M.Weitz has documented that he has no relevant financial relationships to disclose or conflict of interest to resolve.

M.Weitz has documented that he has no relevant financial relationships to disclose or conflict of interest to resolve.

Prophylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndrome Marcus Weitz Paediatric Nephrology Department Zurich

Clinical presentation of the patient 6-months old boy with vomiting and edema blood analysis: hemolytic anemia, thrombocytopenia, renal impairment no underlying coexisting disease no signs of infection Loirat et al., Pediatr Nephrol 2015 Suspected diagnosis: atypical hemolytic uremic syndrome (ahus)

Initial treatment of the patient frequent (> 18 sessions), high-volume (1.5 plasma volume) plasma exchange therapy (including fresh frozen plasma) Ariceta et al., Pediatr Nephrol 2009 end-stage renal failure within 2 months Johnson et al., Pediatr Nephrol 2014 Fremeaux-Bacchi et al, Clin J Am Soc Nephrol 2013

Diagnostics for ahus Factor H (FH) Mutation FH level (%) FH function C3 level (g/l) E1198stop (heterzygous) 132 (range: 69-154) Reduced 0.83 (range: 0.77-1.38) Stahl et al., Blood 2008 Negative genetic results for CFI MCP CFHR 1/2/3 Negative antibodies results for Anti-ADAMTS13 antibodies Anti-CFH-antibodies

Further clinical course Start of peritoneal dialysis (APD) at 8 months of age Ambiguous abdominal pain during peritoneal dialysis Start of hemodialysis at 4 years of age with central venous line Vascular access difficulties at 7 years of age Johnson et al., Pediatr Nephrol 2014

Last treatment option: Renal transplantation, but high recurrence rate of CFH-associated ahus after kidney transplantation unsatisfactory results of combined liver-kidney transplantation awareness of plasma exchange therapy resistance during infancy Le Quintrec et al., Am J Transplant 2013 Kavanagh et al., Semin Thromb Hemost 2010 Complement C5 inhibitor eculizumab: A promising solution?

When should we administer eculizumab? We decided to administer eculizumab prior to renal transplantation to prevent uncontrolled complement activation at renal transplantation Legendre et al., NEJM 2013 Loirat et al., Pediatr Nephrol 2015

Renal transplantation Successful renal transplantation without any medical or surgical complications Decision for deceased renal transplantation, because mother was heterozygous carrier of the same genetic mutation Zuber et al., Nat Rev Nephrol 2012 Kavanagh et al., Semin Nephrol 2013 father was not accepted (arterial hypertension, obesity, kidney stones)

What is the most useful monitoring strategy of eculizumab? Blood count Hemolysis parameter Complement factors Complement diagnostics C3/C4 CH50/APH50 C3d C5b-9 Weekly Biweekly

Part I: Monitoring strategy nowadays Checking complement blockade at day 7 after initiation of treatment no recommendation for checking complement blockade in the long-term except in clinical situation with potential complement activation Loirat et al., Pediatr Nephrol 2015

Part II: Monitoring strategy nowadays C5b-9 may be normal or elevated C3 may be normal or low C5a may be normal or elevated CH50 (target < 10%) eculizumab trough level (target > 100 mcg/ml) C5b-9 deposits on ADP-activated HME-cells 1 Noris et al., Blood 2014 Gilbert et al., Pediatr Nephrol 2013 Noris et al., CJASN 2010 Noris et al., Blood 2014 Loirat et al., Pediatr Nephrol 2015 Hillmen et al., Br J Haematol 2013 Legendre et al., NEJM 2013 Noris et al., Blood 2014

The patient 5 years after deceased renal transplantation maintenance of eculizumab infusion scheme European Medicines Agency Alexion Pharmaceuticals Inc. Soliris Renal transplant function egfr (Shwartz): 90 ml/min/1.73m 2 Proteinuria: 140 mg/g creatinine (with ACE-inhibitor therapy) Unremarkable clinical course since renal transplantation no episodes of (acute/chronic) rejection no episodes of complement-associated renal dysfunction renal biopsy: no signs of thrombotic microangiopathy Patient at age of 12 years (with friendly permission of the parents)

Thanks for your attention And to the Co-authors: O. Amon, D. Bassler, A. Koenigsrainer, S. Nadalin Zurich City of 2015 Zurich

C5b-9: Sensitive marker for eculizumab therapy monitoring? C5b-9 values (reference < 320 ng/ml) 6000 5000 4000 3000 2000 1000 0 First dose of eculizumab BK-Viremia Upper respiratory tract infection -24-17 -10 0 1 11 28 46 63 78 92 106119 134148162 Days