Abstract
OBJECTIVES: The purpose of this research is to clarify the connection between the serum Klotho levels and diabetic kidney disease (DKD) in American adults with diabetes. METHODS: Statistic from the 2007-2016 National Health and Nutrition Examination Survey was used to explore correlation between Klotho levels and the risk of diabetic kidney disease (DKD) with multivariate linear regression models. Smoothed curve fitting was conducted to find potential non-linear relationships. Subsequently, a two-sample Mendelian randomization (MR) analysis was conducted utilizing summary statistics from genome-wide association studies (GWAS). The primary method employed was inverse variance weighting (IVW), complemented by additional MR techniques to investigate the causal link between Klotho levels and diabetic kidney disease (DKD). Furthermore, sensitivity analyses were conducted to evaluate the robustness of the findings. RESULTS: The cross-sectional study included a total of 3,214 individuals with diabetes mellitus from NHANES, with 1,967 of these participants being diagnosed as diabetic kidney disease (DKD).The multivariate logistic regression model showed that the higher the Klotho levels were, the lower incidence of DKD was. The MR results suggested the serum Klotho concentration to be a direct protective factor of diabetic nephropathy (IVW odds ratio (OR): 0.859 (95% confidence interval 0740-0.998), p<0.05), which was consistent with conclusion from observational study from NHANES. CONCLUSION: This investigation uncovered an inverse relationship between the serum Klotho levels and diabetic kidney disease. To further authenticate these findings, additional randomized controlled trials are essential, as they suggest a robust negative correlation between Klotho levels and DKD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-025-01623-7.