A Narrative Review of C3 Glomerulopathy: From Pathogenesis to Targeted Therapy

Abstract

Purpose of the review: Complement factor 3 (C3) glomerulopathy (C3G) is an ultra-rare, progressive, complement-mediated kidney disease. Despite many advances in the understanding of its underlying pathophysiology, C3G remains a clinical challenge due to the overall burden of disease, diagnostic complexity, poor prognosis, lack of approved therapies, and limited access to drugs for kidney diseases in Canada. This narrative review explores the diagnosis and management of individuals with C3G, including novel complement-mediated therapies and their potential impact on patients and outcomes. Sources of information: This narrative review is based on the best available data, current treatment guidelines, and the authors’ clinical experiences. Information for the patient perspective section was collected through discussions with two individuals with C3G. Methods: A panel of Canadian nephrologists who actively care for individuals with C3G was assembled. A rare disease advocate and two individuals with C3G were invited to share their lived experiences. The authors conducted a comprehensive review of the literature to explore the state of the science and future directions in C3G, highlighting current limitations and unmet needs. Key findings: C3 glomerulopathy is caused by dysregulation of the alternative complement pathway, leading to the deposition of complement proteins and their cleavage products in kidney glomeruli. The consequence of deposition of C3 is glomerular inflammation and tissue damage, which lead to proliferative glomerulonephritis and remodeling of the glomerular capillary walls. Individuals diagnosed with C3G experience significant symptoms that adversely impact their quality of life. Nearly half of patients develop kidney failure within 10 years of diagnosis. C3 glomerulopathy recurrence after kidney transplant occurs in more than half of patients. Severity of proteinuria and reduced estimated glomerular filtration rate (eGFR) are among the most important clinical predictors of kidney failure with further research required for the utility of biomarkers to guide prognosis. There is no established standard of care and no therapies specifically approved for individuals with C3G in Canada. Complement-directed therapies, iptacopan and pegcetacoplan, have demonstrated significant reductions in proteinuria and stabilization in kidney function, offering hope for individuals with C3G, including post-transplant. This review offers an up-to-date synthesis of current knowledge on C3G for Canadian nephrologists at a juncture where targeted therapies are becoming available. Limitations: A systematic review of the literature was not undertaken. Key takeaways are based on currently available evidence, of which head-to-head clinical trials are lacking. The possibility for bias based on the authors’ clinical experiences may have occurred.