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Clinical Assessment of Vascular Calcification
Clinical Assessment of Vascular Calcification Paolo Raggi and Antonio Bellasi Cardiovascular calcification poses an increased risk for cardiovascular events in advanced phases of chronic kidney disease. This evidence has brought many investigators to focus their attention on the importance of detection of calcification and avoidance of further development of it with appropriate therapeutic choices. Physicians can use a variety of noninvasive imaging tools to identify cardiovascular calcification, some with merely qualitative and others with both qualitative and quantitative capabilities. Plain x-rays and ultrasonography can be used to identify macroscopic calcification of aorta and peripheral arteries, echocardiography is helpful for assessment of valvular calcification, and computed tomography technologies constitute the gold standard for quantification of cardiovascular calcification. The latter is also useful to monitor calcification progression and to assess the effect of different therapeutic strategies directed at modifying calcification progression. In this article, we review the clinical significance of vascular calcification and some of the evidence surrounding the most commonly employed noninvasive imaging techniques. © 2007 by the National Kidney Foundation, Inc. Index Words: Vascular calcifications; computed tomography; echocardiography; chronic kidney disease
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ardiovascular calcification has been associated with a substantially increased risk of cardiovascular morbidity and mortality in dialysis patients, as well as in the general population.1-3 Diffuse calcification of the large-conduit arteries promotes arterial stiffness, with deleterious hemodynamic consequences.4 The systolic blood pressure increases in conjunction with a decrease in diastolic blood pressure, with altered coronary perfusion and subsequent left ventricular hypertrophy all predisposing to myocardial ischemia and arrhythmias.5 Because the progression of vascular calcification appears to be slowed by some therapies, screening for the presence of cardiovascular calcification is important. Plain x-rays of abdomen and extremities, two-dimensional ultrasound, and echocardiography can be used to identify vascular calcifications in various blood vessels such as carotid arteries, femoral arteries, and aorta, as well as the cardiac valves. More sophisticated and expensive imaging technologies, such as electronbeam computed tomography (EBCT) and multislice computed tomography (MSCT), have emerged as tools to evaluate and accurately quantify cardiovascular calcification. These modalities allow not only detection but also monitoring of calcification progression and effectiveness of different therapeutic strategies applied to slow progression. A clinical approach based on application of some of these techniques may provide sub-
stantial aid in improving outcomes in dialysis patients. In this article, we review the strengths and limitations and some of the clinical evidence linked with commonly employed noninvasive techniques for imaging of vascular calcification.
Roentgenography Plain radiography is a helpful and inexpensive tool for identification of vascular calcification (VC), both in the general population6 and in chronic kidney disease (CKD) patients (Fig 1).7 Plain radiographs may localize calcification patterns in the arterial wall, which helps distinguish intimal from media calcification. Medial calcification is usually considered present when linear, tram-track, radiopaque lesions are visible along the course of an artery, whereas intimal calcification is more characteristically identified by patchy and irregular radiopaque lesions. Both types of calcifications have been associated with adverse clinical outcomes. In fact, despite the absence of luminal obstruction, the loss From the Emory University School of Medicine, Division of Cardiology and Department of Radiology, Atlanta, GA; and Ospedale San Paolo and University of Milan, Department of Nephrology, Milan, Italy. Address correspondence to Paolo Raggi, MD, FACP, FACC, Emory University School of Medicine, 1365 Clifton Road NE, AT-504, Atlanta, GA 30322. E-mail: [email protected] © 2007 by the National Kidney Foundation, Inc. 1548-5595/07/1401-0007$32.00/0 doi:10.1053/j.ackd.2006.10.006
Advances in Chronic Kidney Disease, Vol 14, No 1 (January), 2007: pp 37-43
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Raggi and Bellasi
Figure 1. Plain radiographs of the right foot of a 54-year-old Caucasian patient with diabetes mellitus and hypertension on maintenance hemodialysis for 16 months. Note the heavy calcification of the calcaneal-plantar (a) and plantar interdigital (b) arteries (white arrows).
of arterial compliance ultimately reduces end-organ perfusion and increases myocardial afterload, with an attendant increase in cardiovascular morbidity and mortality. Some clinical evidence supports this notion. In a cross-sectional study of 202 hemodialysis patients, medial and intimal calcification were detected in 27% and 37% of the x-ray films of the pelvis and thighs. In that study, both medial and intimal calcification were independently associated with all-cause mortality (RR ⫽ 15.7 [95% CI: 4.8 to 51.4; P ⬍ .00001] and 4.85 [95% CI: 1.68 to 14.1; P ⫽ .0036], respectively).7 Adragao et al8 used plain x-rays of the pelvis and hands in a cross-sectional study of 123 hemodialysis patients to generate a simple VC score. The score was devised by assigning
a point each for the presence of calcification in the iliac, femoral, digital, and radial arteries of either limb (score 0 for no calcification to 8 if all four vessels were calcified bilaterally). VC was detected in 75% of the study patients, and almost half of the patients had a score equal to or greater than 3. During 37 months of followup, mortality was approximately fivefold higher in patients with a baseline score equal to or greater than 3, compared with patients with a score less than 3 (23% v 5%; P ⫽ .01). Even after adjustment for confounding variables, this simple score of VC was predictive of mortality (hazard ratio for score ⱖ 3: 3.9 [95% CI: 1.1 to 12.4; P ⫽ .03]). Plain radiographs are qualitative and do not allow for an accurate assessment of temporal changes of VC. Nonetheless, they seem to provide valid prognostic information, and, given the low cost and risk to the patient, they may be worth implementing as an in-office tool to screen for the presence of VC. Indeed, radiographs of the lumbar spine to visualize abdominal aorta calcification were recommended by a group of experts of the National Kidney Foundation9 and were shown to hold a good correlation with CT-derived calcium scores.10 In a series of 140 hemodialysis patients, a semiquantitative score of abdominal aorta calcification seen on a lateral lumbar plain x-ray demonstrated a sensitivity of 76% for the prediction of a coronary artery calcium score greater than 30 on CT.10 This information should provide guidance as to the presence and extent of VC for the clinician who could then modify his treatment approach in accordance with the most recent K/DOQI guidelines for cardiovascular disease in CKD stage 5 (CKD-5) patients.
Ultrasonography Ultrasound studies rely on the universal availability of the tool, the relative inexpensive nature of the test, and the ease of identification of superficial vessels such as the carotid and femoral arteries. These methods, however, like plain radiography, provide only a qualitative assessment of VC. Nonetheless, good evidence supports their prognostic utility. Blacher et al1 used a combination of vascular ultrasound and plain radiographs to de-
Clinical Assessment of Vascular Calcification
tect VC of the common carotid arteries, the abdominal aorta, and the femorotibial axes. They prospectively followed 110 patients on maintenance hemodialysis for an average of 53 ⫾ 21 months after having stratified them according to a score generated by the combination of ultrasound and x-ray findings. These investigators showed that the mere presence of VC and the number of affected sites were associated with all-cause mortality, as well as cardiovascular mortality. The adjusted hazard ratios for all-cause and cardiovascular mortality for each point increase in calcification severity were 1.9 (95% CI: 1.4 to 2.6) and 2.6 (95% CI: 1.2 to 2.4), respectively (P ⬍ .01 for both).1 The portability, safety, and low cost of ultrasound imaging make it desirable for inoffice applications.
Echocardiography Echocardiography is the gold standard for assessment of cardiac-valve morphology and function; it is noninvasive, uses no radiation, and is only moderately expensive. Calcification of the cardiac valves is found in dialysis patients, with a prevalence 4 to 5 times higher than in the general population.11 Although a less frequent finding than VC, valvular calcification shares common risk factors and pathogenic features with VC.11 It appears that calcification of valves and vessels follows similar pathophysiologic pathways, as inflammatory cells, lipoproteins, and bone-matrix proteins have been found in both structures.12 Mounting clinical evidence suggests that calcification of the mitral and the aortic valve is associated with poor prognosis in the general population, 13 as well as in CKD-stage 5 patients.14 In an earlier publication, Riberio et al11 noted that valvular calcification is more prevalent in hemodialysis patients than in patients with normal kidney function (mitral calcification 44.5% v 10%, P ⫽ .02; aortic calcification 52% v 4.3%, P ⫽ .01). In that study, mitral and aortic calcification were significantly associated with peripheral-arterial calcification (P ⫽ .009) and alterations of mineral metabolism.11 More recently, valvular calcification has been associated with an adverse outcome. During a mean follow-up of 18
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months, Wang et al,14 showed a marked increase in all-cause mortality, as well as cardiovascular mortality, in 192 peritoneal dialysis patients with no (15%, 7%), one (40%, 26%), or two (57%, 45%) calcified valves, respectively. All-cause and cardiovascular mortality did not differ significantly between patients with either valvular calcification or atherosclerotic vascular disease, which reinforces the hypothesis that valvular calcification represents a marker of systemic cardiovascular disease. In a later publication, the same group demonstrated the interaction between serum fetuin-A levels, malnutrition, inflammation, atherosclerosis, and valvular calcification, with a negative outcome in 238 peritoneal dialysis patients.15 The serum fetuin-A level was inversely related to the presence of valvular calcification and cardiovascular outcome of these patients. Valvular calcification has also been demonstrated to relate well to another marker of atherosclerosi, carotid intimamedia thickness (CIMT).16 For each 1-mm increase in CIMT, the investigators demonstrated a 6.5-fold (95% CI: 1.58 to 26.73; P ⫽ .009) increased risk of valvular calcification in a cohort of 92 continuous ambulatory peritoneal-dialysis patients.16 Furthermore, the presence of carotid calcification and carotid plaques was associated with a 7.2-fold (95% CI: 2.39 to 21.51; P ⫽ .001) and 5.0-fold (95% CI: 1.77 to 14.13; P ⫽ .002) increased risk of valvular calcification.16 Of interest, attenuation of valvular calcification progression has been demonstrated in the general population with statins17 and in CKD-5 patients receiving sevelamer treatment.18 Valvular calcification is a marker of systemic cardiovascular disease and an indicator of risk in CKD patients. Therefore, possibly in the near future, identification of valvular calcification in dialysis patients may be advocated as a method to assess risk and may lead to changes in management of these patients.
Computed Tomography Techniques Electron-beam computed tomography (EBCT) and multislice computed tomography (MSCT) represent the gold standard for assessing the extent of cardiovascular calcification (VC) and its progression (Fig 2). Although EBCT pro-
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Raggi and Bellasi
Figure 2. Volume-rendered image of the heart and ascending aorta on CT imaging. The soft tissues are semitransparent, and calcified areas are reproduced as a dense white signal. AsAo: ascending aorta; LAD: left anterior descending coronary artery; LCX: left circumflex coronary artery; LM: left main coronary artery; LV: left ventricle; RCA: right coronary artery; RV: right ventricle.
vides better temporal resolution (can image at higher heart rates), and MSCT provides better spatial resolution (the scanner is slower but the picture is “crispy”), the two technologies can be considered equivalent, especially when comparing EBCT to the most recent MSCT scanners (16 slice or greater).19-21 With CT imaging, VC can be accurately detected and its extent precisely quantified by means of scores such as the Agatston22 and the volume score.23 The Agatston score is calculated as the product of area (total surface of calcification) by peak density (also known as attenuation), measured in the context of the plaque. Hence, it incorporates information relating to size, as well as calcium content, of the plaque.22 The volume score takes into consideration all pixels in the context of a plaque, with a minimum density of 130 Hounsfield units (a CT measure of density).23 This technique is a more direct evaluation of the size of a plaque not influenced by the calcium content. Computed tomography (CT) technologies have been employed to investigate the natural history of VC and the impact of different
therapeutic strategies in CKD-5. By use of CT, the prevalence of coronary-artery calcification was reported to be 40% in 85 CKD stage 4 (CKD-4) patients24 and approximately 85% in 205 maintenance-hemodialysis patients.25 On the contrary, VC was found only in 13% of control subjects with normal kidney function.24 Consistent with these findings, Sigrist et al.26 reported a prevalence of coronary calcification of 46% in 46 CKD-4 patients compared with 70% and 73 %, respectively in 60 hemodialysis and 28 peritoneal- dialysis patients (P ⫽ .02). Obviously, the prevalence of VC increases dramatically after initiation of dialysis. Extensive coronary-artery calcium can be found not only in adult but also in pediatric and young hemodialysis patients (aged 19 to 39 years),27,28 and both groups show a strong trend toward rapid progression of VC. In early studies, CT-generated calcium scores appear to be predictive of an unfavorable outcome in dialysis patients.2 Matsuoka et al2 followed 104 long-term hemodialysis patients for an average of 43 months after a screening EBCT. Patients with a baseline coronary-calcium score above the median (score ⬃200) had a significantly lower (all-cause) survival than did patients with a score below the median (67.9% v 84.2% P ⫽ .0003). Several factors seem to affect progression of VC in dialysis patients. Among others were age, baseline calcium score, dialysis vintage, diabetes mellitus abnormalities of mineral metabolism,14,25,28-30 and use and dose of calcium-based phosphate binders.30,31 Sevelamer and calcium-based phosphate binders were compared in a randomized clinical trial of 200 maintenance-hemodialysis patients, to assess the progression of VC.30 The subjects were randomized to 1 year of open-label treatment with either sevelamer or calcium salts. Throughout the study, both drugs provided comparable phosphate control (P ⫽ .33). However, patients treated with calcium salts had a significantly higher serum-calcium concentration (P ⫽ .002), a greater incidence of hypercalcemic episodes (16% v 5%; P ⫽ .04), and a larger number of subjects with parathyroid hormone (PTH) levels below the lower recommended limit of 150 pg/mL (57% v 30%, P ⫽ .001). At study completion, patients
Clinical Assessment of Vascular Calcification
treated with calcium salts showed a significant progression of VC, whereas sevelamertreated subjects did not (median absolute progression of coronary-artery calcium score 36.6 v 0, P ⫽ .03 and aorta 75.1 v 0, P ⫽ .01, respectively).30 A similar protocol was adopted in a second study of 129 incident hemodialysis patients.32 Subjects treated with calciumcontaining phosphate binders showed a more rapid and more severe increase in coronaryartery calcium score compared with those who received sevelamer (P ⫽ .01 at 18 months follow-up).32 Other therapeutic agents with potential to inhibit VC progression have been utilized in small studies. The effect of cyclic intermittent etidronate therapy to slow progression of VC was assessed in a study of 35 hemodialysis patients by use of MSCT.33 Patients were left untreated for 1 year and were then treated with etidronate. Twenty-six of 35 hemodialysis patients showed a significant decrease in coronary-artery calcium score progression with etidronate treatment (median absolute increase in score without and with treatment 490 mm3 v 195 mm3; P ⬍ .01).33 Interestingly, bone-mineral density measured by DEXA did not change significantly with and without etidronate. On the contrary, by use of quantitative CT technology Raggi et al34 demonstrated an increase in vertebral bone density in patients treated with sevelamer, as compared with calcium salts–treated patients, who showed a progressive loss in density. In summary, modern cardiac CT techniques allow accurate assessment of VC and quantification of its progression. Although assessment of coronary-artery calcium is an accepted and established technique to assess risk of events in the general population, similar data are just emerging in CKD populations. However, the technology has some limitations. Subintimal (atherosclerotic) calcification and medial calcification in the arterial wall cannot be differentiated with the current CT methodologies. This approach is further limited by the cost of CT and the substantial radiation exposure. Thus, other noninvasive imaging techniques may be preferable to screen for the presence of VC, whereas CT may be reserved to study proof of concept of pathogenesis and progression of VC.
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Arterial Compliance Worsening renal function, as well as aging and multiple cardiovascular risk factors, contribute to the development of vascular stiffness. Wang et al 35 demonstrated that arterial stiffness increases as the estimated GFR declines. A well-validated method for the assessment of arterial stiffness is “pulse-wave velocity” (PWV). This method allows measurement of the velocity of propagation of a wave front caused by the ejection of a bolus of blood from the heart into the aortic root (Fig 3). The velocity increases as the stiffness of the vessel increases, and, to a degree, increased PWV could be considered an indirect marker of the presence of VC. Haydar et al36 showed that aortic PWV was significantly and strongly correlated with EBCT-generated coronaryartery calcium scores in a cohort of 82 CKD patients (r ⫽ 0.65; P ⫽ .0001), even after adjustment for confounding variables. Guerin et al31 also showed that PWV increased as the daily dose of calcium carbonate increased and the level of iPTH decreased in a cohort of 120 hemodialysis patients. In the same cohort, increased PWV was associated with a simple calcification score obtained with a combination of carotid ultrasound and plain radiographs of the abdominal aorta and the femorotibial axes.31 A significant increase in PWV was noted across different VC groups (from 9.14 m/s in the group with no evidence of VC to 13.02 m/s in the group with all arterial regions calcified; P ⫽ .001).31 More importantly, increased aortic PWV was shown to be an independent predictor of all-cause and CV mortality.37 Hence, reduced arterial compliance and VC appear closely related, and both are markers of increased mortality risk. Prospective studies will be required to investigate whether changes in VC will also result in changes in arterial stiffness, as well as a reduction in adverse outcomes.
Conclusion Increasing awareness of the negative prognostic impact of VC in patients undergoing dialysis has generated great interest in the natural history and pathogenesis of this condition.
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Raggi and Bellasi
Figure 3. Example of normal and abnormal pulse-wave velocity measurements in two maintenancehemodialysis patients. A normal pulse-wave velocity is approximately 8 m/s. The instrument used in these examples calculates the time interval between the R-wave on the electrocardiogram and the beginning of the pressure upstroke at the carotid and femoral artery. Knowing the distance between the carotid and femoral artery measured on the body surface allows calculation of conduction velocity (distance in meters over time in seconds).
The identification of factors associated with the deposition of VC, as well as its progression, sparked a wave of research into methods to assess VC and to inhibit its progression. Though quantitatively accurate, CT technologies are expensive, deliver a substantial dose of radiation, and cannot be easily performed in an ambulatory setting. Hence, the Global Bone and Mineral Initiative on behalf of the National kidney Foundation,38 recently proposed a simplified approach to identify and semiquantitatively assess the extent of VC in CKD-5 patients. This approach includes a combination of echocardiography to detect valvular calcification, plain x-rays for peripheral and abdominal aorta calcification, and measurement of pulse pressure as an index of arterial stiffness. The prognostic significance of this approach will need to be evaluated in future prospective studies, but preliminary evidence indicates that a combination of sim-
ple in-office methods correlates well with CTbased approaches to assess VC.
References 1. Blacher J, Guerin AP, Pannier B, et al: Arterial calcifications, arterial stiffness, and cardiovascular risk in endstage renal disease. Hypertension 38:938-942, 2001 2. Matsuoka M, Iseki K, Tamashiro M, et al: Impact of high coronary artery calcification score (CACS) on survival in patients on chronic hemodialysis. Clin Exp Nephrol 8:54-58, 2004 3. Shaw LJ, Raggi P, Schisterman E, et al: Prognostic value of cardiac risk factors and coronary artery calcium screening for all-cause mortality. Radiology 228: 826-833, 2003 4. London GM, Guerin AP, Marchais SJ, et al: Cardiac and arterial interactions in end-stage renal disease. Kidney Int 50:600-608, 1996 5. London GM, Guerin AP, Marchais SJ: Pathophysiology of left ventricular hypertrophy in dialysis patients. Blood Purif 12:277-283, 1994 6. Wilson PW, Kauppila LI, O’Donnell CJ, et al: Abdominal aortic calcific deposits are an important predictor
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of vascular morbidity and mortality. Circulation 103:1529-1534, 2001 London GM, Guerin AP, Marchais SJ, et al: Arterial media calcification in end-stage renal disease: Impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 18:1731-1740, 2003 Adragao T, Pires A, Lucas C, et al: A simple vascular calcification score predicts cardiovascular risk in haemodialysis patients. Nephrol Dial Transplant 19:14801488, 2004 K/DOQI: Clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis 45:S1-S153, 2005 (suppl) Bellasi A, Ferramosca E, Muntner P, et al: Correlation of simple imaging tests and coronary calcium score measured by computed tomography in hemodialysis patients. Kidney Int 70:1623-1628, 2006 Ribeiro S, Ramos A, Brandao A, et al: Cardiac valve calcification in haemodialysis patients: Role of calcium-phosphate metabolism. Nephrol Dial Transplant 13:2037-2040, 1998 Kajbaf S, Veinot JP, Ha A, et al: Comparison of surgically removed cardiac valves of patients with ESRD with those of the general population. Am J Kidney Dis 46:86-93, 2005 Otto CM, Lind BK, Kitzman DW, et al: Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. N Engl J Med 341:142147, 1999 Wang AY, Wang M, Woo J, et al: Cardiac valve calcification as an important predictor for all-cause mortality and cardiovascular mortality in long-term peritoneal dialysis patients: A prospective study. J Am Soc Nephrol 14:159-168, 2003 Wang AY, Woo J, Lam CW, 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 Wang AY, Ho SS, Wang M, et al: Cardiac valvular calcification as a marker of atherosclerosis and arterial calcification in end-stage renal disease. Arch Intern Med 165:327-332, 2005 Pohle K, Maffert R, Ropers D, et al: Progression of aortic valve calcification: Association with coronary atherosclerosis and cardiovascular risk factors. Circulation 104:1927-1932, 2001 Raggi P, Bommer J, Chertow GM: Valvular calcification in hemodialysis patients randomized to calciumbased phosphorus binders or sevelamer. J Heart Valve Dis 13:134-141, 2004 Stanford W, Thompson BH, Burns TL, et al: Coronary artery calcium quantification at multi-detector row helical CT versus electron-beam CT. Radiology 230: 397-402, 2004 Moe SM, O’Neill KD, Fineberg N, et al: Assessment of vascular calcification in ESRD patients using spiral CT. Nephrol Dial Transplant 18:1152-1158, 2003 Nitta K, Akiba T, Suzuki K, et al: Assessment of coronary artery calcification in hemodialysis patients using multi-detector spiral CT scan. Hypertens Res 27:527-533, 2004
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22. Agatston AS, Janowitz WR, Hildner FJ, et al: Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 15:827-832, 1990 23. Callister TQ, Cooil B, Raya SP, et al: Coronary artery disease: Improved reproducibility of calcium scoring with an electron-beam CT volumetric method. Radiology 208:807-814, 1998 24. Russo D, Palmiero G, De Blasio AP, et al: Coronary artery calcification in patients with CRF not undergoing dialysis. Am J Kidney Dis 44:1024-1030, 2004 25. 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 39:695-701, 2002 26. Sigrist M, Bungay P, Taal MW, et al: Vascular calcification and cardiovascular function in chronic kidney disease. Nephrol Dial Transplant 21:707-714, 2006 27. Oh J, Wunsch R, Turzer M, et al: Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure. Circulation 106:100105, 2002 28. Goodman WG, Goldin J, Kuizon BD, et al: Coronaryartery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 342:1478-1483, 2000 29. Chertow GM, Raggi P, Chasan-Taber S, et al: Determinants of progressive vascular calcification in haemodialysis patients. Nephrol Dial Transplant 19:14891496, 2004 30. Chertow GM, Burke SK, Raggi P: Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 62:245-252, 2002 31. Guerin AP, London GM, Marchais SJ, et al: Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant 15:1014-1021, 2000 32. Block GA, Spiegel DM, Ehrlich J, et al: Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int 68: 1815-1824, 2005 33. Nitta K, Akiba T, Suzuki 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 34. Raggi P, James G, Burke S, et al: Paradoxical decrease in vertebral bone density with calcium-based phosphate binders in hemodialysis. J Bone Min Res 20:76472, 2005 35. Wang MC, Tsai WC, Chen JY, et al: Stepwise increase in arterial stiffness corresponding with the stages of chronic kidney disease. Am J Kidney Dis 45:494-501, 2005 36. Haydar AA, Covic A, Colhoun H, et al: Coronary artery calcification and aortic pulse wave velocity in chronic kidney disease patients. Kidney Int 65:17901794, 2004 37. Guerin AP, Blacher J, Pannier B, et al: Impact of aortic stiffness attenuation on survival of patients in endstage renal failure. Circulation 103:987-992, 2001 38. Goodman WG, London G, Amann K, et al: Vascular calcification in chronic kidney disease. Am J Kidney Dis 43:572-579, 2004
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ardiovascular calcification has been associated with a substantially increased risk of cardiovascular morbidity and mortality in dialysis patients, as well as in the general population.1-3 Diffuse calcification of the large-conduit arteries promotes arterial stiffness, with deleterious hemodynamic consequences.4 The systolic blood pressure increases in conjunction with a decrease in diastolic blood pressure, with altered coronary perfusion and subsequent left ventricular hypertrophy all predisposing to myocardial ischemia and arrhythmias.5 Because the progression of vascular calcification appears to be slowed by some therapies, screening for the presence of cardiovascular calcification is important. Plain x-rays of abdomen and extremities, two-dimensional ultrasound, and echocardiography can be used to identify vascular calcifications in various blood vessels such as carotid arteries, femoral arteries, and aorta, as well as the cardiac valves. More sophisticated and expensive imaging technologies, such as electronbeam computed tomography (EBCT) and multislice computed tomography (MSCT), have emerged as tools to evaluate and accurately quantify cardiovascular calcification. These modalities allow not only detection but also monitoring of calcification progression and effectiveness of different therapeutic strategies applied to slow progression. A clinical approach based on application of some of these techniques may provide sub-
stantial aid in improving outcomes in dialysis patients. In this article, we review the strengths and limitations and some of the clinical evidence linked with commonly employed noninvasive techniques for imaging of vascular calcification.
Roentgenography Plain radiography is a helpful and inexpensive tool for identification of vascular calcification (VC), both in the general population6 and in chronic kidney disease (CKD) patients (Fig 1).7 Plain radiographs may localize calcification patterns in the arterial wall, which helps distinguish intimal from media calcification. Medial calcification is usually considered present when linear, tram-track, radiopaque lesions are visible along the course of an artery, whereas intimal calcification is more characteristically identified by patchy and irregular radiopaque lesions. Both types of calcifications have been associated with adverse clinical outcomes. In fact, despite the absence of luminal obstruction, the loss From the Emory University School of Medicine, Division of Cardiology and Department of Radiology, Atlanta, GA; and Ospedale San Paolo and University of Milan, Department of Nephrology, Milan, Italy. Address correspondence to Paolo Raggi, MD, FACP, FACC, Emory University School of Medicine, 1365 Clifton Road NE, AT-504, Atlanta, GA 30322. E-mail: [email protected] © 2007 by the National Kidney Foundation, Inc. 1548-5595/07/1401-0007$32.00/0 doi:10.1053/j.ackd.2006.10.006
Advances in Chronic Kidney Disease, Vol 14, No 1 (January), 2007: pp 37-43
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Raggi and Bellasi
Figure 1. Plain radiographs of the right foot of a 54-year-old Caucasian patient with diabetes mellitus and hypertension on maintenance hemodialysis for 16 months. Note the heavy calcification of the calcaneal-plantar (a) and plantar interdigital (b) arteries (white arrows).
of arterial compliance ultimately reduces end-organ perfusion and increases myocardial afterload, with an attendant increase in cardiovascular morbidity and mortality. Some clinical evidence supports this notion. In a cross-sectional study of 202 hemodialysis patients, medial and intimal calcification were detected in 27% and 37% of the x-ray films of the pelvis and thighs. In that study, both medial and intimal calcification were independently associated with all-cause mortality (RR ⫽ 15.7 [95% CI: 4.8 to 51.4; P ⬍ .00001] and 4.85 [95% CI: 1.68 to 14.1; P ⫽ .0036], respectively).7 Adragao et al8 used plain x-rays of the pelvis and hands in a cross-sectional study of 123 hemodialysis patients to generate a simple VC score. The score was devised by assigning
a point each for the presence of calcification in the iliac, femoral, digital, and radial arteries of either limb (score 0 for no calcification to 8 if all four vessels were calcified bilaterally). VC was detected in 75% of the study patients, and almost half of the patients had a score equal to or greater than 3. During 37 months of followup, mortality was approximately fivefold higher in patients with a baseline score equal to or greater than 3, compared with patients with a score less than 3 (23% v 5%; P ⫽ .01). Even after adjustment for confounding variables, this simple score of VC was predictive of mortality (hazard ratio for score ⱖ 3: 3.9 [95% CI: 1.1 to 12.4; P ⫽ .03]). Plain radiographs are qualitative and do not allow for an accurate assessment of temporal changes of VC. Nonetheless, they seem to provide valid prognostic information, and, given the low cost and risk to the patient, they may be worth implementing as an in-office tool to screen for the presence of VC. Indeed, radiographs of the lumbar spine to visualize abdominal aorta calcification were recommended by a group of experts of the National Kidney Foundation9 and were shown to hold a good correlation with CT-derived calcium scores.10 In a series of 140 hemodialysis patients, a semiquantitative score of abdominal aorta calcification seen on a lateral lumbar plain x-ray demonstrated a sensitivity of 76% for the prediction of a coronary artery calcium score greater than 30 on CT.10 This information should provide guidance as to the presence and extent of VC for the clinician who could then modify his treatment approach in accordance with the most recent K/DOQI guidelines for cardiovascular disease in CKD stage 5 (CKD-5) patients.
Ultrasonography Ultrasound studies rely on the universal availability of the tool, the relative inexpensive nature of the test, and the ease of identification of superficial vessels such as the carotid and femoral arteries. These methods, however, like plain radiography, provide only a qualitative assessment of VC. Nonetheless, good evidence supports their prognostic utility. Blacher et al1 used a combination of vascular ultrasound and plain radiographs to de-
Clinical Assessment of Vascular Calcification
tect VC of the common carotid arteries, the abdominal aorta, and the femorotibial axes. They prospectively followed 110 patients on maintenance hemodialysis for an average of 53 ⫾ 21 months after having stratified them according to a score generated by the combination of ultrasound and x-ray findings. These investigators showed that the mere presence of VC and the number of affected sites were associated with all-cause mortality, as well as cardiovascular mortality. The adjusted hazard ratios for all-cause and cardiovascular mortality for each point increase in calcification severity were 1.9 (95% CI: 1.4 to 2.6) and 2.6 (95% CI: 1.2 to 2.4), respectively (P ⬍ .01 for both).1 The portability, safety, and low cost of ultrasound imaging make it desirable for inoffice applications.
Echocardiography Echocardiography is the gold standard for assessment of cardiac-valve morphology and function; it is noninvasive, uses no radiation, and is only moderately expensive. Calcification of the cardiac valves is found in dialysis patients, with a prevalence 4 to 5 times higher than in the general population.11 Although a less frequent finding than VC, valvular calcification shares common risk factors and pathogenic features with VC.11 It appears that calcification of valves and vessels follows similar pathophysiologic pathways, as inflammatory cells, lipoproteins, and bone-matrix proteins have been found in both structures.12 Mounting clinical evidence suggests that calcification of the mitral and the aortic valve is associated with poor prognosis in the general population, 13 as well as in CKD-stage 5 patients.14 In an earlier publication, Riberio et al11 noted that valvular calcification is more prevalent in hemodialysis patients than in patients with normal kidney function (mitral calcification 44.5% v 10%, P ⫽ .02; aortic calcification 52% v 4.3%, P ⫽ .01). In that study, mitral and aortic calcification were significantly associated with peripheral-arterial calcification (P ⫽ .009) and alterations of mineral metabolism.11 More recently, valvular calcification has been associated with an adverse outcome. During a mean follow-up of 18
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months, Wang et al,14 showed a marked increase in all-cause mortality, as well as cardiovascular mortality, in 192 peritoneal dialysis patients with no (15%, 7%), one (40%, 26%), or two (57%, 45%) calcified valves, respectively. All-cause and cardiovascular mortality did not differ significantly between patients with either valvular calcification or atherosclerotic vascular disease, which reinforces the hypothesis that valvular calcification represents a marker of systemic cardiovascular disease. In a later publication, the same group demonstrated the interaction between serum fetuin-A levels, malnutrition, inflammation, atherosclerosis, and valvular calcification, with a negative outcome in 238 peritoneal dialysis patients.15 The serum fetuin-A level was inversely related to the presence of valvular calcification and cardiovascular outcome of these patients. Valvular calcification has also been demonstrated to relate well to another marker of atherosclerosi, carotid intimamedia thickness (CIMT).16 For each 1-mm increase in CIMT, the investigators demonstrated a 6.5-fold (95% CI: 1.58 to 26.73; P ⫽ .009) increased risk of valvular calcification in a cohort of 92 continuous ambulatory peritoneal-dialysis patients.16 Furthermore, the presence of carotid calcification and carotid plaques was associated with a 7.2-fold (95% CI: 2.39 to 21.51; P ⫽ .001) and 5.0-fold (95% CI: 1.77 to 14.13; P ⫽ .002) increased risk of valvular calcification.16 Of interest, attenuation of valvular calcification progression has been demonstrated in the general population with statins17 and in CKD-5 patients receiving sevelamer treatment.18 Valvular calcification is a marker of systemic cardiovascular disease and an indicator of risk in CKD patients. Therefore, possibly in the near future, identification of valvular calcification in dialysis patients may be advocated as a method to assess risk and may lead to changes in management of these patients.
Computed Tomography Techniques Electron-beam computed tomography (EBCT) and multislice computed tomography (MSCT) represent the gold standard for assessing the extent of cardiovascular calcification (VC) and its progression (Fig 2). Although EBCT pro-
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Figure 2. Volume-rendered image of the heart and ascending aorta on CT imaging. The soft tissues are semitransparent, and calcified areas are reproduced as a dense white signal. AsAo: ascending aorta; LAD: left anterior descending coronary artery; LCX: left circumflex coronary artery; LM: left main coronary artery; LV: left ventricle; RCA: right coronary artery; RV: right ventricle.
vides better temporal resolution (can image at higher heart rates), and MSCT provides better spatial resolution (the scanner is slower but the picture is “crispy”), the two technologies can be considered equivalent, especially when comparing EBCT to the most recent MSCT scanners (16 slice or greater).19-21 With CT imaging, VC can be accurately detected and its extent precisely quantified by means of scores such as the Agatston22 and the volume score.23 The Agatston score is calculated as the product of area (total surface of calcification) by peak density (also known as attenuation), measured in the context of the plaque. Hence, it incorporates information relating to size, as well as calcium content, of the plaque.22 The volume score takes into consideration all pixels in the context of a plaque, with a minimum density of 130 Hounsfield units (a CT measure of density).23 This technique is a more direct evaluation of the size of a plaque not influenced by the calcium content. Computed tomography (CT) technologies have been employed to investigate the natural history of VC and the impact of different
therapeutic strategies in CKD-5. By use of CT, the prevalence of coronary-artery calcification was reported to be 40% in 85 CKD stage 4 (CKD-4) patients24 and approximately 85% in 205 maintenance-hemodialysis patients.25 On the contrary, VC was found only in 13% of control subjects with normal kidney function.24 Consistent with these findings, Sigrist et al.26 reported a prevalence of coronary calcification of 46% in 46 CKD-4 patients compared with 70% and 73 %, respectively in 60 hemodialysis and 28 peritoneal- dialysis patients (P ⫽ .02). Obviously, the prevalence of VC increases dramatically after initiation of dialysis. Extensive coronary-artery calcium can be found not only in adult but also in pediatric and young hemodialysis patients (aged 19 to 39 years),27,28 and both groups show a strong trend toward rapid progression of VC. In early studies, CT-generated calcium scores appear to be predictive of an unfavorable outcome in dialysis patients.2 Matsuoka et al2 followed 104 long-term hemodialysis patients for an average of 43 months after a screening EBCT. Patients with a baseline coronary-calcium score above the median (score ⬃200) had a significantly lower (all-cause) survival than did patients with a score below the median (67.9% v 84.2% P ⫽ .0003). Several factors seem to affect progression of VC in dialysis patients. Among others were age, baseline calcium score, dialysis vintage, diabetes mellitus abnormalities of mineral metabolism,14,25,28-30 and use and dose of calcium-based phosphate binders.30,31 Sevelamer and calcium-based phosphate binders were compared in a randomized clinical trial of 200 maintenance-hemodialysis patients, to assess the progression of VC.30 The subjects were randomized to 1 year of open-label treatment with either sevelamer or calcium salts. Throughout the study, both drugs provided comparable phosphate control (P ⫽ .33). However, patients treated with calcium salts had a significantly higher serum-calcium concentration (P ⫽ .002), a greater incidence of hypercalcemic episodes (16% v 5%; P ⫽ .04), and a larger number of subjects with parathyroid hormone (PTH) levels below the lower recommended limit of 150 pg/mL (57% v 30%, P ⫽ .001). At study completion, patients
Clinical Assessment of Vascular Calcification
treated with calcium salts showed a significant progression of VC, whereas sevelamertreated subjects did not (median absolute progression of coronary-artery calcium score 36.6 v 0, P ⫽ .03 and aorta 75.1 v 0, P ⫽ .01, respectively).30 A similar protocol was adopted in a second study of 129 incident hemodialysis patients.32 Subjects treated with calciumcontaining phosphate binders showed a more rapid and more severe increase in coronaryartery calcium score compared with those who received sevelamer (P ⫽ .01 at 18 months follow-up).32 Other therapeutic agents with potential to inhibit VC progression have been utilized in small studies. The effect of cyclic intermittent etidronate therapy to slow progression of VC was assessed in a study of 35 hemodialysis patients by use of MSCT.33 Patients were left untreated for 1 year and were then treated with etidronate. Twenty-six of 35 hemodialysis patients showed a significant decrease in coronary-artery calcium score progression with etidronate treatment (median absolute increase in score without and with treatment 490 mm3 v 195 mm3; P ⬍ .01).33 Interestingly, bone-mineral density measured by DEXA did not change significantly with and without etidronate. On the contrary, by use of quantitative CT technology Raggi et al34 demonstrated an increase in vertebral bone density in patients treated with sevelamer, as compared with calcium salts–treated patients, who showed a progressive loss in density. In summary, modern cardiac CT techniques allow accurate assessment of VC and quantification of its progression. Although assessment of coronary-artery calcium is an accepted and established technique to assess risk of events in the general population, similar data are just emerging in CKD populations. However, the technology has some limitations. Subintimal (atherosclerotic) calcification and medial calcification in the arterial wall cannot be differentiated with the current CT methodologies. This approach is further limited by the cost of CT and the substantial radiation exposure. Thus, other noninvasive imaging techniques may be preferable to screen for the presence of VC, whereas CT may be reserved to study proof of concept of pathogenesis and progression of VC.
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Arterial Compliance Worsening renal function, as well as aging and multiple cardiovascular risk factors, contribute to the development of vascular stiffness. Wang et al 35 demonstrated that arterial stiffness increases as the estimated GFR declines. A well-validated method for the assessment of arterial stiffness is “pulse-wave velocity” (PWV). This method allows measurement of the velocity of propagation of a wave front caused by the ejection of a bolus of blood from the heart into the aortic root (Fig 3). The velocity increases as the stiffness of the vessel increases, and, to a degree, increased PWV could be considered an indirect marker of the presence of VC. Haydar et al36 showed that aortic PWV was significantly and strongly correlated with EBCT-generated coronaryartery calcium scores in a cohort of 82 CKD patients (r ⫽ 0.65; P ⫽ .0001), even after adjustment for confounding variables. Guerin et al31 also showed that PWV increased as the daily dose of calcium carbonate increased and the level of iPTH decreased in a cohort of 120 hemodialysis patients. In the same cohort, increased PWV was associated with a simple calcification score obtained with a combination of carotid ultrasound and plain radiographs of the abdominal aorta and the femorotibial axes.31 A significant increase in PWV was noted across different VC groups (from 9.14 m/s in the group with no evidence of VC to 13.02 m/s in the group with all arterial regions calcified; P ⫽ .001).31 More importantly, increased aortic PWV was shown to be an independent predictor of all-cause and CV mortality.37 Hence, reduced arterial compliance and VC appear closely related, and both are markers of increased mortality risk. Prospective studies will be required to investigate whether changes in VC will also result in changes in arterial stiffness, as well as a reduction in adverse outcomes.
Conclusion Increasing awareness of the negative prognostic impact of VC in patients undergoing dialysis has generated great interest in the natural history and pathogenesis of this condition.
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Figure 3. Example of normal and abnormal pulse-wave velocity measurements in two maintenancehemodialysis patients. A normal pulse-wave velocity is approximately 8 m/s. The instrument used in these examples calculates the time interval between the R-wave on the electrocardiogram and the beginning of the pressure upstroke at the carotid and femoral artery. Knowing the distance between the carotid and femoral artery measured on the body surface allows calculation of conduction velocity (distance in meters over time in seconds).
The identification of factors associated with the deposition of VC, as well as its progression, sparked a wave of research into methods to assess VC and to inhibit its progression. Though quantitatively accurate, CT technologies are expensive, deliver a substantial dose of radiation, and cannot be easily performed in an ambulatory setting. Hence, the Global Bone and Mineral Initiative on behalf of the National kidney Foundation,38 recently proposed a simplified approach to identify and semiquantitatively assess the extent of VC in CKD-5 patients. This approach includes a combination of echocardiography to detect valvular calcification, plain x-rays for peripheral and abdominal aorta calcification, and measurement of pulse pressure as an index of arterial stiffness. The prognostic significance of this approach will need to be evaluated in future prospective studies, but preliminary evidence indicates that a combination of sim-
ple in-office methods correlates well with CTbased approaches to assess VC.
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