The direct effect of fibroblast growth factor 23 on vascular smooth muscle cell phenotype and function.

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.

Control of hyperparathyroidism with the intravenous calcimimetic etelcalcetide in dialysis patients adherent and non-adherent to oral calcimimetics.

BACKGROUND: In dialysis patients, non-adherence to oral cinacalcet adds complexity to the control of secondary hyperparathyroidism. The present study aims to evaluate the use of intravenous calcimimetic, etelcalcetide, in the control of secondary hyperparathyroidism in patients adherent and non-adherent to oral calcimimetics. METHOD: The Simplified Medication Adherence Questionnaire was used to identify non-adherence. Almost half of the patients were non-adherent to the treatment with cinacalcet. Twenty-five patients (15 non-adherent) were switched from cinacalcet to etelcalcetide and were followed-up monthly for 8 months. RESULTS: Cinacalcet was discontinued for 1 week before the initiation of etelcalcetide. After this period, the serum PTH levels increased by2-fold in adherent patients, whereas it did not change in non-adherent patients suggesting that they were not taking the medication. Etelcalcetide progressively reduced serum parathyroid hormone (PTH) (mean ± standard deviation) from 818 ± 395 to 367 ± 289 pg/mL (P < 0.001) in non-adherents, and from 496 ± 172 to 228 ± 111 pg/mL (P < 0.01) in adherent patients with a mean dose of 7.0 ± 2.3 and 5.1 ± 1.2 mg in non-adherent and in adherent patients, respectively. Etelcalcetide increased the percentage of patients with PTH on target from 28% to 58%. Patients with serum calcium <8.4 mg/dL increased from 8% to 40%, although they remained asymptomatic. The percent of patients with serum phosphate on target increased from 40% to 65%. CONCLUSION: The lack of adherence to cinacalcet is a possible cause of the apparent lack of response to oral calcimimetic. The use of etelcalcetide ensures compliance and control of secondary hyperparathyroidism in both non-adherent and adherent patients.