Defining Nephritic Factors as Diverse Drivers of Systemic Complement Dysregulation in C3 Glomerulopathy

Abstract

C3 glomerulopathy (C3G) is an ultrarare renal disease characterized by deposition of complement component C3 in the glomerular basement membrane (GBM). Rare and novel genetic variation in complement genes and autoantibodies to complement proteins are commonly identified in the C3G population and thought to drive the underlying complement dysregulation that results in renal damage. However, disease heterogeneity and rarity make accurately defining characteristics of the C3G population difficult. Here, we present a retrospective analysis of the Molecular Otolaryngology and Renal Research Laboratories C3G cohort. This study integrated complement biomarker testing and invitro tests of autoantibody function to achieve the following 3 primary goals: (i) define disease profiles of C3G based on disease drivers, complement biomarkers, and age; (ii) determine the relationship between invitro autoantibody tests and invivo complement dysregulation; and (iii) evaluate the association between autoantibody function and disease progression. The largest disease profiles of C3G included patients with autoantibodies to complement proteins (48%) and patients for whom no genetic and/or acquired drivers of disease could be identified (43%). The correlation between the stabilization of convertases by complement autoantibodies as measured by invitro modified hemolytic assays and systemic biomarkers that reflect invivo complement dysregulation was remarkably strong. In patients positive for autoantibodies, the degree of stabilization capacity predicted worse renal function. This study implicates complement autoantibodies as robust drivers of systemic complement dysregulation in approximately 50% of C3G but also highlights the need for continued discovery-based research to identify novel drivers of disease.