Abstract
Chronic kidney disease (CKD) has been associated with a higher risk of cardiovascular disease (CVD). CKD patients present a decrease in the levels of the protein Klotho that accompanies the decrease in kidney function. This protein has been related to protective effects against CVD. However, it is unclear whether circulating Klotho, and its expression in peripheral blood cells (PBCs) are also associated with subclinical atherosclerosis in CKD. The present study aimed to study the relationship between Klotho and subclinical atherosclerosis in a population of patients with moderate to severe CKD. We determined the serum levels and gene expression in PBCs levels of Klotho and three inflammatory cytokines in 103 patients with CKD and investigated their relationship with two surrogate markers of subclinical atherosclerotis: ankle-brachial index (ABI) and carotid intima-media thickness (CIMT). Patients with subclinical atherosclerosis presented lower serum and PBCs expression levels of Klotho. Both variables were associated with the presence of subclinical atherosclerosis, being directly related with ABI and inversely with CIMT (P < 0.0001 for both). Multiple regression analysis demonstrated that both variables were significant determinants for ABI (adjusted R2 = 0.511, P < 0.0001) and CIMT (adjusted R2 = 0.445, P < 0.0001), independently of traditional and emergent cardiovascular risk factors. Moreover, both constituted protective factors against subclinical atherosclerosis [OR: 0.993 (P = 0.002) and 0.231 (P = 0.025), respectively]. Receiver operating characteristic analysis pointed to the utility of serum Klotho (area under the curve [AUC]: 0.817, 95% CI: 0.736–0.898, P < 0.001) and its gene expression in PBCs (AUC: 0.742, 95% CI: 0.647–0.836, P < 0.001) to distinguish subclinical atherosclerosis. The reductions in serum and PBCs expression levels of Klotho in CKD patients are independently associated with the presence of for subclinical atherosclerosis. Further research exploring whether therapeutic approaches to maintain or elevate Klotho could reduce the impact of CVD in CKD patients is warranted.
Highlights
Chronic kidney disease (CKD) has been associated with a higher risk of cardiovascular disease (CVD)
Forty-four of patients (42.7%) presented subclinical atherosclerosis: 41 patients had ankle-brachial index (ABI) < 0.9 and 10 had carotid intima-media thickness (CIMT) ≥ 0.9 mmWe compared the differences between this group of patients to those without subclinical atherosclerosis
The results showed that serum and blood mRNA Klotho levels, together with serum IL6, were positively related and significantly associated with the values of ABI and CIMT (Table 3)
Summary
Chronic kidney disease (CKD) has been associated with a higher risk of cardiovascular disease (CVD). CKD patients present a decrease in the levels of the protein Klotho that accompanies the decrease in kidney function This protein has been related to protective effects against CVD. It is unclear whether circulating Klotho, and its expression in peripheral blood cells (PBCs) are associated with subclinical atherosclerosis in CKD. Multiple regression analysis demonstrated that both variables were significant determinants for ABI (adjusted R2 = 0.511, P < 0.0001) and CIMT (adjusted R2 = 0.445, P < 0.0001), independently of traditional and emergent cardiovascular risk factors Both constituted protective factors against subclinical atherosclerosis [OR: 0.993 (P = 0.002) and 0.231 (P = 0.025), respectively]. Several studies have reported an increase in the incidence and severity of coronary heart disease as the GFR decreases[10,11,12] and the prevalence of atheromatous plaques in asymptomatic CKD patients throughout all stages of CKD13
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