Soluble Klotho is associated with mortality and cardiovascular events in hemodialysis

Abstract

Background Klotho is a transmembrane protein acting as a co-receptor for FGF-23 and thus exerts clinical actions on mineral metabolism. The association of secreted Klotho with outcomes in CKD patients is unclear. This study examined the relation between plasma Klotho and cardiovascular events in dialysis patients, accounting for common and CKD-MBD related risk factors, arterial stiffness and atherosclerotic burden. Methods Seventy-nine chronic hemodialysis patients were observed for a median follow-up of 5.5 years. Klotho levels as well as carotid–femoral pulse wave velocity (cfPWV) and common carotid intima-media thickness (ccIMT) measurements were performed at baseline. The primary end-point was first occurrence of all-cause death, non-fatal myocardial infarction or non-fatal stroke. Secondary end-points were: (i) all-cause mortality; (ii) cardiovascular mortality; (iii) a combination of cardiovascular death, non-fatal MI, non-fatal stroke, resuscitation after cardiac arrest, coronary revascularization, heart failure hospitalization and atrial fibrillation. Results Cumulative freedom from the primary endpoint was 31% for the low-Klotho group (≤745 pg/ml) and 53% for the high-Klotho group (logrank p = 0.017); HR: 2.137, 95%CI 1.124–4.065. Cumulative survival was insignificantly lower (44% vs 56%, p = 0.107), but cumulative cardiovascular survival (63% vs 88%, p = 0.029) and cumulative freedom from the cardiovascular composite outcome (18% vs 45%, p = 0.009) were significantly lower in the low-Klotho group. In modelled Cox-regression analysis the association of low Klotho with the primary endpoint remained significant after stepwise adjustment for cFGF3, PTH, Ca x P product, established risk factors (age, dialysis vintage, diabetes, hypertension, smoking, history of cardiovascular disease) as well as cfPWV and ccIMT [Model 6: HR:2.759, 95%CI 1.223–6.224, p = 0.014]. Conclusions Low Klotho is associated with cardiovascular events in hemodialysis patients, independently from factors associated with mineral-bone disease, common risk factors and intermediate outcomes, such as cfPWV and ccIMT.

The Protective Role of Klotho in CKD-Associated Cardiovascular Disease

“…In dialysis patients, Marçais et al [101] reported that conservation of serum Klotho above 280 ng/L is associated with a better 2-year cardiovascular protection. This is consistent with a recent prospective study -lower serum level of Klotho is associated with cardiovascular events in hemodialysis patients [102]. In CKD patients without dialysis, we demonstrated that lower serum Klotho levels are independently associated with overall mortality and CVD events [103].…”

Low serum Klotho level as a predictor of calcification of the heart and blood vessels in patients with CKD stages 2–5D

“…Традиционные факторы риска кардиоваскулярных заболеваний, такие как артериальная гипертензия (АГ), дислипидемия, сахарный диабет, достаточно характерны для популяции больных ХБП. Однако в последние годы показано, что другие кардиоваскулярные факторы риска, специфичные для уремии, могут вносить вклад в увеличение сердечно-сосудистого риска при ХБП [3][4][5]. Эти факторы включают среди других изменение уровня морфогенетических белков (фактор роста фибробластов 23 -FGF-23, Klotho) и гликопротеина склеростина, которые участвуют в поддержании костно-минерального гомеостаза.…”

Should We Consider the Cardiovascular System While Evaluating CKD-MBD?

“…In patients with CKD 3 stage, a change in FGF23/klotho ratio correlated with the changes in left ventricular mass [114]. In hemodialysis patients, low klotho levels were associated with CV events, independently from other CKD-MBD factors [115]. Analysis of the LURIC (Ludwigshafen Risk and Cardiovascular Health) study did not show any additional predictive power of CV and mortality risk in patients with normal kidney function [116].…”