Advanced CKM Stages Linked to Mortality and Liver Fibrosis in MASLD

Adults with metabolic dysfunction-associated steatotic liver disease (MASLD) and advanced stages of cardiovascular-kidney-metabolic (CKM) syndrome are at an increased risk for mortality and liver fibrosis.1

Findings from the retrospective, observational cohort study highlight the need for integrated cardiometabolic-kidney management, early identification, and risk stratification in patients with shared metabolic pathophysiology.

“Worsening renal function in patients with CVD is associated with a higher morbidity and mortality due to further derangement of the cardiovascular system,” wrote Jei Li, PhD, the department of infectious disease at the Medical School of Nanjing University, and colleagues. “This vicious cycle is particularly pronounced in MASLD patients, exacerbating the overall disease burden.”

Previous research has established MASLD as a key contributor to lipid dysregulation, systemic inflammation, and insulin resistance, the driving core mechanisms of the development of CKM syndrome. However, whether CKM syndrome is associated with poor prognosis for patients with comorbidity of MASLD has been largely unexplored.2

To address this gap in research, investigators collected data from the National Health and Nutrition Examination Survey (NHANES) III and the Chinese Kailuan cohort, a prospective study conducted in Tangshan, China. From these databases, investigators identified MASLD patients and classified them by CKM stage to assess prevalence, mortality risk, and liver fibrosis associations.

The study included 22,865 MASLD participants from the Kailuan cohort and 2159 from NHANES III. Participants were grouped by CKD stages, defined as stage 1: excess weight, central obesity, or prediabetes without additional metabolic abnormalities or CKD, stage 2: presence of additional metabolic risk factors or moderate- to high-risk CKD, or stages 3-4: very high-risk CKD and established cardiovascular disease (stroke, heart failure, or coronary artery disease), respectively.

Cardiovascular mortality was defined according to ICD-10. MASLD was defined as hepatic steatosis detected by liver ultrasound examinations. From NHANES III, mortality was referenced from the Nationwide Death Index provided by the National Center for Health Statistics (NCHS) of the Centers for Disease Control, up to December 2019.

From NHANES III, investigators determined 84.5% of patients with MASLD met the criteria for CKM stage ≥2, with a rate of 36.9% deaths. Using stage 1 as a reference, there was an increasing trend in all-cause mortality as CKD stage advanced:

• Stage 2: Adjusted Hazard Ratio [aHR], 1.55; 95% CI, 1.17-2.07; P = .003;
• Stages 3-4: aHR, 2.69; 95% CI, 1.92-3.76; P < .001

There was a similar association between CKM stage and cardiovascular mortality as was observed for all-cause mortality, with the highest risks seen in stages 3–4.

• Overall cohort (aHR, 4.60; 95% CI, 2.56-8.25)
• Participants aged ≥60 years (aHR, 3.19; 95% CI, 1.53-6.65)
• Participants aged <60 years (aHR, 20.94; 95% CI, 7.75-56.53)

After adjusting for confounding factors, investigators noted CKM stages 3-4 as an independent risk factor for liver fibrosis (Adjusted Odds Ratio [aOR], 2.24; 95% CI, 1.14-4.40; P = 0.019).

Investigators used the Kailuan cohort to validate their findings, discerning similar patterns with the NHANES III cohort.

“Early identification and intervention in patients showing signs of CKM syndrome can help break the vicious cycle of worsening metabolic dysfunction, cardiovascular disease, and renal impairment,” concluded investigators.

References

1. Chen Q, Zhu Y, Gao J, et al. Cardiovascular-kidney-metabolic (CKM) syndrome is associated with increased mortality in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD). Communications Medicine. 2025;5(1):492-492. doi:https://doi.org/10.1038/s43856-025-01195-w

2. Goodheart RH, Ayonrinde OT. Connecting the Dots: Hepatic Steatosis as a Central Player in the Choreography of the Liver-Cardiovascular-Kidney-Metabolic Syndrome. Heart, Lung and Circulation. 2025;34(10):1050-1059. doi:https://doi.org/10.1016/j.hlc.2025.08.009