*3.1. Role of FGF23*

FGF23, a 32 kDa glycoprotein, has been defined as a phosphaturic hormone produced by osteocytes and osteoblasts [89]. In the physiological state, its main role is to maintain normal phosphate levels in the blood through downregulation of sodium-phosphate (NaPi) cotransporters in kidney proximal tubule and, thus, reducing the phosphate reabsorption in the kidney [89]. In addition, FGF23 downregulates 1- α-hydroxylase in proximal tubules, the enzyme responsible for converting 25-OH-vitamin D into his active form, 1,25(OH)2-vitamin D [89]. In this way, FGF23 regulates phosphate levels both directly, through NaPi cotransporters, and indirectly, through vitamin D metabolism and phosphate absorption in the gut.

FGF23 acts by binding with the transmembrane protein, α-klotho, which is expressed mainly in kidney proximal and distal convoluted tubule, parathyroid and pituitary glands, but also in other organs [90,91]. As FGF23 suppresses α-klotho expression in the kidney, it may decrease levels of secreted klotho in the circulation [90,92].

Studies performed so far confirmed that patients with CKD have increased FGF23 levels even from the early stages of the disease [93,94]. As high mortality in CKD patients is well known, the role of FGF23 in CV mortality was intensively investigated, both in experimental and clinical settings. A recent meta-analysis concluded that elevated FGF23 levels are positively associated with CV events and all-cause mortality in HD patients [95]. Data on repeated measurements of FGF23 levels in patients with CKD may identify subpopulation of patients that have higher mortality risk, as it was shown that those patients with slower rise in FGF23 levels in the course of five years have five times higher risk of death and those with rapid rise in FGF23 levels have 15 times higher risk of death compared to the patients with stabile FGF23 levels [96]. These data indicate that FGF23 acts as a toxin in developed CKD-MBD. Most of the studies investigating the association of FGF23 and mortality in CKD patients analyzed the presence of cardiac hypertrophy, known to be very common in CKD, and activation of the renin–angiotensin–aldosterone (RAAS) system. In patients with diabetic nephropathy and early CKD (stages 2 and 3), lower plasmatic Klotho and higher FGF23 levels were associated with a higher risk of concentric hypertrophy, and, thus, higher cardiovascular hospitalization [97]. It was shown that FGF23 stimulates the renin–angiotensin system by suppressing the expression of angiotensin-converting enzyme-2 (ACE2) in the kidney [98]. The study, which included both in vitro investigation of cardiac fibroblasts and myocytes and myocardial autopsy samples of patients with end-stage CKD, demonstrated that RAAS activation is responsible for the induction of FGF23 expression in cardiac myocytes and stimulation of pro-fibrotic crosstalk between cardiac myocytes and fibroblasts [99]. Besides, FGF23 also increases the production of transforming growth factor-β (TGF-β), lipocalin-2, and tumor necrosis factorα (TNFα), which are well known inflammatory markers [98].


**Table 1.** The importance of the FGF-23–klotho–sclerostin axis in left ventricular hypertrophy in CKD.

factor β; TNF-α—tumor necrosis factor α.

Anemia is an important CKD complication that contributes to higher CV risk and mortality. It is important to underline that FGF23 also contributes to renal anemia development and inhibition of FGF23 signaling may decrease erythroid cell apoptosis, attenuate inflammation, and result in increased serum iron and ferritin levels [100]. Hence, it may be concluded that FGF23 increases CV risk either directly (by action on heart) and/or indirectly (RAAS activation, contribution to renal anemia, and inflammation), and also stimulates other pathophysiological factors that contribute to further disease progression. Regarding the relation to LVH, experimental data indicate that FGF23 can exert its action even if α-klotho is not present and to induce hypertrophy of cardiac myocytes [101]. Indeed, it has been shown that FGF23 directly induces LVH by activation of fibroblast growth factor receptor-4 (FGFR-4) in the absence of membrane α-klotho and that administration of soluble klotho attenuates hypertrophy in mice [102]. LVH, on the other hand, is shown to be associated with an increase in both myocardial and serum intact FGF23 [103].

Clinical data sugges<sup>t</sup> the association of FGF23 levels and increased CV risk throughout the CKD stages. FGF23 is shown to be associated with increased risk of CV events and mortality in diabetic patients even with normal or mildly impaired kidney function [104]. Furthermore, FGF23 levels correlated positively with LVH and negatively to left ventricular ejection fraction in patients on hemodialysis, in whom FGF23 was shown to be an independent predictor of overall mortality [105].

Some authors pointed that predictive potential of FGF23 of CV mortality is more emphasized in patients in intermediate eGFR tercile (with mean value of 60 mL/min) [106].

These clinical data strongly support the role of FGF23 as direct cardiac toxin, which causes hypertrophy of cardiomyocytes that are exposed to less blood supply in the further course of the disease. Apart from the association with CV risk and mortality, the relationship of FGF23 with overall mortality can be explained through the stimulation of other pathways (inflammation for instance) that lead to CKD progression and mortality.

Experimental data, on the other hand, indicate that the progression of LVH in CKD could be ameliorated. It is important to note that specific blockade of FGFR4, as shown in 5/6 nephrectomy rat model, attenuates LVH [107]. Moreover, experimental data in uremic rats indicated that vitamin D treatment reduced LVH, FGFR-4 expression, and calcineurin/nuclear factor of activated T cells (NFAT) signaling activation, and, therefore, showing calcitriol cardioprotective e ffects [108]. Encouraging experimental data also indicate that early administration of ferric citrate slows CKD progression, lowers FGF23 levels, and improves cardiac function and survival [109]. Hence, LVH can be treated in CKD and CV risk can be reduced, either by lowering FGF23 levels or by inhibiting its e ffect on the FGFR-4. To conclude, FGF23 acts as a toxin in CKD and has an important role in CKD-MBD development and, most importantly, is associated with increased CV risk in CKD patients. Therapeutic strategies to lower FGF23 serum levels and/or to inhibit its action on FGFR-4 might be beneficial for the CV and overall outcome improvement.

Early diagnosis of CKD-MBD is an appropriate time for prevention of CKD complications and reduction of CV risk. Monitoring FGF-23 levels could detect patients with higher CV risk and suggests more regular visits at nephrology departments.
