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Background In chronic kidney disease (CKD) patients, increased levels of fibroblast growth factor 23 (FGF23) are associated with cardiovascular mortality. The relationship between FGF23 and heart hypertrophy has been documented, however, it is not known whether FGF23 has an effect on vasculature. Vascular smooth muscle cells VSMCs may exhibit different phenotypes; our hypothesis is that FGF23 favours a switch from a contractile to synthetic phenotype that may cause vascular dysfunction. Our objective was to determine whether FGF23 may directly control a change in VSMC phenotype. Methods This study includes in vitro, in vivo and ex vivo experiments and evaluation of patients with CKD stages 2–3 studying a relationship between FGF23 and vascular dysfunction. Results In vitro studies show that high levels of FGF23, by acting on its specific receptor FGFR1 and Erk1/2, causes a change in the phenotype of VSMCs from contractile to synthetic. This change is mediated by a downregulation of miR-221/222, which augments the expression of MAP3K2 and PAK1. miR-221/222 transfections recovered the contractile phenotype of VSMCs. Infusion of recombinant FGF23 to rats increased vascular wall thickness, with VSMCs showing a synthetic phenotype with a reduction of miR-221 expression. Ex-vivo studies on aortic rings demonstrate also that high FGF23 increases arterial stiffening. In CKD 2–3 patients, elevation of FGF23 was associated with increased pulse wave velocity and reduced plasma levels of miR-221/222. Conclusion In VSMCs, high levels of FGF23, through the downregulation of miR-221/222, causes a change to a synthetic phenotype. This change in VSMCs increases arterial stiffening and impairs vascular function, which might ultimately worsen cardiovascular disease.

Fibroblast growth factor 23 (FGF23) increases phosphorus excretion and decreases calcitriol (1,25(OH)2D) levels. FGF23 increases from early stages of renal failure. We evaluated whether strict control of phosphorus intake in renal failure prevents the increase in FGF23 and to what extent inflammation impairs regulation of FGF23. The study was performed in 5/6 nephrectomized (Nx) Wistar rats fed diets containing 0.2–1.2% phosphorus for 3 or 15 days. FGF23 levels significantly increased in all Nx groups in the short-term (3-day) experiment. However, at 15 days, FGF23 increased in all Nx rats except in those fed 0.2% phosphorus. In a second experiment, Nx rats fed low phosphorus diets (0.2 and 0.4%) for 15 days received daily intraperitoneal lipopolysaccharide (LPS) injections to induce inflammation. In these rats, FGF23 increased despite the low phosphorus diets. Thus, higher FGF23 levels were needed to maintain phosphaturia and normal serum phosphorus values. Renal Klotho expression was preserved in Nx rats on a 0.2% phosphorus diet, reduced on a 0.4% phosphorus diet, and markedly reduced in Nx rats receiving LPS. In ex vivo experiments, high phosphorus and LPS increased nuclear β-catenin and p65-NFκB and decreased Klotho. Inhibition of inflammation and Wnt signaling activation resulted in decreased FGF23 levels and increased renal Klotho. In conclusion, strict control of phosphorus intake prevented the increase in FGF23 in renal failure, whereas inflammation independently increased FGF23 values. Decreased Klotho may explain the renal resistance to FGF23 in inflammation. These effects are likely mediated by the activation of NFkB and Wnt/β-catenin signaling.

In chronic kidney disease (CKD) patients, it would be desirable to reduce the intake of inorganic phosphate (P) rather than limit the intake of P contained in proteins. Urinary excretion of P should reflect intestinal absorption of P(inorganic plus protein-derived). The aim of the present study is to determine whether the ratio of urinary P to urinary urea nitrogen (P/UUN ratio) helps identify patients with a high intake of inorganic P.A cross-sectional study was performed in 71 patients affected by metabolic syndrome with CKD (stages 2&ndash, 3) with normal serum P concentration. A 3-day dietary survey was performed to estimate the average daily amount and the source of P ingested. The daily intake of P was 1086.5 &plusmn, 361.3 mg/day, 64% contained in animal proteins, 22% in vegetable proteins, and 14% as inorganic P. The total amount of P ingested did not correlate with daily phosphaturia, but it did correlate with the P/UUN ratio (p &lt, 0.018). Patients with the highest tertile of the P/UUN ratio &gt, 71.1 mg/g presented more abundant inorganic P intake (p &lt, 0.038).The P/UUN ratio is suggested to be a marker of inorganic P intake. This finding might be useful in clinical practices to identify the source of dietary P and to make personalized dietary recommendations directed to reduce inorganic P intake.

Background Inflammation is a common feature in chronic kidney disease (CKD) that appears specifically associated with cardiovascular derangements in CKD patients. Observational studies have revealed a link between low Mg levels and inflammation. In this study, we hypothesize that Mg might have a modulatory effect on the inflammation induced under the uraemic milieu. Methods In vivo studies were performed in a 5/6 nephrectomized rat model of CKD. Furthermore, a possible direct effect of Mg was addressed through in vitro studies with vascular smooth muscle cells (VSMCs). Results Uraemic rats fed a normal (0.1%) Mg diet showed a systemic inflammatory response evidenced by the elevation in plasma of the pro‐inflammatory cytokines TNF‐α, IL‐1β and IL‐6, and GPx activity, a marker of oxidative stress. Importantly, an increased expression of these cytokines in the aortic tissue was also observed. In contrast, a dietary Mg supplementation (0.6%) greatly prevented the oxidative stress and the pro‐inflammatory response. In vitro, in VSMCs cultured in a pro‐inflammatory high phosphate medium, incubation with Mg 1.6 mM inhibited the increase in the production of ROS, the rise in the expression of TNF‐α, IL‐1β, IL‐6 and IL‐8 and the activation of NF‐κB signalling that was observed in cells incubated with a normal (0.8 mM) Mg. Conclusion Mg supplementation reduced inflammation associated with CKD, exerting a direct effect on vascular cells. These findings support a possible beneficial effect of Mg supplementation along the clinical management of CKD patients.

Background and Aims In chronic kidney disease (CKD) patients, phosphate (P) restriction is crucial for the control of mineral metabolism. Many reports indicate that P intake doesnot correlate with 24-hour phosphaturia. Different sources of P (organic or inorganic) have different intestinal absorption rates. Different proportions of organic and inorganic P in diet might be the reason for the lack of correlation between phosphorus intake and phosphaturia. Therefore, we aimed to evaluate if the source of dietary P rather than the total amount of P ingested determines total phosphaturia and it was accessed to what extent inorganic P intake modifies phosphaturia Method A 3-day dietary survey was performed in 71 stages G2-3 CKD patients with metabolic syndrome to estimate the amount and source of P in the diet. Blood and 24-hour urine-samples were collected. Total phosphaturia, fractional excretion of P (FeP%), urinary P/eGFR ratio (mg/day/GFR that reflects the urine P excretion relative to renal function), P/creatinine ratio, urinary urea /Cr ratio, and urinary P/urea ratio (that reflects daily intestinal absorption of P relative to the amount of proteins absorbed and metabolized) were evaluated. P/urea ratio was categorized into tertiles and contrasted in terms of the other variables analyzed (T1=0.033 mg/mg). Statistics were performed using R 3.6.2, RStudio, Tidyverse, and tableone v0.10.0 packages. Results Patients` age was 61±9 years, and eGFR was 68±21 ml/min/1.73m2. Estimated P intake was 869±289 mg/day. According to sources, P intake was 64% from animal sources, 22% from vegetable sources, and 14% from inorganic P. Total P intake did not correlate with urinary P (r=0.18, p=0.12), urinary P/eGFR (r=-0.32, p=0.79), or FeP (r=-0.08, p=0.48). Figure 1 shows that patients ingesting more P have a greater intake of inorganic P. There was a correlation between P intake and P/Urea ratio (p=0.008). Patients in the upper urinary P/urea tertile showed the highest daily P intake (p=0.04), and inorganic P (p=0.03). These patients from tertile 3 also showed the highest amount of urinary P excretion (p=0.04). Conclusion Urinary P/urea reflects the total P intake and, more importantly, provides information about the amount of inorganic P. Therefore, the P/urea ratio may be used to guide the appropriate nutritional advice for CKD patients.