment, outcome
  2. 2. Hemolytic uremic syndrome (HUS) a disease of the microvessels
  3. 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. 4. The endothelial cell is the thrombotic microangiopathy target Endothelial cells Small arteriola
  5. 5. Thrombotic Microangiopathy : Change in the endothelium-platelets balance due to an anatomical and functional alteration of endothelium
  6. 6. 2011 Orphanet Frameaux-Bacchi
  7. 7. Athypical HUS Infection-induced
  8. 8. 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
  9. 9. Intestinal epithelium VTEC-induced enteropathy E.Coli Distruction of brush border: diarrhea Enteral vessel cytotoxic damage involving vessels: intestinal hemorrhages 10
  10. 10. Vessels VTEC Gb3 polymorphonucleates Gb3 platelets endothelium 11
  11. 11. platelets activation cytokines, prostanoids, chemokines • platelets recruitment • parietal thrombus incresase • damage amplification loop progressive vascular occlusion Shear stress
  12. 12. Shear stress
  13. 13. 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)
  14. 14. genetic HUS
  15. 15. 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
  16. 16. Complement and endothelial damage endothelial surface Inhibitors: CFH CFI in plasma MCP bound to cell surface
  17. 17. Complement disorders and athypical HUS
  18. 18. 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
  19. 19. 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.
  20. 20. Diarrhea negative HUS constitute 10-30% of HUS . (genetic mutation of complement components 10-15%) 5% 10% 30%
  21. 21. ADAMTS 13 and thrombotic microangiopathy
  22. 22. Eculizumab anti C5 monoclonal antibody Eculizumab 20 mg/kg
  23. 23. 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
  24. 24. 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)
  25. 25. 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
  26. 26. 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
  27. 27. 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
  28. 28. • 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
  29. 29. 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.
  30. 30. 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
  31. 31. Complement and innate immunity
  32. 32. Treating a child with atypical HUS is still a challenge. We are planning for this child a liver transplantation under the effect of eculizumab
  33. 33. • Thank you

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