The cardiovascular-kidney-liver-metabolic (CKLM) risk spectrum: synergistic mortality from liver fibrosis and cardiometabolic disease

Aims Hepatic fibrosis impacts cardiovascular-kidney-metabolic (CKM) health and both are significant risk factors for mortality. However, their combined effect in the general population remains unclear. This study aimed to clarify the individual and synergistic impact of liver risk, defined by the FIB-4 index, and cardiovascular risk, defined by CKM stage, on mortality outcomes. Methods We included 28,056 U.S. adults from NHANES (2005-2016; median follow-up 9.08 years). Composite risk phenotypes were constructed based on CKM stage (primary analysis: stage 0-2 vs. 3-4) and FIB-4 index (low, intermediate, and high risk). Associations with all-cause and cardiovascular mortality were examined using Cox regression, RCS, and sensitivity analyses. Results During the study period, the proportion of individuals with early CKM (stage 0-2) but intermediate FIB-4 risk increased significantly. Each increase in FIB-4 risk level was associated with a proportional rise in all-cause and cardiovascular mortality, while progression from CKM stage 0-2 to 3-4 approximately doubled the relative increase in cardiovascular versus all-cause mortality. Compared with the “dual-low-risk” group (CKM 0-2 and low FIB-4), isolated high FIB-4 risk significantly increased all-cause (HR=5.88) and cardiovascular (HR=4.17) mortality; isolated CKM 3-4 also increased both mortality risks (HR=2.58 and 4.42, respectively). When both risks co-existed, a synergistic surge was observed: CKM 3-4 and high FIB-4 risk increased all-cause and cardiovascular mortality by 621% (HR=7.21) and 1307% (HR=14.07), respectively. Stratified analysis showed that as either CKM stage or FIB-4 risk level increased, the additional mortality risk contributed by the other factor gradually diminished; when FIB-4 risk was high, CKM stage no longer contributed significantly to increased mortality. Conclusions Liver fibrosis risk (FIB-4) and CKM stage independently and synergistically increase mortality. Elevated FIB-4 alone confers significant risk even with low CKM stage. Because FIB-4 elevation is more common, occurs earlier, and carries high absolute risk, integrating FIB-4 into CKM assessment is clinically critical. These findings support a “Cardiovascular-Kidney-Liver-Metabolic (CKLM)” management framework.