#2890 Role of alternative pathway of complement system in membranous nephropathy: a study from STARMEN clinical trials

Abstract

Abstract Background and Aims Membranous nephropathy (MN) is an antibody-mediated autoimmune disease characterized by glomerular immune complexes containing complement components. A recent animal model of PLA2r antibody-induced MN induced has demonstrated the crucial role of complement pathway, although is still unclear which complement pathway is most involved in its pathogenesis This study aimed to explore the role of alternative pathway of complement cascade in a cohort of patients from STARMEN clinical trial. Method We analyzed longitudinal plasma samples from 51 patients from STARMENT cohort stored in a biobank. Samples were stored at enrollment and longitudinally throughout the follow up at 3, 6, 9, 12, 18 and 24 months. We measured the circulating plasma levels of C3, FB, FH, FHR1, FHR2 and FHR5 in every time. Results Fifty-two patients with a mean age of 56 ± 10 years and 60% male were included. 44% were treated with tacrolimus+Rituximab and 56% with ponticelli regimen. The basal creatinine was 0.9 ± 0.3 mg/dl, median proteinuria/day was 8.8 g/day (IQR 5.7-11.6 gr/day) and serum albumin of 2.6 g/dl (IQR 2.3-2.9 g/dl). All patients were followed-up for two years. Thirty-four patients achieved complete remission (CR), 11 patients partial remission (PR) and 15 did not respond (including relapse). During active disease, the mean concentration of FH, FHR-1 and FHR-2 were significantly increased compared with remission status (complete or partial). We did not find different in other factors: FB or FHR-5. Moreover, a positive correlation was observed between FH and FB with C3. There were no differences according to treatment arm. PLA2r antibodies tested positive in 68%. The median of baseline anti-PLA2R title levels was 80 RU/ml (IQR 43-141). Circulating plasma levels of FHR1 at baseline were significantly higher in PLA2r testing negative vs positive patients (199 ± 108 vs 249 ± 41 µg/ml, p = 0.021). This significant difference was present when remission was achieved (205 ± 97 vs 264 ± 49 µg/ml, p = 0.023). Similar tendency was observed for FB. Conclusion These data provide evidence of complement system activation through the alternative pathway in membranous nephropathy. We know that different subtypes of IgG are behind the different antibodies-induced MN induced, and that every subtype active different complement pathway. The results of this study lead to speculate that not all the antigens that induced MN active complement pathway in the same way.