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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 R 2  = 0.511, P < 0.0001) and CIMT (adjusted R 2  = 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., (© 2021. The Author(s).)

Decrease in soluble anti-aging Klotho protein levels is associated to cardiovascular disease (CVD). Diverse studies have shown a bidirectional relationship between Klotho and inflammation, a risk factor for the development of CVD. In this work we aimed to evaluate the association between Klotho and inflammatory cytokines levels in the context of human CVD.The study included 110 patients with established CVD and preserved renal function, and a control group of 22 individuals without previous history of cardiovascular events. Serum Klotho and IL10 levels were significantly lower in the CVD group. Inflammatory status, marked by the TNFα/IL10 ratio and the C-reactive protein (CRP) levels, was significantly increased in the group of patients with established CVD. Soluble Klotho levels were directly correlated with eGFR (r=0.217) and IL10 (r=0.209) and inversely correlated with age (r=-0.261), CRP (r=-0.203), and TNFα/IL10 (r=-0.219). This association with TNFα/IL10 remained significant in age-matched subgroups. Multiple logistic regression analysis showed that age, smoking and the neutrophil-to-lymphocyte ratio (NLR) constituted risk factors for the presence of CVD, while Klotho was a protective factor.In conclusion, in patients with established CVD, the reduction in soluble Klotho is associated with a pro-inflammatory status marked by lower IL10 concentrations and higher TNFα/IL10 ratio and CRP levels.

Objective: The effect of pentoxifylline on Klotho levels in patients with type 2 diabetes mellitus with chronic kidney disease (CKD) was assessed in a post hoc analysis of the Pentoxifylline for Renoprotection in Diabetic Nephropathy (PREDIAN) trial., Research Design and Methods: Circulating and urinary tumor necrosis factor-α (TNF-α) and Klotho were measured before and after 1 year of pentoxifylline. The effect on Klotho expression was assessed in cultured renal tubular cells., Results: Pentoxifylline administration resulted in decreased serum and urinary TNF-α, whereas serum and urinary Klotho increased significantly. Changes in urinary Klotho, urinary TNF-α, and phosphorus were associated with changes in serum Klotho; changes in estimated glomerular filtration rate, urinary TNF-α, and albuminuria were related to urinary Klotho variation. In renal tubular cells, pentoxifylline prevented the decrease in Klotho expression induced by inflammatory cytokines or albumin., Conclusions: Pentoxifylline increased Klotho levels in patients with diabetes with stage 3-4 CKD and prevented reduced Klotho expression in vitro. This beneficial effect may be related to anti-inflammatory and antialbuminuric activity., (© 2018 by the American Diabetes Association.)

Atherosclerosis is a chronic inflammatory disorder affecting the artery wall. Klotho, an anti-aging factor expressed in the vessel walls that participates in the maintenance of vascular homeostasis, can be down-regulated by inflammation. In this proof-of-concept work we seek to characterize the arterial KLOTHO expression in the vascular wall, as well as the serum concentration of this protein, in a group of patients with clinical atherosclerotic disease. In addition, we aim to analyze the relationship between Klotho and inflammation. Vascular samples were obtained from 27 patients with atherosclerotic disease under an elective vascular surgery procedure, and from 11 control subjects (cadaveric organ donation programme). qRT-PCR was performed to analyze the gene expression of KLOTHO, TNF-α, IL-6 , and IL-10 Serum levels of soluble KLOTHO were measured by ELISA. As compared with control subjects, serum concentrations and vascular expression of Klotho were lower in patients with atherosclerotic vascular disease, whereas inflammatory status was significantly higher. There was a negative and significant correlation between inflammatory parameters and Klotho. After controlling for the effect of other variables, partial correlation showed a direct relationship between vascular KLOTHO gene expression and IL-10 mRNA levels, whereas there was a negative association with serum LDL concentrations and vascular TNF-α expression. Our study indicates an inverse interrelationship between inflammation and Klotho in atherosclerosis. Further studies are necessary to elucidate whether the inflammatory state causes Klotho deficiency or, on the contrary, reduction of Klotho could be responsible for greater inflammation, and finally, to investigate the potential clinical relevance of this association., (© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Background: Paricalcitol decreases intact parathyroid hormone and the frequency of secondary hyperparathyroidism after kidney transplantation. This proof-of-concept study aimed to assess the effect of paricalcitol on fibroblast growth factor-23/KLOTHO axis in renal transplants., Methods: Twenty-nine subjects with secondary hyperparathyroidism received oral paricalcitol 1 μg/d for 3 months, and 8 patients matched by age, sex, and creatinine clearance, but with intact parathyroid hormone less than 100 pg/mL, were included as controls., Results: Intact parathyroid hormone decreased in paricalcitol-treated patients (P < 0.0001). Serum fibroblast growth factor-23 enhanced (P < 0.01), whereas KLOTHO concentrations showed a trend to increase (P = 0.067). KLOTHO gene expression in peripheral blood mononuclear cells increased by 45.7% in paricalcitol-treated patients (P < 0.01), without change in controls. Paricalcitol administration resulted in a median percent decrease of 56% in methylated DNA levels of KLOTHO promoter (P < 0.001). The ratio of the unmethylated/methylated KLOTHO promoter DNA did not change in controls, but it increased by 177% in paricalcitol-treated subjects (P < 0.0001). The increase in this ratio was independently associated with the change in serum KLOTHO (r = 0.55, P < 0.01) and messenger RNA expression levels (r = 0.40, P < 0.05)., Conclusions: Paricalcitol administration to renal transplant patients significantly reduced intact parathyroid hormone and increased fibroblast growth factor-23, with a trend to increase in serum KLOTHO. Paricalcitol-treated patients showed a decrease in the methylation of the KLOTHO promoter with an increment in the ratio of un-methyated/methylated DNA, which was associated with an increase of KLOTHO gene expression levels and serum KLOTHO concentrations. Long-term studies are needed to assess whether paricalcitol-induced increase in KLOTHO gene expression and serum concentrations may translate into beneficial clinical effects.

Klotho protein has been associated with beneficial effects that contribute to the maintenance of cardiovascular health. Diverse studies suggest that alterations in the levels of this molecule may be associated with pathophysiological abnormalities that result in increased cardiovascular risk. The primary aim of this proof-of-concept study was to analyse the existence of a potential link between Klotho gene polymorphisms and the expression level of this gene in the vascular wall, and additionally with the incidence of cardiovascular disease and cardiovascular risk factors. Our results indicate that the variant G-395A, located in the promoter region, influences Klotho gene vascular expression and is associated with the incidence of diabetes. Similarly, the exonic variant KL-VS was associated with the incidence of atherosclerotic vascular disease and coronary artery disease. Moreover, vascular expression levels of Klotho were related with the incidence of diabetes mellitus and coronary artery disease. These findings, which need to be confirmed in larger studies, suggest a potential role of Klotho in the pathogenesis of vascular damage., (© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)