Complement activation in acute kidney injury a convergent mechanism

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Frontiers in Medicine Published May 23, 2026 Medically reviewed May 23, 2026 Study authors: Dan Yi, Rong Yang, Yue Guo, Hua Zhou, Junjun Luan DOI ↗ By Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

Key Takeaway

Complement activation is a contributory mechanism in AKI, supporting biomarker-guided precision therapy.

This review synthesizes current evidence on complement activation as a convergent mechanism in acute kidney injury (AKI). The authors propose an integrative framework that uses complement biomarkers to stratify patients and guide precision therapy, moving beyond associative findings toward mechanistic understanding.

The analysis highlights that complement activation likely contributes to injury across diverse AKI etiologies, though its relative role varies. This perspective helps clinicians identify patients who may benefit from targeted interventions, even as definitive causal links remain under investigation.

Limitations include the largely associative nature of current clinical evidence and the need for more robust, etiology-specific data. The review emphasizes that complement activation is a potential contributory factor rather than a universally causal driver in AKI.

Practice relevance lies in providing a structured approach for biomarker-guided stratification, which could improve patient selection for future trials and personalized treatment strategies in AKI care.

Study Details

Study typeSystematic review

EvidenceLevel 1

PublishedMay 2026

View Original Abstract ↓

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. Moreover, complement activation exhibits pronounced spatiotemporal heterogeneity, with its pathogenic effects shaped by the renal compartment, injury stage, and persistence of activation. This review summarizes the dynamic regulatory network of complement activation and its pathogenic mechanisms across diverse AKI etiologies, providing an integrative framework for biomarker-guided stratification and precision therapy in AKI.