The published observational data show similarly sized epidemiologic associations between increased fibroblast growth factor-23 (FGF-23) concentration and risk of a range of cardiovascular (atherosclerotic and nonatherosclerotic) and noncardiovascular outcomes. There is also an absence of any clear exposure-response relationship.1
Pelletier and Fouque2 have hypothesized that Klotho modifies FGF-23 associations with cardiovascular outcomes, and confirmation in large-scale studies is of interest. Such analyses, however, are unlikely to provide an explanation for the nonspecificity of FGF-23 associations. Instead, as recommended by Zhou et al.,3 further mechanistic experiments are needed. We suggest that such studies include the full range of noncardiovascular outcomes identified as associated with FGF-23. In the absence of good mechanistic evidence clearly supporting FGF-23’s role in a much wider range of disease processes, residual confounding is currently the most plausible explanation for the nonspecific associations. The epidemiology is suggesting the relationship between FGF-23 and cardiovascular disease risk may not be one of cause and effect.
Disclosures
None.
Acknowledgments
W.G.H. is supported by a Medical Research Council and Kidney Research UK Professor David Kerr Clinician Scientist Award.
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
References
- 1.Marthi A, Donovan K, Haynes R, Wheeler DC, Baigent C, Rooney CM, et al. : Fibroblast growth factor-23 and risks of cardiovascular and noncardiovascular diseases: A meta-analysis. J Am Soc Nephrol 29: 579–590, 2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Pelletier S, Fouque D: Fibroblast growth factor-23 is not a single bystander in chronic kidney disease mortality. J Am Soc Nephrol 29: XXX–XXX, 2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Zhou C, Mei C, Dai B, Xue C: Fibroblast growth factor-23 may follow cardiovascular disease rather than causing it in chronic kidney disease. J Am Soc Nephrol 29: 2602, 2018 [DOI] [PMC free article] [PubMed] [Google Scholar]