慢性肾脏病患者铜暴露与肾纤维化之间的关联：孟德尔随机化和一项回顾性研究的证据

Association between copper exposure and renal fibrosis in patients with chronic kidney disease: evidence from Mendelian randomization and a retrospective study.

作者信息

Liu Kaixiang, Yu Min, He Yangyang, Wang Ting, Hu Honghua, Wan Zhengwei, Shuai Ping, Chen Shasha, Li Guisen, Wang Li, Zhong Xiang

机构信息

Department of Nephrology and Institute of Nephrology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.

Department of Clinical Laboratory, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.

出版信息

Front Public Health. 2025 Aug 25;13:1657180. doi: 10.3389/fpubh.2025.1657180. eCollection 2025.

DOI:10.3389/fpubh.2025.1657180

PMID:40927337

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12414938/

Abstract

BACKGROUND

Chronic kidney disease (CKD), a global health challenge, is closely linked to renal fibrosis progression. Copper, an essential trace element, influences cellular functions, yet its role in CKD-related fibrosis remains unclear. This study explores the causal relationship between serum copper levels and renal fibrosis in CKD.

METHODS

A two-sample Mendelian Randomization (MR) analysis integrated GWAS and FinnGen data. Serum copper and other metals were quantified via ICP-MS in 505 CKD patients and 50 controls. Renal fibrosis was histologically assessed in 168 biopsy-confirmed cases. Multivariable logistic regression and restricted cubic splines (RCS) evaluated associations between copper levels, renal function, and fibrosis severity, adjusting for demographics and biochemical parameters.

RESULTS

MR confirmed causality between elevated copper and CKD risk. CKD patients had higher serum copper than controls (957.10 ± 273.82 vs. 795.50 ± 143.85 ng/ml,  < 0.001), with progressive increases from stage 1 to 5 ( < 0.001). In biopsy-proven cases, severe fibrosis (>5%) correlated with higher copper levels and lower eGFR versus mild fibrosis (≤5%). Adjusted analysis identified quartile 4 copper levels (>961.64 ng/ml) as an independent predictor of severe fibrosis (OR = 2.75, 95% CI: 1.06-7.16,  < 0.001). RCS revealed non-linear relationships between copper, fibrosis (P for non-linear = 0.038), and eGFR (P for non-linear = 0.005).

CONCLUSION

Elevated serum copper is independently associated with renal fibrosis in CKD, suggesting copper dysregulation may contribute to fibrotic pathogenesis. These findings underscore the therapeutic potential of targeting copper metabolism to mitigate CKD progression.

摘要

背景

慢性肾脏病（CKD）是一项全球性的健康挑战，与肾纤维化进展密切相关。铜作为一种必需的微量元素，会影响细胞功能，但其在CKD相关纤维化中的作用仍不明确。本研究探讨了CKD患者血清铜水平与肾纤维化之间的因果关系。

方法

采用两样本孟德尔随机化（MR）分析，整合了全基因组关联研究（GWAS）和芬兰基因研究（FinnGen）的数据。通过电感耦合等离子体质谱法（ICP-MS）对505例CKD患者和50例对照者的血清铜及其他金属元素进行定量分析。对168例经活检确诊的病例进行肾纤维化的组织学评估。采用多变量逻辑回归和限制性立方样条（RCS）分析评估铜水平、肾功能和纤维化严重程度之间的关联，并对人口统计学和生化参数进行校正。

结果

MR分析证实血清铜升高与CKD风险之间存在因果关系。CKD患者的血清铜水平高于对照组（957.10±273.82 vs. 795.50±143.85 ng/ml，P<0.001），且从1期到5期逐渐升高（P<0.001）。在经活检证实的病例中，与轻度纤维化（≤5%）相比，重度纤维化（>5%）与更高的铜水平和更低的估算肾小球滤过率（eGFR）相关。校正分析确定铜水平处于第4四分位数（>961.64 ng/ml）是重度纤维化的独立预测因素（OR=2.75，95%CI：1.06-7.16，P<0.001）。RCS分析显示铜与纤维化（非线性P=0.038）和eGFR（非线性P=0.005）之间存在非线性关系。