Fibroblast growth factor 23 and renal function among young and healthy individuals
-
Raffaele Bernasconi
, Stefanie Aeschbacher
Abstract
Background:
Fibroblast growth factor 23 (FGF-23), an osteocyte hormone involved in the regulation of phosphate metabolism, is associated with incident and progressive chronic kidney disease. We aimed to assess the association of FGF-23 with renal parameters, vascular function and phosphate metabolism in a large cohort of young and healthy individuals.
Methods:
Healthy individuals aged 25–41 years were included in a prospective population-based study. Fasting venous blood and morning urinary samples were used to measure plasma creatinine, cystatin C, endothelin-1, phosphate and plasma FGF-23 as well as urinary creatinine and phosphate. Multivariable regression models were constructed to assess the relationship of FGF-23 with parameters of renal function, endothelin-1 and fractional phosphate excretion.
Results:
The median age of 2077 participants was 37 years, 46% were males. The mean estimated glomerular filtration rate (eGFR – CKD-EPI creatinine-cystatin C equation) and fractional phosphate excretion were 110 mL/min/1.73 m2 and 8.7%, respectively. After multivariable adjustment, there was a significant inverse relationship of FGF-23 with eGFR (β per 1 log-unit increase −3.81; 95% CI [−5.42; −2.20]; p<0.0001). Furthermore, we found a linear association between FGF-23 and endothelin-1 (β per 1 log-unit increase 0.06; [0.01, 0.11]; p=0.01). In addition, we established a significant relationship of FGF-23 with fractional phosphate excretion (β per 1 log-unit increase 0.62; [0.08, 1.16]; p=0.03).
Conclusions:
Increasing plasma FGF-23 levels are strongly associated with decreasing eGFR and increasing urinary phosphate excretion, suggesting an important role of FGF-23 in the regulation of kidney function in young and healthy adults.
Acknowledgments
We thank the staff and participants of the GAPP study for their important contributions.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: The Swiss National Science Foundation (Funder Id: 10.13039/501100001711), the Liechtenstein Government, the Swiss Heart Foundation (Funder Id: 10.13039/501100004362), the Swiss Society of Hypertension, the University of Basel (Funder Id: 10.13039/100008375), the University Hospital Basel, the Mach-Gaensslen Foundation, the Hanela Foundation, Schiller AG and Novartis (Funder Id: 10.13039/100004336) supported the GAPP study. Endothelin-1 was measured free of charge by Singulex, Inc., Alameda, CA 94502, USA. Reagents for FGF-23 measurements were provided at a reduced cost by Diasorin Switzerland AG, Rotkreuz, Switzerland.
Employment or leadership: John Todd, Joel Estis and Niamh Nolan are employees of Singulex, Inc.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004;19:429–35.10.1359/JBMR.0301264Search in Google Scholar PubMed
2. Kovesdy CP, Quarles LD. FGF23 from bench to bedside. Am J Physiol Renal Physiol 2016;310:F1168–74.10.1152/ajprenal.00606.2015Search in Google Scholar PubMed PubMed Central
3. Viaene L, Bammens B, Meijers BK, Vanrenterghem Y, Vanderschueren D, Evenepoel P. Residual renal function is an independent determinant of serum FGF-23 levels in dialysis patients. Nephrol Dial Transplant 2012;27:2017–22.10.1093/ndt/gfr596Search in Google Scholar PubMed
4. Martin KJ, Gonzalez EA. Prevention and control of phosphate retention/hyperphosphatemia in CKD-MBD: what is normal, when to start, and how to treat? Clin J Am Soc Nephrol 2011;6:440–6.10.2215/CJN.05130610Search in Google Scholar PubMed
5. Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest 2011;121:4393–408.10.1172/JCI46122Search in Google Scholar PubMed PubMed Central
6. Hsu HJ, Wu MS. Fibroblast growth factor 23: a possible cause of left ventricular hypertrophy in hemodialysis patients. Am J Med Sci 2009;337:116–22.10.1097/MAJ.0b013e3181815498Search in Google Scholar PubMed
7. Gorriz JL, Molina P, Cerveron MJ, Vila R, Bover J, Nieto J, et al. Vascular calcification in patients with nondialysis CKD over 3 years. Clin J Am Soc Nephrol 2015;10:654–66.10.2215/CJN.07450714Search in Google Scholar PubMed PubMed Central
8. Nasrallah MM, El-Shehaby AR, Osman NA, Fayad T, Nassef A, Salem MM, et al. The association between fibroblast growth factor-23 and vascular calcification is mitigated by inflammation markers. Nephron Extra 2013;3:106–12.10.1159/000356118Search in Google Scholar PubMed PubMed Central
9. Munoz Mendoza J, Isakova T, Ricardo AC, Xie H, Navaneethan SD, Anderson AH, et al. Fibroblast growth factor 23 and Inflammation in CKD. Clin J Am Soc Nephrol 2012;7:1155–62.10.2215/CJN.13281211Search in Google Scholar PubMed PubMed Central
10. Rebholz CM, Grams ME, Coresh J, Selvin E, Inker LA, Levey AS, et al. Serum fibroblast growth factor-23 is associated with incident kidney disease. J Am Soc Nephrol 2015;26:192–200.10.1681/ASN.2014020218Search in Google Scholar PubMed PubMed Central
11. Scialla JJ, Astor BC, Isakova T, Xie H, Appel LJ, Wolf M. Mineral metabolites and CKD progression in African Americans. J Am Soc Nephrol 2013;24:125–35.10.1681/ASN.2012070713Search in Google Scholar PubMed PubMed Central
12. Ix JH, Katz R, Kestenbaum BR, de Boer IH, Chonchol M, Mukamal KJ, et al. Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study). J Am Coll Cardiol 2012;60:200–7.10.1161/circ.125.suppl_10.AP241Search in Google Scholar
13. Conen D, Schon T, Aeschbacher S, Pare G, Frehner W, Risch M, et al. Genetic and phenotypic determinants of blood pressure and other cardiovascular risk factors (GAPP). Swiss Med Wkly 2013;143:w13728.10.4414/smw.2013.13728Search in Google Scholar PubMed
14. Souberbielle JC, Prie D, Piketty ML, Rothenbuhler A, Delanaye P, Chanson P, et al. Evaluation of a new fully automated assay for plasma intact FGF23. Calcif Tissue Int 2017;101:510–18.10.1007/s00223-017-0307-ySearch in Google Scholar PubMed
15. LIAISON® FGF 23. In: S.p.A. D, ed: DiaSorin S.p.A.; 2016-08:11. Available at: https://drive.google.com/file/d/1xF3aGZcKZf9yuo8OLvttCEFtOmaiPf5l/view?usp=sharing.Search in Google Scholar
16. Bossard M, Pumpol K, van der Lely S, Aeschbacher S, Schoen T, Krisai P, et al. Plasma endothelin-1 and cardiovascular risk among young and healthy adults. Atherosclerosis 2015;239:186–91.10.1016/j.atherosclerosis.2014.12.061Search in Google Scholar PubMed
17. Ginsberg JM, Chang BS, Matarese RA, Garella S. Use of single voided urine samples to estimate quantitative proteinuria. N Engl J Med 1983;309:1543–6.10.1056/NEJM198312223092503Search in Google Scholar PubMed
18. Levin A, Stevens PE, Bilous RW, Coresh J, de Francisco AL, de Jong PE, et al. 2012 Clinical Practice Guideline for the Evaluation and Management of CKD. Kidney Int 2013;3:1–150.Search in Google Scholar
19. Barth JH, Jones RG, Payne RB. Calculation of renal tubular reabsorption of phosphate: the algorithm performs better than the nomogram. Ann Clin Biochem 2000;37:79–81.10.1258/0004563001901371Search in Google Scholar PubMed
20. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604–12.10.7326/0003-4819-150-9-200905050-00006Search in Google Scholar PubMed PubMed Central
21. Ketteler M, Block GA, Evenepoel P, Fukagawa M, Herzog CA, McCann L, et al. Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what’s changed and why it matters. Kidney Int 2017;92:26–36.10.1016/j.kint.2017.04.006Search in Google Scholar PubMed
22. Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 2012;367:20–9.10.1056/NEJMoa1114248Search in Google Scholar PubMed PubMed Central
23. Filler G, Liu D, Huang SH, Casier S, Chau LA, Madrenas J. Impaired GFR is the most important determinant for FGF-23 increase in chronic kidney disease. Clin Biochem 2011;44:435–7.10.1016/j.clinbiochem.2011.01.009Search in Google Scholar PubMed
24. Fliser D, Kollerits B, Neyer U, Ankerst DP, Lhotta K, Lingenhel A, et al. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol 2007;18:2600–8.10.1681/ASN.2006080936Search in Google Scholar PubMed
25. Isakova T, Xie H, Yang W, Xie D, Anderson AH, Scialla J, et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. J Am Med Assoc 2011;305:2432–9.10.1001/jama.2011.826Search in Google Scholar PubMed PubMed Central
26. Dai B, David V, Martin A, Huang J, Li H, Jiao Y, et al. A comparative transcriptome analysis identifying FGF23 regulated genes in the kidney of a mouse CKD model. PLoS One 2012;7:e44161.10.1371/journal.pone.0044161Search in Google Scholar PubMed PubMed Central
27. Kari JA, Donald AE, Vallance DT, Bruckdorfer KR, Leone A, Mullen MJ, et al. Physiology and biochemistry of endothelial function in children with chronic renal failure. Kidney Int 1997;52:468–72.10.1038/ki.1997.354Search in Google Scholar PubMed
28. Yilmaz MI, Sonmez A, Saglam M, Yaman H, Kilic S, Demirkaya E, et al. FGF-23 and vascular dysfunction in patients with stage 3 and 4 chronic kidney disease. Kidney Int 2010;78:679–85.10.1038/ki.2010.194Search in Google Scholar PubMed
29. Haffner D, Leifheit-Nestler M. Extrarenal effects of FGF23. Pediatr Nephrol 2017;32:753–65.10.1007/s00467-016-3505-3Search in Google Scholar PubMed
30. Kohan DE, Inscho EW, Wesson D, Pollock DM. Physiology of endothelin and the kidney. Compr Physiol 2011;1: 883–919.10.1002/cphy.c100039Search in Google Scholar PubMed PubMed Central
31. Fischer A, Bossard M, Aeschbacher S, Egli P, Cordewener C, Estis J, et al. Plasma levels of endothelin-1 and renal function among young and healthy adults. Clin Chem Lab Med 2017;55:1202–8.10.1515/cclm-2016-0920Search in Google Scholar PubMed
32. Iglarz M, Clozel M. Mechanisms of ET-1-induced endothelial dysfunction. J Cardiovasc Pharmacol 2007;50:621–8.10.1097/FJC.0b013e31813c6cc3Search in Google Scholar PubMed
33. Antoniucci DM, Yamashita T, Portale AA. Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men. J Clin Endocrinol Metab 2006;91:3144–9.10.1210/jc.2006-0021Search in Google Scholar PubMed
34. Desjardins L, Liabeuf S, Renard C, Lenglet A, Lemke HD, Choukroun G, et al. FGF23 is independently associated with vascular calcification but not bone mineral density in patients at various CKD stages. Osteoporos Int 2012;23:2017–25.10.1007/s00198-011-1838-0Search in Google Scholar PubMed
35. Schoppet M, Hofbauer LC, Brinskelle-Schmal N, Varennes A, Goudable J, Richard M, et al. Serum level of the phosphaturic factor FGF23 is associated with abdominal aortic calcification in men: the STRAMBO study. J Clin Endocrinol Metab 2012;97:E575–83.10.1210/jc.2011-2836Search in Google Scholar PubMed
36. Lundberg S, Qureshi AR, Olivecrona S, Gunnarsson I, Jacobson SH, Larsson TE. FGF23, albuminuria, and disease progression in patients with chronic IgA nephropathy. Clin J Am Soc Nephrol 2012;7:727–34.10.2215/CJN.10331011Search in Google Scholar PubMed PubMed Central
37. Vervloet MG, van Zuilen AD, Heijboer AC, ter Wee PM, Bots ML, Blankestijn PJ, et al. Fibroblast growth factor 23 is associated with proteinuria and smoking in chronic kidney disease: an analysis of the MASTERPLAN cohort. BMC Nephrol 2012;13:20.10.1186/1471-2369-13-20Search in Google Scholar PubMed PubMed Central
38. Ozeki M, Fujita S, Kizawa S, Morita H, Sohmiya K, Hoshiga M, et al. Association of serum levels of FGF23 and α-Klotho with glomerular filtration rate and proteinuria among cardiac patients. BMC Nephrol 2014;15:147.10.1186/1471-2369-15-147Search in Google Scholar PubMed PubMed Central
Supplementary Material:
The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2017-1183).
©2018 Walter de Gruyter GmbH, Berlin/Boston
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- The Theranos saga and the consequences
- Innovative approaches in diabetes diagnosis and monitoring: less invasive, less expensive… but less, equally or more efficient?
- Reviews
- Exploring the microbiota to better understand gastrointestinal cancers physiology
- Linking type 2 diabetes and gynecological cancer: an introductory overview
- Mini Reviews
- MicroRNAs as predictive biomarkers of response to tyrosine kinase inhibitor therapy in metastatic renal cell carcinoma
- Salivary biomarkers and cardiovascular disease: a systematic review
- Opinion Paper
- The meteoric rise and dramatic fall of Theranos: lessons learned for the diagnostic industry
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- Uncertainty evaluation in clinical chemistry, immunoassay, hematology and coagulation analytes using only external quality assessment data
- Measurement uncertainty and metrological traceability of whole blood cyclosporin A mass concentration results obtained by UHPLC-MS/MS
- Computer-assisted interventions in the clinical laboratory process improve the diagnosis and treatment of severe vitamin B12 deficiency
- Trueness, precision and stability of the LIAISON 1-84 parathyroid hormone (PTH) third-generation assay: comparison to existing intact PTH assays
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- Optimizing charge state distribution is a prerequisite for accurate protein biomarker quantification with LC-MS/MS, as illustrated by hepcidin measurement
- Quantification of human complement C2 protein using an automated turbidimetric immunoassay
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