Microalbuminuria as an intermediate endpoint in essential hypertension

Large randomized, controlled trials and their meta-analyses provide the strongest evidence about several aspects of antihypertensive therapy. Nonetheless, the assessment and monitoring of intermediate objectives play an important role in providing scientific evidence for delineating the best antihypertensive treatment. Additionally, they provide information about the success of therapy in an individual subject above and beyond blood pressure values. Left ventricular hypertrophy (LVH), intima–media thickness, renal function and new onset diabetes are some of the potential surrogate endpoints [1]. Over recent years, microalbuminuria has become a prognostic marker for cardiovascular and/or renal risk in diabetic and non-diabetic subjects [2–12], and its assessment is now recommended in a risk stratification strategy for hypertension management [1,13]. The potential of microalbuminuria as an intermediate endpoint during antihypertensive treatment remains unclear. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) [12,14], a double-blind study of hypertensives with LVH in which subjects were randomized in parallel arms to losartan or atenolol, is the largest study ever published involving microalbuminuria assessment upon entry and at yearly intervals during study follow-up. Although the study is limited by urinary albumin excretion (UAE) assessment being performed using a yearly unique spot urine sample, the large number of subjects analysed partly overcomes this limitation. The study amply demonstrates that the rate of the primary composed cardiovascular endpoint of cardiovascular death, fatal or non-fatal stroke, and fatal or non-fatal myocardial infarction, increases four- to five-fold from the lowest to the highest decile of the albumin/creatinine ratio [12]. The risk increased linearly, at a much lower urinary albumin excretion than has been reported among diabetic patients, without any threshold or plateau value. The UAE threshold required to define increased risk in individuals with hypertension was far below the threshold UAE for the current definition of microalbuminuria. This likely reflects the fact that mircoalbuminuria was originally defined on the basis of an increased risk of developing diabetic nephropathy [15]. It is now clear that its significance extends beyond nephropathy and that it is a marker for generalized vascular dysfunction in the diabetic and non-diabetic population. The LIFE study reinforced previous evidence from cross-sectional and prospective studies supporting the adoption of a lower UAE rate for the detection of enhanced risk in individuals with hypertension. The additional information now released by the LIFE investigators, and published in this issue of the journal [16], yields interesting information that can contribute to clarifying the potential role of microalbuminuria in the hypertensive patient. It was not surprising that losartan, an angiotensin II receptor blocker (ARB), caused a greater reduction in microalbuminuria with a similar blood pressure reduction compared to atenolol [16]. The difference in UAE between losartan- and atenolol-based treatments, which was marked at the first year, was maintained throughout the study. This outcome has been demonstrated in a large number of short-term studies [17], and long-term studies are also underway. Agents blocking the renin–angiotensin system are superior to other antihypertensive agents in reducing the UAE, mainly in subjects with a high range of blood pressure. In those subjects for whom treatment reduces blood pressure enough to achieve blood pressure goals, differences in the UAE achieved among antihypertensive classes either become smaller or no differences are observed [18]. Indeed, blood pressure reduction is the most important determinant for diminishing UAE during antihypertensive treatment. Reducing the activity of angiotensin II may offer an additional beneficial effect beyond blood pressure-lowering [19], a benefit which becomes smaller as the blood pressure goal is near. In the LIFE study, whichever drug was used, ARB or β-blockers, the initial reduction in UAE declined over time, indicating that endothelial dysfunction probably continued to progress in many patients. Multiple mechanisms may account for this escape. Factors related to the presence of microalbuminuria in essential hypertension have been analysed in cross-sectional studies during the last decade. Although there are several determinants that appear to be important in all the studies, other determinants depend on the selection of the study population and on the interest of the authors vis-à-vis specific factors. Thus, microalbuminuria has been related to blood pressure values [20–23] and to hyperinsulinemia as an expression of insulin resistance [24,25]. However, obesity [26], smoking [27] and genetics [28,29] have also been implicated as determinants of microalbuminuria in some of the studies. Long-term surveys of microalbuminuria in essential hypertension are rare [30–32], and information about the contribution of factors other than blood pressure reduction to changes of UAE over time are scarce. In one study by our group [32], conducted in young adults who were never previously treated for essential hypertension, the main factors influencing the occurrence of microalbuminuria during antihypertensive treatment were the values of UAE at baseline and the slopes of systolic blood pressure and fasting glucose. The smaller the blood pressure reduction, the higher the risk, and the progressive increment in glucose over time contributed as an additional element of risk. Therefore, in the LIFE study, the progressive increment of UAE after the initial decline was not unexpected because the final blood pressure was 144/81 mmHg for losartan and 145/81 mmHg for atenolol [16]. The significance of microalbuminuria in essential hypertension appears to be much broader than was initially expected, and several factors may influence the presence and outcome of microalbuminuria. Considering those factors related to the presence and development of microalbuminuria, the role of other interventions in addition to blood pressure reduction must be considered. Statins, the inhibitors of hydroxymethylglutaryl-coenzyme A reductase, and which are agents with ancillary properties beyond their lipid-lowering capabilities, have been shown to ameliorate the course of renal function in type 2 diabetic patients [33], and to favourably affect microalbuminuria [34] in hypercholesterolemia subjects. It remains to be seen whether this effect can be attributed to lipid-lowering alone, to improved endothelial function or to lowered low- density lipoprotein oxidation. Whatever their mechanism, statins appear to produce a significant reduction of UAE. Whether statins still significantly reduce UAE when added to antihypertensive therapy needs to be assessed in carefully designed studies. Thiazolidinediones, a group of peroxisome proliferator-activated receptor-γ agonists that reduce insulin- resistance and the accompanying hyperinsulinemia, have also demonstrated their ability to reduce UAE. Treatment with thiazolidinediones has been shown to reduce blood pressure, modify the atherogenic lipid profile, reduce microalbuminuria and ameliorate the prothrombotic state in type 2 diabetes [35,36]. Further evidence suggests that thiazolidinedione therapy inhibits the inflammatory processes that may be involved in endothelial dysfunction. The role of these drugs in individuals with metabolic syndrome, together with their impact on blood pressure and microalbuminuria, is the subject of intense research. However, the most important observation of the LIFE study, as published in this issue of the journal [16], is the finding that the in-treatment levels of urinary albumin are closely related to the risk of a subsequent cardiovascular event, and that this effect is mostly independent of the drug used. To date, the prognostic value of microalbuminuria has been analysed in small groups of subjects [30,37]. Although more information is required to acknowledge microalbuminuria as an intermediate endpoint, the data presented in the LIFE study [16] provide the first large and long-term information concerning the prognostic value of therapeutically achieved UAE in cardiovascular disease and, consequently, represent a major step forward in considering microalbuminuria as a surrogate endpoint in hypertension.