ORIGINAL ARTICLE
Risk factors of accelerated progression of peripheral
artery disease in hemodialysis
Shang-Reu Hsu
a, Ho-Ming Su
b,c, Ming-Chia Hsieh
a, Shin-Li Su
a, Szu-Chia Chen
d,*,
Hung-Chun Chen
d,ea
Division of Endocrinology and Metabolism, Department of Medical, Changhua Christian Hospital, Changhua, Taiwan
b
Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
c
Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
d
Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
e
Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
Received 13 December 2011; accepted 6 March 2012 Available online 11 October 2012
KEYWORDS Ankle-brachial index; Arterial stiffness; Brachial-ankle pulse wave velocity; Hemodialysis; Peripheral artery occlusive disease
Abstract Ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) are markers for peripheral artery occlusive disease (PAOD) and arterial stiffness, respectively. The aims of this study were to assess whether PAOD and arterial stiffness progressed and to determine the risk factors for ABI and baPWV progression in patients on hemodialysis. This study enrolled 173 routine patients on hemodialysis. Both ABI and baPWV were measured by an ABI-form device at baseline and at 1 year of follow-up. Progression in ABI was defined as reduction in ABI exceeding 0.3, while baPWV measured at 1 year of follow-up exceeding that at baseline indicated baPWV progression. Comparison with baseline data showed increase in both prevalence of ABI< 0.9 (p Z 0.045) and baPWV (p Z 0.028) at 1 year of follow-up. Multiple linear regression analyses identified high fasting glucose and old age as independent factors of annual change in ABI and baPWV, respectively. Good control of blood sugar may contribute to delay the progression of peripheral artery disease in patients on hemodialysis. Copyrightª 2012, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. All rights reserved.
* Corresponding author. Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou First Road, Kaohsiung 807, Taiwan.
E-mail address:[email protected](S.-C. Chen).
1607-551X/$36 Copyrightª 2012, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. All rights reserved.
http://dx.doi.org/10.1016/j.kjms.2012.08.014
Available online atwww.sciencedirect.com
Introduction
A high prevalence of peripheral artery occlusive disease (PAOD) and increased artery stiffness have been reported in the end-stage renal disease (ESRD) population and are associated with increased morbidity and mortality [1e4]. There is growing evidence that uremia may predispose sufferers to PAOD progression and increased arterial stiff-ness with multiple pathogenic mechanisms involved, including deranged calcium/phosphate balance, secondary hyperparathyroidism, homocysteine, lipoprotein(a) metabolism, fluid overload, alterations in the angiotensin and endothelin systems, malnutrition, uremic toxins, oxidative stress, insulin resistance, and alterations in inflammatory and coagulation pathways[4,5].
A clinical device has been developed to automatically and simultaneously record the pulse waves of the brachial and posterior tibial arteries, using an automated oscillometric method. Using this device, we can easily and automatically calculate the ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV)
[6,7]. ABI has been reported to be a good marker for atherosclerosis and an ABI of <0.9 was useful in the diagnosis of PAOD[8e10], while baPWV has been taken as a good marker for arterial stiffness [11,12]. Previous cross-sectional studies have identified the risk factors of PAOD and increased artery stiffness in advanced chronic kidney disease and patients on hemodialysis, including old age, hypertension, diabetes mellitus (DM), previous coronary artery disease, previous cerebrovascular disease, wider pulse pressure, hyperlipidemia, malnu-trition, and smoking[4,13,14]. However, there have been few studies evaluating the progression of PAOD and arterial stiffness longitudinally, or determining the risk factors of ABI and baPWV progression in patients on hemodialysis in Taiwan, an area with the highest preva-lence of ESRD[15]. The aims of the present study were to assess the progression in PAOD and arterial stiffness and to determine the risk factors for ABI and baPWV progression in patients on hemodialysis.
Methods
Study design and participants
This is a prospective and observational study conducted at a single dialysis clinic in a regional hospital in Taiwan. All routine patients on hemodialysis in this hospital were included, except two patients who refused to be examined by an ABI-form device, four patients with atrial fibrilla-tion, and six patients with both legs amputated due to complications of DM. Initially, 196 patients (91 men and 105 women) were included in this study. The ABI was measured twice within 1 year. During the follow-up period, 11 deaths were recorded in these 196 patients (5.6%), 10 patients were transferred to other hospitals, and two patients refused further examinations. Finally, 173 patients (80 men and 93 women) completed the study. The protocol was approved by our Institutional Review Board and all enrolled patients gave written, informed consent.
Hemodialysis
All patients underwent routine hemodialysis three times a week using a Toray 321 machine (Toray Medical Company, Tokyo, Japan). Each hemodialysis session lasting 3e4 hours was performed using a dialyzer with a blood flow rate of 250-300 mL/minute and a dialysate flow rate of 500 mL/minute.
Assessment of ABI and baPWV
Both ABI and baPWV might be influenced by hemodialysis
[16]; hence, all measurements were made 10e30 minutes
before hemodialysis. The measurements were taken using an ABI-form device (VP1000; Colin Co. Ltd., Komaki, Japan)
[6,7,17] in a room with a temperature of around 25C following a 5-minute rest upon arrival at the clinic. Occlu-sion and monitoring cuffs were placed tightly around the upper arms without blood access and with both sides of the lower extremities in the supine position. Dividing the ankle systolic blood pressure by the arm systolic blood pressure gave the ABI and the lower value of the ankle systolic blood pressure was used in the calculation. For measuring baPWV, pulse waves obtained from the brachial and tibial arteries were recorded simultaneously, and the transmission time, defined as the time interval between the initial increase in brachial and tibial waveforms, was determined. The transmission distance from the arm to each ankle was calculated according to body height. The baPWV value was automatically computed as the transmission distance divided by the transmission time. After obtaining bilateral baPWV values, the highest one was taken as the represen-tative value for each participant. Both ABI and baPWV measurements were made at baseline and at the 1 year of follow-up. The automatic device and its reproducibility have been validated in previous research[17].
Collection of demographic, medical, and laboratory data
Demographic and medical data including age, sex, smoking history, and comorbidities were obtained from medical records and interviews with patients. Body mass index (BMI) was calculated as the ratio of weight in kilograms divided by the square of height in meters. Laboratory data were ob-tained from fasting blood samples using an autoanalyzer (Roche Diagnostics GmbH, D-68298 COBAS Integra 400, Mannheim, Germany). High-sensitivity C-reactive protein (Dade Behring Marburg GmbH, Germany) was measured using commercially available kits. Serum intact parathyroid hormone concentration was evaluated using a commercially available two-sided immunoradiometric assay (CIS Bio International, Gif Sur Yvette, France). Blood samples were centrifuged within 1 hour of collection and frozen at 20C until analysis. Plasma homocysteine levels were determined by fluorescence polarization immunoassay using an IMx Homocysteine kit (Abbott Laboratories, Abbott Park, IL, USA). Blood samples were obtained within 1 month of enrollment. In addition, information regarding patient medications including aspirin, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, b-blocker, calcium channel b-blocker, and HMG-CoA reductase
inhibitors (statins) during the study period was obtained from medical records.
Definitions of progression of ABI and baPWV
OABI was defined as ABI measured at 1-year follow-up minus ABI measured at baseline. Reduction in ABI exceeding 0.3 was considered as progression of ABI [18].
ObaPWV was defined as baPWV measured at 1-year follow-up minus baPWV measured at baseline. A positiveObaPWV indicated progression of baPWV.
Statistical analysis
Statistical analysis was performed using SPSS 12.0 for windows (SPSS Inc., Chicago, IL, USA). Data are expressed
as numbers and percentages, or mean standard devia-tion. The differences between groups were analyzed by Chi-square test for categorical variables or by independent t-test for continuous variables. Paired t-test was performed to compare the prevalence of ABI< 0.9 and baPWV values at baseline and 1-year follow-up. Linear regression analysis was employed to identify the factors associated with the ratio of OABI to baseline ABI and ObaPWV to baseline baPWV. Age, sex, and the independent variables with a p < 0.2 in the univariate analysis were selected in the multivariate analysis. A p value of less than 0.05 indicated significant difference.
Results
The clinical characteristics of the study patients are shown in Table 1. The mean age of the 173 patients was 57.3 12.7 years and there were 80 men and 93 women. Among our patients, 39.3% were diabetic and 70.5% received medications for high blood pressure. Pre-existing and documented coronary arterial and cerebrovascular diseases were noted in 24.3% and 9.2% of patients, respectively. Biochemical data were listed in the Table 1. At baseline, the prevalence of ABI< 0.9 was 23.1% and the average baPWV was 1795.0 458.5 cm/s. The underlying etiologies of hemodialysis in our study patients included
Table 1 Baseline characteristics of the study patients. Characteristics Study patients (nZ 173)
Age (yr) 57.3 12.7
Male sex (%) 46.2
Smoking history (%) 24.9 Diabetes mellitus (%) 39.3 Hypertension (%) 70.5 Coronary artery disease (%) 24.3 Cerebrovascular disease (%) 9.2 Duration of hemodialysis (mo) 72.4 53.4 Systolic blood pressure (mmHg) 148.8 24.6 Diastolic blood pressure (mmHg) 80.4 14.5 Pulse pressure (mmHg) 68.7 16.9 Heart rate (beats/min) 82.1 13.9 Body mass index (kg/m2) 24.3 3.7 ABI< 0.9 (%) 23.1 baPWV (cm/s) 1795.0 458.5 Laboratory parameters Albumin (g/dL) 3.97 0.25 Fasting glucose (mg/dL) 119.5 57.9 Triglyceride (mg/dL) 152.9 98.4 Total cholesterol (mg/dL) 180.1 40.7 HDL-cholesterol (mg/dL) 41.1 10.7 LDL-cholesterol (mg/dL) 90.6 28.3 Hematocrit (%) 30.5 3.7 Calcium-phosphorous product 47.1 10.7 Uric acid (mg/dL) 7.7 1.5 PTH (pg/mL) 425.6 329.8 hsCRP (mg/L) 0.70 1.00 Homocysteine (mmol/L) 29.4 9.9 Cardio-thoracic ratio> 50% 36.4 Medications Aspirin use (%) 17.9 ACEI and/or ARB use (%) 26.0 b-blocker use (%) 16.8 Calcium channel blocker use (%) 35.3 Statins use (%) 32.9
ABI Z ankle-brachial index; ACEI Z angiotensin converting enzyme inhibitor; ARB Z angiotensin II receptor blocker; baPWV Z brachial-ankle pulse wave velocity; HDL Z high-density lipoprotein; hsCRP Z high-sensitivity C-reactive protein; LDL Z low-density lipoprotein; PTH Z parathyroid hormone.
Figure 1. (A) The prevalence of ABI< 0.9 increased yearly during 1-year follow-up (23.1%, and 30.1%; p Z 0.045); (B) values of baPWV increased yearly during 1-year follow-up (1795.0 458.5, and 1880.7 604.0; p Z 0.028). ABI Z ankle-brachial index; baPWV Z brachial-ankle pulse wave velocity.
nondiabetic glomerular diseases (42.2%), diabetic kidney disease (35.3%), hypertension (11.6%), tubulointerstitial diseases (8.7%), and other diseases (2.3%).
The incidence of de novo ABI < 0.9 is 18.0%. Fig. 1A shows increasing prevalence of ABI < 0.9 among the participants during the 1-year follow-up (23.1%, and 30.1%; pZ 0.045); while Fig. 1B illustrates increasing baPWV in the same period (1795.0 458.5, and 1880.7 604.0; pZ 0.028).
The comparison of baseline characteristics between study patients with and without ABI progression is shown in
Table 2. As can be seen, patients with ABI progression were significantly associated with lower serum albumin levels than those without. Multiple linear regression analysis revealed that covariates in the model included age, sex, a history of DM, serum albumin level, fasting glucose,
homocysteine level, and use of statins. In addition, the ratio ofOABI to baseline ABI were significantly and nega-tively associated with fasting glucose (b Z e0.222, pZ 0.018).
Table 3shows the comparison of baseline characteris-tics between study patients with and without baPWV progression. As can be seen, patients with baPWV progression were significantly associated with a higher serum creatinine level than those without. Multiple linear regression analysis revealed that covariates in the model included age, sex, a history of coronary artery disease, serum triglyceride level, high-density lipoprotein choles-terol, creatinine level, and cardiothoracic ratio> 50%. In addition, the ratio of ObaPWV to baseline baPWV was independently correlated with age (b Z 0.192, pZ 0.045).
Table 2 Comparison of baseline characteristics between progressors and non-progressors of ABI.
Parameters Progressors of ABI
(nZ 10) Non-progressors of ABI (nZ 163) p Age (yr) 59.5 10.2 57.1 12.9 0.567 Male sex (%) 50.0 46.0 0.806 Smoking history (%) 30.0 24.5 0.711 Diabetes mellitus (%) 60.0 38.0 0.194 Hypertension (%) 70.0 70.6 > 0.99
Coronary artery disease (%) 30.0 23.9 0.707
Cerebrovascular disease (%) 10.0 9.2 > 0.99
Duration of hemodialysis (mo) 71.0 65.2 72.4 52.8 0.933 Systolic blood pressure (mmHg) 147.8 18.3 148.9 25.0 0.891 Diastolic blood pressure (mmHg) 75.0 11.4 80.7 14.6 0.226
Pulse pressure (mmHg) 72.8 19.0 68.4 16.8 0.426
Heart rate (beats/min) 82.2 8.1 82.1 14.2 0.984
Body mass index (kg/m2) 23.9 4.0 24.3 3.7 0.716
baPWV (cm/s) 1813.3 498.0 1793.8 457.6 0.897 Laboratory parameters Albumin (g/dL) 3.81 0.22 4.00 0.28 0.042 Fasting glucose (mg/dL) 156.6 55.7 120.8 62.5 0.079 Triglyceride (mg/dL) 161.3 92.5 154.3 103.1 0.833 Total cholesterol (mg/dL) 178.9 40.2 177.9 40.2 0.936 HDL-cholesterol (mg/dL) 40.6 7.7 41.1 10.9 0.897 LDL-cholesterol (mg/dL) 89.9 24.8 90.7 28.6 0.933 Creatinine (mg/dL) 10.1 2.4 10.3 2.3 0.690 Hematocrit (%) 31.7 3.9 31.0 3.8 0.547 Calcium-phosphorous product 41.9 6.4 46.2 12.8 0.300 Uric acid (mg/dL) 7.6 1.3 7.7 1.6 0.838 PTH (pg/mL) 531.4 379.9 418.7 360.9 0.341 hsCRP (mg/L) 0.55 0.46 0.71 1.01 0.667 Homocysteine (mmol/L) 33.9 8.9 29.2 9.9 0.189 Cardio-thoracic ratio> 50% 40.0 36.2 > 0.99 Medications Aspirin use (%) 30.0 17.2 0.388
ACEI and/or ARB use (%) 20.0 26.4 > 0.99
b-blocker use (%) 20.0 16.6 0.675
Calcium channel blocker use (%) 20.0 36.2 0.497
Statins use (%) 60.0 31.3 0.083
ABIZ ankle-brachial index; ACEI Z angiotensin converting enzyme inhibitor; ARB Z angiotensin II receptor blocker; baPWV Z brachial-ankle pulse wave velocity; HDLZ high-density lipoprotein; hsCRP Z high-sensitivity C-reactive protein; LDL Z low-density lipoprotein; PTHZ parathyroid hormone.
Discussion
The present longitudinal study evaluated the progression of PAOD and arterial stiffness and the influence of athero-sclerotic risk factors on ABI and baPWV progression in patients with hemodialysis. We found increase in both prevalence of ABI< 0.9 and baPWV during 1 year of follow-up. High fasting glucose and old age were identified as major factors responsible for the accelerated progression in ABI and baPWV, respectively.
We have reported the associated risk factors for abnormal ABI and baPWV in chronic kidney disease and patients on hemodialysis [13,14]. However, the reported results were from cross-sectional studies. There are some recent longitudinal studies examining the risk factors for PAOD and artery stiffness progression [19e21]. Ohnishi et al.[20] evaluated longitudinally the risk factors of de
novo PAOD in 468 adult elderly men for 5 years. They found that older age, smoking, cerebrovascular disease, and coronary artery disease were the risk factors for PAOD. In our study, we examined the annual change in ABI, not de novo PAOD, and found that high fasting glucose was asso-ciated with accelerated progression of ABI. Uremia may worsen metabolic syndrome features including insulin resistance, glucose intolerance, and hyperglycemia, resulting in high cardiovascular morbidity and mortality
[22]. Takenaka et al.[21]studied the associated factors of annual change in heart-tibial PWV in 72 patients on hemo-dialysis, and found that higher triglyceride levels and longer duration of dialysis were associated with greater increase in heart-tibial PWV. Jung et al.[19]also examined the factors associated with changes in heart-femoral PWV over one year in 67 peritoneal dialysis patients, and identified change in mean arterial pressure and triglyceride as risk
Table 3 Comparison of baseline characteristics between progressors and non-progressors of baPWV.
Parameters Progressors of baPWV (nZ 90) Non-progressors of baPWV (nZ 83) P Age (yr) 56.4 12.8 58.2 12.7 0.360 Male sex (%) 46.7 45.8 0.907 Smoking history (%) 26.7 22.9 0.566 Diabetes mellitus (%) 40.0 38.6 0.846 Hypertension (%) 71.1 69.9 0.859
Coronary artery disease (%) 18.8 30.1 0.085
Cerebrovascular disease (%) 6.7 12.0 0.222
Duration of hemodialysis (mo) 68.6 46.4 76.4 60.1 0.338 Systolic blood pressure (mmHg) 149.2 27.1 148.5 21.8 0.841 Diastolic blood pressure (mmHg) 80.7 15.0 80.0 13.9 0.762
Pulse pressure (mmHg) 68.9 19.1 68.4 14.3 0.850
Heart rate (beats/min) 82.4 15.4 81.8 12.2 0.781
Body mass index (kg/m2) 24.3 3.6 24.2 3.9 0.905
ABI< 0.9 23.3 22.9 0.945 Laboratory parameters Albumin (g/dL) 3.98 0.26 3.95 0.24 0.496 Fasting glucose (mg/dL) 122.5 60.6 116.2 55.0 0.475 Triglyceride (mg/dL) 139.9 77.4 166.9 115.9 0.071 Total cholesterol (mg/dL) 178.8 39.1 181.4 42.5 0.674 HDL-cholesterol (mg/dL) 42.3 11.1 39.7 10.3 0.122 LDL-cholesterol (mg/dL) 90.9 29.5 90.4 27.1 0.908 Creatinine (mg/dL) 10.6 2.4 9.9 2.2 0.047 Hematocrit (%) 30.6 4.0 30.4 3.2 0.800 Calcium-phosphorous product 46.1 10.2 48.2 13.1 0.248 Uric acid (mg/dL) 7.8 1.6 7.6 1.4 0.410 PTH (pg/mL) 406.3 309.9 446.6 350.8 0.423 hsCRP (mg/L) 0.62 0.85 0.78 1.12 0.299 Homocysteine (mmol/L) 30.1 10.5 28.7 9.2 0.375 Cardio-thoracic ratio>50% 30.0 43.4 0.068 Medications Aspirin use (%) 18.9 16.9 0.729
ACEI and/or ARB use (%) 28.9 22.9 0.369
b-blocker use (%) 14.4 19.3 0.395
Calcium channel blocker use (%) 36.7 33.7 0.687
Statins use (%) 34.4 31.3 0.663
ABIZ ankle-brachial index; ACEI Z angiotensin converting enzyme inhibitor; ARB Z angiotensin II receptor blocker; baPWV Z brachial-ankle pulse wave velocity; HDLZ high-density lipoprotein; hsCRP Z high-sensitivity C-reactive protein; LDL Z low-density lipoprotein; PTHZ parathyroid hormone.
factors for heart-femoral PWV progression. In their studies, serum triglyceride levels were evaluated monthly or every 3 months during the observation period, and those measurements were averaged for analysis. In our study, only a single measurement of triglyceride level was made, which might explain the discrepancy between our results and those obtained by Takenaka and Jung[19,21]. Shino-hara et al. [5] compared the aortic pulse wave velocity (PWV) of 71 uremic patients before initiation of hemodial-ysis with that of 144 patients on chronic hemodialhemodial-ysis, and found that the predialysis patients had greater aortic PWV than the patients on hemodialysis. They attributed their findings to good volume control and reversed insulin resis-tance in patients with hemodialysis, which might have favorable effects on arterial stiffness. The same reason may account for the lack of correlation between the duration of dialysis and arterial stiffness progression in our study patients.
In summary, the present study demonstrated increase in both prevalence of ABI< 0.9 and baPWV during 1 year of follow-up in patients on hemodialysis. High fasting glucose and old age were independent determinants of accelerated progression in ABI and baPWV, respectively. Good control of blood sugar may help delay the progression of peripheral artery disease in patients on hemodialysis.
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