Association between cardiovascular-kidney-metabolic syndrome and chronic obstructive pulmonary disease: a cross-national analysis from global, US, and Chinese populations

Chronic obstructive pulmonary disease (COPD) increasingly demonstrates metabolic underpinnings in its pathogenesis. The newly defined cardiovascular-kidney-metabolic (CKM) syndrome represents an integrative clinical entity, yet its relationship with COPD remains inadequately investigated. We analyzed data from the Global Burden of Disease (GBD) study 2021, the US National Health and Nutrition Examination Survey (NHANES), and the China Health and Retirement Longitudinal Study (CHARLS). CKM stages (0–4) were classified through American Heart Association criteria. In NHANES, COPD was determined through post-bronchodilator spirometry in 2011–2012 and self-reported physician diagnosis in 2013–2020; in CHARLS, COPD was identified through self-reported physician diagnosis. Weighted multinomial logistic regression assessed CKM-COPD associations with adjustment for sociodemographic factors, lifestyle behaviors, and anthropometric measures. Multiple-mediator analyses explored inflammatory and protein pathways. Global COPD incidence and prevalence were 197 (95% uncertainty interval [UI] 181–213) and 2512 (95% [UI] 2293–2748) per 100,000 population. Meta-analysis of 18,918 participants from four cohorts demonstrated significant dose–response relationships between CKM stages and COPD. Compared to stage 0, advanced stages (2–4) showed progressively higher odds of chronic obstructive pulmonary disease: stage 2 (odds ratio [OR] 1.34, 95% confidence interval [CI] 1.02–1.76), stage 3 (OR 1.47, 95% CI 1.10–1.98), and stage 4 (OR 2.92, 95% CI 2.22–3.83, p-trend < 0.001). These associations remained consistent across both spirometry-defined and physician-reported chronic obstructive pulmonary disease definitions. Subgroup analyses revealed stronger associations in younger adults aged 20–45 years, females, and current smokers. Mediation analyses in the US cohort identified albumin as the strongest mediator (7.5%, p < 0.001), followed by white blood cell count (6.2%, p < 0.001), systemic immune-inflammatory index (5.6%, p < 0.001), neutrophil to monocyte ratio (4.3%, p < 0.001), and high-sensitivity C-reactive protein (3.8%, p < 0.001). The mediating role of high-sensitivity C-reactive protein was validated in the Chinese cohort. CKM syndrome demonstrates robust dose–response associations with COPD across diverse populations and diagnostic methods. These relationships appear to be partially mediated by inflammatory and protein markers. Our findings support integrated cardiometabolic-respiratory assessment and suggest promising strategies for COPD prevention, with special clinical relevance for younger adults, females, and smokers.