ABSTRACT Background Social isolation is increasingly recognized as a critical determinant of health. This study aimed to systematically evaluate the association between social isolation trajectories spanning childhood to adulthood and all‐cause mortality in patients with cardiovascular‐kidney‐metabolic (CKM) syndrome stages 1–4 and to investigate the potential mediating role of renal function. Methods We analyzed data from 5019 participants aged 45 years or older with CKM stages 1–4 from the China Health and Retirement Longitudinal Study (CHARLS). Four life‐course social isolation trajectories were identified: no isolation, childhood‐only, adulthood‐only, and persistent isolation. Cox proportional hazards models and exploratory mediation analyses were used to assess all‐cause mortality risk and potential mediating effects. Additionally, Kaplan‐Meier curves, subgroup analyses, and sensitivity analyses were performed. Results Persistent isolation was linked to an elevated likelihood of all‐cause mortality (HR = 1.92, 95% CI: 1.25–2.97). The mediation analysis suggested that cystatin C contributed to the pathway linking persistent isolation with mortality, explaining 6.31% of the overall effect ( p < 0.05). Conclusions Persistent social isolation shows a clear association with elevated mortality risk among middle‐aged and older Chinese individuals living with CKM syndrome, and this association is partially explained by cystatin C levels, serving as a potential mechanistic link. Integrating long‐term psychosocial assessment into CKM risk stratification and management is crucial.
Liang et al. (Mon,) studied this question.