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FGF23 and klotho at the intersection of kidney and cardiovascular disease

Nature Reviews Cardiology volume 21, pages 11–24 (2024)Cite this article

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Abstract

Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). As CKD progresses, CKD-specific risk factors, such as disordered mineral homeostasis, amplify traditional cardiovascular risk factors. Fibroblast growth factor 23 (FGF23) regulates mineral homeostasis by activating complexes of FGF receptors and transmembrane klotho co-receptors. A soluble form of klotho also acts as a ‘portable’ FGF23 co-receptor in tissues that do not express klotho. In progressive CKD, rising circulating FGF23 levels in combination with decreasing kidney expression of klotho results in klotho-independent effects of FGF23 on the heart that promote left ventricular hypertrophy, heart failure, atrial fibrillation and death. Emerging data suggest that soluble klotho might mitigate some of these effects via several candidate mechanisms. More research is needed to investigate FGF23 excess and klotho deficiency in specific cardiovascular complications of CKD, but the pathophysiological primacy of FGF23 excess versus klotho deficiency might never be precisely resolved, given the entangled feedback loops that they share. Therefore, randomized trials should prioritize clinical practicality over scientific certainty by targeting disordered mineral homeostasis holistically in an effort to improve cardiovascular outcomes in patients with CKD.

Key points

  • Chronic kidney disease causes a state of fibroblast growth factor 23 (FGF23) excess and klotho deficiency that increases the risk of cardiovascular disease.

  • FGF23 acts through FGF receptor 4, independently of klotho, to promote pathological left ventricular hypertrophy and increase the risk of heart failure.

  • Whereas transmembrane klotho mediates canonical effects of FGF23 in the kidneys, soluble klotho functions as a ‘portable’ co-receptor for FGF23 in tissues that do not express klotho.

  • Soluble klotho might attenuate the adverse cardiovascular effects of FGF23.

  • Soluble klotho deficiency promotes arterial calcification and atherosclerotic disease, either independently or via concomitant hyperphosphataemia.

  • Until targeted therapies are available, randomized cardiovascular outcomes trials could test combined interventions with drugs that target mineral homeostasis, and these are already in use in patients with end-stage kidney disease.

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Fig. 1: Evolution of cardiovascular disease and risk factors across the spectrum of CKD.
Fig. 2: FGF23, klotho and disordered mineral homeostasis in CKD.
Fig. 3: FGF23–klotho interaction and independent effects on the kidneys and heart.
Fig. 4: Predominant signalling mechanisms of FGF23 and klotho in cardiomyocytes and cardiac fibroblasts.

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Authors and Affiliations

  1. Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA

    Daniel Edmonston, Alexander Grabner & Myles Wolf

  2. Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA

    Daniel Edmonston & Myles Wolf

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  1. Daniel Edmonston
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  2. Alexander Grabner
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D.E. and A.G. researched data for the article. All the authors contributed substantially to discussion of the content, wrote the article, and reviewed and/or edited the manuscript before submission.

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Correspondence to Myles Wolf.

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M.W. has equity interests in Akebia, Unicycive and Walden, and has served as a consultant for Bayer, Enyo, Jnana, Launch, Pharmacosmos and Reata. The other authors declare no competing interests.

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Edmonston, D., Grabner, A. & Wolf, M. FGF23 and klotho at the intersection of kidney and cardiovascular disease. Nat Rev Cardiol 21, 11–24 (2024). https://doi.org/10.1038/s41569-023-00903-0

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