Abstract
Purpose
To characterize the relationship between the cFGF23/Klotho ratio and phosphate level in patients with chronic kidney disease (CKD).
Methods
A total of 152 patients with CKD stage 3–5 (CKD stage 3: n = 74; CKD stage 4: n = 60; CKD stage 5: n = 18) were included in the study. Thirty healthy volunteers served as controls. Intact-FGF23, cFGF23, Klotho, serum calcium, serum phosphate, and serum creatinine were measured, and estimated glomerular filtration rate (eGFR) was calculated. The Kruskal–Wallis H test was used for comparison between groups, and the Spearman test was used for correlation analysis.
Results
In CKD stage 3–5, creatinine and iFGF23 levels, as well as the cFGF23/Klotho ratio, were higher (P < 0.01), phosphate levels were higher (P < 0.05), and Klotho levels were lower (P < 0.01), compared with controls. C-terminal-FGF23 levels were higher in CKD phase 4–5 (P < 0.05). In CKD stage 4–5, creatinine, iFGF23, and phosphate levels, as well as the cFGF23/Klotho ratio, were higher (P < 0.01), cFGF23 levels were higher (P < 0.05), and Klotho levels were lower (P < 0.05), compared with CKD stage 3. In CKD stage 5, creatinine and cFGF23 levels, as well as the cFGF23/Klotho ratio, were higher (P < 0.01), phosphate and iFGF23 levels were higher (P < 0.05), and Klotho levels were lower (P < 0.01), compared with CKD stage 4. Phosphate was positively correlated with the cFGF23/Klotho ratio (r = 0.235, P < 0.01).
Conclusions
EGFR reduction was associated with an increased cFGF23/Klotho ratio, and the cFGF23/Klotho ratio was positively correlated with phosphate. This suggests that the phosphate level can be controlled by modifying the cFGF23/Klotho ratio.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Eddington H, Hoefield R, Sinha S et al (2010) Serum phosphate and mortality in patients with chronic kidney disease. Clin J Am Soc Nephrol 5:2251–2257. https://doi.org/10.2215/CJN.00810110
Goetz R, Nakada Y, Hu MC et al (2010) Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation. Proc Natl Acad Sci USA 107:407–412. https://doi.org/10.1073/pnas.0902006107
Takaiwa M, Aya K, Miyai T et al (2010) Fibroblast growth factor 23 concentrations in healthy term infants during the early postpartum period. Bone 47:256–262
Urakawa I, Yamazaki Y, Shimada T et al (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444:770–774. https://doi.org/10.1038/nature05315
Isakova T, Wahl P, Vargas GS et al (2011) Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int 79:1370–1378. https://doi.org/10.1038/ki.2011.47
Erben RG, Andrukhova O (2016) FGF23-Klotho signaling axis in the kidney. Bone. https://doi.org/10.1016/j.bone.2016.09.010
Quarles LD (2012) Role of FGF23 in vitamin D and phosphate metabolism: implications in chronic kidney disease. Exp Cell Res 318:1040. https://doi.org/10.1016/j.yexcr.2012.02.027
Tagliabracci VS, Engel JL, Wiley SE et al (2014) Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis. Proc Natl Acad Sci USA 111:5520–525. https://doi.org/10.1073/pnas.1402218111
Zhou Q, Lin S, Tang R, Veeraragoo P, Peng W, Wu R (2010) Role of fosinopril and valsartan on Klotho gene expression induced by angiotensin II in rat renal tubular epithelial cells. Kidney Blood Press Res 33:186. https://doi.org/10.1159/000316703
de Borst MH, Vervloet MG, ter Wee PM, Navis G (2011) Cross talk between the renin-angiotensin-aldosterone system and vitamin D-FGF-23-klotho in chronic kidney disease. J Am Soc Nephrol 22:1603. https://doi.org/10.1681/ASN.2010121251
Sun CY, Chang SC, Wu MS (2012) Suppression of Klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase expression and DNA hypermethylation. Kidney Int 81:640. https://doi.org/10.1038/ki.2011.445
Hu MC, Shi M, Cho HJ et al (2015) Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J Am Soc Nephrol 26:1290. https://doi.org/10.1681/ASN.2014050465
Yoon HE, Ghee JY, Piao S et al (2011) Angiotensin II blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy. Nephrol Dial Transpl 26:800–813. https://doi.org/10.1093/ndt/gfq537
Haussler MR, Whitfield GK, Kaneko I et al (2012) The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis. Rev Endocr Metab Dis 13:57–69. https://doi.org/10.1007/s11154-011-9199-8
Karalliedde J, Maltese G, Hill B, Viberti G, Gnudi L (2013) Effect of renin-angiotensin system blockade on soluble Klotho in patients with type 2 diabetes, systolic hypertension, and albuminuria. Clin J Am Soc Nephrol 8:1899–1905. https://doi.org/10.2215/CJN.02700313
Asai O, Nakatani K, Tanaka T et al (2012) Decreased renal α-Klotho expression in early diabetic nephropathy in humans and mice and its possible role in urinary calcium excretion. Kidney Int 81:539–547. https://doi.org/10.1038/ki.2011.423
Acknowledgements
We thank S. Win, PhD, and Ryan Chastain-Gross, PhD, from Liwen Bianji, Edanz Editing China (http://www.liwenbianji.cn/ac) for editing a draft of this manuscript.
Funding
This study was supported by the Chinese Medicine Science and Technology Project of Fujian Provincial Health Department (Grant no. WZSb201316).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
There are no conflicts of interest to declare.
Rights and permissions
About this article
Cite this article
Liu, Z., Zhou, H., Chen, X. et al. Relationship between cFGF23/Klotho ratio and phosphate levels in patients with chronic kidney disease. Int Urol Nephrol 51, 503–507 (2019). https://doi.org/10.1007/s11255-019-02079-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11255-019-02079-4