STUDY THE CORRELATION BETWEEN MATRIX GLA PROTEIN, FIBROBLAST GROWTH FACTOR-23 AND BONE METABOLIC MARKERS IN HEMODIALYSIS PATIENTS
Main Article Content
Keywords
Matrix Gla protein, Fat-soluble vitamins, Parathyroid hormone, Fibroblast growth factor-23
Abstract
Introduction: Vitamin K-dependent matrix Gla protein (MGP) acts as a calcification inhibitor in vitro and in vivo. Chronic kidney disease (CKD) patients have an extremely high risk for developing vascular disease as most CKD patient’s exhibit vitamin K intake lower than recommended levels. Since MGP is an extracellular protein responsible for inhibiting mineralization and it inhibits osteoblast mineralization and bone formation by regulating the deposition of bone matrix, therefore, the proposed research aims to the evaluation of the relationship between MGP and bone markers (parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) in hemodialysis patients and healthy individuals.
Methods: In this research, 54 hemodialysis (HD) patients and 30 age-matched healthy subjects were enrolled. Vitamin D, vitamin K, MGP, and FGF-23 were determined by ELISA kit and compared with control subjects. All values were expressed as mean ± standard deviation (SD), and the Shapiro-Wilk test was performed to check data distribution. Kruskal Wallis was done for comparing groups.
Results: According to the results the vitamin K level (0.47±0.16 ng/ml versus 1.25±0.28 ng/ml, P<0.0001) was significantly lower and total MGP (257.20±40.65 ng/ml versus 153.93±39.89 ng/ml, P<0.0001), i-PTH (461.57±336.29 pg/ml versus 33.23±12.05 pg/ml, P<0.0001) and FGF-23 (9077.09±2116.03 RU/ml versus 95.93±37.86 RU/ml, P<0.0001) were significantly higher in CKD patients. However, there is no significant difference in the level of vitamin D between the studied groups.
Conclusion: Plasma total MGP increased progressively in CKD patients and was associated with the severity of vascular calcification. Also, since total MGP has a significant positive association with FGF-23, therefore, controlling the level of MGP may have a clinical improvement on dysregulated FGF-23.
References
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[2] Jassim, M., Dehghan, G., Tayebi-Khosroshahi, H., Haghi, M. Genetic Polymorphism of SOD2 and GPX1 Modify Oxidative Stress Biomarkers in an Iranian Population with Chronic Kidney Disease. Population Therapeutics and Clinical Pharmacology, 30(1), 593–603 (2023). https://doi.org/10.53555/jptcp.v30i1.2735.
[3] Ronco, C., Grammaticopoulos, S., Rosner, M., De Cal, M., Soni, S., Lentini, P., Piccinni, P. Oliguria, creatinine and other biomarkers of acute kidney injury. Contributions to Nephrology164, 118-127 (2010). https://doi.org/10.1159/000313725
[4] Markis, M., Spanou, L. Acute Kidney Injury: Diagnostic Approaches and Controversies. Clinical Biochemist Reviews 37(4), 153–175 (2016). PMID: 28167845; PMCID: PMC5242479.
[5] Barrett, H., O’Keeffe, M., Kavanagh, E., Walsh, M., O’Connor, E.M., Is Matrix Gla Protein Associated with Vascular Calcification? A Systematic Review. Nutrients 10(4): 415 (2018). https://doi.org/10.3390/nu10040415
[6] Mizuiri, S., Nishizawa, Y., Yamashita, K., Ono, K., Naito, T., Tanji, C., Usui, K., Doi, S., Masaki, T., Shigemoto, K. Relationship of matrix Gla protein and vitamin K with vascular calcification in hemodialysis patients. Renal Failure 41(1), 770-777 (2019). https://doi.org/10.1080/0886022X.2019.1650065
[7] Hao, Z., Jin, D.Y., Stafford, D.W., Tie, J.K., Vitamin K-dependent carboxylation of coagulation factors: insights from a cell-based functional study. Haematologica 105(8): 2164–2173 (2020). https://doi.org/10.3324/haematol.2019.229047
[8] Jankowski, J., Floege, J., Fliser, D., Böhm, M., Marx, M., Cardiovascular Disease in Chronic Kidney Disease: Pathophysiological Insights and Therapeutic Options. Circulation 143(11):1157-1172 (2021). https://doi.org/10.1161/CIRCULATIONAHA.120.050686
[9] Matsushita, K., Ballew, S.H., Wang, A.YM., Kalyesubula, R., Schaeffner, E., Agarwal, R., Epidemiology and risk of cardiovascular disease in populations with chronic kidney disease. Nature Reviews Nephrology 18: 696–707 (2022). https://doi.org/10.1038/s41581-022-00616-6
[10] Düsing, P., Zietzer, A., Goody, P.R. et al. Vascular pathologies in chronic kidney disease: pathophysiological mechanisms and novel therapeutic approaches. Journal of Molecular Medicine 99, 335–348 (2021). https://doi.org/10.1007/s00109-021-02037-7
[11] Westenfeld, R. et al. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: a randomized trial. American Journal of Kidney Diseases 59, 186–195 (2012). https://doi.org/10.1053/j.ajkd.2011.10.041
[12] Delanaye, P. et al. Dephosphorylated-uncarboxylated Matrix Gla protein concentration is predictive of vitamin K status and is correlated with vascular calcification in a cohort of hemodialysis patients. BMC Nephrology 15, 145 (2014). https://doi.org/10.1186/1471-2369-15-145
[13] Schurgers, L. J. et al. The circulating inactive form of matrix gla protein is a surrogate marker for vascular calcification in chronic kidney disease: a preliminary report. Clinical Journal of the American Society of Nephrology 5, 568–575 (2010). 10.2215/CJN.07081009
[14] Fusaro, M., Plebani, M., Iervasi, G., et al. Vitamin K deficiency in chronic kidney disease: evidence is building up. American Journal of Nephrology 45:1-3 (2017). https://doi.org/10.1159/000451070
[15] Wuyts J, Dhondt A. The role of vitamin K in vascular calcification of patients with chronic kidney disease. Acta Clinica Belgica 71:462–467 (2016). doi: 10.1080/17843286.2016.1180770
[16] Hu, L., Napoletano, A., Provenzano, M., Garofalo, C., Bini, C., Comai, G., La Manna, G. Mineral Bone Disorders in Kidney Disease Patients: The Ever-Current Topic. International Journal of Molecular Sciences 23(20): 12223 (2022). doi: 10.3390/ijms232012223
[17] Miller, P. Chronic kidney disease and the skeleton. Bone Research 2: 14044 (2014). doi: 10.1038/boneres.2014.44
[18] Ahmed Fadhil Idan, & Mostafa Adnan Abdalrahman. Effect of hyperparathyroidism on anemia management in patients with hemodialysis dependent end-stage renal disease. Journal of Population Therapeutics and Clinical Pharmacology, 30(1), 293–300 (2023). https://doi.org/10.47750/jptcp.2023.1062.
[19] Delanaye, P., Warling, X., Moonen, M. et al. Variations of parathyroid hormone and bone biomarkers are concordant only after a long term follow-up in hemodialyzed patients. Scientific Reports 7: 12623 (2017). doi: 10.1038/s41598-017-12808-3
[20] Scialla, J.J., Wolf, M. Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease. Nature Reviews Nephrology 10: 268–278 (2014). doi: 10.1038/nrneph.2014.49
[21] Isakova, T., Wahl, P., Vargas, G.S., Gutierrez, O.M., Scialla, J., Xie, H., et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney International 79: 1370–1378 (2011). doi: 10.1038/ki.2011.47
[22] Mehta, R., Cai, X., Hodakowski, A., Lee, J., Leonard, M., Ricardo, A., et al. Fibroblast growth factor 23 and anemia in the chronic renal insufficiency cohort study. Clinical Journal of the American Society of Nephrology 12:1795–803 (2017). doi: 10.2215/CJN.03950417
[23] Li F, Ye X, Yang G, Huang H, Bian A, Xing C, Tang S, Zhang J, Jiang Y, Chen H, Yin C, Zhang L, Wang J, Huang Y, Zhou W, Wan H, Zha X, Zeng M, Wang N. Relationships between blood bone metabolic biomarkers and anemia in patients with chronic kidney disease. Ren Fail. 2023 Dec;45(1):2210227. doi: 10.1080/0886022X.2023.2210227
[24] Fusaro M, Pereira L, Bover J. Current and Emerging Markers and Tools Used in the Diagnosis and Management of Chronic Kidney Disease-Mineral and Bone Disorder in Non-Dialysis Adult Patients. J Clin Med. 2023 Sep 30;12(19):6306. doi: 10.3390/jcm12196306
[25] Caluwe, R., Vandecasteele, S., Van, V.B., Vermeer, C., De Vriese, A.S., Vitamin K2 supplementation in hemodialysis patients: a randomized dose-finding study. Nephrology Dialysis Transplantation 29: 1385-1390 (2014). doi: 10.1093/ndt/gft464
[26] Li, T., Wang, Y., Tu, W.P. Vitamin K supplementation and vascular calcification: a systematic review and meta-analysis of randomized controlled trials. Frontiers in Nutrition. 12; 10:1115069. (2023). doi: 10.3389/fnut.2023
[27] Dalmeijer, G.W., van der Schouw, Y.T., Vermeer, C., Magdeleyns, E.J., Schurgers, L.J., et al., Circulating matrix Gla protein is associated with coronary artery calcification and vitamin K status in healthy women. Journal of Nutritional Biochemistry 24: 624-628 (2013). doi: 10.1016/j.jnutbio.2012.02.012
[28] Mizuiri, S., Nishizawa, Y., Yamashita, K., Ono, K., et al., Relationship of matrix Gla protein and vitamin K with vascular calcification in hemodialysis patients. Renal Failure 41(1): 770–777 (2019). doi: 10.1080/0886022X.2019.1650065
[29] Thamratnopkoon, S., Susantitaphong, P., Tumkosit, M., Katavetin, P., et al., Correlations of Plasma Desphosphorylated Uncarboxylated Matrix Gla Protein with Vascular Calcification and Vascular Stiffness in Chronic Kidney Disease. Nephron 135:167-172 (2017). doi: 10.1159/000453368
[30] Gutierrez, O., Isakova, T., Rhee, E., Shah, A., Holmes, J., Collerone, G., Jüppner, H., Wolf, M. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. Journal of the American Society of Nephrology 16, 2205–2215 (2005). doi: 10.1681/ASN.2005010052
[31] Fliser, D., Kollerits, B., Neyer, U., Ankerst, D.P., Lhotta, K., Lingenhel, A., Ritz, E., Kronenberg, F., MMKD Study Group: Kuen, E., Konig, P., Kraatz, G., Mann, J.F., Muller, G.A., Kohler, H., Riegler, P., Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: The Mild to Moderate Kidney Disease (MMKD) Study. Journal of the American Society of Nephrology 18: 2600–2608 (2007). doi: 10.1681/ASN.2006080936
[32] Saito, T., Fukumoto, S., Fibroblast Growth Factor 23 (FGF23) and Disorders of Phosphate Metabolism. International Journal of Pediatric Endocrinology 2009: 496514 (2009). doi: 10.1155/2009/496514
[33] Stubbs, J., Liu, S., Quarles, L.D., Role of fibroblast growth factor 23 in phosphate homeostasis and pathogenesis of disordered mineral metabolism in chronic kidney disease. Seminars in Dialysis 20: 302–308 (2007). doi: 10.1111/j.1525-139X.2007.00308.x
[34] Takashi, Y., Kawanami, D., Fukumoto, S., FGF23 and Hypophosphatemic Rickets/Osteomalacia. Current Osteoporosis Reports 19: 669–675 (2021). doi: 10.1007/s11914-021-00709-4
[35] Beck-Nielsen, S.S., Mughal, Z., Haffner, D., et al. FGF23 and its role in X-linked hypophosphatemia-related morbidity. Orphanet Journal of Rare Diseases 14: 58 (2019). doi: 10.1186/s13023-019-1014-8
[36] Leaf, D.E., Pereira, R.C., Bazari, H., Jüppner, H. Oncogenic Osteomalacia due to FGF23-Expressing Colon Adenocarcinoma, The Journal of Clinical Endocrinology and Metabolism 98, 887-891 (2013). doi: 10.1210/jc.2012-3473
[37] Florez, H., Mandelikova, S., Filella, X., Monegal, A., Guañabens, N., Peris, P., Clinical significance of increased serum levels of FGF-23 in fibrous dysplasia. Medicina Clínica 151: 65-67 (2018). doi: 10.1016/j.medcli.2017.11.036
[38] Kurnatowska, I., Grzelak, P., Masajtis-Zagajewska, A., Kaczmarska, M., Stefańczyk, L., Vermeer, C., Maresz, K., Nowicki, M. Plasma Desphospho-Uncarboxylated Matrix Gla Protein as a Marker of Kidney Damage and Cardiovascular Risk in Advanced Stage of Chronic Kidney Disease. Kidney and Blood Pressure Research 41: 231–239 (2016). doi: 10.1159/000443426
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Dec 9, 2023
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Enmar Ali Jassim Aljalawee, Gholamreza Dehghan, & Hamid Tayebi Khosroshahi. (2023). STUDY THE CORRELATION BETWEEN MATRIX GLA PROTEIN, FIBROBLAST GROWTH FACTOR-23 AND BONE METABOLIC MARKERS IN HEMODIALYSIS PATIENTS. Journal of Population Therapeutics and Clinical Pharmacology, 30(19), 348–354. https://doi.org/10.53555/jptcp.v30i19.3524
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Author Biographies
Enmar Ali Jassim Aljalawee
Department of Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran
Gholamreza Dehghan
Department of Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran
Hamid Tayebi Khosroshahi
Department of Nephrology, Tabriz University of Medical Sciences, Tabriz, Iran