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  • Review Article
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FGF-23 and secondary hyperparathyroidism in chronic kidney disease

Nature Reviews Nephrology volume 9, pages 641–649 (2013)Cite this article

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Abstract

The metabolic changes that occur in patients with chronic kidney disease (CKD) have a profound influence on mineral and bone metabolism. CKD results in altered levels of serum phosphate, vitamin D, calcium, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23); the increased levels of serum phosphate, PTH and FGF-23 contribute to the increased cardiovascular mortality in affected patients. FGF-23 is produced by osteocytes and osteoblasts and acts physiologically in the kidney to induce phosphaturia and inhibit the synthesis of 1,25-dihydroxyvitamin D3. PTH acts directly on osteocytes to increase FGF-23 expression. In addition, the high levels of PTH associated with CKD contribute to changes in bone remodelling that result in decreased levels of dentin matrix protein 1 and the release of low-molecular-weight fibroblast growth factors from the bone matrix, which stimulate FGF-23 transcription. A prolonged oral phosphorus load increases FGF-23 expression by a mechanism that includes local changes in the ratio of inorganic phosphate to pyrophosphate in bone. Other factors such as dietary vitamin D compounds, calcium, and metabolic acidosis all increase FGF-23 levels. This Review discusses the mechanisms by which secondary hyperparathyroidism associated with CKD stimulates bone cells to overexpress FGF-23 levels.

Key Points

  • Secondary hyperparathyroidism and increased serum fibroblast growth factor 23 (FGF-23) levels in chronic kidney disease (CKD) are intimately related; secondary hyperparathyroidism has a crucial role in increasing the expression of FGF-23

  • Parathyroid hormone (PTH) increases FGF-23 expression in osteoblast-like cells in vitro by activating protein kinase A and Wnt signalling pathways

  • The ratio of inorganic phosphate to pyrophosphate in the bone matrix is increased in CKD, which increases FGF-23 expression

  • The loss of FGF-23 transcriptional inhibition by dentin matrix protein 1 and the release of low-molecular-weight fibroblast growth factors increase FGF-23 expression in CKD

  • FGF-23 acts on the kidney to decrease 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) synthesis, which contributes to the secondary hyperparathyroidism of CKD, whereas 1,25(OH)2D3 itself increases FGF-23 transcription

  • The FGF-23-receptor complex, Klotho–fibroblast growth factor receptor 1, is downregulated in the parathyroid gland of patients with CKD, resulting in loss of FGF-23's ability to decrease PTH expression

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Figure 1: Factors that regulate FGF-23 synthesis and secretion.
Figure 2: Local regulation of FGF-23 transcription.
Figure 3: A cascade of factors leading to CKD–mineral bone disorder.

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Acknowledgements

The authors' work is supported the Harold and Ethel Pupkewitz Fund for Renal Research and Amgen. T. Naveh-Many's work is also supported by the Israel Science Foundation.

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  1. Hadassah Hebrew University Medical Center, Minerva Center for Calcium and Bone Metabolism, Nephrology, Ein Karem, 91120, Jerusalem, Israel

    Justin Silver & Tally Naveh-Many

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  1. Justin Silver
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  2. Tally Naveh-Many
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J. Silver wrote the article. J. Silver and T. Naveh-Many contributed equally to researching data for the article, discussions of the content, and review and/or editing of the manuscript before submission.

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Correspondence to Justin Silver.

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Competing interests

J. Silver and T. Naveh-Many have received a research grant from Amgen. J. Silver has received honoraria and lecture fees from Amgen, Fresenius, KAI Pharmaceuticals, Shire, and Teva Pharmaceutical Industries.

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Silver, J., Naveh-Many, T. FGF-23 and secondary hyperparathyroidism in chronic kidney disease. Nat Rev Nephrol 9, 641–649 (2013). https://doi.org/10.1038/nrneph.2013.147

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