Sepsis-Associated Acute Kidney Injury

Summary

Acute kidney injury (AKI) is a common complication of sepsis and significantly increases patient morbidity and mortality. Nearly two-thirds of patients with septic shock develop AKI, resulting in a six- to eightfold increase in mortality. Despite progress in understanding its pathophysiology and biomarkers, there are still limited effective therapies. This review outlines the epidemiology, pathophysiological mechanisms, diagnosis, biomarkers, and therapeutic strategies for sepsis-associated AKI (S-AKI).

Key Points:

1. Sepsis and AKI Relationship: Sepsis is one of the leading causes of AKI in ICU patients, and S-AKI carries a significantly higher mortality rate compared to AKI of other etiologies, with up to a six- to eightfold increased risk of death.
2. Diagnostic Criteria: Sepsis is defined by the Sepsis-3 criteria as life-threatening organ dysfunction (SOFA ≥2), while AKI is diagnosed per KDIGO guidelines, which consider a rise in serum creatinine and/or reduced urine output, although both metrics have diagnostic limitations in sepsis.
3. Epidemiology Challenges: Accurate global estimates of S-AKI are difficult due to overlapping definitions and diagnostic challenges; however, it is estimated that 6–11 million global cases occur annually, with high ICU mortality.
4. Inflammatory Cascade: Sepsis triggers innate immune responses via TLRs on immune and renal tubular cells, leading to increased oxidative stress, mitochondrial damage, and inflammatory mediator release that contributes to kidney injury.
5. Microvascular Dysfunction: Sepsis causes vasodilation and shunting in renal vasculature, impairing medullary perfusion and oxygenation. Microcirculatory alterations play a critical role, with endothelial dysfunction and leukocyte activation contributing to nephron ischemia.
6. Cell Cycle Arrest and Apoptosis: Mitochondrial damage during sepsis leads to energy deficits that induce renal tubular cell cycle arrest, helping prevent apoptosis. TIMP-2 and IGFBP7 are notable biomarkers for detecting early injury.
7. Metabolic Reprogramming: Inflammatory stimuli shift cellular metabolism from oxidative phosphorylation to aerobic glycolysis, supporting pro-inflammatory phenotypes and adaptive responses to injury, which may influence repair and outcomes.
8. Biomarkers for Early Detection: Besides creatinine and urine output, biomarkers like NGAL, KIM-1, cystatin C, and proenkephalin provide earlier and more sensitive detection of S-AKI. Urinary TIMP-2 and IGFBP7 are particularly predictive.
9. Therapeutic Management: Treatment focuses on early infection control, appropriate fluid resuscitation with balanced crystalloids, avoiding nephrotoxic drugs, and, when indicated, renal replacement therapy. Alkaline phosphatase shows promise in improving long-term renal outcomes.
10. Renal Replacement Therapy (RRT): Early RRT initiation remains debated; current recommendations favor individualized timing based on clinical context. Higher RRT doses have not improved outcomes over standard dosing.

Conclusion

S-AKI remains a critical, life-threatening complication of sepsis with poor outcomes despite advancements in understanding its pathophysiology and diagnostic tools. Early recognition using emerging biomarkers, cautious fluid and drug management, and targeted interventions may improve outcomes. Further research into specific treatments and individualized strategies is essential for reducing mortality and enhancing recovery.

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