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Renal and extrarenal effects of fibroblast growth factor 23

Abstract

Fibroblast growth factor 23 (FGF23) is a hormone with a central role in the regulation of phosphate homeostasis. This regulation is accomplished by the coordinated modulation of renal phosphate handling, vitamin D metabolism and parathyroid hormone secretion. Patients with kidney disease have increased circulating levels of FGF23 and in other patient populations and in healthy individuals, FGF23 levels also rise following an increase in dietary phosphate intake. Maladaptive increases in FGF23 have a detrimental effect on several organs and tissues and, importantly, these pathological changes most likely contribute to increased morbidity and mortality. For example, in the context of heart disease, FGF23 is involved in the development of pathological hypertrophy that can lead to congestive heart failure. Increased FGF23 concentrations can also lead to microcirculatory changes, in particular reduced vasodilatory capacity, and collectively these cardiovascular changes can compromise tissue perfusion. In addition, FGF23 is associated with inflammation and an increased risk of infection; other potentially detrimental effects of FGF23 are likely to emerge in the future. Most importantly, recent insights demonstrate that FGF23 can be therapeutically targeted, which holds promise for the treatment of many patients in a variety of clinical settings.

Key points

  • Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that functions as the central endocrine factor that regulates phosphate balance.

  • Findings from epidemiological studies, both in the general population and in patients with kidney disease, are remarkably consistent and demonstrate an association of FGF23 with important clinical events related to mortality, cardiovascular disease and inflammation.

  • Biological plausibility for a causal relation between FGF23 and clinical events exists; experimental studies suggest, in particular, a link between FGF23 and left ventricular hypertrophy, and possibly also vasomotor function, inflammation and immunological defence.

  • Given the possibility that residual confounding might have distorted findings from cohort analyses and experimental studies, definite proof that FGF23 induces clinically relevant outcomes is needed.

  • The discovery of therapeutic interventions that can either lower FGF23 concentrations or block its effects should prompt the design of clinical trials that aim to establish whether targeting FGF23 can reduce clinically relevant outcomes.

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Fig. 1: The central role of FGF23 in the regulation of phosphate balance.
Fig. 2: Potential mechanisms for FGF23-induced signal transduction.
Fig. 3: Key FGFR signalling pathways.
Fig. 4: Putative reduction in the risk of death in response to FGF23 targeting.
Fig. 5: Crosstalk between the cardiovascular system and FGF23.
Fig. 6: The vicious cycle of inflammation and FGF23 secretion.

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Acknowledgements

The author’s work on FGF23 is supported by the Dutch Kidney Foundation.

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Nature Reviews Nephrology thanks M. Fukugawa, A. Zarbock and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Correspondence to Marc Vervloet.

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Glossary

Osteomalacia

Bone disease that leads to softening or weakening of the bones and is characterized by abnormal mineralization of osteoid, which is the unmineralized matrix produced by osteoblasts.

Uraemic syndrome

Set of clinical features that result from the metabolic abnormalities induced by kidney failure.

Fractional excretion of phosphate

The percentage of phosphate that is filtered at the glomerulus and is eventually secreted in the urine.

Diastolic heart failure

Impaired cardiac dilatation, especially of the left ventricle, during diastole that typically leads to congestive heart failure.

Mediation analysis

Statistical analysis technique that aims to unravel a causal path of sequential events.

Phosphate binders

Drugs that bind phosphate derived from diet, thereby impairing phosphate absorption from the gastrointestinal tract and lowering serum phosphate concentrations; frequently prescribed in end-stage renal disease.

Calcimimetic

Drug prescribed for secondary hyperparathyroidism in patients treated by dialysis that enhances the sensitivity of the calcium-sensing receptor in the parathyroid gland, thereby inhibiting parathyroid hormone secretion.

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Vervloet, M. Renal and extrarenal effects of fibroblast growth factor 23. Nat Rev Nephrol 15, 109–120 (2019). https://doi.org/10.1038/s41581-018-0087-2

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