Objectives The association between night shift work and chronic kidney disease (CKD) risk remains uncertain. We investigated the associations of current/lifetime night shift work with incident CKD, assessed joint effects with genetic susceptibility, and explored the mediating roles of obesity and metabolomic alterations.

Methods Utilizing UK Biobank data, current (N=242 721) and lifetime (N=63 659) night shift duration/frequency were assessed via questionnaires. The primary outcome was incident CKD. Polygenic risk scores (PRS) for cardiometabolic diseases (diabetes, hypertension, and cardiovascular disease) were calculated. Plasma metabolomics (249 measures, N=122 681) were analyzed.

Results Over 13.7 years of follow-up, 5654 incident CKD cases were identified. Compared to day workers, those who usually or always worked night shifts had a 25% higher CKD risk [adjusted hazard ratio (HR_adj) 1.25, 95% confidence interval (CI) 1.10–1.41] and developed CKD 2.06 years earlier (95% CI 0.75–3.25). Lifetime night shift exposure showed consistent dose–response relationships, with 16–17% increased risks for either ≥5 cumulative years (HR_adj 1.17, 95% CI1.01–1.36) or ≥3 monthly night shifts (HR_adj 1.16, 95% CI1.01–1.33). Participants with both usual/always night shift exposure and high PRS for cardiometabolic diseases exhibited the greatest CKD risk. Obesity-related parameters (body mass index and waist circumference) mediated 14.7–14.8% of the observed night shift–CKD association. A novel 9-metabolite signature reflective of night shift mediated 5.47% of this association, primarily through disrupted fatty acid metabolism.

Conclusions Night shift work exhibits a dose-dependent association with CKD risk, exacerbated by cardiometabolic genetic predisposition and partially mediated through metabolic dysregulation and obesity. These findings underscore the need for workplace interventions targeting shift scheduling and metabolic health among high-risk workers.

Key terms cardiometabolic disease; cardiometabolic genetic risk; dose–response; kidney disease; metabolomic mediator; night shift; night work; polygenic risk score; shift work; shift worker

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