Prevalence and Predictors of Cardiovascular Calcium in Chronic Kidney Disease (from the Prospective Longitudinal RRI-CKD Study)

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1 Prevalence and Predictors of Cardiovascular Calcium in Chronic Kidney Disease (from the Prospective Longitudinal RRI-CKD Study) Santo Dellegrottaglie, MD a, *, Rajiv Saran, MD d, Brenda Gillespie, PhD d, Xiaotong Zhang, MA d, Soyoung Chung, MA d, Fredric Finkelstein, MD e, Margaret Kiser, MD f, Javier Sanz, MD a, George Eisele, MD c, Alan L. Hinderliter, MD g, Martin Kuhlmann, MD b, Nathan W. Levin, MD b, and Sanjay Rajagopalan, MD a Although the determinants of cardiovascular calcium have been well described in dialysis patients, the prevalence and predictors in predialysis chronic kidney disease (CKD) are less known. One hundred six patients with CKD from the Renal Research Institute-CKD Study underwent multidetector computed tomography for the assessment of calcium deposition at the level of coronary arteries, thoracic aorta, aortic valve, and mitral valve. Cardiovascular risk factors and renal function-related parameters (glomerular filtration rate, glomerular filtration rate slope, serum creatinine, serum urea nitrogen, hemoglobin, albumin, calcium, phosphate, and parathyroid hormone) were included in multivariate regression models to predict cardiovascular calcium. Prevalences of calcium deposition at the level of coronary arteries, thoracic aorta, aortic valve, and mitral valve were 69%, 46%, 39%, and 16%, respectively. On multivariate analysis, coronary artery calcium score was predicted by age (p <0.0001), gender (p ), diabetes (p 0.024), and history of coronary artery disease (p 0.016), but not by renal function related parameters. Similarly, renal function related parameters were not predictive of aortic or valvular calcium. In conclusion, predialysis CKD is associated with a high prevalence of cardiovascular calcium. The extent of cardiovascular calcium in patients with predialysis CKD is related to some of the traditional risk factors for atherosclerosis but not to indexes of abnormal renal function or progression in renal dysfunction Elsevier Inc. All rights reserved. (Am J Cardiol 2006;98: ) Chronic kidney disease (CKD) is associated with a high incidence of cardiovascular events. 1 3 Cardiovascular calcium deposition has long been recognized as a common finding in patients with renal failure. 4,5 This study investigated the prevalence of cardiovascular calcium deposition and its relation to cardiovascular risk factors and renal function related parameters in a prospective cohort of patients with predialysis CKD who were included in the Renal Research Institute (RRI)-CKD study. Methods Study design: The RRI-CKD study is a multicenter, prospective, observational study involving 799 adult patients with The a Zena and Michael A. Wiener Cardiovascular Institute and Marie- Josée and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai Medical Center, and the b Renal Research Institute, New York, and the c Division of Nephrology, Department of Internal Medicine, Albany Medical Center, Albany, New York; the d Division of Nephrology and Kidney Epidemiology and Cost Center, University of Michigan, Ann Arbor, Michigan; the e Division of Nephrology, Hospital of St. Raphael, Yale University, New Haven, Connecticut; and the f Division of Nephrology, Department of Internal Medicine, and the g Division of Cardiology, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina. Manuscript received December 17, 2005; revised manuscript received and accepted March 8, *Corresponding author: Tel: ; fax: address: santo.dellegrottaglie@mssm.edu (S. Dellegrottaglie). moderate to severe predialysis CKD (stages III to V). 6 Patients with a glomerular filtration rate (GFR) 50 ml/min/1.73 m 2 (as calculated by the abbreviated Modification of Diet in Renal Disease equation at 2 separate measurements 1 month apart) 7 were invited to participate in the main study. The institutional review boards of the participating centers approved the protocol. A subset of the recruited subjects agreed to undergo investigations specific to the cardiovascular substudy and signed a separate informed consent form. In total, 106 patients in the cardiovascular cohort underwent multidetector computed tomography at the time of recruitment and were included in the present analysis. Overall, the clinical characteristics of this subgroup were not significantly different from those included in the overall RRI- CKD registry. Other variables collected at the time of multidetector computed tomography included demographic characteristics, cardiovascular co-morbidities, and biochemical parameters (including serum creatinine, serum urea nitrogen, electrolytes, hemoglobin, albumin, calcium, phosphate, intact parathyroid hormone, glucose, lipid panel, and C-reactive protein). The rate of change in renal function during the time since referral to the nephrology clinics was expressed as GFR slope (milliliters per minute per 1.73 m 2 per month). This was calculated using linear regression on the GFR /06/$ see front matter 2006 Elsevier Inc. All rights reserved. doi: /j.amjcard

2 572 The American Journal of Cardiology ( values over time for each patient. At least 2 GFR values obtained at different time points were required. An average of 10 measurements per patient (median 9 values, range 2 to 20) was used to derive a slope in each patient over a mean duration of 4.4 years (range 0.2 to 18.7). Based on the GFR slope, patients were dichotomized into those with stable renal function (slope 0, group 1) and those with deteriorating renal function (slope 0, group 2). Patients were considered to have coronary artery disease if there was a history of myocardial infarction, angina pectoris, or evidence of obstructive disease by angiography or previous revascularization. Congestive heart failure was diagnosed in patients with clinical manifestations of heart failure associated with evidence (typically obtained by echocardiography) of left ventricular dysfunction at rest. Hypertension was defined as a systolic blood pressure 140 mm Hg, a diastolic blood pressure 90 mm Hg, or use of medications specifically to optimize blood pressure control. Subjects with fasting glycemic values 130 mg/dl and/or receiving oral antihyperglycemic agents or insulin treatment were defined as diabetic. Dyslipidemia was defined as present if the low-density cholesterol level was 130 mg/dl, the highdensity cholesterol level was 40 mg/dl, or if the patient was treated with lipid-lowering medications. Obesity was defined by a body mass index 30 kg/m 2. The level of self-reported physical activity was evaluated in each patient and was quantified using scale units (from 1 to 6) based on the frequency of exercise sessions per week (1 daily or almost daily; 2 4 to 5 times a week; 3 2 to 3 times a week; 4 about 1 time a week; 5 1 time a week; 6 almost never or never). A condition of decreased physical activity was excluded if the patient exercised 1 time per week. Multidetector computed tomographic protocol: All subjects underwent multidetector computed tomography using a 4-slice LightSpeed QXi or 8-slice LightSpeed Ultra multidetector computed tomographic scanner (General Electric Medical Systems, Milwaukee, Wisconsin) with prospective cardiac gating. Patients were instructed to hyperventilate briefly just before scanning. Images were obtained during a single breath-hold ( 20 seconds). Tomographic imaging proceeded from the level of the carina to the diaphragm, thus excluding the entire aortic arch in most patients. Imaging parameters consisted of an x-ray tube at 120 kv and 320 ma, 2.5-mm collimation, and 0.5-second gantry rotation time. Images were acquired in diastole (60% of RR interval) and reconstructed with a 2.5-mm slice width and using a medium sharp convolution kernel (B35f). All scans were scored for coronary calcium using a coronary artery calcium (CAC) scoring software (Smart- Score, General Electric Medical Systems) by an expert investigator who was unaware of subjects identities. Clusters of calcified lesions were automatically highlighted in color based on a threshold of 130 HU. After manual confirmation of each cluster of calcium, total values for the Agatston score and the volumetric score were obtained. 8,9 Figure 1. Distribution of CAC scores in the total study population of 106 subjects with CKD. Max maximum; Min minimum. Because the Agatston score and volumetric score were highly correlated at all levels (r 0.99, p ), only the Agatston score was included in subsequent analyses. Calcium scores were separately obtained at the levels of the coronary arteries, thoracic aorta, aortic valve, and mitral valve. Each final score was the sum of the values obtained in each single axial image of the scan. In a subgroup of 85 patients, the CAC score was calculated again by a second observer. Statistical analyses: Descriptive statistics of continuous variables included means, medians, and SDs. With respect to demographics, cardiovascular risk factors, and renal function related parameters, patients were characterized in intervals of CAC scores defined by cutpoints (e.g., 0 to 100, 101 to 400, and 400) that in previous reports identified populations with significantly different cardiovascular risks. 10 Comparisons between categories of CAC score were made by using analysis of variance with Tukey s adjustment for multiple comparisons. Multiple regression analysis was also performed to identify patient characteristics associated with log-transformed calcium scores, which was adjusted for age, race, gender, diabetes mellitus, hypertension, serum albumin, C-reactive protein, body mass index, systolic blood pressure, and GFR slope. In addition, 100 and 100 cut-off points were used as binary dependent variables for the CAC score, with odds ratios and confidence intervals subsequently calculated. Comparisons across mean CAC scores measured in the 2 groups defined by GFR slope as group 1 (stable renal function) and group 2 (deteriorating renal function) were performed with a t test and Wilcoxon s test. CAC scores that were reread in the subgroup of 85 patients showed excellent values of interobserver correlation (Pearson s r 0.95 for log-transformed values, p ). All analyses were conducted with SAS 9.1 (SAS Institute, Cary, North Carolina). Results The mean age of the population was years; 58% of patients were men and 75% were Caucasian. The mean

3 Coronary Artery Disease/Vascular Calcium in CKD 573 Table 1 Renal function-related parameters measured in the study population stratified by coronary artery calcium score Characteristics CAC Score p Value (n 56) (n 20) 400 (n 30) GFR (ml/min/1.73 m 2 ) Creatinine (mg/dl) Blood urea nitrogen (mg/dl) Serum potassium (meq/l) Hemoglobin (g/dl) Albumin (g/dl) Calcium* (mg/dl) Phosphorus (mg/dl) Calcium phosphorus (mg 2 /dl 2 ) Intact parathyroid hormone (pg/ml) Values are means SD. * Albumin-adjusted serum calcium. Table 2 Clinical characteristics of the study population stratified by coronary artery calcium score Characteristics CAC Score p Value 100 (n 56) (n 20) 400 (n 30) Age (yrs) Men 24 (43%) 15 (75%) 22 (73%) White 37 (66%) 17 (85%) 26 (87%) Diabetes mellitus* 11 (20%) 4 (20%) 13 (43%) Hypertension* 46 (82%) 18 (90%) 27 (90%) Dyslipidemia* 20 (36%) 9 (45%) 10 (33%) Obesity* 18 (32%) 5 (25%) 12 (40%) Decreased physical activity* 19 (34%) 2 (10%) 14 (47%) Coronary artery disease* 4 (7%) 3 (15%) 14 (47%) Congestive heart failure* 0 1 (5%) 6 (20%) Cardiovascular risk-related parameters Systolic blood pressure (mm Hg) Total cholesterol (mg/dl) Low-density lipoprotein cholesterol (mg/dl) High-density lipoprotein cholesterol (mg/dl) Triglycerides (mg/dl) Body mass index (kg/m 2 ) Exercise training length (U) C-reactive protein (mg/l) Values are means SD or numbers of patients (percentages). * See Methods for definition. GFR in the overall study population was ml/ min/1.73 m 2. Most patients were in CKD stage IV (n 78 patients, 73%), and the remainder were in stage III (n 21 patients, 20%) and stage V (n 7 patients, 7%). The etiology of CKD was largely related to hypertension (58%) and diabetes (25%), with polycystic kidney disease, interstitial nephritis, and glomerulonephritis constituting the remainder of cases. Prevalence and severity of cardiovascular calcium: Overall, 73 patients (69%) exhibited some coronary calcium (Figure 1), with a mean CAC score of 809 1,336 (range 1 to 8,547, median 277) in this group. More than 37% of patients had CAC score 75th percentile for age- and gender-matched subjects without CKD from previously published nomograms, and 15% of patients showed values 90th percentile. 11 Calcium was present at the level of thoracic aorta in 46% of patients (n 85), with a mean value of 1,458 2,056 (median 683, range 2 to 8,427). A positive aortic valve calcium score was seen in 39% of patients (mean , median 176, range 1 to 3,352) and was more frequent than a positive mitral valve calcium score (prevalence 16%, mean 708 1,202, median 135, range 4 to 3,512). CAC score was correlated with thoracic aortic calcium score (r 0.60, p ), aortic valve calcium score (r 0.47, p ), and mitral valve calcium score (r 0.24, p 0.026) on a logarithmic scale.

4 574 The American Journal of Cardiology ( Table 3 Predictors of coronary artery calcium score (natural log-transformed) by multiple regression analysis Parameter Estimate 95% CI p Value Age to White race to Male gender to Diabetes mellitus* to Coronary artery disease* to Hypertension* to Congestive heart failure* to Total cholesterol to High-density lipoprotein to cholesterol Low-density lipoprotein to cholesterol Triglycerides to Serum albumin to C-reactive protein to Body mass index to Systolic blood pressure to GFR slope to Overall model: p Reported estimate values were obtained individually after adjusting for the first 5 variables. * See Methods for definition. CI confidence interval. Table 4 Predictors of coronary artery calcium score 100 by logistic regression Parameter Odds Ratio 95% CI p Value Age per 10 yrs White race Male gender Hypertension* Coronary artery disease* C-reactive protein Diabetes mellitus* Body mass index Total cholesterol High-density lipoprotein cholesterol Low-density lipoprotein cholesterol Triglycerides Serum albumin Systolic blood pressure GFR Reported estimate values were obtained individually after adjusting for the first 6 variables. * See Methods for definition. Abbreviation as in Table 3. Correlates of cardiovascular calcium: Table 1 presents the values of biochemical renal function-related variables measured in the total population, with subjects categorized in 3 groups based on CAC scores ( 100, 101 to 400, and 400). With the exception of serum urea nitrogen, all parameters showed nonsignificant changes in relation to severity of CAC. Table 2 lists descriptive clinical characteristics for the study population stratified according to CAC score. Older age, male gender, and positive histories of coronary artery disease and congestive heart failure were significantly associated with extent of CAC, whereas highdensity lipoprotein cholesterol was associated negatively with severity of calcium deposition. A diagnosis of diabetes was more frequent in the group with the highest CAC scores. The prevalence of other conventional risk factors, such as hypertension, dyslipidemia, and obesity, was not significantly different across the stratified CAC groups. Table 3 present the results of a multiple linear regression analysis predicting CAC score. Age, gender, diabetes, history of coronary artery disease, and high-density lipoprotein cholesterol were the best correlates for CAC score prediction. In separate analyses, to investigate the predictors of thoracic aortic, mitral valve, and aortic valve calcium scores, only age (and white race for the aortic valve) remained a consistent predictor. Table 4 lists predictors of high ( 100) versus low ( 100) CAC scores. Overall, advanced age, male gender, and hypertension were the strongest predictors of high CAC scores. Relation of GFR slope to CAC score: The mean GFR slope in the overall patient population (n 101) was ml/min/1.73 m 2 /month (range 1.49 to 1.09). Seventynine subjects had decreasing renal function (negative GFR slope, group 1), whereas 22 subjects showed stable renal function by GFR slope (group 2). No significant differences were observed between patients in groups 1 and 2 with regard to mean age (58 15 vs years, p 0.097), systolic blood pressure ( vs mm Hg, p 0.67), and prevalence of hypertension (89% vs 73%, p 0.065). Higher serum phosphate ( vs mg/dl, p 0.024), free parathyroid hormone ( vs pg/ml, p NS), and prevalence of diabetes (32% vs 9%, p 0.035) values were observed in group 1 than in group 2. Figure 2 shows the distribution of log-transformed CAC scores in groups 1 and 2. Overall, there were no significant differences in CAC values between the 2 groups (p 0.7). Discussion The main findings of this prospectively designed study are as follows. (1) Cardiovascular calcium detected by multidetector computed tomography at the level of coronary arteries, thoracic aorta, and cardiac valves is a common finding in subjects with predialysis CKD. (2) Some traditional atherosclerosis risk factors (i.e., advanced age, male gender, diabetes, and hypertension) constitute significant determinants of the extent of cardiovascular calcium measured in CKD. (3) Renal functionrelated parameters were not found to be important predictors of cardiovascular calcium deposition in patients with predialysis CKD; further, CAC scores did not differ significantly between subjects with CKD showing a gradual decrease in renal function and those with stable renal function. Using electron beam computed tomography, Braun et al 12 first reported higher CAC scores in hemodialysis patients than in subjects with normal renal function. This finding has

5 Coronary Artery Disease/Vascular Calcium in CKD 575 Figure 2. Relation between GFR slope and CAC scores as shown by 25th and 75th percentiles (box), median (straight line in box), mean log-transformed CAC score (cross), and range (error bars). Abbreviations as in Figure 1. been confirmed in multiple subsequent studies of subjects undergoing long-term hemodialysis Our data extend these observations to patients with predialysis CKD and confirm previous retrospective studies that suggested that cardiovascular calcium deposition is also a common finding in predialysis CKD Approximately 70% of our population had some evidence of CAC, with 28% demonstrating CAC scores 400, a value acknowledged to be associated with a high probability of obstructive coronary artery disease in non-ckd populations. 22 Overall, the CAC scores reported in our study were 75th percentile of age- and gender-matched controls from large asymptomatic subject cohorts, thus confirming that patients with CKD are at high risk for future cardiovascular events. Detection of calcium at the level of the thoracic aorta (46% of patients), aortic valve (39%), and mitral valve (16%) was also common. In general, these values are lower than those reported in subjects with end-stage renal disease. 23 The CAC extent noted in patients with renal failure (even in young subjects who are otherwise not at risk for vascular calcification) has prompted the investigation into potential renal-specific mechanisms that may be operative in this patient population. In this regard, at least some of the previous studies have demonstrated an association between calcium-phosphate product or serum phosphate levels and degree of CAC in patients with end-stage renal disease. 13,14,23 Fewer data are available regarding the determinants of CAC deposition in patients with predialysis CKD. Mehrotra et al 19 retrospectively studied a group of 60 subjects with diabetic nephropathy (mean GFR 39 4 ml/min) and reported a higher prevalence and severity of CAC compared with matched diabetic controls with normal renal function. In their population, the high degree of CAC was not related to any measurement of disordered mineral metabolism. Our findings extend these observations to a predominantly nondiabetic CKD cohort with more advanced renal impairment. In our population of patients with predialysis CKD, we also found no relevant relations between alterations in mineral metabolism and extent of cardiovascular calcium deposition. Several potential factors may have contributed to these findings. The preponderance of subjects in our study had only mild abnormalities of mineral metabolism and greater alterations may potentially influence the extent of cardiovascular calcium. 24 The large effect of age, gender, and diabetic status on vascular calcium deposition may have attenuated a more subtle effect of mineral parameters. In atherosclerosis, calcium deposition is typically localized in the intimal layer of the vessel wall. An additional process of medial vascular calcification has been demonstrated in subjects with diabetes, advanced age, or renal failure. 25 The potential co-existence of these 2 separate processes may be in part responsible for the lack of association between levels of vascular calcification and some of the main predictors of atherosclerosis observed in our population. 26 The limitations of the study include the relative homogeneity of the study cohort (most subjects in CKD stage IV), which may limit the applicability of these findings to the entire CKD population. The relation between clinical and laboratory variables with CAC was derived during a single baseline evaluation and may not be reflective of the influence of these factors over time. The association between

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