广义加性混合模型揭示原发性肾小球疾病患者尿蛋白排泄的昼夜节律特征

Characteristics and influencing factors of circadian rhythm in urinary protein excretion in patients with primary glomerular diseases: A generalized additive mixed model analysis

  • 摘要: 背景 蛋白尿是原发性肾小球疾病的核心表现及进展危险因素,但其排泄的昼夜节律特征尚缺乏系统研究。目的 应用广义加性混合模型,描绘原发性肾小球疾病(primary glomerular disease,PGD) G1-G4 期患者尿蛋白排泄的昼夜节律特征,并探讨其与病理类型及肾功能的关系。方法 本研究为单中心横断面探索性研究,连续纳入2024 年7 月至2025年7 月于解放军总医院肾脏病医学部住院、经肾活检确诊的PGD患者。通过24 h 密集不等间隔自然留尿法收集尿液样本,记录每次排尿时间及尿量。采用广义加性混合模型(generalized additive mixed model,GAMM) 分析尿蛋白排泄率的昼夜波动,构建阶梯式模型验证节律存在并逐步调整协变量,并探讨病理类型(IgA 肾病vs 膜性肾病) 和慢性肾脏病(chronic kidney disease,CKD) 分期与时间的交互效应。使用间隔时间加权校正稀释效应,并进行敏感性分析验证结果的稳健性。结果 共纳入116 例,其中男性70 例,女性46 例,平均年龄45.7±11.5 岁,906 份尿样进行分析。GAMM模型显示,在充分校正混杂因素后,尿蛋白排泄存在显著的昼夜节律(时间平滑项P<0.001),整体呈现“夜高昼低”模式,预测峰值时间为04:54,谷值时间为13:54。病理交互模型表明,IgA肾病与膜性肾病的节律形态存在差异:IgA肾病的节律振幅更大(峰值/谷值比1.44 vs 1.36),且曲线形态更复杂(有效自由度edf=4.60 vs 3.50)。CKD分期交互模型揭示,随着肾功能下降,节律振幅进行性减弱并趋于“平坦化”:G1、G2 期节律显著且振幅大(P<0.001),G3a 期临界不显著(P=0.083),而G3b 和G4 期无显著节律(P>0.05)。敏感性分析支持上述发现。结论 本研究通过GAMM模型证实了PGD患者的尿蛋白排泄存在显著的昼夜节律,呈现夜间主导模式,且节律特征和病理类型、CKD分期显著相关。

     

    Abstract: Background Proteinuria is a core manifestation and a key risk factor for progression in primary glomerular diseases, yet the circadian rhythm characteristics of its excretion remain insufficiently studied.Objective To apply the generalized additive mixed model (GAMM) to characterize the circadian rhythm of urinary protein excretion in patients with primary glomerular diseases (CKD stages G1-G4) and explore its relationship with pathological type and renal function.Methods This single-center, cross-sectional exploratory study employed a cross-sectional design. A total of 116 consecutive patients with biopsy-proven primary glomerular diseases, hospitalized at the Nephrology Department of PLA General Hospital from July 2024 to July 2025 were enrolled. Urine samples were collected using a 24-hour intensive, unequal-interval natural voiding protocol, with detailed recording of each voiding time and urine volume. The GAMM was used to analyze the circadian fluctuation of the urinary protein excretion rate. A stepwise modeling approach was applied to verify the existence of the rhythm and to gradually adjust for covariates. The interaction effects of pathological type (IgA nephropathy vs membranous nephropathy) and CKD stage with time were explored. The dilution effect was corrected using inter-voiding interval weighting, and sensitivity analyses were conducted to validate the findings. Results A total of 116 participants (70 males and 46 females) with a mean age of 45.7 ± 11.5 years were enrolled, and 906 urine samples were analyzed. The GAMM revealed a significant circadian rhythm in urinary protein excretion after full adjustment for confounders (P<0.001 for the time smooth term), exhibiting an overall 'nocturnal high, diurnal low' pattern. The predicted peak time was 04:54, and the trough was at 13:54. The pathological interaction model indicated differences in rhythm patterns between IgA nephropathy and membranous nephropathy: IgA nephropathy showed a greater rhythm amplitude (peak/trough ratio 1.44 vs 1.36) and a more complex curve shape (effective degrees of freedom, edf = 4.60 vs 3.50). The CKD stage interaction model revealed that as renal function declined, the rhythm amplitude progressively attenuated, tending toward a 'flattened' pattern: significant rhythms with large amplitudes were present in stages G1 and G2 (P<0.001), marginal significance was observed in stage G3a (P=0.083), while no significant rhythm was detected in stages G3b and G4 (P>0.05). Sensitivity analyses supported the robustness of these findings.Conclusion Using the GAMM, this study confirmed a significant circadian rhythm in urinary protein excretion in patients with primary glomerular diseases, characterized by a nocturnal-dominant pattern. The rhythm features were significantly associated with pathological type and CKD stage.

     

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