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Mechanisms and treatment of extraosseous calcification in chronic kidney disease

Nature Reviews Nephrology volume 7, pages 509–516 (2011)Cite this article

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Abstract

Strong and unidirectional associations exist between the severity of cardiovascular calcifications and mortality in patients with advanced chronic kidney disease. In the past 10 years, a wealth of experimental and clinical information has been published on the key pathophysiological events that contribute to the development and progression of vascular and soft-tissue calcifications. These processes involve a sensitive balance of calcification inhibition, induction and removal. The traditional view of regarding secondary hyperparathyroidism and elevated calcium × phosphate product as the pivotal risk factors for calcification has been challenged by data demonstrating a role for other, more subtle and complex pathomechanisms. These mechanisms include the loss of endogenous calcification inhibitors, deficient clearance of calcified debris, effects of vitamin K and vitamin D, and the action of calcification inducers as in osteogenic transdifferentiation. In this Review, we describe our current knowledge of the factors involved in the passive and active regulation of extraosseous calcification processes, with an assessment of their importance as targets for future diagnostic and therapeutic interventions.

Key Points

  • Extraosseous calcification is highly prevalent in patients with chronic kidney disease and may contribute to impaired outcomes

  • Defective clearance mechanisms of calcified debris, such as fetuin-A-dependent calciprotein particles, may contribute to increased calcification and serve as a future therapeutic target

  • Both phosphate and calcium contribute to osteogenic transdifferentiation in the vessel wall and serum levels of these elements should thus be closely controlled in patients with chronic kidney disease

  • Vitamin D and vitamin K have been linked to the regulation of calcification mechanisms, and controlled supplementation of these vitamins may be required in patients with chronic kidney disease

  • Drugs with anticalcific therapeutic potential include sodium thiosulfate, bisphosphonates and calcimimetics, which intervene with extraosseous calcification processes through various molecular mechanisms

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Figure 1: Microcalcifications from a uremic iliac artery visualized by transmission electron microscopy.
Figure 2: Centrifugation procedure of FMC purification from human blood.
Figure 3: The two forms of vitamin K, vitamin K1 (phylloquinone, mainly derived from vegetables) and vitamin K2 (menaquinone, mainly derived from fermented food such as cheese), are differentially distributed in the body.

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References

  1. Goodman, W. G. et al. for the Vascular Calcification Work Group. Vascular calcification in chronic kidney disease. Am. J. Kidney Dis. 43, 572–579 (2004).

    Article  Google Scholar 

  2. Ketteler, M., Schlieper, G. & Floege, J. Calcification and cardiovascular health: new insights into an old phenomenon. Hypertension 47, 1027–1034 (2006).

    Article  CAS  Google Scholar 

  3. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int. Suppl. 113, S1–S130 (2009).

  4. Guérin, A. P., Pannier, B., Métivier, F., Marchais, S. J. & London, G. M. Assessment and significance of arterial stiffness in patients with chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 17, 635–641 (2008).

    Article  Google Scholar 

  5. Ohara, T., Hashimoto, Y., Matsumura, A., Suzuki, M. & Isobe, M. Accelerated progression and morbidity in patients with aortic stenosis on chronic dialysis. Circ. J. 69, 1535–1539 (2005).

    Article  Google Scholar 

  6. Schlieper, G. et al. Ultrastructural analysis of vascular calcifications in uremia. J. Am. Soc. Nephrol. 21, 689–696 (2010).

    Article  CAS  Google Scholar 

  7. Price, P. A. & Lim, J. E. The inhibition of calcium phosphate precipitation by fetuin is accompanied by the formation of a fetuin-mineral complex. J. Biol. Chem. 278, 22144–22152 (2003).

    Article  CAS  Google Scholar 

  8. Price, P. A., Williamson, M. K., Nguyen, T. M. & Than, T. N. Serum levels of the fetuin-mineral complex correlate with artery calcification in the rat. J. Biol. Chem. 279, 1594–1600 (2004).

    Article  CAS  Google Scholar 

  9. Heiss, A. et al. Hierarchical role of fetuin-A and acidic serum proteins in the formation and stabilization of calcium phosphate particles. J. Biol. Chem. 283, 14815–14825 (2008).

    Article  CAS  Google Scholar 

  10. Hamano, T. et al. Fetuin-mineral complex reflects extraosseous calcification stress in CKD. J. Am. Soc. Nephrol. 21, 1998–2007 (2010).

    Article  CAS  Google Scholar 

  11. Matsui, I. et al. Fully phosphorylated fetuin-A forms a mineral complex in the serum of rats with adenine-induced renal failure. Kidney Int. 75, 915–928 (2009).

    Article  CAS  Google Scholar 

  12. Ketteler, M. et al. Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 361, 827–833 (2003).

    Article  CAS  Google Scholar 

  13. Stenvinkel, P. et al. Low fetuin-A levels are associated with cardiovascular death: impact of variations in the gene encoding fetuin. Kidney Int. 67, 2383–2392 (2005).

    Article  CAS  Google Scholar 

  14. Wang, A. Y. et al. Associations of serum fetuin-A with malnutrition, inflammation, atherosclerosis and valvular calcification syndrome and outcome in peritoneal dialysis patients. Nephrol. Dial. Transplant. 20, 1676–1685 (2005).

    Article  CAS  Google Scholar 

  15. Mehrotra, R. et al. Serum fetuin-A in nondialyzed patients with diabetic nephropathy: relationship with coronary artery calcification. Kidney Int. 67, 1070–1077 (2005).

    Article  CAS  Google Scholar 

  16. Ix, J. H. et al. Fetuin-A is not associated with mortality in chronic kidney disease. Kidney Int. 72, 1394–1399 (2007).

    Article  CAS  Google Scholar 

  17. Jahnen-Dechent, W., Schäfer, C., Ketteler, M. & McKee, M. D. Mineral chaperones: a role for fetuin-A and osteopontin in the inhibition and regression of pathologic calcification. J. Mol. Med. 86, 379–389 (2008).

    Article  CAS  Google Scholar 

  18. Lebreton, J. P. et al. 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 (1979).

    Article  CAS  Google Scholar 

  19. Brandenburg, V. M. et al. Serological cardiovascular and mortality risk predictors in dialysis patients receiving sevelamer: a prospective study. Nephrol. Dial. Transplant. 25, 2672–2679 (2010).

    Article  CAS  Google Scholar 

  20. Caglar, K. et al. Short-term treatment with sevelamer increases serum fetuin-A concentration and improves endothelial dysfunction in chronic kidney disease stage 4 patients. Clin. J. Am. Soc. Nephrol. 3, 61–68 (2008).

    Article  CAS  Google Scholar 

  21. Jono, S. et al. Phosphate regulation of vascular smooth muscle cell calcification. Circ. Res. 87, E10–E17 (2000).

    Article  CAS  Google Scholar 

  22. Giachelli, C. M. The emerging role of phosphate in vascular calcification. Kidney Int. 75, 890–897 (2009).

    Article  CAS  Google Scholar 

  23. Reynolds, J. L. et al. Multifunctional roles for serum protein fetuin-A in inhibition of human vascular smooth muscle cell calcification. J. Am. Soc. Nephrol. 16, 2920–2930 (2005).

    Article  CAS  Google Scholar 

  24. Moe, S. M. et al. Medial artery calcification in ESRD patients is associated with deposition of bone matrix proteins. Kidney Int. 61, 638–647 (2002).

    Article  Google Scholar 

  25. Moe, S. M., Duan, D., Doehle, B. P., O'Neill, K. D. & Chen, N. X. Uremia induces the osteoblast differentiation factor Cbfa1 in human blood vessels. Kidney Int. 63, 1003–1011 (2003).

    Article  CAS  Google Scholar 

  26. Shroff, R. C. et al. Chronic mineral dysregulation promotes vascular smooth muscle cell adaptation and extracellular matrix calcification. J. Am. Soc. Nephrol. 21, 103–112 (2010).

    Article  CAS  Google Scholar 

  27. van den Broek, F. A. & Beynen, A. C. The influence of dietary phosphorus and magnesium concentrations on the calcium content of heart and kidneys of DBA/2 and NMRI mice. Lab. Anim. 32, 483–491 (1998).

    Article  CAS  Google Scholar 

  28. Schafer, C. et al. The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J. Clin. Invest. 112, 357–366 (2003).

    Article  Google Scholar 

  29. Meema, H. E., Oreopoulos, D. G. & Rapoport, A. Serum magnesium level and arterial calcification in end-stage renal disease. Kidney Int. 32, 388–394 (1987).

    Article  CAS  Google Scholar 

  30. Tzanakis, I. et al. Intra- and extracellular magnesium levels and atheromatosis in haemodialysis patients. Magnes. Res. 17, 102–108 (2004).

    CAS  PubMed  Google Scholar 

  31. Ishimura, E. et al. Significant association between the presence of peripheral vascular calcification and lower serum magnesium in hemodialysis patients. Clin. Nephrol. 68, 222–227 (2007).

    Article  CAS  Google Scholar 

  32. de Francisco, A. L. et al. Evaluation of calcium acetate/magnesium carbonate as a phosphate binder compared with sevelamer hydrochloride in haemodialysis patients: a controlled randomized study (CALMAG study) assessing efficacy and tolerability. Nephrol. Dial. Transplant. 25, 3707–3717 (2010).

    Article  CAS  Google Scholar 

  33. Krueger, T., Westenfeld, R., Ketteler, M., Schurgers, L. J. & Floege, J. Vitamin K deficiency in CKD patients: a modifiable risk factor for vascular calcification? Kidney Int. 76, 18–22 (2009).

    Article  CAS  Google Scholar 

  34. Luo, G. et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 386, 78–81 (1997).

    Article  CAS  Google Scholar 

  35. Murshed, M., Schinke, T., McKee, M. D. & Karsenty, G. Extracellular matrix mineralization is regulated locally; different roles of two gla-containing proteins. J. Cell Biol. 165, 625–630 (2004).

    Article  CAS  Google Scholar 

  36. Schurgers, L. J. et al. Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats. Blood 109, 2823–2831 (2007).

    Article  CAS  Google Scholar 

  37. Koos, R. et al. Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography. Am. J. Cardiol. 96, 747–749 (2005).

    Article  CAS  Google Scholar 

  38. Wilmer, W. A. & Magro, C. M. Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment. Semin. Dial. 15, 172–186 (2002).

    Article  Google Scholar 

  39. Schlieper, G. et al. Circulating nonphosphorylated carboxylated matrix gla protein predicts survival in ESRD. J. Am. Soc. Nephrol. 22, 387–395 (2011).

    Article  CAS  Google Scholar 

  40. Parker, B. D. et al. The associations of fibroblast growth factor 23 and uncarboxylated matrix Gla protein with mortality in coronary artery disease: the Heart and Soul Study. Ann. Intern. Med. 152, 640–648 (2010).

    Article  Google Scholar 

  41. Schurgers, L. J. et al. The circulating inactive form of matrix gla protein is a surrogate marker for vascular calcification in chronic kidney disease: a preliminary report. Clin. J. Am. Soc. Nephrol. 5, 568–575 (2010).

    Article  CAS  Google Scholar 

  42. Cranenburg, E. C., Schurgers, L. J. & Vermeer, C. Vitamin K: the coagulation vitamin that became omnipotent. Thromb. Haemost. 98, 120–125 (2007).

    Article  CAS  Google Scholar 

  43. Nakagawa, K. et al. Identification of UBIAD1 as a novel menaquinone-4 biosynthetic enzyme. Nature 468, 117–121 (2010).

    Article  CAS  Google Scholar 

  44. Chan, K. E., Lazarus, J. M., Thadhani, R. & Hakim, R. M. Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation. J. Am. Soc. Nephrol. 20, 2223–2233 (2009).

    Article  CAS  Google Scholar 

  45. Price, P. A., Omid, N., Than, T. N. & Williamson, M. K. The amino bisphosphonate ibandronate prevents calciphylaxis in the rat at doses that inhibit bone resorption. Calcif. Tissue Int. 71, 356–363 (2002).

    Article  CAS  Google Scholar 

  46. Haffner, D. et al. Systemic cardiovascular disease in uremic rats induced by 1,25(OH)2D3. J. Hypertens. 23, 1067–1075 (2005).

    Article  CAS  Google Scholar 

  47. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am. J. Kidney Dis. 42 (Suppl. 3), S1–S201 (2003).

  48. Mizobuchi, M., Finch, J. L., Martin, D. R. & Slatopolsky, E. Differential effects of vitamin D receptor activators on vascular calcification in uremic rats. Kidney Int. 72, 709–715 (2007).

    CAS  Google Scholar 

  49. Mathew, S., Lund, R. J., Chaudhary, L. R., Geurs, T. & Hruska, K. A. Vitamin D receptor activators can protect against vascular calcification. J. Am. Soc. Nephrol. 19, 1509–1519 (2008).

    Article  CAS  Google Scholar 

  50. Francis, M. D., Russell, R. G. & Fleisch, H. Diphosphonates inhibit formation of calcium phosphate crystals in vitro and pathological calcification in vivo. Science 165, 1264–1266 (1969).

    Article  CAS  Google Scholar 

  51. Towler, D. A. Inorganic pyrophosphate: a paracrine regulator of vascular calcification and smooth muscle phenotype. Arterioscler. Thromb. Vasc. Biol. 25, 651–654 (2005).

    Article  CAS  Google Scholar 

  52. Okawa, A. et al. Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine. Nat. Genet. 19, 271–273 (1998).

    Article  CAS  Google Scholar 

  53. Ho, A. M., Johnson, M. D. & Kingsley, D. M. Role of the mouse ank gene in control of tissue calcification and arthritis. Science 289, 265–270 (2000).

    Article  CAS  Google Scholar 

  54. Rutsch, F. et al. Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification. Nat. Genet. 34, 379–381 (2003).

    Article  CAS  Google Scholar 

  55. O'Neill, W. C., Sigrist, M. K. & McIntyre, C. W. Plasma pyrophosphate and vascular calcification in chronic kidney disease. Nephrol. Dial. Transplant. 25, 187–191 (2010).

    Article  CAS  Google Scholar 

  56. O'Neill, W. C., Lomashvili, K. A., Malluche, H. H., Faugere, M. C. & Riser, B. L. Treatment with pyrophosphate inhibits uremic vascular calcification. Kidney Int. 79, 512–517 (2011).

    Article  CAS  Google Scholar 

  57. van der Sluis, I. M., Boot, A. M., Vernooij, M., Meradji, M. & Kroon, A. A. Idiopathic infantile arterial calcification: clinical presentation, therapy and long-term follow-up. Eur. J. Pediatr. 165, 590–593 (2006).

    Article  Google Scholar 

  58. Nitta, K. et al. Effects of cyclic intermittent etidronate therapy on coronary artery calcification in patients receiving long-term hemodialysis. Am. J. Kidney Dis. 44, 680–688 (2004).

    Article  CAS  Google Scholar 

  59. Monney, P., Nguyen, Q. V., Perroud, H. & Descombes, E. Rapid improvement of calciphylaxis after intravenous pamidronate therapy in a patient with chronic renal failure. Nephrol. Dial. Transplant. 19, 2130–2132 (2004).

    Article  Google Scholar 

  60. St Hilaire, C. et al. NT5E mutations and arterial calcifications. N. Engl. J. Med. 364, 432–442 (2011).

    Article  CAS  Google Scholar 

  61. Schlieper, G., Brandenburg, V., Ketteler, M. & Floege, J. Sodium thiosulfate in the treatment of calcific uremic arteriolopathy. Nat. Rev. Nephrol. 5, 539–543 (2009).

    Article  CAS  Google Scholar 

  62. Meade, D. et al. Sodium thiosulfate therapy for calciphylaxis in hemodialysis patients [abstract]. American Society of Nephrology Renal Week TH-PO459 (2010).

  63. Pasch, A. et al. Sodium thiosulfate prevents vascular calcifications in uremic rats. Kidney Int. 74, 1444–1453 (2008).

    Article  CAS  Google Scholar 

  64. Adirekkiat, S. et al. Sodium thiosulfate delays the progression of coronary artery calcification in haemodialysis patients. Nephrol. Dial. Transplant. 25, 1923–1929 (2010).

    Article  CAS  Google Scholar 

  65. Mathews, S. J. et al. Effects of sodium thiosulfate on vascular calcification in end-stage renal disease: a pilot study of feasibility, safety and efficacy. Am. J. Nephrol. 33, 131–138 (2011).

    Article  CAS  Google Scholar 

  66. O'Neill, W. C., Hardcastle, K. & Dubyak, G. R. Thiosulfate inhibits vascular calcification in vitro independent of interactions with calcium or hydroxyapatite [abstract]. American Society of Nephrology Renal Week TH-PO131 (2010).

  67. Block, G. A. et al. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N. Engl. J. Med. 350, 1516–1525 (2004).

    Article  CAS  Google Scholar 

  68. Henley, C. et al. The calcimimetic AMG 641 abrogates parathyroid hyperplasia, bone and vascular calcification abnormalities in uremic rats. Eur. J. Pharmacol. 616, 306–313 (2009).

    Article  CAS  Google Scholar 

  69. Lopez, I. et al. Calcimimetic R-568 decreases extraosseous calcifications in uremic rats treated with calcitriol. J. Am. Soc. Nephrol. 17, 795–804 (2006).

    Article  CAS  Google Scholar 

  70. Lopez, I. et al. The effect of calcitriol, paricalcitol, and a calcimimetic on extraosseous calcifications in uremic rats. Kidney Int. 73, 300–307 (2008).

    Article  CAS  Google Scholar 

  71. Lopez, I. et al. The calcimimetic AMG 641 accelerates regression of extraosseous calcification in uremic rats. Am. J. Physiol. Renal Physiol. 296, F1376–F1385 (2009).

    Article  CAS  Google Scholar 

  72. Raggi, P. et al. for the ADVANCE Study Group. The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis. Nephrol. Dial. Transplant. 26, 1327–1339 (2010).

    Article  Google Scholar 

  73. Chertow, G. M. et al. Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE): rationale and design overview. Clin. J. Am. Soc. Nephrol. 2, 898–905 (2007).

    Article  CAS  Google Scholar 

  74. Shroff, R. C. et al. Dialysis accelerates medial vascular calcification in part by triggering smooth muscle cell apoptosis. Circulation 118, 1748–1757 (2008).

    Article  CAS  Google Scholar 

  75. Hofmann Bowman, M. A. et al. S100A12 in vascular smooth muscle accelerates vascular calcification in apolipoprotein E-null mice by activating an osteogenic gene regulatory program. Arterioscler. Thromb. Vasc. Biol. 31, 337–344 (2011).

    Article  CAS  Google Scholar 

  76. Shiotsu, Y. et al. Plasma S100A12 level is associated with cardiovascular disease in hemodialysis patients. Clin. J. Am. Soc. Nephrol. 6, 718–723 (2011).

    Article  CAS  Google Scholar 

  77. Wolf, M. Forging forward with 10 burning questions on FGF23 in kidney disease. J. Am. Soc. Nephrol. 21, 1427–1435 (2010).

    Article  CAS  Google Scholar 

  78. Van Campenhout, A. & Golledge, J. Osteoprotegerin, vascular calcification and atherosclerosis. Atherosclerosis 204, 321–329 (2009).

    Article  CAS  Google Scholar 

  79. Mathew, S. et al. The mechanism of phosphorus as a cardiovascular risk factor in CKD. J. Am. Soc. Nephrol. 19, 1092–1105 (2008).

    Article  CAS  Google Scholar 

  80. Shao, J. S., Cheng, S. L., Sadhu, J. & Towler, D. A. Inflammation and the osteogenic regulation of vascular calcification: a review and perspective. Hypertension 55, 579–592 (2010).

    Article  CAS  Google Scholar 

  81. Pai, A., Leaf, E. M., El-Abbadi, M. & Giachelli, C. M. Elastin degradation and vascular smooth muscle cell phenotype change precede cell loss and arterial medial calcification in a uremic mouse model of chronic kidney disease. Am. J. Pathol. 178, 764–773 (2011).

    Article  CAS  Google Scholar 

  82. Tonelli, M., Sacks, F., Pfeffer, M., Gao, Z. & Curhan, G. for the Cholesterol And Recurrent Events Trial Investigators. Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation 112, 2627–2633 (2005).

    Article  CAS  Google Scholar 

  83. Dhingra, R. et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch. Intern. Med. 167, 879–885 (2007).

    Article  CAS  Google Scholar 

  84. Bolland, M. J. et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 341, c3691 (2010).

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine III, Division of Nephrology, Klinikum Coburg GmbH, Ketschendorfer Straβe 33, Coburg, 96450, Germany

    Markus Ketteler, Hansjörg Rothe & Patrick H. Biggar

  2. Department of Medicine II, Division of Nephrology and Clinical Immunology, University Hospital of the RWTH Aachen, Pauwelsstraβe 30, Aachen, 52074, Germany

    Thilo Krüger & Georg Schlieper

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M. Ketteler, P. H. Biggar and G. Schlieper wrote the article. All the authors contributed equally to researching data for the article, substantial contribution to discussion of the content, and reviewing and editing of the manuscript before submission.

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M. Ketteler has worked as a consultant for and received speakers bureau honoraria from Abbott, Amgen, Fresenius Medical Care, Genzyme and Shire, and received grant/research support from Abbott and Amgen. P. H. Biggar has received speakers bureau honoraria from Abbott, Amgen and Genzyme. G. Schlieper has received speakers bureau honoraria from Amgen, Gambro and Genzyme and received grant/research support from Genzmye. H. Rothe and T. Krüger declare no competing interests.

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Ketteler, M., Rothe, H., Krüger, T. et al. Mechanisms and treatment of extraosseous calcification in chronic kidney disease. Nat Rev Nephrol 7, 509–516 (2011). https://doi.org/10.1038/nrneph.2011.91

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