Complement blockade: Therapeutic promises and remaining challenges in clinical practice

Understanding of the complement system in glomerulopathies has advanced significantly, revealing that this system-beyond its role in innate immunity-is a key mediator of kidney injury across a wide spectrum of nephropathies, from those driven by immune complexes to those caused by primary dysregulation of the alternative pathway. The introduction of complement inhibitors, such as C5 blockade with eculizumab, marked a milestone: in aHUS it significantly improved renal function and patient survival, and in paroxysmal nocturnal hemoglobinuria it reduced thrombotic complications, achieving survival rates comparable to the general population. These advances have spurred the extension of this approach to other nephropathies and the development of new anti-complement agents. However, the heterogeneity of complement dysregulation among glomerulopathies-and even among patients with the same disease-limits the application of a uniform therapeutic strategy. This scenario calls for a more precise characterization of the underlying pathophysiological mechanisms and the identification of critical points of intervention in each clinical context. Currently, inhibitors targeting both proximal and terminal steps of the cascade are being investigated to achieve more individualized therapies, although challenges remain, such as the lack of reliable biomarkers, uncertainty regarding optimal treatment duration, scarcity of disease-specific trials, high costs, and the integration of these agents with immunosuppressive regimens. The aim of this review is to analyze the role of the complement system in glomerulopathies and to summarize current and future therapeutic advances, with particular emphasis on the challenges and opportunities on the path toward more personalized medicine.