RESUMO
BACKGROUND: Mineral bone disorder (MBD) is an early complication of chronic kidney disease (CKD), with complex interactions in the bone-kidney-energy axis. These events lead to impaired bone remodelling, which in turn is associated with cardiovascular disease. Recently, we reported on a positive effect of phosphate binder treatment on bone remodelling markers and a reduction in serum FGF-23 levels in predialysis-CKD patients. The goal of the present study of this trial was to examine the effects of phosphate binders on energy-regulating hormones and Wnt pathway. METHODS: In this present post hoc analysis of the above randomized, open-label, 8-week trial, which compared the effects of increasing doses of sevelamer-HCl or calcium acetate on various CKD-MBD parameters in 40 normophosphatemic CKD Stage 3-4 patients, we measured serum sclerostin, Dickkopf-1, leptin, adiponectin and serotonin concentrations. RESULTS: Serum sclerostin, Dickkopf-1 and leptin were elevated at baseline despite normal calcium, phosphorus levels and daily urinary phosphorus excretion. There were significant and positive correlations between sclerostin and FGF-23, as well between leptin and Dickkopf-1. Treatment with both phosphate binders led to a significant decrease in phosphate overload. However, sevelamer-HCl, but not with calcium acetate, led to a significant decrease in serum FGF-23, sclerostin and leptin, and to a significant increase in bone alkaline phosphatase levels. CONCLUSIONS: Early stages of CKD are associated with an impairment of the Wnt pathway, as reflected by elevated sclerostin, and a dysregulation of energy-regulating hormones. Many of these disturbances can be ameliorated by phosphate binder treatment, more with sevelamer-HCl than with calcium acetate.
Assuntos
Acetatos/farmacologia , Biomarcadores/sangue , Doenças Ósseas/metabolismo , Metabolismo Energético/fisiologia , Poliaminas/farmacologia , Insuficiência Renal Crônica/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Adiponectina/sangue , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas/tratamento farmacológico , Proteínas Morfogenéticas Ósseas/sangue , Compostos de Cálcio/farmacologia , Quelantes/farmacologia , Feminino , Fator de Crescimento de Fibroblastos 23 , Marcadores Genéticos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/tratamento farmacológico , Serotonina/sangue , SevelamerRESUMO
BACKGROUND: Fibroblast growth factor 23 (FGF23) concentrations increase early in chronic kidney disease (CKD), and the influence of current CKD-mineral and bone disorder (MBD) therapies on serum FGF23 levels is still under investigation. METHODS: In this post-hoc analysis of a randomized clinical trial, phosphate binders and calcitriol were washed out of 72 hemodialysis patients who were then submitted to bone biopsy, coronary tomography and biochemical measures, including FGF23. They were randomized to receive sevelamer or calcium acetate for 1 year and the prescription of calcitriol and the calcium concentration in the dialysate were adjusted according to serum calcium, phosphate and PTH and bone biopsy diagnosis. RESULTS: At baseline, bone biopsy showed that 58.3% had low-turnover bone disease, whereas 38.9% had high-turnover bone disease, with no significant differences between them with regard to FGF23. Median baseline FGF23 serum levels were elevated and correlated positively with serum phosphate. After 1 year, serum FGF23 decreased significantly. Repeated measures ANOVA analysis showed that the use of a 3.5-mEq/l calcium concentration in the dialysate, as well as the administration of calcitriol and a calcium-based phosphate binder were associated with higher final serum FGF23 levels. CONCLUSIONS: Taken together, our results confirm that the current CKD-MBD therapies have an effect on serum levels of FGF23. Since FGF23 is emerging as a potential treatment target, our findings should be taken into account in the decision on how to manage CKD-MBD therapy.
Assuntos
Doenças Ósseas/tratamento farmacológico , Osso e Ossos/patologia , Calcinose/diagnóstico por imagem , Doença da Artéria Coronariana/diagnóstico por imagem , Soluções para Diálise/uso terapêutico , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/efeitos dos fármacos , Falência Renal Crônica/terapia , Acetatos/administração & dosagem , Acetatos/farmacologia , Adulto , Análise de Variância , Biópsia , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/farmacologia , Doenças Ósseas/complicações , Doenças Ósseas/patologia , Calcitriol/administração & dosagem , Calcitriol/farmacologia , Cálcio/administração & dosagem , Cálcio/farmacologia , Compostos de Cálcio/administração & dosagem , Compostos de Cálcio/farmacologia , Quelantes/administração & dosagem , Quelantes/farmacologia , Soluções para Diálise/química , Feminino , Fator de Crescimento de Fibroblastos 23 , Seguimentos , Humanos , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Fosfatos/sangue , Poliaminas/administração & dosagem , Poliaminas/farmacologia , Sevelamer , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND AND OBJECTIVES: Levels of parathyroid hormone (PTH) and the phosphaturic hormone FGF23, a fibroblast growth factor (FGF) family member, increase early in chronic kidney disease (CKD) before the occurrence of hyperphosphatemia. This short-term 6-wk dose titration study evaluated the effect of two phosphate binders on PTH and FGF23 levels in patients with CKD stages 3 to 4. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Patients were randomized to receive over a 6-wk period either calcium acetate (n = 19) or sevelamer hydrochloride (n = 21). RESULTS: At baseline, patients presented with elevated fractional excretion of phosphate, serum PTH, and FGF23. During treatment with both phosphate binders there was a progressive decline in serum PTH and urinary phosphate, but no change in serum calcium or serum phosphate. Significant changes were observed for FGF23 only in sevelamer-treated patients. CONCLUSIONS: This study confirms the positive effects of early prescription of phosphate binders on PTH control. Prospective and long-term studies are necessary to confirm the effects of sevelamer on serum FGF23 and the benefits of this decrease on outcomes.