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
Disclosures
None.
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
2. Bacchetta J, Pelletier S: Vitamin D deficiency is associated with mortality in maintenance dialysis: Moving forward from epidemiology to clinical trials [published online ahead of print May 22, 2018]. Nephrol Dial Transplant doi:10.1093/ndt/gfy122
3. Kuro-O M: Klotho and endocrine fibroblast growth factors: Marker of chronic kidney disease progression and cardiovascular complications [published online ahead of print May 25, 2018]? Nephrol Dial Transplant doi:10.1093/ndt/gfy126
4. Marçais C, Maucort-Boulch D, Drai J, Dantony E, Carlier MC, Blond E, et al.; ARNOGENE Project: Circulating Klotho associates with cardiovascular morbidity and mortality during hemodialysis. J Clin Endocrinol Metab 102: 3154–3161, 201728402487
5. Grabner A, Amaral AP, Schramm K, Singh S, Sloan A, Yanucil C, et al.: Activation of cardiac fibroblast growth factor receptor 4 causes left ventricular hypertrophy. Cell Metab 22: 1020–1032, 201526437603
6. Hu MC, Shi M, Cho HJ, Adams-Huet B, Paek J, Hill K, et al.: Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J Am Soc Nephrol 26: 1290–1302, 201525326585
