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- Materials and Methods
Vascular calcification of the coronary arteries or aorta is an independent risk factor for cardiovascular outcome, but clinical significance of arterial micro-calcification (AMC) of vascular access is unclear in hemodialysis (HD) patients. Sixty-five patients awaiting vascular access operation were enrolled. We compared surrogate markers of cardiovascular morbidity such as aortic arch calcification (AoAC) by chest radiography, arterial stiffness by brachial-ankle pulse wave velocity (baPWV) and endothelial dysfunction by flow-mediated dilatation (FMD) between patients with and without AMC of vascular access on von Kossa staining. AMC of vascular access was detected in 36 (55.4%). The AMC-positive group had significantly higher incidence of AoAC (63.9% vs. 20.7%, p < 0.001) and higher baPWV (26.5 ± 9.4 m/s vs. 19.8 ± 6.6 m/s, p = 0.006) than the AMC-negative group. There was no significant difference in FMD between the two groups (5.4 ± 2.6% vs. 5.7 ± 3.5%, p = 0.764). The AMC-positive group had higher incidence of diabetes mellitus, higher systolic blood pressure and wider pulse pressure than the AMC-negative group. This study suggests that AMC of vascular access may be associated with cardiovascular morbidity via AoAC and arterial stiffness in HD patients.
- Top of page
- Materials and Methods
It is clinically difficult to obtain an arterial specimen without an operation; therefore, there are limited studies on histological evaluation of vascular calcification. However, it is easy to acquire an arterial specimen from HD patients because most of the patients undergo a vascular access operation. We previously reported that an arterial biopsy during the vascular access surgery did not influence the vascular access patency (13). We undertook this study to identify the relationship between AMC of vascular access by histological evaluation and cardiovascular outcomes by investigating the association between AMC of vascular access, aortic stiffness and endothelial dysfunction. This is the first study to demonstrate the value of assessing AMC of vascular access to predict cardiovascular morbidity in ESRD patients.
Wang et al. (14) reported that the incidence of AMC of vascular access accounted for 36.6% of HD patients. In this study, it was found in 54.5% of the patients. Although there was a difference in incidence depending on biopsy sites, a higher incidence of AMC in this study might be due to the high incidence of DM at a rate of 70.8%. Vascular calcification is known to be more common and more severe in DM patients (15). DM patients had a higher incidence of AMC than non-DM patients in this study. Although patients with AMC had lower levels of iPTH than those without, in subgroup analysis of DM patients, there was no significant difference in iPTH levels between the AMC-positive and negative groups. In multivariate analysis, the presence of DM was the only significant risk factor for AMC of vascular access. Therefore, we postulate that DM of the pro-calcification factors had a critical role in the development of AMC in this study.
Schlieper et al. (16) suggested that vascular access calcification on plain X-ray was seen in 23% and it was a predictor of mortality in HD patients. In this study, gross calcification of vascular access site was seen in 18.5% and there was no significant association between gross calcification at vascular access site and baPWV, or FMD. However, the number of patients who had a wrist X-ray was only 27 of the 65 patients, so further studies will be required. In our opinion, biopsy at a vascular access site during surgery is technically simple and not risky. Moreover, it allows early detection and more precise information of the arteriosclerosis status of patients, compared with plain radiography. In this study, AMC was detected in about a half of patients without gross calcification of vascular access site.
Aortic arch calcification is significantly associated with cardiovascular disease, which is the leading cause of death in ESRD patients (17,18). Assessment of aortic arch calcification on plain chest radiography is easily performed and useful, because its grade reflects the magnitude of calcified change in the whole aorta and is highly correlated with aortic arch calcification volume on computed tomography (CT) (8,19). Vascular calcification induces arterial wall stiffness and reduces vascular compliance, which is associated with an increased left ventricular afterload and hypertrophy (20). Therefore, many previous studies have demonstrated a strong association between vascular calcification and pulse wave velocity, which serves as useful tool for cardiovascular risk assessment in ESRD patients as well as in the general population (4,21–23). Our data show that patients with AMC of vascular access have a greater average systolic blood pressure, pulse pressure, AoAC score and baPWV than those without.
Recent studies showed a direct relationship between vascular calcification and endothelial dysfunction. Decreased serum fetuin-A, the major inhibitor of vascular calcification, was associated with the development of endothelial dysfunction in patients with CKD (24). Another study showed that the use of sevelamer, which is a calcium-free phosphate binder and can help to reduce vascular calcification, led to a significant increase in serum fetuin-A concentrations with improvement of endothelial function in CKD patients (25). In addition, endothelial function was also inversely correlated with coronary artery calcification by multidetector CT in patients with coronary risk factor (5).
However, in this study, AMC of vascular access was not related to endothelial dysfunction. Vascular calcification may be one of the important mechanisms involved in endothelial dysfunction. Endothelial dysfunction, characterized by decreased bioavailability of nitric oxide, is an early event in arteriosclerosis and is observed even as early as stage 1 CKD patients (24), therefore, it should be further aggravated in ESRD patients. We assumed that there was a relative lack of influence of the degree of vascular calcification on endothelial function in advanced arteriosclerosis status in ESRD patients. Almost all patients in this study showed abnormal PWV and FMD, which must be considered as a significant sign of advanced arteriosclerosis. Kopec et al. (26) demonstrated that endothelial dysfunction is associated with the aortic stiffness and that this association is limited by the progression of atherosclerosis. The correlation between baPWV and FMD was not significant in patients with significant coronary artery stenosis (26). Kobayashi et al. (6) reported similar results, there was no correlation between endothelial dysfunction and arterial stiffness in the lowest tertile of the FMD group. As a result, this reverse correlation between arterial stiffness (increased PWV) and endothelial function (decreased FMD) may be limited in advanced arteriosclerosis status such as ESRD patients.
In our results, patients with AMC of vascular access had lower levels of iPTH, compared with patients without AMC. These results are consistent with data, suggesting that low-turnover bone disease, characterized by a low iPTH level (<150 pg/ml) is more likely to be associated with vascular calcification, partly due to the decreased calcium phosphate-buffering capacity of bone (27–29). However, the incidence of low iPTH was not significantly different between patients with and without AMC (60.6% vs. 48.0%, p = 0.339). In contrast to previous studies (30), we found no association between mineral metabolism and AMC of vascular access. Chronic mineral dysregulation could contribute to the progression of vascular calcification. There was no difference in serum calcium and phosphate levels between patients with and without AMC, and the mean serum mineral concentrations were almost within the normal range, which may explain the lack of a significant relationship between mineral metabolism and AMC of vascular access in this study.
The duration of dialysis is also known to be a strong determinant of vascular calcification (31,32). In this study, 55 (84.6%) of 65 patients started unplanned HD with a central venous catheter. The mean duration of HD before the operation for vascular access was 28.8 days, and there was no difference of HD duration between the two groups (26.7 days vs. 31.1 days, p = 0.690). Having a HD duration of less than a month might be a lesser influence on vascular calcification.
In conclusion, this study demonstrates that AMC of vascular access is related to aortic arch calcification and arterial stiffness but not to endothelial dysfunction in ESRD patients. Such parameters including aortic arch calcification, PWV and FMD were known as good surrogate markers of clinical arteriosclerosis. This result indicates that AMC of vascular access site reflects, not just about vascular access patency, but also, the degree of arteriosclerosis. The sample size of this study was relatively small and this was not a prospective controlled study. Further studies involving a larger sample size and with follow up of the cardiovascular morbidity and mortality of the patients with AMC of vascular access are required. Nevertheless, our data emphasize that AMC of vascular access may be associated with cardiovascular morbidity and mortality in ESRD patients.