Complement in acute kidney injury: a convergent pathogenic pathway in multifactorial renal damage

Acute kidney injury (AKI) is a common clinical syndrome characterized by substantial etiologic heterogeneity, whose pathophysiology encompasses inflammatory amplification, microcirculatory dysfunction, tubular injury, and maladaptive repair. Evidence from preclinical models and clinical samples indicates that dysregulated complement activation represents a potential convergent mechanism of injury in multiple forms of AKI, although its relative contribution varies across etiologies.

Experimental models support mechanistic and pathogenic roles for complement activation, whereas clinical evidence in many AKI settings remains largely associative, suggesting a contributory rather than universally causal role. Diverse insults, including ischemia-reperfusion injury, nephrotoxins, and sepsis, can initiate complement activation, which converges on C3 and C5, fueling inflammatory escalation and tissue injury.

In addition to cytotoxicity mediated by the terminal pathway, the complement system participates in the initiation, progression, and outcome of injury by orchestrating endothelial activation, leukocyte recruitment, tubular epithelial stress, and innate immune amplification. Concurrently, dysregulation of complement regulatory proteins, persistent activation of the C5a/C5aR axis, and crosstalk with Toll-like receptor signaling and neutrophil extracellular trap (NET) formation further amplify the damaging effects, thereby exacerbating AKI progression.