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

Abstract

IntroductionC3 Glomerulopathy (C3G) is an ultra-rare renal disease characterized by deposition of complement component C3 in the glomerular basement membrane. 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.MethodsHere we present a retrospective analysis of the Molecular Otolaryngology and Renal Research Laboratories C3G cohort. This study integrated complement biomarker testing and in vitro tests of autoantibody function to achieve three primary goals: 1) define disease profiles of C3G based on disease drivers, complement biomarkers and age; 2) determine the relationship between in vitro autoantibody tests and in vivo complement dysregulation; and 3) evaluate the association between autoantibody function and disease progression.ResultsThe 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 in vitro modified hemolytic assays and systemic biomarkers that reflect in vivo complement dysregulation was remarkably strong. In patients positive for autoantibodies, the degree of stabilization capacity predicted worse renal function.ConclusionThis study implicates complement autoantibodies as robust drivers of systemic complement dysregulation in ∼50% of C3G but also highlights the need for continued discovery-based research to identify novel drivers of disease.

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