Safety and Long-Term Efficacy of Eculizumab in a Renal Transplant Patient with Recurrent Atypical Hemolytic–Uremic Syndrome (2009)

To the Editor: Atypical HUS develops as the result of unregulated complement progression and has been shown to cause microangiopathic hemolytic anemia. Plasmapheresis is currently used in an attempt to control the progression of the complement cascade, but this therapy is cumbersome and not effective in all patients. Eculizumab, a monoclonal antibody that targets complement factor C5, blocks activation of the terminal complement cascade and the generation of the proinflammatory and prothrombotic molecules C5a and C5b-9. Eculizumab has been approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) (1Hillmen P Hall C Marsh JCW et al.Effect of Eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria.N Engl J Med. 2004; 350: 552-559Crossref PubMed Scopus (490) Google Scholar). In a recent study, a single dose of 600 mg of eculizumab appeared to resolve hemolysis and thrombocytopenia, and led to recovery of renal function in a transplant patient during an episode of aHUS (2Nürnberger J Witzke O Opazo Saez A et al.Eculizumab for atypical hemolytic–uremic syndrome.N Engl J Med. 2009; 360: 542-544Crossref PubMed Scopus (306) Google Scholar). We report here on the efficacy of eculizumab in a patient who presented a recurrence of atypical hemolytic syndrome 3 years after renal transplantation. The patient is a previously described 42-year woman with familial aHUS and a heterozygous gain of function mutation (R570Q) in the C3 gene (3Frémeaux-Bacchi V Miller EC Liszewski MK et al.Mutations in complement C3 predispose to development of atypical haemolytic uremic syndrome.Blood. 2008; 112: 4948-4952Crossref PubMed Scopus (327) Google Scholar). She developed end-stage renal disease at age 30. Kidney transplantation was performed at age 34, and aHUS recurred 5 months later, leading to the loss of the graft after 2 years. She received a second transplantation with a recurrence of aHUS 3 years later, but recovered renal graft function under intensive plasma exchanges over 9 months (47 plasmaphereses). Four months later, the patient presented with septicemia and acute renal failure. Her haptoglobin became undetectable (<0.15 g/L), and schistocytes increased to 3.7% suggesting an acute thrombotic microangiopathic (TMA) exacerbation, which was confirmed by renal biopsy. The administration of plasma exchanges (19 treatments over 5 weeks) resulted in an improvement in the ongoing TMA. However, the patient continued to suffer from severe fatigue and daily episodes of diarrhea and chose to discontinue plasmapheresis because of its perceived negative impact on her quality of life. Eculizumab was proposed as an alternative therapy, the patient being fully informed of the lack of both registered clinical trials and evidence concerning its efficacy in aHUS patient. The recommended ‘meningococcal polysaccharide, diphtheria toxoid conjugate vaccine’ and patient consent form were provided before initiating eculizumab. Treatment with eculizumab was initiated 4 days after the final plasmapheresis. Based upon the dose regimen determined for PNH, the patient received four doses of eculizumab, 900 mg IV every 7 days, followed by a maintenance dose of 1200 mg every 14 days. Schistocyte count, hemolysis and renal function were monitored. After 7 months of eculizumab treatment, and without concomitant plasmapheresis, schistocytes decreased to 0.5%, haptoglobin increased to within normal limits, creatinine levels stabilized and no further episodes of diarrhea were reported. The need for blood transfusions was significantly reduced and they were stopped 4 months after continued eculizumab treatment. Interestingly, the ninth infusion of eculizumab was delayed by 6 days due to an episode of chest pain. This delay was temporarily associated with a return of hemolysis, deterioration of transplant function and the need for a final transfusion (Figure 1). We hypothesize that complement breakthrough due to a lapse in eculizumab dosing resulted in the return of TMA. In view of the stabilization of her aHUS, one may argue that eculizumab should be considered as permanent treatment for this particular patient. In summary, these data suggest that chronic blockade of complement C5 with eculizumab in a patient with aHUS previously dependent on frequent plasmapheresis is safe, and leads to maintained renal function, reduced need for blood transfusions and control of TMA and hemolysis in the absence of plasmapheresis. It is obvious that a study aimed to confirm the efficacy of eculizumab in aHUS is needed. Valérie Chatelet, Véronique Frémeaux-Bacchi, Thierry Lobbedez, Maxence Ficheux and Bruno Hurault de Ligny declare no competing financial interests with Alexion Pharmaceuticals. Eculizumab was provided by Alexion Pharmaceuticals on an individual patient compassionate basis.