Understanding Metabolic Alterations in Advanced Stage Chronic Kidney Disease Patients by NMR-based metabolomics

Understanding metabolic alterations in CKD is crucial, as serum creatinine-based diagnosis lacks precision, affecting key clinical decisions. In this study, a 1H NMR-based metabolomics approach was employed to distinguish between advanced-stage CKD (ASCKD) patients and healthy controls (HC), as well as within the ASCKD stages (Stage 4 and Stage 5). Serum samples from 52 ASCKD (S4, S5) and 25 HC were analyzed. Multivariate and univariate analysis revealed distinct metabolic patterns across groups, providing insights into CKD pathophysiology and associated pathway alterations. Compared to HC, six metabolites were significantly altered in both stage 4 and 5 CKD patients with upregulated creatinine, urea, myoinositol, choline, N, N-dimethylglycine, and downregulated tyrosine, showing potential as biomarkers with AUC above 0.8 in ROC analysis. Additionally, myo-inositol, dimethylamine, N, N-dimethylglycine, and choline correlate positively with creatinine while tyrosine correlates negatively. Amino acid metabolism was downregulated in S5 indicating more severity. Within ASCKD patients, significant alterations were observed in metabolites such as glutamate, glutamine, alanine, threonine, myo-inositol, dimethylamine, citrulline, urea, citrate, and betaine. Pathway analysis identified five distinct metabolic pathways associated with CKD progression. Consequently, we propose a panel of serum metabolites as an alternative diagnostic marker of CKD progression. Markers of oxidative stress, inflammation, and gut dysbiosis were evident in the perturbed metabolic profile due to the systemic impact of CKD.

明确慢性肾脏病（Chronic Kidney Disease, CKD）的代谢异常机制至关重要，因基于血清肌酐的诊断方法精度不足，会对关键临床决策造成不利影响。本研究采用基于氢谱核磁共振（Proton Nuclear Magnetic Resonance, 1H NMR）的代谢组学方法，用于区分晚期慢性肾脏病（Advanced-stage Chronic Kidney Disease, ASCKD）患者与健康对照（Healthy Controls, HC），同时还对ASCKD的不同分期（4期与5期）进行了区分分析。本研究共纳入52例ASCKD患者（涵盖4期、5期）与25例健康对照的血清样本进行分析。多变量与单变量分析结果显示，各组间存在显著差异的代谢模式，为CKD的病理生理机制及相关代谢通路异常提供了新的研究视角。与健康对照相比，4期与5期CKD患者共有6种代谢物发生显著改变：肌酐、尿素、肌醇、胆碱、N,N-二甲基甘氨酸表达上调，酪氨酸表达下调；经受试者工作特征（Receiver Operating Characteristic, ROC）分析证实，这些代谢物的曲线下面积（Area Under Curve, AUC）均高于0.8，具备作为临床生物标志物的潜力。此外，肌醇、二甲胺、N,N-二甲基甘氨酸与胆碱均与肌酐水平呈正相关，而酪氨酸则与肌酐水平呈负相关。5期ASCKD患者的氨基酸代谢通路表达下调，提示病情更为严重。在ASCKD患者亚组中，谷氨酸、谷氨酰胺、丙氨酸、苏氨酸、肌醇、二甲胺、瓜氨酸、尿素、枸橼酸及甜菜碱等代谢物均存在显著异常。代谢通路分析共鉴定出5条与CKD进展密切相关的特异性代谢通路。据此，本研究提出一组血清代谢物可作为CKD进展的替代诊断标志物。由于CKD具有全身性影响，其紊乱的代谢谱中可观察到氧化应激、炎症及肠道菌群失调相关标志物的异常表达。