Determination of the Elimination Half-Life of Fibroblast Growth Factor-23

Khosravi, Azarmindokht; Cutler, Carolee M.; Kelly, Marilyn H.; Chang, Richard; Royal, Richard E.; Sherry, Richard M.; Wodajo, Felasfa M.; Fedarko, Neal S.; Collins, Michael T.

doi:10.1210/jc.2006-2865

Cited by 131 publications

(91 citation statements)

References 29 publications

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“…Metabolic production and clearance rates of vitamin D metabolites are slow, resulting in circulating half-lives of hours to weeks, 17 in contrast to the rapid clearance and short half-lives of PTH and FGF23. 18,19 There were three study participants with higher phosphate concentrations in the renal vein compared with the aorta (vein to artery ratio 1.05%-1.10%). These differences are slightly above the assay variability for singlicate runs of phosphate (approximately 5%).…”

Section: Discussionmentioning

confidence: 99%

Renal Clearance of Mineral Metabolism Biomarkers

Ballegooijen

Rhee

Elmariah

et al. 2016

Journal of the American Society of Nephrology

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CKD leads to disturbances in multiple interrelated hormones that regulate bone and mineral metabolism. The renal handling of mineral metabolism hormones in humans is incompletely understood. We determined the single-pass renal clearance of parathyroid hormone, fibroblast growth factor 23, vitamin D metabolites, and phosphate from paired blood samples collected from the abdominal aorta and renal vein in 17 participants undergoing simultaneous right and left heart catheterization and estimated associations of eGFR with the renal elimination of metabolites. The mean age 6SD of the study population was 71.4610.0 years and 11 participants (65%) were male. We found a relatively large mean6SD single-pass renal extraction of parathyroid hormone (44.2%610.3%) that exceeded the extraction of creatinine (22.1%67.9%). The proportionate renal extraction of parathyroid hormone correlated with eGFR. The renal extraction of fibroblast growth factor 23 was, on average, lower than that of parathyroid hormone with greater variability across individuals (17.1%619.5%). There were no differences in the mean concentrations of vitamin D metabolites across the renal vein and artery. In summary, we demonstrate substantial single-pass renal extraction of parathyroid hormone at a rate that exceeds glomerular filtration. Impaired renal clearance of parathyroid hormone may contribute to secondary hyperparathyroidism in CKD. Known causes of these hormonal changes include alterations in circulating calcium and phosphate concentrations and inadequate production of 1,25(OH) 2 D and klotho by the failing kidneys.The renal handling of mineral metabolism hormones in humans is incompletely understood. Older studies using early PTH antibodies suggested renal clearance of PTH via peritubular uptake and, to a lesser extent, glomerular filtration. Some experimental studies also indicate that impaired degradation of PTH contributes to the high circulating levels of PTH in CKD. [4][5][6] FGF23 is produced in bone and cleaved in the circulation; however, little is known about the renal clearance of FGF23. It is possible that reduced renal clearance of mineral metabolism hormones contributes to their accumulation in CKD.To understand how the human kidney modulates circulating biomarkers of mineral metabolism, we determined the single-pass renal clearance of PTH, FGF23, vitamin D metabolites, and phosphate from paired blood samples collected from the abdominal aorta and renal vein among patients undergoing left and right heart catheterization. RESULTSThe mean age of the study population was 71610 years; 11 participants (65%) were male. There were seven participants who were using vitamin D supplements; none of the study participants used calcitriol (Table 1 The single-pass renal elimination of creatinine was 22.167.9% (Table 2). The mean concentrations of PTH, FGF23, and phosphate were significantly lower in the renal vein compared with the renal artery. The mean concentration of

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Section: Discussionmentioning

confidence: 99%

Renal Clearance of Mineral Metabolism Biomarkers

Ballegooijen

Rhee

Elmariah

et al. 2016

Journal of the American Society of Nephrology

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“…For example, in TIO only cFGF23 is found in the circulation immediately after iFGF23-secreting tumors are removed. (30) This presumed cFGF23 ''overproduction'' may represent a physiologic process by which the body attempts to dampen the effect of high levels of iFGF23 secreted by TIO tumors by secreting only cFGF23, which can potentially block the action of iFGF23. This concept that cFGF23 fragments may block the action of iFGF23 is supported by the work of Goetz and colleagues.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of FGF23 processing in fibrous dysplasia

Bhattacharyya

Wiench

Dumitrescu

et al. 2012

Journal of Bone and Mineral Research

108

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Fibroblast growth factor-23 (FGF23) is a phosphate-and vitamin D-regulating hormone derived from osteoblasts/osteocytes that circulates in both active (intact, iFGF23) and inactive (C-terminal, cFGF23) forms. O-glycosylation by O-glycosyl transferase Nacetylgalactosaminyltransferase 3 (ppGalNAcT3) and differential cleavage by furin have been shown to be involved in regulating the ratio of active to inactive FGF23. Elevated iFGF23 levels are observed in a number of hypophosphatemic disorders, such as X-linked, autosomal recessive, and autosomal dominant hypophosphatemic rickets, whereas low iFGF23 levels are found in the hyperphosphatemic disorder familial tumoral calcinosis/hyperphosphatemic hyperostosis syndrome. Fibrous dysplasia of bone (FD) is associated with increased total FGF23 levels (cFGF23 þ iFGF23); however, classic hypophosphatemic rickets is uncommon. Our results suggest that it can be explained by increased FGF23 cleavage leading to an increase in inactive cFGF23 relative to active iFGF23. Given the fact that FD is caused by activating mutations in the small G-protein G s a that results in increased cyclic adenosine monophosphate (cAMP) levels, we postulated that there may be altered FGF23 cleavage in FD and that the mechanism may involve alterations in cAMP levels and ppGalNacT3 and furin activities. Analysis of blood specimens from patients with FD confirmed that the elevated total FGF23 levels are the result of proportionally increased cFGF23 levels, consistent with less glycosylation and enhanced cleavage by furin. Analysis of primary cell lines of normal and mutation-harboring bone marrow stromal cells (BMSCs) from patients with FD demonstrated that BMSCs harboring the causative G s a mutation had higher cAMP levels, lower ppGalNAcT3, and higher furin activity. These data support the model wherein glycosylation by ppGalNAcT3 inhibits FGF23 cleavage by furin and suggest that FGF23 processing is a regulated process that controls overall FGF23 activity in FD patients. ß

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“…By exerting an inhibitory activity on the type IIa and IIc sodium-phosphate co-transport system in proximal tubules, FGF23 inhibits renal 1α-hydroxylation of 25-hydroxyvitamin D, thus promoting hyperphosphaturia [6][7][8]. Excessive FGF23 action is therefore known to cause severe hypophosphatemia, whereas its deficiency has been found to result in hyperphosphatemic tumoral calcinosis [7].…”

Section: Discussionmentioning

confidence: 99%

Ga68-DOTA Peptide PET/CT to Detect Occult Mesenchymal Tumor-Inducing Osteomalacia: A Case Series of Three Patients

2015

Nucl Med Mol Imaging

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Tumor-induced osteomalacia (TIO) is a rare disease that manifests with paraneoplasic syndrome and overproduction of fibroblast growth factor 23 (FGF23), leading to renal phosphate wasting and hyperphosphaturia, eventually leading to acquired hypophosphatemic osteomalacia. Diagnosis of this disease is often challenging because of the small size of the lesion, which can be localized in bone or soft tissue anywhere in the body. Detecting these occult mesenchymal tumors (OMT) is of great importance as they are potentially curable after tumor resection. The purpose of this case series is to provide some insight into the diagnosis and localization of OMT associated with osteomalacia, particularly using functional imaging with Ga68-DOTA peptide PET/CT scans.

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Determination of the Elimination Half-Life of Fibroblast Growth Factor-23

Abstract: The plasma half-life of serum FGF-23 is in the range of 46-58 min.

Cited by 131 publications

References 29 publications

Renal Clearance of Mineral Metabolism Biomarkers

Renal Clearance of Mineral Metabolism Biomarkers

Mechanism of FGF23 processing in fibrous dysplasia

Ga68-DOTA Peptide PET/CT to Detect Occult Mesenchymal Tumor-Inducing Osteomalacia: A Case Series of Three Patients

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