Translating the Pathophysiology of Sepsis-Associated Acute Kidney Injury: from Bench to Bedside

Sepsis-associated acute kidney injury (SA-AKI) is a major complication in the intensive care unit (ICU), associated with increased mortality and progression to chronic kidney disease (CKD) and end-stage renal disease (ESRD). This review summarizes current advances in the definition, epidemiology, pathophysiology, diagnosis, experimental modeling, and therapeutic strategies of SA-AKI, with emphasis on translational challenges. The conceptual framework of SA-AKI has evolved from global renal hypoperfusion to a multifactorial, predominantly non-ischemic process characterized by inflammatory dysregulation, microcirculatory dysfunction, and adaptive metabolic reprogramming. Tubular metabolic shutdown is increasingly recognized as a protective yet maladaptive response contributing to functional decline. Regulated cell death pathways, including pyroptosis and ferroptosis, further drive tubular injury. In parallel, organ crosstalk—particularly along the lung–gut–heart–kidney axis—amplifies renal dysfunction during sepsis. Recent diagnostic advances are highlighted, including the 2023 Acute Disease Quality Initiative (ADQI) consensus and emerging biomarkers reflecting distinct pathophysiological domains: tubular injury (neutrophil gelatinase-associated lipocalin [NGAL] and kidney injury molecule-1 [KIM-1]), cell cycle arrest (Tissue Inhibitor of Metalloproteinases-2[TIMP-2]·insulin-like growth factor-binding protein 7 [IGFBP7]), and endothelial dysfunction (angiopoietin-2 [Angpt-2] and the tyrosine kinase with immunoglobulin-like and EGF-like domains 2 receptor [Tie2]), supporting early risk stratification beyond serum creatinine (sCr). Experimental models ranging from endotoxemia and cecal ligation and puncture to two-hit and comorbidity-based paradigms are critically appraised. Finally, current and investigational therapies—including hemodynamic optimization, extracorporeal cytokine removal, mitochondria-targeted interventions, and regenerative approaches—are discussed in the context of persistent barriers to clinical translation.