Klotho: a link between cardiovascular and non-cardiovascular mortality

Klotho is a membrane-bound protein acting as an obligatory coreceptor for fibroblast growth factor 23 (FGF23) in the kidney and parathyroid glands. The extracellular portion of its molecule may be cleaved and released into the blood and produces multiple endocrine effects. Klotho exerts anti-inflammatory and antioxidative activities that may explain its ageing suppression effects evidenced in mice; it also modulates mineral metabolism and FGF23 activities and limits their negative impact on cardiovascular system. Clinical studies have found that circulating Klotho is associated with myocardial hypertrophy, coronary artery disease and stroke and may also be involved in the pathogenesis of salt-sensitive hypertension with a mechanism sustained by inflammatory cytokines. As a consequence, patients maintaining high serum levels of Klotho not only show decreased cardiovascular mortality but also non-cardiovascular mortality. Klotho genetic polymorphisms may influence these clinical relationships and predict cardiovascular risk; rs9536314 was the polymorphism most frequently involved in these associations. These findings suggest that Klotho and its genetic polymorphisms may represent a bridge between inflammation, salt sensitivity, hypertension and mortality. This may be particularly relevant in patients with chronic kidney disease who have decreased Klotho levels in tissues and blood.