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Pathogenesis of vascular calcification in dialysis patients

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Abstract

Soft-tissue and vascular calcification are highly prevalent in end-stage renal disease (ESRD). Vascular calcifications manifest as both medial and intimal calcification of arteries and are a hallmark of the accelerated atherosclerosis observed in uremia. The nature of vascular calcification is progressive, and is associated with arterial stiffness and increased cardiovascular mortality. Age, duration of dialysis, and diabetes mellitus are clear determinants of the severity of vascular calcification; however, more recently novel insights into the pathomechanisms of unwanted calcification processes have been gained. Disturbances of mineral metabolism such as hyperphosphatemia and hypercalcemia appear to contribute to progressive calcification, not only by passive precipitation but by actively inducing changes in vascular smooth muscle cell behavior toward an osteoblast-like phenotype. Specific calcium-regulatory proteins may act locally or systemically as calcification inhibitors. Dysregulations of calcification inhibitors, including fetuin-A, matrix Gla protein, osteoprotegerin, and pyrophosphates may also be pathophysiologically relevant factors in the context of uremic extraosseous calcification. In this context, low serum fetuin-A levels were recently found to be associated with increased mortality in cohorts of dialysis patients. This overview intends to summarize current knowledge of the scientific concepts involved in the pathogenesis of extraosseous calcification in ESRD.

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References

  1. InstitutionalAuthorNameUS Renal Data System (1999) ArticleTitleUSRDS 1999 annual data report Am J Kidney Dis 34 IssueID2 suppl 1 S87–94

    Google Scholar 

  2. WG Goodman J Goldin BD Kuizon et al. (2000) ArticleTitleCoronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis N Engl J Med 342 1478–83 Occurrence Handle1:STN:280:DC%2BD3c3ls1OjtA%3D%3D Occurrence Handle10.1056/NEJM200005183422003 Occurrence Handle10816185

    Article  CAS  PubMed  Google Scholar 

  3. J Oh R Wunsch M Turzer M Bahner P Raggi U Querfeld et al. (2002) ArticleTitleAdvanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure Circulation 106 100–5 Occurrence Handle10.1161/01.CIR.0000020222.63035.C0 Occurrence Handle12093777

    Article  PubMed  Google Scholar 

  4. J Blacher AP Guerin B Pannier et al. (2001) ArticleTitleArterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease Hypertension 38 938–42 Occurrence Handle1:CAS:528:DC%2BD3MXotVGlsr4%3D Occurrence Handle10.1161/hy1001.096358 Occurrence Handle11641313

    Article  CAS  PubMed  Google Scholar 

  5. GM London AP Guerin SJ Marchais et al. (2003) ArticleTitleArterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality Nephrol Dial Transplant 18 1731–40 Occurrence Handle10.1093/ndt/gfg414 Occurrence Handle12937218

    Article  PubMed  Google Scholar 

  6. SK Ganesh AG Stack NW Levin et al. (2001) ArticleTitleAssociation of elevated serum PO(4), Ca × PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients J Am Soc Nephrol 12 2131–8 Occurrence Handle1:CAS:528:DC%2BD3MXnsFWiurk%3D Occurrence Handle11562412

    CAS  PubMed  Google Scholar 

  7. GA Block PS Klassen JM Lazarus et al. (2004) ArticleTitleMineral metabolism, mortality, and morbidity in maintenance hemodialysis J Am Soc Nephrol 15 2208–18 Occurrence Handle1:CAS:528:DC%2BD2cXlvVKmu7w%3D Occurrence Handle10.1097/01.ASN.0000133041.27682.A2 Occurrence Handle15284307

    Article  CAS  PubMed  Google Scholar 

  8. S Jono MD McKee CE Murry et al. (2000) ArticleTitlePhosphate regulation of vascular smooth muscle cell calcification Circ Res 87 E10–17 Occurrence Handle1:CAS:528:DC%2BD3MXhslOisbs%3D Occurrence Handle10.1161/01.RES.87.7.e10 Occurrence Handle11009570

    Article  CAS  PubMed  Google Scholar 

  9. NX Chen KD O'Neill D Duan SM Moe (2002) ArticleTitlePhosphorus and uremic serum up-regulate osteopontin expression in vascular smooth muscle cells Kidney Int 62 1724–31 Occurrence Handle1:CAS:528:DC%2BD38Xos1ekt70%3D Occurrence Handle10.1046/j.1523-1755.2002.00625.x Occurrence Handle12371973

    Article  CAS  PubMed  Google Scholar 

  10. SM Moe KD O'Neill D Duan et al. (2002) ArticleTitleMedial artery calcification in ESRD patients is associated with deposition of bone matrix proteins Kidney Int 61 638–47 Occurrence Handle10.1046/j.1523-1755.2002.00170.x Occurrence Handle11849407

    Article  PubMed  Google Scholar 

  11. SM Moe D Duan BP Doehle KD O'Neill NX Chen (2003) ArticleTitleUremia induces the osteoblast differentiation factor Cbfa1 in human blood vessels Kidney Int 63 1003–11 Occurrence Handle1:CAS:528:DC%2BD3sXivV2jtr4%3D Occurrence Handle10.1046/j.1523-1755.2003.00820.x Occurrence Handle12631081

    Article  CAS  PubMed  Google Scholar 

  12. JL Reynolds AJ Joannides JN Skepper et al. (2004) ArticleTitleHuman vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD J Am Soc Nephrol 15 2857–67 Occurrence Handle1:CAS:528:DC%2BD2cXos1Gjtbw%3D Occurrence Handle10.1097/01.ASN.0000141960.01035.28 Occurrence Handle15504939

    Article  CAS  PubMed  Google Scholar 

  13. M Ketteler C Wanner T Metzger P Bongartz R Westenfeld U Gladziwa et al. (2003) ArticleTitleDeficiencies of calcium-regulatory proteins in dialysis patients: a novel concept of cardiovascular calcification in uremia Kidney Int Suppl 84 S84–7 Occurrence Handle1:CAS:528:DC%2BD3sXjslCrsrc%3D Occurrence Handle10.1046/j.1523-1755.63.s84.21.x

    Article  CAS  Google Scholar 

  14. G Luo P Ducy MD McKee GJ Pinero E Loyer RR Behringer et al. (1997) ArticleTitleSpontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein Nature 386 78–81 Occurrence Handle1:CAS:528:DyaK2sXhslCnsLk%3D Occurrence Handle10.1038/386078a0 Occurrence Handle9052783

    Article  CAS  PubMed  Google Scholar 

  15. CM Shanahan NR Cary JC Metcalfe PL Weissberg (1994) ArticleTitleHigh expression of genes for calcification-regulating proteins in human atherosclerotic plaques J Clin Invest 93 2393–402 Occurrence Handle1:CAS:528:DyaK2cXlsFClsbo%3D Occurrence Handle10.1172/JCI117246 Occurrence Handle8200973 Occurrence Handle294446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. WG Goodman G London K Amann GA Block C Giachelli KA Hruska et al. (2004) ArticleTitleVascular Calcification Work Group. Vascular calcification in chronic kidney disease Am J Kidney Dis 43 572–9 Occurrence Handle10.1053/j.ajkd.2003.12.005 Occurrence Handle14981617

    Article  PubMed  Google Scholar 

  17. LJ Schurgers KJ Teunissen MH Knapen P Geusens D van der Heijde M Kraijtaal et al. (2005) ArticleTitleCharacteristics and performance of an immunosorbent assay for human matrix Gla-protein Clin Chim Acta 351 131–8 Occurrence Handle1:CAS:528:DC%2BD2cXhtVant73J Occurrence Handle10.1016/j.cccn.2004.08.003 Occurrence Handle15563881

    Article  CAS  PubMed  Google Scholar 

  18. N Bucay I Sarosi CR Dunstan S Morony J Tarpley C Capparelli et al. (1998) ArticleTitleOsteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification Genes Dev 12 1260–8 Occurrence Handle1:CAS:528:DyaK1cXjtVejsrs%3D Occurrence Handle10.1101/gad.12.9.1260 Occurrence Handle9573043 Occurrence Handle316769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. WS Simonet DL Lacey CR Dunstan M Kelley MS Chang R Luthy et al. (1997) ArticleTitleOsteoprotegerin: a novel secreted protein involved in the regulation of bone density Cell 89 309–19 Occurrence Handle1:CAS:528:DyaK2sXislCgtLc%3D Occurrence Handle10.1016/S0092-8674(00)80209-3 Occurrence Handle9108485

    Article  CAS  PubMed  Google Scholar 

  20. WJ Boyle WS Simonet DL Lacey (2003) ArticleTitleOsteoclast differentiation and activation Nature 423 337–42 Occurrence Handle1:CAS:528:DC%2BD3sXjs1ynu7g%3D Occurrence Handle10.1038/nature01658 Occurrence Handle12748652

    Article  CAS  PubMed  Google Scholar 

  21. K Nitta T Akiba K Uchida A Kawashima W Yumura T Kabaya et al. (2003) ArticleTitleThe progression of vascular calcification and serum osteoprotegerin levels in patients on long-term hemodialysis Am J Kidney Dis 42 303–9 Occurrence Handle1:CAS:528:DC%2BD3sXmvFymsLY%3D Occurrence Handle10.1016/S0272-6386(03)00655-3 Occurrence Handle12900812

    Article  CAS  PubMed  Google Scholar 

  22. LC Hofbauer M Schoppet (2001) ArticleTitleOsteoprotegerin: a link between osteoporosis and arterial calcification? Lancet 358 257–8 Occurrence Handle1:STN:280:DC%2BD3MvltFanuw%3D%3D Occurrence Handle10.1016/S0140-6736(01)05494-0 Occurrence Handle11498208

    Article  CAS  PubMed  Google Scholar 

  23. Harmey D, Hessle L, Narisawa S, Johnson KA, Terkeltaub R, Millan JL. Concerted regulation of inorganic pyrophosphate and osteopontin by akp2, enpp1, and ank: an integrated model of the pathogenesis of mineralization disorders. Am J Pathol 2004;1199–209

  24. AM Ho MD Johnson DM Kingsley (2000) ArticleTitleRole of the mouse ank gene in control of tissue calcification and arthritis Science 289 265–70 Occurrence Handle1:CAS:528:DC%2BD3cXltFejs7k%3D Occurrence Handle10.1126/science.289.5477.265 Occurrence Handle10894769

    Article  CAS  PubMed  Google Scholar 

  25. F Rutsch N Ruf S Vaingankar MR Toliat A Suk W Hohne et al. (2003) ArticleTitleMutations in ENPP1 are associated with “idiopathic” infantile arterial calcification Nat Genet 34 379–81 Occurrence Handle1:CAS:528:DC%2BD3sXmt1Skurg%3D Occurrence Handle10.1038/ng1221 Occurrence Handle12881724

    Article  CAS  PubMed  Google Scholar 

  26. K Nitta T Akiba K Suzuki K Uchida R Watanabe K Majima et al. (2004) ArticleTitleEffects of cyclic intermittent etidronate therapy on coronary artery calcification in patients receiving long-term hemodialysis Am J Kidney Dis 44 680–8 Occurrence Handle1:CAS:528:DC%2BD2cXptFOht7c%3D Occurrence Handle10.1016/S0272-6386(04)00937-0 Occurrence Handle15384019

    Article  CAS  PubMed  Google Scholar 

  27. F Gejyo JL Chang W Bürgi K Schmid GD Offner RF Troxler et al. (1983) ArticleTitleCharacterization of the B-chain of human plasma α2HS-glycoprotein J Biol Chem 258 4966–71 Occurrence Handle1:CAS:528:DyaL3sXktVWqtb4%3D Occurrence Handle6833285

    CAS  PubMed  Google Scholar 

  28. Y Yoshioka F Gejyo T Marti EE Rickli W Bürgi GD Offner et al. (1986) ArticleTitleThe complete amino acid sequence of the A-chain of human plasma α2HS-glycoprotein J Biol Chem 261 1665–76 Occurrence Handle1:CAS:528:DyaL28XhsVCiu7Y%3D Occurrence Handle3944104

    CAS  PubMed  Google Scholar 

  29. JP Lebreton F Joisel JP Raoult et al. (1979) ArticleTitleSerum concentration of human alpha 2 HS glycoprotein during the inflammatory process: evidence that alpha 2 HS glycoprotein is a negative acute-phase reactant J Clin Invest 64 1118–29 Occurrence Handle1:CAS:528:DyaL3cXktFGn Occurrence Handle10.1172/JCI109551 Occurrence Handle90057 Occurrence Handle372224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. M Demetriou C Binkert B Sukhu et al. (1996) ArticleTitleFetuin/alpha2-HS glycoprotein is a transforming growth factor-beta type II receptor mimic and cytokine antagonist J Biol Chem 271 12755–61 Occurrence Handle1:CAS:528:DyaK28XjtlGjtL4%3D Occurrence Handle10.1074/jbc.271.22.12755 Occurrence Handle8662721

    Article  CAS  PubMed  Google Scholar 

  31. ST Mathews GP Singh M Ranalletta et al. (2002) ArticleTitleImproved insulin sensitivity and resistance to weight gain in mice null for the Ahsg gene Diabetes 51 2450–8 Occurrence Handle1:CAS:528:DC%2BD38XlvFKiu74%3D Occurrence Handle10.2337/diabetes.51.8.2450 Occurrence Handle12145157

    Article  CAS  PubMed  Google Scholar 

  32. C Schafer A Heiss A Schwarz et al. (2003) ArticleTitleThe serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification J Clin Invest 112 357–66 Occurrence Handle10.1172/JCI17202 Occurrence Handle12897203 Occurrence Handle166290

    Article  PubMed  PubMed Central  Google Scholar 

  33. R Westenfeld C Smeets C Schäfer et al. (2003) ArticleTitleExtraosseous mRNA expression of bone associated proteins in uremic mice lacking Ahsg/fetuin-A Nephrol Dial Transplant 18 IssueIDSuppl 4 593 Occurrence Handle10.1093/oxfordjournals.ndt.a004650

    Article  Google Scholar 

  34. MW Merx C Schafer R Westenfeld V Brandenburg S Hidajat C Weber et al. (2005) ArticleTitleMyocardial stiffness, cardiac remodeling, and diastolic dysfunction in calcification-prone fetuin-a-deficient mice J Am Soc Nephrol 16 3357–64 Occurrence Handle1:CAS:528:DC%2BD2MXht1Cnsr3J Occurrence Handle10.1681/ASN.2005040365 Occurrence Handle16177000

    Article  CAS  PubMed  Google Scholar 

  35. M Ketteler P Bongartz R Westenfeld et al. (2003) ArticleTitleAssociation of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study Lancet 361 827–33 Occurrence Handle1:CAS:528:DC%2BD3sXitVKmtLo%3D Occurrence Handle10.1016/S0140-6736(03)12710-9 Occurrence Handle12642050

    Article  CAS  PubMed  Google Scholar 

  36. P Stenvinkel K Wang AR Qureshi et al. (2005) ArticleTitleLow fetuin-A levels are associated with cardiovascular death: impact of variations in the gene encoding fetuin Kidney Int 67 2383–92 Occurrence Handle1:CAS:528:DC%2BD2MXlsFyjuro%3D Occurrence Handle10.1111/j.1523-1755.2005.00345.x Occurrence Handle15882283

    Article  CAS  PubMed  Google Scholar 

  37. SM Moe M Reslerova M Ketteler et al. (2005) ArticleTitleRole of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease Kidney Int 67 2295–304 Occurrence Handle1:CAS:528:DC%2BD2MXlsFyjtbY%3D Occurrence Handle10.1111/j.1523-1755.2005.00333.x Occurrence Handle15882271

    Article  CAS  PubMed  Google Scholar 

  38. R Mehrotra R Westenfeld P Christenson et al. (2005) ArticleTitleSerum fetuin-A in non-dialyzed patients with diabetic nephropathy: relationship with coronary artery calcification Kidney Int 67 1070–7 Occurrence Handle1:CAS:528:DC%2BD2MXis1Gru7c%3D Occurrence Handle10.1111/j.1523-1755.2005.00172.x Occurrence Handle15698447

    Article  CAS  PubMed  Google Scholar 

  39. JJ Kazama F Gejyo I Ei (2005) ArticleTitleThe immunohistochemical localization of a2-Heremans-Schmid-glycoprotein/fetuin-A (AHSG) Nephrol Dial Transplant 20 851–2 Occurrence Handle1:CAS:528:DC%2BD2MXisVGqt7s%3D Occurrence Handle10.1093/ndt/gfh690 Occurrence Handle15772277

    Article  CAS  PubMed  Google Scholar 

  40. BK Kishore F Gejyo M Arakawa (1983) ArticleTitleAlpha2HS-glycoprotein in the serum and urine of patients with renal diseases Postgrad Med J 59 304–7 Occurrence Handle1:STN:280:DyaL3s3ntlaiug%3D%3D Occurrence Handle10.1136/pgmj.59.691.304 Occurrence Handle6878101 Occurrence Handle2417412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Nephrology and Clinical Immunology, University Hospital Aachen, Pauwelsstrasse 30, D-52057, Aachen, Germany

    Markus Ketteler, Ralf Westenfeld, Georg Schlieper & Vincent Brandenburg

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  1. Markus Ketteler
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  2. Ralf Westenfeld
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  3. Georg Schlieper
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  4. Vincent Brandenburg
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Correspondence to Markus Ketteler.

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Ketteler, M., Westenfeld, R., Schlieper, G. et al. Pathogenesis of vascular calcification in dialysis patients. Clin Exp Nephrol 9, 265–270 (2005). https://doi.org/10.1007/s10157-005-0385-4

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  • DOI: https://doi.org/10.1007/s10157-005-0385-4

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