Assessment of 24,25(OH)2D levels does not support FGF23-mediated catabolism of vitamin D metabolites

Dai, Bing; David, Véronique; Alshayeb, Hala M.; Showkat, Arif; Gyamlani, Geeta; Horst, Ronald L.; Wall, Barry M.; Quarles, L. Darryl

doi:10.1038/ki.2012.222

Cited by 37 publications

(29 citation statements)

References 43 publications

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“…In support of this theory, studies in rodent models of kidney disease demonstrate upregulation of the renal 24-hydroxylase gene (9,12,13); however, follow-up studies have revealed that serum 24,25(OH) 2 D concentrations are actually lower in CKD animals than in wild-type controls (13). Similarly, cross-sectional studies in humans suggest lower 24,25(OH) 2 D concentrations in patients with advanced CKD and a negative correlation with FGF23 concentrations (14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 76%

“…Because parathyroid hormone has purported effects to promote the destabilization and degradation of 24-hydroxylase (CYP24A1) mRNA (37), it is plausible that increments in parathyroid hormone might inhibit the translation of 24-hydroxylase mRNA signals in CKD, although supplemental analyses in our study suggested no obvious correlation between parathyroid hormone and increments in 24,25(OH) 2 D 3 in patients with CKD (Supplemental Figure 1). Likewise, the increased renal expression of 24-hydroxylase mRNA observed in CKD rodent models would contradict a potential role of parathyroid hormone to stimulate 24-hydroxylase mRNA degradation in this setting (12,13).…”

Section: Discussionmentioning

confidence: 99%

“…However, no clinical trials have prospectively tested this hypothesis. Furthermore, crosssectional data from humans and rodent models of CKD suggest that 24,25(OH) 2 D concentrations are lower in the setting of impaired kidney function (13,(15)(16)(17)26). Given the apparent disparity between these clinical observations and current theories regarding vitamin D metabolism in CKD, further in vivo investigation of the 24-hydroxylase pathway can provide valuable insight into the pathophysiology of mineral metabolism derangements in CKD.…”

Section: Discussionmentioning

confidence: 99%

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Decreased Conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 Following Cholecalciferol Therapy in Patients with CKD

Stubbs

Zhang

Friedman

et al. 2014

Clinical Journal of the American Society of Nephrology

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concentrations were lower in the CKD group; moreover, the absolute increase in 24,25(OH) 2 D 3 after therapy was markedly smaller in patients with CKD (change, 2.8 ng/ml [2.3-3.5 ng/ml] for controls versus 1.2 ng/ml [0.6-1.9 ng/ml] for patients with CKD; P,0.001). Furthermore, higher baseline FGF23 concentrations were associated with smaller increments in 24,25(OH) 2 D 3 for individuals with CKD; this association was negated after adjustment for eGFR by multivariate analysis.Conclusions Patients with CKD exhibit an altered ability to increase serum 24,25(OH) 2 D 3 after cholecalciferol therapy, suggesting decreased 24-hydroxylase activity in CKD. The observed relationship between baseline FGF23 and increments in 24,25(OH) 2 D 3 further refutes the idea that FGF23 directly contributes to 25(OH)D insufficiency in CKD through stimulation of 24-hydroxylase activity.

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Section: Introductionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Decreased Conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 Following Cholecalciferol Therapy in Patients with CKD

Stubbs

Zhang

Friedman

et al. 2014

Clinical Journal of the American Society of Nephrology

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“…The main effective role of FGF23 is to decrease the reabsorption phosphate as well as to increase its tubal secretion leading phosphaturia that mediated by FGF receptors on renal tubes (3,4). Additionally, FGF23 can also suppress 1-alpha-hydroxylase which mediates calcium and phosphorus reabsorption (5). In this regard, inactivation of FGF23 can result in elevating the level of phosphate.…”

Section: Introductionmentioning

confidence: 99%

Association of serum fibroblast growth factor 23 with calcium metabolism in patients with end-stage renal disease undergoing hemodialysis

Alimohammadi¹,

Javadian²,

Malekpour³

et al. 2017

J Nephropathol

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Background:The association between the function of fibroblast growth factor 23 (FGF23) and different components of calcium metabolism has remained unclear in patients with renal dysfunction undergoing hemodialysis. Objectives: The present study aimed to assess the association of the level of FGF23 and calcium metabolism status in hemodialysis patients. Patients and Methods:This cross-sectional study conducted on 90 consecutive patients suffering end-stage renal disease (ESRD) who underwent hemodialysis. The serum levels of FGF23 and intact parathyroid hormone (iPTH) levels were measured using the ELISA technique.Results: The serum levels of FGF23 were directly associated with iPTH level (r = 0.251, P = 0.020) and slightly with the duration of dialysis (r = 0.203, P = 0.063). However serum FGF23 was not significantly related to other indices including levels of calcium, phosphorus, magnesium, vitamin D, albumin, and even body mass index (BMI). No difference was found in the level of FGF23 between men and women with ESRD under hemodialysis. Conclusions: In ESRD patients undergoing hemodialysis, the association of FGF23 with iPTH was detected, while there was not any relationship of FGF23 with other indices including calcium, phosphorus, and vitamin D.

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“…Although FGF23 regulation of 24-hydroxylation appears to play an important role in mice, this may not be true in humans. Dai and colleagues (52) failed to find evidence of a significant FGF23-associated effect on catabolism of vitamin D as assessed by 24,25-vitamin D levels. Nor did we find either elevated 24,25-vitamin D or 1,24,25-vitamin D levels in patients with TIO before treatment, or a significant change in 24,25-vitamin D or 1,24,25-vitamin D levels after surgical cure at a time when 1,25-D levels rose dramatically in response to a rapid decline in FGF23 (unpublished data and Chong and colleagues (14) ).…”

mentioning

confidence: 99%

1,25-Dihydroxyvitamin D as Monotherapy for XLH: Back to the Future?

Ovejero

Gafni

Collins

2016

Journal of Bone and Mineral Research

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T he identification in the year 2000 of mutations in fibroblast growth factor 23 (FGF23) as the genetic cause of autosomal dominant hypophosphatemic rickets (ADHR) was a seminal discovery in the field of bone and mineral homeostasis.(1)Alterations in FGF23 levels were subsequently identified as the common abnormality in a number of phosphate homeostasis disorders, including X-linked hypophosphatemic rickets (XLH), (2) tumor-induced osteomalacia (TIO), (3) fibrous dysplasia of bone, (4) autosomal recessive hypophosphatemic rickets (ARHR), (5) cutaneous skeletal hypophosphatemia syndrome (CSHS), (6) familial tumoral calcinosis, (7) and others. The primary actions of FGF23 are to regulate blood phosphate and 1,25-dihydroxyvitamin D 3 (1,25-D) levels by its actions on renal sodium/phosphate cotransporters and 25-hydroxyvitamin D hydroxylation. (8) The fact that PTH, like FGF23, is also important in regulating phosphate and vitamin D homeostasis invokes the existence of an FGF23-Vitamin D-PTH axis that is key to many important aspects of bone and mineral biology. It is a complicated axis that involves the interaction of multiple receptors, a coreceptor, Klotho, (9) and multiple disparate but interacting signaling and enzymatic pathways. (10,11) Unraveling, in a hierarchical fashion, the roles of these complicated, intersecting, and overlapping pathways is important for both understanding mineral homeostasis physiology, and for the treatment of phosphate disorders. This has proved a significant challenge. Although a large number of very informative mouse models have been developed to understand and query this axis, at times the complexity of these models introduces potential confounders that are difficult to control for, and yield results inconsistent with observed human physiology. Thus, it is often difficult to understand and contextualize the findings and apply them to human mineral physiology and pathophysiology. The number of clinical studies conducted in this area is limited, and often focused on renal failure cohorts, the physiology of which differs significantly from those with normal renal function.Although a complete understanding of the FGF23-Vitamin D-PTH axis is lacking, there are a number of findings that are generally accepted to be true. These include: (1) FGF23 directly inhibits phosphate reabsorption and the generation of active vitamin D, 1,25-dihydroxyvitamin D 3 (1,25-D) at the level of the proximal renal tubule leading to a lowering of blood phosphate and 1,25-D levels (8) ; (2) in a classical feedback fashion, increases in blood phosphate and 1,25-D increase FGF23 levels (12,13) ; and (3) frank or relative FGF23-mediated reductions in serum 1,25-D lead to a compensatory increase in PTH, especially evident in the more severe forms of FGF23 excess such as TIO and renal failure. (14,15) The phosphaturic effects of increased PTH exacerbate the phosphate-lowering effects of FGF23 in patients with intact renal function such as TIO and XLH (reviewed in Blau and Collins (11) ). As for the hierarchic...

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Assessment of 24,25(OH)2D levels does not support FGF23-mediated catabolism of vitamin D metabolites

Cited by 37 publications

References 43 publications

Decreased Conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 Following Cholecalciferol Therapy in Patients with CKD

Decreased Conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 Following Cholecalciferol Therapy in Patients with CKD

Association of serum fibroblast growth factor 23 with calcium metabolism in patients with end-stage renal disease undergoing hemodialysis

1,25-Dihydroxyvitamin D as Monotherapy for XLH: Back to the Future?

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