Associations of frailty with the incidence and progression trajectory of cardiometabolic-kidney multimorbidity: insights from multi-state modelling

Background: The American Heart Association recently introduced the cardiovascular-kidney-metabolic concept, but the impacts of frailty status on the disease trajectories remain unknown. We aimed to investigate the role of frailty status in the trajectories from being free of cardiometabolic-kidney disease (CMKD) to first CMKD (FCMKD), then to cardiometabolic-kidney multimorbidity (CMKM), and finally to death. Methods: In this prospective cohort study, we included 392 902 participants aged 37-73 years from the UK Biobank. We assessed frailty using the Fried criteria's frailty phenotype, based on five individual components. We used multistate models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Among 392 902 participants, 53 845 developed FCMKD, 8025 developed CMKM, and 25 538 died during a median follow-up of 13.49 years. Frailty was associated with a higher risk of transition from healthy to FCMKD (HR = 2.08; 95% CI = 1.99-2.17) than from FCMKD to CMKM (HR = 1.47; 95% CI = 1.34-1.62) (P < 0.001). Frailty showed a stronger association for healthy to death than that of transitions from FCMKD or CMKM to death (HR = 2.52; 95% CI = 2.34-2.72, P < 0.001). When splitting FCMKD into four CMKDs, the risks of disease-specific transitions associated with frailty varied, with the higher risk for chronic kidney disease to CMKM observed than that for other CMKDs to CMKM (HR = 2.11; 95% CI = 1.66-2.68). Consistent associations were also observed for pre-frailty. Conclusions: Both frailty and pre-frailty played key but different roles in disease transitions from healthy to FCMKD, to CMKM, and further to death, and had diverse impacts on disease-specific transitions of CMKDs. Our findings underscore the significance of early detection and interventions for frailty to prompt the comprehensive care of CMKM.