Abstract
BackgroundKlotho was originally identified in a mutant mouse strain unable to express the gene that consequently showed shortened life spans. In humans, low serum Klotho levels are related to the prevalence of cardiovascular diseases in community-dwelling adults. However, it is unclear whether the serum Klotho levels are associated with signs of vascular dysfunction such as arterial stiffness, a major determinant of prognosis, in human subjects with chronic kidney disease (CKD).MethodsWe determined the levels of serum soluble Klotho in 114 patients with CKD using ELISA and investigated the relationship between the level of Klotho and markers of CKD-mineral and bone disorder (CKD-MBD) and various types of vascular dysfunction, including flow-mediated dilatation, a marker of endothelial dysfunction, ankle-brachial pulse wave velocity (baPWV), a marker of arterial stiffness, intima-media thickness (IMT), a marker of atherosclerosis, and the aortic calcification index (ACI), a marker of vascular calcification.ResultsThe serum Klotho level significantly correlated with the 1,25-dihydroxyvitamin D level and inversely correlated with the parathyroid hormone level and the fractional excretion of phosphate. There were significant decreases in serum Klotho in patients with arterial stiffness defined as baPWV≥1400 cm/sec, atherosclerosis defined as maximum IMT≥1.1 mm and vascular calcification scores of ACI>0%. The serum Klotho level was a significant determinant of arterial stiffness, but not endothelial dysfunction, atherosclerosis or vascular calcification, in the multivariate analysis in either metabolic model, the CKD model or the CKD-MBD model. The adjusted odds ratio of serum Klotho for the baPWV was 0.60 (p = 0.0075).ConclusionsDecreases in the serum soluble Klotho levels are independently associated with signs of vascular dysfunction such as arterial stiffness in patients with CKD. Further research exploring whether therapeutic approaches to maintain or elevate the Klotho level could improve arterial stiffness in CKD patients is warranted.
Highlights
Chronic kidney disease (CKD) may fundamentally underlie the development of cardiovascular disease (CVD) and appears to be a risk factor for CVD [1]
CKD leads to increased levels of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) and decreased levels of circulating 1,25dihydroxyvitamin D (1,25-hydroxyvitamin D (25D)) along with hypocalcemia, hyperphosphatemia, bone disease, vascular calcification and cardiovascular morbidities collectively referred to as chronic kidney diseasemineral and bone disorder (CKD-MBD) [3,4,5]
A total of 83 patients were on antihypertensive therapy (71 patients were being treated with angiotensin receptor blockers (ARBs) or angiotensin converting enzyme inhibitors (ACEIs), 58 with calcium channel antagonists and 14 with other agents)
Summary
Chronic kidney disease (CKD) may fundamentally underlie the development of cardiovascular disease (CVD) and appears to be a risk factor for CVD [1]. Klotho was originally identified in a mutant mouse strain that could not express the gene, which developed multiple disorders resembling human aging and had a shortened life span [10]. Secreted Klotho is involved in the regulation of nitric oxide production in the endothelium [20,21], maintenance of endothelial integrity and permeability [22], calcium homeostasis in the kidneys [23] and inhibition of intracellular insulin and insulin-like growth factor-1 signaling [24]. Low serum Klotho levels are related to the prevalence of cardiovascular diseases in community-dwelling adults It is unclear whether the serum Klotho levels are associated with signs of vascular dysfunction such as arterial stiffness, a major determinant of prognosis, in human subjects with chronic kidney disease (CKD)
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