Advertisement

Altered Mineral Metabolism and Disequilibrium Between Calcification Promoters and Inhibitors in Chronic Hemodialysis Patients

  • Chia-Liang Wang
  • Kuan-Pin Lin
  • Guoo-Shyng W. Hsu
  • Kai-Li LiuEmail author
  • Chih-Hung GuoEmail author
Article
  • 51 Downloads

Abstract

Patients undergoing long-term hemodialysis (HD) are known to have abnormal blood concentrations of antioxidant minerals; concurrent oxidative stress can contribute to increased vascular calcification. This study aims to evaluate the associations between circulating antioxidant minerals and clinical biomarkers of vascular calcification in HD patients. Blood biochemical parameters, antioxidant minerals (selenium (Se), zinc (Zn), copper (Cu), and magnesium (Mg)), and several promoters and inhibitors of calcification (matrix Gla protein (MGP), fibroblast growth factor-23 (FGF-23), matrix metalloproteinases (MMP-2 and -9), and tissue inhibitors of metalloproteinase (TIMP-1 and -2)) were determined in HD patients (n = 62) and age- and sex-matched healthy individuals (n = 30). Compared with healthy subjects, HD patients had significantly lower plasma concentrations of Se and Zn, increased Cu and Mg, and higher levels of oxidative stress and inflammatory markers (Cu/Zn ratios, malondialdehyde (MDA), advanced glycation end products (AGEs), and C-reactive protein (CRP)). We observed that HD patients had significantly lower concentrations of MGP and higher levels of FGF-23, MMP-2 and -9, TIMP-1 and -2, and MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios. We also observed significant relationships between the concentrations of these minerals and calcification biomarkers in HD patients. These results suggest that changes in the homeostasis of antioxidant minerals (Se, Zn, Cu, and Mg) may contribute to the effects of oxidative stress and inflammatory status, thereby participating in the mechanism for accelerated vascular calcification in patients undergoing long-term HD.

Keywords

Vascular calcification antioxidant minerals oxidative stress inflammation hemodialysis patients 

Notes

Author Contributions

C-L Wang, K-L Liu, and C-H Guo conceived and designed the experiments. C-L Wang, K-L Liu, and C-H Guo performed the experiments. G-S-W Hsu, KP Lin, and C-H Guo analyzed the data. C-L Wang and C-H Guo wrote the paper.

Funding Information

Research supported in part by the grant from the Kuang-Tien General Hospital and the Hung-Kuang University, Taichung, Taiwan.

Compliance with Ethical Standards

The research protocol was approved by the ethics in human research committee of the Kuang-Tien General Hospital.

Competing Interests

The authors declare that they have no competing interests.

References

  1. 1.
    Palit S, Kendrick J (2014) Vascular calcification in chronic kidney disease: role of disordered mineral metabolism. Curr Pharm Des 20:5829–5833CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Karwowsk W, Naumnik B, Szczepański M, Myśliwiec M (2012) The mechanism of vascular calcification - a systematic review. Med Sci Monit 18:RA1–RA11Google Scholar
  3. 3.
    Jono S, Shioi A, Ikari Y, Nishizawa Y (2006) Vascular calcification in chronic kidney disease. J Bone Miner Metab 24:176–181CrossRefPubMedGoogle Scholar
  4. 4.
    Chen NX, Moe SM (2012) Vascular calcification: pathophysiology and risk factors. Curr Hypertens Rep 14:228–237CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Nasrallah MM, El-Shehaby AR, Salem MM, Osman NA, EI-Sheikh E, El Din UAAS (2010) Fibroblast growth factor-23 (FGF-23) is independently correlated to aortic calcification in haemodialysis patients. Nephrol Dial Transplant 25:2679–2685CrossRefPubMedGoogle Scholar
  6. 6.
    Felsenfeld AJ, Levine BS, Rodriguez M (2015) Pathophysiology of calcium, phosphorus, and magnesium dysregulation in chronic kidney disease. Semin Dial 28:564–577CrossRefPubMedGoogle Scholar
  7. 7.
    Julien M, Magne D, Masson M, Rolli-Derkinderen M, Chassande O, Cario- Toumaniantz C et al (2007) Phosphate stimulates matrix Gla protein expression in chondrocytes through the extracellular signal regulated kinase signaling pathway. Endocrinology 148:530–537CrossRefPubMedGoogle Scholar
  8. 8.
    Hecht E, Freise C, Websky KV, Nasser H, Kretzschmar N, Stawowy P et al (2016) The matrix metalloproteinases 2 and 9 initiate uraemic vascular calcifications. Nephrol Dial Transplant 31:789–797CrossRefPubMedGoogle Scholar
  9. 9.
    NasrAllah MM, El-Shehaby AR, Osman NA, Fayad T, Nassef A, Salem MM et al (2013) The association between fibroblast growth factor-23 and vascular calcification is mitigated by inflammation markers. Nephron Extra 3:106–112CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Pawlak K, Mysliwiec M, Pawlak D (2011) Peripheral blood level alterations of MMP-2 and MMP-9 in patients with chronic kidney disease on conservative treatment and on hemodialysis. Clin Biochem 44:838–843CrossRefPubMedGoogle Scholar
  11. 11.
    Guo CH, Wang CL (2013) Effects of zinc supplementation on plasma copper/zinc ratio, oxidative stress, and immunological status in hemodialysis patients. Int J Med Sci 10:79–89CrossRefPubMedGoogle Scholar
  12. 12.
    Zheltova AA, Kharitonova MV, Iezhitsa IN, Spasov AA (2016) Magnesium deficiency and oxidative stress: an update. BioMedicine 6:20CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Guo CH, Wang CL, Chen PC, Yang TC (2011) Linkage of some trace elements, peripheral blood lymphocytes, inflammation, and oxidative stress in ESRD patients undergoing either hemodialysis or peritoneal dialysis. Perit Dial Int 31:583–591CrossRefPubMedGoogle Scholar
  14. 14.
    de Roij van Zuijdewijn CLM, MPC G, Bots ML, Blankestijn PJ, Steppan S, Büchel J et al (2015) Serum magnesium and sudden death in European hemodialysis patients. PLoS One 10:e0143104CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Molnar AO, Biyani M, Hammond I, Harmon JP, Lavoie S, McCormick B, Sood MM, Wagner J, Pena E, Zimmerman DL (2017) Lower serum magnesium is associated with vascular calcification in peritoneal dialysis patients: a cross sectional study. BMC Nephrol 18:129CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Chen PC, Guo CH, Tseng CJ, Wang KC, Liu PJ (2013) Blood trace minerals concentrations and oxidative stress in patients with obstructive sleep apnea. J Nutr Health Aging 17:639–644CrossRefPubMedGoogle Scholar
  17. 17.
    Turgut A, Özler A, Görük NY, Tunc SY, Evliyaoglu O, Gül T (2013) Copper, ceruloplasmin and oxidative stress in patients with advanced-stage endometriosis. Eur Rev Med Pharmacol Sci 17:1472–1478PubMedGoogle Scholar
  18. 18.
    Malavolta M, Giacconi R, Piacenza F, Santarelli L, Cipriano C, Costarelli L et al (2010) Plasma copper/zinc ratio: an inflammatory/nutritional biomarker as predictor of all-cause mortality in elderly population. Biogerontology 11:309–319CrossRefPubMedGoogle Scholar
  19. 19.
    Gaier ED, Kleppinger A, Ralle M, Mains RE, Kenny AM, Eipper BA (2012) High serum Cu and Cu/Zn ratios correlate with impairments in bone density, physical performance and overall health in a population of elderly men with frailty characteristics. Exp Gerontol 47:491–496CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Nagane NS, Ganu JV, Jagtap PE (2013) Study of oxidative stress in pre- and post-hemodialysis in chronic renal failure patients. Biomed Res 24:498–502Google Scholar
  21. 21.
    Wang Z, Yu C, Li XH, Deng BQ (2017) The prognostic value of oxidative stress and inflammation in Chinese hemodialysis patients. Ren Fail 39:54–58CrossRefPubMedGoogle Scholar
  22. 22.
    Spittle MA, Hoenich NA, Handelman GJ, Adhikarla R, Homel P, Levin NW (2001) Oxidative stress and inflammation in hemodialysis patients. Am J Kidney Dis 38:1408–1413CrossRefPubMedGoogle Scholar
  23. 23.
    Filiopoulos V, Hadjiyannakos D, Vlassopoulos D (2016) Optimal plasma and dialysate magnesium concentrations in hemodialysis patients: the unsettled issues. Am J Kidney Dis 67:341–347CrossRefPubMedGoogle Scholar
  24. 24.
    Cunningham J, Rodríguez M, Messa P (2012) Magnesium in chronic kidney disease stages 3 and 4 and in dialysis patients. Clin Kidney J 5(Suppl 1):i39–i51CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Ishimura E, Okuno S, Yamakawa T, Inaba M, Nishizawa Y (2007) Serum magnesium concentration is a significant predictor of mortality in maintenance hemodialysis patients. Magnes Res 20:237–244PubMedGoogle Scholar
  26. 26.
    Ohya M, Negi S, Sakaguchi T, Koiwa F, Ando R, Komatsu Y et al (2014) Significance of serum magnesium as an independent correlative factor on the parathyroid hormone level in uremic in uremic patients. J Clin Endocrinol Metab 99:3873–3878CrossRefPubMedGoogle Scholar
  27. 27.
    Chan YH, Siu CW, Yiu KH, Chan HT, Li SW, Tam S et al (2012) Adverse systemic arterial function in patients with selenium deficiency. J Nutr Health Aging 16:85–88CrossRefPubMedGoogle Scholar
  28. 28.
    Stupin A, Cosic A, Novak S, Vesel M, Jukic I, Popovic B et al (2017) Reduced dietary selenium impairs vascular function by increasing oxidative stress in Sprague-Dawley rat aortas. Int J Environ Res Public Health 14:591CrossRefPubMedCentralGoogle Scholar
  29. 29.
    Liu H, Li X, Qin F, Huang K (2014) Selenium suppresses oxidative-stress-enhanced vascular smooth muscle cell calcification by inhibiting the activation of the PI3K/AKT and ERK signaling pathways and endoplasmic reticulum stress. J Biol Inorg Chem 19:375–388CrossRefPubMedGoogle Scholar
  30. 30.
    Shin MY, Kwun IS (2014) Zinc restored the decreased vascular smooth muscle cell viability under atherosclerotic calcification conditions. Prev Nutr Food Sci 19:363–366CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Iskra M, Patelski J, Majewski W (1997) Relationship of calcium, magnesium, zinc and copper concentrations in the arterial wall and serum in atherosclerosis obliterans and aneurysm. J Trace Elem Med Biol 11:248–252CrossRefPubMedGoogle Scholar
  32. 32.
    Sun W, Sun M, Zhang M, Liu Y, Lin X, Zhao S, Ma L (2015) Correlation between conjunctival and corneal calcification and cardiovascular calcification in patients undergoing maintenance hemodialysis. Hemodial Int 19:270–278CrossRefPubMedGoogle Scholar
  33. 33.
    Ter Braake AD, Shanahan CM, de Baaij JHF (2017) Magnesium counteracts vascular calcification: passive interference or active modulation? Arterioscler Thromb Vasc Biol 37:1431–1445CrossRefPubMedGoogle Scholar
  34. 34.
    Schurgers LJ, Barreto DV, Barreto FC, Liabeuf S, Renard C, Magdeleyns EJ et al (2010) The circulating inactive form of matrix Gla protein is a surrogatmarker for vascular calcification in chronic kidney disease: a preliminary report. Clin J Am Soc Nephrol 5:568–575CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Schurgers LJ, Cranenburg EC, Vermeer C (2008) Matrix Gla-protein: the calcification inhibitor in need of vitamin K. Thromb Haemost 100:593–603CrossRefPubMedGoogle Scholar
  36. 36.
    Yao Y, Bennett BJ, Wang X, Rosenfeld ME, Giachelli C, Lusis AJ et al (2010) Inhibition of bone morphogenetic proteins protects against atherosclerosis and vascular calcification. Circ Res 107:485–494CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Epstein M (2016) Matrix Gla-protein (MGP) not only inhibits calcification in large arteries but also may be renoprotective: connecting the dots. EBioMedicine 4:16–17CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Quarles LD (2012) Role of FGF23 in vitamin D and phosphate metabolism: implications in chronic kidney disease. Exp Cell Res 318:1040–1048CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Quarles LD (2012) Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism. Nat Rev Endocrinol 8:276–286CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Shimada T, Yamazaki Y, Takahashi M (2005) Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism. Am J Phys 289:1088–1095Google Scholar
  41. 41.
    Silver J, Naveh-Many T (2013) FGF-23 and secondary hyperparathyroidism in chronic kidney disease. Nat Rev Nephrol 9:641–649CrossRefPubMedGoogle Scholar
  42. 42.
    Filler G, Liu D, Huang SH, Casier S, Chau LA, Madrenas J (2011) Impaired GFR is the most important determinant for FGF-23 increase in chronic kidney disease. Clin Biochem 44:435–437CrossRefPubMedGoogle Scholar
  43. 43.
    Suzuki T, Kajita Y, Katsumata S, Matsuzaki H, Suzuki K (2015) Zinc deficiency increases serum concentrations of parathyroid hormone through a decrease in serum calcium and induces bone fragility in rats. J Nutr Sci Vitaminol (Tokyo) 61:382–390CrossRefGoogle Scholar
  44. 44.
    Silva AP, Gundlach K, Büchel J, Jerónimo T, Fragoso A, Silva G et al (2015) Low magnesium levels and FGF-23 dysregulation predict mitral valve calcification as well as intima media thickness in predialysis diabetic patients. Int J Endocrinol 2015:1–10CrossRefGoogle Scholar
  45. 45.
    Iguchi A, Watanabe Y, Iino N, Kazama JJ, Iesato H, Narita I (2014) Serum magnesium concentration is inversely associated with fibroblast growth factor 23 in haemo- dialysis patients. Nephrology 19:667–671CrossRefPubMedGoogle Scholar
  46. 46.
    Dimas G, Iliadis F, Grekas D (2013) Matrix metalloproteinases, atherosclerosis, proteinuria and kidney disease: linkage-based approaches. Hippokratia 17:292–297PubMedPubMedCentralGoogle Scholar
  47. 47.
    Marson BP, Poli de Figueiredo CE, Tanus-Santos JE (2012) Imbalanced matrix metallo- proteinases in cardiovascular complications of end-stage kidney disease: a potential pharmacological target. Basic Clin Pharmacol Toxicol 110:409–415CrossRefPubMedGoogle Scholar
  48. 48.
    Musial K, Zwolinska D (2011) Matrix metalloproteinases and soluble Fas/FasL system as novel regulators of apoptosis in children and young adults on chronic dialysis. Apoptosis 16:653–659CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Park JM, Kim A, Oh JH, Chung AS (2007) Methylseleninic acid inhibits PMA-stimulated pro-MMP-2 activation mediated by MT1-MMP expression and further tumor invasion through suppression of NF-kappaB activation. Carcino-genesis 28:837–847CrossRefGoogle Scholar
  50. 50.
    Guo H, Lee JD, Uzui H, Yue H, Wang J, Toyoda K, Geshi T, Ueda T (2006) Effects of folic acid and magnesium on the production of homocysteine-induced extracellular matrix metalloproteinase-2 in cultured rat vascular smooth muscle cells. Circ J 70:141–146CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of NephrologyKuang-Tien General HospitalTaichungTaiwan, Republic of China
  2. 2.Institute of Biomedical NutritionHung-Kuang UniversityTaichungTaiwan, Republic of China
  3. 3.Department of NutritionChung-Shan Medical UniversityTaichungTaiwan, Republic of China
  4. 4.Department of NursingHung-Kuang UniversityTaichungTaiwan, Republic of China
  5. 5.Department of Nutritional ScienceFu Jen UniversityNew Taipei CityTaiwan, Republic of China
  6. 6.Department of NutritionChung Shan Medical University HospitalTaichungTaiwan, Republic of China
  7. 7.Department of Medical ResearchChina Medical University HospitalTaichungTaiwan, Republic of China
  8. 8.Taiwan Nutraceutical AssociationTaipeiTaiwan, Republic of China

Personalised recommendations