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“Missing” inhibitors of calcification: general aspects and implications in renal failure

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Abstract

In the recent past, it has become increasingly clear that extracellular calcium and phosphate homeostasis is a tightly regulated process. Since the physiological serum concentrations of calcium and phosphate are several orders of magnitude above their solubility product, mechanisms inhibiting precipitation must be operative to prevent extraosseous calcification. A number of local and systemic calcification inhibitors, including fetuin-A, matrix Gla protein, and osteoprotegerin, have been identified in recent years. Deficiency and dysregulation of such factors may contribute to morbidity and even mortality. Extraosseous calcifications occur with high prevalence in patients with end-stage renal disease. In particular, vascular manifestations are clearly associated with cardiovascular events and decreased survival. In addition to the well-established roles of hyperphosphatemia and an increased calcium×phosphate product, the biological and potential clinical roles of disturbances in calcification inhibition in uremia are discussed in this overview.

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References

  1. US Renal Data System (1999) USRDS 1999 annual data report. Am J Kidney Dis 34 [Suppl 1]:S87–S94

    Google Scholar 

  2. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM (2001) Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 38:938–942

    CAS  PubMed  Google Scholar 

  3. Wang AY, Wang M, Woo J, Lam CW, Li PK, Lui SF, Sanderson JE (2003) Cardiac valve calcification as an important predictor for all-cause mortality and cardiovascular mortality in long-term peritoneal dialysis patients: a prospective study. J Am Soc Nephrol 14:159–168

    PubMed  Google Scholar 

  4. Block GA, Hulbert-Shearon TE, Levin NW, Port FK (1998) Association of serum phosphorus and calcium×phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 31:607–617

    CAS  PubMed  Google Scholar 

  5. Ganesh SK, Stack AG, Levin NW, Hulbert-Shearon T, Port FK (2001) Association of elevated serum PO(4), Ca x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 12:2131–2138

    CAS  PubMed  Google Scholar 

  6. Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J, Emerick A, Greaser L, Elashoff RM, Salusky IB (2000) Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 342:1478–1483

    Article  CAS  PubMed  Google Scholar 

  7. Oh J, Wunsch R, Turzer M, Bahner M, Raggi P, Querfeld U, Mehls O, Schaefer F (2002) Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure. Circulation 106:100–105

    Article  PubMed  Google Scholar 

  8. Wang TJ, Larson MG, Levy D, Benjamin EJ, Kupka MJ, Manning WJ, Clouse ME, D’Agostino RB, Wilson PW, O’Donnell CJ (2002) C-reactive protein is associated with subclinical epicardial coronary calcification in men and women: the Framingham Heart Study. Circulation 106:1189–1191

    Article  CAS  PubMed  Google Scholar 

  9. Jono S, McKee MD, Murry CE, Shioi A, Nishizawa Y, Mori K, Morii H, Giachelli CM (2000) Phosphate regulation of vascular smooth muscle cell calcification. Circ Res 87:E10–E17

    CAS  PubMed  Google Scholar 

  10. Moe SM, O’Neill KD, Duan D, Ahmed S, Chen NX, Leapman SB, Fineberg N, Kopecky K (2002) Medial artery calcification in ESRD patients is associated with deposition of bone matrix proteins. Kidney Int 61:638–647

    Article  PubMed  Google Scholar 

  11. Moe SM, Duan D, Doehle BP, O’Neill KD, Chen NX (2003) Uremia induces the osteoblast differentiation factor Cbfa1 in human blood vessels. Kidney Int 63:1003–1011

    Article  CAS  PubMed  Google Scholar 

  12. Ketteler M, Wanner C, Metzger T, Bongartz P, Westenfeld R, Gladziwa U, Schurgers LJ, Vermeer C, Jahnen-Dechent W, Floege J (2003) Deficiencies of calcium-regulatory proteins in dialysis patients: a novel concept of cardiovascular calcification in uremia. Kidney Int [Suppl] 84:S84–S87

    Google Scholar 

  13. Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G (1997) Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 386:78–81

    Article  CAS  PubMed  Google Scholar 

  14. Munroe PB, Olgunturk RO, Fryns JP, Van Maldergem L, Ziereisen F, Yuksel B, Gardiner RM, Chung E (1999) Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome. Nat Genet 21:142–144

    Article  CAS  PubMed  Google Scholar 

  15. Shanahan CM, Cary NR, Metcalfe JC, Weissberg PL (1994) High expression of genes for calcification-regulating proteins in human atherosclerotic plaques. J Clin Invest 93:2393–2402

    CAS  PubMed  Google Scholar 

  16. Case Records of the Massachussets General Hospital (2001) N Engl J Med 345:1119–1124

    Article  PubMed  Google Scholar 

  17. Coates T, Kirkland GS, Dymock RB, Murphy BF, Brealey JK, Mathew TH, Disney AP (1998) Cutaneous necrosis from calcific uremic arteriolopathy. Am J Kidney Dis 32:384–391

    CAS  PubMed  Google Scholar 

  18. Goodman WG, London G, Amann K, Block GA, Giachelli C, Hruska KA, Ketteler M, Levin A, Massy Z, McCarron DA, Raggi P, Shanahan CM, Yorioka N; Vascular Calcification Work Group (2004) Vascular calcification in chronic kidney disease. Am J Kidney Dis 43:572–579

    Article  PubMed  Google Scholar 

  19. Schinke T, Amendt C, Trindl A, Poschke O, Muller-Esterl W, Jahnen-Dechent W (1996) The serum protein alpha2-HS glycoprotein/fetuin inhibits apatite formation in vitro and in mineralizing calvaria cells. A possible role in mineralization and calcium homeostasis. J Biol Chem 271:20789–20796

    Article  CAS  PubMed  Google Scholar 

  20. Jahnen-Dechent W, Schinke T, Trindl A, Muller-Esterl W, Sablitzky F, Kaiser S, Blessing M (1997) Cloning and targeted deletion of the mouse fetuin gene. J Biol Chem 272:31496–31503

    Article  CAS  PubMed  Google Scholar 

  21. Lebreton JP, Joisel F, Raoult JP, Lannuzel B, Rogez JP, Humbert G (1979) Serum 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 64:1118–1129

    CAS  PubMed  Google Scholar 

  22. Heiss A, DuChesne A, Denecke B, Grotzinger J, Yamamoto K, Renne T, Jahnen-Dechent W (2003) Structural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles. J Biol Chem 278:13333–13341

    Article  CAS  PubMed  Google Scholar 

  23. Schafer C, Heiss A, Schwarz A, Westenfeld R, Ketteler M, Floege J, Muller-Esterl W, Schinke T, Jahnen-Dechent W (2003) The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest 112:357–366

    Article  PubMed  Google Scholar 

  24. Price PA, Nguyen TM, Williamson MK (2003) Biochemical characterization of the serum fetuin-mineral complex. J Biol Chem 278:22153–22160

    Article  CAS  PubMed  Google Scholar 

  25. Ketteler M, Bongartz P, Westenfeld R, Wildberger JE, Mahnken AH, Bohm R, Metzger T, Wanner C, Jahnen-Dechent W, Floege J (2003) Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 361:827–833

    Article  CAS  PubMed  Google Scholar 

  26. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319

    Article  CAS  PubMed  Google Scholar 

  27. Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS (1998) Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12:1260–1268

    CAS  PubMed  Google Scholar 

  28. Cundy T, Hegde M, Naot D, Chong B, King A, Wallace R, Mulley J, Love DR, Seidel J, Fawkner M, Banovic T, Callon KE, Grey AB, Reid IR, Middleton-Hardie CA, Cornish J. (2002) A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype. Hum Mol Genet 11:2119–2127

    Google Scholar 

  29. Nitta K, Akiba T, Uchida K, Kawashima A, Yumura W, Kabaya T, Nihei H (2003) The progression of vascular calcification and serum osteoprotegerin levels in patients on long-term hemodialysis. Am J Kidney Dis 42:303–309

    Article  CAS  PubMed  Google Scholar 

  30. Hofbauer LC, Schoppet M (2001) Osteoprotegerin: a link between osteoporosis and arterial calcification? Lancet 358:257–258

    Article  CAS  PubMed  Google Scholar 

  31. Dudley AT, Lyons KM, Robertson EJ (1995) A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Genes Dev 9:2795–2807

    CAS  PubMed  Google Scholar 

  32. Dorai H, Vukicevic S, Sampath TK (2000) Bone morphogenetic protein-7 (osteogenic protein-1) inhibits smooth muscle cell proliferation and stimulates the expression of markers that are characteristic of SMC phenotype in vitro. J Cell Physiol 184:37–45

    Article  CAS  Google Scholar 

  33. Wang SN, Lapage J, Hirschberg R (2001) Loss of tubular bone morphogenetic protein-7 in diabetic nephropathy. J Am Soc Nephrol 12:2392–2399

    CAS  PubMed  Google Scholar 

  34. Davies MR, Lund RJ, Hruska KA (2003) BMP-7 is an efficacious treatment of vascular calcification in a murine model of atherosclerosis and chronic renal failure. J Am Soc Nephrol 14:1559–1567

    PubMed  Google Scholar 

  35. Ho AM, Johnson MD, Kingsley DM (2000) Role of the mouse ank gene in control of tissue calcification and arthritis. Science 289:265–270

    Article  CAS  PubMed  Google Scholar 

  36. Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, Hohne W, Schauer G, Lehmann M, Roscioli T, Schnabel D, Epplen JT, Knisely A, Superti-Furga A, McGill J, Filippone M, Sinaiko AR, Vallance H, Hinrichs B, Smith W, Ferre M, Terkeltaub R, Nurnberg P (2003) Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet 34:379–381

    Article  CAS  PubMed  Google Scholar 

  37. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390:45–51

    Article  CAS  PubMed  Google Scholar 

  38. Arking DE, Krebsova A, Macek M Sr, Macek M Jr, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC (2002) Association of human aging with a functional variant of klotho. Proc Natl Acad Sci USA 99:856–861

    Article  CAS  PubMed  Google Scholar 

  39. Arking DE, Becker DM, Yanek LR, Fallin D, Judge DP, Moy TF, Becker LC, Dietz HC (2003) KLOTHO allele status and the risk of early-onset occult coronary artery disease. Am J Hum Genet 72:1154–1161

    Google Scholar 

  40. Nabeshima Y (2002) Klotho: a fundamental regulator of aging. Ageing Res Rev 1:627–638

    Article  CAS  PubMed  Google Scholar 

  41. Lindner A, Charra B, Sherrard DJ, Scribner BH (1974) Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 290:697–701

    CAS  PubMed  Google Scholar 

  42. Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C (1999) Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 55:648–658

    Article  CAS  PubMed  Google Scholar 

  43. Wang AY, Woo J, Lam CW, Wang M, Sea MM, Lui SF, Li PK, Sanderson J (2003) Is a single time point C-reactive protein predictive of outcome in peritoneal dialysis patients? J Am Soc Nephrol 14:1871–1879

    CAS  PubMed  Google Scholar 

  44. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR (2002) Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 347:1557–1565

    Article  CAS  PubMed  Google Scholar 

  45. London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H (2003) Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 18:1731–1740

    Article  PubMed  Google Scholar 

  46. Wang AY, Woo J, Wang M, Sea MM, Ip R, Li PK, Lui SF, Sanderson JE (2001) Association of inflammation and malnutrition with cardiac valve calcification in continuous ambulatory peritoneal dialysis patients. J Am Soc Nephrol 12:1927–1936

    CAS  PubMed  Google Scholar 

  47. Asanuma Y, Oeser A, Shintani AK, Turner E, Olsen N, Fazio S, Linton MF, Raggi P, Stein CM (2003) Premature coronary-artery atherosclerosis in systemic lupus erythematosus. N Engl J Med 349:2407–2415

    Article  CAS  PubMed  Google Scholar 

  48. Tintut Y, Patel J, Parhami F, Demer LL (2000) Tumor necrosis factor-alpha promotes in vitro calcification of vascular cells via the cAMP pathway. Circulation 102:2636–2642

    CAS  PubMed  Google Scholar 

  49. Tintut Y, Patel J, Territo M, Saini T, Parhami F, Demer LL (2002) Monocyte/macrophage regulation of vascular calcification in vitro. Circulation 105:650–655

    Article  CAS  PubMed  Google Scholar 

  50. Cheng X, Kinosaki M, Takami M, Choi Y, Zhang H, Murali R (2004) Disabling of receptor activator of nuclear factor-kappaB (RANK) receptor complex by novel osteoprotegerin-like peptidomimetics restores bone loss in vivo. J Biol Chem 279:8269–8277

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

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

    Markus Ketteler, Ralf Westenfeld, Georg Schlieper, Vincent Brandenburg & Jürgen Floege

Authors
  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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  5. Jürgen Floege
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Corresponding author

Correspondence to Markus Ketteler.

Additional information

This work was presented in part at the IPNA Seventh Symposium on Growth and Development in Children with Chronic Kidney Disease: The Molecular Basis of Skeletal Growth, 1–3 April 2004, Heidelberg, Germany

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Ketteler, M., Westenfeld, R., Schlieper, G. et al. “Missing” inhibitors of calcification: general aspects and implications in renal failure. Pediatr Nephrol 20, 383–388 (2005). https://doi.org/10.1007/s00467-004-1614-x

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  • DOI: https://doi.org/10.1007/s00467-004-1614-x

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