How fibroblast growth factor 23 works
ABSTRACT There is a discontinuum of hereditary and acquired disorders of phosphate homeostasis that are caused by either high or low circulating levels of the novel phosphaturic hormone fibroblastic growth factor 23 (FGF23). Disorders that are caused by high circulating levels of FGF23 are characterized by hypophosphatemia, decreased production of 1,25-dihydroxyvitamin D, and rickets/osteomalacia. On the other end of the spectrum are disorders that are caused by low circulating levels of FGF23, which are characterized by hyperphosphatemia, elevated production of 1,25-dihydroxyvitamin D, soft tissue calcifications, and hyperostosis. Knowledge of the genetic basis of these hereditary disorders of phosphate homeostasis and studies of their mouse homologues have uncovered a bone-kidney axis and new systems biology that govern bone mineralization, vitamin D metabolism, parathyroid gland function, and renal phosphate handling. Further understanding of this primary phosphate homeostatic pathway has the potential to have a significant impact on the diagnosis and treatment of disorders of bone and mineral metabolism.
SourceAvailable from: Jose M Valdivielso[Show abstract] [Hide abstract]
ABSTRACT: RESUMEN La hiperfosfatemia es una complicación que aparece ya en estadios tempranos de la enfermedad renal crónica (ERC) y que ha demostrado tener graves consecuencias en los pa-cientes con nefropatía. En la actualidad se están estudiado nuevos reguladores del fósforo como son el FGF-23, una hormona fosfatúrica y contra-reguladora de la vitamina D, y kloto, co-factor necesario para la activación del FGF-23. Las principales consecuencias de la hiperfosfatemia descri-tas en pacientes con ERC no en diálisis son la calcificación ectópica, el incremento de la mortalidad y la más rápida progresión de la ERC. Todo ello indica la necesidad de bus-car un control estricto del Pi. Para ello, destacan en la ac-tualidad dos fármacos como son el carbonato de lantano y el sevelamer. Aunque no existen estudios diseñados espe-cíficamente para esta población aún no en diálisis, parecen ser fármacos eficaces y seguros. Otra complicación de la ERC es el defecto en la síntesis de vitamina D que según los estudios publicados recientemente, ha resultado ser más prevalente y aparecer en estadios más tempranos de la enfermedad de lo que se creía inicialmente. Existe un amplio debate respecto a la necesidad de administrar su-plementos de vitamina D de forma sistemática por los efectos pleiotrópicos de dicha hormona, ajenos al desarro-llo de la enfermedad ósea renal. Por esas dudas, si bien no hay acuerdo en la administración rutinaria, sí hay consen-so en la necesidad de medir los valores de 1,25-dihidroxivi-tamina D y 25-hidroxivitamina D, así como esperar el re-sultado de los numerosos estudios que se están llevando acabo acerca del impacto de la vitamina D en la progresión de factores de riesgo cardiovascular, en la ERC y las posi-bles consecuencias de su administración indiscriminada. Palabras clave: Progresión. Enfermedad renal crónica. Pre-diálisis. Hiperfosfatemia. Vitamina D. Tratamiento. SUMMARY Hyperphosphatemia is a complication that appears in the early stages of chronic kidney disease (CKD) and that has been shown to have serious consequences in kidney disease patients. New phosphate regulators are currently being studied such as FGF-23, a counter-regulatory phosphaturic hormone for vitamin D, and klotho, a cofactor necessary for activation of FGF-23. The main consequences of hyperphosphatemia described in CKD pa-tients not on dialysis are ectopic calcification, increased mortality and more rapid progression of CKD. All this indicates the need for strict control of Pi. The two most currently used drugs for this purpose are lanthanum carbonate and sevelamer. Although there are no studies specifically designed for this predialysis po-pulation, these drugs appear to be effective and safe. Another complication of CKD is vitamin D deficiency which, according to recently published studies, is more prevalent and appears in ear-lier stages of the disease than was initially thought. There is wide debate on the need to administer vitamin D supplements syste-matically due to the pleiotropic effects of this hormone and which are unrelated to development of renal bone disease. Be-cause of these doubts, there is no agreement on routine admi-nistration, although there is consensus on the need to measure 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D values and to wait for the result of numerous studies that are being carried out on the impact of vitamin D on progression of cardiovascular risk factors in CKD and the possible consequences of its indiscri-minate administration.
Article: FGF23 and Klotho
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ABSTRACT: Elevated fibroblast growth factor 23 (FGF-23) concentrations are associated with greater risk of cardiovascular events and mortality, especially among people with chronic kidney disease (CKD). Because individuals with CKD are at an increased risk of sudden cardiac death (SCD), we sought to understand whether FGF-23 level is a stronger risk factor for SCD versus non-SCD. Cohort study. 3,244 participants 65 years or older in the community-based Cardiovascular Health Study. Plasma FGF-23 concentrations. We assessed SCD and non-SCD in these analyses. SCD was adjudicated rigorously and was defined as a sudden pulseless condition of cardiac origin in a previously stable person occurring out of hospital or in the emergency department. We estimated associations of baseline FGF-23 concentrations with SCD and non-SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, comorbid conditions, and kidney function. We also tested whether associations differed by CKD status. During a median follow-up of 8.1 years, there were 118 adjudicated SCD and 570 non-SCD events. After multivariable adjustment for demographics, cardiovascular risk factors, comorbid conditions, and parameters of kidney function, higher FGF-23 concentrations were an independent risk factor for non-SCD (HR [per doubling], 1.17; 95% CI, 1.06-1.30). However, elevated FGF-23 concentrations were not associated independently with SCD (HR [per doubling], 1.07; 95% CI, 0.85-1.35). In stratified analysis by CKD status (36.5% of cohort), doubling of FGF-23 concentrations was associated independently with non-SCD (adjusted HR, 1.26; 95% CI, 1.10-1.45). A similar magnitude of association was observed between FGF-23 level and SCD in the CKD subgroup; however, it was not significant (HR, 1.20; 95% CI, 0.89-1.62). Limited power to detect moderate-sized effects between FGF-23 level and SCD in both the primary and stratified analyses. In this population-based study, FGF-23 level elevations were associated independently with non-SCD. Among individuals with CKD, the associations between FGF-23 level and SCD and non-SCD were similar. Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.American Journal of Kidney Diseases 01/2015; DOI:10.1053/j.ajkd.2014.10.025 · 5.76 Impact Factor