Supplementary Material for: Isolated non-albumin proteinuria was associated with the progression of chronic kidney disease in hypertensive patients: a retrospective cohort study

Objectives: Isolated non-albumin proteinuria (iNAP) has been linked to kidney function decline in diabetes, but its prognostic role in hypertensive patients with chronic kidney disease (CKD) and normal albuminuria remains uncertain. We evaluated whether baseline iNAP predicts longitudinal estimated glomerular filtration rate (eGFR) decline and kidney events in this setting.
Methods: In a retrospective cohort of 166 hypertensive CKD outpatients with normal albuminuria, iNAP was defined as total 24-hour proteinuria ≥150 mg/day with albuminuria <30 mg/day. Kidney function change was assessed as (i) eGFR trajectory over 6 years using linear mixed-effects models and (ii) a composite kidney endpoint (≥30% eGFR decline or incident end-stage kidney disease) using cumulative incidence and Fine–Gray competing-risk regression (death as competing event). Confounding control was guided by a directed acyclic graph (DAG), yielding a minimal adjustment set (age, sex, diabetes, on-treatment mean arterial pressure, baseline eGFR). Sensitivity analyses examined alternative model specifications and endpoint definitions.
Results: Median follow-up was 5.4 years (interquartile range 4.5–6.0). iNAP was present in 41/166 participants; 32 reached the composite kidney endpoint and 25 died. Baseline eGFR was similar in iNAP versus normal proteinuria (57±24 vs 61±24 mL/min/1.73 m²; p=0.318). In mixed-effects models, eGFR declined by −0.61 mL/min/1.73 m²/year (95% CI −0.96 to −0.25) in normal proteinuria and by −1.53 mL/min/1.73 m²/year (95% CI −2.15 to −0.91) in iNAP, with a between-group slope difference of −0.92 mL/min/1.73 m²/year (95% CI −1.63 to −0.22; time×iNAP interaction p=0.011). In competing-risk analyses, iNAP was associated with a higher risk of the composite kidney endpoint (Fine–Gray subdistribution hazard ratio 3.15, 95% CI 1.58–6.31; p=0.001), while cumulative incidence of death without prior kidney endpoint (the competing event) did not differ between groups (Gray’s test p=0.920). Findings were consistent after DAG-minimal adjustment and across sensitivity analyses.
Conclusions: In hypertensive CKD patients with normal albuminuria, baseline iNAP is associated with faster eGFR decline and a higher risk of kidney events, independent of key baseline risk factors in DAG-guided analyses.

研究目的：此前有研究表明孤立性非白蛋白蛋白尿（isolated non-albumin proteinuria, iNAP）与糖尿病患者的肾功能下降相关，但该指标在伴正常白蛋白尿的高血压慢性肾脏病（chronic kidney disease, CKD）患者中的预后价值仍不明确。本研究旨在评估该人群中基线孤立性非白蛋白蛋白尿能否预测纵向估算肾小球滤过率（estimated glomerular filtration rate, eGFR）下降及肾脏不良事件。
研究方法：本研究纳入166例伴正常白蛋白尿的高血压慢性肾脏病门诊患者作为回顾性队列，将孤立性非白蛋白蛋白尿定义为24小时总蛋白尿≥150mg/日且白蛋白尿<30mg/日。肾功能变化通过两方面评估：①采用线性混合效应模型分析6年内的eGFR变化轨迹；②采用累积发生率模型与Fine-Gray竞争风险回归（以死亡为竞争事件）评估复合肾脏终点事件（eGFR下降≥30%或新发终末期肾脏病）。混杂因素控制采用有向无环图（directed acyclic graph, DAG）指导，确定最小调整变量集：年龄、性别、糖尿病史、治疗中平均动脉压及基线eGFR。敏感性分析针对不同模型设定与终点定义展开验证。
研究结果：中位随访时间为5.4年（四分位间距4.5~6.0年）。166例受试者中41例存在孤立性非白蛋白蛋白尿；32例达到复合肾脏终点事件，25例死亡。基线eGFR在孤立性非白蛋白蛋白尿组与正常蛋白尿组间无显著差异（57±24 vs 61±24 mL/min/1.73m²；p=0.318）。线性混合效应模型分析显示，正常蛋白尿组eGFR年下降速率为-0.61 mL/min/1.73m²（95%CI：-0.96~-0.25），孤立性非白蛋白蛋白尿组为-1.53 mL/min/1.73m²（95%CI：-2.15~-0.91），组间斜率差值为-0.92 mL/min/1.73m²（95%CI：-1.63~-0.22；时间×iNAP交互作用p=0.011）。竞争风险回归分析显示，孤立性非白蛋白蛋白尿与更高的复合肾脏终点事件风险相关（Fine-Gray亚分布风险比3.15，95%CI：1.58~6.31；p=0.001），而两组间未发生肾脏终点事件即死亡的累积发生率无显著差异（Gray检验p=0.920）。经有向无环图指导的最小化调整后，以及所有敏感性分析中，上述结果均保持一致。
研究结论：在伴正常白蛋白尿的高血压慢性肾脏病患者中，基线孤立性非白蛋白蛋白尿与更快的eGFR下降速率及更高的肾脏不良事件风险相关，且该关联不受有向无环图指导分析中关键基线风险因素的影响。