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Serum osteoprotegerin is associated with vascular stiffness and the onset of new cardiovascular events in hemodialysis patients

  • Lee, Jung Eun (Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine) ;
  • Kim, Hyung Jong (Department of Internal Medicine, CHA Bundang Medical Center, CHA University) ;
  • Moon, Sung Jin (Department of Internal Medicine, Myongji Hospital) ;
  • Nam, Ji Sun (Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine) ;
  • Kim, Jwa-Kyung (Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine) ;
  • Kim, Seung Kyu (Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine) ;
  • Yun, Gi Young (Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine) ;
  • Ha, Sung Kyu (Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine) ;
  • Park, Hyeong Cheon (Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine)
  • Received : 2012.09.18
  • Accepted : 2012.12.04
  • Published : 2013.11.01

Abstract

Background/Aims: Osteoprotegerin (OPG) and fetuin-A are vascular calcification regulators that may be related to high cardiovascular (CV) mortality in hemodialysis (HD) patients. We evaluated the relationship between OPG, fetuin-A, and pulse wave velocity (PWV), a marker of vascular stiffness, and determined whether OPG and fetuin-A were independent predictors of CV events in HD patients. Methods: We conducted a prospective observational study in 97 HD patients. OPG and fetuin-A were measured at baseline and arterial stiffness was evaluated by PWV. All patients were stratified into tertiles according to serum OPG levels. Results: A significant trend was observed across increasing serum OPG concentration tertiles for age, HD duration, systolic blood pressure, cholesterol, triglycerides, and PWV. Multiple linear regression analysis revealed that diabetes (${\beta}$ = 0.430, p = 0.000) and OPG levels (${\beta}$ = 0.308, p = 0.003) were independently associated with PWV. The frequency of new CV events was significantly higher in the upper OPG tertiles compared with those in the lower OPG tertiles. In Cox proportional hazards analysis, upper tertiles of OPG levels were significantly associated with CV events (hazard ratio = 4.536, p = 0.011). Conclusions: Serum OPG, but not fetuin-A, levels were closely associated with increased vascular stiffness, and higher OPG levels may be independent predictors of new CV events in HD patients.

Keywords

References

  1. Guerin AP, London GM, Marchais SJ, Metivier F. Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant 2000;15:1014-1021. https://doi.org/10.1093/ndt/15.7.1014
  2. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM. Arterial calficications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 2001;38:938-942. https://doi.org/10.1161/hy1001.096358
  3. Asmar R, Benetos A, Topouchian J, et al. Assesment of arterial distensibility by automatic pulse wave velocity measurement: validation and clinical application studies. Hypertension 1995;26:485-490. https://doi.org/10.1161/01.HYP.26.3.485
  4. Lacey DL, Dunstan CR, Kelley M, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997;89:309-319. https://doi.org/10.1016/S0092-8674(00)80209-3
  5. Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998; 93:165-176. https://doi.org/10.1016/S0092-8674(00)81569-X
  6. Westenfeld R, Jahnen-Dechent W, Ketteler M. Vascular calcification and fetuin-A deficiency in chronic kidney disease. Trends Cardiovasc Med 2007;7:124-128.
  7. Nishiura R, Fujimoto S, Sato Y, et al. Elevated osteoprotegerin levels predict cardiovascualr events in new hemodialysis patients. Am J Nephrol 2009;9:257-263.
  8. Sigrist MK, Levin A, Er L, McIntyre CW. Elevated osteoprotegerin is associated with all-cause mortality in CKD stage 4 and 5 patients in addition to vascular calcification. Nephrol Dial Transplant 2009;24:3157-3162. https://doi.org/10.1093/ndt/gfp253
  9. Nakashima A, Carrero JJ, Qureshi AR, et al. Plasma osteoprotegerin, arterial stiffness, and mortality in normoalbuminemic Japanese hemodialysis patients. Osteoporosis Int 2011;22:1695-1701. https://doi.org/10.1007/s00198-010-1377-0
  10. Speer G, Fekete BC, El Hadj Othmane T, et al. Serum osteoprotegerin level, carotid-femoral pulse wave velocity and cardiovascular survival in haemodialysis patients. Nephrol Dial Transplant 2008;23:3256-3262. https://doi.org/10.1093/ndt/gfn242
  11. Hermans MM, Brandenburg V, Ketteler M, et al. Study on the relationship of serum fetuin-A concentration with aortic stiffness in patients on dialysis. Nephrol Dial Transplant 2006;21:1293-1299. https://doi.org/10.1093/ndt/gfk045
  12. Ix JH, Shlipak MG, Sarnak MJ, et al. Fetuin-A is not associated with mortality in chronic kidney disease. Kidney Int 2007;72:1394-1399. https://doi.org/10.1038/sj.ki.5002549
  13. Ketteler M, Bongartz P, Westenfeld R, et al. Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a crosssectional study. Lancet 2003;361:827-833. https://doi.org/10.1016/S0140-6736(03)12710-9
  14. Swedberg K, Cleland J, Dargie H, et al. Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology: guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): the task force for the diagnosis and treatment of chronic heart failure of the European Society of Cardiology. Eur Heart J 2005;26:1115-1140. https://doi.org/10.1093/eurheartj/ehi204
  15. O'Rourke MF, Staessen JA, Vlachopoulos C, Duprez D, Plante GE. Clinical application of arterial stiffness: definitions and reference values. Am J Hypertens 2002;15:426-444. https://doi.org/10.1016/S0895-7061(01)02319-6
  16. Park S, Kim JB, Shim CY, et al. The influence of serum aldosterone and the aldosterone-renin ratio on pulse wave velocity in hypertensive patients. J Hypertens 2007;25:1279-1283. https://doi.org/10.1097/HJH.0b013e3280f31b6e
  17. Kuzniar J, Porazko T, Klinger M. Relationship between fetuin-A concentration, elevated levels of inflammatory markers, and arterial wall stiffness in end stage kidney disease. J Ren Nutr 2008;18:83-86. https://doi.org/10.1053/j.jrn.2007.10.017
  18. Nitta K, Akiba T, Uchida K, et al. The progression of vascular calcification and serum osteoprogerin levels in patients on long-term hemodialysis. Am J Kidney Dis 2003;42:303-309. https://doi.org/10.1016/S0272-6386(03)00655-3
  19. Barreto DV, Barreto FC, Carvalho AB, et al. Coronary calcification in hemodialysis patients: the contribution of traditional and uremia-related risk factors. Kidney Int 2005;67:1576-1582. https://doi.org/10.1111/j.1523-1755.2005.00239.x
  20. London GM, Guerin AP, Verbeke FH, et al. Mineral metabolism and arterial functions in end-stage renal disease: potential role of 25-hydroxyvitamin D deficiency. J Am Soc Nephrol 2007;18:613-620. https://doi.org/10.1681/ASN.2006060573
  21. Lebreton JP, Joisel F, Raoult JP, Lannuzel B, Rogez JP, Humbert G. Serum concentration of human alpha 2 HS glycoprotein during the inflammatory process: evidence that alpha 2 HS glycoprotein is a negative acutephase reactant. J Clin Invest 1979;64:1118-1129. https://doi.org/10.1172/JCI109551
  22. Stenvinkel P, Wang K, Qureshi AR, et al. Low fetuin-A levels are associated with cardiovascular death: impact of variations in the gene encoding fetuin. Kindey Int 2005;67:2383-2392. https://doi.org/10.1111/j.1523-1755.2005.00345.x
  23. Luo G, Ducy P, McKee MD, et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 1997;386:78-81. https://doi.org/10.1038/386078a0
  24. Schinke T, Amendt C, Trindl A, Poschke O, Muller-Esterl W, Jahnen-Dechent W. The serum protein alpha 2-HS glycoprotein/fetuin inhibits apatite formation in vitro and in mineralizing calvaria cells: a possible role in mineralization and calcium homeostasis. J Biol Chem 1996;271:20789-20796. https://doi.org/10.1074/jbc.271.34.20789
  25. Metry G, Stenvinkel P, Qureshi AR, et al. Low serum fetuin-A concentration predicts poor outcome only in the presence of inflammation in prevalent haemodialysis patients. Eur J Clin Invest 2008;38:804-811. https://doi.org/10.1111/j.1365-2362.2008.02032.x
  26. Honda H, Qureshi AR, Heimburger O, et al. Serum albumin, C-reactive protein, interleukin 6, and fetuin a as predictors of malnutrition, cardiovascular disease, and mortality in patients with ESRD. Am J Kidney Dis 2006;47:139-148. https://doi.org/10.1053/j.ajkd.2005.09.014
  27. Chen HY, Chiu YL, Hsu SP, et al. Association of serum fetuin A with truncal obesity and dyslipidemia in non-diabetic hemodialysis patients. Eur J Endocrinol 2009;160:777-783. https://doi.org/10.1530/EJE-08-0813
  28. Scialla JJ, Leonard MB, Townsend RR, et al. Correlates of osteoprotegerin and association with aortic pulse wave velocity in patients with chronic kidney disease. Clin J Am Soc Nephrol 2011;6:2612-2619. https://doi.org/10.2215/CJN.03910411
  29. Raggi P, Bellasi A, Ferramosca E, Islam T, Muntner P, Block GA. Association of pulse wave velocity with vascular and valvular calcification in hemodialysis patients. Kidney Int 2007;71:802-807. https://doi.org/10.1038/sj.ki.5002164
  30. Haydar AA, Covic A, Colhoun H, Rubens M, Goldsmith DJ. Coronary artery calcification and aortic pulse wave velocity in chronic kidney disease patients. Kidney Int 2004;65:1790-1794. https://doi.org/10.1111/j.1523-1755.2004.00581.x
  31. Hjelmesaeth J, Ueland T, Flyvbjerg A, et al. Early posttransplant serum osteoprotegerin levels predict long-term (8-year) patient survival and cardiovascular death in renal transplant patients. J Am Soc Nephrol 2006;17:1746-1754. https://doi.org/10.1681/ASN.2005121368
  32. Kiechl S, Schett G, Wenning G, et al. Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease. Circulation 2004;109:2175-2180. https://doi.org/10.1161/01.CIR.0000127957.43874.BB
  33. Morena M, Terrier N, Jaussent I, et al. Plasma osteoprotegerin is associated with mortality in hemodialysis patients. J Am Soc Nephrol 2006;17:262-270. https://doi.org/10.1681/ASN.2006080924

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