Xie Peichen, Wang Dingding, Zhang Meng, Jiang Lanping, Qiu Yagui, Wang Yiqin, Ye Siyang, Zhang Manhuai, Tan Li, Chen Sixiu, Liu Qianling, Peng Huajing, Li Suchun, Li Jianbo, Wen Qiong, Jin Leigang, Wu Xiaoping, Chan Kam Wa, Tang Sydney C W, Chen Wei, Li Bin
Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
NHC Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, People's Republic of China.
Diabetol Metab Syndr. 2025 Jun 7;17(1):198. doi: 10.1186/s13098-025-01729-1.
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.
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.
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.
Serum Klotho is inversely associated with the prevalence of DKD and is also linked to reduced all-cause mortality in individuals with DKD.
血清α-klotho是一种与抗衰老相关的生物标志物，与肾脏疾病有关。然而，血清α-klotho与糖尿病肾病（DKD）之间的关系缺乏有力证据。本研究旨在探讨血清α-klotho水平与DKD的关联，并评估血清α-klotho与DKD患者全因死亡率之间的关系。
我们利用了2007 - 2016年美国国家健康与营养检查调查（NHANES）的数据，采用了横断面和队列研究设计。使用加权逻辑回归模型检验血清α-klotho与DKD之间的关联。为了估计全因死亡率的风险比（HRs）和95%置信区间（95% CIs），应用了加权Cox比例风险模型。采用受限立方样条分析来评估血清α-klotho与DKD或全因死亡率之间的线性或非线性关系。此外，进行中介分析以确定全身免疫炎症指数（SII）是否介导血清α-klotho对全因死亡率的影响。
我们的研究结果显示在模型2中调整社会人口统计学和生活方式因素后，血清α-klotho与DKD之间存在显著的负相关（优势比[OR] 0.65，95% CI 0.47 - 0.90，P = 0.01）。然而，在模型3中进一步调整合并症、SII、估计肾小球滤过率和尿白蛋白/肌酐比值后，这种关联减弱且失去统计学意义（OR 0.65，95% CI 0.32 - 1.31，P = 0.2）。在平均76个月的随访期内，共有795名个体（34%）死亡。加权多变量Cox回归模型表明，DKD患者血清α-klotho每增加一个单位，全因死亡风险降低（HR 0.48，95% CI 0.29 - 0.82，P = 0.008）。此外，受限立方样条分析确定血清α-klotho与DKD之间存在非线性关系（非线性P < 0.001），而在DKD人群中血清α-klotho与全因死亡率之间观察到线性关系（非线性P = 0.3480）。分层和交互分析证实了这些核心发现的稳健性。此外，发现SII部分介导了血清α-klotho与全因死亡率之间的关联，占该效应的5.7%。
血清α-klotho与DKD的患病率呈负相关，也与DKD患者全因死亡率降低有关。
