Nephrology Dialysis Transplantation

NDT Advance Access published online on March 29, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm031

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Risk factors of the progression of abdominal aortic calcification in patients on chronic haemodialysis

Kazuhiro Yamada¹, Shouichi Fujimoto¹, Ryosuke Nishiura¹, Hiroyuki Komatsu¹, Mariko Tatsumoto¹, Yuji Sato¹, Seiichiro Hara¹, Shuichi Hisanaga³, Hideyuki Ochiai⁴, Hiroyuki Nakao² and Tanenao Eto¹

¹First Department of Internal Medicine, ²Department of Public Health, Miyazaki Medical College, University of Miyazaki, ³Koga General Hospital and ⁴Miyazaki Junkanki Hospital, Miyazaki, Japan

Correspondence and offprint requests to: Kazuhiro Yamada, MD, First Department of Internal Medicine, Miyazaki Medical College, University of Miyazaki, Kihara 5200, Kiyotake, Miyazaki 889-1692, Japan Email: yamakazu{at}xqb.biglobe.ne.jp

	Abstract

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Background. Vascular calcification is an independent determinant of cardiovascular events in maintenance haemodialysis (HD) patients. It is not known whether acute changes of the serum calcium concentration before and after HD (Ca) are associated with the development of aortic calcification.

Methods. We enrolled 71 patients dialysed with a dialysate with 3.0 mEq/l calcium and determined their aortic calcification index (ACI) by abdominal computed tomography twice at an interval of 3 years. To identify the factors contributing to the rate of progression of aortic calcification, we analysed the average values for clinical and laboratory data obtained between the first and second evaluations of ACI.

Results. The second ACI (mean ± SD: 80.2 ± 63.9) was significantly greater than the first ACI (61.0 ± 61.0) after an interval of 35.8 ± 4.2 months. The annualized change of ACI (ACI/year) was significantly and directly associated with the Ca and C-reactive protein (CRP) (both P < 0.001, P for trend). Stepwise multivariate regression analysis revealed that ACI/year was positively and independently associated with CRP, presence of diabetes mellitus and Ca, but negatively associated with a premenopausal status in women. Similarly, Ca was positively and independently associated with ACI/year and the ultrafiltration rate, but was negatively associated with pre-HD Ca.

Conclusion. The increase of serum calcium after HD was related to the rate of progression of aortic calcification. Excess calcium is transferred into patients on HD when using a dialysate of 3.0 mEq/l calcium. This may be a risk factor for the development of vascular calcification.

Keywords: aortic calcification; calcium; C-reactive protein; dialysate; haemodialysis; premenopausal women

	Introduction

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Patients on haemodialysis (HD) frequently experience cardiovascular events associated with accelerated atherosclerosis and vascular calcification [1,2]. Several studies [3,4] have demonstrated that the arterial calcification scores and chronic inflammation can predict cardiovascular mortality, and those are mutually and closely associated with each other in HD patients. Besides the traditional risk factors, other factors known to contribute to vascular calcification are elevated serum phosphate and parathyroid hormone (PTH) and an elevated calcium x phosphate product [5,6]. In addition, inflammation may be related to the down-regulation of the calcification inhibitor, fetuin-A [6]. Recent reports [7,8] have indicated that calcium overload due to, for example, the administration of excessive calcium-containing phosphate binders, may be related to arterial calcification. ‘The Kidney Disease Outcome Quality Initiative (K/DOQI) Guideline’ recently recommended, as ‘OPINION’, that the dialysate calcium concentration be 2.5 mEq/l to prevent the metastatic calcification that results from calcium overloading during HD [9]. However, few studies have determined whether calcium transfer into patients in HD influences vascular calcification.

In the present study, we tried to ascertain whether acute changes of the serum calcium concentration that result from using a dialysate containing 3.0 mEq/l of calcium were related to the progression of abdominal aortic calcification in HD patients.

	Subjects and methods

Top Abstract Introduction Subjects and methods Results Discussion References

 
Subjects
Between April 2000 and October 2004, a total of 105 patients were on maintenance HD at our two dialysis units in Miyazaki, Japan. We scheduled them to undergo abdominal computed tomography (CT) twice, with an interval of approximately 3 years, in order to detect renal cancer. All patients were being dialysed for 4–5 h, 3 times weekly, with a dialysate containing 3.0 mEq/l of calcium. Of the potentially eligible patients, 32 who refused routine abdominal CT scanning and two who had persistent inflammation were excluded from the study. Thus, we enrolled 71 patients (43 men and 28 women) with a mean age of 57.2 ± 12.4 years (mean ± SD). Their mean duration on HD was 74 ± 79 months. Their underlying renal diseases were chronic glomerulonephritis (n = 36), diabetic nephropathy (n = 15), nephrosclerosis (n = 14) and others (n = 6). All patients were informed of the purpose of the study and written consent was obtained from each patient.

We administered oral phosphate binders and vitamin D analogues to achieve the following target serum levels of calcium (Ca), phosphate (P) and intact PTH just before HD: from 8.5 to 9.5 mg/dl for Ca; <6 mg/dl for P; <60 mg²/dl² for the Ca x P product; and from 100 to 300 pg/ml for intact PTH. All patients received calcium carbonate (2.8 ± 1.3 g/day) as the phosphate binder. Only oral vitamin D (n = 32), statin (n = 9) and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (n = 38) had been prescribed to them for 24 months or more during the study period. Because sevelamer became available in Japan only after June 2003, this drug had been used by 10 patients for a period of <1.5 years. The seven patients with serum intact PTH levels >400 pg/ml had been treated with an intravenous vitamin D analogue for at least 6 months. During the study period, three patients underwent parathyroidectomy for severe secondary hyperparathyroidism.

Abdominal aortic calcification index (ACI)
To evaluate the abdominal aortic calcification, we scanned each subject to 15 CT slices at 1 cm intervals above the bifurcation of the common iliac arteries [10]. The cross-section of the abdominal aorta on each slice was divided into 16 sectors. The ACI was calculated as the total number of sectors with calcification in each CT slice (range of ACI, 0–240: 16 sectors x 15 slices). Where aortic calcification was observed in more than two adjacent sectors, we counted only the sectors which covered more than half of the total surface. A second ACI was determined on a scan obtained about 3 years after the first (35.8 ± 4.2 months); and the ACI/year was calculated as follows to assess the annual change of ACI: second ACI – first ACI value/interval (years) between the two evaluations. The recorded ACI values were the mean values of measurements made by two independent observers. The differences between their measurements were 5% and 10% or less in the patients with ACI above 20 and below 20, respectively.

Clinical and laboratory measurements
Blood pressure, serum Ca (pre-HD Ca), P, alkaline phosphatase (Alp), albumin (Alb) and C-reactive protein (CRP) were measured monthly just before HD session. Serum Ca was measured, also, just after HD (post-HD Ca). Then the Ca was calculated by subtracting the pre-HD Ca value from the post-HD Ca value [Ca = (post-HD Ca) – (pre-HD Ca)]. Serum intact PTH was measured every 3 months. Total cholesterol (T-Cho) and high-density lipoprotein cholesterol were measured once a year. All blood samples were taken on Mondays or Tuesdays, 3 days after HD, in each month. We calculated average values for clinical and laboratory data, averaged over the period between the first and second evaluations of ACI. CRP and intact PTH were measured using the latex agglutination method (Denka, Tokyo, Japan) and electrochemiluminescence immunoassay (ECLIA) using Elecsys analyzer (Roche Diagnostics), respectively.

Statistical analysis
All data are expressed as the mean ± SD. Relationships between variables were initially assessed by univariate regression analysis and then evaluated by step-wise multiple regression analysis. Differences between two mean values were evaluated by the Wilcoxon signed-rank test and differences between three mean values were assessed by P for trend. A probability value of <0.05 was considered significant. Statistical analysis was performed using the Macintosh Stat View programme (version 4.5; Abacus Concepts Inc., Berkeley, USA).

	Results

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The ACI values and the averages of clinical and laboratory parameters for the 71 HD patients are shown in Table 1. The first and second ACI were 61.0 ± 61.0 and 80.2 ± 63.9, respectively and the second ACI showed a significant increase in comparison with the first ACI (P <0.0001, Wilcoxon signed-rank test). The interval between the first and second examinations was 35.8 ± 4.2 months and the ACI/year was 6.6 ± 5.1. The mean pre-HD Ca and Ca values were 8.99 ± 0.57 mg/dl and 0.63 ± 0.42 mg/dl, respectively. In two patients, pre-HD Ca was >10 mg/dl; in three, the post-HD Ca level was lower than the pre-HD Ca. The mean P level and Ca x P product was 4.97 ± 0.89 mg/dl and 45.0 ± 10.0 mg²/dl², respectively. Fourteen patients had a P level >6 mg/dl and seven had a Ca x P product >60 mg²/dl². Six patients had an intact PTH level >300 pg/ml, while 19 patients had an intact PTH level <100 pg/ml. Representative cases with or without ACI progression between the first and second examinations are shown in Figure 1.

View this table: [in this window] [in a new window]   Table 1. Patient characteristics and laboratory parameters (n = 71)

 

View larger version (49K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1. Change of abdominal aortic calcification in two representative cases. Case 1 is a 65-year-old man with rapid ACI progression (ACI/year 16.7; Ca 1.52 mg/dl; intact PTH 208 pg/ml; CRP 0.51 mg/dl; CT interval 36 months; primary disease: chronic glomerulonephritis). Case 2 is a 65-year-old woman without slow ACI progression (ACI/year 1.0; Ca, 0.05 mg/dl; intact PTH 204 pg/ml; CRP, 0.04 mg/dl; CT interval 37 months; primary disease: chronic glomerulonephritis).

 
Table 2 shows univariate regression analyses between ACI/year, Ca, CRP and the other parameters. ACI/year showed a significant positive correlation with Ca, CRP, age, gender and Alp, but negative correlation with premenopausal status in women, duration of HD, diastolic blood pressure and pre-HD Ca. The dose of calcium carbonate was not correlated with ACI/year. Ca showed a significant positive correlation with ACI/year and CRP, but a negative correlation with the duration of HD, vitamin D or sevelamer therapy, first ACI, pre-HD Ca and Ca x P product. CRP showed a significant positive correlation with age, ACI/year and Ca, while there was a negative correlation with the diastolic blood pressure, pre-HD Ca and Alb.

View this table: [in this window] [in a new window]   Table 2. Univariate regression analysis between ACI/year, Ca, CRP, and other parameters (n = 71)

 
After the patients were divided into tertiles according to their Ca or CRP values, we examined the relationships between these parameters and the extent of progression of the aortic calcification. As shown in Figure 2, the rate of the increase of ACI was significantly greater along with the increases of Ca or CRP (P = 0.0005 and P = 0.0003 respectively, P for trend).

View larger version (14K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2. Progression of ACI/year as a function of Ca tertiles (A) and serum CRP tertiles (B), respectively.

 
To assess the risk factors for an increase of ACI, we performed step-wise multiple regression analyses using the parameters listed in Table 2. As shown in Table 3, ACI/year showed an independent positive association with CRP, the presence of diabetes mellitus and Ca; at the same time, there was an independent negative association with premenopausal status in women. Similarly, Ca showed an independent positive association with ACI/year and the ultrafiltration rate, but there was an independent negative association with pre-HD Ca, systolic blood pressure and vitamin D therapy. Furthermore, CRP showed an independent positive association with ACI/year, first ACI and Ca. Excluding diabetic or premenopausal patients, ACI/year also showed an independent positive association with CRP and Ca by step-wise multiple regression analysis (n = 51, R² = 0.506, F value = 24.544, P < 0.0001, CRP: ß = 0.543; t = 4.912; P < 0.0001, Ca: ß = 0.293; t = 2.651; P = 0.0108).

View this table: [in this window] [in a new window]   Table 3. Stepwise multivariate regression analysis of factors associated with ACI/year, Ca, and CRP in HD patients (n = 71)

 

	Discussion

Top Abstract Introduction Subjects and methods Results Discussion References

 
Hyperphosphataemia and an increased Ca x P product are closely related to arterial calcification, which may be implicated in the occurrence of cardiovascular events in HD patients [5,6]. Hypercalcaemia induced by the use of calcium-based phosphate binders and vitamin D analogues, or hyperparathyroidism are also associated with an increased risk of vascular calcification. The benefit of PTH suppression is acknowledged, but careful attention should be paid to the possibility of the adverse effects of metastatic arterial calcification in patients with hypoparathyroidism, who often show adynamic bone disease and are incapable of buffering excess calcium [8,11,12]. To avoid a positive calcium balance, the use of high concentrations of calcium salts in the dialysate is no longer recommended. There are no reports, however, on the relationships between the acute changes of serum calcium from just before to after HD (Ca) and vascular calcification. To our knowledge, this is the first study to reveal that Ca has an independent positive association with the development of aortic calcification. These results fit well with the results of in vitro experiments that show that peak calcium concentrations have a major dose-dependent impact on vascular smooth muscle cell calcifications [13]. Our results may be related to our use of a dialysate with a calcium level of 3.0 mEq/l, which is higher than that recommended by the K/DOQI guidelines [9]. Lowering of the dialysate calcium has been suggested as a possible approach to the prevention of vascular calcification in HD patients. While the reasons for recommending a dialysate calcium concentration of 2.5 mEq/l may appear clear from the historical changes, there is little experimental evidence to support this choice. Sigrist et al. [14] recently suggested that the cyclical changes of the level of serum calcium level (which do not occur with peritoneal dialysis) may play an important role in the frequent development of vascular calcification in HD patients, but they did not refer to the influence of the Ca concentration in the dialysate. Our study suggests that excess calcium transfer may occur in patients who are on HD with a dialysate with a calcium concentration of 3.0 mEq/l, if their serum calcium before HD is maintained at around 9 mg/dl. In order to check the loading of calcium from the dialysate, a low pre-HD serum Ca and an excessive ultrafiltration should be avoided in HD.

In the present study, pre-HD Ca and P and the Ca x P product were not associated with the progression of aortic calcification (Table 3). This result may be related to the fact that the group was characterized by overall good mineral control and only a small number of patients had a pre-HD Ca >10 mg/dl, a P >6 mg/dl, or a Ca x P product >60 mg²/dl². Furthermore, we had only 10 patients in this study with low PTH (<60 pg/ml), which indicates adynamic bone disease predisposing to metastatic calcification. However, the most probable reason for our result, which did not show a significant association between the progression of vascular calcification and Ca, P, or the Ca x P product, may be the relatively small number of patients.

Although several studies have suggested that inflammation is closely associated with atherosclerosis and cardiovascular events [15,16], it remains unclear whether inflammation simply reflects vascular injury or is a cause of it. In addition to traditional risk factors for cardiovascular diseases observed in the general population, chronic inflammation, calcium overload and a high Ca x P product may play an important role in the pathogenesis of arterial calcification and accelerated atherosclerosis in HD patients [16]. The Dialysis Outcomes and Practice Patterns Study (DOPPS) recently revealed that a higher all-cause mortality rate was significantly associated with a higher dialysate calcium concentration [17]. Our study showed the progression of aortic calcification (ACI) to be strongly correlated with CRP or the acute change of serum calcium by HD (Ca). Previous reports [18] have indicated that sevelamer reduces the CRP level, in addition to reducing serum P, the Ca x P product, or arterial calcification. This reduction of CRP may result from a decline of vascular calcification due to a lower serum P and Ca x P product. Although our results may suggest a possible direct influence of abnormal mineral metabolism (including vascular calcification) on inflammation in HD patients, this needs to be examined in the future—including the measurements of calcification inhibitory factors, such as fetuin-A and matrix Gla protein.

A novel finding of our present study was that aortic calcification is unlikely to progress in premenopausal women: step-wise multiple regression analyses have revealed that ACI/year was negatively and independently associated with the premenopausal status. The possibility that sex hormones, such as oestrogens, exert cardioprotective effects by suppressing inflammation and atherosclerosis has been suggested [19]. In patients with end-stage renal disease, chronic inflammation strongly predicts a poor outcome in men, while such an effect is not observed in women [20]. Thus, female sex hormones may ameliorate inflammation-induced vascular injury and vascular calcification.

Like previous studies using plain abdominal CT, we measured aortic wall calcification on CT scans, which only provides a measure of the calcium content of the vessel wall. Thus, we could not evaluate plaque formation and occlusion of major vessels, including the coronary and cerebral arteries. In addition, our method of measuring ACI was a semiquantitative one, unlike quantitative ones such as multiple slice CT (MSCT) or electron-beam CT (EBCT). Further prospective studies will be needed to determine whether the rate of progression of aortic calcification in HD patients, evaluated with MSCT or EBCT, is related to cardiovascular events.

In conclusion, the increase of serum Ca immediately after HD was related to the rate of progression of aortic calcification. Excess calcium transfer may occur in some patients haemodialysed with 3.0 mEq/l dialysate calcium and those may be one of the risk factors for the development of vascular calcification. To further elucidate the effects of dialysate calcium concentration on vascular calcification, we would need to determine whether using a dialysate with a lower calcium concentration might reduce the acute changes of serum Ca associated with HD and prevent the progression of aortic calcification—although the ideal Ca level of dialysate should be isocalcaemic.

	References

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Received for publication: 2. 3.06
Accepted in revised form: 10. 1.07

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This Article Abstract FREE Full Text (PDF) All Versions of this Article: 22/7/2032    most recent gfm031v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Request Permissions Disclaimer Google Scholar Articles by Yamada, K. Articles by Eto, T. Search for Related Content PubMed PubMed Citation Articles by Yamada, K. Articles by Eto, T. Social Bookmarking          What's this?

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