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Current Vascular Pharmacology

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ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

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Review Article

New Insights into the Role of FGF-23 and Klotho in Cardiovascular Disease in Chronic Kidney Disease Patients

Author(s): Evangelos Memmos and Aikaterini Papagianni*

Volume 19, Issue 1, 2021

Published on: 20 April, 2020

Page: [55 - 62] Pages: 8

DOI: 10.2174/1570161118666200420102100

Price: $65

Abstract

Alterations of fibroblast growth factor 23 (FGF-23) and Klotho levels are considered to be the earliest biochemical abnormality of chronic kidney disease – mineral and bone disease (CKDMBD) syndrome. Moreover, emerging data suggests that the dysregulated FGF-23 and Klotho axis has many effects on the cardiovascular (CV) system and contributes significantly to the increased CV morbidity and mortality rates of CKD patients. This review examines recent evidence on the role of FGF-23 and Klotho in the development and progression of CV complications of uremia namely cardiac hypertrophy, uremic cardiomyopathy, and atherosclerotic and arteriosclerotic vascular lesions. Moreover, the available evidence on their associations with adverse clinical outcomes are summarized. Undoubtedly, more studies are needed to further elucidate the effects of FGF-23 and Klotho on the heart and vessels and to gain insights into their prognostic value as CV risk factors. Finally, large prospective studies are required to test the hypothesis that modification of their levels would have a favourable impact on the unacceptably high mortality rates of these patient populations.

Keywords: Cardiovascular disease, chronic kidney disease, fibroblast growth factor-23, Klotho, uremic vasculopathy.

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[1]
London GM, Drueke TB. Atherosclerosis and arteriosclerosis in chronic renal failure. Kidney Int 1997; 51(6): 1678-95.
[http://dx.doi.org/10.1038/ki.1997.233] [PMID: 9186855]
[2]
Georgianos PI, Sarafidis PA, Lasaridis AN. Arterial stiffness: a novel cardiovascular risk factor in kidney disease patients. Curr Vasc Pharmacol 2015; 13(2): 229-38.
[http://dx.doi.org/10.2174/15701611113119990147] [PMID: 24007427]
[3]
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospital-ization. N Engl J Med 2004; 351(13): 1296-305.
[http://dx.doi.org/10.1056/NEJMoa041031] [PMID: 15385656]
[4]
Saran R, Li Y, Robinson B, et al. US renal data system 2015 annual data report: epidemiology of kidney disease in the United States. Am J Kidney Dis 2016; 67(3)(Suppl. 1): S1-S305.
[http://dx.doi.org/10.1053/j.ajkd.2015.12.014] [PMID: 26925525]
[5]
Da J, Xie X, Wolf M, et al. Serum phosphorus and progression of CKD and mortality: a meta-analysis of cohort studies. Am J Kidney Dis 2015; 66(2): 258-65.
[http://dx.doi.org/10.1053/j.ajkd.2015.01.009] [PMID: 25804679]
[6]
Georgianos PI, Sarafidis PA, Sinha AD, Agarwal R. Adverse effects of conventional thrice-weekly hemodialysis: is it time to avoid 3-day interdialytic intervals? Am J Nephrol 2015; 41(4-5): 400-8.
[http://dx.doi.org/10.1159/000435842] [PMID: 26139107]
[7]
Shimada T, Urakawa I, Yamazaki Y, et al. FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of so-dium phosphate cotransporter type IIa. Biochem Biophys Res Commun 2004; 314(2): 409-14.
[http://dx.doi.org/10.1016/j.bbrc.2003.12.102] [PMID: 14733920]
[8]
Wolf M. Update on fibroblast growth factor 23 in chronic kidney disease. Kidney Int 2012; 82(7): 737-47.
[http://dx.doi.org/10.1038/ki.2012.176] [PMID: 22622492]
[9]
Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997; 390(6655): 45-51.
[http://dx.doi.org/10.1038/36285] [PMID: 9363890]
[10]
Nitta K, Nagano N, Tsuchiya K. Fibroblast growth factor 23/klotho axis in chronic kidney disease. Nephron Clin Pract 2014; 128(1-2): 1-10.
[http://dx.doi.org/10.1159/000365787] [PMID: 25402964]
[11]
Kim HR, Nam BY, Kim DW, et al. Circulating α-klotho levels in CKD and relationship to progression. Am J Kidney Dis 2013; 61(6): 899-909.
[http://dx.doi.org/10.1053/j.ajkd.2013.01.024] [PMID: 23540260]
[12]
Imanishi Y, Inaba M, Nakatsuka K, et al. FGF-23 in patients with end-stage renal disease on hemodialysis. Kidney Int 2004; 65(5): 1943-6.
[http://dx.doi.org/10.1111/j.1523-1755.2004.00604.x] [PMID: 15086938]
[13]
Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest 2011; 121(11): 4393-408.
[http://dx.doi.org/10.1172/JCI46122] [PMID: 21985788]
[14]
Grabner A, Amaral AP, Schramm K, et al. Activation of cardiac fibroblast growth factor receptor 4 causes left ventricular hypertrophy. Cell Metab 2015; 22(6): 1020-32.
[http://dx.doi.org/10.1016/j.cmet.2015.09.002] [PMID: 26437603]
[15]
Matsui I, Oka T, Kusunoki Y, et al. Cardiac hypertrophy elevates serum levels of fibroblast growth factor 23. Kidney Int 2018; 94(1): 60-71.
[http://dx.doi.org/10.1016/j.kint.2018.02.018] [PMID: 29751971]
[16]
Pastor-Arroyo EM, Gehring N, Krudewig C, et al. The elevation of circulating fibroblast growth factor 23 without kidney disease does not increase cardiovascular disease risk. Kidney Int 2018; 94(1): 49-59.
[http://dx.doi.org/10.1016/j.kint.2018.02.017] [PMID: 29735309]
[17]
Touchberry CD, Green TM, Tchikrizov V, et al. FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy. Am J Physiol Endocrinol Metab 2013; 304(8): E863-73.
[http://dx.doi.org/10.1152/ajpendo.00596.2012] [PMID: 23443925]
[18]
Navarro-García JA, Delgado C, Fernández-Velasco M, et al. Fibroblast growth factor-23 promotes rhythm alterations and contractile dysfunction in adult ventricular cardiomyocytes. Nephrol Dial Transplant 2019; 34(11): 1864-75.
[http://dx.doi.org/10.1093/ndt/gfy392] [PMID: 30629224]
[19]
Gutiérrez OM, Januzzi JL, Isakova T, et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 2009; 119(19): 2545-52.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.108.844506] [PMID: 19414634]
[20]
Hsu HJ, Wu MS. Fibroblast growth factor 23: a possible cause of left ventricular hypertrophy in hemodialysis patients. Am J Med Sci 2009; 337(2): 116-22.
[http://dx.doi.org/10.1097/MAJ.0b013e3181815498] [PMID: 19214027]
[21]
Kirkpantur A, Balci M, Gurbuz OA, et al. Serum fibroblast growth factor-23 (FGF-23) levels are independently associated with left ven-tricular mass and myocardial performance index in maintenance haemodialysis patients. Nephrol Dial Transplant 2011; 26(4): 1346-54.
[http://dx.doi.org/10.1093/ndt/gfq539] [PMID: 20813767]
[22]
Papagianni A. Fibroblast growth factor-23: a novel biomarker for cardiovascular disease in chronic kidney disease patients.Pril Makedon Akad Nauk Umet Odd Med Nauki 2017; 38(2): 19-27.
[http://dx.doi.org/10.1515/prilozi-2017-0018] [PMID: 28991773]
[23]
Leifheit-Nestler M, Große Siemer R, Flasbart K, et al. Induction of cardiac FGF23/FGFR4 expression is associated with left ventricular hypertrophy in patients with chronic kidney disease. Nephrol Dial Transplant 2016; 31(7): 1088-99.
[http://dx.doi.org/10.1093/ndt/gfv421] [PMID: 26681731]
[24]
Mitsnefes MM, Betoko A, Schneider MF, et al. FGF23 and left ventricular hypertrophy in children with CKD. Clin J Am Soc Nephrol 2018; 13(1): 45-52.
[http://dx.doi.org/10.2215/CJN.02110217] [PMID: 29025789]
[25]
Mathew JS, Sachs MC, Katz R, et al. Fibroblast growth factor-23 and incident atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS). Circulation 2014; 130(4): 298-307.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.113.005499] [PMID: 24920722]
[26]
Alonso A, Misialek JR, Eckfeldt JH, et al. Circulating fibroblast growth factor-23 and the incidence of atrial fibrillation: the Atherosclerosis Risk in Communities study. J Am Heart Assoc 2014; 3(5)e001082
[http://dx.doi.org/10.1161/JAHA.114.001082] [PMID: 25237047]
[27]
Mehta R, Cai X, Lee J, et al. Association of fibroblast growth factor 23 with atrial fibrillation in chronic kidney disease, from the chronic renal insufficiency cohort study. JAMA Cardiol 2016; 1(5): 548-56.
[http://dx.doi.org/10.1001/jamacardio.2016.1445] [PMID: 27434583]
[28]
Takeshita K, Fujimori T, Kurotaki Y, et al. Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression. Circulation 2004; 109(14): 1776-82.
[http://dx.doi.org/10.1161/01.CIR.0000124224.48962.32] [PMID: 15037532]
[29]
Xie J, Cha SK, An SW, Kuro-O M, Birnbaumer L, Huang CL. Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. Nat Commun 2012; 3: 1238.
[http://dx.doi.org/10.1038/ncomms2240] [PMID: 23212367]
[30]
Hu MC, Shi M, Cho HJ, et al. Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J Am Soc Nephrol 2015; 26(6): 1290-302.
[http://dx.doi.org/10.1681/ASN.2014050465] [PMID: 25326585]
[31]
Xie J, Yoon J, An SW, Kuro-o M, Huang CL. Soluble Klotho protects against uremic cardiomyopathy independently of fibroblast growth factor 23 and phosphate. J Am Soc Nephrol 2015; 26(5): 1150-60.
[http://dx.doi.org/10.1681/ASN.2014040325] [PMID: 25475745]
[32]
Hu MC, Shi M, Gillings N, et al. Recombinant α-Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy. Kidney Int 2017; 91(5): 1104-14.
[http://dx.doi.org/10.1016/j.kint.2016.10.034] [PMID: 28131398]
[33]
Silswal N, Touchberry CD, Daniel DR, et al. FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability. Am J Physiol Endocrinol Metab 2014; 307(5): E426-36.
[http://dx.doi.org/10.1152/ajpendo.00264.2014] [PMID: 25053401]
[34]
Six I, Okazaki H, Gross P, et al. Direct, acute effects of Klotho and FGF23 on vascular smooth muscle and endothelium. PLoS One 2014; 9(4)e93423
[http://dx.doi.org/10.1371/journal.pone.0093423] [PMID: 24695641]
[35]
Scialla JJ, Lau WL, Reilly MP, et al. Chronic Renal Insufficiency Cohort Study Investigators. Fibroblast growth factor 23 is not associated with and does not induce arterial calcification. Kidney Int 2013; 83(6): 1159-68.
[http://dx.doi.org/10.1038/ki.2013.3] [PMID: 23389416]
[36]
Larsson T, Marsell R, Schipani E, et al. Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. Endocrinology 2004; 145(7): 3087-94.
[http://dx.doi.org/10.1210/en.2003-1768] [PMID: 14988389]
[37]
Saito H, Kusano K, Kinosaki M, et al. Human fibroblast growth factor-23 mutants suppress Na+-dependent phosphate co-transport activity and 1alpha,25-dihydroxyvitamin D3 production. J Biol Chem 2003; 278(4): 2206-11.
[http://dx.doi.org/10.1074/jbc.M207872200] [PMID: 12419819]
[38]
Shimada T, Kakitani M, Yamazaki Y, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 2004; 113(4): 561-8.
[http://dx.doi.org/10.1172/JCI200419081] [PMID: 14966565]
[39]
Kanbay M, Nicoleta M, Selcoki Y, et al. Fibroblast growth factor 23 and fetuin A are independent predictors for the coronary artery disease extent in mild chronic kidney disease. Clin J Am Soc Nephrol 2010; 5(10): 1780-6.
[http://dx.doi.org/10.2215/CJN.02560310] [PMID: 20576822]
[40]
Cancela AL, Santos RD, Titan SM, et al. Phosphorus is associated with coronary artery disease in patients with preserved renal function. PLoS One 2012; 7(5)e36883
[http://dx.doi.org/10.1371/journal.pone.0036883] [PMID: 22590632]
[41]
Mizobuchi M, Towler D, Slatopolsky E. Vascular calcification: the killer of patients with chronic kidney disease. J Am Soc Nephrol 2009; 20(7): 1453-64.
[http://dx.doi.org/10.1681/ASN.2008070692] [PMID: 19478096]
[42]
Nasrallah MM, El-Shehaby AR, Salem MM, Osman NA, El Sheikh E, Sharaf El Din UA. Fibroblast growth factor-23 (FGF-23) is independently correlated to aortic calcification in haemodialysis patients. Nephrol Dial Transplant 2010; 25(8): 2679-85.
[http://dx.doi.org/10.1093/ndt/gfq089] [PMID: 20176609]
[43]
Panwar B, Judd SE, Wadley VG, et al. Association of fibroblast growth factor 23 with risk of incident coronary heart disease in community-living adults. JAMA Cardiol 2018; 3(4): 318-25.
[http://dx.doi.org/10.1001/jamacardio.2018.0139] [PMID: 29516098]
[44]
Hsu JJ, Katz R, Ix JH, de Boer IH, Kestenbaum B, Shlipak MG. Association of fibroblast growth factor-23 with arterial stiffness in the multi-ethnic study of atherosclerosis. Nephrol Dial Transplant 2014; 29(11): 2099-105.
[http://dx.doi.org/10.1093/ndt/gfu101] [PMID: 24782533]
[45]
Marthi A, Donovan K, Haynes R, et al. Fibroblast growth factor-23 and risks of cardiovascular and noncardiovascular diseases: A meta-analysis. J Am Soc Nephrol 2018; 29(7): 2015-27.
[http://dx.doi.org/10.1681/ASN.2017121334] [PMID: 29764921]
[46]
Kusaba T, Okigaki M, Matui A, et al. Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca2+ channel to maintain endothelial integrity. Proc Natl Acad Sci USA 2010; 107(45): 19308-13.
[http://dx.doi.org/10.1073/pnas.1008544107] [PMID: 20966350]
[47]
Lim K, Lu TS, Molostvov G, et al. Vascular Klotho deficiency potentiates the development of human artery calcification and mediates resistance to fibroblast growth factor 23. Circulation 2012; 125(18): 2243-55.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.111.053405] [PMID: 22492635]
[48]
Hu MC, Shi M, Zhang J, et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 2011; 22(1): 124-36.
[http://dx.doi.org/10.1681/ASN.2009121311] [PMID: 21115613]
[49]
Chang JR, Guo J, Wang Y, et al. Intermedin1-53 attenuates vascular calcification in rats with chronic kidney disease by upregulation of α-Klotho. Kidney Int 2016; 89(3): 586-600.
[http://dx.doi.org/10.1016/j.kint.2015.12.029] [PMID: 26880455]
[50]
Hum JM, O’Bryan LM, Tatiparthi AK, et al. Chronic hyperphosphatemia and vascular calcification are reduced by stable delivery of soluble Klotho. J Am Soc Nephrol 2017; 28(4): 1162-74.
[http://dx.doi.org/10.1681/ASN.2015111266] [PMID: 27837149]
[51]
Kitagawa M, Sugiyama H, Morinaga H, et al. A decreased level of serum soluble Klotho is an independent biomarker associated with arterial stiffness in patients with chronic kidney disease. PLoS One 2013; 8(2)e56695
[http://dx.doi.org/10.1371/journal.pone.0056695] [PMID: 23431388]
[52]
Buiten MS, de Bie MK, Bouma-de Krijger A, et al. Soluble Klotho is not independently associated with cardiovascular disease in a population of dialysis patients. BMC Nephrol 2014; 15: 197.
[http://dx.doi.org/10.1186/1471-2369-15-197] [PMID: 25495997]
[53]
Navarro-González JF, Donate-Correa J, Muros de Fuentes M, Pérez-Hernández H, Martínez-Sanz R, Mora-Fernández C. Reduced Klotho is associated with the presence and severity of coronary artery disease. Heart 2014; 100(1): 34-40.
[http://dx.doi.org/10.1136/heartjnl-2013-304746] [PMID: 24165855]
[54]
Gutiérrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008; 359(6): 584-92.
[http://dx.doi.org/10.1056/NEJMoa0706130] [PMID: 18687639]
[55]
Jean G, Terrat JC, Vanel T, et al. High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients. Nephrol Dial Transplant 2009; 24(9): 2792-6.
[http://dx.doi.org/10.1093/ndt/gfp191] [PMID: 19395730]
[56]
Nowak A, Friedrich B, Artunc F, et al. Prognostic value and link to atrial fibrillation of soluble Klotho and FGF23 in hemodialysis patients. PLoS One 2014; 9(7)e100688
[http://dx.doi.org/10.1371/journal.pone.0100688] [PMID: 24991914]
[57]
Kendrick J, Cheung AK, Kaufman JS, et al. FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis. J Am Soc Nephrol 2011; 22(10): 1913-22.
[http://dx.doi.org/10.1681/ASN.2010121224] [PMID: 21903574]
[58]
Isakova T, Xie H, Yang W, et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kid-ney disease. JAMA 2011; 305(23): 2432-9.
[http://dx.doi.org/10.1001/jama.2011.826] [PMID: 21673295]
[59]
Scialla JJ, Xie H, Rahman M, et al. Fibroblast growth factor-23 and cardiovascular events in CKD. J Am Soc Nephrol 2014; 25(2): 349-60.
[http://dx.doi.org/10.1681/ASN.2013050465] [PMID: 24158986]
[60]
Seiler S, Rogacev KS, Roth HJ, et al. Associations of FGF-23 and sKlotho with cardiovascular outcomes among patients with CKD stages 2-4. Clin J Am Soc Nephrol 2014; 9(6): 1049-58.
[http://dx.doi.org/10.2215/CJN.07870713] [PMID: 24677555]
[61]
Chonchol M, Greene T, Zhang Y, Hoofnagle AN, Cheung AK. Low vitamin D and high fibroblast growth factor 23 serum levels associate with infectious and cardiac deaths in the HEMO Study. J Am Soc Nephrol 2016; 27(1): 227-37.
[http://dx.doi.org/10.1681/ASN.2014101009] [PMID: 25971439]
[62]
Pichler G, Haller MC, Kainz A, Wolf M, Redon J, Oberbauer R. Prognostic value of bone- and vascular-derived molecular biomarkers in hemodialysis and renal transplant patients: a systematic review and meta-analysis. Nephrol Dial Transplant 2017; 32(9): 1566-78.
[PMID: 28025385]
[63]
Isakova T, Cai X, Lee J, et al. Longitudinal FGF23 trajectories and mortality in patients with CKD. J Am Soc Nephrol 2018; 29(2): 579-90.
[http://dx.doi.org/10.1681/ASN.2017070772] [PMID: 29167351]
[64]
Seiler S, Wen M, Roth HJ, et al. Plasma Klotho is not related to kidney function and does not predict adverse outcome in patients with chronic kidney disease. Kidney Int 2013; 83(1): 121-8.
[http://dx.doi.org/10.1038/ki.2012.288] [PMID: 22895520]
[65]
Otani-Takei N, Masuda T, Akimoto T, et al. Association between serum soluble Klotho levels and mortality in chronic hemodialysis patients. Int J Endocrinol 2015; 2015406269
[http://dx.doi.org/10.1155/2015/406269] [PMID: 26604925]
[66]
Marçais C, Maucort-Boulch D, Drai J, et al. Circulating Klotho associates with cardiovascular morbidity and mortality during hemodialysis. J Clin Endocrinol Metab 2017; 102(9): 3154-61.
[http://dx.doi.org/10.1210/jc.2017-00104] [PMID: 28402487]
[67]
Zheng S, Zheng Y, Jin L, Zhou Z, Li Z. Relationship between serum soluble Klotho protein and coronary artery calcification and prognosis in patients on maintenance hemodialysis. Iran J Public Health 2018; 47(4): 510-8.
[PMID: 29900135]
[68]
Memmos E, Sarafidis P, Pateinakis P, et al. Soluble Klotho is associated with mortality and cardiovascular events in hemodialysis. BMC Nephrol 2019; 20(1): 217.
[http://dx.doi.org/10.1186/s12882-019-1391-1] [PMID: 31185930]

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