#1940 Plasma complement activation profile in kidney transplant recipients with IgAN supports the importance of the complement alternative pathway in IgAN

Abstract Background and Aims The alternative complement and lectin pathways are key players in IgA nephropathy (IgAN). However, the precise dynamics of complement activation in IgAN remain poorly understood. Non-invasive complement biomarkers are urgently needed in view of the evolving landscape of complement-targeting therapies under evaluation in IgAN. Method We analyzed plasma complement activation biomarkers in a cohort of 87 kidney transplant recipients (KTR) with IgAN and 30 controls consisting of autosomal dominant polycystic kidney disease (ADPKD) KTR (NCT05234463, DC-2013-1990). Patients were excluded if 1) they had a biological inflammatory syndrome at the time of sampling or 2) they had experienced a cellular/humoral rejection in the year prior to or after sampling. We simultaneously measured a large panel of complement activation and regulation fragments (C3a, C5a, C4a, sC5b-9, Ba, Bb) and intact proteins (C3, C4, FI, FH, properdin) in plasma using multiplex ELISA (Quidel Ortho®, A900), nephelometry and in-house ELISA. Results There was no consumption of C3 and C4 proteins in IgAN patients. However, C3a and Bb concentrations were elevated in IgAN patients compared to ADPKD patients (161 [98-227] vs. 102 [66-172] ng/mL, p = 0.007; 3.0 [2.6-4.0] vs. 2.5 [2.0-2.8] µg/mL, p < 0.0001). Overall, 70/87 IgAN patients (80.5%) had elevated Bb levels. The plasma concentration of C5a was elevated in IgAN patients compared to ADPKD patients (6.3 [3.8-9.2] vs. 4.9 [2.8-6.3] ng/mL, p = 0.0274), with values within the reference range in 92.0% of IgAN patients. There was no difference in plasma levels of sC5b-9 between the two groups (p = 0.186). The combined analysis of C3a, C5a and sC5b-9 allowed us to distinguish 4 clusters of patients (Fig. 1). A total of 48 patients (55.2%) show evidence of C3 convertase activity in plasma (clusters 3 and 4), including 16 patients (18.4%) with the highest plasma concentrations of sC5b-9, C3a and Bb. In contrast, 15 patients (17.2%, cluster 1) have no (or very low) complement activation. The last group (n = 32, 36.8%, cluster 2) shows an isolated increase in sC5b-9 without evidence of plasma C3 convertase activity. Proteinuria was significantly increased in groups 3 and 4, which had the highest C3a concentrations, compared to groups 1 and 2 (p = 0.0051). Conclusion This study provides insights into the mechanisms of complement activation in IgAN, with a pivotal role for the activity and regulation of the alternative C3 pathway convertase. In addition, the combined analysis of complement biomarkers identified, for the first time, clusters of patients who may benefit from complement targeting therapies.