Association Between Early Acetaminophen Exposure and Sepsis-Associated Acute Kidney Injury: A Retrospective Cohort Study

Background Emerging evidence suggests that acetaminophen may confer renoprotective effects by inhibiting lipid peroxidation. This study aimed to investigate whether early acetaminophen administration is associated with a reduced risk of sepsis-associated acute kidney injury (SA-AKI). Methods We conducted a multicenter retrospective cohort study by using data from the two large clinical databases: MIMIC-IV (Medical Information Mart for Intensive Care-IV) and eICU-CRD (eICU Collaborative Research Database). Adult patients with sepsis were included, with acetaminophen exposure defined as administration within 24 hours of ICU admission. The primary outcome was severe SA-AKI (stage 2/3 AKI according to KDIGO criteria) developed within 7 days of sepsis diagnosis. Multivariable logistic regression model, adjusted for established AKI-related risk factors, were used to evaluate associations between early acetaminophen exposure and the risk of severe SA-AKI. Several sensitivity and subgroup analyses were performed to validate findings of multivariable logistic regression. Results The primary (MIMIC-IV) and validation (eICU-CRD) cohorts comprised 13,708 and 20,740 qualified patients, respectively. The incidence of severe SA-AKI was 56% (7,665/13,708) in the primary cohort and 49% (10,149/20,740) in the validation cohort. Acetaminophen was administered to 7,563 patients (55%) in the primary cohort and 10,161 patients (49%) in the validation cohort within 24 hours following ICU admission. After adjusting for AKI-related risk factors, multivariable analysis revealed that early acetaminophen use was independently associated with a reduced risk of severe SA-AKI in both the primary (odds ratio [OR], 0.70; 95% CI, 0.64–0.76; P  < 0.001) and validation (OR, 0.62; 95% CI, 0.57–0.68; P  < 0.001) cohorts. These associations remained consistent across sensitivity analyses and subgroup evaluations. Conclusions Early acetaminophen use was independently associated with a lower risk of severe SA-AKI in critically ill patients with sepsis. Prospective studies are warranted to confirm causality and evaluate the therapeutic potential of acetaminophen in either preventing SA-AKI or mitigating its severity.