Plasma FGF23 levels increase rapidly after acute kidney injury

Christov, Marta; Waikar, Sushrut S.; Pereira, Renata C.; Havasi, Andrea; Leaf, David E.; Goltzman, David; Pajevic, Paola Divieti; Wolf, Myles; Jüppner, Harald

doi:10.1038/ki.2013.150

Cited by 154 publications

(192 citation statements)

References 65 publications

(81 reference statements)

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“…A growing number of studies suggest that renal clearance contributes minimally to FGF23 elimination (39,89), and unlike other peptide hormones, the high levels in CKD do not seem to be caused by accumulation of inactive hormone fragments (20,38). Additional clues come from the study of murine AKI, where renal impairment was found to only have a relatively modest effect on plasma FGF23 half-life (approximately 50% reduction) (81). The fact that neither increased osteocytic synthesis nor reduced renal clearance seems to account for the high levels typically seen in CKD suggests that extraskeletal sites of FGF23 synthesis and/or extrarenal routes of elimination may be important determinants in the evolution of FGF23 levels in this setting.…”

Section: Rise Of Fgf23 In Ckd-unanswered Questionsmentioning

confidence: 99%

“…The source of circulating FGF23, particularly in early CKD, would, therefore, seem uncertain. Theoretically, very rapid changes in FGF23 levels, which were recently reported in mice with folic acidinduced AKI (81), may reflect the release of preformed hormone from bone matrix rather than de novo cellular synthesis of new protein. An alternative explanation of these data is that extraskeletal production of FGF23 may also contribute to the circulating pool.…”

Section: Rise Of Fgf23 In Ckd-unanswered Questionsmentioning

confidence: 99%

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The Use of Fibroblast Growth Factor 23 Testing in Patients with Kidney Disease

Smith

2014

Clinical Journal of the American Society of Nephrology

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The emergence of fibroblast growth factor 23 as a potentially modifiable risk factor in CKD has led to growing interest in its measurement as a tool to assess patient risk and target therapy. This review discusses the analytical and clinical challenges faced in translating fibroblast growth factor 23 testing into routine practice. As for other bone mineral markers, agreement between commercial fibroblast growth factor 23 assays is poor, mainly because of differences in calibration, but also, these differences reflect the variable detection of hormone fragments. Direct comparison of readout from different assays is consequently limited and likely hampers setting uniform fibroblast growth factor 23-directed targets. Efforts are needed to standardize assay output to enhance clinical use. Fibroblast growth factor 23 is robustly associated with cardiovascular and renal outcomes in patients with CKD and adds value to risk assessments based on conventional risk factors. Compared with most other mineral markers, fibroblast growth factor 23 shows better intraindividual temporal stability, with minimal diurnal and week-to-week variability, but substantial interindividual variation, maximizing discriminative power for risk stratification. Conventional therapeutic interventions for the CKD-mineral bone disorder, such as dietary phosphate restriction and use of oral phosphate binders or calcimimetics, are associated with variable efficacy at modulating circulating fibroblast growth factor 23 concentrations, like they are for other mineral metabolites. Dual therapy with dietary phosphate restriction and noncalcium-based binder use achieves the most consistent fibroblast growth factor 23-lowering effect and seems best monitored using an intact assay. Additional studies are needed to evaluate whether strategies aimed at reducing levels or antagonizing its action have beneficial effects on clinical outcomes in CKD patients. Moreover, a better understanding of the mechanisms driving fibroblast growth factor 23 elevations in CKD is needed to inform the use of therapeutic interventions targeting fibroblast growth factor 23 excess. This evidence must be forthcoming to support the use of fibroblast growth factor 23 measurement and fibroblast growth factor 23-directed therapy in the clinic.

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Section: Rise Of Fgf23 In Ckd-unanswered Questionsmentioning

confidence: 99%

Section: Rise Of Fgf23 In Ckd-unanswered Questionsmentioning

confidence: 99%

The Use of Fibroblast Growth Factor 23 Testing in Patients with Kidney Disease

Smith

2014

Clinical Journal of the American Society of Nephrology

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“…[34][35][36] Folic acid induced uremia in both genotypes with no change in serum calcium (not shown) and increases in serum phosphate and PTH levels that were smaller in rpS6 P2/2 mice ( Figure 7, A-C). There was an increase in phosphorylated rpS6 in wt mice, showing activation of mTORC1 in the parathyroids of AKI wt mice ( Figure 7D).…”

Section: Rps6mentioning

confidence: 99%

Phosphorylation of Ribosomal Protein S6 Mediates Mammalian Target of Rapamycin Complex 1–Induced Parathyroid Cell Proliferation in Secondary Hyperparathyroidism

Volovelsky

Cohen

Kenig

et al. 2016

Journal of the American Society of Nephrology

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Secondary hyperparathyroidism is characterized by increased serum parathyroid hormone (PTH) level and parathyroid cell proliferation. However, the molecular pathways mediating the increased parathyroid cell proliferation remain undefined. Here, we found that the mTOR pathway was activated in the parathyroid of rats with secondary hyperparathyroidism induced by either chronic hypocalcemia or uremia, which was measured by increased phosphorylation of ribosomal protein S6 (rpS6), a downstream target of the mTOR pathway. This activation correlated with increased parathyroid cell proliferation. Inhibition of mTOR complex 1 by rapamycin decreased or prevented parathyroid cell proliferation in secondary hyperparathyroidism rats and in vitro in uremic rat parathyroid glands in organ culture. Knockin rpS6 p2/2 mice, in which rpS6 cannot be phosphorylated because of substitution of all five phosphorylatable serines with alanines, had impaired PTH secretion after experimental uremia-or folic acid-induced AKI. Uremic rpS6 p2/2 mice had no increase in parathyroid cell proliferation compared with a marked increase in uremic wild-type mice. These results underscore the importance of mTOR activation and rpS6 phosphorylation for the pathogenesis of secondary hyperparathyroidism and indicate that mTORC1 is a significant regulator of parathyroid cell proliferation through rpS6. Secondary hyperparathyroidism (SHP) is a major complication of CKD and characterized by increases in parathyroid hormone (PTH) expression and parathyroid cell proliferation. 1-5 Decreased expression of the calcium, vitamin D, and fibroblast growth factor-23 receptors contributes to the increased parathyroid proliferation in uremia. [6][7][8][9][10][11] Expression of TGF-a and its receptor, EGF receptor (EGFR), is increased in uremic rats and patients. 12-14 TGF-a activation of EGFR decreases the CCAAT/ enhancer-binding protein-b liver-enriched activator protein:liver-enriched inhibitory protein, inducing parathyroid growth in uremia. A dominant negative EGFR gene expressed specifically in the parathyroid glands prevented the activation of endogenous EGFR and the increase in parathyroid gland enlargement and serum PTH. 15,16 Parathyroid cell proliferation is increased in transgenic mice overexpressing cyclin D1 only in the parathyroid. 17 The mammalian target of rapamycin (mTOR) integrates signaling pathways to regulate cell growth

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“…Acute kidney injury (AKI) or CKD-induced GFR regression predisposes to bone metabolism disturbances via upregulating serum P (18), which accelerates FGF-23 and PTH secretion. Previous studies have demonstrated that increased FGF-23 is associated with CKD or AKI severity (19,20).…”

Section: Resultsmentioning

confidence: 99%

High calcium diet alleviates 5/6 nephrectomy-induced bone deteriorations of lumbar vertebrae in mice

et al. 2018

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Abstract. Dietary calcium (Ca) supplementation has beneficial effects on bone health. However, it is not clear whether a high calcium diet (HCD) following 5/6 nephrectomy (5/6 Nx) is beneficial to bone health. The aim of the present study was to examine the effects of an HCD on bone metabolism using a chronic kidney disease (CKD) mouse model. Male C57BL/6J mice were divided into three groups: Sham group, 5/6 Nx group and 5/6 Nx + HCD group. Mice were sacrificed 12 weeks post-surgery. Calcium (Ca) and creatinine (Cr) were measured using standard colorimetric methods and picric acid methods, respectively. Bone metabolism-associated markers, FGF-23, PTH, ALP-b and TRAP-5b were measured using ELISA kits. Lumbar vertebrae histomorphological analysis was performed using hematoxylin and eosin staining. The expression of osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) mRNA was detected using reverse transcription-quantitative polymerase chain reaction. Impaired renal function and histopathological damage was indicated in 5/6 Nx mice. However, HCD had no significant effects on these changes in 5/6 Nx mice. Notably, mineral metabolism disorder and histopathological damage to lumbar vertebrae were markedly improved in HCD-treated 5/6 Nx mice. Compared with 5/6 Nx mice, HCD supplementation significantly elevated the ratio of OPG/RANKL and inhibited RANKL mRNA expression in lumbar vertebrae. To conclude, the present findings indicated that increased Ca intake is effective in increasing bone mineral content of the lumbar vertebrae in 5/6 Nx mice. These results may provide a basis for the clinical use of dietary Ca supplementation as a therapeutic approach to treat CKD-induced disturbance of mineral metabolism and bone loss.

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Plasma FGF23 levels increase rapidly after acute kidney injury

Cited by 154 publications

References 65 publications

The Use of Fibroblast Growth Factor 23 Testing in Patients with Kidney Disease

The Use of Fibroblast Growth Factor 23 Testing in Patients with Kidney Disease

Phosphorylation of Ribosomal Protein S6 Mediates Mammalian Target of Rapamycin Complex 1–Induced Parathyroid Cell Proliferation in Secondary Hyperparathyroidism

High calcium diet alleviates 5/6 nephrectomy-induced bone deteriorations of lumbar vertebrae in mice

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