Is Klotho deficiency independently associated with cardiovascular risk in chronic kidney disease?

Patients with chronic kidney disease (CKD) suffer from a high burden of cardiovascular disease (CVD) [1]. This is partly due to progressive deterioration of calciumephosphate homeostasis. Although the molecular mechanism of action of Klotho is not well understood, fibroblast growth factor-23 (FGF-23) and its coreceptor Klotho have emerged as pivotal players in calciumephosphate homeostasis. Klotho was first identified in mice, where mutations of the gene led to a syndrome resembling premature aging [2]. The Klotho protein exists in both a membrane bound and a soluble form (sKlotho). sKlotho is derived from the extracellular part of membranous Klotho through alternative splicing of the Klotho gene and has a unique role in renal calcium and phosphate excretion independent of FGF-23 [3]. There is growing interest in using sKlotho as an important biomarker of kidney function, based largely on studies showing that blood and urine concentrations of sKlotho decrease early in the course of CKD [4,5]. In addition, sKlotho has also been explored for a potential biomarker for CVD. In this issue, Abdallah et al [6] investigated the association between sKlotho and CVD risk in hemodialysis patients. They measured sKlotho and FGF-23 in 88 regular hemodialysis patients and 28 normal populations (control group), using a commercially available enzyme-linked immunosorbent assay. For evaluationof CVD, carotid intimal-media thickness and left ventricular (LV) dysfunction were estimated by ultrasonography. The sKlotho level was significantly low in hemodialysis patients compared to controls, and FGF-23 was significantly high in hemodialysis patients compared to controls. The concentrations of parathyroid hormone, FGF-23, and phosphate were significantly higher when the Klotho level was lower (< 476 pg/mL, n1⁄4 44). In contrast, serum calcium was significantly lower when the sKlotho level was lower. Notably, the prevalence of coronaryartery disease (CAD)washigher inpatients with a lower sKlotho level. Regression analysis of sKlotho for the relationship with different markers of CVD revealed that sKlotho was significantly associated with carotid intimal-media thickness, LV ejection fraction, and CAD. However, these data have some limitations. Data on dietary phosphate intake, a knowndeterminant for both serumphosphate andFGF-23 levels, were not collected. Because sKlotho has a circadian variation, measurement at fixed time is necessary [7]. Similarly, a reduced Klotho level was associated with the presence and severity of