CARDIOVASCULAR HEALTH, END-STAGE KIDNEY DISEASE, AND SYSTEMIC INFLAMMATION: EVIDENCE FROM THE PROSPECTIVE UK BIOBANK COHORT

Promoting cardiovascular health (CVH) has been proposed as a primordial prevention strategy to address the cardiovascular-kidney-metabolic (CKM) syndrome. However, most evidence to date has focused on cardiovascular disease with limited understanding of how CVH relates to the progression to end-stage kidney disease (ESKD). Systemic inflammation, a driver of chronic kidney disease (CKD) progression, has emerged as a potential therapeutic target as higher inflammatory burden is linked to greater ESKD risk. Yet, clinical trials of anti-inflammatory therapies in CKD have yielded inconclusive results. Favorable CVH is inversely associated with systemic inflammation but little is known about its impact on ESKD risk. Hence, we aimed to examine the association between CVH and incident ESKD and to assess whether systemic inflammation mediates this relationship in a large population-based cohort.

We analyzed UK Biobank participants recruited between 2006 and 2010 who were alive and free of ESKD at baseline. CVH was assessed using the American Heart Association’s Life’s Essential 8 (LE8) metrics, which encompasses diet, physical activity, nicotine exposure, sleep, Body Mass Index, blood lipids, blood glucose, and blood pressure. Each LE8 component was scored from 0 to 100, and the unweighted average of these scores was used to calculate the total LE8 score. LE8 scores were categorized as low (0-49), moderate (50-79), and high (80-100) CVH levels. Incident ESKD was identified through validated algorithms using disease and procedure codes. Cox proportional hazards models estimated hazard ratios (HR) for incident ESKD per 10-point increase in LE8 score and across CVH levels. We employed the restricted cubic spline (RCS) model with three knots to examine the dose-response relationship. Mediation analysis evaluated high-sensitivity C-reactive protein (hs-CRP; >3 mg/L indicating elevated systemic inflammation) as a mediator. Covariates included sociodemographic factors, alcohol use, baseline eGFR, and comorbidities.

The analytical sample had 303,025 participants with 542 incident ESKD events over a median follow-up of 13.6 years. The mean age was 56.3 years; 46.8% was male and 95.4% were White; mean baseline eGFR was 94.9 mL/min/1.73 m². Mean hs-CRP was 2.4 mg/L and 20.2% had elevated systemic inflammation. CVH levels were  low (6.1%), moderate (83.1%), and high (10.8%). In fully adjusted models, higher LE8 scores were associated with markedly lower ESKD risk (per 10-point increase: HR = 0.71, 95% CI, 0.65-0.77). Compared individuals with low CVH, those with moderate and high CVH had progressively lower ESKD risks (HR = 0.50, 95% CI: 0.40-0.63; and HR = 0.32, 95% CI: 0.20-0.52, respectively). In Figure 1, RCS analysis showed a nonlinear relationship with a steeper slope at lower scores and a plateau at higher scores. Mediation analysis indicated that elevated systemic inflammation accounted for 19% of CVH-ESKD association.

Better CVH was strongly associated with lower risk of ESKD with about one-fifth of the association explained by systemic inflammation. Our findings extend evidence beyond cardiovascular outcomes, reinforcing the importance of primordial prevention by promoting CVH within the CKM framework and highlight systemic inflammation as a potentially modifiable target to delay CKD progression.