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Eculizumab and Intravenous Immunoglobulins for the Treatment of Acute Antibody-Mediated Rejection after Lung and Liver Transplantation

Introduction Acute antibody-mediated rejection (aAMR) management remains challenging. We report 2 cases of aAMR treated with a single dose of eculizumab (ECZ) 600 mg, followed by 3 weekly high-dose intravenous immunoglobulins (IVIG) 2 g/kg (“ECZ-IVIG”), in a lung and a liver recipients. One single dose of rituximab (RTX) was administered to the lung recipient, however the liver recipient refused it. Case 1 A 48-year-old female received a bilateral lung transplantation (Tx) because of lymphangioleiomyomatosis. A preformed class II (anti-DR17 mean fluorescence intensity [MFI] 1783) donor-specific antibody (DSA) was detectable prior to Tx, but flow cytometry T and B crossmatches were negative. The patient developed rapidly progressive dyspnea and hypoxemia at post-operative day (POD) 7, with new pulmonary infiltrates. A repeat Luminex® assay on POD9 revealed class I (anti-A24 MFI 3978, anti-B8 MFI 1886) and class II (anti-DR17 MFI 19088, anti-DQ2 MFI 3440) DSA, along with de novo positive flow cytometry crossmatches. Lung biopsy showed C4d deposits in the pulmonary capillaries but without acute cellular rejection. The ECZ-IVIG treatment was administered, followed by one infusion of RTX 375 mg/m2 at POD28. Hypoxemia strikingly improved after ECZ administration and oxygenotherapy could be stopped at POD14. DSA progressively decreased (MFI<2000 by POD41) and remained at low-titers thereafter. The patient is well more than 3 years post-Tx. Case 2 A 52-year-old female, who had received 4 years earlier a liver Tx for toxic acute liver failure, stopped her immunosuppression without medical advice. One month later, abnormal liver function tests (AST 236 U/l, ALT 286 U/l, alkaline phosphatase 420 U/l, &ggr;-GT 310 U/l, total bilirubin 85 &mgr;mol/l), along with high-titers de novo DSA (anti-DQ2 MFI 19576 and anti-DR7 MFI 2368), were detected. Liver biopsy showed severe acute rejection (rejection activity index 7/9) with diffuse endothelitis, destructive ductulitis (ductopenia <50%) and moderate fibrosis (F2), without endothelial C4d deposits. The ECZ-IVIG treatment was administered, along with 500 mg/d iv methylprednisolone for 4 days, with a progressive normalization of liver function tests and decrease in DSA titers. A liver biopsy one month after this combined treatment showed disappearance of the acute rejection and stabilization of the biliary lesions and ductopenia. Discussion ECZ administration was associated in both cases with a rapid improvement in lung and liver allograft function, likely highlighting the humoral mechanistic process of rejection involving DSA and complement activation. Because ECZ does not suppress DSA production, ECZ was followed by IVIG administration. No thymoglobulin treatment was necessary. Conclusion The ECZ-IVIG treatment was safe and associated with clinical, immunological and histological improvement in both recipients diagnosed with aAMR. This regimen should be further prospectively studied in the setting of aAMR after lung and liver Tx.