*3.2. Role of Klotho*

In close relation to FGF23 levels elevation, it is known that patients with CKD are in klotho-deficiency, which, according to the existing knowledge, contributes to high CV mortality among CKD patients. Decreased soluble klotho levels in the circulation could be detected very early in CKD, from stage 2, and in urine even from CKD stage 1 [110].

On the cellular level, it has been shown that circulating klotho has a cardioprotective e ffect by downregulation of TRPC6 channels in heart as an antagonist of the Wnt/b-catenin pathway [111]. Klotho-deficient CKD mice had more pronounced cardiac hypertrophy than wild-type CKD mice and even after normalization of serum phosphate and FGF23 levels, cardiac hypertrophy was not improved, meaning that klotho-deficiency is an important cause of cardiac hypertrophy in CKD, independently of FGF23 and phosphate [112]. Klotho deficiency in CKD results not only in cardiac hypertrophy but is involved in cardiac fibrosis development. It has been shown that endogenous klotho is expressed both by human cardiomyocytes (HCMs) and cardiac fibroblasts (HCFs) and that uremic serum or TGF-β1 suppressed klotho expression by HCMs [113]. Klotho upregulation inhibits TGF-β1-induced fibrosis and pathogenic Wnt/ β-catenin signaling in HCMs [113].

Clinical studies also support the cardioprotective role of klotho. 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]. On the contrary, in patients with CKD, as presented by the KNOW-CKD study, serum klotho was shown to be an independent biomarker of a left ventricular mass index, but not of arterial stiffness [117].

Klotho deficiency also contributes indirectly to increased CV risk in CKD. Known to be expressed in the vasculature, klotho deficiency is involved in VC and endothelial dysfunction development [118] and, therefore, contributes to increased arterial stiffness and pressure overload.

Experimental data indicate that calcified human aortic valves have lower klotho levels and that treatment with recombinant klotho reduces high phosphate-induced osteogenic activity in human aortic valve interstitial cells [119]. Another study confirmed that klotho administration attenuated high-phosphate induced renal and cardiac fibrosis and improved both renal and cardiac function in the absence of previous kidney disease [120]. Taken together, experimental data encourage that treatment of klotho deficiency in CKD may have a beneficial effect on heart disease in CKD.

Whereas klotho did not predict CV events (death, atherosclerotic events, and decompensated heart failure) in patients CKD stages 2–4, FGF23, on the other hand, was significantly associated with future decompensated heart failure [121].

Bearing in mind klotho/FGF23 axis disturbance, the klotho deficiency, and high FGF23 levels, in patients with CKD, it has been suggested that the klotho/FGF23 axis could be not only diagnostic and prognostic biomarkers of CKD and CV disease but could be treatment targets as they contribute to the CKD progression and development of CV disease as complication [122].
