Fibroblast Growth Factor-23 Is Not a Single Bystander in Chronic Kidney Disease Mortality

• fibroblast growth factor
• klotho
• cardiovascular events
• hemodialysis
• survival

We read with great interest the relationship reported by Marthi et al.¹ between fibroblast growth factor-23 (FGF-23), morbidity, and mortality in the general population and patients with CKD. The FGF-23 increase has been described in patients with CKD who are unable to clear phosphate from blood, leading to a rapid increase in FGF-23 production and serum concentration. However, FGF-23 does not stand alone in this early metabolic disorder,² and Klotho, its cofactor, is also a major compound to consider.³

We recently reported two important observations⁴ on FGF-23/Klotho related to the findings of Marthi et al.¹ In a 2-year prospective cohort of 235 patients on maintenance hemodialysis, we found that a serum FGF-23 increase by 10 RU/ml was associated with a 7% greater cardiovascular morbidity and mortality, whereas a serum Klotho above 280 ng/L was associated with a 14% lower event rate. Importantly, these significant associations were independent from each other. Thus, the protection brought by Klotho seems greater than the deleterious FGF-23 effect on cardiovascular events.⁴ Furthermore, patients with a high Klotho did not present increased morbidity and mortality associated with a high FGF-23. This key information may decipher the pathogenic role of FGF-23 in specific organs.⁵ FGF-23 may exert its cardiac toxicity only if serum Klotho is reduced, such as has been convincingly shown in an animal model by Hu et al.⁶ and advocated in our clinical study.⁴

Thus, the well established association between FGF-23 and mortality is confirmed here by Marthi et al.¹ However, analyzing the FGF-23 effect without Klotho data may overemphasize the deleterious effect of FGF-23. It should be interesting to measure Klotho in long-term studies addressing cardiovascular events and FGF23 determination. This may confirm an independent pathogenic FGF23 effect as proposed by Grabner et al.⁵ or support the absence of causality between high FGF23 and survival suggested by Marthi et al.¹

• Copyright © 2018 by the American Society of Nephrology