Association between Copper Exposure and Renal Fibrosis in Patients with Chronic Kidney Disease: Evidence from Mendelian Randomization and a Retrospective Study

Kaixiang Liu¹Min Yu¹Yangyang He¹Ting Wang¹Honghua Hu²Zhengwei Wan³Ping Shuai³Shasha Chen¹Guisen Li¹Li Wang¹Xiang Zhong^1*

• ¹Department of Nephrology and Institute of Nephrology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
• ²Department of Clinical Laboratory, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
• ³Institute of Health Management & Department of Health Management Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China

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, P < 0.001), with progressive increases from stage 1 to 5 (P < 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, P < 0.001). RCS revealed non-linear relationships between copper, fibrosis (P for non-linear = 0.038), and eGFR (P for non-linear = 0.005). Conclusions: 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.