Biology of vascular calcification in chronic kidney disease
- Behdad Afzali, MRCP, PhD, PGDip, FHEA, MAcadMEd
Behdad Afzali, MRCP, PhD, PGDip, FHEA, MAcadMEd
- Wellcome Trust Intermediate Research Fellow
- King's College Honorary Consultant Nephrologist
- Guy's and St Thomas's Hospitals, NHS Trust, UK
- Guest Researcher, National Institutes of Health, USA
- David JA Goldsmith, MA, FRCP
David JA Goldsmith, MA, FRCP
- Department of Nephrology and Transplantation
- Guy's Hospital, London
The most common cause of death in chronic kidney disease (CKD) patients is cardiovascular disease (CVD), often related to sudden cardiac death (SCD). (See "Myocardial dysfunction in end-stage renal disease" and "Evaluation of sudden cardiac arrest and sudden cardiac death in dialysis patients".)
It is hypothesized that SCD is related, at least in part, to excess vascular calcification (VC), particularly in the form of extensive coronary artery calcification (CAC) affecting epicardial and smaller arteries [1-4]. (See "Patient survival and maintenance dialysis" and "Diagnostic and prognostic implications of coronary artery calcification detected by computed tomography".)
Vascular or valvular arterial calcifications may also contribute to microembolic disease, an increased risk of cardiac valvular dysfunction and infection (endocarditis), and surgical difficulties placing an arteriovenous fistula or transplanting a kidney.
This topic reviews the definition and pathogenesis of VC, particularly CAC, in dialysis patients. Risk factors, epidemiology, and clinical implications of VC in renal disease are discussed separately. (See "Vascular calcification in chronic kidney disease".)
All large and medium-sized muscular arteries and arterioles can calcify. By comparison, veins hardly ever undergo calcification, unless injured or arterialized . As examples, calcification associated with arteriolization may occur after coronary artery bypass grafting or arteriovenous fistula formation or in the pulmonary arterial tree of patients with pulmonary hypertension .
- Braun J, Oldendorf M, Moshage W, et al. Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis 1996; 27:394.
- Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000; 342:1478.
- Chertow GM, Burke SK, Raggi P, Treat to Goal Working Group. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 2002; 62:245.
- London GM, Guérin AP, Marchais SJ, et al. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 2003; 18:1731.
- Leu HJ, Brunner U. [Calcified and ossified phlebosclerosis]. Vasa 1992; 21:11.
- Smith JC, Stanton LW, Kramer NC, Parrish AE. Nodular pulmonary calcification in renal failure. Report of a case. Am Rev Respir Dis 1969; 100:723.
- Jablonski KL, Chonchol M. Vascular calcification in end-stage renal disease. Hemodial Int 2013; 17 Suppl 1:S17.
- Mohler ER 3rd. Vascular calcification: good, bad or ugly? Vasc Med 2002; 7:161.
- Virchow R. Kalk metastasen. Virchows Arch F Path Anat 1855; 8:103.
- Shantouf R, Kovesdy CP, Kim Y, et al. Association of serum alkaline phosphatase with coronary artery calcification in maintenance hemodialysis patients. Clin J Am Soc Nephrol 2009; 4:1106.
- Ahmed S, O'Neill KD, Hood AF, et al. Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells. Am J Kidney Dis 2001; 37:1267.
- Moe SM, O'Neill KD, Duan D, et al. Medial artery calcification in ESRD patients is associated with deposition of bone matrix proteins. Kidney Int 2002; 61:638.
- Cozzolino M, Gallieni M, Brancaccio D. Vascular calcification in uremic conditions: new insights into pathogenesis. Semin Nephrol 2006; 26:33.
- Fukagawa M, Kazama JJ. The making of a bone in blood vessels: from the soft shell to the hard bone. Kidney Int 2007; 72:533.
- Nakahara T, Kawai-Kowase K, Matsui H, et al. Fibroblast growth factor 23 inhibits osteoblastic gene expression and induces osteoprotegerin in vascular smooth muscle cells. Atherosclerosis 2016; 253:102.
- Hu MC, Shi M, Zhang J, et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 2011; 22:124.
- Mencke R, Hillebrands JL, NIGRAM consortium. The role of the anti-ageing protein Klotho in vascular physiology and pathophysiology. Ageing Res Rev 2016.
- Lindberg K, Olauson H, Amin R, et al. Arterial klotho expression and FGF23 effects on vascular calcification and function. PLoS One 2013; 8:e60658.
- Rutsch F, Nitschke Y, Terkeltaub R. Genetics in arterial calcification: pieces of a puzzle and cogs in a wheel. Circ Res 2011; 109:578.
- Mathew S, Lund RJ, Strebeck F, et al. Reversal of the adynamic bone disorder and decreased vascular calcification in chronic kidney disease by sevelamer carbonate therapy. J Am Soc Nephrol 2007; 18:122.
- Stubbs JR, Liu S, Tang W, et al. Role of hyperphosphatemia and 1,25-dihydroxyvitamin D in vascular calcification and mortality in fibroblastic growth factor 23 null mice. J Am Soc Nephrol 2007; 18:2116.
- Jono S, McKee MD, Murry CE, et al. Phosphate regulation of vascular smooth muscle cell calcification. Circ Res 2000; 87:E10.
- Huybers S, Bindels RJ. Vascular calcification in chronic kidney disease: new developments in drug therapy. Kidney Int 2007; 72:663.
- Slatopolsky E, Martin K, Hruska K. Parathyroid hormone metabolism and its potential as a uremic toxin. Am J Physiol 1980; 239:F1.
- Garcia de la Torre N, Wass JA, Turner HE. Parathyroid adenomas and cardiovascular risk. Endocr Relat Cancer 2003; 10:309.
- Vestergaard P, Mollerup CL, Frøkjaer VG, et al. Cardiovascular events before and after surgery for primary hyperparathyroidism. World J Surg 2003; 27:216.
- Neves KR, Graciolli FG, dos Reis LM, et al. Vascular calcification: contribution of parathyroid hormone in renal failure. Kidney Int 2007; 71:1262.
- Covic A, Kothawala P, Bernal M, et al. Systematic review of the evidence underlying the association between mineral metabolism disturbances and risk of all-cause mortality, cardiovascular mortality and cardiovascular events in chronic kidney disease. Nephrol Dial Transplant 2009; 24:1506.
- Shroff RC, McNair R, Skepper JN, et al. Chronic mineral dysregulation promotes vascular smooth muscle cell adaptation and extracellular matrix calcification. J Am Soc Nephrol 2010; 21:103.
- Tukaj C, Kubasik-Juraniec J, Kraszpulski M. Morphological changes of aortal smooth muscle cells exposed to calcitriol in culture. Med Sci Monit 2000; 6:668.
- Shioi A, Mori K, Jono S, et al. Mechanism of atherosclerotic calcification. Z Kardiol 2000; 89 Suppl 2:75.
- Duguid JB. Vitamin D sclerosis in the rat's aorta. J Path 1933; 33:697.
- Lopez I, Mendoza FJ, Aguilera-Tejero E, et al. The effect of calcitriol, paricalcitol, and a calcimimetic on extraosseous calcifications in uremic rats. Kidney Int 2008; 73:300.
- Goldsmith DJ, Covic A, Sambrook PA, Ackrill P. Vascular calcification in long-term haemodialysis patients in a single unit: a retrospective analysis. Nephron 1997; 77:37.
- EISENSTEIN R, ZERUOLIS L. VITAMIN D-INDUCED AORTIC CALCIFICATION. Arch Pathol 1964; 77:27.
- Mallick NP, Berlyne GM. Arterial calcification after vitamin-D therapy in hyperphosphatemic renal failure. Lancet 1968; 2:1316.
- Irnell L. Metastatic calcification of soft tissue on overdosage of vitamin D. Acta Med Scand 1969; 185:147.
- Milliner DS, Zinsmeister AR, Lieberman E, Landing B. Soft tissue calcification in pediatric patients with end-stage renal disease. Kidney Int 1990; 38:931.
- Braam LA, Hoeks AP, Brouns F, et al. Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study. Thromb Haemost 2004; 91:373.
- Jono S, Nishizawa Y, Shioi A, Morii H. 1,25-Dihydroxyvitamin D3 increases in vitro vascular calcification by modulating secretion of endogenous parathyroid hormone-related peptide. Circulation 1998; 98:1302.
- Drissi H, Pouliot A, Koolloos C, et al. 1,25-(OH)2-vitamin D3 suppresses the bone-related Runx2/Cbfa1 gene promoter. Exp Cell Res 2002; 274:323.
- Mizobuchi M, Finch JL, Martin DR, Slatopolsky E. Differential effects of vitamin D receptor activators on vascular calcification in uremic rats. Kidney Int 2007; 72:709.
- Tamashiro M, Iseki K, Sunagawa O, et al. Significant association between the progression of coronary artery calcification and dyslipidemia in patients on chronic hemodialysis. Am J Kidney Dis 2001; 38:64.
- Achenbach S, Ropers D, Pohle K, et al. Influence of lipid-lowering therapy on the progression of coronary artery calcification: a prospective evaluation. Circulation 2002; 106:1077.
- Parhami F, Basseri B, Hwang J, et al. High-density lipoprotein regulates calcification of vascular cells. Circ Res 2002; 91:570.
- Nitta K, Ishizuka T, Horita S, et al. Soluble osteopontin and vascular calcification in hemodialysis patients. Nephron 2001; 89:455.
- Westenfeld R, Schäfer C, Krüger T, et al. Fetuin-A protects against atherosclerotic calcification in CKD. J Am Soc Nephrol 2009; 20:1264.
- Jersmann HP, Dransfield I, Hart SP. Fetuin/alpha2-HS glycoprotein enhances phagocytosis of apoptotic cells and macropinocytosis by human macrophages. Clin Sci (Lond) 2003; 105:273.
- Proudfoot D, Shanahan CM. Biology of calcification in vascular cells: intima versus media. Herz 2001; 26:245.
- Price PA, Lim JE. The inhibition of calcium phosphate precipitation by fetuin is accompanied by the formation of a fetuin-mineral complex. J Biol Chem 2003; 278:22144.
- Price PA, Nguyen TM, Williamson MK. Biochemical characterization of the serum fetuin-mineral complex. J Biol Chem 2003; 278:22153.
- 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. Kidney Int 2005; 67:2383.
- Ketteler M, Wanner C, Metzger T, et al. Deficiencies of calcium-regulatory proteins in dialysis patients: a novel concept of cardiovascular calcification in uremia. Kidney Int Suppl 2003; :S84.
- Oh J, Wunsch R, Turzer M, et al. Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure. Circulation 2002; 106:100.
- Stompór T, Pasowicz M, Sulłowicz W, et al. An association between coronary artery calcification score, lipid profile, and selected markers of chronic inflammation in ESRD patients treated with peritoneal dialysis. Am J Kidney Dis 2003; 41:203.
- 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 cross-sectional study. Lancet 2003; 361:827.
- 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.
- Coen G, Manni M, Agnoli A, et al. Cardiac calcifications: Fetuin-A and other risk factors in hemodialysis patients. ASAIO J 2006; 52:150.
- Hermans MM, Brandenburg V, Ketteler M, et al. Association of serum fetuin-A levels with mortality in dialysis patients. Kidney Int 2007; 72:202.
- Ketteler M, Vermeer C, Wanner C, et al. Novel insights into uremic vascular calcification: role of matrix Gla protein and alpha-2-Heremans Schmid glycoprotein/fetuin. Blood Purif 2002; 20:473.
- Zannettino AC, Holding CA, Diamond P, et al. Osteoprotegerin (OPG) is localized to the Weibel-Palade bodies of human vascular endothelial cells and is physically associated with von Willebrand factor. J Cell Physiol 2005; 204:714.
- Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circ Res 2004; 95:1046.
- Stenvinkel P, Ketteler M, Johnson RJ, et al. IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia--the good, the bad, and the ugly. Kidney Int 2005; 67:1216.
- Moe SM, Reslerova M, Ketteler M, et al. Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD). Kidney Int 2005; 67:2295.
- O'Neill WC, Sigrist MK, McIntyre CW. Plasma pyrophosphate and vascular calcification in chronic kidney disease. Nephrol Dial Transplant 2010; 25:187.
- Davies MR, Hruska KA. Pathophysiological mechanisms of vascular calcification in end-stage renal disease. Kidney Int 2001; 60:472.
- Atkinson J. [Aging of arterial extracellular matrix elastin: etiology and consequences]. Pathol Biol (Paris) 1998; 46:555.
- Atkinson J. Arterial calcification. Mechanisms, consequences and animal models. Pathol Biol (Paris) 1999; 47:677.
- Moe SM, Duan D, Doehle BP, et al. Uremia induces the osteoblast differentiation factor Cbfa1 in human blood vessels. Kidney Int 2003; 63:1003.