Long-term dynamic effect of body mass index on adverse cardiovascular outcomes with targeted maximum likelihood estimation method: result from the KNOW-CKD study

The relationship between body mass index (BMI) and cardiovascular outcomes in chronic kidney disease (CKD) remains controversial. While the obesity paradox has been observed in this population, the impact of longitudinal BMI patterns over time is not well established. In this study, we investigated the association between BMI trajectories and the risk of cardiovascular events (CVEs) using data from 1061 patients enrolled in the Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD). BMI was categorized as high (≥ 23 kg/m2) or low (< 23 kg/m2), and assessed at three time points over a 7-year period. We applied targeted maximum likelihood estimation (TMLE) and marginal structural models (MSMs) to adjust for time-varying covariates, including estimated glomerular filtration rate, blood pressure, hemoglobin, albumin, and C-reactive protein, as well as baseline demographic and clinical characteristics. Patients with persistently high BMI had a significantly reduced risk of CVEs (relative risk 0.279; 95% CI 0.143–0.546; P < 0.001) compared to those with consistently low BMI. Transient increases or decreases in BMI did not show the same benefit. Our findings suggest that sustained high BMI may be protective against cardiovascular events in patients with CKD, challenging current weight management recommendations and supporting individualized approaches based on long-term risk profiles.