Novel insights to local complement activity in C3 glomerulopathy

C3 glomerulopathy is a chronic kidney disease cause by overactivation of the alternative pathway of complement, a branch of the innate immune system. The alternative pathway is the first line of defense against infection, triggering inflammation and clearance of infected/damaged cells; dysregulated activity can lead to inflammation and damage of kidney tissue as seen in C3 glomerulopathy. Specialized laboratory tests have been developed to identify drivers of uncontrolled alternative pathway activity in C3 glomerulopathy patients, however in many patients, a cause for disease is not found. Here we explore the relationship between three proteins a regulator of the alternative pathway termed Factor H and the two predicted activators of the alternative pathway termed Factor H-related 1 and Factor H-related 5 to test the hypothesis that improper balance between these proteins leads to complement activation and C3 glomerulopathy pathogenesis. These studies provide evidence that local complement dysregulation can occur in the kidney secondary to an imbalance between Factor H and Factor H-related proteins and that in the setting of chronic kidney disease, thresholds for complement activity are lowered. These findings inform our understanding of C3 glomerulopathy and chronic kidney disease and offer insight into potential therapeutics aimed at addressing localized complement dysregulation in the setting of C3 glomerulopathy.