Cardiovascular–kidney–metabolic syndrome ups mortality, ESKD risks

Individuals with more components of cardiovascular–kidney–metabolic (CKM) syndrome, as defined by the American Heart Association, are at increased risks of all-cause mortality, cardiovascular disease (CVD) mortality, and end-stage kidney disease (ESKD), suggests a study.

Furthermore, the population-attributable fractions (PAFs) of CKM syndrome for all-cause and CVD mortality are 18.7 percent and 55.0 percent, respectively.

"We estimated that failing to include chronic kidney disease (CKD) in CKM syndrome could result in the missed attribution of approximately 11 percent of CVD deaths,” the investigators said.

A total of 515,602 participants (49.9 percent female) aged ≥20 years from a health screening programme conducted between 1996 and 2017 in Taiwan were included in the analysis. Of these, 71.5 percent met the criteria for CKM syndrome, with prevalence rates of 19.5 percent, 46.3 percent, 1.9 percent, and 3.8 percent for stages 1, 2, 3, and 4, respectively. [PLoS Med 2025;22:e1004629]

CKM syndrome showed a significant association with elevated risks of all-cause mortality (hazard ratio [HR], 1.33, 95 percent confidence interval [CI], 1.28–1.39), CVD mortality (HR, 2.81, 95 percent CI, 2.45–3.22), and incident ESKD (HR, 10.15, 95 percent CI, 7.54–13.67).

Moreover, individuals with more components of CKM had a 22-percent increase in the risk of all-cause mortality (HR, 1.22, 95 percent CI, 1.21–1.23) and a 37-percent increase in the risk of CVD mortality (HR, 1.37, 95 percent CI, 1.35–1.40) relative to those without any CKM components. Notably, each additional component resulted in a 3-year decrease in the average life expectancy.

CKD inclusion

“The most significant difference between CKM syndrome and previous frameworks that emphasized CVD risk factors is the inclusion of CKD,” according to the investigators.

The PAFs of CKM syndrome were 18.7 percent (95 percent CI, 15.8–21.7) for all-cause mortality and 55.0 percent (95 percent CI, 49.0–60.4) for CVD mortality.

Historically, CKD has been overlooked in deaths attributed to CVD. Several reports even suggest that CKD is overdiagnosed. [Lancet 2013;382:339-352; JAMA Intern Med 2021;181:1366-1368]

“In our analysis, CKD also independently contributed a significant risk to CVD mortality even when controlling for blood pressure (130/80 mm Hg), blood glucose (<126 mg/dL), absence of metabolic syndrome, and triglycerides (<135 mg/dL),” the investigators said. 

“These independent cases of CKD, accounting for approximately 28 percent of CKD participants, represent a high-risk population that should not be ignored,” they added. 

Given that the PAF of CKD was 7.6 percent for CVD mortality, failure to include CKD in the definition of CKM syndrome could result in the missed attribution of nearly 11 percent of CVD deaths.

"When considering the actual number of deaths, the number of individuals with CKD who die from CVD is nearly half that of all individuals with hypertension (130/80 mm Hg),” the investigators said. “Therefore, incorporating CKD into the new CKM definition would account for a greater number of CVD-related deaths.”

The present study explored the relationship of all-cause, CVD, and cause-specific mortality with CKM stages and its components, namely hypertension, diabetes mellitus, CKD, metabolic syndrome, and hyperlipidemia. Participants were followed for a median of 16.5 years.

The investigators calculated HRs using multivariate Cox proportional hazard models, adjusted for age, sex, educational level, smoking status, alcohol drinking status, and physical activity groups. They also estimated the years of life lost due to each CKM component using Chiang’s life table method.

“Future studies should investigate the interrelated and multifaceted nature of CKM syndrome,” the investigators said.