Successful treatment of acute thrombotic microangiopathy by eculizumab after combined lung and kidney transplantation.

Thrombotic microangiopathy (TMA) can be frequently observed after lung transplantation with various causes, for example, calcineurin inhibitor (CNI) toxicity or infectious disease (1). Atypical hemolytic-uremic syndrome (aHUS) is a disease related to unregulated complement progression also associated with TMA lesions (2). Plasma exchange or infusion was used to control the progression of the disease, but this therapy is invasive and not effective in all patients. The treatment and the prognosis of aHUS and its recurrence on the renal graft have been modified by the use of eculizumab, a monoclonal antibody that targets complement factor C5 and blocks the activation of the terminal complement cascade. This humanized monoclonal antibody used for the treatment of paroxysmal nocturnal hemoglobinuria has been recently approved for the treatment of aHUS or its recurrence (3, 4). We report here on the efficacy of eculizumab in a combined lung and kidney transplant recipient who presented TMA in the initial period after transplantation. The patient was a 45-yearfemale who developed end-stage lung disease because of pulmonary fibrosis related to sarcoidosis. She presented an end-stage renal disease (ESRD) with TMA lesion on the renal biopsies of her native kidney performed in 1998 and 2006. The initial nephropathy was considered to be aHUS. However, screening for regulatory factors of the complement system mutations or antibodies against complement factor H was negative. Hemodialysis therapy was initiated in 2008 and she was enlisted for a combined lung and kidney transplantation in 2010. She received a lung and kidney transplant from a deceased donor aged 22. She was not sensitized. Initial immunosuppressive regimen associated polyclonal antithymocyte antibodies, cyclosporine, mycophenolate mofetil, and steroids. The evolution of the lung transplant was uneventful. The initial evolution of kidney transplant was excellent with a serum creatinine at 72 Kmol/L on day 5. From day 3, the platelet count falls to reach 22,000/mm, the hemoglobin was 11.4 g/dL, the lactate dehydrogenase level was 857 UI/mL, haptoglobin was decreased to 0.07 g/L, and the creatinine was 91 Kmol/L. The suspected etiologies of this TMA were either a recurrence of aHUS or acute CNI toxicity, although the cyclosporine through levels were within target (145 ng/mL). The renal evolution was unfavorable leading to the initiation of dialysis at performed with no improvement of renal function or platelet count. Eculizumab therapy was started consisting in 900 mg on day 15 and weekly thereafter until day 36. She had received prior meningococcal vaccine and antibioprophylaxis by oracillin maintained during the whole period of treatment. Hemolysis resolved, haptoglobin, and platelet count increased to normal limits and progressively renal graft recovered function leading to dialysis interruption. A renal biopsy was performed on day 20. It revealed no TMA lesion but acute tubular necrosis compatible with CNI toxicity. Histologically, we cannot definitely discriminate between aHUS recurrence and CNI toxicity. The ESRD occurred frequently after transplantation because of CNI nephrotoxicity. On native kidney biopsies in lung transplant recipients, CNI nephrotoxicity is present in 93.3% associated with TMA in 46.7% (1). We know that genetic polymorphisms of complement increased susceptibility to CNI toxicity (5). In our case, we postulate that CNI toxicity could induce an inappropriate regulation of the alternative complement pathway and so an aHUS recurrence. Our observation suggests the positive effect of eculizumab when ESRD occurs after transplantation secondary to CNI toxicity. In this context, eculizumab may be an interesting therapeutic option. FIGURE 1. Treatment effects on posttransplantation TMA: platelet count and haptoglobin evolution with treatment. LETTERS TO THE EDITOR