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

Figures

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  Figure 1. Pathophysiological context of RAAS dysregulation in SA-AKI. SA-AKI is driven by interconnected microcirculatory dysfunction, inflammatory injury, metabolic stress, and inter-organ crosstalk. Endothelial activation, glycocalyx shedding, capillary flow disturbances, pericyte dysfunction, and microthrombus formation impair renal perfusion and oxygen utilization, while inflammatory activation and mitochondrial injury further aggravate tubular damage. Persistent stress and maladaptive repair may promote fibrosis, AKI-to-CKD transition, and multi-organ dysfunction. These processes provide the pathological basis for RAAS dysregulation in SA-AKI.

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  Figure 2. Imbalance of the RAAS in SA-AKI. Under physiological conditions, a balance is maintained between the classical and counter-regulatory RAAS axes. In sepsis, this equilibrium is disrupted. The classical axis is activated, with elevated renin and angiotensin I but inadequate effective Ang II generation, contributing to relative Ang II insufficiency. At the same time, endothelial injury may promote ACE2 shedding and alter the function of the protective axis. Ang-(1-7), acting through MasR, exerts anti-inflammatory, antioxidant, and vasodilatory effects. Together, these changes illustrate the heterogeneous and compartment-dependent dysregulation of the RAAS in SA-AKI.

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  Figure 3. Framework for biomarker-guided RAAS-targeted interventions in SA-AKI. This figure illustrates a proposed framework for stratifying patients with septic shock into distinct pathophysiological endotypes using biomarkers. The central problem is an imbalance between the injury-promoting classical axis (ACE/Ang II/AT1R) and the counter-regulatory protective axes (ACE2/Ang-(1-7)/MasR and AT2R). Biomarkers such as plasma renin, cDPP3, and the Ang I/Ang II ratio may help identify patients with different patterns of RAAS dysregulation and guide targeted therapeutic interventions. Potential interventions include Ang II supplementation, rhACE2, Ang-(1-7) analogues, AT2R agonists, and anti-DPP3 strategies. Potential goals include short-term hemodynamic stabilization and renal recovery, as well as long-term reduction in progression from AKI to CKD and major adverse cardiovascular events.