1 Department of Medicine and 3 Department of Radiology, Indiana University School of Medicine and 2 Roudebush Veterans Affairs Medical Center, Indianapolis, IN, USA
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Abstract |
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Methods. Two groups of patients with ESRD were evaluated: group 1, those receiving a renal transplant (n=38); and group 2, those remaining on dialysis (n=33). All patients underwent quad-slice spiral CT with retrospective gating to evaluate coronary artery and aorta calcification scores. Both area (Agatston method) and volume calculations were utilized, with retrospective gating in all but 16 subjects. Laboratory tests, medications and clinical characteristics were analysed.
Results. Using spiral CT, the intra-reader variability for coronary artery calcification (after correction for very low scores) was 0.9% mean / 0% median using the area (Agatston method) and 2.9% mean / 0% median using volume calculations. Group 1 patients were younger, more likely to be Caucasian and on peritoneal dialysis, had lower serum calcium and higher C-reactive protein levels than group 2. In patients without vs those with coronary artery calcification, only longer duration of dialysis (34±64 vs 55±50 months, P=0.004; r=0.39, P=0.005) and increasing age (39±13 vs 54±10 years, P<0.001; r=0.29, P=0.039) were associated, whereas only increasing age was associated with aorta calcification.
Conclusion. In ESRD patients, the factors correlating with coronary calcification were duration of dialysis and advancing age, whereas only age correlated with aorta calcification. Spiral CT offers an alternative technique for the assessment of these changes.
Keywords: coronary artery disease; dialysis; spiral CT; transplant; vascular calcification
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Introduction |
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These results imply that the use of EBCT may also have prognostic implications for dialysis patients. Unfortunately, EBCT machines are not readily available due to relatively high initial and maintenance costs and limited uses other than the quantification of CAC. A more widely available technology is that of spiral (or helical) CT scan. Recent new software adaptations and increased speed of gantry rotation have allowed the use of spiral CT scans also to quantify CAC. The purpose of the present study was to determine the utility of retrospectively gated spiral CT for the assessment of coronary artery and aorta vascular calcification and to identify potential risk factors for calcification in ESRD patients on haemodialysis and patients undergoing renal allograft surgery utilizing this new technique. In addition, the present study evaluated the variability and effect of gating on calcification scores.
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Subjects and methods |
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Medical charts were reviewed for clinical history and medications, and supplemented with information obtained directly from the patient. Patients were considered to have a history of coronary artery disease if there was an abnormal angiogram or stress test, myocardial infarction or history of angina. Diabetes was defined as present if it was the cause of ESRD and/or there was current need for insulin or oral anti-hyperglycaemic agents. Hypertension was defined as taking a blood pressure-lowering medication. Peripheral vascular disease was defined by history, abnormal arterial Dopplers or arteriogram. The dialysis modality was that modality the patient was receiving at the time of the study. Tobacco use was defined as ever using a tobacco product. The medications (other than phosphate binders) were those prescribed at the time of the spiral CT scan. Elemental calcium intake from phosphate binders was determined by taking the number of pills per day multiplied by the elemental calcium content as described in the Physician's Desk Reference. For group 1 patients, this was the binder type and dose prescribed at the time of the transplantation. For group 2 patients, this was the cumulative dose of calcium in the year preceding the spiral CT scan divided by the number of days to achieve an average g/day.
Serum assays
Serum was analysed for calcium, phosphorus and total alkaline phosphatase by colorimetric methods using a Roche Autoanalzyer (Boehringer Manheim, Indianapolis, IN); intact PTH by immunoradiometric assay (Nichols Institute, San Juan Capistrano, CA); bone-specific alkaline phosphatase by enzyme-linked immunosorbent assay (ELISA; Metra Biosystems, Mountain View, CA); homocysteine by ELISA (Biorad); and CRP by ELISA (Alpha Diagnostics, San Antonio, TX). Values for total cholesterol, if available, were obtained from the patients' medical record from the previous 6 months.
Spiral CT scan
CT scans were performed with the quad-slice technique on the model MX 8000 scanner (Philips Medical Systems, Cleveland, OH). The data acquisition parameters were: 120 kVp, 400 mAs, nominal slice width 2.5 mm (effective width 3.2 mm), gantry rotation time 0.5 s, table feed 7.5 mm/s [pitch 0.375 (x4 slices/rotation)]. Data were reconstructed with a 180° linear interpolation algorithm providing a temporal resolution of 270 ms, retrospective ECG gating during diastole, 1.3 mm longitudinal increment, 512x512 matrix, field of view 25 cm2, medium body (C) filter, and no edge enhancement. Data were transferred to a workstation and analysed with HeartBeat-CS software (MX View, Marconi Medical Systems, Cleveland, OH). On the basis of the ECG tracing, the software program automatically selected a reduced set of diastolic images from each cardiac cycle. The proximal coronary arteries were scored, beginning with the first image in which a coronary artery was seen (usually the left anterior descending) and continuing for 6 cm along the long axis of the patient [6]. All pixels with density 130 Hounsfield units (HU) were highlighted automatically in colour on the images. The observer placed an electronic region of interest (ROI) around each highlighted CAC and assigned one of four locations to each calcified plaque: left main, left anterior descending (LAD), circumflex or right coronary artery. Branches of the LAD, circumflex and right coronary arteries were considered parts of those arteries. The descending aorta was evaluated over the 6 cm in the z-axis direction. A minimum plaque area of 0.5 mm2 was used to reduce errors due to noise. Calcium scoring was performed using two scoring systems and identical ROIs by the same viewer (CM).
One scoring system which simulates the Agatston method [6] determines the density of the highest density pixel in each plaque and applies a weighting factor to each plaque, dependent upon the peak density in the plaque:Density (HU) of 130199=weight of 1; density of 200299=weight of 2; density of 300399=weight of 3; density of 400+=weight of 4.
The score for each plaque equals the plaque areaxweighting factorxincrement/slice width. The score for the entire specimen equals the sum of the scores for each plaque. This score is then normalized to the original Agatston score by multiplying the total score by 3.2/3.0 (=1.07) to correct for the increase in slice thickness. (The original Agatston method used a slice thickness of 3 mm, whereas this method used an effective slice thickness of 3.2 mm.) It is of note that the slices were reconstructed at 1.3 mm overlap to avoid over-scoring. This technique is called calcification score by area.
The second scoring method, called average-continuous, uses a weighting factor (F)=(A/100)0.5, where A is the average density of each plaque on each image. The score for each plaque is calculated by multiplying the area of each plaque in mm2 (to generate a volume determination) by the weighting factor. The score for the entire specimen equals the sum of the scores for each plaque. As above, this score is then multiplied by 1.07. This technique is called calcification score by volume.
Statistical methods
Demographic and descriptive data from the two study groups were compared using t-tests for continuous variables, Fisher's exact test for discrete variables and the MannWhitney U-test for ordinal variables (number of medications and calcium binder content). For patients who had only non-gated calcification scores (13/71), the linear regressions described below were used to convert them to gated scores. Calcification scores were skewed to the right and were log transformed before conversion from non-gated to gated scores. They were then back-transformed to the original unit. The log transformation reduced the skewness to levels acceptable for linear regression.
Two analyses were performed to examine the relationships between calcification scores and other variables. The first looked at factors related to development of calcification. Patients with no calcification were compared with those with calcification using the MannWhitney U-test for continuous variables and Fisher's exact test for discrete variables. The second analysis looked at factors related to the amount of calcification present in those who had some calcification in the coronary arteries or aorta. The levels of calcification were correlated with continuous variables using the Spearman rank correlation coefficient and compared in categories of discrete variables using the MannWhitney U-test.
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Results |
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To compare the effect of gating on spiral CT scores, the relationship of non-gated to gated scores was examined for ESRD patients participating in a reliability substudy who had scores >0 (presence of calcification) for each of the four spiral CT assessments. The scores were log transformed because of skewed data for this analysis as described in the statistical methods section. The results demonstrate that there was a very close correlation between the two techniques for each of the determinations: calcification score by area for CAC [R2=0.90; P<0.001; log (CAC score by area gated)=0.712+0.843xlog (CAC score by area non-gated), n=16]; calcification score by area for AoC [R2=0.99, P<0.001; log (AoC score by area gated)=0.089+0.972xlog (AoC score by area non-gated), n =12]; calcification score by volume for CAC [R2=0.88, P<0.001, log (CAC score by volume gated)=0.908+0.767xlog (CAC score by volume non-gated), n =16]; calcification score by volume for AoC [R2=0.99, P<0.001; log (AoC score by volume gated)=0.193+0.935xlog (AoC score by volume non-gated), n =12].
Patient characteristics and calcification scores
The demographic, medication use and laboratory values of the ESRD patients are shown in Table 1, and differences between groups 1 and 2 noted. The patients in group 1 (undergoing renal transplantation) were younger, had been on dialysis for a shorter time, were more likely to be on peritoneal dialysis as a modality, were more likely to be Caucasian, and smoked less than group 2 (dialysis patients that were not transplanted). Three patients in group 1 had never been dialysed. There was no difference in the prescribed medications between the two groups except that the patients receiving dialysis had a lower intake of calcium-containing phosphate binders for unclear reasons, although it should be emphasized that the collection methods for calcium intake for these two groups differed (see Subjects and methods). Laboratory tests revealed that the dialysis patients had a lower serum calcium and albumin level, and a higher CRP level.
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The CAC score by area method was 567±1291 (median 49), and slightly greater by the volume method (Table 2). The low median scores are a result of several patients without calcification. Fifty patients had evidence of CAC (26 group 1, 24 group 2) and 21 patients did not have CAC (seven group 1, 14 group 2). If patients with and without calcification are compared, the only identifiable risk factors (Table 3
) are age (r=0.29, P=0.039) and duration of dialysis (r=0.39, P=0.005). The relationships among age, duration of dialysis and CAC score are depicted in Figure 1
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Discussion |
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EBCT uses a gun of electrons to generate a beam focused on a tungsten ring target. The beam then sweeps from side to side along the tungsten ring generating a fan of X-rays. This allows for excellent temporal resolution (100 ms per image). Generally the faster the scanning is, the less the radiation dose delivered, and the more image noise. Multidetector spiral CT (MDCT) such as quad-slice with retrospective ECG gating, uses an X-ray tube and an array of detectors attached to a gantry that rotates around the patient. For state-of-the-art CT scanners, gantry rotation time is 0.5 s. Since data are then segmented to reconstruct images with every 180° plus fan angle of gantry revolution, an effective temporal resolution of
270 ms is achieved. Newer methods may offer improved resolution [9]. The advantage of MDCT over EBCT is improved signal to noise ratio and improved spatial resolution (9 lp/cm for MDCT vs 6 lp/cm for EBCT). Because this is a volumetric data set, there is also improved z-axis (longitudinal) resolution.
Using a protocol of overlapping increments of 1.5 mm similar to the one utilized in the present study, a recent comparison in 50 patients demonstrated that multislice spiral CT with ECG gating with volume scoring had a variability of 8% compared with EBCT with Agatston methodology (22%) or volume methodology (15%) [10]. The sensitivity of spiral CT with gating software is significantly better with a 130 HU threshold for scoring compared with 90 HU with non-gated spiral scans [11]. The intra-reader variability was comparable in the present study. Thus, the use of spiral CT with new methodologies offers at least comparable, if not improved, variability over EBCT, and greater availability of machines, although the methodologies for spiral CT are still evolving [9]. The disadvantages of spiral CT compared with EBCT are that of increased radiation exposure, with a 3- to 4-fold radiation exposure for spiral CT compared with EBCT, and decreased temporal resolution, which may lead to increased motion artefact at rapid heart rates. However, a recent study in beating phantoms demonstrated low variability with MDCT compared with EBCT, and no change at different heart rates [9], but this needs confirmation in humans.
We found minimal and expected differences in the group 1 (transplant) and group 2 (dialysis) patient populations: younger age, shorter duration of dialysis and more use of peritoneal dialysis in those in group 1. The latter is probably an artifact of ease of recruiting with haemodialysis patients compared with peritoneal dialysis patients. In both groups of patients, age and duration of dialysis correlated with CAC, whereas only age correlated with AoC. These risk factors have prevailed across multiple studies evaluating various techniques for the quantification of vascular calcification in ESRD, including EBCT [4,5], B-mode ultrasound [12] and now spiral CT in the present study. However, unlike other studies [5], we did not find a significant difference in parameters of mineral metabolism. Unfortunately, we were unable to assess cumulative laboratory data or phosphate binder use in the group 1 patient population, and thus the results are not comparable with other studies and should be interpreted cautiously. However, despite a diverse patient population and a relatively small sample size, the major findings of this study are similar to previous studies: calcification of the coronary arteries was a prominent finding, and of much greater quantity than found in previous studies in non-ESRD patients. Of concern was the prevalence and magnitude of calcification in patients undergoing renal transplant. A study comparing longitudinal changes in calcification in these two patient populations is currently ongoing.
The mean CAC score by area was 567±1291 (range 08772, median 49, inter-quartile range 0575). These values obtained are of the same level as non-dialysis patients with angiographically proven two vessel disease (341±796; mean±SD) [13].While the mean scores in the present study are similar to the coronary artery calcium scores in a recent study assessed with EBCT, the median is less [14]. The differences may reflect a lower mean age of our patient population (49 vs 57 years), and shorter duration of dialysis (25 vs 37 months). In addition, a greater percentage of patients had no evidence of CAC in the present study (32%) vs only 17% in the study by Raggi et al. [14], contributing to the greater median score in the latter.
In non-dialysis patients, the magnitude of CAC correlates with angiographically proven obstructive (atheromatous) coronary artery disease by both EBCT [1] and spiral CT [11,15]. In addition, CAC correlates with cardiac events in non-ESRD patients [2]. At this time, there are no published data comparing EBCT or spiral CT with angiographic findings or prospective cardiac events in the ESRD patient population. However, Blacher et al. recently found that the extent of calcification by ultrasound was predictive of both all-cause and cardiovascular mortality [12], and Raggi et al. found a significant relationship of coronary artery calcification by EBCT to a history of various cardiovascular events [14]. Given the difference in the magnitude of calcification in the coronary arteries of dialysis patients compared with non-ESRD patients, and the substantial risk for cardiovascular disease in ESRD patients compared with the general population, it is possible that this excess calcification may be an additional cardiovascular risk factor unique to the ESRD population. Clearly, longitudinal studies are required to evaluate fully its predictive value in assessing cardiovascular risk.
Although we were unable to identify mineral metabolism as a significant risk factor for vascular calcification in the present study, other studies in dialysis patients using alternative techniques (EBCT, ultrasound) demonstrated an elevated serum phosphorus, an elevated serum calciumxphosphorus product or increased calcium load as risk factors [5,8,16]. However, the mechanism by which the elevated concentration of these ions leads to calcification in dialysis patients is unknown. Jono et al. [17] found in cultured human vascular smooth muscle cells that a concentration of 2 mM phosphorus in the medium induced Cbfa1, a bone differentiation factor. Recently, we have found evidence of osteopontin, bone sialoprotein, alkaline phosphatase and type I collagen expression at the site of calcification in small arterioles in the skin of patients with calcific uraemic arteriolopathy [16] and in the inferior epigastric artery of dialysis patients [18]. We also demonstrated the expression of Cbfa1 in calcified areas in both the intima and media of inferior epigastric arteries [19]. This would imply that the deposition of mineral into vascular tissue in dialysis patients is not simply metastatic, but rather an active process. The duration of dialysis as a major risk factor for vascular calcification in nearly all studies implies accumulation of some as yet unidentified uraemic toxin(s). Recent studies from our laboratory demonstrated that pooled uraemic serum of dialysis patients could induce osteopontin expression in cultured bovine vascular smooth muscle cells, even with a low final phosphorus concentration in the medium of 0.6 mM. The addition of an exogenous phosphorus source to the uraemic serum, such that final phosphorus concentrations were 1012 mM, failed to augment the effect of uraemic serum alone [20]. Thus, while phosphorus levels and calcium load are critical, additional uraemic factors are likely to be involved.
In conclusion, the use of new generation spiral CT scans with gating is a viable and widely available technique for the assessment of coronary artery and aortic vascular calcification in ESRD patients. Longitudinal studies assessing the predictive value of this technique in determining cardiac events are needed, as is further understanding of the pathogenesis of this process.
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Acknowledgments |
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Notes |
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References |
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