CKM Multimorbidity Burden and Phenotype Differentially Influence Cardiovascular and Renal Risk in Advanced CKD

Introduction Chronic kidney disease (CKD) frequently coexists with cardiovascular disease, diabetes and obesity through shared biological pathways encompassed within the American Heart Association cardiovascular–kidney–metabolic (CKM) construct. Whether adverse cardiovascular and renal outcomes in CKD are driven predominantly by cumulative multimorbidity burden or by distinct CKM disease phenotypes remains uncertain. Methods We conducted a retrospective longitudinal cohort study of participants in the Salford Kidney Study with non-dialysis-dependent CKD and at least one other CKM comorbidity. Patients were evaluated according to CKM multimorbidity burden (2, 3 or 4 conditions) and in predefined CKM phenotypes. Co-primary outcomes were major adverse cardiovascular event (MACE: cardiovascular mortality, non-fatal myocardial infarction, non-fatal cerebrovascular accident or heart failure event), composite kidney endpoint (CKE: ≥40% eGFR decline, eGFR <15 mL/min/1.73 m² or renal replacement therapy initiation) and all-cause mortality. Associations were evaluated using multivariable time-to-event models. Results Among 2,003 participants (mean age 68 years; median follow-up 4.7 years), 279 (13.9%) experienced MACE and 1,010 (50.4%) reached the CKE. Compared with 2 CKM conditions, 4 conditions conferred an almost two-fold higher MACE risk (HR 1.93, 95% CI 1.48–2.53), with the CKD–CVD–diabetes–obesity phenotype demonstrating the highest MACE risk. Diabetes-containing phenotypes were consistently associated with higher CKE risk, whereas increasing multimorbidity burden showed limited discriminatory value for kidney progression. The CKD–diabetes–CVD phenotype had the highest all-cause mortality (27.1 deaths per 100 patient-years). Conclusions Increasing CKM multimorbidity burden predicted cardiovascular events and mortality in keeping with the American Heart Association staging framework, but kidney progression was more strongly determined by disease phenotype, particularly diabetic kidney disease. This cardiovascular–renal dissociation suggests that phenotypic refinement of the CKM staging model may improve risk stratification in advanced CKD populations.