Abstract

Background

Microalbuminuria is recognized as a marker of generalized vascular dysfunction. However, the associations between microalbuminuria and pulse wave velocity (PWV), carotid intima-media thickness (IMT), and ambulatory blood pressure (ABP), respectively, have not been investigated.

Methods

Brachial–ankle PWV (baPWV), IMT, and ABP were determined in 328 individuals (mean age, 65.7 ± 6.4 years) from the general population of Ohasama, a rural Japanese community. The participants were assigned to groups with microalbuminuria and with normoalbuminuria, and their characteristics were compared. We also examined the association between microalbuminuria and baPWV, IMT, and ABP, respectively, using multivariate analyses.

Results

Seventy-nine participants (24%) with microalbuminuria had significantly higher baPWV (P < 0.001) and 24-h systolic BP (SBP) (P = 0.006) than those with normoalbuminuria, although 24-h pulse pressure and mean IMT did not significantly differ between the groups. Multiple logistic regression analyses showed that baPWV, but not 24-h ABP, was independently associated with microalbuminuria (P = 0.002) when adjusted for various confounding factors. After further adjustment for 24-h SBP, the association between baPWV and microalbuminuria remained significant (P = 0.012). The trend was significant even when daytime or nighttime SBP was used instead of 24-hour SBP in this model.

Conclusions

Microalbuminuria appears to be associated with baPWV more closely than with IMT and ABP, and its association with baPWV is independent of ABP and other cardiovascular risk factors.

Microalbuminuria is not only an indicator of early renal disorder but is also a marker of generalized vascular dysfunction.1 Urinary albumin excretion shows an increase in patients with diabetes or hypertension.2,3 Moreover, microalbuminuria predicts the risk of cardiovascular morbidity and mortality in patients with hypertension,2 those with diabetes,4 as well as the general population.5 However, the mechanisms of pathogenesis of microalbuminuria remain unknown.

The development of cardiovascular diseases is attributed to pathological changes in the structure and function of arteries. Noninvasive techniques have been developed for assessing the properties of arterial walls, including measurement of pulse wave velocity (PWV) and carotid ultrasonography. The measurement of PWV is one of the most representative methods for assessing arterial stiffness.6,7 Carotid-femoral PWV represents the gold standard among the PWV parameters and, likewise, measurement of the brachial–ankle PWV (baPWV) can provide useful information about arterial stiffness.8,9,10,11 Structural changes in the carotid artery can be noninvasively detected by carotid ultrasonography, which can detect intima-media thickness (IMT) and the presence of plaques.12 Carotid IMT and plaques predict the risk of future myocardial infarction and stroke more accurately than do traditional risk factors.13

Previous clinical studies have related microalbuminuria not only to PWV14,15,16 or carotid IMT3,16 but also to ambulatory blood pressure (ABP).17,18 ABP is used widely19 and serves as a better marker of target-organ damage than casual blood pressure (CBP).17,20 However, the relationships of PWV, carotid IMT, and ABP to microalbuminuria had not been defined in the general population, and which of the three indices is the most closely related to microalbuminuria remained unclear. We therefore decided to compare the associations of these three indices with microalbuminuria in a segment of the general Japanese population.

Methods

Subjects. This study was based on a health survey implemented in Ohasama town, Japan. The geographic and demographic characteristics of Ohasama have been reported elsewhere.10,21 The Ohasama study started in 1987, and is still ongoing. From 2002 to 2005, 548 people who were ≥50 years of age participated in the Ohasama study, and in 373 of them baPWV measurement, carotid ultrasonography, ABP measurement, anthropometric and biochemical examinations were completed. Those with diabetes (n = 33) were excluded from this study, because the mechanisms responsible for the increase in albumin excretion in subjects without diabetes may be different from those in subjects with diabetes. Individuals with macroalbuminuria (n = 12) were also excluded from this study. A total of 328 individuals who met the inclusion criteria were admitted as subjects. Microalbuminuria was defined as a urine albumin:creatinine ratio (ACR) of ≥30 mg/g.Cr but <300 mg/g.Cr, and macroalbuminuria as ACR ≥300 mg/g.Cr.22 The Department of Health of the Ohasama Town Government approved the study protocol and the participants provided written, informed consent to all procedures associated with the study.

Physical and biochemical examination. Height and weight were measured for each of the subjects. Blood samples were collected to determine plasma total cholesterol, high-density lipoprotein–cholesterol, hemoglobin A1c, serum creatinine, and glucose. Information concerning current smoking status, alcohol intake, use of medication for hypertension, hypercholesterolemia, diabetes, history of cardiovascular disease, cerebrovascular disease diabetes, hypercholesterolemia, and diabetes was obtained on the same day as the baPWV measurement. Subjects were on antihypertensive medication at the time of BP and baPWV measurements. Hypercholesterolemia was defined as plasma total cholesterol ≥240 mg/dl, or currently on medication for hypercholesterolemia; diabetes mellitus was defined as fasting blood glucose ≥126 mg/dl, or postprandial glucose ≥200 mg/dl, or currently on medication for diabetes.

Measurement of baPWV. The baPWV was measured with the individuals in a supine position, after at least 5 min of rest, using an automatic device (form PWV/ABI; Colin, Komaki Japan) as described.8,9,10,11 Briefly, pressure waveforms of the brachial and tibial arteries were simultaneously recorded by placing occlusion cuffs connected to a plethysmographic sensor around both the brachia and ankles. The time delay (T) of the two waveforms between one foot and the other was measured. The lengths of the paths from the suprasternal notch to the brachium (Lb) and from the suprasternal notch to the ankle (La), were automatically calculated according to the height of each individual. The baPWV was calculated using the following equation:

 
formula

The values of baPWV (we used right brachial-to-right ankle baPWV) were calculated for measurements made for an average of 10 s.

The validity and reproducibility of this method have been reported; the intraobserver repeatability coefficient is 0.87 and the interobserver repeatability coefficient is 0.98 (ref. 8). The rationale for the use of baPWV is that it is a parameter determinable by non-invasive methods, and closely correlates with aortic PWV which requires an invasive method.8

Carotid ultrasonography. Carotid ultrasound was performed using a real-time, B-mode ultrasound imaging unit (Toshiba Sonolayer SSA-250A; Toshiba, Tokyo, Japan) with a 7.5 MHz annular array probe with an axial resolution of 0.25 mm as described.23 Standardized ultrasound was performed by trained physicians who were blinded to the clinical and biochemical parameters of each individual. The study procedure involved scanning the near and far walls of both common carotid arteries, ∼1 cm proximal to the carotid bulb on the longitudinal view. During each examination, different scanning angles (anterior, lateral posterior) identified the maximal IMT in each wall. Mean IMT was defined as the mean value of the maximal wall thickness for the near and far walls of both the left and right common carotid arteries. We looked for plaques on both sides of the common carotid artery and carotid bifurcation, as well as the internal carotid and external carotid arteries. Plaques were defined as focal widening relative to adjacent segments, with protrusion into the lumen composed either of calcified deposits alone or a combination of calcified and non-calcified material.13 All participants were examined in the seated position. The reproducibility of the IMT measurement has been reported.23

Blood pressure measurements. We monitored ABP using an automated device (ABPM630; Nippon Colin, Komaki, Japan)24 preset to measure blood pressure (BP) every 30 min. A minimum of 12 valid daytime readings and 6 valid nighttime readings were required. The mean values ± s.d. for the number of valid BP readings recorded for 24 hours, during daytime, and during nighttime were 43 ± 5, 28 ± 5, and 15 ± 3, respectively. The mean 24-h, daytime, and nighttime values for ABP were calculated for each participant. Daytime and nighttime values were estimated from diaries maintained by the participants.

CBP was measured in seated individuals after at least 2 min of rest, using an automated device based on the cuff oscillometric method (HEM-907; Omron Healthcare, Kyoto, Japan). Individual BP and heart rate were defined as the average of two readings.

The devices used for measuring ABP and CBP have been validated24 and have met the criteria established by the Association for the Advancement of Medical Instrumentation.25 White-coat hypertension was defined as a recording of CBP ≥140/90 mm Hg and daytime ABP <135/85 mm Hg without antihypertensive medication.

Statistical analysis. When ACR was entered as a continuous variable, the natural logarithm of ACR was used because the ACR distribution was skewed. Associations between natural logarithm of ACR and continuous variables were assessed by correlation coefficients (r).

The participants were assigned to groups according to microalbuminuria and normoalbuminuria, and their characteristics were compared using Student's t- test for continuous variables and the χ2-test for categorical variables. We then compared baPWV, mean IMT, and ABP variables between the groups, using Student's t -test for univariate analysis and analysis of covariance for multivariate analysis. We subsequently analyzed quartiles of baPWV, mean IMT, and ABP variables, and used multivariate logistic regression analysis for examining the association of each of the variables with microalbuminuria. Finally, we entered baPWV and 24 h, daytime, or nighttime systolic BP (SBP) as linear terms (per s.d.) into the model. We adjusted for age, gender, BMI, use of antihypertensive medication, history of cardiovascular and/or cerebrovascular diseases, high-density lipoprotein–cholesterol, hemoglobin A1c, and ambulatory heart rate. All statistical analyses were conducted using SPSS software version 11.0 (SPSS, Chicago, IL). Statistical significance was accepted at P < 0.05.

Results

Table 1 shows the baseline characteristics of the participants. The study population comprised 86 men and 242 women with a mean age of 65.7 ± 6.4 years (range, 52–83 y). The mean CBP was 152/80 mm Hg and the mean 24-h ABP was 122/71 mm Hg. Of the 328 participants, 110 (34%) were on antihypertensive medication and 79 (24%) had microalbuminuria.

Table 1

Characteristics of myocardial infarction (MI) and ischemic stroke cases and controls

Univariate analyses showed that the natural logarithm of ACR was significantly correlated with baPWV (r = 0.256, P < 0.001), 24-h SBP (r = 0.252, P < 0.001), and 24-h pulse pressure (r = 0.190, P = 0.001), but not with mean IMT (r = 0.079, P = not significant).

Individuals with microalbuminuria had significantly higher baPWV than those with normoalbuminuria (16.1 ± 2.9 vs. 17.7 ± 3.3 m/s, P < 0.001) and also higher 24-h SBP (121 ± 11 vs. 125 ± 11 mm Hg, P = 0.006). On the other hand, there was no significant difference between the groups in 24-h pulse pressure (50.3 ± 7.1 vs. 51.7 ± 6.7 mm Hg, P = not significant), presence of carotid plaques (29% vs. 35%, P = not significant) and mean IMT (0.72 ± 0.14 vs. 0.74 ± 0.13 mm, P = not significant). Multivariate analyses showed that baPWV and 24-h SBP were significantly higher in individuals with microalbuminuria, after adjusting for age, gender, and other cardiovascular risk factors (Table 2). Similar results were found even when 24-h ABP values were replaced by daytime or nighttime ABP values (Tables 1 and 2).

Table 2

Adjusted mean values of baPWV, mean IMT, and ABP in relation to the presence of microalbuminuria

Variables Normoalbuminuria Microalbuminuria P 
24-h SBPa 121.2 ± 0.7 124.6 ± 1.3 0.020 
24-h PPa 50.4 ± 0.4 51.4 ± 0.8 0.24 
Daytime SBPb 126.9 ± 0.8 130.2 ± 1.4 0.034 
Daytime PPb 52.1 ± 0.5 52.9 ± 0.8 0.43 
Nighttime SBPc 110.2 ± 0.8 113.6 ± 1.4 0.033 
Nighttime PPc 46.9 ± 0.5 48.5 ± 0.9 0.11 
Mean IMTa 0.72 ± 0.01 0.74 ± 0.02 0.27 
BaPWVa 16.1 ± 0.2 17.5 ± 0.3 <0.001 
Variables Normoalbuminuria Microalbuminuria P 
24-h SBPa 121.2 ± 0.7 124.6 ± 1.3 0.020 
24-h PPa 50.4 ± 0.4 51.4 ± 0.8 0.24 
Daytime SBPb 126.9 ± 0.8 130.2 ± 1.4 0.034 
Daytime PPb 52.1 ± 0.5 52.9 ± 0.8 0.43 
Nighttime SBPc 110.2 ± 0.8 113.6 ± 1.4 0.033 
Nighttime PPc 46.9 ± 0.5 48.5 ± 0.9 0.11 
Mean IMTa 0.72 ± 0.01 0.74 ± 0.02 0.27 
BaPWVa 16.1 ± 0.2 17.5 ± 0.3 <0.001 

Values are expressed as mean values ± s.e.m.

ABP, ambulatory blood pressure; baPMV, brachial–ankle pulse wave velocity; IMT, intima-media thickness; PP, pulse pressure; SBP, systolic blood pressure.

aAdjusted for age, gender, body mass index (BMI), use of medication for hypertension, history of cardiovascular and/or cerebrovascular diseases, high-density lipoprotein (HDL)-cholesterol, hemoglobin A1c (HbA1c), and 24-h heart rate (HR). bAdjusted for age, gender, BMI, use of medication for hypertension, history of cardiovascular and/or cerebrovascular diseases, HDL-cholesterol, HbA1c, and daytime HR. cAdjusted for age, gender, BMI, use of medication for hypertension, history of cardiovascular and/or cerebrovascular diseases, HDL-cholesterol, HbA1c, and nighttime HR.

Table 3 shows the adjusted odds ratio for microalbuminuria among the quartiles of 24-h SBP, 24-h pulse pressure, mean IMT, and baPWV. The results showed that baPWV was independently associated with microalbuminuria (P for trend = 0.002), whereas the association of 24-h SBP with microalbuminuria ceased to exist after adjustments had been made for various confounding factors. When further adjusted for 24-h SBP, the significant association between baPWV and microalbuminuria remained (P for trend = 0.012, Figure 1). Even when daytime or nighttime ABP was introduced into these models instead of 24-h ABP, the results were identical with those obtained using 24-h ABP (Table 3).

Table 3

Association of β2-adrenergic receptor gene variation with myocardial infarction and ischemic stroke

Adjusted Odds ratios for microalbuminuria among the quartiles of brachial–ankle pulse-wave velocity (baPWV). Odds ratios were adjusted for age, gender, body mass index, use of medication for hypertension, history of cardiovascular and/or cerebrovascular diseases, high-density lipoprotein–cholesterol, hemoglobin A1c, 24-h heart rate, and 24-h systolic blood pressure.

Multivariate logistic regression analysis revealed that only baPWV was significantly and independently associated with microalbuminuria, and that the risk for microalbuminuria increased by 67% with each 1-s.d. (3.1 m/s) increase in baPWV (Table 4). By contrast, 24-h SBP was not significantly associated with microalbuminuria. As before, the results were similar when daytime or nighttime SBP was used in this model instead of 24-h SBP (Table 4).

Table 4

Odds ratio (OR) and 95% CI with baPWV and ABP increases of 1 s.d. for microalbuminuria

Models/variables OR (95% CI) P 
Model 1 (baPWV + 24-h SBP)   
baPWV increase of 1 s.d.a 1.67 (1.21–2.31) 0.002 
24-h SBP increase of 1 s.d.b 1.19 (0.89–1.59) 0.24 
Model 2 (baPWV + daytime SBP)   
baPWV increase of 1 s.d. 1.69 (1.23–2.33) 0.001 
Daytime SBP increase of 1 s.d.c 1.16 (0.87–1.54) 0.31 
Model 3 (baPWV + nighttime SBP)   
baPWV increase of 1 s.d. 1.68 (1.22–2.31) 0.001 
Nighttime SBP increase of 1 s.d.d 1.18 (0.89–1.57) 0.25 
Models/variables OR (95% CI) P 
Model 1 (baPWV + 24-h SBP)   
baPWV increase of 1 s.d.a 1.67 (1.21–2.31) 0.002 
24-h SBP increase of 1 s.d.b 1.19 (0.89–1.59) 0.24 
Model 2 (baPWV + daytime SBP)   
baPWV increase of 1 s.d. 1.69 (1.23–2.33) 0.001 
Daytime SBP increase of 1 s.d.c 1.16 (0.87–1.54) 0.31 
Model 3 (baPWV + nighttime SBP)   
baPWV increase of 1 s.d. 1.68 (1.22–2.31) 0.001 
Nighttime SBP increase of 1 s.d.d 1.18 (0.89–1.57) 0.25 

Model 1 was adjusted for age, gender, body mass index (BMI), use of medication for hypertension, history of cardiovascular and/or cerebrovascular diseases, high-density lipoprotein (HDL)-cholesterol, hemoglobin A1c (HbA1c), and 24-h heart rate (HR). Model 2 was adjusted for age, gender, BMI, use of medication for hypertension, history of cardiovascular and/or cerebrovascular diseases, HDL-cholesterol, HbA1c, and daytime HR. Model 3 was adjusted for age, gender, BMI, use of medication for hypertension, history of cardiovascular and/or cerebrovascular diseases, HDL-cholesterol, HbA1c, and nighttime HR.

ABP, ambulatory blood pressure; baPMV; brachial–ankle pulse wave velocity; CI, confidence interval; SBP, systolic blood pressure.

a1 s.d. = 3.1 m/s. b1 s.d. = 11.4 mm Hg. c1 s.d. = 12.5 mm Hg. d1 s.d. = 12.9 mm Hg.

Discussion

The principal findings of this study were that patients with microalbuminuria had significantly higher baPWV and systolic ABP values than those with normoalbuminuria, whereas mean IMT did not significantly differ between the groups. The association between baPWV and microalbuminuria remained significant in multivariate logistic regression analysis, but the association between systolic ABP and microalbuminuria disappeared after adjustment for various confounding factors. The relationship between baPWV with microalbuminuria remained significant even after further adjustment for systolic ABP.

Some studies have shown a relationship between arterial stiffness and microalbuminuria. Munakata et al. recently reported that baPWV is related to microalbuminuria independently of CBP.14 We used ABP rather than CBP for adjustment in this study, because ABP is more closely associated with target-organ damage than CBP.17,20 We demonstrated an ABP-independent relationship between baPWV and urinary albumin excretion, providing more direct evidence that arterial stiffness is an important contributor to renal vascular damage. Only one study has shown a 24-h ABP-independent relationship between carotid-femoral PWV and microalbuminuria.15 However, that study did not examine the effects of nighttime ABP, although previous reports have shown that, among various ambulatory measures, it is nighttime ABP that is most closely associated with microalbuminuria.18,26 We discovered here that the relationship between arterial stiffness and microalbuminuria is independent of nighttime ABP.

We also discovered that baPWV is more closely associated with microalbuminuria than 24-h, daytime, and nighttime ABP. To the best of our knowledge, no other study has examined whether it is PWV or ABP that is more closely associated with microalbuminuria. Our finding suggests that PWV is superior to brachial arterial pressure in assessing early renal dysfunction.

In this study, in contrast to the results obtained for baPWV, carotid IMT was shown not to be significantly associated with microalbuminuria. This supports the findings of some earlier studies,3,27 whereas other studies16 have reported different results. Carotid IMT provides information chiefly on local atherosclerotic changes in the intima, whereas PWV provides information chiefly on arteriosclerotic changes in the media. This could explain our results. Microvascular damage in the kidney may be influenced by medial, rather than intimal, lesions.

This study showed a higher prevalence of microalbuminuria than reported by other population-based studies, such as the Prevention of Renal and Vascular End-stage Disease study,5 although it was similar to that observed previously in hypertensive populations.14 The high prevalence could be explained by the inclusion of relatively older subjects with higher BP in our study population.

The mechanism of pathogenesis involved in the relationship between elevated PWV and microalbuminuria remains unknown. It has been suggested that increased arterial stiffness enhances pressure and flow pulsations to the kidney, thereby inducing microvascular damage.28

This study has some limitations. First, we used one-spot urine samples to evaluate microalbuminuria. Urinary albumin excretion tends to vary during the day and 24-h urine collection is recommended for albuminuria assessment. Nonetheless, single urine sampling has gained acceptance, because studies have shown the same results as with 24-h urine collection.29,30 Second, the inclusion of patients with hypertension who were under treatment with medication might have affected the results; however, the study has adjusted for antihypertensive medication. Third, the possible inclusion of subjects with impaired glucose tolerance might have had some influence on the observed difference between normoalbuminuric and microalbuminuric groups.

In summary, this study demonstrated that microalbuminuria is more closely associated with baPWV than with carotid IMT and ABP. In addition, baPWV might be related to microalbuminuria independently of ABP and other cardiovascular risk factors. Further studies are required to clarify causal relationships between arterial stiffness and microalbuminuria.

Disclosure:

The authors declared no conflict of interest.

We are grateful to the staff members of the Iwate Prefectural Stroke Registry and to the public health nurses in Ohasama for their valuable support to this project.

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