Metabolic Dysfunction-Associated Fatty Liver Disease-Cardiovascular-Kidney-Metabolic (MAFLD-CKM): A Modified Framework to Predict Long-Term Mortality.

BACKGROUND Cardiovascular-kidney-metabolic (CKM) syndrome reframes cardio-renal-metabolic risk but omits hepatic dysfunction, particularly metabolic dysfunction-associated fatty liver disease (MAFLD). This study assesses whether integrating MAFLD into the CKM framework improves mortality risk discrimination compared with the original CKM framework. MATERIAL AND METHODS We used data of 10 335 adults aged 20 to 74 years from the third National Health and Nutrition Examination Survey (NHANES III) with mortality follow-up through 2019. CKM was classified based on the American Heart Association framework, and MAFLD was identified based on hepatic steatosis and metabolic dysfunction according to established criteria. A modified CKM score was proposed, incorporating MAFLD into CKM staging. We compared the association of each staging system with all-cause and cardiovascular mortality using Cox regression. RESULTS While both staging systems are significantly associated with mortality, the proposed modified CKM staging showed superior risk stratification than the original definition, particularly in stage 3. The modified CKM system showed a notably higher hazard ratio than the original CKM system in all-cause mortality (3.84, 95% CI: 3.38-4.37 vs 3.49, 95% CI: 3.07-3.95) and CVD-related mortality (6.38, 95% CI: 4.80-8.48 vs 5.41, 95% CI: 4.12-7.12). CONCLUSIONS Integrating MAFLD into the CKM framework (modified CKM) provided an incremental improvement in prognostic discrimination for allcause and cardiovascular mortality, with stronger risk stratification observed in stage 3, highlighting the key role of the liver in the cardio-renal-metabolic axis. These findings underscore the need for a broader, multi-organ approach to provide incremental refinement for defining and managing metabolic risk.