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Large artery stiffness and microalbuminuria: a causal relationship?

van den Meiracker, Anton H; Mattace-Raso, Francesco US

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doi: 10.1097/HJH.0b013e32832d2149
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Large artery stiffness is the principal determinant of an increase in pulse pressure and is a strong independent predictor of coronary artery disease and stroke in community-based populations and in populations with hypertension, renal function impairment and diabetes mellitus [1–6]. Apart from being a risk determinant of atherothrombosis of large arteries, large artery stiffness might also associate with small vessel disease [7]. Exposure of organs to a high pulsatile pressure as a direct consequence of elevated large artery stiffness may damage small vessels. In this regard, low impedance organs such as the brain and kidney are especially vulnerable. Cerebral lacunar infarctions and consequent vascular dementia, increased urinary albumin excretion and renal insufficiency may all be clinical sequelae of small vessel disease. On the basis of the pathophysiological link between large artery stiffness and albuminuria, mediated by a high pulsatile pressure, an association between these two parameters might be expected. Conversely, this association could also explain why microalbuminuria is an indicator of increased cardiovascular risk in individuals with and without diabetes mellitus, although, undoubtedly, other factors are involved as well.

Reported studies about associations between large artery stiffness and microalbuminuria in nondiabetic individuals are scarce. In a relatively small cross-sectional study by Mulè et al.[8], hypertensive individuals with microalbuminuria had higher values of carotid–femoral pulse wave velocity (cfPWV) as a measure of aortic stiffness than normoalbuminuric hypertensive individuals after adjusting for confounders such as blood pressure (BP), renal function, sex, BMI, smoking status and serum glucose values. cfPWV was higher in patients with metabolic syndrome than in those without this syndrome. Using multiple variable regression analysis, it appeared that the main explanatory factors for this association were age, systolic BP and microalbuminuria [9].

In the present issue of the Journal of Hypertension, Munakata et al. [10] have further explored the association between brachial–ankle PWV (baPWV) and microalbuminuria in patients with primary hypertension. In their study, hypertensive patients without diabetes were followed for 2 years. At the end of the follow-up period, 45 of the 321 participants had microalbuminuria; of these, 14 had new-onset and 31 had persistent microalbuminuria. When the baseline data of the groups of participants with and without microalbuminuria at the end of the follow-up period were compared, those with new-onset or persistent microalbuminuria had a higher baPWV (1950 vs. 1800 cm/s), a higher urinary albumin-to-creatinine ratio (72 vs. 22 mg/g Cr), a lower high-density lipoprotein (HDL)-cholesterol concentration (54 vs. 60 mg/dl) and the use of inhibitors of the renin–angiotensin system was less (55% vs. 71%). Remarkably, and difficult to explain, no differences for variables such as age, sex, BMI, BP levels, smoking status and fasting plasma glucose concentration between the groups of participants with and without microalbuminuria were observed. Using multiple logistic regression analysis with microalbuminuria as dependent variable, odds ratios (ORs) after 2 years of follow-up were 11.7 for microalbuminuria at study entry, 1.6 for a 400 cm/s increase in baPWV, 0.34 for use of inhibitors of the renin–angiotensin system and 0.44 for a HDL of more than 50 mg/dl at entry. On the basis of this analysis, the authors conclude that a higher baPWV is an independent risk factor for future microalbuminuria in primary hypertension, although this conclusion is somewhat weakened in the abstract of their paper.

The study by Munakata et al. [10] is interesting because it focuses on the relationship between raised PWV as a reflection of large artery disease to microvascular damage as reflected by microalbuminuria. Whether an elevated baPWV is a risk factor or marker for future microalbuminuria might be debatable because of the design of their study and the way the data have been analysed. First, the participants of their study were treated with different classes of antihypertensive agents. The selection of antihypertensive agents was not made according to a strict protocol, and could comprise either angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists or calcium entry blockers as first-line treatment, extended with diuretics or sympathicolytic agents if, after 3 months of treatment, the target BP was not achieved. Although not mentioned by the authors, the initial choice of the antihypertensive agent might have been guided by the magnitude of urinary albumin excretion and hence might have influenced the outcome of their study. Second, the distinction between microalbuminuria and normoalbuminuria for risk prediction is arbitrary, as it has been well demonstrated that the increase in cardiovascular risk associated with albuminuria is already present below the cut-off value of microalbuminuria [11,12]. To explore associations with other risk factors or risk markers or cardiovascular outcome, especially in individuals without diabetes, albuminuria can better be used as a quantitative or continuous measure rather than as a qualitative or categorical measure (microalbuminuria or normoalbuminuria). Third, albuminuria is subject to large within-individual variation, with reported variation coefficients of 50% [13]. Therefore, the conclusion as to whether microalbuminuria is present or not should be based preferably on repeated measurements. Although albuminuria was repeatedly measured during the follow-up period of their study, it cannot be extracted from their paper whether the average of these measurements was used for analysis or whether the analysis was based only on the measurement at the end of the 2-year follow-up period. Fourth, to conclude whether baPWV is an independent risk factor for future microalbuminuria, it would have been more straightforward to exclude the participants who already had microalbuminuria at the start of their study. Probably, this analysis was not performed because only 14 of the 238 individuals with normoalbuminuria at entry developed microalbuminuria during follow-up. It should also be mentioned that the OR of baPWV for predicting future microalbuminuria was quite low. For a 400 cm/s increase in baPWV, which can be regarded as a considerable increase, the estimated OR was 1.6 (95% confidence interval = 1.05–2.5). For comparison, the OR for microalbuminuria at entry for future microalbuminuria was 11.7 (5.4–25.4). This low OR for baPWV is not surprising in light of the knowledge that the cause of microalbuminuria is multifactorial.

Microalbuminuria is usually considered to be a reflection of (generalized) endothelial dysfunction [14]. In addition, markers of low-grade vascular inflammation are associated with the development and progression of microalbuminuria [15]. Although advancing age is by far the most important determinant of large artery stiffness, it is possible that endothelial dysfunction and low-grade vascular inflammation, by promoting both large artery stiffness and microalbuminuria, in part accounted for the observed association between large artery stiffness and future microalbuminuria. Further research to test this hypothesis is necessary.

An important aspect of the study of Munakata et al. [10] is the demonstration that treatment of hypertension was associated with a generalized reduction of albuminuria as well as a reduction of the proportion of patients with microalbuminuria. At baseline, 83 of their participants had microalbuminuria. This number decreased to 45 after 2 years of treatment. This is a favourable outcome in view of the evidence that a reduction in albuminuria associates with a reduction in cardiovascular risk, independent of the BP-lowering effect [16]. In this regard, albuminuria and its change during antihypertensive treatment are suitable for risk stratification and, accordingly, measurement of urinary albumin excretion has been advocated in the 2007 European Society of Hypertension/European Society of Cardiology guidelines for cardiovascular risk assessment [17].

Some other points relating to their study deserve a short comment. The authors used baPWV instead of the gold standard of the cfPWV. As compared with cfPWV, baPWV is less intrusive because measurement in the groin region can be skipped. In addition, this measurement using the AT-form ankle brachial index device (Nippon Colin, Komaki, Japan) requires no special investigator's skills [18]. Compared with the gold standard of cfPWV, baPWV has potential disadvantages. In patients with severe atherosclerosis of the lower limbs, reliable measurements may be difficult to obtain. The prognostic value of baPWV compared with the gold standard of cfPWV is still limited. Compared with cfPWV, baPWV is about 1.5 times higher, and both measurements are well correlated (r = 0.75) [18]. Compared with the elastic arteries, muscular arteries are less prone to the process of vascular stiffening or arteriosclerosis, and at least theoretically, baPWV may be a less ideal measure of large artery stiffness than cfPWV. To better appreciate the value of baPWV for risk stratification, large prospective population-based studies, in which the prognostic value baPWV and cfPWV for the development of cardiovascular disease are compared, are necessary. Previous findings in patients with end-stage renal disease showed that the cfPWV, but neither the brachial nor the femoral PWV, is predictive of cardiovascular mortality [19].

In conclusion, the study by Munakata et al. [10] is interesting because it emphasizes potential relationships between large artery stiffness and future microvascular damage in the kidney as reflected by microalbuminuria. At this moment, however, it appears premature to conclude that such a relationship indeed exists. Moreover, as discussed, the association might be much more complicated than simply being a consequence of the increased pulsatile stress to the microvasculature in the kidney.


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