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Archakova et al. Vessel Plus 2018;2:34 I http://dx.doi.org/10.20517/2574-1209.2018.52 Page 5 of 10
[39]
valves was combined with a greater frequency of IHD, HF and dilatation of the left atrium . Taking into
account the research data, one can come to the conclusion that hyperphosphataemia, hypercalcemia and an,
increase in the level of calcium-phosphate ratio are risk factors for the development of VC.

Other potential mechanisms of VC are associated with fibroblast growth factor-23 (FGF-23) and the
activity of the transmembrane Klotho protein, which play an important role in the systemic regulation of
[40]
phosphate homeostasis .
FGF-23 is a protein consisting of 251 amino acids (32 kDa molecular weight), which is secreted from
[41]
osteocytes, mainly from osteoblasts . FGF-23 exerts its biological effects through the activation of FGF
receptors. FGF1s receptors, binding to the Klotho protein, become 1000 times more sensitive to interaction
with FGF-23 than other FGF receptors or Klotho protein alone. Klotho is a 130 kDa transmembrane
protein. In the kidneys, FGF-23 induces phosphaturia, suppressing the expression of the sodium-phosphate
[42]
cotransporter type IIa and IIc in the proximal tubule .

The correlation between elevated levels of FGF-23 and adverse clinical outcomes in patients with CKD, such
[43]
as cardiovascular morbidity and mortality , has been shown. The relationship between an increase in the
concentration of FGF-23 and the progression of CKD from stage I to V was revealed; a higher level of FGF-23
was observed in the group of patients on LTH. The same correlation was observed between the elevated FGF-
[45]
[44]
23 level in the blood serum and the Pourcelot resistive index (according to Doppler ultrasound) . Jean et al.
obtained data indicating that mortality in dialysis patients is directly correlated with the level of FGF-23.
[46]
Basic research of Grabner et al. convincingly showed that FGF-23 can directly lead to the development
of LVH. The study revealed that the increase in FGF-23 led to LVH of de novo, and a high level of FGF-23
caused an increase in the frequency of LVH irrespective of the presence or absence of hypertension. FGF-23
causes LVH independently of the Klotho coreceptor, which is expressed predominantly in the kidneys and
parathyroid glands and is absent in the cardiomyocytes. High levels of FGF-23 were also independently
associated with endothelial dysfunction.

[47]
Inaba et al. studied the effect of FGF-23 on the development of aorta and peripheral artery calcification in
men on LTH suffering from diabetes, and without diabetes. It was shown that an elevated level of FGF-23 in
plasma in type 2 diabetes is significantly correlated with VC compared to patients without diabetes.

[48]
Chan et al. , confirmed the link between an increase in FGF-23 concentration in plasma, diabetes and the
calcification of coronary arteries.

[49]
Gutiérrez et al. studied mortality associated with elevated levels of phosphorus and FGF-23 in patients on
LTH. The researchers concluded that an elevated level of FGF-23 is independently correlated with mortality
among patients on LTH. Studies put forward the main role of FGF-23 as a future biomarker of cardiovascular
morbidity and mortality.

Hyperphosphatemia is one of the main risk factors for the development of cardiovascular pathology and
mortality among patients with chronic renal failure.

Hyperphosphatemia directly associates with HF and cardiomyopathy, which can explain the direct
correlation between phosphorus levels, cardiovascular morbidity and mortality. Hyperphosphatemia is
associated with densification of the vascular wall, increased pulse wave velocity, LVH, decreased coronary
blood flow and cardiovascular mortality . In recent years, it has been proven that HF is an active and
[50]
regulated process (similar to bone mineralization), in which various bone-related proteins participate.
In addition to decreasing arterial compliance and their increased stiffness, hyperphosphatemia is closely