Fibroblast Growth Factor 23 and Left Ventricular Hypertrophy in Hemodialysis Patients

Ayaka Saito^1,2, Takako Onuki², Yoshihisa Echida², Shigeru Otsubo³, Kosaku Nitta^1*

¹Department of Medicine, Kidney Center, Tokyo Women’s Medical University, Tokyo, Japan.
²Department of Medicine, Towa Hospital, Tokyo, Japan.
³Department of Blood Purification, Sangenjaya Hospital, Tokyo, Japan.

DOI: 10.4236/ijcm.2014.517141                

Abstract

Background: Left ventricular hypertrophy (LVH) is a common cardiovascular complication and an independent risk factor for cardiovascular death in hemodialysis (HD) patients. Previous studies have shown that fibroblast growth factor 23 (FGF23), which has an important role in phosphate metabolism, is elevated in HD patients. Objectives: The aim of this study was to determine the association of FGF23 and LVH and the prognostic value of serum FGF23 level in HD patients. One hundred seven HD patients were evaluated for LVH by echocardiography. Serum FGF23 levels were measured using a commercial enzyme-linked immunosorbent assay kit. Results: Patients with LVH were more likely to have higher systolic blood pressure (BP) and LVH was significantly associated with female gender and higher serum levels of phosphate and calcium ×phosphate products. LVH was also associated with higher serum FGF23 level. Multivariate analysis indicated that serum FGF23 level, systolic BP, and serum phosphate level remained correlated with LVH. This suggested that serum FGF23 level is independently associated with LVH in our HD patients. Cox analysis indicated no significant difference in risk of death for patients with elevated serum FGF23 level. Conclusion: LVH has a high prevalence in HD patients, and FGF23 is independently associated with LVH but is not a predictor for prognosis during a 4-year follow-up period.

Keywords

Fibroblast Growth Factor 23, Hemodialysis, Left Ventricular Hypertrophy, Prognosis

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Nakai, S., Watanabe, Y., Masakane, I., Wada, A., Shoji, T. Hasegawa, T., et al. (2013) Overview of Regular Dialysis Treatment in Japan (as of 31 December 2011). Therapeutic Apheresis and Dialysis, 17, 567-611. http://dx.doi.org/10.1111/1744-9987.12147
[2]	Foley, R.N., Parfrey, P.S., Harnett, J.D., Kent, G.M., Murray, D.C. and Barre, P.E. (1995) Clinical and Echocardiographic Disease in Patients starting End-Stage Renal Disease Therapy. Kidney International, 47, 186-192. http://dx.doi.org/10.1038/ki.1995.22
[3]	Middleton, R.J., Parfrey, P.S. and Foley, R.N. (2001) Left Ventricular Hypertrophy in the Renal Patient. Journal of American Society of Nephrology, 12, 1079-1084.
[4]	Silberberg, J.S., Barre, P.E., Prichard, S.S. and Sniderman, A.D. (1989) Impact of Left Ventricular Hypertrophy on Survival in End-Stage Renal Disease. Kidney International, 36, 286-290. http://dx.doi.org/10.1038/ki.1989.192
[5]	London, G.M., Pannier, B., Guerin, A.P., Blacher, J., Marchais, S.J., Darne, B., et al (2001) Alterations of Left Ventricular Hypertrophy in and Survival of Patients receiving Hemodialysis: Follow-Up of an Interventional Study. Journal of American Society of Nephrology, 12, 2759-2767.
[6]	Glassock, R.J., Pecoits-Filho, R. and Barberato, S.H. (2009) Left Ventricular Mass in Chronic Kidney Disease and ESRD. Clinical Journal of American Society of nephrology, Suppl 1, S79-S91. http://dx.doi.org/10.2215/CJN.04860709
[7]	Ayus, J.C., Mizani, M.R., Achinger, S.G., Thadhani, R., Go, A.S. and Lee, S. (2005) Effects of Short Daily versus Conventional Hemodialysis on Left Ventricular Hypertrophy and Inflammatory Markers: A Prospective, Controlled Study. Journal of American Society of Nephrology, 16, 2778-2788. http://dx.doi.org/10.1681/ASN.2005040392
[8]	Block, G.A., Klassen, P.S., Lazarus, J.M., Ofsthun, N., Lowrie, E.G. and Chertow, G.M. (2004) Mineral Metabolism, Mortality, and Morbidity in Maintenance Hemodialysis. Journal of American Society of Nephrology, 15, 2208-2218. http://dx.doi.org/10.1097/01.ASN.0000133041.27682.A2
[9]	Berndt, T. and Kumar, R. (2007) Phosphatonins and the Regulation of Phosphate Homeostasis. Annual Review of Physiology, 69, 341-359. http://dx.doi.org/10.1146/annurev.physiol.69.040705.141729
[10]	Schiavi, S.C. and Kumar, R. (2004) The Phosphatonin Pathway: New Insights in Phosphate Homeostasis. Kidney International, 65, 1-14. http://dx.doi.org/10.1111/j.1523-1755.2004.00355.x
[11]	Imanishi, Y., Inaba, M., Nakatsuka, K., Nagasue, K., Okuno, S., Yoshihara, A., et al. (2004) FGF-23 in Patients with End-Stage Renal Disease on Hemodialysis. Kidney International, 65, 1943-1946. http://dx.doi.org/10.1111/j.1523-1755.2004.00604.x
[12]	Koeda, M., Ogawa, T., Ito, K., Tsutsui, T. and Nitta, K. (2014) Echocardiographic Parameters as Cardiovascular Mortality Predictors in Chronic Hemodialysis Patients. International Journal of Clinical Medicine, 5, 635-643.
[13]	Devereux, R.B. and Reichek, N. (1977) Echocardiographic Determination of Left Ventricular Mass in Man. Anatomic Validation of the Method. Circulation, 55, 613-618. http://dx.doi.org/10.1161/01.CIR.55.4.613
[14]	Devereux, R.B., Koren, M.J., de Simone, G., Okin, P.M. and Kligfield, P. (1993) Methods for Detection of Left Ventricular Hypertrophy: Application to Hypertensive Heart Disease. European Heart Journal, 14, 8-15.
[15]	Dubois, D. and Dubois, E.F. (1916) Clinical Calorimetry Tenth Paper. A Formula to Estimate the Approximate Surface Area if Height and Weight be Known. JAMA Internal Medicine, 17, 863-871. http://dx.doi.org/10.1001/archinte.1916.00080130010002
[16]	Sugimoto, H., Ogawa, T., Iwabuchi, Y., Otsuka, K. and Nitta, K. (2014) Relationship between Serum Fibroblast Growth Factor-23 Level and Mortality in Chronic Hemodialysis Patients. International Urology and Nephrology, 46, 99-106. http://dx.doi.org/10.1007/s11255-013-0386-2
[17]	Gutierrez, O.M., Januzzi, J.L., 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. http://dx.doi.org/10.1161/CIRCULATIONAHA.108.844506
[18]	Hsu, H.J. and Wu, M.S. (2009) Fibroblast Growth Factor 23: A Possible Cause of Left Ventricular Hypertrophy in Hemodialysis Patients. American Journal of Medical Sciences, 337, 116-122. http://dx.doi.org/10.1097/MAJ.0b013e3181815498
[19]	Kirkpantur, A., Balci, M., Gurbuz, O.A., Afsar, B., Canbakan, B., Akdemir, R., et al. (2011) Serum Fibroblast Growth Factor-23 (FGF-23) Levels Are Independently Associated with Left Ventricular Mass and Myocardial Performance Index in Maintenance Haemodialysis Patients. Nephrology Dialysis Transplantation 26, 1346-1354. http://dx.doi.org/10.1093/ndt/gfq539
[20]	Canziani, M.E., Tomiyama, C., Higa, A., Draibe, S.A. and Carvalho, A.B. (2011) Fibroblast Growth Factor 23 in Chronic Kidney Disease: Bridging the Gap between Bone Mineral Metabolism and Left Ventricular Hypertrophy. Blood Purification, 31, 26-32. http://dx.doi.org/10.1159/000321368
[21]	Knap, B., Veceric-Haler, Z., Benedik, M., Buturovic-Ponikvar, J., Ponikvar, R. and Bren, A.F. (2013) Fibroblast Growth Factor 23 and Left Ventricular Mass Index in Maintenance Hemodialysis Patients: Standard versus Long Nocturnal Hemodialysis. Therapeutic Apheresis and Dialysis, 17, 407-411. http://dx.doi.org/10.1111/1744-9987.12087
[22]	Isakova, T. (2013) Fibroblast Growth Factor 23 and Adverse Clinical Outcomes in Chronic Kidney Disease. Current Opinion in Nephrology and Hypertension, 21, 334-340. http://dx.doi.org/10.1097/MNH.0b013e328351a391
[23]	Zoccali, C., Yilmaz, M.I. and Mallamaci, F. (2013) FGF23: A Mature Renal and Cardiovascular Risk Factor? Blood Purification, 36, 52-57. http://dx.doi.org/10.1159/000351001
[24]	Levin, A., Thompson, C.R., Ethier, J., Carlisle, E.J., Tobe, S., Mendelssohn, D., et al. (1999) Left Ventricular Mass Index Increase in Early Renal Disease: Impact of Decline in Hemoglobin. American Journal of Kidney Diseases, 34, 125-134. http://dx.doi.org/10.1016/S0272-6386(99)70118-6
[25]	Chang, S.T., Chen, C.C., Chen, C.L., Cheng, H.W., Chung, C.M. and Yang, T.Y. (2004) Changes of the Cardiac Architectures and Functions for Chronic Hemodialysis Patients with Dry Weight Determined by Echocardiography. Blood Purification, 22, 351-359. http://dx.doi.org/10.1159/000080031
[26]	Kutlay, S., Dincer, I., Sengul, S., Nergizoglu, G., Duman, N. and Erturk, S. (2006) The Long-Term Behavior and Predictors of Left Ventricular Hypertrophy in Hemodialysis Patients. American Journal of Kidney Diseases, 47, 485-492. http://dx.doi.org/10.1053/j.ajkd.2005.12.029
[27]	Strozecki, P., Adamowicz, A., Nartowicz, E., Odrowaz-Sypniewska, G., Wlodarczyk, Z. and Manitius, J. (2001) Parathormon, Calcium, Phosphorus, and Left Ventricular Structure and Function in Normotensive Hemodialysis Patients. Renal Failure, 23, 115-126. http://dx.doi.org/10.1081/JDI-100001291
[28]	Jono, S., McKee, M.D., Murry, C.E., Shioi, A., Nishizawa, Y., Mori, K., Morii, H. and Giachelli, C.M. (2000) Phosphate Regulation of Vascular Smooth Muscle Cell Calcification. Circulation Research, 87, e10-e17. http://dx.doi.org/10.1161/01.RES.87.7.e10
[29]	Arnlov, J., Carlsson, A.C., Sundstrom, J., Ingelsson, E., Larsson, A., Lind, L. and Larsson, T.E. (2013) High Fibroblast Growth Factor-23 Increased the Risk of All-Cause and Cardiovascular Mortality in the Community. Kidney International, 83, 160-166. http://dx.doi.org/10.1038/ki.2012.327
[30]	Faul, C., Amaral, A.P., Oskouei, B., Hu, M.C., Sloan, A., Isakova, T., et al. (2011) FGF23 Induces Left Ventricular Hypertrophy. Journal of Clinical Investigation, 121, 4393-4408. http://dx.doi.org/10.1172/JCI46122
[31]	Dai, B., David, V., Martin, A., Huang, J., Li, H., Jiao, Y., et al. (2012) A Comparative Transcriptome Analysis Identifying FGF23 Regulated Genes in the Kidney of a Mouse CKD Model. PLoS ONE, 7, e44161. http://dx.doi.org/10.1371/journal.pone.0044161
[32]	Munoz Mendoza, J., Isakova, T., Ricardo, A.C., Xie, H., Navaneethan, S.D., Anderson, A.H., et al. (2012) Fibroblast Growth Factor 23 and Inflammation in CKD. Clinical Journal of the American Society of Nephrology, 7, 1155-1162. http://dx.doi.org/10.2215/CJN.13281211
[33]	Quarles, L.D. (2012) Role of FGF23 in Vitamin D and Phosphate Metabolism: Implications in Chronic Kidney Disease. Experimental Cell Research, 318, 1040-1048. http://dx.doi.org/10.1016/j.yexcr.2012.02.027
[34]	Zhang, X., Ibrahimi, O.A., Olsen, S.K., Umemori, H., Mohammadi, M. and Ornitz, D.M. (2006) Receptor Specificity of the Fibroblast Growth Factor Family. The Complete Mammalian FGF Family. Journal of Biological Chemistry, 281, 15694-15700. http://dx.doi.org/10.1074/jbc.M601252200
[35]	Nitta, K. (2011) Vascular Calcification in Patients with Chronic Kidney Disease. Therapeutic Apheresis and Dialysis, 15, 513-521. http://dx.doi.org/10.1111/j.1744-9987.2011.00979.x
[36]	Scialla, J.J., Lau, W.L., Reilly, M.P., Isakova, T., Yang, H.Y., Crouthamel, M.H., et al. (2013) Fibroblast Growth Factor 23 Is not Associated with and Does not Induce Arterial Calcification. Kidney International, 83, 1159-1168. http://dx.doi.org/10.1038/ki.2013.3