Association Between Cardio-Kidney-Metabolic Syndrome and Overactive Bladder: Mediation by Systemic Inflammation, Depression, and Shared Metabolic Signatures

Introduction Overactive bladder (OAB) frequently co-occurs with cardiovascular-kidney-metabolic (CKM) syndrome; however, the complex interplay of systemic inflammation, psychological distress, and metabolic dysregulation driving this connection remains poorly defined. This study aimed to elucidate these multidimensional associations and identify shared metabolic patterns between OAB and CKM-related conditions. Methods We analyzed data from 11,836 participants in the National Health and Nutrition Examination Survey (2005–2018). CKM stages were classified using American Heart Association criteria, while OAB severity, systemic inflammation, and depression were assessed via the Overactive Bladder Symptom Score, neutrophil-to-high-density lipoprotein cholesterol ratio (NHR), and Patient Health Questionnaire-9, respectively. We utilized survey-weighted multivariable regression and mediation analysis. Furthermore, two-sample Mendelian randomization (MR) analyses using genome-wide association study datasets were conducted to identify causal metabolites. Results Higher CKM stages were significantly associated with increased OAB severity. Elevated NHR and depression scores were independently linked to OAB. Notably, a significant synergistic interaction was observed: moderate inflammation amplified the impact of depressive symptoms on OAB. Mediation analyses demonstrated that NHR, depression, and their interaction significantly mediated the relationship between CKM stage and OAB. MR analysis identified specific causal lipid, amino acid, and energy-related metabolites for OAB, exhibiting substantial overlap with CKM metabolic signatures. Discussion & Conclusion CKM progression, systemic inflammation, and depression are robustly associated with OAB, linked through neuro-inflammatory and psychological pathways. OAB appears to be a manifestation of systemic dysregulation shared with CKM syndrome, necessitating integrated management strategies addressing cardiometabolic health and psychological well-being.