Complement mediated renal disease. Tim Goodship Institute of Genetic Medicine Newcastle University

Complement mediated renal disease Tim Goodship Institute of Genetic Medicine Newcastle University

Evidence of complement activation is IgA and HSP Membranous Lupus nephritis ANCA associated Anti-GBM MPGN, C3 GN ahus found in

Normal Patient Haemolytic uraemic syndrome Microangiopathic hemolytic anaemia Thrombocytopenia Acute renal failure

Haemolytic uraemic syndrome Typical STEC HUS 90% - preceding EHEC infection Atypical HUS 10% - Sporadic 9% - Familial 1%

Newcastle family 2013

Exeter family

Belgian family 3 affected male siblings All successfully transplanted with no recurrence

ahus and linkage to the RCA cluster 1p RCA GENE CLUSTER Factor XIIIb Complement Factor H Factor H related proteins HUS 1q 1q 32 C4bp DAF CR2 CR1 MCP Warwicker et al, KI 1998

Classical Lectin Alternative Inflammation (C3a/C5a) C3b Lysis (C5b-C9) Opsonization (C3b/C4b)

Complement activation C3 B C3b Bb Cell membrane

Complement regulation Factor I C3 B Factor H C3b Bb MCP Cell membrane

Factor H functional domains 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Regulatory Recognition

c.351delg c.371-397 Pro258Leu Factor H mutations in ahus c.1494dela Pro621Thre Ser714stop Val835Leu Glu850Lys Gln950His Tyr951His Thr956Met Ile970Val Cys973Tyr Trp978Cys Val1060Ala Gln1076Glu Glu1172Stop Arg1182Ser c.3546_3581dup36 Trp1183Arg Trp1183Leu Trp1183Phe Trp1183Stop Thr1184Arg Leu1189Arg Leu1189Phe Ser1191Leu Ser1191Trp Gly1194Asp Val1197Ala Glu1198Ala Glu1198Lys Glu1198Stop Phe1199Ser Gly1204Glu Arg1210Cys Arg1215Gly Arg1215 Gln Thr1216 c.3674a>t, c.3675_3699 del Pro1226Ser c.3695_3696 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20.79-82delAGAA rg53cys rg78gly Glu189Stop Gln400Lys Cys536Arg Cys630Trp Cys673Tyr c.2303_2304dupa Ile881Leu Ser890Ile His893Arg c.2686-2700 Tyr899Stop Cys915Ser Gln925Stop Val1007Cys c.3032delg Tyr1021Phe Cys1043Arg Asp1119Gly Val1134Gly Tyr1142Asp Tyr1142Cys Trp1157Arg c.3486dela Cys1163Trp c.3493+1g>a

Inherited and acquired abnormalities of complement are found in up to 70% of ahus patients C3 (5%) C3 Factor B (1%) B Factor I (10%) CFHRs (5%) Factor H (30%) (1%) C3b Bb Thrombomodulin (5%) (10%) CD46 (10%)

Newcastle family 2013

The RCA (regulation of complement activation) gene cluster has arisen through a series of duplication events

Deletion of CFHR3 and CFHR1

~4% of the normal population have no factor related 1 or 3 protein Feifel et al, Immunogenetics 1992 kda 1 2 3 4 5 6 7 8 175 83 Factor H 62 47.5 32.5 Factor H related 1 kda 1 2 3 4 5 6 7 8 175 83 Factor H Factor H related 4 62 47.5 32.5 Factor H related 3 25

Deletion of CFHR3 and CFHR1

Genomic disorders affecting CFH/CFHRs - macrohomology CFHR3/1 AMD protective ahus predisposition to fh Ab if homozygous SLE predisposes IgA protective CFHR1/4 ahus predisposition to fh Ab CFH/CFHR1 hybrid ahus CFHR1/CFH hybrid ahus

Acquired defects Trigger Disease Rare genetic variants Common genetic variants

A patient from Belfast Female aged 22 - acute hepatic vein thrombosis (Budd Chiari syndrome). Admitted to liver unit Kings College Hospital London. No underlying abnormality on thrombophilia screen. Cadaver liver transplant successful with no major complications. Maintenance immunosuppression with tacrolimus

A patient from Belfast Age 25 Successful pregnancy but 3/52 post partum develops ahus. No recovery of renal function despite PE. C3 0.95 g/l (0.68-1.38) C4 0.41 g/l (0.18 0.6) Factor H 0.45 g/l (0.35 0.59) Factor I 64 mg/l (38 58) CD 46 expression normal Mutation screening of CFH, CFI, CD46, C3, CFB, THBD - negative Factor H and thrombomodulin autoantibodies - negative

A patient from Belfast What about the donor? 41 year old female intracranial haemorrhage FBC, CUE and LFTs all normal Urine output of 4.4 litres in the 24 hours No family history Mutation screening of the donor DNA showed a CFH mutation c.1107 G>A; p.trp369stop. Not previously described.

Additional susceptibility factors MCP GGAAC

Acquired defects Trigger Pregnancy Disease Rare genetic Variants CFH mutant Common genetic variants Homozygous CD46 GGAAC

Differential diagnosis of TMA STEC HUS TTP ahus Malignant hypertension Scleroderma APL antibody syndrome SLE HIV Malignancy Cobalamin C disease

Investigation of incident patients ADAMTS13 activity to exclude TTP Exclude STEC associated HUS C3, C4, factor H and factor I levels MCP (CD46) expression on PBMCs Mutation screening of CFH, CFI, CD46, CFB, C3 and THBD Identification of genomic disorders deletions and hybrid genes Factor H autoantibodies

Stool culture Diagnosis of EHEC associated HUS Serodiagnosis Detection of Stx Polyvalent IgG IgM Chart et al, J Med Microbiol 2002

Initial management Recommendations. All patients presenting with ahus should be offered a trial of plasma exchange and/or plasma infusions. (weak, low) Noris et al, CJASN 2010

Recurrence post transplant according to underlying gene Mutation Recurrence rate Loss of graft CFH 75-90% 60-90% CFI 45-80% 90% C3 40-70% 60% CFB 100% 100% CD46 <20% 30%

Recurrence post transplant in patients known to have a factor H mutation No Factor H mutations Factor H mutations Bresin et al, CJASN 2006

Sibling LRD

Developed HUS 3/12 later graft lost to recurrent HUS

Liver* and Liver/kidney Tx in ahus Age Reference 1 year survival 2 years Remuzzi, Lancet 2002 Alive 3 months* Cheong, Ped Nephrol 2004 Deceased 2 years Remuzzi, Am J Transplant 2005 Deceased 5 years Saland, Am J Transplant 2006 Alive 1 year Jalanko, Am J Transplant 2007 Alive 16 year Jalanko, Am J Transplant 2007 Alive 4 years Saland, CJASN 2009 Alive Adult Jalanko, Personal communication Alive Adult Sanchez-Corral, Br J Haematol 2010 Alive 4 years* Haller, Am J Transplant 2010 Alive 5 years Milner, Personal communication Alive 12 years Saland, Personal communication Deceased 8 years Saland, Personal communication Deceased Child Cohn, Personal communication Alive 64 years Wilson, Am J Kidney Dis 2011 Alive 1 year patient survival of 74% (88%) cf. primary hyperoxaluria 86% (Jamieson, Am J Nephrol 2005)

Gruppo RA, et al. N Engl J Med. 2009;360(5):544-6. Patient continues to do well at home (and school) on chronic eculizumab (34 months)

Cfh +/+ Normal Cfh -/- MPGN Cfh -/- FH 16-20 HUS Cfh -/-, C5 -/- FH 16-20 Normal

What is the prevalence/incidence of ahus in the UK? Data for all UK renal units At least 177 patients in the UK 139 England 23 Scotland 12 Wales 3 Northern Ireland 49 are under the age of 18 109 female and 68 male 9 patients undergoing plasma therapy 6 adults and 8 children on eculizumab 62 patients undergoing dialysis 9 are on the transplant list Prevalence of ~ 2.7/million but 5.5/million in North East 2009 and 2010 31 new patients : incidence of 0.25 (0.4)

A national ahus service for England Very rare diseases in England are managed through a National Specialised Service PNH is managed through such a service Application considered by the Advisory Group for National Specialised Services in June 2012 referred to NICE If successful Based in Newcastle Shared care service for both paediatric/adults Special investigations (genetics/autoantibodies) Eculizumab administered locally but paid for out of a central budget 24 hr on-call service for advice

ahus treatment in the future Incident patients -patient groups Prevalent patients on plasma therapy Prevalent patients on dialysis - transplant Prevalent patients with infrequent relapses Prevalent patients in remission Prevalent patients with a functioning transplant Unaffected carriers

Treatment of prevalent patients on dialysis- transplant with eculizumab Median follow up of 14.5 months Mean creatinine 72 µmol No recurrence Zuber et al, Am J Transplant 2012

Lessons from using eculizumab in PNH Meningococcal disease 0.5 events per 100 year 2 deaths with delay in diagnosis/therapy UK, all patients get antibiotics, throat swab Serology post tetravalent vaccine Eculizumab dosage measure levels <50mg/ml susceptible to breakthrough >100mg/ml blocked Pregnancy Does not cross the placenta Higher doses needed No neutralising antibodies detected

Drugs costing over $200,000/year Drug Indication Company Soliris (eculizumab) Elaprase (idursulfase) Naglazyme (galsulfase) Cinryze (C1 esterase inhibitor) Myozyme (alglucosidase) Arcalyst (rilonacept) Fabrazyme (agalsidase beta) Cerezyme (imiglucerase) Aldurazyme (laronidase) PNH and ahus Hunter syndrome Maroteaux Lamy syndrome Hereditary angiodema Pompe disease Cryopyrin-associated periodic syndromes Fabry disease Gaucher disease Hurler syndrome Alexion Shire BioMarin ViroPharma ViroPharma Regeneron Genzyme Genzyme Genzyme BioMarin

Justification for the cost of drugs such as eculizumab Very small number of patients with PNH and ahus Substantial investment in previous trials using pexelizumab and eculizumab 2142 patients in PRIMO-CABG 5100 patients in APEX-AMI 350 patients in rheumatoid arthritis trial $800m investment before approval for PNH $150m investment in manufacturing $200m investment in rare disease R&D

Unresolved issues What is the risk of recurrence if eculizumab is withdrawn? 18 patients have stopped therapy and the disease has relapsed in 5. What are the renal risks of long term therapy? Ongoing C3 deposition. Binding to C5 in renal tissues Herlitz et al, JASN 2012