Targeting the renin-angiotensin system in sepsis-associated AKI: from pathophysiology to precision medicine

Sepsis-associated acute kidney injury (SA-AKI) is a common and life-threatening complication of sepsis. Increasing evidence suggests that dysregulation of the renin-angiotensin-aldosterone system (RAAS) is involved in its pathogenesis, but the direction of this dysregulation is not uniform. In some patients and experimental settings, elevated renin and angiotensin I levels are accompanied by an inadequate rise in circulating angiotensin II (Ang II), suggesting impaired effective Ang II generation and relative Ang II deficiency. In other contexts, persistent or excessive local Ang II signaling may continue to promote vasoconstriction, inflammation, oxidative stress, and fibrosis. These differences likely reflect the heterogeneity of sepsis across disease stages, models, biological compartments, and measurement methods. Accordingly, RAAS-targeted therapy in SA-AKI should be interpreted within a context-dependent framework: exogenous Ang II may benefit selected patients with impaired effective Ang II generation, whereas ACE2/Ang-(1-7)/Mas-based or anti-angiotensin II type 1 receptor (AT1R) strategies may be more relevant in settings of maladaptive Ang II signaling. These observations support a biomarker- and endotype-guided approach to RAAS-targeted therapy in SA-AKI.