Associations of serum Klotho with diabetic kidney disease prevalence and mortality: insights from a nationally representative U.S. cohort

Background: Serum Klotho, a biomarker associated with anti-aging, has been implicated in kidney disease. However, there is a lack of robust evidence for the relationship between the serum Klotho and diabetic kidney disease (DKD). This study aimed to investigate the association of the serum Klotho levels with DKD and assess the relationship between serum Klotho and all-cause mortality in individuals with DKD. Methods: We utilized data from the 2007–2016 National Health and Nutrition Examination Survey (NHANES), incorporating both cross-sectional and cohort study designs. The association between the serum Klotho and DKD was examined using weighted logistic regression models. To estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for all-cause mortality, weighted Çox proportional hazards models were applied. Restricted cubic spline analysis was used to assess the linear or nonlinear relationships between the serum Klotho and DKD or all-cause mortality. Additionally, mediation analysis was conducted to determine whether the systemic immune-inflammatory index (SII) mediated the effect of serum Klotho on all-cause mortality. Results: Our findings revealed a significant reverse association between serum Klotho and DKD after adjusting for sociodemographic and lifestyle factors in Model 2 (odds ratio [OR] 0.65, 95% CI 0.47–0.90, P = 0.01). However, this association was attenuated and lost statistical significance after further adjustment for comorbidities, SII, estimated glomerular filtration rate, and urine albumin/creatinine ratio in Model 3 (OR 0.65, 95% CI 0.32–1.31, P = 0.2). During an average follow-up period of 76 months, a total of 795 individuals (34%) experienced mortality. Weighted multivariate Cox regression models indicated that each one-unit increase in the serum Klotho was associated with a reduced risk of all-cause mortality (HR 0.48, 95% CI 0.29–0.82, P = 0.008) in DKD patients. Furthermore, restricted cubic spline analysis identified a nonlinear relationship between the serum Klotho and DKD (P for nonlinearity < 0.001), while a linear relationship was observed between serum Klotho and all-cause mortality (P for nonlinearity = 0.3480) among DKD populations. Stratified and interaction analysis confirmed the robustness of these core findings. Additionally, SII was found to partially mediate the association between serum Klotho and all-cause mortality, accounting for 5.7% of the effect. Conclusions: Serum Klotho is inversely associated with the prevalence of DKD and is also linked to reduced all-cause mortality in individuals with DKD.