Soluble Klotho is not independently associated with cardiovascular disease in a population of dialysis patients

Abstract

BackgroundDialysis patients suffer from a high burden of cardiovascular disease (CVD). Partly this is due to progressive deterioration of calcium-phosphate homeostasis. Previous studies suggested that besides FGF-23, low levels of Klotho, a protein linked to aging, might constitute a key factor in this detrimental relationship. The purpose of the present study was to determine the relationship between serum Klotho (sKlotho) and the presence of CVD in dialysis patients.MethodsPlasma levels of sKlotho were measured in a cohort of dialysis patients and related to left ventricular (LV) dysfunction (defined as a LV ejection fraction <45%) and LV mass using echocardiography. Coronary artery disease (CAD) and calcification score were assessed using computed tomography angiography. Abdominal aortic calcification score (AACscore) was measured by abdominal X-ray.ResultsWe included 127 dialysis patients, 67 ± 7 years old, 76% male, 67% on hemodialysis, median sKlotho 460 pg/mL (25th-75th percentile 350-620 pg/mL). Patients with a low sKlotho (<460 pg/mL) showed significantly more CAD (81% versus 61%; p = 0.02) and LV dysfunction (19% versus 3%; p < 0.01). However, after adjusting for confounders, sKlotho was not independently associated with the presence of CVD or the AACscore.ConclusionsIn the present cohort of dialysis patients, sKlotho was not independently associated with CVD. However, patients with a low sKlotho level (<460 pg/mL) did show CAD and LV dysfunction more frequently. Therefore, while sKlotho might be a marker for CVD in dialysis patients, the current data does not support a direct cardioprotective effect of sKlotho.

Soluble klotho and mortality: The Ludwigshafen Risk and Cardiovascular Health Study

“…While female gender and non-smoking are prototypic cardioprotective factors, the associated higher s-klotho levels do not translate into reduced mortality in the entire cohort and thus, these findings remain of undetermined biological significance. A previous study reported comparable associations between s-klotho levels and diabetes status but this study was too small to provide conclusive evidence (n = 62 patients) (33).Further studies are clearly needed to evaluate the potential link between smoking and sklotho.…”

“…These two studies were performed in patients either with moderate to severe CKD (24) or end-stage renal disease (23) (23). However, all these studies were all performed in patients with a significant degree of comorbidities such as chronic kidney disease, prevalent coronary artery disease or diabetes.…”

Relationship of Serum Soluble Klotho Levels and Echocardiographic Parameters in Patients on Maintenance Hemodialysis

“…But in a more recent cross-sectional study including 88 patients with end-stage renal disease on regular hemodialysis, s-Klotho showed significant association with LVEF, but not with LVM and LVMI [10]. Similarly, Buiten et al [25] also failed to find a relationship between serum s-Klotho and LVMI in 127 dialysis patients. Our results are in agreement with those of the latter two studies from dialysis patients.…”

Gender Specific Association between Serum Fibroblast Growth Factor 23/α-Klotho and Coronary Artery and Aortic Valve Calcification

“…Osawa et al recently reported that higher coro- . In contrast, Buiten found that the association between FGF23 or -Klotho and coronary calcification was insignificant 36) ; however, they did not assess the relationship in each gender separately. Whether FGF23/ -Klotho might be a therapeutic target for modulating vascular calcification ultimately awaits studies investigating the alteration of FGF23/ -Klotho can reduce the extent of arteriosclerosis.…”

“…In addition, in the study by Kitagawa et al, the relation between -Klotho and aortic calcification lost statistical significance after other covariates, including calcium/phosphate metabolism-related parameters (calcium, phosphate, intact PTH, and 1,25(OH)2D), were considered 32) . The possible association between FGF23 and CAC has been examined also in a few previous studies 23,36) ; for example, Masai et al found a significant association between FGF23 and coronary calcifica- and that female subjects who had high bone mineral density had higher coronary artery calcium score but not aortic valve calcium score 38) . We cannot conclude whether -Klotho has really opposite effects, if at all, on the coronary artery and aortic valve calcification because the association between the highest -Klotho tertile and CAC did not reach statistical significance, This point should be re-evaluated in future studies.…”