Plasma C4d levels correlate with treatment response and renal activity in proliferative lupus nephritis

Objective Investigation of complement factors in lupus nephritis (LN) in relation to treatment response and the impact of underlying genetics of C4. Methods Seventy-seven patients with active LN confirmed by a kidney biopsy and in whom second biopsies had been performed after immunosuppressive treatment were included. Complement factors C3, C4, C4d and C4d/C4 ratio were evaluated at the biopsy time-points. The gene copy number variations of C4 (C4A and C4B) were also investigated. Results At baseline, 60 patients had class III/IV±V, proliferative LN (PLN) and 17 class V, membranous LN (MLN). Levels of C3 and C4 increased and C4d and C4d/C4 decreased after treatment (p< 0.0001), observed in treatment-responding PLN patients but not in MLN. C4d, C4 and C4d/C4 at second biopsies were associated with clinical response in PLN, and low C4d levels were found in PLN with histopathological response (p= 0.008). Renal activity index at second biopsies correlated to C4d and C4d/C4, but not to C3 or C4. C4 gene copy number variations were not associated with clinical or histopathological response. Conclusion All complement markers were affected by immunosuppressive therapy and associated with response to therapy. Levels of C4d and C4d/C4 at follow-up biopsies showed a strong association with both clinical and histopathological response in PLN. The correlation with elevated C4d and C4d/C4 and persisting high activity index on repeated biopsies strengthens the findings on C4d as a promising biomarker for treatment response in PLN. The C4 genetic variations did not influence C4 levels or response to treatment.