Media-to-lumen ratio as predictor of renal abnormalities in hypertension: new findings, new questions

An important condition for a marker of subclinical organ damage to be considered for the assessment of patients' cardiovascular risk profile and as a surrogate endpoint in hypertension is its ability to predict future cardiovascular events. This requirement is fulfilled by several markers of end-organ damage, such as electrocardiographic or echocardiographic left ventricular mass, left ventricular diastolic dysfunction, carotid intima–media thickness, arterial stiffness, ankle–brachial index, endothelial dysfunction, glomerular filtration rate and microalbuminuria [1]. Similar evidence, albeit less consistently, has also been shown for another marker of target-organ damage affecting microcirculation, that is, the media-to-lumen ratio of small resistance arteries with a lumen diameter measuring less than 400 μm. Studies [2–4] performed by different investigators have shown that structural alterations of subcutaneous small resistance arteries of humans with essential or secondary hypertension are able, during a follow-up ranging from 6 to 10 years, to independently predict fatal and nonfatal cerebrovascular and coronary events. Structural alterations of small resistance arteries may precede and, with time, be associated with the development and progression of hypertension-related target-organ damage in different vascular beds, such as the brain, the heart and large arteries [5–7]. Taken together, these findings indicate that small artery remodelling is linked to cardiovascular prognosis and target-organ damage in different areas of the cardiovascular system (Figure 1). Surprisingly, the prognostic relevance played by the small resistance artery network appears to be confined to changes in structure of these vessels, although this remains controversial. In a study published a few years ago by Rizzoni et al. [8] with a follow-up averaging 5.5 years, endothelium-dependent vasodilatation was similarly impaired in hypertensive patients who developed or did not develop cardiovascular events, indicating that endothelial dysfunction in the microcirculation appeared unrelated to cardiovascular events. This is, however, in contrast with the evidence that endothelial dysfunction assessed in large-size and medium-size arteries may indeed represent a marker of future coronary events [9,10].Fig. 1In the present issue of the Journal, Boari et al.[11] report a study in which they evaluated retrospectively the behavior of the media-to-lumen ratio of small arteries in normotensive and hypertensive patients in relation to changes in renal function during follow-up. The data provide evidence that patients who exhibit a reduced media-to-lumen ratio are at greater risk of developing reduced renal function. The predictive value of microvascular alterations was confirmed by stepwise multivariate regression analysis, which identified the media-to-lumen ratio as the variable most closely related to time-dependent changes in renal function. Media-to-lumen ratio: a new marker of renal function? The most novel information provided by the study of Boari et al. [11] is the evidence that at the baseline evaluation, media-to-lumen ratio of small resistance arteries in subcutaneous tissue correlates not only with blood pressure values but also with indices of renal function such as serum creatinine and blood urea nitrogen. An inverse correlation was found with estimated glomerular filtration rate (calculated with the Modification of Diet Renal in Disease formulae). A further element of novelty was the finding that at 9 years of follow-up, media-to-lumen ratio was the most important independent predictor of changes in renal function. Taken together, these data suggest, although indirectly, that in hypertension, structural alterations of the microcirculation are likely to occur not only in subcutaneous tissue but also in the renal microcirculation, as previously shown in experimental models of hypertension. Indeed, many studies have demonstrated in rodents similar alterations in the structure of small arteries in the mesenteric circulation, the heart and the kidney [12], which resemble the ones found in humans in the subcutaneous tissue [13]. This represents a further demonstration that the structural alterations detected in the microcirculation of hypertensive patients and target-organ damage leading to outcomes are linked together in a cause/effect relationship. Another result of the study deserving a comment is the evidence that in both patients with diabetes (about 45% of the entire population enrolled in the study) and nondiabetic patients, percentage and mean yearly changes in estimated glomerular filtration rate did not correlate with media-to-lumen ratio [11]. This indicates that the two phenomena develop at different rates, resulting in different temporal patterns. Unresolved questions and study limitations As happens often in longitudinal studies, several confounders that affect the findings of this study need to be considered. Among these is drug treatment, particularly with antihypertensive drugs. Drug treatment may directly affect arterial remodelling [14], and indeed renal protection has been demonstrated for various classes of antihypertensive agents [1]. Basal and achieved blood pressure could also have confounding effects on the structure of small arteries [6]. A limitation of the present study is the absence of clinic blood pressure measurements on reported follow-up. The degree of blood pressure control with antihypertensive treatment may have varied in different patients, which could play a significant role in determining the study results and apparent correlations. A further limitation is the lack of information on microalbuminuria, whose relationship with media-to-lumen ratio of small arteries may not necessarily mirror that of other parameters of renal function. This calls for additional studies, although the invasive nature of the investigation of subcutaneous small arteries, as well as the long follow-up required for such studies, makes them difficult to perform. A new opportunity for investigating the relationship of small artery parameters with other surrogate markers and with outcomes may be found in the computer-based evaluation of retinal arteries. The latter provides interesting information on relationships between structural alterations of small arteries and other hemodynamic parameters and additional surrogate endpoints [15]. A recent cross-sectional study [16] has indeed shown that media-to-lumen ratio of retinal vessels relates to urinary albumin-to-creatinine ratio and may thus serve as an in-vivo marker of renal vascular damage.