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FGF23-klotho axis, bone fractures, and arterial stiffness in dialysis: a case-control study

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Abstract

Summary

We performed a case-control study on 130 age- and sex-matched hemodialysis patients. In multivariate analysis, we observed that FGF23 levels were associated with fracture incidence and that soluble α-klotho levels were associated with the aortic-brachial arterial stiffness ratio.

Introduction

New bone markers such as sclerostin, Dickkopf-related protein 1 (DKK1), fibroblast growth factor-23 (FGF23), and α-klotho have been identified as potential key players in bone and vascular abnormalities of chronic kidney disease. Therefore, we aimed to assess whether these markers are associated with fractures, bone metabolism, and vascular stiffness in dialysis patients.

Methods

In a prospective hemodialysis cohort, where plasma samples and vascular assessment were performed at baseline, we matched patients who experienced a fracture during follow-up with sex- and age-matched non-fractured patients on a 1:4 ratio. Sclerostin, DKK1, α-klotho, FGF23, and markers of bone formation (alkaline phosphatase and procollagen type 1-N terminal propeptide [P1NP]) and bone resorption (tartrate-resistant acid phosphatase 5b [TRAP5b]) were measured in baseline plasma samples. Aortic-brachial pulse wave velocity ratio, a blood pressure independent measure of arterial stiffness, was used to assess vascular stiffness at baseline.

Results

We included 130 hemodialysis patients (26 fractured, 104 non-fractured) with a median follow-up of 42 months and a median age of 72 years. In multivariate Cox regression models, high FGF23 levels were associated with increased fracture incidence (adjusted HR = 2.97; 95% CI 1.18, 7.43). α-Klotho levels were associated with bone formation but not resorption markers. In both univariate and multivariable adjusted models, α-klotho levels were inversely associated with the aortic-brachial pulse wave velocity ratio (β = − 0.070; 95% CI − 0.133, − 0.006).

Conclusions

These results suggest a role for FGF23/klotho axis on bone and vascular metabolism in dialysis populations.

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References

  1. Moe S, Drueke T, Cunningham J et al (2006) Definition, evaluation, and classification of renal osteodystrophy: a position statement from kidney disease: improving global outcomes (KDIGO). Kidney Int 69:1945–1953

    Article  CAS  Google Scholar 

  2. Carrillo-Lopez N, Panizo S, Alonso-Montes C, Roman-Garcia P, Rodriguez I, Martinez-Salgado C, Dusso AS, Naves M, Cannata-Andia JB (2016) Direct inhibition of osteoblastic Wnt pathway by fibroblast growth factor 23 contributes to bone loss in chronic kidney disease. Kidney Int 90:77–89

    Article  CAS  Google Scholar 

  3. Evenepoel P, D'Haese P, Brandenburg V (2015) Sclerostin and DKK1: new players in renal bone and vascular disease. Kidney Int 88:235–240

    Article  CAS  Google Scholar 

  4. Yamada S, Giachelli CM (2017) Vascular calcification in CKD-MBD: roles for phosphate, FGF23, and klotho. Bone 100:87–93

    Article  CAS  Google Scholar 

  5. Malluche HH, Davenport DL, Cantor T, Monier-Faugere MC (2014) Bone mineral density and serum biochemical predictors of bone loss in patients with CKD on dialysis. Clin J Am Soc Nephrol 9:1254–1262

    Article  CAS  Google Scholar 

  6. Thambiah S, Roplekar R, Manghat P, Fogelman I, Fraser WD, Goldsmith D, Hampson G (2012) Circulating sclerostin and Dickkopf-1 (DKK1) in predialysis chronic kidney disease (CKD): relationship with bone density and arterial stiffness. Calcif Tissue Int 90:473–480

    Article  CAS  Google Scholar 

  7. Qureshi AR, Olauson H, Witasp A, Haarhaus M, Brandenburg V, Wernerson A, Lindholm B, Söderberg M, Wennberg L, Nordfors L, Ripsweden J, Barany P, Stenvinkel P (2015) Increased circulating sclerostin levels in end-stage renal disease predict biopsy-verified vascular medial calcification and coronary artery calcification. Kidney Int 88:1356–1364

    Article  CAS  Google Scholar 

  8. Moe SM, Chertow GM, Parfrey PS, Kubo Y, Block GA, Correa-Rotter R, Drüeke TB, Herzog CA, London GM, Mahaffey KW, Wheeler DC, Stolina M, Dehmel B, Goodman WG, Floege J, Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial Investigators* (2015) Cinacalcet, fibroblast growth Factor-23, and cardiovascular disease in hemodialysis: the evaluation of Cinacalcet HCl therapy to lower cardiovascular events (EVOLVE) trial. Circulation 132:27–39

    Article  CAS  Google Scholar 

  9. Kaludjerovic J, Komaba H, Lanske B (2017) Effects of klotho deletion from bone during chronic kidney disease. Bone 100:50–55

    Article  CAS  Google Scholar 

  10. Komaba H, Kaludjerovic J, Hu DZ, Nagano K, Amano K, Ide N, Sato T, Densmore MJ, Hanai JI, Olauson H, Bellido T, Larsson TE, Baron R, Lanske B (2017) Klotho expression in osteocytes regulates bone metabolism and controls bone formation. In: Kidney Int, vol 92, pp 599–611

    Google Scholar 

  11. Fortier C, Mac-Way F, Desmeules S, Marquis K, De Serres SA, Lebel M, Boutouyrie P, Agharazii M (2015) Aortic-brachial stiffness mismatch and mortality in dialysis population. Hypertension Dallas Tex 1979(65):378–384

    Article  Google Scholar 

  12. Utescu MS, Couture V, Mac-Way F, De Serres SA, Marquis K, Lariviere R, Desmeules S, Lebel M, Boutouyrie P, Agharazii M (2013) Determinants of progression of aortic stiffness in hemodialysis patients: a prospective longitudinal study. Hypertension Dallas Tex 1979(62):154–160

    Article  Google Scholar 

  13. Tanaka S, Fujita S, Kizawa S, Morita H, Ishizaka N (2016) Association between FGF23, alpha-klotho, and cardiac abnormalities among patients with various chronic kidney disease stages. PLoS One 11:e0156860

    Article  Google Scholar 

  14. Gattineni J, Bates C, Twombley K, Dwarakanath V, Robinson ML, Goetz R, Mohammadi M, Baum M (2009) FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J Physiol Renal Physiol 297:F282–F291

    Article  CAS  Google Scholar 

  15. Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G, Juppner H, Wolf M (2005) Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol : JASN 16:2205–2215

    Article  CAS  Google Scholar 

  16. Souma N, Isakova T, Lipiszko D, Sacco RL, Elkind MSV, DeRosa JT, Silverberg SJ, Mendez AJ, Dong C, Wright CB, Wolf M (2016) Fibroblast growth factor 23 and cause-specific mortality in the general population: the northern Manhattan study. J Clin Endocrinol Metab 101:3779–3786

    Article  CAS  Google Scholar 

  17. Lima F, El-Husseini A, Monier-Faugere MC, David V, Mawad H, Quarles D, Malluche HH (2014) FGF-23 serum levels and bone histomorphometric results in adult patients with chronic kidney disease on dialysis. Clin Nephrol 82:287–295

    Article  CAS  Google Scholar 

  18. Desjardins L, Liabeuf S, Renard C, Lenglet A, Lemke HD, Choukroun G, Drueke TB, Massy ZA, European Uremic Toxin Work G (2012) FGF23 is independently associated with vascular calcification but not bone mineral density in patients at various CKD stages. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 23:2017–2025

    Article  CAS  Google Scholar 

  19. Manghat P, Fraser WD, Wierzbicki AS, Fogelman I, Goldsmith DJ, Hampson G (2010) Fibroblast growth factor-23 is associated with C-reactive protein, serum phosphate and bone mineral density in chronic kidney disease. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 21:1853–1861

    Article  CAS  Google Scholar 

  20. Lane NE, Parimi N, Corr M, Yao W, Cauley JA, Nielson CM, Ix JH, Kado D, Orwoll E, Osteoporotic Fractures in Men Study G (2013) Association of serum fibroblast growth factor 23 (FGF23) and incident fractures in older men: the Osteoporotic Fractures in Men (MrOS) study. J Bone Miner Res 28:2325–2332

    Article  CAS  Google Scholar 

  21. Jovanovich A, Buzkova P, Chonchol M et al (2013) Fibroblast growth factor 23, bone mineral density, and risk of hip fracture among older adults: the cardiovascular health study. J Clin Endocrinol Metab 98:3323–3331

    Article  CAS  Google Scholar 

  22. Wei K, Yin Z, Xie Y (2016) Roles of the kidney in the formation, remodeling and repair of bone. J Nephrol 29:349–357

    Article  Google Scholar 

  23. Kuro-o M, Matsumura Y, Aizawa H et al (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390:45–51

    Article  CAS  Google Scholar 

  24. Sasaki M, Hasegawa T, Yamada T, Hongo H, de Freitas PHL, Suzuki R, Yamamoto T, Tabata C, Toyosawa S, Yamamoto T, Oda K, Li M, Inoue N, Amizuka N (2013) Altered distribution of bone matrix proteins and defective bone mineralization in klotho-deficient mice. Bone 57:206–219

    Article  CAS  Google Scholar 

  25. Hum JM, O'Bryan L, Smith RC, White KE (2017) Novel functions of circulating klotho. Bone 100:36–40

    Article  CAS  Google Scholar 

  26. Atteritano M, Di Mauro E, Canale V, Bruzzese AM, Ricciardi CA, Cernaro V, Lacquaniti A, Buemi M, Santoro D (2017) Higher serum sclerostin levels and insufficiency of vitamin D are strongly associated with vertebral fractures in hemodialysis patients: a case control study. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 28:577–584

    Article  CAS  Google Scholar 

  27. Danese MD, Kim J, Doan QV, Dylan M, Griffiths R, Chertow GM (2006) PTH and the risks for hip, vertebral, and pelvic fractures among patients on dialysis. American journal of kidney diseases : the official journal of the National Kidney Foundation 47:149–156

    Article  Google Scholar 

  28. Heidari B, Hosseini R, Javadian Y, Bijani A, Sateri MH, Nouroddini HG (2015) Factors affecting bone mineral density in postmenopausal women. Arch Osteoporos 10:15

    Article  Google Scholar 

  29. Kim BJ, Lee SH, Koh JM, Kim GS (2013) The association between higher serum ferritin level and lower bone mineral density is prominent in women >/=45 years of age (KNHANES 2008-2010). Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 24:2627–2637

    Article  CAS  Google Scholar 

  30. David V, Martin A, Isakova T, Spaulding C, Qi L, Ramirez V, Zumbrennen-Bullough KB, Sun CC, Lin HY, Babitt JL, Wolf M (2016) Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int 89:135–146

    Article  CAS  Google Scholar 

  31. Blacher JGA, Pannier B, Marchais SJ, London GM (2001) Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 38:938–942

    Article  CAS  Google Scholar 

  32. Fortier C, Agharazii M (2016) Arterial Stiffness Gradient. Pulse (Basel) 3:159–166

    Article  Google Scholar 

  33. Fortier C, Sidibe A, Desjardins MP, Marquis K, De Serres SA, Mac-Way F, Agharazii M (2017) Aortic-brachial pulse wave velocity ratio: a blood pressure-independent index of vascular aging. Hypertension Dallas Tex 1979(69):96–101

    Article  Google Scholar 

  34. Marcais C, Maucort-Boulch D, Drai J et al (2017) Circulating klotho associates with cardiovascular morbidity and mortality during hemodialysis. J Clin Endocrinol Metab 102:3154–3161

    Article  Google Scholar 

  35. Kitagawa M, Sugiyama H, Morinaga H, Inoue T, Takiue K, Ogawa A, Yamanari T, Kikumoto Y, Uchida HA, Kitamura S, Maeshima Y, Nakamura K, Ito H, Makino H (2013) A decreased level of serum soluble klotho is an independent biomarker associated with arterial stiffness in patients with chronic kidney disease. PLoS One 8:e56695

    Article  CAS  Google Scholar 

  36. Hu MC, Shi M, Zhang J, Quinones H, Griffith C, Kuro-o M, Moe OW (2011) Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol : JASN 22:124–136

    Article  CAS  Google Scholar 

  37. Kim HJ, Kang E, Oh YK, Kim YH, Han SH, Yoo TH, Chae DW, Lee J, Ahn C, Oh KH (2018) The association between soluble klotho and cardiovascular parameters in chronic kidney disease: results from the KNOW-CKD study. BMC Nephrol 19:51

    Article  Google Scholar 

  38. Jin S, Zhu M, Yan J, Fang Y, Lu R, Zhang W, Zhang Q, Lu J, Qi C, Shao X, Zhang H, Jiang R, Ni Z (2016) Serum sclerostin level might be a potential biomarker for arterial stiffness in prevalent hemodialysis patients. Biomark Med 10:689–699

    Article  CAS  Google Scholar 

  39. Krishnasamy R, Tan SJ, Hawley CM, Johnson DW, Stanton T, Lee K, Mudge DW, Campbell S, Elder GJ, Toussaint ND, Isbel NM (2017) Progression of arterial stiffness is associated with changes in bone mineral markers in advanced CKD. BMC Nephrol 18:281

    Article  Google Scholar 

  40. Heijboer AC, Blankenstein MA, Hoenderop J, de Borst MH, Vervloet MG, consortium N (2013) Laboratory aspects of circulating alpha-klotho. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 28:2283–2287

    Article  Google Scholar 

  41. Piec I, Washbourne C, Tang J, Fisher E, Greeves J, Jackson S, Fraser WD (2016) How accurate is your Sclerostin measurement? Comparison between three commercially available Sclerostin ELISA kits. Calcif Tissue Int 98:546–555

    Article  CAS  Google Scholar 

  42. Smith ER (2014) The use of fibroblast growth factor 23 testing in patients with kidney disease. Clin J Am Soc Nephrol : CJASN 9:1283–1303

    Article  CAS  Google Scholar 

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Funding

This work was supported by the Department of Medicine, Fondation du CHU de Québec from Université Laval, by a Biomedical Project Grant from the Kidney Foundation of Canada (KFOC160013) and by the KRESCENT program from CIHR/CSN/KFOC/FRQS (KRES150006). LCD holds masters scholarship from Canadian Institutes of Health Research (CIHR) and Fonds de Recherche du Québec Santé (FRQS). AS holds a doctorate scholarship from Société Québécoise d’Hypertension Artérielle. CF holds a scholarship from the Kidney Foundation of Canada (KFOC). YPW and SKB hold masters scholarships from CIHR. MA holds a research chair in nephrology from Université Laval. FMW holds a scholarship from FRQS and KRESCENT program from CIHR, Canadian Society of Nephrology and the Kidney Foundation of Canada.

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Authors and Affiliations

  1. CHU de Québec Research Center, Endocrinology and Nephrology Axis, Quebec, Canada

    L.-C. Desbiens, A. Sidibé, R.-V. Ung, C. Fortier, M. Munger, Y.-P. Wang, S.-K. Bisson, K. Marquis, M. Agharazii & F. Mac-Way

  2. Faculty and Department of Medicine, Université Laval, Quebec, Canada

    L.-C. Desbiens, C. Fortier, M. Munger, Y.-P. Wang, S.-K. Bisson, M. Agharazii & F. Mac-Way

  3. Department of Social and Preventive Medicine, Faculty of Medicine, Université Laval, Quebec, Canada

    A. Sidibé

  4. CHU de Québec Research Center, L’Hôtel-Dieu de Québec Hospital, 10 McMahon, Quebec City, G1R 2J6, Canada

    F. Mac-Way

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  1. L.-C. Desbiens
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  2. A. Sidibé
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Correspondence to F. Mac-Way.

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Desbiens, LC., Sidibé, A., Ung, RV. et al. FGF23-klotho axis, bone fractures, and arterial stiffness in dialysis: a case-control study. Osteoporos Int 29, 2345–2353 (2018). https://doi.org/10.1007/s00198-018-4598-2

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