Recent progress in the treatment of vascular calcification
2010; Elsevier BV; Volume: 78; Issue: 12 Linguagem: Inglês
10.1038/ki.2010.334
ISSN1523-1755
AutoresW. Charles O’Neill, Koba A. Lomashvili,
Tópico(s)Trace Elements in Health
ResumoVascular calcification is common in patients with advanced chronic kidney disease and is associated with poorer outcomes. Although the pathophysiology is not completely understood, it is clear that it is a multifactorial process involving altered mineral metabolism, as well as changes in systemic and local factors that can promote or inhibit vascular calcification, and all of these are potential therapeutic targets. Current therapy is closely linked to strategies for preventing disordered bone and mineral metabolism in advanced kidney disease and involves lowering the circulating levels of both phosphate and calcium. The efficacy of compounds that specifically target calcification, such as bisphosphonates and thiosulfate, has been shown in animals but only in small numbers of humans, and safety remains an issue. Additional therapies, such as pyrophosphate, vitamin K, and lowering of pH, are supported by animal studies, but are yet to be investigated clinically. As the mineral composition of vascular calcifications is the same as in bone, potential effects on bone must be addressed with any therapy for vascular calcification. Vascular calcification is common in patients with advanced chronic kidney disease and is associated with poorer outcomes. Although the pathophysiology is not completely understood, it is clear that it is a multifactorial process involving altered mineral metabolism, as well as changes in systemic and local factors that can promote or inhibit vascular calcification, and all of these are potential therapeutic targets. Current therapy is closely linked to strategies for preventing disordered bone and mineral metabolism in advanced kidney disease and involves lowering the circulating levels of both phosphate and calcium. The efficacy of compounds that specifically target calcification, such as bisphosphonates and thiosulfate, has been shown in animals but only in small numbers of humans, and safety remains an issue. Additional therapies, such as pyrophosphate, vitamin K, and lowering of pH, are supported by animal studies, but are yet to be investigated clinically. As the mineral composition of vascular calcifications is the same as in bone, potential effects on bone must be addressed with any therapy for vascular calcification. Vascular calcification is restricted to arteries and occurs in two locations, the intima and the media. Although the endpoint of both is hydroxyapatite formation, the pathophysiology and clinical significance are different.1.Amann K. Media calcification and intima calcification are distinct entities in chronic kidney disease.J Am Soc Nephrol. 2008; 3: 1599-1605Crossref Scopus (119) Google Scholar (The term hydroxyapatite will be used here, even though in vivo it is primarily carbonate apatite with partial substitutions of other ions, such as Mg2+ and F−.) Intimal (actually neointimal) calcification is part of the atherosclerotic process and can occur in any person with atherosclerosis whether or not they have kidney disease. It occurs in areas devoid of smooth muscle cells and is associated with lipid, macrophages, and mast cells.2.Jeziorska M. McCollum C. Woolley D.E. Calcification in atherosclerotic plaque of human carotid arteries: associations with mast cells and macrophages.J Pathol. 1998; 185: 10-17Crossref PubMed Scopus (96) Google Scholar Medial calcification occurs in elastin fibers around smooth muscle cells in the absence of atherosclerosis or inflammation1.Amann K. Media calcification and intima calcification are distinct entities in chronic kidney disease.J Am Soc Nephrol. 2008; 3: 1599-1605Crossref Scopus (119) Google Scholar,2.Jeziorska M. McCollum C. Woolley D.E. Calcification in atherosclerotic plaque of human carotid arteries: associations with mast cells and macrophages.J Pathol. 1998; 185: 10-17Crossref PubMed Scopus (96) Google Scholar and is seen primarily in chronic renal failure or diabetes. The prevalence of medial calcification clearly increases with age,3.Reddy J. Son H. Smith S.J. et al.Prevalence of breast arterial calcifications in an ethnically diverse population of women.Ann Epidemiol. 2005; 15: 344-350Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar,4.Iribarren C. Go A.S. Tolstykh I. et al.Breast vascular calcification and risk of coronary heart disease, stroke, and heart failure.J Womens Health. 2004; 13: 381-389Crossref PubMed Google Scholar but whether this is a specific effect of age or is related to underlying diseases is unclear. The pattern of vascular involvement differs as well. Neointimal calcification is limited to the large and medium-sized conduit arteries in which atherosclerosis occurs,5.Moore S. Blood vessels and lymphatics.in: Damjanov I. Linder J. Anderson's Pathology. 10th edn. Mosby, St Louis1996: 1401Google Scholar whereas medial calcification occurs in arteries of any size, including small arteries in which atherosclerosis does not occur.6.Lachman A.S. Spray T.L. Kerwin D.M. et al.Medial Calcinosis of Monckeberg. A review of the problem and a description of a patient with involvement of peripheral, visceral and coronary arteries.Am J Med. 1977; 63: 615-622Abstract Full Text PDF PubMed Scopus (73) Google Scholar, 7.Chowdhury U.K. Airan B. Mishra P.K. et al.Histopathology and morphometry of radial artery conduits: basic study and clinical application.Ann Thorac Surg. 2004; 78: 1614-1621Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 8.Nielsen B.B. Holm N.V. Calcification in breast arteries. The frequency and severity of arterial calcification in female breast tissue without malignant changes.Acta Pathol Microbiol Immunol Scand A. 1985; 93: 13-16PubMed Google Scholar A recent autopsy study of chronic kidney disease (CKD) patients with known coronary artery disease revealed that most of the calcification was atherosclerotic with very little medial calcification,9.Nakamura S. Ishibashi-Ueda H. Niizuma S. et al.Coronary calcification in patients with chronic kidney disease and coronary artery disease.Clin J Am Soc Nephrol. 2009; 4: 1892-1900Crossref PubMed Scopus (68) Google Scholar whereas a study of mammograms (presented in abstract form) showed that breast arterial calcification (which is exclusively medial) was present in close to 70% of women with end-stage renal disease (ESRD).10.Duhn V. Johnson S.A. D'Orsi C.J. et al.Detection of medial vascular calcification in ESRD by mammography.J Am Soc Nephrol. 2008; 19 (abstract): 112AGoogle Scholar Involvement can extend to arterioles, which is observed in calcific uremic arteriolopathy (CUA), a particularly virulent form of medial calcification previously known as calciphylaxis. Although there is debate about whether the CUA has a pathophysiology distinct from medial calcification in larger vessels, it will be considered as a form of medial calcification for the purposes of this review. Renal failure increases the extent of calcification in atherosclerotic plaques,11.Schwarz U. Buzello M. Ritz E. et al.Morphology of coronary atherosclerotic lesions in patients with end-stage renal failure.Nephrol Dial Transplant. 2000; 15: 218-223Crossref PubMed Google Scholar but the effect on medial calcification is probably greater as it rarely occurs in individuals without renal insufficiency under the age of 60 years. The histological prevalence of medial calcification in radial arteries was 45-fold greater in patients with CKD compared with those without CKD,7.Chowdhury U.K. Airan B. Mishra P.K. et al.Histopathology and morphometry of radial artery conduits: basic study and clinical application.Ann Thorac Surg. 2004; 78: 1614-1621Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar and the preliminary report of breast arterial calcification showed a four-fold higher prevalence in women with ESRD compared with age-matched women without renal disease.10.Duhn V. Johnson S.A. D'Orsi C.J. et al.Detection of medial vascular calcification in ESRD by mammography.J Am Soc Nephrol. 2008; 19 (abstract): 112AGoogle Scholar Coronary artery calcification scores are almost three-fold greater in ESRD patients than in the age and sex-matched general population.12.Raggi P. Boulay A. Chasan-Taber S. et al.Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease?.J Am Coll Cardiol. 2002; 39: 695-701Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar Because the ESRD patients probably have some medial calcification as well, the increase in intimal calcification is probably less. In unselected autopsy cases, the prevalence of calcified coronary plaques was 52% in 27 patients with renal insufficiency compared with 37% in 30 subjects without CKD.13.Campean V. Neureiter D. Nonnast-Daniel B. et al.CD40-CD154 expression in calcified and non-calcified coronary lesions of patients with chronic renal failure.Atherosclerosis. 2007; 190: 156-166Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Treatment of vascular calcification in renal failure rests on the assumption that it is harmful and that a reduction will be beneficial. The morbidity of atherosclerosis is related to vascular occlusion, but it is unclear whether this is exacerbated by plaque calcification. Medial calcification does not narrow vessels, but is assumed to stiffen them,14.Blacher J. Guerin A.P. Pannier B. et al.Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease.Hypertension. 2001; 38: 938-942Crossref PubMed Google Scholar predisposing to heart failure. This is supported by the fact that heart failure is the cause of death in children with infantile arterial calcification, a disorder of severe medial calcification.15.Rutsch F. Vaingankar S. Johnson K. et al.PC-1 nucleotide triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification.Am J Pathol. 2001; 158: 543-554Abstract Full Text Full Text PDF PubMed Google Scholar Lack of arterial distensibility may also transmit greater pulse pressures to the distal arterial bed, leading to arteriolosclerosis with resulting vascular insufficiency and tissue damage.14.Blacher J. Guerin A.P. Pannier B. et al.Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease.Hypertension. 2001; 38: 938-942Crossref PubMed Google Scholar Of course, without a specific treatment, these hypotheses cannot be confirmed. Despite this, a large body of indirect data indicates poorer outcomes in patients with vascular calcification, and recent clinical trials suggest a benefit with treatment. A number of studies have shown that arterial calcification14.Blacher J. Guerin A.P. Pannier B. et al.Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease.Hypertension. 2001; 38: 938-942Crossref PubMed Google Scholar,16.London G.M. Guerin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality.Nephrol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (992) Google Scholar and progression of calcification17.Sigrist M.K. Taal M.W. Bungay P. et al.Progressive vascular calcification over 2 years is associated with arterial stiffening and increased mortality in CKD 4 and 5 patients.Clin J Am Soc Nephrol. 2007; 2: 1241-1248Crossref PubMed Scopus (138) Google Scholar correlate with cardiovascular events or death, and with hemodynamic parameters, such as pulse wave velocity. A study of new hemodialysis patients found a decrease in mortality associated with the reduced progression of coronary artery calcification (CAC) in patients treated with sevelamer compared with calcium-containing phosphate binders, suggesting a beneficial effect of treating vascular calcification.18.Block G.A. Raggi P. Bellasi A. et al.Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients.Kidney Int. 2007; 71: 438-441Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar Another study of prevalent dialysis patients treated with sevelamer found improved mortality that was not significant in the entire cohort, but was significant in predetermined subgroups.19.Suki W. Zabaneh R. Cangiano J.L. et al.Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients.Kidney Int. 2007; 72: 1130-1137Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar This mortality effect is unlikely to be explained by the reduction in low-density lipoprotein cholesterol that occurs with sevelamer since cholesterol-lowering therapy does not alter mortality in ESRD patients.20.Fellstrom B.C. Jardine A.G. Schmieder R.E. et al.Rosuvastatin and cardiovascular events in patients undergoing hemodialysis.New Eng J Med. 2009; 360: 1395-1407Crossref PubMed Scopus (0) Google Scholar,21.Wanner C. Krane V. Marz W. et al.Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.New Eng J Med. 2005; 353: 238-248Crossref PubMed Scopus (0) Google Scholar An additional, clinically important effect of vascular calcification in renal failure is the unsuitability of arteries for vascular surgery, including creation of arteriovenous fistulae and renal transplantation. Lastly, CUA is a severe, life-threatening condition. Despite the lack of definitive data, it is hard to envision that vascular calcification is not detrimental. The evaluation of therapies for vascular calcification is problematic because of the lack of good methods to quantify it. The sensitivity of the various imaging modalities that have been used is unknown and the precision can be poor. Computed tomography of the aorta or coronary arteries is commonly used and is the only modality that can yield truly quantitative results, but different scoring systems can yield different results. In addition, the progression of vascular calcification is quite variable and has a very skewed distribution so that large numbers of patients are required and statistical analyses are not straightforward. Lastly, none of the methods can reliably distinguish between atherosclerotic and medial calcification and, therefore, measure the combined changes in two different pathophysiological processes. Calcification of coronary arteries, the site most commonly studied, is mostly atherosclerotic in ESRD patients,9.Nakamura S. Ishibashi-Ueda H. Niizuma S. et al.Coronary calcification in patients with chronic kidney disease and coronary artery disease.Clin J Am Soc Nephrol. 2009; 4: 1892-1900Crossref PubMed Scopus (68) Google Scholar and any changes detected could be due to progression or regression of atherosclerosis rather than to changes in calcification. Vascular calcification and its treatment are linked to the management of the disordered bone and mineral metabolism that accompanies CKD. However, there are a number of potential therapies that directly target the calcification process. In addition to efficacy and overall safety, two important issues affect potential therapies for vascular calcification. First, is the treatment only preventative or can it reverse calcification? Second, can vascular calcification be treated without adversely affecting calcification in normal sites, such as bone and teeth? Although reversal of calcification is a desirable therapeutic goal, hydroxyapatite is extremely insoluble and stable under physiological conditions. Vascular calcifications also contain whitlockite, which is equally insoluble, and amorphous calcium phosphate, which may be more soluble.22.Verberckmoes S.C. Persy V. Behets G.J. et al.Uremia-related vascular calcification more than apatite deposition.Kidney Int. 2007; 71: 298-303Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar However, medial vascular calcification, in rats treated with calcitriol or warfarin, does regress when calcitriol is withheld23.Henley C. Davis J. Miller G. et al.The calcimimetic AMG 641 abrogates parathyroid hyperplasia, bone and vascular calcification abnormalities in uremic rats.Eur J Pharmacol. 2009; 616: 306-313Crossref PubMed Scopus (27) Google Scholar or vitamin K is supplemented,24.Schurgers L.J. Spronk H.M.H. Soute B.A.M. et al.Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats.Blood. 2007; 109: 2823-2831Crossref PubMed Scopus (104) Google Scholar indicating that there are endogenous mechanisms for the dissolution of ectopic hydroxyapatite. Whether this occurs in more longstanding calcification is unknown, but has been reported in humans,25.Verberckmoes R. Bouillon R. Krempien B. Disappearance of vascular calcifications during treatment of renal osteodystrophy. Two patients treated with high doses of vitamin D and aluminum hydroxide.Annal of Intern Med. 1975; 82: 529-533Crossref PubMed Google Scholar suggesting that prevention of calcification may eventually lead to reversal. Unwanted effects on bone is an extremely important therapeutic issue as mineralized vessels and bone are both composed of hydroxyapatite and the mechanisms of formation may be similar. Therefore, an understanding of differences between vascular calcification and bone formation is essential for targeting therapy specifically to vessels, and effects on bone must be addressed with any therapy for vascular calcification. Secondary hyperparathyroidism (sHPT) is a universal consequence of renal failure and is central in the clinical approach to disordered bone and mineral metabolism. However, it is unlikely that parathyroid hormone (PTH) itself causes vascular calcification. Serum levels do not correlate positively with vascular calcification in patients12.Raggi P. Boulay A. Chasan-Taber S. et al.Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease?.J Am Coll Cardiol. 2002; 39: 695-701Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar, 16.London G.M. Guerin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality.Nephrol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (992) Google Scholar, 26.Goodman W.G. Goldin J. Kuizon B.D. et al.Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.New Eng J Med. 2000; 342: 1478-1483Crossref PubMed Scopus (1853) Google Scholar and PTH does not induce calcification in vascular smooth muscle cells (VSMCs)27.Jono S. Nishizawa Y. Morii H. Parathyroid hormone-related peptide as a local regulator of vascular calcification.Arterioscler Thromb Vasc Biol. 1997; 17: 1135-1142Crossref PubMed Google Scholar or intact aortas in culture.28.Lomashvili K. Garg P. O'Neill W.C. Chemical and hormonal determinants of vascular calcification in vitro.Kidney Int. 2006; 69: 1464-1470Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar Although exogenous PTH produces vascular calcification in parathyroidectomized rats, this is most likely due an increase in circulating calcium levels.29.Neves K.R. Graciolli F.G. Dos Reis L.M. et al.Vascular calcification: contribution of parathyroid hormone in renal failure.Kidney Int. 2007; 71: 1262-1270Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar Management of sHPT focuses on minimizing hyperphosphatemia and hypocalcemia without producing hypercalcemia and overly suppressing PTH. This is accomplished with oral phosphate binders, active vitamin D compounds, calcimimetics, and adjusting the calcium concentration in the dialysate, all of which could potentially affect vascular calcification. Consequently, a significant amount of research has been directed at optimizing these therapies to minimize vascular calcification. Phosphate concentrations above physiological serum levels have been shown to promote vascular calcification in experimental models in vivo and in vitro. Supraphysiological concentrations of phosphate are necessary to induce calcification in vessels in vitro28.Lomashvili K. Garg P. O'Neill W.C. Chemical and hormonal determinants of vascular calcification in vitro.Kidney Int. 2006; 69: 1464-1470Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 30.Rosenheim A.H. Robinson R. The calcification in vitro of kidney, lung and aorta.Biochem J. 1934; 28: 712-719Crossref PubMed Google Scholar, 31.Lomashvili K.A. Cobbs S. Hennigar R.A. et al.Phosphate-induced vascular calcification: role of pyrophosphate and osteopontin.J Am Soc Nephrol. 2004; 15: 1392-1401Crossref PubMed Scopus (154) Google Scholar, 32.Eilberg R. Mori K. Early stages of in vitro calcification of human aortic tissue.Nature. 1969; 223: 518-520Crossref PubMed Scopus (2) Google Scholar and the extent of calcification varies directly with the phosphate concentration.28.Lomashvili K. Garg P. O'Neill W.C. Chemical and hormonal determinants of vascular calcification in vitro.Kidney Int. 2006; 69: 1464-1470Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar Similarly, vascular calcification in uremic rats or mice requires a high phosphorus diet with substantial hyperphosphatemia.33.Lomashvili K.A. Monier-Faugere M.-C. Wang X. et al.Effect of bisphosphonates on vascular calcification and bone metabolism in experimental renal failure.Kidney Int. 2009; 75: 617-625Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar,34.El-Abbadi M.M. Pai A.S. Leaf E.M. et al.Phosphate feeding induces arterial medial calcification in uremic mice: role of serum phosphorus, fibroblast growth factor-23, and osteopontin.Kidney Int. 2009; 24: 1297-1307Abstract Full Text Full Text PDF Scopus (0) Google Scholar Although a higher serum phosphorus level has been observed in patients with CKD and ESRD who have vascular calcification,12.Raggi P. Boulay A. Chasan-Taber S. et al.Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease?.J Am Coll Cardiol. 2002; 39: 695-701Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar, 16.London G.M. Guerin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality.Nephrol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (992) Google Scholar, 35.Adeney K.L. Siscovick D.S. Ix J.H. et al.Association of serum phosphate with vascular and valvular calcification in moderate CKD.J Am Soc Nephrol. 2009; 20: 381-387Crossref PubMed Scopus (156) Google Scholar, 36.Chertow G.M. Raggi P. Chasan-Taber S. et al.Determinants of progressive vascular calcification in haemodialysis patients.Nephrol Dial Transplant. 2004; 19: 1489-1496Crossref PubMed Scopus (205) Google Scholar, 37.London G.M. Marty C. Marchais S.J. et al.Arterial calcifications and bone histomorphometry in end-stage renal disease.J Am Soc Nephrol. 2004; 15: 1943-1951Crossref PubMed Scopus (384) Google Scholar a significant correlation has not been found in many studies.17.Sigrist M.K. Taal M.W. Bungay P. et al.Progressive vascular calcification over 2 years is associated with arterial stiffening and increased mortality in CKD 4 and 5 patients.Clin J Am Soc Nephrol. 2007; 2: 1241-1248Crossref PubMed Scopus (138) Google Scholar, 26.Goodman W.G. Goldin J. Kuizon B.D. et al.Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.New Eng J Med. 2000; 342: 1478-1483Crossref PubMed Scopus (1853) Google Scholar, 38.Barreto D.V. Barreto F.C. Carvalho A.B. et al.Coronary calcification in hemodialysis patients: the contribution of traditional and uremia-related risk factors.Kidney Int. 2006; 67: 1576-1582Abstract Full Text Full Text PDF Scopus (91) Google Scholar, 39.Mehrotra R. Budoff M. Christenson P. et al.Determinants of coronary artery calcification in diabetics with and without nephropathy.Kidney Int. 2004; 66: 2022-2031Abstract Full Text Full Text PDF PubMed Google Scholar Furthermore, atherosclerotic calcification in the general population and medial vascular calcification in diabetics clearly occurs in the absence of hyperphosphatemia. The effect of reduced phosphate intake on vascular calcification is confounded by the concomitant calcium load from calcium-containing phosphate binders. Studies in VSMC and cultured aortas have shown dramatic increases in calcification with incremental calcium concentrations in culture medium.28.Lomashvili K. Garg P. O'Neill W.C. Chemical and hormonal determinants of vascular calcification in vitro.Kidney Int. 2006; 69: 1464-1470Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar,40.Yang H. Curinga G. Giachelli C.M. Elevated extracellular calcium levels induce smooth muscle cell matrix mineralization in vitro.Kidney Int. 2004; 66: 2293-2299Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar In cultured rat aortas, calcification was proportional to the calcium concentration when the [Ca] × [PO4] product was kept constant, and no calcification was observed in vessels exposed to high phosphate concentrations when the calcium concentration was kept low.28.Lomashvili K. Garg P. O'Neill W.C. Chemical and hormonal determinants of vascular calcification in vitro.Kidney Int. 2006; 69: 1464-1470Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar This effect of calcium is likely to be physicochemical, not only as a constituent of apatite but also in the initiation (nucleation) through binding to elastin41.Urry D.W. Neutral sites for calcium ion binding to elastin and collagen: a charge neutralization theory for calcification and its relationship to atherosclerosis.Proc Natl Acad Sci USA. 1971; 68: 810-814Crossref PubMed Google Scholar and through formation of nascent crystals in matrix vesicles.42.Reynolds J.L. Joannides A.J. Skepper J.N. et al.Human 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. 2004; 15: 2857-2867Crossref PubMed Scopus (432) Google Scholar It is not surprising that calcium intake has correlated with vascular calcification in several studies in ESRD patients.12.Raggi P. Boulay A. Chasan-Taber S. et al.Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease?.J Am Coll Cardiol. 2002; 39: 695-701Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar, 16.London G.M. Guerin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality.Nephrol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (992) Google Scholar, 26.Goodman W.G. Goldin J. Kuizon B.D. et al.Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.New Eng J Med. 2000; 342: 1478-1483Crossref PubMed Scopus (1853) Google Scholar Several prospective studies have shown a markedly reduced rate of CAC in ESRD patients treated with sevelamer (a calcium-free phosphate binder) compared with patients treated with calcium carbonate or calcium acetate. In the treat-to-goal study of dialysis patients with existing CAC, the increase in calcification was 0 and 6% at 26 and 52 weeks with sevelamer compared with 14 and 25% increases with calcium carbonate or acetate.43.Chertow G.M. Burke S.K. Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.Kidney Int. 2002; 62: 245-252Abstract Full Text Full Text PDF PubMed Scopus (1082) Google Scholar Aortic calcification was also significantly reduced. Doses were titrated to the serum phosphorus level, which did not differ between the two groups at the end of the study. However, the serum calcium concentration was significantly lower in the sevelamer group. Similar results were obtained in a subsequent study of patients enrolled at the initiation of dialysis.44.Block G.A. Spiegel D.M. Ehrlich J. et al.Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis.Kidney Int. 2005; 68: 1815-1824Abstract Full Text Full Text PDF PubMed Scopus (530) Google Scholar A recent study suggests that this beneficial effect extends to predialysis patients, with yearly increases in CAC of 48, 39, and 9% for patients on low phosphorus diet alone, with calcium carbonate or with sevelamer, respectively.45.Russo D. Miranda I. Ruocco C. et al.The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer.Kidney Int. 2007; 72: 1255-1261Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar In all of these studies, sevelamer (but not calcium-containing binders) produced a significant decrease in the serum calcium concentration and this is presumably the explanation for the lower rates of vascular calcification. PTH levels and vitamin D usage were greater in the sevelamer-treated patients, but these would not be expected to contribute to a reduction in calcification. Although sevelamer also lowers low-density lipoprotein levels, a reduction in atherosclerosis is an unlikely explanation for the reduction in vascular calcification, as low-density lipoprotein-reduction therapy has not been successful at reducing coronary artery disease in ESRD.20.Fellstrom B.C. Jardine A.G. Schmieder R.E. et al.Rosuvastatin and cardiovascular events in patients undergoing hemodialysis.New Eng J Med. 2009; 360: 1395-1407Crossref PubMed Scopus (0) Google Scholar,21.Wanner C. Krane V. Marz W. et al.Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.New Eng J Med. 2005; 353: 238-248Crossref PubMed Scopus (0) Google Scholar Two studies have shown no benefit of sevelamer over calcium-based phosphate binders.46.Barreto D.V. Barreto F.C
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