Associations of vascular calcification, calcium phosphate disturbances, FGF 23 and Matrix Gla protein with mortality of hemodialysis patients: one center cohort study

Open access


Background and objectives: Vascular calcification (VC) is one of the factors associated with mortality in hemodialysis (HD) patients. The purpose of the study was to assess associations between prevalent VC and disturbances of calcium-phosphate metabolism as well as changes in vitamin D (25(OH)D), FGF 23 and MGP levels and to evaluate the possible impact of VC and changes of these biomarkers on survival in HD patients.

Methods: The study population consisted of 81 prevalent patients in the hemodialysis unit of Hospital of Lithuanian University of Health Sciences Kaunas Clinics. A simple vascular calcification score (SVCS) was evaluated as it is described by Adragao et al. 25(OH)D (nmol/L), FGF 23 (ng/L) and MGP (ng/mL) were measured and analysed.

Results: Patients were divided into two groups: SVCS<3 (31 patient (38.3%) and SVCS ≥3 (50 patients (61.7%)). In multivariate logistic regression, age (odds ratio 1.062, 95% CI [1.024-1.1] p=0.001) and diabetes (odds ratio 6.9, 95% CI [1.5-31], p=0.012) were associated with SVCS ≥3. The multivariate logistic regression revealed the highest negative impact of SVCS ≥3, age and 25(OH)D level for death risk.

Conclusion: VC in HD patients is highly influenced by age and presence of diabetes and associated with higher risk of death. No significant association was found between MGP and FGF 23 and VC as well as between these two biomarkers and risk of death. Lower 25(OH)D levels were associated with mortality in this dialysis patients cohort.

1. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004 Sep 23;351(13):1296-1305. DOI: 10.1056/NEJMoa041031

2. Foley RN, Parfrey PS. Cardiovascular disease and mortality in ESRD. J Nephrol 1998 Sep-Oct;11(5):239-45.

3. Collins AJ, Foley RN, Chavers B, Gilbertson D, Herzog C, Ishani A, et al. US Renal Data System 2013 Annual Data Report. Am J Kidney Dis 2014 Jan;63(1 Suppl):A7. DOI: 10.1053/j.ajkd.2013.11.001

4. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998 Nov;32(5 Suppl 3):S112-9. DOI: 10.1053/ajkd.1998.v32.pm9820470

5. Herzog CA, Ma JZ, Collins AJ. Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med 1998 Sep 17;339(12):799-805. DOI: 10.1056/NEJM199809173391203

6. Moe S, Drueke T, Cunningham J, Goodman W, Martin K, Olgaard K, et al. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006 Jun;69(11):1945-53. DOI: 10.1038/

7. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 2001 Oct;38(4):938-42. DOI: 10.1161/hy1001.096358

8. London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 2003 Sep;18(9):1731-40. DOI: 10.1093/ndt/gfg414

9. Shanahan CM, Cary NR, Salisbury JR, Proudfoot D, Weissberg PL, Edmonds ME. Medial localization of mineralization-regulating proteins in association with Monckeberg’s sclerosis: evidence for smooth muscle cell-mediated vascular calcification. Circulation 1999 Nov 23;100(21):2168-76. DOI: 10.1161/01.CIR.100.21.2168

10. Steitz SA, Speer MY, Curinga G, Yang HY, Haynes P, Aebersold R, et al. Smooth muscle cell phenotypic transition associated with calcification: upregulation of Cbfa1 and downregulation of smooth muscle lineage markers. Circ Res 2001 Dec 7;89(12):1147-54. DOI: 10.1161/hh2401.101070

11. Bhuriya R, Li S, Chen SC, McCullough PA, Bakris GL. Plasma parathyroid hormone level and prevalent cardiovascular disease in CKD stages 3 and 4: an analysis from the Kidney Early Evaluation Program (KEEP). Am J Kidney Dis 2009 Apr;53(4 Suppl 4):S3-10. DOI: 10.1053/j.ajkd.2008.11.029

12. Kimata N, Albert JM, Akiba T, Yamazaki S, Kawaguchi T, Fukuhara S, et al. Association of mineral metabolism factors with all-cause and cardiovascular mortality in hemodialysis patients: the Japan dialysis outcomes and practice patterns study. Hemodial Int 2007 Jul;11(3):340-8. DOI: 10.1111/j.1542-4758.2007.00190.x

13. Wolf M, Thadhani R. Vitamin D in patients with renal failure: a summary of observational mortality studies and steps moving forward. J Steroid Biochem Mol Biol 2007 Mar;103(3-5):487-90. DOI: 10.1016/j.jsbmb.2006.11.009

14. Hermans MM, Vermeer C, Kooman JP, Brandenburg V, Ketteler M, Gladziwa U, et al. Undercarboxylated matrix GLA protein levels are decreased in dialysis patients and related to parameters of calcium-phosphate metabolism and aortic augmentation index. Blood Purif 2007;25(5-6):395-401. DOI: 10.1159/000108629

15. Cranenburg EC, Vermeer C, Koos R, Boumans ML, Hackeng TM, Bouwman FG, et al. The circulating inactive form of matrix Gla Protein (ucMGP) as a biomarker for cardiovascular calcification. J Vasc Res 2008;45(5):427-36. DOI: 10.1159/000124863

16. Pop D, Sitar-Taut A, Gligor E, Bodizs G, Cebanu M, Buduru S, et al. The relationship between matrix GLA protein (MGP) and carotid stenosis. Rev Romana Med Lab 2011;19(2):169-75.

17. Schlieper G, Westenfeld R, Kruger T, Cranenburg EC, Magdeleyns EJ, Brandenburg VM, et al. Circulating nonphosphorylated carboxylated matrix gla protein predicts survival in ESRD. J Am Soc Nephrol 2011 Feb;22(2):387-95. DOI: 10.1681/ASN.2010040339

18. Gutierrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008 Aug 7;359(6):584-92. DOI: 10.1056/NEJMoa0706130

19. Isakova T. Fibroblast growth factor 23 and adverse clinical outcomes in chronic kidney disease. Curr Opin Nephrol Hypertens 2012 May;21(3):334-40. DOI: 10.1097/MNH.0b013e328351a391

20. Desjardins L, Liabeuf S, Renard C, Lenglet A, Lemke HD, Choukroun G, et al. FGF23 is independently associated with vascular calcification but not bone mineral density in patients at various CKD stages. Osteoporos Int 2012 Jul;23(7):2017-25. DOI: 10.1007/s00198-011-1838-0

21. Inaba M, Okuno S, Imanishi Y, Yamada S, Shioi A, Yamakawa T, et al. Role of fibroblast growth factor-23 in peripheral vascular calcification in non-diabetic and diabetic hemodialysis patients. Osteoporos Int 2006 Oct;17(10):1506-13. DOI: 10.1007/s00198-006-0154-6

22. Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC. Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis 1996 Mar;27(3):394-401. DOI: 10.1016/S0272-6386(96)90363-7

23. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003 Oct;42(4 Suppl 3):S1-201.

24. Petrauskiene V, Vaiciuniene R, Bumblyte IA, Kuzminskis V, Ziginskiene E, Grazulis S, et al. Association between vascular calcification assessed by simple radiography and non-fatal cardiovascular events in hemodialysis patients. Nephrol Ther 2016 Dec;12(7):503-7. DOI: 10.1016/j.nephro.2016.06.005

25. Adragao T, Pires A, Lucas C, Birne R, Magalhaes L, Goncalves M, et al. A simple vascular calcification score predicts cardiovascular risk in haemodialysis patients. Nephrol Dial Transplant 2004 Jun;19(6):1480-8. DOI: 10.1093/ndt/gfh217

26. Kurnatowska I, Grzelak P, Stefanczyk L, Nowicki M. Tight relations between coronary calcification and atherosclerotic lesions in the carotid artery in chronic dialysis patients. Nephrology (Carlton) 2010 Mar;15(2):184-9. DOI: 10.1111/j.1440-1797.2009.01169.x

27. Shanahan CM, Crouthamel MH, Kapustin A, Giachelli CM. Arterial calcification in chronic kidney disease: key roles for calcium and phosphate. Circ Res 2011 Sep 2;109(6):697-711. DOI: 10.1161/CIRCRESAHA.110.234914

28. El-Abbadi MM, Pai AS, Leaf EM, Yang HY, Bartley BA, Quan KK, et al. Phosphate feeding induces arterial medial calcification in uremic mice: role of serum phosphorus, fibroblast growth factor-23, and osteopontin. Kidney Int 2009 Jun;75(12):1297-307. DOI: 10.1038/ki.2009.83

29. Liabeuf S, Okazaki H, Desjardins L, Fliser D, Goldsmith D, Covic A, et al. Vascular calcification in chronic kidney disease: are biomarkers useful for probing the pathobiology and the health risks of this process in the clinical scenario? Nephrol Dial Transplant 2014 Jul;29(7):1275-84. DOI: 10.1093/ndt/gft368

30. Shanahan CM. Mechanisms of vascular calcification in renal disease. Clin Nephrol 2005 Feb;63(2):146-57. DOI: 10.5414/CNP63146

31. Schurgers LJ, Cranenburg EC, Vermeer C. Matrix Gla-protein: the calcification inhibitor in need of vitamin K. Thromb Haemost 2008 Oct;100(4):593-603.

32. Xiao DM, Wu Q, Fan WF, Ye XW, Niu JY, Gu Y. Effect of serum FGF-23, MGP and fetuin-A on calcium-phosphate metabolism in maintenance hemodialysis patients. Hemodial Int 2013 Oct;17(4):483-492. DOI: 10.1111/hdi.12033

33. Delanaye P, Krzesinski JM, Warling X, Moonen M, Smelten N, Medart L, 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 Nephrol 2014 Sep 4;15:145-2369-15-145.

34. Aoun M, Makki M, Azar H, Matta H, Chelala DN. High Dephosphorylated-Uncarboxylated MGP in Hemodialysis patients: risk factors and response to vitamin K2, A pre-post intervention clinical trial. BMC Nephrol 2017 Jun 7;18(1):191-017-0609-3.

35. Isakova T, Wahl P, Vargas GS, Gutierrez OM, Scialla J, Xie H, et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int 2011 Jun;79(12):1370-8. DOI: 10.1038/ki.2011.47

36. Seiler S, Reichart B, Roth D, Seibert E, Fliser D, Heine GH. FGF-23 and future cardiovascular events in patients with chronic kidney disease before initiation of dialysis treatment. Nephrol Dial Transplant 2010 Dec;25(12):3983-9. DOI: 10.1093/ndt/gfq309

37. Kim HJ, Park M, Park HC, Jeong JC, Kim DK, Joo KW, et al. Baseline FGF23 is Associated with Cardiovascular Outcome in Incident PD Patients. Perit Dial Int 2016 Jan-Feb;36(1):26-32. DOI: 10.3747/pdi.2013.00343

38. Scialla JJ, Lau WL, Reilly MP, Isakova T, Yang HY, Crouthamel MH, et al. Fibroblast growth factor 23 is not associated with and does not induce arterial calcification. Kidney Int 2013 Jun;83(6):1159-68. DOI: 10.1038/ki.2013.3

39. Moldovan D, Moldovan I, Rusu C, Kacso I, Patiu IM, Gherman-Caprioara M. FGF-23, vascular calcification, and cardiovascular diseases in chronic hemodialysis patients. Int Urol Nephrol 2014 Jan;46(1):121-8. DOI: 10.1007/s11255-013-0422-2

40. Zittermann A, Iodice S, Pilz S, Grant WB, Bagnardi V, Gandini S. Vitamin D deficiency and mortality risk in the general population: a meta-analysis of prospective cohort studies. Am J Clin Nutr 2012 Jan;95(1):91-100. DOI: 10.3945/ajcn.111.014779

41. Zhang Y, Darssan D, Pascoe EM, Johnson DW, Pi H, Dong J. Vitamin D status and mortality risk among patients on dialysis: a systematic review and meta-analysis of observational studies. Nephrol Dial Transplant 2018 Feb 21. DOI: 10.1093/ndt/gfy016

Revista Romana de Medicina de Laborator

Romanian Journal of Laboratory Medicine

Journal Information

IMPACT FACTOR 2018: 0,800
5-year IMPACT FACTOR: 0,655

CiteScore 2017: 0.31

SCImago Journal Rank (SJR) 2018: 0.194
Source Normalized Impact per Paper (SNIP) 2018: 0.306


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 159 159 24
PDF Downloads 84 84 7