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  • Review Article
  • Published:

Klotho, phosphate and FGF-23 in ageing and disturbed mineral metabolism

Nature Reviews Nephrology volume 9, pages 650–660 (2013)Cite this article

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Abstract

High concentrations of extracellular phosphate are toxic to cells. Impaired urinary phosphate excretion increases serum phosphate level and induces a premature-ageing phenotype. Urinary phosphate levels are increased by dietary phosphate overload and might induce tubular injury and interstitial fibrosis. Extracellular phosphate exerts its cytotoxic effects by forming insoluble nanoparticles with calcium and fetuin-A; these nanoparticles are referred to in this Review as calciprotein particles. Calciprotein particles are highly bioactive ligands that can induce various cellular responses, including the osteogenic transformation of vascular smooth muscle cells and cell death of vascular endothelial cells and renal tubular epithelial cells. Calciprotein particles are detected in the serum of animal models of kidney disease and in patients with chronic kidney disease (CKD) and might be associated with a (mal)adaptation of the endocrine axes mediated by fibroblast growth factors and Klothos that regulate phosphate homeostasis and ageing. These observations raise the possibility that calciprotein particles contribute to the pathogenesis of CKD. This theory, if verified, is expected to provide novel diagnostic markers and therapeutic targets in CKD.

Key Points

  • Calciprotein particles are cytotoxic nanoparticles composed of inorganic calcium–phosphate crystals and mineral binding proteins, such as fetuin-A

  • Calciprotein particles circulate in the blood of patients with chronic kidney disease (CKD) and may contribute to vascular calcification, chronic inflammation and a premature-ageing phenotype

  • Raised phosphate intake and/or decreased nephron number increase the rate of phosphate excretion per nephron, potentially causing calciprotein particle formation in the tubular lumen and tubular injury

  • Serum fibroblast growth factor 23 (FGF-23) level correlates with phosphate excretion per nephron and, when combined with 24 h urinary phosphate excretion, may be useful for estimating changes in residual nephron number

  • A new paradigm for phosphate restriction proposed in this Review argues for phosphate binders to be used in patients with CKD and an abnormally high FGF-23 level, regardless of serum phosphate level

  • The therapeutic goal is to reduce serum FGF-23 level but not serum phosphate level, with the primary aim of preventing histological kidney damage and progression of CKD without increasing vascular calcification and cardiovascular events

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Figure 1: FGF–Klotho endocrine axes.
Figure 2: The formation of calciprotein particles.

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Acknowledgements

The author's work is supported in part by NIH (R01 AG019712 and DK091392).

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  1. Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390-9072, TX, USA

    Makoto Kuro-o

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M. Kuro-o has received honararia from Chugai Pharmaceutical and has received research funding from Genzyme.

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Kuro-o, M. Klotho, phosphate and FGF-23 in ageing and disturbed mineral metabolism. Nat Rev Nephrol 9, 650–660 (2013). https://doi.org/10.1038/nrneph.2013.111

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