#4356 dynamic effect of proteinuria on adverse kidney outcomes with targeted maximum likelihood estimation method: result from the know-ckd study

Abstract Background and Aims Proteinuria is a risk factor for the progression of chronic kidney disease (CKD), but its causal inference may be challenging due to time varying exposure and confounding, the changing its degree, and loss to follow up. Method A total of 1,223 patients enrolled as part of The Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) were analyzed at 3 observational points (baseline, 3-year; early, and 7-year; late) at which spot urine protein creatinine ratio (UPCR) was measured. We used longitudinal targeted minimum loss-based estimation (TMLE) and marginal structural models (MSM) to estimate the cumulative incidence of adverse kidney outcomes (eGFR halving and kidney failure requiring replacement therapy) of dynamic exposure to high proteinuria (UPCR≥1g/g) comparing counterfactuals (UPCR<1g/g) adjusted for time varying confounding (systolic blood pressure, estimated glomerular filtration rate, and renin-angiotensin-aldosterone blockers) and baseline covariates (age, sex, diabetes, cardiovascular disease, and smoking). Results Patients with sustained high proteinuria throughout 7-year follow-up had significant higher risk of renal events than those with counterfactuals (relative risk [RR], 3.120; 95% confidence interval, 2.150-4.528; P < 0.001). The RR were 0.168 (0.055-0.517; P = 0.002) and 0.613 (0.337-1.114; P = 0.108) for early and late proteinuria reduction comparing sustained high proteinuria, respectively. In MSM, hazard ratio (HR) of accumulative high proteinuria frequency were 1.612 (1.463-1.844; P <0.001) up to 3 years and 1.102 (0.877-1.387; P = 0.404) up to 7 years, respectively. Conclusion In CKD patients, sustained higher proteinuria is the main risk factor during the entire observation period. However, considering dynamic exposure, proteinuria reduction from the beginning has a protective effect on renal progression, but the effect weakens as the observation period becomes longer.