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

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

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

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

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

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

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

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)

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

Factor H Mutation

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

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

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

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

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

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

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)

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

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

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