Complement Inhibition with Eculizumab to Prevent Antibody Mediated Rejection (AbMR) in Patients with Donor Specific Anti-HLA Antibody (DSAb) and a Positive Cross Match

Abstract

Introduction: Patients with DSAb & a positive crossmatch risk early AbMR & graft loss. We evaluated the use of the C5 inhibitor eculizumab to prevent AbMR in patients with DSAb and a positive cross match. Methods: 5 patients with DSAb & positive crossmatch received pretransplant plasmapheresis (PP), & Eculizumab pre and post-transplant. Eculizumab was ceased if/when tissue typing and histology suggested significantly reduced DSAb and/or negative crossmatch & normal histology. Results: At a median of 27mths (range 15 to 31), patient and graft survival are 100% with stable renal function and no proteinuria. Eculizumab has been withdrawn in all patients. Patient # 1 had low level DSAb and this has remained so, while patient #3 showed rapid and near complete loss of DSAb. Patient #4 lost a previous graft to AbMR on day 8, & on this occasion developed severe AbMR (biopsy proven d 4) despite eculizumab. Pharmacokinetic & pharmacodynamic studies confirmed binding to & inhibition of C5. The patient received PP & Eculizumab. PP was weaned & ceased after 2months, with improving but persistent AbMR. The patient was maintained on infusions of IVIG and 3 months after IVIG was ceased, there was acute clinical and histological exacerbation of AbMR. C4d staining was absent throughout. Patient #2 maintained stable graft function, with no AbMR or transplant glomerulopathy despite high DSAb (MFI > 10 000) for > 6 mths; C4d staining was strongly +ve suggesting complement activation proximal to C5. Beyond 6months post transplant, the DSAb level has dropped progressively (from MFI > 10000, to under 3000) with corresponding changes in flow cross matching. Patient #5 maintained stable graft function, with no AbMR or transplant glomerulopathy despite DSAb (MFI > 10 000) persisting for more than a month; C4d staining was +ve suggesting complement activation proximal to C5. DSAb level has dropped progressively with corresponding changes in flow cross matching.Table: [Outcomes of DSAb +ve Patients Receiving Eculizumab]Conclusion: Eculizumab (i) may enable transplantation in some patients with DSAb & a positive crossmatch without post transplant plasma exchange(ii) can prevent AbMR despite binding of DSAb to graft & complement activation (C4d staining, normal histology) (iii) AbMR can occur despite inhibition of C5, suggesting damage mediated by proximal complement factors (C3a, C5a) or direct activation by antibody. Further studies are necessary to determine pathways involved in AbMR, & the role of Eculizumab in prevention and management of AbMR.