Background
Patients with chronic kidney disease (CKD) present with a higher burden of cardiovascular disease (CVD) and cardiovascular mortality than the general population [
1,
2]. Left ventricular myocardial hypertrophy, the most commonly diagnosed cardiovascular abnormality in CKD patients, is secondary to both volume and pressure overload [
3]. Cardiac hypertrophy is an important cause of cardiovascular morbidity and mortality for CKD patients because it can lead to congestive heart failure, arrhythmia, ischemic cardiomyopathy, even in the absence of coronary artery disease, and sudden death in CKD patients [
4‐
6]. Arterial stiffness in CKD patients caused by arteriosclerosis with thickening and stiffening of the arterial wall [
7] brings about cardiac hypertrophy and a negative prognostic value for CVD [
8,
9].
Mineral bone metabolism is important in CKD, and progressive deterioration of calcium-phosphorus homeostasis is associated with cardiovascular complications. Impaired calcium-phosphorus homeostasis can cause cardiac hypertrophy and vascular calcification. Klotho has emerged as a pivotal player in calcium-phosphorus homeostasis and mineral metabolism regulation in CKD, and it might explain the relationship between CKD and CVD. The
Klotho gene, which was originally identified as an aging suppressor gene, is closely associated with CKD. In a previous study, klotho knock-out mice had similarities with CKD patients, such as hyperphosphatemia, ectopic soft tissue calcification, and arteriosclerosis [
10], suggesting that CKD might result from a state of klotho deficiency. Thus, in addition to serving as a biomarker for CKD, klotho deficiency is also a pathogenetic indicator for both renal and extra-renal complications in CKD [
11]. In previous experimental studies, restoration of serum klotho levels ameliorated cardiac hypertrophy and vascular calcification [
12,
13], and haplodeficiency of the
Klotho gene caused arterial stiffness [
14]. Clinical data supporting the above experimental studies are scarce and present mixed results [
15]. Yang et al. [
16] showed that cardiac hypertrophy evaluated by left ventricular mass index (LVMI) was negatively associated with serum klotho in 86 CKD patients. They did not show the association between klotho and LVMI for CKD patients in an adjustment model. In another study, there was no significant association between serum klotho and LVMI in dialysis patients [
17]. Previous studies have been conducted on a small number of patients and few studies have focused on CKD patients for the association between klotho and LVMI. Given the negative effects of klotho deficiency, its associated cardiovascular complications in preclinical studies, and the limited number of clinical studies, the current study aimed to investigate the association between serum klotho and cardiovascular parameters in CKD patients, using the baseline cross-sectional data set of a large-scale Korean CKD cohort.
Discussion
The kidney is the principal organ for production of klotho, and CKD is known to be associated with a klotho-deficiency state. CKD patients suffer from a high burden of CVD. In the present study, the serum klotho level was lower in advanced CKD stages. Klotho exhibited an independent negative association with LVMI. However, there was no significant association between klotho and PWV after adjustment in our subjects. Abdominal aorta calcification and coronary artery calcification were not significantly different among the klotho quartile groups. No differences in systolic or diastolic heart dysfunction were observed across klotho quartiles.
Previous studies showed that CKD patients were more likely to have cardiac structural changes in the absence of decreased LV ejection fraction [
34,
35]. Lower prevalence of systolic and diastolic heart dysfunction was not surprising, given the exclusion of subjects with severe heart failure (New York Heart Association Class III or IV) from enrollment in the present study.
Xieet al. [
12] showed that klotho-deficient CKD mice have aggravated cardiac hypertrophy and cardiac fibrosis compared with wild-type CKD mice. Intravenous delivery of a transgene encoding soluble klotho attenuated cardiac hypertrophy in the klotho-deficient CKD mice. The authors explained that downregulation of the stress-induced transient receptor potential canonical 6 (TRPC6)-mediated gene amplification loop by soluble klotho may play a role in the cardioprotection of uremic hearts [
36].Yang et al.[16]reported that klotho protects against indoxyl sulphate-induced cardiac hypertrophy in CKD mice. They also showed that serum klotho levels are associated with the development of LVH in patients with CKD. They did not show an association between klotho and LVMI for CKD patients in an adjustment model. Most animal study results have suggested that klotho deficiency is associated with cardiac hypertrophy. However, clinical studies have shown mixed results with regards to serum klotho and cardiac hypertrophy. Tanaka et al. [
37] reported that the lowest klotho tertile was associated with LV hypertrophy and systolic dysfunction only among patients with CKD stage G3a and G3b, respectively. Buiten et al. [
17] showed that serum klotho was not independently associated with CVD, including LVMI, among 127 dialysis patients. This study was conducted with a small number of dialysis patients compared to our study. They also described that the association of soluble klotho with cardiovascular parameters might be diminished since the patients already developed end stage renal disease [
17]. Seiler
et al. [
38] showed that soluble klotho was not significantly associated with cardiovascular outcomes for 444 patients with CKD stage 2–4. They did not assess each of cardiovascular parameters and mean eGFR was lower than that of our study subjects (45 ± 16 vs. 53.0 ± 30.7 ml/min/1.73m
2). Our study included all stages of CKD patients and presented that klotho could be a marker of LVMI in predialysis CKD patients. The reason for the discrepancies between those studies and ours remains uncertain. However, there are possible explanations. First, these studies differed in race, kidney function, and number of subjects. Second, we examined cardiovascular parameters, rather than cardiovascular outcomes. Thirdly, patients with severe heart failure (New York Heart Association Class III or IV) were excluded in our study. However, the present study has a much greater statistical power, due to a larger number of CKD subjects analyzed. Soluble klotho plays important roles in anti-aging, anti-oxidant, and anti-vascular calcification [
39],and CKD as a klotho-deficient state may have a close association with chronic cardiovascular complications. The present study showed the association of klotho with LVMI in a large number of CKD patients, with adjustment for markers of mineral bone metabolism such as phosphorous and calcium.
In an experimental study,
klotho gene delivery into skeletal muscle inhibited medial hypertrophy of the aorta in an animal model of atherosclerotic disease [
40], and klotho deficiency–induced arterial stiffening was mediated by upregulation of aldosterone levels [
14]. Soluble klotho protects endothelial integrity by regulating calcium entry into vascular endothelial cells [
40,
41]. Kitagawa et al. [
42] reported that the serum klotho level was a significant determinant of arterial stiffness, defined as baPWV ≥1400 cm/s in 114 CKD patients. They showed a significant association only at baPWV ≥1400 cm/s. In our study, we also analyzed hfPWV as a central arterial stiffness marker. In another clinical study, arterial stiffness measured by baPWV increased in 109 CKD patients, but it was not related to klotho [
43]. This study was performed only with a small number of diabetic CKD patients. Thus, there have been discrepancies among clinical study results. Further studies are needed to elucidate the association between klotho and arterial stiffness in CKD patients. This study has several limitations. First, owing to the cross-sectional nature of the study, it is hard to demonstrate the cause-effect inferences about the relationship between serum klotho levels and cardiac hypertrophy or arterial stiffness. Second, serum klotho has a circadian variation, meaning that examination at a fixed time is necessary [
44]. Thirdly, we measured c-terminal FGF23 in this study. Lack of agreement between c-terminal and intact FGF23 measurements and also differences in their association with other biochemical parameters have been reported [
45]. However, both the higher c-terminal and intact FGF23 values have been associated with increased mortality and poor outcomes in CKD patients.
Acknowledgments
The authors gratefully thank to the clinical research staff and nurses of KNOW-CKD study.