Fibroblast growth factor 23 and soluble Klotho in chidren with chronic Kidney disease

1Renal Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Nephrology Dialysis Transplantation (Impact Factor: 3.58). 11/2012; 28(1). DOI: 10.1093/ndt/gfs411
Source: PubMed


Fibroblast growth factor 23 (FGF23), a bone-derived phosphaturic hormone, is elevated in chronic kidney disease (CKD). There are scarce data on the levels of its essential co-receptor klotho, and longitudinal changes in FGF23 levels are also unknown.Methods
We examined FGF23 and soluble klotho (s-klotho) levels over 1 year in 154 children with CKD Stages 1-5 (CKD1-5), were on dialysis or who have received a transplantation.ResultsIn children with CKD1-5 and who were receiving dialysis, FGF23 correlated inversely with the estimated glomerular filtration rate (eGFR) (P < 0.001), whereas a decrease in s-klotho was observed with a lower eGFR (P = 0.01). There was no correlation between FGF23 and serum phosphate (P) or parathyroid hormone (PTH) in our cohort wherein 89 and 66%, respectively, had normal levels. FGF23 increased by 6-fold over a 12-month period in children with eGFR of 15-29 mL/min/1.73 m(2), with an overall 5% annual increase in the CKD1-5 and dialysis cohort. High FGF23 levels were seen with high calcium (Ca) levels (P < 0.001). FGF23 levels were high when 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] were deficient (P = 0.05 and P < 0.001, respectively). s-klotho levels correlated positively with 25(OH)D (P < 0.001) and negatively with PTH (P = 0.04) and age (P = 0.03). Multivariate regression analysis demonstrated a strong relationship between FGF23 and eGFR, whereas the association between s-klotho and eGFR as observed in univariate analysis was lost following the adjustment of confounders. In transplanted patients, FGF23 correlated with eGFR (P = 0.02) and 25(OH)D (P = 0.05).Conclusions
This study shows increasing FGF23 and reduced s-klotho levels with progressive renal failure even in a population of children with well-controlled P levels. Novel associations between FGF23 and serum Ca as well as 25(OH)D warrant further investigation.

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Available from: Rukshana Shroff, Nov 18, 2015
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    ABSTRACT: Purpose of review: The wealth of data regarding fibroblast growth factor-23 (FGF23) and Klotho in chronic kidney disease (CKD) has risen exponentially over the past decade. This review is an attempt to summarize pivotal aspects of previous research, provide an update of recent findings and define important areas for future investigation. Recent findings: The phosphaturic hormone FGF23 increases dramatically as renal function declines. Identification of contributing stimuli to the rise in FGF23 is fundamental and recent evidence suggest a multifactorial cause which entails perturbed osteocyte function and renal mechanisms such as Klotho deficiency and, somewhat paradoxically, systemic Klotho excess. Circulating FGF23 predicts adverse outcomes, particularly cardiovascular disease, in CKD as well as in the general population. The concept of FGF23 merely as a biomarker and regulator of mineral metabolism is currently challenged by data linking FGF23 to pathological processes such as cardiac hypertrophy. Conversely, tissue level of the FGF23 coreceptor Klotho declines in early CKD and this deficiency is linked to accelerated ageing, cellular senescence, vascular calcification, oxidative stress and renal fibrosis. At present, methodological difficulties limit the utility of soluble Klotho measurements. Animal proof-of-concept studies have demonstrated beneficial effects of Klotho delivery in CKD, whereas anti-FGF23 therapy using neutralizing antibodies improved biochemical and bone parameters at the expense of increased vascular calcification and mortality. Summary: Pathological alterations of FGF23-Klotho in CKD are implicated as clinical biomarkers and may provide novel therapeutic strategies to alleviate the cardiovascular risk and slow CKD progression.
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    ABSTRACT: Abstract Objective: α-klotho, a protein with anti-aging properties, has been involved in important biological processes, such as calcium/phosphate metabolism, resistance to oxidative stress, and nitric oxide production in the endothelium. Recent studies have suggested a role of α-klotho in endocrine regulation of mineral metabolism and postnatal growth in infants. Yet, the role of α-klotho during pregnancy remains largely unknown. The aim of this study was to determine whether maternal plasma concentration of α-klotho change during pregnancy and evaluate its expression in pregnancies complicated by preeclampsia with or without small for gestational age (SGA) neonate. Study design: This cross-sectional study included patients in the following groups: (1) non pregnant women (n = 37); (2) uncomplicated pregnancy (n = 130); (3) preeclampsia with an appropriate weight for gestational age (AGA) neonate (PE; n = 58); (4) preeclampsia with an SGA neonate (PE and SGA; n = 52); and (5) SGA neonate without preeclampsia (SGA; n = 52). Plasma concentrations of α-klotho were determined by ELISA. Results: The median plasma α-klotho concentration was higher in pregnant than in non-pregnant women. Among women with an uncomplicated pregnancy, the median plasma concentration of α-klotho increases as a function of gestational age (Spearman Rho = 0.2; p = 0.006). The median (interquartile range) plasma concentration of α-klotho in women with PE and SGA [947.6 (762 - 2013) pg/mL] and SGA without [1000 (585-1567) pg/mL] were 21% and 17% lower than that observed in women with an uncomplicated pregnancy [1206.6 (894-2012) pg/mL], (p= 0.005 and p = 0.02), respectively. Additionally, there were no significant differences in the median plasma concentration of α-klotho between uncomplicated pregnancies and women with PE who deliver an AGA neonate. Conclusion: Maternal plasma concentrations of α-klotho are higher during pregnancy than in a non-pregnant state. Moreover, the median maternal plasma concentration of α-klotho was lower among mothers who deliver an SGA neonate regardless of the presence or absence of preeclampsia than in those with an uncomplicated pregnancy.
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