Synergistic association of the copper/zinc ratio under inflammatory conditions with diabetic kidney disease in patients with type 2 diabetes: The Asahi Diabetes Complications Study

Aims/Introduction: We aimed to study the relationships among the copper (Cu)/zinc (Zn) ratio, inflammatory biomarkers, and the prevalence of diabetic kidney disease (DKD) in patients with type 2 diabetes. Materials and Methods: A cross-sectional study was performed on 651 patients with type 2 diabetes. DKD was defined as a urinary albumin-to-creatinine ratio of >= 30 mg/g creatinine and/or an estimated glomerular filtration rate using cystatin C of < 60 mL/min/1.73 m(2). Areas under the curves (AUCs), cutoff values, and thresholds for detecting DKD were determined for the Cu/Zn ratio, soluble tumor necrosis factor-alpha receptor 1 (sTNF alpha R1), and high-sensitivity C-reactive protein (hsCRP). Patients were categorized by each cutoff value of sTNF alpha R1 and the Cu/Zn ratio. Odds ratios (ORs) and biological interactions for the prevalence of DKD were determined. Results: DKD was identified in 220 patients. AUC/optimal cutoff values were 0.777/1300 pg/mL for sTNF alpha R1, 0.603/1.1648 for the Cu/Zn ratio, and 0.582/305 ng/mL for hsCRP. The ORs for DKD were higher, but not significantly, in the sTNF alpha R1 < 1300 and Cu/Zn >= 1.1648 group, significantly higher in the sTNF alpha R1 >= 1300 and Cu/Zn < 1.1648 group (P < 0.0001), and further synergistically elevated in the sTNF alpha R1 >= 1300 and Cu/Zn >= 1.1648 group (P < 0.0001) compared with the sTNF alpha R1 < 1300 and Cu/Zn < 1.1648 group after multivariable adjustment. Levels of sTNF alpha R1 were significantly higher in the sTNF alpha R1 >= 1300 and Cu/Zn >= 1.1648 group than in the sTNF alpha R1 >= 1300 and Cu/Zn < 1.1648 group (P = 0.0006). Conclusions: Under an inflammatory initiation signal of elevated serum sTNF alpha R1 levels, an increase in the Cu/Zn ratio may further exacerbate inflammation and is synergistically associated with a high prevalence of DKD in patients with type 2 diabetes.