Milovanova Ludmila Yu, Nezhdanov Kirill S, Milovanova Svetlana Yu, Lebedeva Marina V, Beketov Vladimir D, Volkov Alexey V, Kamyshova Elena S, Suvorov Aleksandr Yu, Moiseev Sergey V
Sechenov First Moscow State Medical University (Sechenov University), 8/2 Trubetskaya st., Moscow, 119991, Russian Federation.
Department of Internal, Occupational Diseases and Rheumatology, Sechenov University, Moscow, Russian Federation.
J Nephrol. 2025 Jan;38(1):171-179. doi: 10.1007/s40620-024-02069-5. Epub 2024 Sep 2.
α-Klotho deficiency may increase cardiovascular risks and worsen survival. We evaluated the association of α-Klotho with cardiovascular and all-cause mortality in pre-dialysis chronic kidney disease (CKD) patients.
In this prospective study, 75 non-diabetic CKD stage 3b-4 patients were followed-up for a median of 8 years. Primary and secondary outcomes were all-cause and cardiovascular mortality, respectively. Human soluble α-Klotho ELISA Assay (IBL-Takara 27,998-96Well), Human Fibroblast Growth Factor-23 ELISA Assay (intact FGF23, Merck Millipore MILLENZ FGF23-32 K), and Human Sclerostin ELISA kits (Biomedica, Vienna, BI-20492) were used to measure serum α-Klotho, FGF23 and sclerostin levels in the certified laboratory at the Sechenov University according to the manufacturers' protocols. All patients underwent echocardiography to evaluate left ventricular mass index (LVMI), left ventricular ejection fraction by Simpson method, and cardiac (valve) calcification score by a semi-quantitative point scale. Lateral abdominal radiography by Kauppila method was used to estimate calcification of the abdominal aorta. Cox multivariate regression and receiver-operating characteristic curve (ROC)-analysis were used to evaluate risk factors for death and their cut-off values.
Primary and secondary endpoints were reached in 15 (20%) and 9 (12%) patients, respectively. Median α-Klotho levels in deceased and surviving patients were 344 and 484 pg/ml, respectively (p = 0.002). In a multivariate Cox regression model, baseline α-Klotho levels (HR 0.99, 95% CI 0.98-1.00, p = 0.023), aortic calcification (HR 1.18, 95% CI 1.02-1.36, p = 0.029) and left ventricular mass index (LVMI) (HR 1.04, 95% CI 1.00-1.08, p = 0.033) were associated with the primary endpoint, whereas α-Klotho (HR 0.99, 95% CI 0.98-1.00, p = 0.029), aortic calcification (HR 1.23, 95% CI 1.07-1.42, p = 0.003) and LVMI (HR 1.04, 95% CI 1.00-1.08, p = 0.021) were associated with the secondary endpoint. α-Klotho levels had the highest area under the curve (AUC) by ROC analysis, that is, 0.766 (95% CI 0.70-0.82) for the primary endpoint and 0.842 (95% CI 0.79-0.90) for the secondary endpoint with cut-off values of 412 pg/ml (HR 3.06, 95% CI 1.36-6.89, p = 0.007) and 368 pg/ml (HR 4.84, 95% CI 1.59-14.73, p = 0.005), respectively.
In pre-dialysis CKD patients, α-Klotho levels are associated with all-cause and cardiovascular mortality and may be considered an early prognostic marker.
α-klotho缺乏可能会增加心血管疾病风险并降低生存率。我们评估了α-klotho与透析前慢性肾脏病（CKD）患者心血管疾病及全因死亡率之间的关联。
在这项前瞻性研究中，对75例非糖尿病CKD 3b-4期患者进行了中位时间为8年的随访。主要和次要结局分别为全因死亡率和心血管疾病死亡率。采用人可溶性α-klotho ELISA检测试剂盒（IBL- Takara 27,998-96Well）、人成纤维细胞生长因子-23 ELISA检测试剂盒（完整FGF23，默克密理博MILLENZ FGF23-32K）和人硬化蛋白ELISA试剂盒（维也纳生物医学公司，BI-20492），按照制造商的方案在谢马什克夫大学认证实验室测量血清α-klotho、FGF23和硬化蛋白水平。所有患者均接受超声心动图检查，以评估左心室质量指数（LVMI）、采用Simpson法测量的左心室射血分数以及通过半定量评分法评估的心脏（瓣膜）钙化评分。采用考皮拉法进行腹部侧位X线摄影，以评估腹主动脉钙化情况。采用Cox多因素回归分析和受试者工作特征曲线（ROC）分析评估死亡风险因素及其临界值。
分别有15例（20%）和9例（12%）患者达到主要和次要终点。死亡患者和存活患者的中位α-klotho水平分别为344 pg/ml和484 pg/ml（p = 0.002）。在多因素Cox回归模型中，基线α-klotho水平（HR 0.99，95%CI 0.98-1.00，p = 0.023）、主动脉钙化（HR 1.18，95%CI 1.02-1.36，p = 0.029）和左心室质量指数（LVMI）（HR 1.04，95%CI 1.00-1.08，p = 0.033）与主要终点相关，而α-klotho（HR 0.99，95%CI 0.98-1.00，p = 0.029）、主动脉钙化（HR 1.23，95%CI 1.07-1.42，p = 0.003）和LVMI（HR 1.04，95%CI 1.00-1.08，p = 0.021）与次要终点相关。通过ROC分析，α-klotho水平的曲线下面积（AUC）最高，即主要终点为0.766（95%CI 0.70-0.82），次要终点为0.842（95%CI 0.79-0.90），临界值分别为412 pg/ml（HR 3.06，95%CI 1.36-6.89，p = 0.007）和368 pg/ml（HR 4.84，95%CI 1.59-14.73，p = 0.005）。
在透析前CKD患者中，α-klotho水平与全因死亡率和心血管疾病死亡率相关，可被视为早期预后标志物。
