Is albuminuria a marker of arterial remodeling?

Several cardiovascular risk factors such as aging, male gender, smoking, obesity, hypertension, diabetes, dyslipemia and metabolic syndrome are associated with microalbuminuria. It is, however, widely accepted that microalbuminuria is an independent risk factor for cardiovascular disease (CVD) and mortality [1–4]. Moreover, the relationship between urinary albumin excretion (UAE) and cardiovascular risk is continuous and, like blood pressure, the concept of a strict threshold level to define normality is inconsistent with epidemiological data [2,4,5]. The Heart Outcomes Prevention Evaluation (HOPE) study showed that an increased risk may be present with albumin/creatinine ratios in the normal range, even as low as 0.5 mg/mmol [6]. With this background, it makes no sense to define a rigid cutoff level, and probably the term microalbuminuria should be modified to albuminuria or albuminuria associated disease. The pathophysiological processes linking albuminuria and CVD are unclear. Probably, preliminary questions analyzing this issue should be: how plasma albumin reaches the urine and why the amount of urinary albumin is linked to CVD. Under physiological conditions, the glomerular filtration barrier prevents most of the plasma albumin from reaching the urinary space, although the glomerular sieving coefficient for albumin has recently become controversial [7,8]. When albumin gets into the renal tubules, it is reabsorbed by receptor mediated-endocytosis and metabolized [7]. The final urine contains none or only small quantities of albumin. Therefore, any damage to the capillar–glomerular barrier and/or to the reabsorptive or metabolic activities of the proximal tubule might lead to increased excretion of albumin in the urine. Additionally, ‘structural modifications’ in plasma albumin may facilitate its filtration through the glomerular barrier (to date, no study has been done to support this point). The Steno hypothesis has postulated that albumin leakage into the urine is a reflection of widespread vascular damage [9]. The kidney is a vascular organ where vascular–endothelial damage is manifested by an increased UAE (the kidney as a window to the vasculature). On the contrary, greater amounts of albumin excretion may damage the kidney. The leaking of albumin may damage glomeruli and the increase in tubular reabsorption of albumin may damage the proximal tubule by increasing protein trafficking and inducing proinflammatory and profibrotic pathways, leading to interstitial inflammation, progressive scarring and loss of kidney function. Indeed, this process seems to be reflected in the progressive loss of kidney function with persistent albuminuria. This pathogenic role of albuminuria is clear at the kidney level, but is not so evident at the systemic vascular level. Important questions remain unsolved with the Steno hypothesis: why is albuminuria such a powerful predictor of CVD? Why are greater levels of albuminuria already found in young children without apparently acquired vascular disease? A new hypothesis has been postulated stating that albuminuria could be a marker of vascular function with a wide range of excretion, reflecting the susceptibility of the vascular tree to different pathogenic factors (such as hypertension, diabetes, dyslipemia etc.) inducing organ damage, and that the mechanism responsible for the increase in albumin excretion may be different from patient to patient. According to this new view, differences between individuals in their level of albumin excretion are already observed at a very early age as well as individual variabilities in renal and systemic endothelial functions that are fairly constant in the first decades of life, indicating that UAE is not necessarily a consequence of vascular damage at a later age [1]. Furthermore, the level of UAE not only predicts cardiovascular risk but also the development of hypertension and type 2 diabetes in the general population [10]. As already mentioned, the level of UAE is a good predictor of cardiovascular risk and also seems to be a sensitive marker of systemic vascular damage. Recent population-based studies highlight the strong association between the level of UAE and cerebrovascular disease [3]. Moreover, after stratifying by stroke subtype, the level of UAE was predictive of ischaemic but not haemorrhagic stroke, suggesting an atherosclerotic pathway. In this regard, other studies have shown a close relationship between the level of UAE and parameters of vascular structural alteration such as arterial stiffness and others [11]. Changes in vascular structural properties over time are processes known as arterial remodeling. In healthy arteries, remodeling is a homeostatic response to changes in the flow and circumferential stretch to restore normal shear stress and wall tension, respectively. Arterial remodeling is characterized by wall thickening [indicated by an increase in intima–media thickness (IMT)] and diameter widening [indicated by an increase in interadventitial diameter (IAD)]. Three different patterns of arterial remodeling have been identified: inward [characterized by a decrease in lumen diameter (LD) resulting from a greater change in IMT than in IAD], outward (characterized by an increase in LD resulting from a greater change in IAD than in IMT), and compensatory remodeling (characterized by LD preservation despite changes in IMT and IAD) [12]. In this issue of the Journal of Hypertens, Hermans et al.[13] present a substudy of the Hoorn Study showing an association between UAE and maladaptive arterial remodeling. Hoorn is a Dutch cohort study of diabetes and its related complications in the general population that began in 1989 [14]. In this work, the authors investigated the possible association between several parameters of arterial remodeling with UAE and the estimated glomerular filtration rate (eGFR). The vascular parameters analyzed were IMT, IAD, LD, circumferential wall tension and circumferential wall stress from the right common carotid artery. The authors observed that a greater UAE, but not a lower eGFR, was associated with greater LD and IAD, but not with a significant increase in IMT. Thus, they concluded that in this population greater albuminuria was associated with a maladaptive carotid remodeling process manifested by both an increase in circumferential tension and wall stress. As the maladaptive outward carotid remodeling has been associated with plaque instability and rupture, the authors suggest that these results point to a possible explanation of why greater albuminuria is associated with cardiovascular risk and especially stroke. The article is very interesting and well written. The main conclusions of the study may open new ways of research and discussion because the results of this work are not uniform as compared with other works. Several cross-sectional studies found that microalbuminuria was associated with higher IMT [15], but these studies were limited by the focus on high-risk adults in selected settings or by the lack of statistical adjustments. Recently, Rodondi et al. [16] published the association between semiquantitative microalbuminuria and IMT but in a younger African cohort mostly with mild or no renal dysfunction. The study has some limitations. The authors are, however, perfectly aware of the majority of them: (1) it is a cross-sectional study; ideally human studies of remodeling should be longitudinal, (2) measuring change in vessel area in response to plaque growth, measurements were done in a single point and this could not reflect the entire artery, (3) the study was performed in elderly Caucasian population and thus, inferences to other populations should be made with care, (4) the severity of certain conditions (e.g. diabetes) and the presence of unmeasured confounders (e.g. salt intake, drug treatment) might have interfered with the results, (5) ultrasound cannot discriminate between the intimal and medial layers of the artery and (6) the presented data give no insight into the intrinsic mechanisms linking albuminuria and arterial remodeling. Unfortunately, the effect of angiotensin-converting enzyme (ACE)-inhibitors and angiotensin II receptor blockers (ARBs) on arterial remodeling could not be properly addressed with this design. One of the conclusions of the study is that eGFR is not associated with maladaptive arterial remodeling. The study does not, however, mention anything regarding the etiologies of chronic kidney disease (CKD). This is an important point since diabetic nephropathy and nephroangiosclerosis are common causes of CKD and there is extensive vascular damage in these pathologies. Kidney damage can also be secondary to other pathologies that are limited to the kidney, such as glomerulopathies or renal vasculitis where it would be surprising to see maladaptive arterial remodeling in the early stages of the disease. Although CVD is a risk factor of CKD, CKD is also increasingly recognized as an important independent cardiovascular risk. This risk seems to begin to rise exponentially when the eGFR drops below 60 ml/min per 1.73 m2[17]. This could be an explanation of the lack of association in the present study in which the mean eGFR was as high as 60.3 ml/min per 1.73 m2. A similar absence of association with GFR, measured by cystatin C, has recently been described in a cohort with mild or no renal dysfunction [16]. Another possible explanation is that eGFR has essentially become synonymous only with renal function. The kidney performs many other functions apart from regulating fluid volume, acid–base and electrolyte homeostasis. The kidney produces some hormones, metabolizes many substances and thus there may not be reliable parameters yet to measure these other functions at an early state of CKD. On the other hand, carotid artery remodeling and renal insufficiency were found to be related to other studies [18]. Significant data indicate that greater UAE reflects impaired vascular and endothelial function and that it is associated with a higher susceptibility to cardiovascular and renal events [1–3]. UAE should not only be measured for the routine assessment of subclinical organ damage in hypertensive or diabetic patients, but also in patients at risk of CVD. Moreover, if the albuminuria decreases during follow-up, the cardiovascular risk also seems to diminish [1,19]. Although it is still a matter of debate, albuminuria may become a therapy target itself or a marker that a more aggressive cardiovascular risk factor reduction should be accomplished [4]. For clinical practice, it is essential to detect atherosclerosis before the occurrence of fatal events. Thus, it is necessary to find tests that are safe, noninvasive, quick and inexpensive which correlate with the severity of atherosclerotic disease. These parameters should be reliable and reproducible with elevated predictive values. These parameters should allow individualizing cardiovascular risk and monitoring the efficacy of therapeutic strategies. UAE appears to be an excellent candidate. Acknowledgements There are no conflicts of interest.