血清可溶性Klotho蛋白与维持性血液透析患者心血管疾病及预后的关系

Association of serum soluble Klotho with episode of nonfatal cardiovascular disease and mortality in maintenance hemodialysis patients

目的探讨维持性血液透析（MHD）患者血清可溶性Klotho蛋白（sKlotho）与心血管疾病（CVD）及全因死亡、CVD死亡的关系，了解sKlotho对MHD患者预后的影响。方法以2011年10月在本院接受MHD治疗大于6个月的终末期肾衰竭成年患者（132例）为研究对象，收集患者临床资料，ELISA法检测血清sKlotho表达。随访60个月，记录新发的非致死性CVD及患者死亡的原因和时间。根据sKlotho四分位数，将患者分为Ⅰ组（sKlotho〈361．34ng／L）、Ⅱ组（361．34ng／L≤sKlotho〈398．81ng／L）、Ⅲ组（398．81ng／L≤sKlotho〈445．99ng/L）、Ⅳ组（sKlotho≥445．99ng/L）。Spearman相关分析和多因素二元Logistic回归分析评估sKlotho与各新发非致死性CVD事件的相关性。Kaplan-Meier生存曲线分析4组患者全因死亡、CVD死亡的生存率。Cox回归模型评估sKlotho对MHD患者全因死亡、CVD死亡的影响。结果132例患者血清sKlotho波动于304．02—550．62ng／L，随访期间有87例患者新发各类非致死性CVD，共计192例次。sKlotho与冠状动脉疾病、充血性心力衰竭、脑血管意外及外周动脉闭塞均呈负相关（r分别为-0．286、-0．190、-0．240、-0．243，均P〈0．05）；低sKlotho是冠状动脉疾病（OR=0．989，P=0．023）、外周动脉闭塞（OR=0．988，P=0．046）的危险因素。MHD患者共死亡35例，其中CVD死亡27例，4组患者全因死亡率及CVD病死率差异均有统计学意义（P=0．036，P=0．047）。4组患者全因死亡、CVD死亡的生存率差异均有统计学意义（χ2=8．076，P=0．044；r=7．866，P=0．049），其中Ⅳ组全因死亡、CVD死亡生存率均高于Ⅰ组、Ⅱ组，差异均有统计学意义（均P〈0．05）。多因素Cox回归分析发现糖尿病、年龄是预测MHD患者全因死亡及CVD死亡的独立危险因素（均P〈0．05），未提示sKlotho是患者全因死亡及CVD死亡的影响因素（HR=0．996，P=0．256;HR=0．996，P=0．287）。结论MHD患者sKlotho水平与冠状动脉疾病、外周动脉闭塞密切相关，sKlotho降低可能增加CVD的发生。不同sKlotho水平的患者生存率差异有统计学意义，但sKlotho不是患者全因死亡及CVD死亡的独立影响因素。

Objective To explore the association of serum soluble Klotho （sKlotho） with nonfatal cardiovascular disease （CVD） and all- cause/CVD mortality in maintenance hemodialysis （MHD） patients. Methods A total of 132 MHD patients admitted during October 2011 were enrolled. Serum sKlotho was measured by ELISA. Demographic data, including age, gender and comorbid conditions, were obtained from their medical histories, and parameters including calcium, phosphorus and albumin were assessed. The occurrence time of nonfatal CVD and all-cause mortality were recorded during the 60 months followup. MI-ID patients were categorized into four groups according to the quartiles of sKlotho： group Ⅰ （sKlotho 〈 361.34 ng/L）, group Ⅱ （361.34 ng/L≤sKlotho〈398.81 ng/L）, group Ⅲ （398.81 ng/L≤sKlotho〈445.99 ng/L） and group Ⅳ （sKlotho≥ 445.99 ng/L）. Spearman correlation analysis and binary Logistic regression analysis were used to test the association between sKlotho and nonfatal CVD events. The impacts of sKlotho on all- cause mortality and CVD mortality were assessed by Kaplan-Meier method with log-rank test. Cox regression model was applied to evaluate the effect of sKlotho on MHD patients outcomes. Results All 132 MHD patients had sKlotho ranging from 304.02 ng/L to 550.62 ng/L. And 87 patients suffered from nonfatal CVD, with 192 episodes of nonfatal CVD during the followup period. The sKlotho had negative correlations with coronary artery disease （r=-0.286, P=0.001）, congestive heart failure （r=-0.190, P=0.029）, cerebrovascular accident （r=-0.240, P=0.006） and peripheral arterial occlusion （r=-0.243, P=0.005）. The sKlotho were risk factors of coronary artery disease （OR=0.989, P=0.023） and peripheral artery occlusion （OR=0.988, P=0.046）. 35 patients died in the follow-up period, including 27 death from CVD. The all-cause mortality and CVD mortality rates were significantly different among four groups （P=0.036, P=0.047）. Survival rates of all-cause death and CVD death varied among four groups （χ2=8.076, P=0.044; χ2=7.866, P=0.049）. Patients in group IV had higher survival rates of allcause death and CVD death than those in group Ⅰand group Ⅱ （all P 〈 0.05）. Multivariate Cox regression analyses revealed diabetes and age were independent risk factors for all-cause mortality and CVD mortality （all P 〈 0.05）, but sKlotho was not associated with the poor prognosis （HR=0.996, P= 0.256; HR=0.996, P=0.287）. Conclusions Patients with lower sKlotho have worse nonfatal CVD ratio, especially coronary artery disease and peripheral arterial occlusion. Reduced serum sKlotho is associated with all-cause and CVD mortality, but sKlotho is still not a predictive indicator of prognosis of MHD patients.