Association between FGF23, α-Klotho, and Cardiac Abnormalities among Patients with Various Chronic Kidney Disease Stages

Suguru Tanaka, Shu-Ichi Fujita, Shun Kizawa, Hideaki Morita, Nobukazu Ishizaka, Suguru Tanaka, Shu-Ichi Fujita, Shun Kizawa, Hideaki Morita, Nobukazu Ishizaka

Abstract

Background: Several experimental studies have demonstrated that fibroblast growth factor 23 (FGF23) may induce myocardial hypertrophy via pathways independent of α-Klotho, its co-factor in the induction of phosphaturia. On the other hand, few studies have clearly demonstrated the relationship between FGF23 level and left ventricular hypertrophy among subjects without chronic kidney disease (CKD; i.e., CKD stage G1 or G2).

Purpose: To investigate the data from 903 patients admitted to the cardiology department with various degrees of renal function, including 234 patients with CKD stage G1/G2.

Methods and results: Serum levels of full-length FGF23 and α-Klotho were determined by enzyme immunoassay. After adjustment for sex, age, and estimated glomerular filtration rate (eGFR), the highest FGF23 tertile was significantly associated with left ventricular hypertrophy among patients with CKD stage G1/G2 and those with CKD stage G3a/G3b/G4 as compared with the lowest FGF23 tertile, and the association retained significance after further adjustment for serum levels of corrected calcium, inorganic phosphate, and C-reactive protein, as well as diuretic use, history of hypertension, and systolic blood pressure. FGF23 was also associated with low left ventricular ejection fraction among patients with CKD stage G1/G2 and those with CKD stage G3a/G3b/G4 after adjusting for age, sex, eGFR, corrected calcium, and inorganic phosphate. On the other hand, compared with the highest α-Klotho tertile, the lowest α-Klotho tertile was associated with left ventricular hypertrophy and systolic dysfunction only among patients with CKD stage G3b and stage G3a, respectively.

Conclusions: An association between FGF23 and cardiac hypertrophy and systolic dysfunction was observed among patients without CKD as well as those with CKD after multivariate adjustment. However, the association between α-Klotho and cardiac hypertrophy and systolic dysfunction was significant only among patients with CKD G3b and G3a, respectively.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Prevalence of each FGF23 or…
Fig 1. Prevalence of each FGF23 or α-Klotho tertile by CKD stage.
A. Percentage of patients in each FGF23 tertile according to CKD stage (P2 test). B. Percentage of patients in each α-Klotho tertile according to CKD stage (P<0.001 by χ2 test).
Fig 2. Correlation between FGF23, α-Klotho, left…
Fig 2. Correlation between FGF23, α-Klotho, left ventricular mass index (LVMI), and left ventricular ejection fraction (LVEF) according to CKD stages.
A. Correlation between FGF23 and LVMI. B. Correlation between FGF23 and LVEF. C. Correlation between α-Klotho and LVMI. D. Correlation between α-Klotho and LVEF. The results of Spearman’s correlation test for each CKD stage subgroup are shown.
Fig 3. Mean left ventricular mass index…
Fig 3. Mean left ventricular mass index (LVMI) and left ventricular ejection fraction (LVEF) according to FGF23 tertile and chronic kidney disease (CKD) stage.
A. Mean LVMI according to FGF23 tertile and CKD stage. B. Mean LVEF according to FGF23 tertile and CKD stage.
Fig 4. Mean left ventricular mass index…
Fig 4. Mean left ventricular mass index (LVMI) and left ventricular ejection fraction (LVEF) according to α-Klotho tertile and chronic kidney disease (CKD) stage.
A. Mean LVMI according to α-Klotho tertile and CKD stage. B. Mean LVEF according to α-Klotho tertile and CKD stage.
Fig 5. Receiver operating characteristic (ROC) analysis…
Fig 5. Receiver operating characteristic (ROC) analysis for the prediction of left ventricular hypertrophy (LVH) and low left ventricular ejection fraction (low LVEF).
A, B, C. ROC curve for the prediction of LVH. D, E, F. ROC curve for the prediction of low LVEF. Green lines show the ROC curve to predict LVH (A, B, C) and low LVEF (D, E, F) for the combination of age, sex, and eGFR, designated model 1. Red lines show the ROC curve to predict LVH (A, B, C) and low LVEF (D, E, F) for model 1 plus FGF23, designated model 2. For the prediction of LVH, the area under the ROC curve was significantly greater in model 2 than in model 1 for patients with CKD stage G1-G4 (A), G1/G2 (B), and G3-G4 (C). For the prediction of low LVEF, the area under the ROC curve was significantly greater in model 2 than in model 1 for patients with CKD stage G1-G4 (D); however, it did not differ significantly between the two models for patients with CKD stage G1/G2 (E) or G3-G4 (F).

References

    1. (2000) Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 26: 345–348. 10.1038/81664 PMICD.
    1. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, et al. (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444: 770–774. nature05315 [pii] 10.1038/nature05315 PMICD.
    1. Scialla JJ, Wolf M (2014) Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease. Nat Rev Nephrol 10: 268–278. 10.1038/nrneph.2014.49 nrneph.2014.49 [pii]. PMICD.
    1. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390: 45–51. 10.1038/36285 PMICD.
    1. Isakova T, Wahl P, Vargas GS, Gutierrez OM, Scialla J, Xie H, et al. (2011) Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int 79: 1370–1378. 10.1038/ki.2011.47 ki201147 [pii]. PMICD. 3134393.
    1. Ozeki M, Fujita S, Kizawa S, Morita H, Sohmiya K, Hoshiga M, et al. (2014) Association of serum levels of FGF23 and alpha-Klotho with glomerular filtration rate and proteinuria among cardiac patients. BMC Nephrol 15: 147 10.1186/1471-2369-15-147 1471-2369-15-147 [pii]. PMICD. 4167507.
    1. Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, et al. (2011) FGF23 induces left ventricular hypertrophy. J Clin Invest 121: 4393–4408. 10.1172/JCI46122 46122 [pii]. PMICD. 3204831.
    1. Gutierrez OM, Januzzi JL, Isakova T, Laliberte K, Smith K, Collerone G, et al. (2009) Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 119: 2545–2552. 10.1161/CIRCULATIONAHA.108.844506 CIRCULATIONAHA.108.844506 [pii]. PMICD. 2740903.
    1. Mirza MA, Larsson A, Melhus H, Lind L, Larsson TE (2009) Serum intact FGF23 associate with left ventricular mass, hypertrophy and geometry in an elderly population. Atherosclerosis 207: 546–551. 10.1016/j.atherosclerosis.2009.05.013 S0021-9150(09)00408-0 [pii]. PMICD.
    1. Negishi K, Kobayashi M, Ochiai I, Yamazaki Y, Hasegawa H, Yamashita T, et al. (2010) Association between fibroblast growth factor 23 and left ventricular hypertrophy in maintenance hemodialysis patients. Comparison with B-type natriuretic peptide and cardiac troponin T. Circ J 74: 2734–2740. JST.JSTAGE/circj/CJ-10-0355 [pii]. PMICD.
    1. Sharma S, Joseph J, Chonchol M, Kaufman JS, Cheung AK, Rafeq Z, et al. (2013) Higher fibroblast growth factor-23 concentrations associate with left ventricular systolic dysfunction in dialysis patients. Clin Nephrol 80: 313–321. 10.5414/CN107991 10783 [pii]. PMICD. 4018462.
    1. Semba RD, Cappola AR, Sun K, Bandinelli S, Dalal M, Crasto C, et al. (2011) Plasma klotho and cardiovascular disease in adults. J Am Geriatr Soc 59: 1596–1601. 10.1111/j.1532-5415.2011.03558.x PMICD. 3486641.
    1. Navarro-Gonzalez JF, Donate-Correa J, Muros de Fuentes M, Perez-Hernandez H, Martinez-Sanz R, Mora-Fernandez C (2014) Reduced Klotho is associated with the presence and severity of coronary artery disease. Heart 100: 34–40. 10.1136/heartjnl-2013-304746 heartjnl-2013-304746 [pii]. PMICD.
    1. Hu MC, Shi M, Cho HJ, Adams-Huet B, Paek J, Hill K, et al. (2015) Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J Am Soc Nephrol 26: 1290–1302. 10.1681/ASN.2014050465 ASN.2014050465 [pii]. PMICD. 4446876.
    1. Yang K, Wang C, Nie L, Zhao X, Gu J, Guan X, et al. (2015) Klotho Protects Against Indoxyl Sulphate-Induced Myocardial Hypertrophy. J Am Soc Nephrol 26: 2434–2446. 10.1681/ASN.2014060543 ASN.2014060543 [pii]. PMICD. 4587686.
    1. Shibata K, Fujita S, Morita H, Okamoto Y, Sohmiya K, Hoshiga M, et al. (2013) Association between circulating fibroblast growth factor 23, alpha-Klotho, and the left ventricular ejection fraction and left ventricular mass in cardiology inpatients. PLoS One 8: e73184 10.1371/journal.pone.0073184 PONE-D-13-15859 [pii]. PMICD. 3767778.
    1. Yamazaki Y, Imura A, Urakawa I, Shimada T, Murakami J, Aono Y, et al. (2010) Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects. Biochem Biophys Res Commun 398: 513–518. 10.1016/j.bbrc.2010.06.110 S0006-291X(10)01250-7 [pii]. PMICD. 4130489.
    1. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. (2009) Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 53: 982–992. 10.1053/j.ajkd.2008.12.034 S0272-6386(09)00389-8 [pii]. PMICD.
    1. Levey AS, de Jong PE, Coresh J, El Nahas M, Astor BC, Matsushita K, et al. (2011) The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int 80: 17–28. 10.1038/ki.2010.483 ki2010483 [pii]. PMICD.
    1. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY (2004) Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 351: 1296–1305. 10.1056/NEJMoa041031 351/13/1296 [pii]. PMICD.
    1. Devereux RB, Reichek N (1977) Echocardiographic determination of left ventricular mass in man. Anatomic validation of the method. Circulation 55: 613–618. PMICD.
    1. Wachtell K, Bella JN, Liebson PR, Gerdts E, Dahlof B, Aalto T, et al. (2000) Impact of different partition values on prevalences of left ventricular hypertrophy and concentric geometry in a large hypertensive population: the LIFE study. Hypertension 35: 6–12. PMICD.
    1. Roman MJ, Pickering TG, Schwartz JE, Pini R, Devereux RB (1996) Relation of arterial structure and function to left ventricular geometric patterns in hypertensive adults. J Am Coll Cardiol 28: 751–756. 0735-1097(96)00225-2 [pii]. PMICD.
    1. Seiler S, Cremers B, Rebling NM, Hornof F, Jeken J, Kersting S, et al. (2011) The phosphatonin fibroblast growth factor 23 links calcium-phosphate metabolism with left-ventricular dysfunction and atrial fibrillation. Eur Heart J 32: 2688–2696. 10.1093/eurheartj/ehr215 ehr215 [pii]. PMICD.
    1. Imazu M, Takahama H, Asanuma H, Funada A, Sugano Y, Ohara T, et al. (2014) Pathophysiological impact of serum fibroblast growth factor 23 in patients with nonischemic cardiac disease and early chronic kidney disease. Am J Physiol Heart Circ Physiol 307: H1504–1511. 10.1152/ajpheart.00331.2014 ajpheart.00331.2014 [pii]. PMICD.
    1. Brandenburg VM, Kleber ME, Vervloet MG, Tomaschitz A, Pilz S, Stojakovic T, et al. (2014) Fibroblast growth factor 23 (FGF23) and mortality: the Ludwigshafen Risk and Cardiovascular Health Study. Atherosclerosis 237: 53–59. 10.1016/j.atherosclerosis.2014.08.037 S0021-9150(14)01364-1 [pii]. PMICD.
    1. Ix JH, Katz R, Kestenbaum BR, de Boer IH, Chonchol M, Mukamal KJ, et al. (2012) Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study). J Am Coll Cardiol 60: 200–207. 10.1016/j.jacc.2012.03.040 S0735-1097(12)01394-0 [pii]. PMICD. 3396791.
    1. Grabner A, Amaral AP, Schramm K, Singh S, Sloan A, Yanucil C, et al. (2015) Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy. Cell Metab 22: 1020–1032. 10.1016/j.cmet.2015.09.002 S1550-4131(15)00459-3 [pii]. PMICD. 4670583.
    1. Leifheit-Nestler M, Grosse Siemer R, Flasbart K, Richter B, Kirchhoff F, Ziegler WH, et al. (2015) Induction of cardiac FGF23/FGFR4 expression is associated with left ventricular hypertrophy in patients with chronic kidney disease. Nephrol Dial Transplant. gfv421 [pii] 10.1093/ndt/gfv421 PMICD.
    1. Andersen IA, Huntley BK, Sandberg SS, Heublein DM, Burnett JC Jr (2015) Elevation of circulating but not myocardial FGF23 in human acute decompensated heart failure. Nephrol Dial Transplant. gfv398 [pii] 10.1093/ndt/gfv398 PMICD.
    1. Seiler S, Wen M, Roth HJ, Fehrenz M, Flugge F, Herath E, et al. (2013) Plasma Klotho is not related to kidney function and does not predict adverse outcome in patients with chronic kidney disease. Kidney Int 83: 121–128. 10.1038/ki.2012.288 S0085-2538(15)55688-3 [pii]. PMICD.
    1. Buiten MS, de Bie MK, Bouma-de Krijger A, van Dam B, Dekker FW, Jukema JW, et al. (2014) Soluble Klotho is not independently associated with cardiovascular disease in a population of dialysis patients. BMC Nephrol 15: 197 10.1186/1471-2369-15-197 1471-2369-15-197 [pii]. PMICD. 4293085.
    1. Xie J, Yoon J, An SW, Kuro-o M, Huang CL (2015) Soluble Klotho Protects against Uremic Cardiomyopathy Independently of Fibroblast Growth Factor 23 and Phosphate. J Am Soc Nephrol 26: 1150–1160. 10.1681/ASN.2014040325 ASN.2014040325 [pii]. PMICD. 4413766.
    1. Xie J, Cha SK, An SW, Kuro OM, Birnbaumer L, Huang CL (2012) Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. Nat Commun 3: 1238 10.1038/ncomms2240 ncomms2240 [pii]. PMICD. 3526952.
    1. Rowell J, Koitabashi N, Kass DA (2010) TRP-ing up heart and vessels: canonical transient receptor potential channels and cardiovascular disease. J Cardiovasc Transl Res 3: 516–524. 10.1007/s12265-010-9208-4 PMICD. 3875464.
    1. Isakova T, Houston J, Santacruz L, Schiavenato E, Somarriba G, Harmon WG, et al. (2013) Associations between fibroblast growth factor 23 and cardiac characteristics in pediatric heart failure. Pediatr Nephrol 28: 2035–2042. 10.1007/s00467-013-2515-7 PMICD. 3755096.
    1. Gruson D, Lepoutre T, Ketelslegers JM, Cumps J, Ahn SA, Rousseau MF (2012) C-terminal FGF23 is a strong predictor of survival in systolic heart failure. Peptides 37: 258–262. 10.1016/j.peptides.2012.08.003 S0196-9781(12)00353-1 [pii]. PMICD.
    1. Leaf DE, Christov M, Juppner H, Siew E, Ikizler TA, Bian A, et al. (2016) Fibroblast growth factor 23 levels are elevated and associated with severe acute kidney injury and death following cardiac surgery. Kidney Int 89: 939–948. 10.1016/j.kint.2015.12.035 S0085-2538(16)00224-6 [pii]. PMICD. 4801748.
    1. Chudek J, Kocelak P, Owczarek A, Bozentowicz-Wikarek M, Mossakowska M, Olszanecka-Glinianowicz M, et al. (2014) Fibroblast growth factor 23 (FGF23) and early chronic kidney disease in the elderly. Nephrol Dial Transplant 29: 1757–1763. 10.1093/ndt/gfu063 gfu063 [pii]. PMICD.
    1. Bhattacharyya N, Wiench M, Dumitrescu C, Connolly BM, Bugge TH, Patel HV, et al. (2012) Mechanism of FGF23 processing in fibrous dysplasia. J Bone Miner Res 27: 1132–1141. 10.1002/jbmr.1546 PMICD.
    1. Wolf M, White KE (2014) Coupling fibroblast growth factor 23 production and cleavage: iron deficiency, rickets, and kidney disease. Curr Opin Nephrol Hypertens 23: 411–419. 10.1097/01.mnh.0000447020.74593.6f PMICD. 4322859.
    1. van Breda F, Emans ME, van der Putten K, Braam B, van Ittersum FJ, Kraaijenhagen RJ, et al. (2015) Relation between Red Cell Distribution Width and Fibroblast Growth Factor 23 Cleaving in Patients with Chronic Kidney Disease and Heart Failure. PLoS One 10: e0128994 10.1371/journal.pone.0128994 PONE-D-14-32533 [pii]. PMICD. 4469605.

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