# Stage-specific risks of mortality and renal outcomes in cardiovascular-kidney-metabolic syndrome: findings from a nationwide Japanese cohort

## TL;DR

This study shows how different stages of cardiovascular-kidney-metabolic syndrome affect mortality and kidney outcomes in a large Japanese population.

## Contribution

The study provides new evidence on the stage-specific risks of renal outcomes and mortality in CKM syndrome.

## Key findings

- Stage 4a of CKM syndrome is most strongly linked to all-cause and cardiovascular mortality.
- Stage 3 is associated with the highest risk of renal deterioration.
- Metabolic dysfunction significantly contributes to CKM progression.

## Abstract

Cardiovascular-kidney-metabolic (CKM) syndrome, integrating cardiovascular disease (CVD), chronic kidney disease (CKD), and metabolic dysfunction, is a construct proposed by the American heart association. Although associations with CVD are well recognized, evidence linking CKM stage to renal outcomes remains limited.

We analyzed health checkup data of 266,256 Japanese aged 40–74 years. Participants were classified into CKM stages 0–4a. Outcomes included all-cause mortality, cardiovascular death, and a composite renal outcome (end-stage kidney disease [eGFR < 15 mL/min/1.73 m2], ≥ 40% eGFR decline, or doubling of serum creatinine). Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs), with CKM stage 0 as the reference.

CKM stage 2 was the most prevalent stage (65.0%). Stage 4a showed the strongest association with all-cause and cardiovascular mortality (HRs 1.79, 3.16; 95% CIs 1.41–2.28, 1.92–5.20, respectively). In contrast, stage 3 conferred the highest risk of renal outcomes (HR 15.29, 95% CI 10.13–23.08). The number and type of metabolic risk factors correlated with outcomes, furthermore, severe CKD and prior CVD were stronger drivers of adverse outcomes than metabolic dysfunction.

CKM staging stratifies risk in the general population. No significant increase in risk was observed until CKM stage 2, and these findings underscore the progressive, cumulative nature of CKM syndrome. Metabolic dysfunction plays a crucial role in progression, stage 3 marks a pivotal inflection point for renal deterioration, and stage 4a identifies individuals at the greatest mortality risk. Early interventions targeting metabolic dysfunction may help prevent progression to advanced CKM stages and improve long-term outcomes.

The online version contains supplementary material available at 10.1007/s10157-025-02800-x.