Serum uric acid and incident sepsis risk: sex-specific nonlinear associations modified by kidney function in the UK Biobank

Abstract Serum uric acid (SUA), the end product of purine metabolism, has opposing biological effects: it acts as an antioxidant at physiological concentrations but contributes to inflammation and endothelial dysfunction at elevated concentrations. Whether these effects translate into a concentration-dependent association with incident sepsis remains uncertain. We included 466,753 UK Biobank participants. Sex-specific associations were examined using restricted cubic splines, two-piecewise Cox regression models, and multivariable Cox models. A three-way interaction among sex, SUA, and eGFR was evaluated to assess whether baseline eGFR modified the SUA-sepsis association differently by sex; following a significant interaction, sex-specific SUA–eGFR interactions were examined separately in males and females. During a mean follow-up of 13.5 years, 17,249 incident sepsis cases occurred. Restricted cubic spline analyses revealed U-shaped associations between SUA and incident sepsis in both sexes, with sex-specific risk nadirs of 6.21 mg/dL (bootstrap 95% CI, 5.75–6.55) in males and 4.47 mg/dL (bootstrap 95% CI, 2.24–5.02) in females. In multivariable analyses, compared with the reference sextile, males in the lowest and highest SUA sextiles had higher risks (Q1: HR, 1.26; 95% CI, 1.18–1.36; Q6: HR, 1.15; 95% CI, 1.08–1.24), as did females (Q1: HR, 1.11; 95% CI, 1.01–1.21; Q6: HR, 1.11; 95% CI, 1.02–1.21). The three-way interaction was significant ( P = 0.0065), indicating that eGFR modification differed by sex. The SUA–eGFR interaction was not significant in males ( P = 0.70) but was significant in females ( P = 1.7 × 10⁻⁵): the SUA–sepsis association was U-shaped at lower eGFR and became progressively monotonic at higher eGFR, with risk rising mainly with increasing SUA. This study provides novel evidence that baseline SUA is associated with incident sepsis in a nonlinear, sex-specific, and kidney function-dependent manner. In males, both low and high SUA concentrations were associated with higher sepsis risk. In females, the SUA–sepsis association was U-shaped at lower eGFR and became progressively monotonic at higher eGFR, with the modification by kidney function evident in females but not in males.