Different Stages of Cardiovascular-Kidney-Metabolic Syndrome Associated With the Risk of All-Cause and Cause-Specific Mortality: Insights From Two Prospective Cohort Studies.

Aims: Stage 3 in cardiovascular-kidney-metabolic (CKM) syndrome, defined as subclinical cardiovascular disease (CVD), diagnosis often relies on risk equivalents (very high-risk CKD or high 10-year CVD risk) due to the limited accessibility of diagnostic tools. A critical unanswered question is whether these two risk-equivalent subgroups exhibit comparable mortality risks. This study compares mortality risks between these subgroups. Methods: The study included 344,515 participants from the UK Biobank and 24,545 participants from the National Health and Nutrition Examination Survey (NHANES). Participants were stratified according to AHA diagnostic criteria into Stage 0, 1, 2, 3, and 4. Stage 3 was further subclassified as 3a (10-year high risk of CVD) and 3b (very high-risk CKD). Cox proportional hazards regression models were applied to assess the risks of all-cause, cardiovascular, renal, and cancer mortality across different stages. Results: In the UK Biobank, compared with Stage 0, Stage 3b was associated with the second-highest multivariable-adjusted hazard ratios (HRs) for all-cause mortality (4.95; 95% CI: 4.41-5.55), cardiovascular mortality (18.75; 95% CI: 14.70-23.91), renal mortality (59.73; 95% CI: 21.53-165.68), and cancer mortality (2.88; 95% CI: 2.33-3.56), second only to Stage 4b. These risks were significantly higher than those observed in Stage 3a and even exceeded those in Stage 4a. The analysis of the NHANES cohort also validated the results for all-cause mortality and cardiovascular mortality risks described above. Conclusion: The patients in Stage 3b with very high-risk CKD, even in the absence of clinical CVD, face a very high risk of mortality and should be given significant attention and early intervention.