Establishing a Case for Anti-Complement Therapy in Membranous Nephropathy

Abstract. Background Membranous nephropathy (MN) is a common cause of adult nephrotic syndrome that progresses to end stage kidney disease in up to 40% of cases. It is an autoimmune disease characterized by glomerular sub-epithelial deposits containing IgG. In experimental MN these deposits activate complement and cause kidney damage. The role of complement in human MN is less clearly defined. To address this, the current study focused on the role of complement in two independent primary (p) MN cohorts. Methods Glomeruli were isolated by laser capture microdissection and analyzed by mass spectrometry, focusing on complement proteins, from kidney biopsies from a pMN cohort (n=11) and from normal controls (n=5). Immunohistological staining of kidney biopsies for complement proteins was also done. In a second pMN cohort (n=13), urine levels of Ba, C5a and C5b-9 (membrane attack complex, MAC) were measured. Results Mass spectrometry identified eight complement pathway components (C1q, C3, C4, C5, C6, C7, C8, and C9) and five complement regulators (complement receptor type 1 [CR1], factor H [FH], FH-related protein 2 [FHR2], vitronectin and clusterin). All complement levels were significantly higher in the MN groups than control, except the level of CR1, which was lower. All pMN biopsies showed negative or trace staining for C1q, positive staining for C3 and C4, and positive staining for at least one component of the lectin pathway. Urine Ba, C5a and MAC were present in pMN, and their levels correlated (rBa,C5a=0.87, rBa,MAC=0.89 and rC5a,MAC=0.97, p=0.001 for each correlation). Conclusion Elevated glomerular levels of C3, C4 and components of MAC (C5b-9) and absent or decreased levels of the complement regulator CR1, along with increased levels of complement activation products in the urine, support the involvement of complement in the pathogenesis of MN. These data raise the possibility that anti-complement therapies may be effective in some forms of MN.