Uremic Toxin Trajectories in Septic Shock-Associated Acute Kidney Injury and Patient Outcomes: The Tox-AKI Study

Emerging evidence suggests that uremic toxins (UTs) may exacerbate organ dysfunction in septic-shock-associated AKI. However, the dynamic changes in serum concentrations of these solutes and their specific prognostic implications remain largely unexplored.

This prospective study enrolled 114 patients with septic shock and AKI, alongside 15 non-AKI septic shock controls. We measured serum levels of seven UTs (indoxyl sulfate, indole-3-acetic acid, para-cresyl sulfate, para-cresyl glucuronide, hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), and trimethylamine N-oxide ) daily from Day 0 to Day 6. We analysed toxin kinetics and their relationship with 28-day mortality and the time to successful liberation from vasopressor and invasive mechanical ventilation, using joint modelling for longitudinal and survival data.

Upon inclusion, 30% of patients had Stage 1, 30% Stage 2, and 40% Stage 3 AKI. Except for CMPF, all toxins accumulated significantly compared to controls and remained significantly higher in severe AKI throughout the observation period (p<0.001). Indoxyl sulfate showed the strongest longitudinal correlations with serum creatinine (r=0.67, p<0.001). Daily kidney replacement therapy (KRT) status was associated with lower levels of most UTs, with the notable exceptions of indoxyl sulfate (unaffected) and hippuric acid (positively associated). Forty-four patients (39%) died within 28 days. After adjusting for baseline SAPS II and nonrenal SOFA scores, UT trajectories were not significantly associated with 28-day mortality or the time to successful liberation from organ support.

Changes in serum UT concentrations correlated with the severity and trajectory of AKI during septic shock, and exhibited variable clearance during KRT, but were not independently associated with 28-day mortality or organ support dependence.