Supplementary Material for: Obesity, Renin-Angiotensin System Blockade and Risk of Adverse Renal Outcomes: A Population-Based Cohort Study

<b><i>Background:</i></b> Obesity substantially increases the risk of the development of chronic kidney disease. Adipose tissue expresses all of the components of the renin-angiotensin system (RAS), contributing to the high prevalence of hypertension in obese patients and driving renal hyperfiltration and subsequent glomerular injury. <b><i>Methods:</i></b> We performed a retrospective cohort study using a United Kingdom primary care database, evaluating the effect of time-updated exposure to RAS blockade versus all other antihypertensive medications in obese, hypertensive, non-diabetic patients. We used Cox proportional hazards modeling with and without marginal structural modeling to assess the hazards of developing a primary outcome of 50% reduction in estimated glomerular filtration rate (eGFR) (across 2 consecutive values), end stage renal disease or death. <b><i>Results:</i></b> A total of 219,701 patients met inclusion criteria, with a median 7.2 years of follow-up. Median baseline eGFR was 72.6 ml/min/1.73 m². Compared to other antihypertensive medications, patients treated with RAS blockade had a modestly elevated hazard of adverse renal outcomes using traditional Cox regression (hazard ratio (HR) 1.04, 95% CI 1.01-1.07) and no significantly increased hazard by marginal structural modeling (HR 1.02, 95% CI 0.97-1.08). Patients treated with RAS blockade had a significantly reduced hazard of incident diabetes, but no significant difference in mortality. <b><i>Conclusion:</i></b> This study, conducted in a large real-world cohort, provides evidence that RAS blockade may not provide benefit with regard to longitudinal renal outcomes in obese, hypertensive patients. Further research is needed to elucidate the hemodynamic and renoprotective role of antihypertensive medications in obese patients.

<b><i>背景：</i></b> 肥胖会显著增加慢性肾脏病的发病风险。脂肪组织可表达肾素-血管紧张素系统（renin-angiotensin system, RAS）的所有组分，这与肥胖患者高血压的高患病率相关，并可推动肾脏高滤过及后续的肾小球损伤。<b><i>方法：</i></b> 本研究采用英国初级医疗数据库开展回顾性队列研究，评估肥胖、高血压且无糖尿病患者中，随时间更新的肾素-血管紧张素系统阻滞剂（RAS blockade）暴露与其他所有降压药物的治疗效果差异。本研究使用Cox比例风险模型（Cox proportional hazards modeling），分别结合与不结合边际结构模型（marginal structural modeling），以评估主要结局的发生风险：连续2次检测值显示估算肾小球滤过率（estimated glomerular filtration rate, eGFR）较基线下降50%、终末期肾病（end stage renal disease）或死亡。<b><i>结果：</i></b> 共计219701名患者符合纳入标准，中位随访时长为7.2年。基线中位eGFR为72.6 ml/min/1.73 m²。与其他降压药物相比，采用传统Cox回归分析时，接受RAS阻滞剂治疗的患者不良肾脏结局的风险比（hazard ratio, HR）轻度升高（HR=1.04，95%置信区间CI：1.01~1.07）；而采用边际结构模型分析时，未观察到风险显著升高（HR=1.02，95%CI：0.97~1.08）。接受RAS阻滞剂治疗的患者新发糖尿病的风险显著降低，但死亡率无显著差异。<b><i>结论：</i></b> 这项基于大型真实世界队列的研究表明，RAS阻滞剂可能无法为肥胖、高血压患者带来长期肾脏结局方面的获益。未来仍需开展进一步研究，以阐明降压药物在肥胖患者中的血流动力学及肾脏保护作用机制。