Chronic Kidney Disease–Mineral-Bone Disorder: A New Paradigm
2007; Elsevier BV; Volume: 14; Issue: 1 Linguagem: Inglês
10.1053/j.ackd.2006.10.005
ISSN1548-5609
AutoresSharon M. Moe, Tilman B. Drüeke, Norbert Lameire, Garabed Eknoyan,
Tópico(s)Magnesium in Health and Disease
ResumoDisturbances in mineral and bone metabolism are prevalent in chronic kidney disease (CKD) and an important cause of morbidity, decreased quality of life, and extraskeletal calcification that have been associated with increased cardiovascular mortality. These disturbances have traditionally been termed renal osteodystrophy and classified on the basis of bone biopsy. Kidney Disease: Improving Global Outcomes (KDIGO) recently sponsored a Controversies Conference to evaluate this definition. The recommendations were that (1) the term renal osteodystrophy be used exclusively to define alterations in bone morphology associated with CKD and (2) the term CKD–mineral and bone disorder (CKD-MBD) be used to describe the broader clinical syndrome that develops as a systemic disorder of mineral and bone metabolism as a result of CKD. CKD-MBD is manifested by an abnormality of any one or a combination of the following: laboratory—abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; bone—changes in bone turnover, mineralization, volume, linear growth, or strength; and calcification—vascular or other soft-tissue calcification. The pathogenesis and clinical manifestations of these components of CKD-MBD are described in detail in this issue of Advances in Chronic Kidney Disease. Disturbances in mineral and bone metabolism are prevalent in chronic kidney disease (CKD) and an important cause of morbidity, decreased quality of life, and extraskeletal calcification that have been associated with increased cardiovascular mortality. These disturbances have traditionally been termed renal osteodystrophy and classified on the basis of bone biopsy. Kidney Disease: Improving Global Outcomes (KDIGO) recently sponsored a Controversies Conference to evaluate this definition. The recommendations were that (1) the term renal osteodystrophy be used exclusively to define alterations in bone morphology associated with CKD and (2) the term CKD–mineral and bone disorder (CKD-MBD) be used to describe the broader clinical syndrome that develops as a systemic disorder of mineral and bone metabolism as a result of CKD. CKD-MBD is manifested by an abnormality of any one or a combination of the following: laboratory—abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; bone—changes in bone turnover, mineralization, volume, linear growth, or strength; and calcification—vascular or other soft-tissue calcification. The pathogenesis and clinical manifestations of these components of CKD-MBD are described in detail in this issue of Advances in Chronic Kidney Disease. Chronic Kidney Disease (CKD) is a worldwide public health problem that affects 5% to 10% of the world population, with increasing prevalence and adverse outcomes, including progressive loss of kidney function, cardiovascular disease, and premature death.1Eknoyan G. Lameire N. Barsoum R. et al.The burden of kidney disease: Improving global outcomes.Kidney Int. 2004; 66: 1310-1314Crossref PubMed Scopus (368) Google Scholar Cardiovascular disease is the leading cause of death in patients with CKD. In individuals with kidney failure on maintenance dialysis who are younger than 65 years, cardiovascular mortality is 10 to 500 times higher than in the general population, even after adjustment for sex, race, and presence of diabetes.2Foley R.N. Parfrey P.S. Sarnak M.J. Clinical epidemiology of cardiovascular disease in chronic renal disease.Am J Kidney Dis. 1998; 32: S112-S119Abstract Full Text PDF PubMed Scopus (3006) Google Scholar For example, cardiovascular disease mortality in young adults (24 to 37 years of age) on maintenance dialysis is similar to the rates of cardiac death for those 70 to 80 years of age in the general population.3National Kidney Foundation Task Force on Cardiovascular DiseaseControlling the epidemic of cardiovascular disease in chronic renal disease: What do we know? What do we need to know? Where do we go from here?.Am J Kidney Dis. 1998; 32: S1-S199PubMed Google Scholar In children and adolescents with end-stage renal disease (ESRD), cardiovascular disease is the second most common cause of death, accounting for 25% of deaths, compared with 3% in the general pediatric population.4Parekh R.S. Carroll C.E. Wolfe R.A. et al.Cardiovascular mortality in children and young adults with end-stage kidney disease.J Pediatr. 2002; 141: 191-197Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar Cardiovascular mortality is also markedly elevated in kidney transplant patients, albeit less than in patients on dialysis.2Foley R.N. Parfrey P.S. Sarnak M.J. Clinical epidemiology of cardiovascular disease in chronic renal disease.Am J Kidney Dis. 1998; 32: S112-S119Abstract Full Text PDF PubMed Scopus (3006) Google Scholar Available data indicate that individuals at earlier stages of CKD are more likely to die of cardiovascular disease than they are to reach the need for dialysis. Only 1% of the population with CKD (defined as an estimated glomerular filtration rate [GFR] less than 60 mL/min/1.73 m2) is receiving therapy with dialysis or transplantation. The majority of patients with CKD die of cardiovascular disease before the need for dialysis. There is an independent, incremental increased risk of all-cause and cardiovascular mortality with an adjusted hazard ratio for all-cause mortality ranges from 1.2 at an estimated glomerular filtration rate (eGFR) of 45 to 59 mL/min/1.73 m2 to 5.9 at an eGFR of less than 15 mL/min/1.73 m2.5Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (9281) Google Scholar The traditional Framingham cardiovascular risk factors such as diabetes, hypertension, smoking, family history, and hyperlipidemia, albeit present in most patients with CKD, do not completely account for the increased cardiovascular mortality of these patients.6Cheung A.K. Sarnak M.J. Yan G. et al.Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients.Kidney Int. 2000; 58: 353-362Crossref PubMed Scopus (660) Google Scholar Many of the nontraditional risk factors shown in Figure 1, which develop after the onset and progression of CKD, have been associated with increased cardiovascular disease in CKD patients. Recently, disorders of bone and mineral metabolism and vascular calcification associated with CKD have been identified as major risk factors for cardiovascular morbidity and mortality. Disturbances in mineral metabolism are common complications of CKD and an important cause of morbidity and decreased quality of life. Importantly, increasing evidence suggests that these disturbances are associated with changes in arterial compliance, cardiovascular calcification, and all-cause and cardiovascular mortality.7Moe S.M. Chen N.X. Pathophysiology of vascular calcification in chronic kidney disease.Circ Res. 2004; 95: 560-567Crossref PubMed Scopus (422) Google Scholar Traditionally, this group of disorders has been termed renal osteodystrophy. However, strictly defined, the term renal osteodystrophy means bone abnormalities. In October 2005, a consensus conference was convened by Kidney Disease Improving Global Outcomes (KDIGO; www.kdigo.orgwww.kdigo.org) to define and classify renal osteodystrophy. The conclusions of this expert panel, described in detail below, was that the manifestations of mineral and bone abnormalities are diverse, include extraskeletal manifestations, and constitute a systemic disorder that should be termed CKD–mineral and bone disorder (CKD-MBD)8Moe S. Drueke T. Cunningham J. et al.Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO).Kidney Int. 2006; 69: 1945-1953Crossref PubMed Scopus (1507) Google Scholar (Table 1). The rationale for linking laboratory abnormalities, bone disease, and extraskeletal calcification in a single disorder is given below. Further details of the clinical consequences and pathogenesis of the components of CKD-MBD are provided in the remaining articles in this issue of Advances in Chronic Kidney Disease.Table 1Kidney Disease Improving Global Outcomes (KDIGO) Classification of CKD-MBD and Renal OsteodystrophyDefinition of CKD-MBDA systemic disorder of mineral and bone metabolism caused by CKD manifested by either one or a combination of the following:•Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism•Abnormalities in bone turnover, mineralization, volume, linear growth, or strength•Vascular or other soft-tissue calcificationDefinition of renal osteodystrophy•Renal osteodystrophy is an alteration of bone morphology in patients with CKD.•It is one measure of the skeletal component of the systemic disorder of CKD-MBD that is quantifiable by histomorphometry of bone biopsy.Adapted with permission.8Moe S. Drueke T. Cunningham J. et al.Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO).Kidney Int. 2006; 69: 1945-1953Crossref PubMed Scopus (1507) Google Scholar Open table in a new tab Adapted with permission.8Moe S. Drueke T. Cunningham J. et al.Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO).Kidney Int. 2006; 69: 1945-1953Crossref PubMed Scopus (1507) Google Scholar Epidemiologic studies that date back to the early 1990s have demonstrated that an increase in serum phosphorus and the calcium × phosphorus product are associated with poor outcomes. The association of elevated serum phosphorus and mortality has been confirmed in several recent studies. Analysis of a large database of more than 40,000 patients undergoing hemodialysis in the United States showed an association with increased mortality for phosphorus levels greater than 5.0 mg/dL, with a progressive increase in mortality at increasing levels of serum phosphorus.9Block G.A. Klassen P.S. Lazarus J.M. et al.Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.J Am Soc Nephrol. 2004; 15: 2208-2218Crossref PubMed Scopus (2250) Google Scholar In this study, the relative risk of death correlated directly to serum-calcium levels, rising 47% as the calcium level increased from 9 to 9.5 mg/dL to greater than 11 mg/dL.9Block G.A. Klassen P.S. Lazarus J.M. et al.Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.J Am Soc Nephrol. 2004; 15: 2208-2218Crossref PubMed Scopus (2250) Google Scholar Elevated serum phosphorus and the calcium × phosphorus product also were associated with poor outcomes in the international Dialysis Outcomes Practice Patters Study (DOPPS),10Young E.W. Albert J.M. Satayathum S. et al.Predictors and consequences of altered mineral metabolism: the Dialysis Outcomes and Practice Patterns Study.Kidney Int. 2005; 67: 1179-1187Crossref PubMed Scopus (672) Google Scholar and in a cohort from the Netherlands that included both hemodialysis and peritoneal dialysis patients.11Noordzij M. Korevaar J.C. Boeschoten E.W. et al.The Kidney Disease Outcomes Quality Initiative (K/DOQI) guideline for bone metabolism and disease in CKD: Association with mortality in dialysis patients.Am J Kidney Dis. 2005; 46: 925-932Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar In a Canadian cohort study, in which different combinations of mineral-metabolism parameters were modeled, the combinations of high serum phosphorus and calcium with either high PTH (RR, 3.71; 95% CI, 1.53 to 9.03; P = .004) or low PTH (RR, 4.30; 95% CI, 2.01 to 9.22; P < .001) had the highest mortality risk compared with high PTH with normal/low phosphorus or calcium. In addition, the overall risk varied with the duration of dialysis.12Stevens L.A. Djurdjev O. Cardew S. et al.Calcium, phosphate, and parathyroid hormone levels in combination and as a function of dialysis duration predict mortality: evidence for the complexity of the association between mineral metabolism and outcomes.J Am Soc Nephrol. 2004; 15: 770-779Crossref PubMed Scopus (318) Google Scholar The importance of multiple biochemical abnormalities was evident in another study that examined the mortality risk attributable to various factors, taking into account the strength of the association (i.e., relative risk) and prevalence across the population.9Block G.A. Klassen P.S. Lazarus J.M. et al.Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.J Am Soc Nephrol. 2004; 15: 2208-2218Crossref PubMed Scopus (2250) Google Scholar, 13Moe S.M. Chertow G.M. The case against calcium-based phosphate binders.Clin J Am Soc Nephrol. 2006; 1: 697-703Crossref PubMed Scopus (92) Google Scholar The results, shown in Figure 2, demonstrated that hyperphosphatemia alone conveyed the highest (11.8%) risk of death (more than anemia or a low urea reduction ratio), and that the combination of hyperphosphatemia, hypercalcemia, and elevated PTH accounted for an even higher (17.5%) mortality risk in hemodialysis patients. Additional epidemiologic studies have confirmed the major cause of death in the presence of hyperphosphatemia and hypercalcemia to be cardiovascular events.14Slinin Y. Foley R.N. Collins A.J. Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: The USRDS waves 1, 3, and 4 study.J Am Soc Nephrol. 2005; 16: 1788-1793Crossref PubMed Scopus (372) Google Scholar Furthermore, studies have demonstrated an association of hyperphosphatemia with increased vascular stiffening,15London 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 (1546) Google Scholar arterial calcification and calciphylaxis,7Moe S.M. Chen N.X. Pathophysiology of vascular calcification in chronic kidney disease.Circ Res. 2004; 95: 560-567Crossref PubMed Scopus (422) Google Scholar and valvular calcification.16Merjanian R. Budoff M. Adler S. et al.Coronary artery, aortic wall, and valvular calcification in nondialyzed individuals with type 2 diabetes and renal disease.Kidney Int. 2003; 64: 263-271Crossref PubMed Scopus (107) Google Scholar Importantly, increases in serum phosphorus have also been associated with increased mortality and cardiovascular events in patients with documented coronary-artery disease but no identifiable CKD.17Tonelli M. Sacks F. Pfeffer M. et al.Relation between serum phosphate level and cardiovascular event rate in people with coronary disease.Circulation. 2005; 112: 2627-2633Crossref PubMed Scopus (722) Google Scholar Vitamin D homeostasis is also altered in CKD. Deficiency in calcitriol (1,25[OH]2 vitamin D) caused by impaired renal conversion of calcidiol (25[OH] vitamin D) to calcitriol has long been known to be a major factor in the development of secondary hyperparathyroidism. In addition, increasing evidence suggests the importance of vitamin D in cell proliferation and differentiation, and in immune response.18Seibert E. Levin N.W. Kuhlmann M.K. Immunomodulating effects of vitamin D analogs in hemodialysis patients.Hemodial Int. 2005; 9: S25-S29Crossref PubMed Scopus (26) Google Scholar The findings of vitamin D effects on multiple genes, and vitamin D receptor expression in multiple-organ systems point to the widespread systemic effects of vitamin D.19Peterlik M. Cross H.S. Vitamin D and calcium deficits predispose for multiple chronic diseases.Eur J Clin Invest. 2005; 35: 290-304Crossref PubMed Scopus (287) Google Scholar Evidence also suggest extrarenal conversion of calcidiol to calcitriol in multiple other organs, with CYP27B1 (1-α hydroxylase) expression and activity in both normal and abnormal cells.20Holick M.F. Vitamin D for health and in chronic kidney disease.Semin Dial. 2005; 18: 266-275Crossref PubMed Scopus (149) Google Scholar Data from recent retrospective cohort studies have demonstrated that the administration of the vitamin D analog paricalcitol (19-nor-1,25[OH]2-vitamin D2) compared with calcitriol improves survival of dialysis patients, and that either form of active vitamin D is better than no vitamin D at all.21Teng M. Wolf M. Lowrie E. et al.Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy.N Engl J Med. 2003; 349: 446-456Crossref PubMed Scopus (911) Google Scholar, 22Teng M. Wolf M. Ofsthun M.N. et al.Activated injectable vitamin D and hemodialysis survival: A historical cohort study.J Am Soc Nephrol. 2005; 16: 1115-1125Crossref PubMed Scopus (761) Google Scholar The protective effects appear to be independent of calcium, phosphorus, and PTH and may be attributed to a direct effect of calcitriol on the cardiovascular system in CKD. Studies have shown that calcitriol can lead to decreased vascular tone, decreased renin-angiotensin activation, decreased cardiac contractility, and decreased myocardial fibrosis, which results in improved blood pressure and reduction in left ventricular mass.23Achinger S.G. Ayus J.C. The role of vitamin D in left ventricular hypertrophy and cardiac function.Kidney Int. 2005; : S37-S42Crossref Scopus (96) Google Scholar Recent studies have also indicated the common occurrence of a deficiency or insufficiency of the precursor of calcitriol, calcidiol, in CKD, with a normal level detected in only 29% and 17% of stage 3 and 4 CKD subjects, respectively.24LaClair R.E. Hellman R.N. Karp S.L. et al.Prevalence of calcidiol deficiency in CKD: A cross-sectional study across latitudes in the United States.Am J Kidney Dis. 2005; 45: 1026-1633Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar, 25Gonzalez E.A. Sachdeva A. Oliver D.A. et al.Vitamin D insufficiency and deficiency in chronic kidney disease: A single center observational study.Am J Nephrol. 2004; 24: 503-510Crossref PubMed Scopus (364) Google Scholar This prevalence of vitamin D deficiency and insufficiency in an ambulatory CKD population is similar to non-CKD nursing home residents, hospitalized patients, and elderly women with hip fractures.26Thomas M.K. Lloyd-Jones D.M. Thadhani R.I. et al.Hypovitaminosis D in medical inpatients.N Engl J Med. 1998; 338: 777-783Crossref PubMed Scopus (1290) Google Scholar Epidemiologic and animal studies indicate that vitamin D deficiency and insufficiency are associated with increased falls, cancer risk, hypertension, fibromyalgia-like symptoms, rheumatologic disease, diabetes, depression, and fractures.19Peterlik M. Cross H.S. Vitamin D and calcium deficits predispose for multiple chronic diseases.Eur J Clin Invest. 2005; 35: 290-304Crossref PubMed Scopus (287) Google Scholar, 20Holick M.F. Vitamin D for health and in chronic kidney disease.Semin Dial. 2005; 18: 266-275Crossref PubMed Scopus (149) Google Scholar Thus, multiple effects of vitamin D occur beyond the skeleton. In summary, abnormalities of serum biochemistry related to mineral metabolism, such as phosphorus, calcium, PTH, and vitamin D, are common in CKD and associated with significant morbidity and mortality. Disorders of mineral metabolism are also associated with abnormal bone. The gold standard test for bone quality is its ability to resist fracture under strain. In animal models, this resistance can be directly tested with three-point bending mechanical tests. Bone quality is impaired in CKD, as the prevalence of hip fracture is increased in dialysis patients compared with the general population in all age groups.27Stehman-Breen C.O. Sherrard D.J. Alem A.M. et al.Risk factors for hip fracture among patients with end-stage renal disease.Kidney Int. 2000; 58: 2200-2205Crossref PubMed Google Scholar, 28Alem A.M. Sherrard D.J. Gillen D.L. et al.Increased risk of hip fracture among patients with end-stage renal disease.Kidney Int. 2000; 58: 396-399Crossref PubMed Scopus (681) Google Scholar, 29Coco M. Rush H. Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone.Am J Kidney Dis. 2000; 36: 1115-1121Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar Dialysis patients in their forties have a relative risk of hip fracture that is 80-fold higher than that of age-matched and sex-matched control subjects.28Alem A.M. Sherrard D.J. Gillen D.L. et al.Increased risk of hip fracture among patients with end-stage renal disease.Kidney Int. 2000; 58: 396-399Crossref PubMed Scopus (681) Google Scholar Furthermore, hip fracture in dialysis patients is associated with a doubling of the mortality observed in hip fractures in nondialysis patients.29Coco M. Rush H. Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone.Am J Kidney Dis. 2000; 36: 1115-1121Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar, 30Danese M.D. Kim J. Doan Q.V. et al.PTH and the risks for hip, vertebral, and pelvic fractures among patients on dialysis.Am J Kidney Dis. 2006; 47: 149-156Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar In multivariate analysis, the risk factors for hip fracture include age, gender, duration of dialysis, and presence of peripheral vascular disease.27Stehman-Breen C.O. Sherrard D.J. Alem A.M. et al.Risk factors for hip fracture among patients with end-stage renal disease.Kidney Int. 2000; 58: 2200-2205Crossref PubMed Google Scholar Other analyses found race, gender, duration of dialysis, and low or very high PTH levels as risk factors for hip fracture.29Coco M. Rush H. Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone.Am J Kidney Dis. 2000; 36: 1115-1121Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar, 30Danese M.D. Kim J. Doan Q.V. et al.PTH and the risks for hip, vertebral, and pelvic fractures among patients on dialysis.Am J Kidney Dis. 2006; 47: 149-156Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar In a study of Japanese men, 21% of prevalent dialysis patients (mean age 54 ± 9 years) had vertebral fractures identified by plain radiographs.31Atsumi K. Kushida K. Yamazaki K. et al.Risk factors for vertebral fractures in renal osteodystrophy.Am J Kidney Dis. 1999; 33: 287-293Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar These data support that both hip and lumbar-spine fractures occur independent of gender and race in CKD patients. Other risk factors for abnormal bone identified in studies from the general population are also common in CKD, including smoking, sedentary lifestyle, and hypogonadism. These factors are likely to increase the risk of bone fragility and fractures in CKD but have not been well evaluated. Extremes of bone turnover found in patients with CKD have significant impact on fragility and are likely additive to bone abnormalities commonly found in the aging and sedentary general population. The high prevalence of vascular calcification in CKD patients is an old observation that has recently gained added attention because of new imaging modalities and increased understanding of the cell-mediated processes involved. Ibels et al32Ibels L.S. Alfrey A.C. Huffer W.E. et al.Arterial calcification and pathology in uremic patients undergoing dialysis.Am J Med. 1979; 66: 790-796Abstract Full Text PDF PubMed Scopus (292) Google Scholar in 1979, demonstrated that both the renal and internal iliac arteries of patients undergoing a kidney transplant had increased atheromatous/intimal disease and increased calcification compared with transplant donors. In addition, the medial layer was thicker and more calcified in the recipients compared with the donors.32Ibels L.S. Alfrey A.C. Huffer W.E. et al.Arterial calcification and pathology in uremic patients undergoing dialysis.Am J Med. 1979; 66: 790-796Abstract Full Text PDF PubMed Scopus (292) Google Scholar A more recent study compared histologic changes in coronary arteries from dialysis patients with the histologic changes of age-matched, nondialysis patients who had died of a cardiac event.33Schwarz 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 Scopus (548) Google Scholar This study found a similar magnitude of atherosclerotic plaque burden and intimal thickness in the dialysis patients compared with control subjects but with more calcification. In addition, morphometry of the arteries demonstrated increased medial thickening.33Schwarz 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 Scopus (548) Google Scholar Using electron beam CT scan (EBCT), studies have shown that coronary artery calcification increases with advancing age in patients on dialysis and that their calcification scores were twofold to fivefold greater than in age-matched individuals with normal kidney function and angiographically proven coronary-artery disease.34Braun 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: 394-401Abstract Full Text PDF PubMed Scopus (739) Google Scholar The magnitude of large-artery calcification assessed by ultrasound has been associated with an increased intake of calcium binders.35Guerin A.P. London G.M. Marchais S.J. et al.Arterial stiffening and vascular calcifications in end-stage renal disease.Nephrol Dial Transplant. 2000; 15: 1014-1021Crossref PubMed Scopus (899) Google Scholar Goodman et al36Goodman W.G. Goldin J. Kuizon B.D. et al.Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.N Engl J Med. 2000; 342: 1478-1483Crossref PubMed Scopus (2475) Google Scholar subsequently demonstrated that advanced calcification can also occur in the coronary arteries of children and young adults and is related to increased doses of calcium-containing phosphate binders and increased calcium × phosphorus product. Data in patients with CKD not yet on dialysis also demonstrates an increased risk of coronary-artery calcification, especially in diabetics.37Mehrotra R. Budoff M. Christenson P. et al.Determinants of coronary artery calcification in diabetics with and without nephropathy.Kidney Int. 2004; 66: 2022-2031Crossref PubMed Scopus (97) Google Scholar Nearly 50% to 60% of patients starting hemodialysis have evidence of coronary-artery calcification,38Block 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: 1815-1824Crossref PubMed Scopus (729) Google Scholar and most series that describe prevalent hemodialysis patients find 70% to 80% of all patients with evidence of coronary-artery calcification (Reviewed in Hujairi et al39Hujairi N.M. Afzali B. Goldsmith D.J. Cardiac calcification in renal patients: What we do and don’t know.Am J Kidney Dis. 2004; 43: 234-243Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). The only risk factors for coronary-artery calcification that are uniform across studies are advanced age and duration of dialysis (Table 2). Mineral metabolism abnormalities, including hyperphosphatemia, elevated calcium × phosphorus product, or excessive calcium load from phosphate binders have been identified as additional risk factors in several, but not all, studies.40McCullough P.A. Sandberg K.R. Dumler F. et al.Determinants of coronary vascular calcification in patients with chronic kidney disease and end-stage renal disease: A systematic review.J Nephrol. 2004; 17: 205-215PubMed Google ScholarTable 2Risk Factors for Vascular CalcificationRisk FactorIntimal/Atherosclerotic CalcificationMedial/Mönkeberg’s CalcificationPresent in the general population DyslipidemiaYesNo Advanced ageYesYes Elevated blood pressureYesReciprocal (medial lesions worsen blood pressure) Male genderYesNo SmokingYesNo InflammationYes (local)Yes (systemic mediators) Diabetes/glucose intoleranceYesYesPresent only in CKD Reduced GFRNoYes HypercalcemiaNoYes Positive calcium balanceNoYes HyperphosphatemiaYesYes Abnormal PTHNoNo Vitamin D administrationNoYes Dialysis vintageNoYesAdapted with permission.51Goodman W.G. London G. Amann K. et al.Vascular calcification in chronic kidney disease.Am J Kidney Dis. 2004; 43: 572-579Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar Open table in a new tab Adapted with permission.51Goodman W.G. London G. Amann K. et al.Vascular calcification in chronic kidney disease.Am J Kidney Dis. 2004; 43: 572-579Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar In the general population, coronary-artery calcification is predictive of future cardiac events in both asymptomatic and symptomatic individuals.41Taylor A.J. Bindeman J. Feuerstein I. et al.Coronary calcium independently predicts incident premature coronary heart disease over measured cardiovascular risk factors: Mean three-year outcomes in the Prospective Army Coronary Calcium (PACC) project.J Am Coll Cardiol. 2005; 46: 807-814Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar, 42Arad Y. Goodman K.J. Roth M. et al.Coronary calcification, coronary disease risk factors, C-reactive protein, and atherosclerotic cardiovascular disease events the St Francis Heart Study.J Am Coll Cardiol. 2005; 46: 158-165Abstract Full Text Full Text PDF PubMed Scopus (872) Google Scholar Less robust data exist for CKD patients. Two small studies have demonstrated an increase in mortality with increased coronary-artery calcification.43Moe S.M. O’Neill K.D. Reselerova M. et al.Natural hi
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