Your SlideShare is downloading. ×
0
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)
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)
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)
5-3. Atypical HUS. Rosanna Coppo (eng)
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×
Saving this for later? Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime – even offline.
Text the download link to your phone
Standard text messaging rates apply

5-3. Atypical HUS. Rosanna Coppo (eng)

200

Published on

Published in: Health & Medicine, Technology
0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
200
On Slideshare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
18
Comments
0
Likes
1
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide

Transcript

  • 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
  • 6. 2011 Orphanet Frameaux-Bacchi
  • 7. Athypical HUS Infection-induced
  • 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. Intestinal epithelium VTEC-induced enteropathy E.Coli Distruction of brush border: diarrhea Enteral vessel cytotoxic damage involving vessels: intestinal hemorrhages 10
  • 10. Vessels VTEC Gb3 polymorphonucleates Gb3 platelets endothelium 11
  • 11. platelets activation cytokines, prostanoids, chemokines • platelets recruitment • parietal thrombus incresase • damage amplification loop progressive vascular occlusion Shear stress
  • 12. Shear stress
  • 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. genetic HUS
  • 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. Complement and endothelial damage endothelial surface Inhibitors: CFH CFI in plasma MCP bound to cell surface
  • 17. Complement disorders and athypical HUS
  • 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. 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. Diarrhea negative HUS constitute 10-30% of HUS . (genetic mutation of complement components 10-15%) 5% 10% 30%
  • 21. ADAMTS 13 and thrombotic microangiopathy
  • 22. Eculizumab anti C5 monoclonal antibody Eculizumab 20 mg/kg
  • 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. 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. 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. 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. 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. • 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. 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. 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. Complement and innate immunity
  • 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. • Thank you

×