Alternative pathway–mediated tubular complement activation in human proteinuric kidney diseases: a proof-of-concept study

ABSTRACT Background Proteinuria, irrespective of the primary disease, may cause progressive kidney injury by several mechanisms, including tubular complement activation. Experimental studies have shown that complement activation at the apical side of the tubules is via the alternative pathway, initiated by properdin binding to syndecan-1. However, it has not been systematically studied in human proteinuric kidney diseases. Methods Twenty-one kidney biopsies of different proteinuric kidney diseases were stained for complement components MASP-2 (lectin pathway), C1q (classical pathway), properdin (alternative pathway) and downstream complement activation (C3d and C5b-9), as well as syndecan-1. Complement deposition was scored semi-quantitatively. Plasma and urinary soluble C5b-9 were measured using enzyme-linked immunosorbent assays. Results All biopsies (21/21) showed apical proximal tubular C3d deposition, of which the majority showed an overlapping distribution with properdin (17/19) and to a lesser extent with C1q (10/19) or C5b-9 (14/21). MASP-2 barely overlapped with the other complement components. Only the intensity and percentage area of the tubular properdin deposition were correlated with that of C5b-9 (ρ = 0.50, P = .030 and ρ = 0.50, P = .029, respectively). Furthermore, properdin-positive tubules were highly positive for syndecan-1. Proteinuria levels were higher in patients with tubular C5b-9 deposition [7.21 (4.35–11.3) g/10 mmol vs 1.64 (0.56–5.29) g/10 mmol, P = .021] and correlated with tubular C5b-9-positive area (ρ = 0.50, P = .020). Similarly, patients with detectable urinary soluble C5b-9 also had higher proteinuria levels (P = .010). Conclusion Apical tubular complement activation in proteinuric patients is mainly via the alternative pathway, potentially initiated by properdin binding to syndecan-1. Inhibition of alternative pathway tubular complement activation may therefore be beneficial for patients with proteinuria.