1. Complement and Haemolytic Uraemic Syndrome – ESPN 2008
Dr Heather Maxwell
Renal Unit
RHSC, Glasgow

2. Haemolytic Uraemic Syndrome
Most common cause of acute renal failure in children in UK
High incidence in Scotland
Mostly D+HUS, usually E. Coli O157
Very occasional patients with D-HUS or atypical HUS
More known about atypical HUS
Implications for treatment

3. Atypical HUS Infections other than diarrhoeal illnesses Drugs
Pneumococcal HUS
HIV, Influenza A
Drugs
Pregnancy
Familial
Complement Abnormalities
ADAMTS13 Deficiency
Disordered Cobalamin Metabolism

4. Atypical HUS
Uncommon
Up to 50% or more may have mutations in genes of complement components and regulators
Poor prognosis
Treatment options depending on the mutation
Early intervention crucial
Implications for recurrence post transplantation
Up to 40% may present with diarrhoea

5. Complement Pathways C3 Classical Alternative Lectin
Immune Complexes
Alternative
Continually activated to produce C3b
Binds to pathogens and host cells
Lectin
Micro organisms C3
Factor B
C3b C3bBb Complement Cascade
Pathogen
Complement Regulatory Proteins
Factor H
Factor I
MCP
Host cell
iC3b

6. Complement Abnormalities in HUS
Factor H
MCP
Factor I C3
Factor B
Endothelial cell damage
Platelet aggregation
Thrombus formation

7. French aHUS Registry Data (n=90)
Complement Abnormality
Frequency
Factor H
19%
Most severe
60% ESRF or death within 1 year
MCP
14%
Often have a relapsing course but with time 30% go into ESRF
Factor I 9%
50-70% ESRF at 5 years C3 7%
Factor B 1%
Rare
Factor H Antibodies
11%
Combined Mutations 8%
None
39%
30% ESRF by 5 years

8. Factor H Most important regulator of the alternative pathway
Synthesized by the liver
Circulating glycoprotein 150kDa
Binds to cell surface
Prevents C3 convertase formation and accelerates C3b decay
Co-factor for Factor I
Gene on chromosome 1
Gene - multiple short consensus repeats (SCR)

9. Factor H Mutations First reported 1981 Abnormal Factor H
Deficiency of Factor H
Majority heterozygous
C3 either normal or low
>100 mutations reported
Mutations vary between countries
50% familial penetrance
Factor H autoantibodies
Clinical Course
Reported in 19-24% aHUS
Early onset 3/12 to 1 year
60% died or had ESRF within 1 year
+/- family history
Treatment
Homozygous – plasma infusions
Heterozygous – Plasma Ex + FFP
Recombinant Factor H
Kidney +/- liver transplant
Complement Inhibitors

10. Factor H Mutation

11. Membrane Co-Factor Protein (CD46)
Widely expressed transmembrane glycoprotein
Cofactor for the cleavage of C3b by Factor I
>20 mutations have been described
80% result in a reduction in MCP expression
Results in inadequate control of complement activation on endothelial cells
MCP mutations can co-exist with other complement mutations
Less likely to develop ESRF than FH mutations

12. MCP Clinical Course Treatment Older age of onset ~ 4years
Severe haemolytic anaemia and thrombocytopenia
Tend to have a relapsing course with recovery
With time 30% will go into ESRF
May predispose to severe D+HUS
Treatment
Theoretically should not respond to P Ex as protein is cell bound
Less likely to develop ESRF
Should not recur in grafts, but MCP can co-exist with other mutations

13. Factor I Is an enzyme – 2 chain serine protease Gene on chromosome 4
Soluble regulator of C3b requiring the co-factors FH and MCP
< 20 mutations described
Usually quantitative deficiency of Factor I
Clinical Course
Young age of onset (median 2 months)
Few reports of details of treatment
88% recurrence risk post transplantation

14. Complement Pathways C3 Classical Alternative Lectin
Immune Complexes
Alternative
Continually activated to produce C3b
Binds to pathogens and host cells
Lectin
Micro organisms C3
Factor B
C3b C3bBb Complement Cascade
Pathogen
Complement Regulatory Proteins
Factor H
Factor I
MCP
Host cell
iC3b

15. Atypical HUS Factor B Mutations Rare (0-3%)
Gain of function mutation described
Increases the stability of C3bBb convertase
Low C3
Children are immunodeficient
Factor B levels normal
C3 Mutations
Low C3 levels
Few reports regarding clinical course, treatment or prognosis

16. Atypical HUS Anti Factor H Antibodies 6-11% in registry data
Presents between 3 and 14 years of age
C3 slightly low
Factor H levels normal
Homozygous gene deletions
Treatment
Plasma exchange
Immunosuppression (steroids and rituximab have been tried)
No Complement Mutations
Detected
Age range 25 days to 15 years
32% in ESRF at 1 and 5 years
Some have a relapsing course

17. Treatment Plasma infusions Plasma exchange with FFP (within 24hours)
Renal transplantation
High incidence of recurrence
High incidence of thrombosis
Combined liver-kidney transplant
Future Treatments
Factor H concentrate
Inhibitors of complement (Anti C5 antibody)

18. Renal Outcome Mutation ESRF 1 year ESRF 5 years Recurrence Post Tx
Graft loss within 1 Year
Factor H
60%
73%
76%
81%
MCP 0%
38%
20%
1 of 2
Factor I
50%
88%
100%
No Mutation
32%
30%
83% - not recurrence

19. Atypical HUS Who is atypical? No proceeding diarrhoea
Non-bloody diarrhoea
Known family history of HUS
Children under 3 months old
Relapsing course
High index of suspicion / absence of typical features
Evidence of VTEC
Refer early

20. Investigation Atypical HUS
Quantitative +/- Qualitative
Activity C3 C4
Factor H
Factor I
Factor B
Membrane expression of MCP
Factor H Antibodies
Genetic testing
Factor H
Factor I
MCP
Non-Complement Testing
ADAMTS 13
Cobalamine metabolism
Homocysteine
Methylmalonic acid
Streptococcal infection