Cardiovascular-kidney-metabolic syndrome and the risk of liver fibrosis progression and liver-related events in MASLD

Background: Cardiovascular-kidney-metabolic (CKM) syndrome, a new framework integrating cardiovascular, renal, and metabolic dysfunction, remains inadequately characterized in metabolic dysfunction-associated steatotic liver disease (MASLD). Objective: We investigated the relationships between CKM stages and liver fibrosis severity, progression, and the risk of liver-related events (LREs) in MASLD. Design: Patients with MASLD from the VCTE-Prognosis cohort were stratified according to CKM stages. Outcomes included the prevalence of advanced liver fibrosis (LSM >= 10 kPa), liver stiffness progression (>= 20% increase and Baveno category upshift), and incident LREs. Associations were assessed using multivariable logistic regression and Cox proportional hazards models. Results : Among 12,097 patients with MASLD, the prevalence of advanced liver fibrosis increased across CKM stages at baseline: 9.6% (CKM stage 0-1), 18.0% (CKM stage 2), and 31.6% (CKM stage 3-4). CKM stage 2 (adjusted OR=1.663, 95% CI 1.444-1.915) and CKM stage 3-4 (adjusted OR=2.575, 95% CI 2.109-3.144) were independently associated with advanced fibrosis. During a 4.5-year median follow-up, 716 patients (6.1%) experienced progression of liver stiffness, and 352 patients (1.7%) developed LRE. Compared with CKM stage 0-1, the risk of liver stiffness progression was higher in CKM stage 2 (adjusted HR=1.321, 95% CI 1.050-1.662; p=0.018) and CKM stage 3-4 (adjusted HR=1.767, 95% CI 1.339-2.330; p<0.001). In contrast, only CKM stage 3-4 were significantly associated with an increased risk of LREs (adjusted HR=1.975, 95% CI 1.245-3.133; p=0.004). Conclusions: CKM stages are independently associated with the severity and progression of liver fibrosis in MASLD. CKM stage 2 significantly increases liver stiffness progression without excess LRE risk, while CKM stage 3-4 confer the highest risk for liver-related outcomes.