Background
Microalbuminuria (MAU) or moderately increased albuminuria usually develops due to changes within the kidneys and is an established marker for early renal disease. MAU is defined as detection of an amount of albumin in the urine of 30-300 mg/day or an albumin/creatinine ratio, preferentially on morning urine, of 30-300 mg/g (2.5–30 mg/mmol in men, 3.5–30 mg/mmol in women) [1].
However, MAU is often found in patients with essential hypertension or glucose intolerance and persons with metabolic syndrome with or without connected renal disease. MAU is thus seen in early vascular damage, and many published studies have proven that its existence can be used as a predictor for cardiovascular disease onset and progression [2-6]. This was evaluated in the Copenhagen city heart study by Klausen et al, in 2,762 patients [6], showing an increased risk of death and cardiovascular disease for even lower cut-off values of MAU (5 µg/min) independently of other risk factors such as the metabolic syndrome [6,7]. These results clearly indicate that even small increases in MAU can signal important changes developing in the cardiovascular system.
Other published data also concluded that urinary albumin excretion (UAE) levels, even lower than the cut-off values used to define MAU, are associated with an increased risk of cardiovascular disease. This correlation has been proven in all patients regardless of the presence of diabetes or existing kidney disease [2-6], but the exact pathophysiology of the relationship between MAU and cardiovascular disease (CVD) is still under investigation. Ibsen et al also argued that, in both diabetic and non-diabetic patients, treatment-induced reduction in urinary protein excretion, especially microalbuminuria, has resulted in a reduced incidence of CV events and slower progression of renal disease [8].
In addition, multiple clinical studies have demonstrated the correlation of MAU and аlbumin excretion rates (AER) with above normal blood pressure (BP) values, with a continuous relationship between these even in high-normal blood pressure values [9]. А study by Mule et al has shown a positive association of AER with short-term blood pressure variability defined as average real variability (ARV) of 24-hr systolic blood pressure suggesting that even short-term BP variability is associated with MAU and early kidney damage [10]. Thus, the latest European Society of Cardiology (ESC) guidelines for the management of arterial hypertension recommended the measurement of the urine albumin:creatinine ratio in all hypertensive patients [11].
This review aims to provide concise, comprehensive and updated information about the relationship between MAU, hypertension and CAD and the usefulness of evaluating MAU in hypertensive patients.
MAU and hypertension
According to published studies, MAU prevalence in hypertensive patients stands at 40% in the untreated population and increases with age and hypertension severity [12]. The most probable causes for MAU in hypertension are changes in haemodynamics that cause an elevation in intraglomerular pressure and a generalised angiopathy due to endothelial dysfunction that causes renal and systemic transvascular albumin leakage [13]. Published data have shown that every increase in the albumin:creatinine ratio of 0.4 mg/mmol increases the hazard ratio for CV events by 6% [14].
A study published by Catena et al demonstrated that an increase of the urine albumin:creatinine ratio (UACR) was associated with significant and progressively higher blood pressure, high-density lipoprotein (HDL) cholesterol, plasma aldosterone levels and glomerular filtration. MAU was detected in 41 (17%) hypertensive patients who had significantly higher BP and plasma aldosterone levels (178 ± 113 vs 128 ± 84 pg/ml; p=0.001) and lower glomerular filtration than patients without MAU. UACR was directly and independently correlated with BP and plasma aldosterone levels. Interestingly, the presence of MAU was associated with plasma aldosterone levels independent of glomerular filtration as well as demographic, anthropometric or metabolic variables [15]. These results are discordant in other rare studies such as that of Rasmussen et al, where the authors concluded that obesity, BP levels, and duration since diagnosis were not associated with albuminuria among rural Africans with hypertension [16].
Adequate risk assessment of patents with hypertension is necessary for treatment optimisation. According to the latest ESC guidelines on hypertension, the Systematic COronary Risk Evaluation (SCORE) system is used for appropriate risk stratification of hypertensive patients (10-year CVD risk assessment). Selection of treatment along with therapeutic targets for BP assessment of hypertension-mediated organ damage (HMOD) should be added to the risk estimation and can increase CV risk to a higher level, even when asymptomatic. The inclusion of HMOD assessment, especially in the presence of MAU, left ventricular hypertrophy and arterial stiffening, helps to identify high-risk or very high-risk (for CAD) hypertensive patients who may otherwise be misclassified by the SCORE system as low risk [11]. The regression of some of these asymptomatic HMOD manifestations by BP control is associated with a reduction in CV risk and can be used as an additional aid in judging the effectiveness of treatment in individual patients [5,9,11].
A study by Oliveras et al sought to evaluate the association between different levels of urinary albumin excretion and BP control in treated hypertensive patients. Albuminuria was categorised into four groups: G0 (UAE <10 mg/g), G1 (UAE 10-29 mg/g), G2 (UAE 30-299 mg/g), and G3 (UAE ≥300 mg/g) with noted differences in BP control among groups (p<0.001). They concluded that lack of BP control is more prevalent among patients with MAU than in patients with normoalbuminuria but found no difference between patients with optimal or high-normal UAE, with significantly higher relevant values than other published studies mentioned previously [17]. As opposed to these values of MAU, the study of Alharf et al compared two definitions of MAU in a cohort of hypertensive patients: conventional (MAU[C]) albumin-to-creatinine ratio (ACR) >2.5-25 mg/mmol(-1) in males or >3.5-25 mg/mmol(-1) in females, and low-grade (MAU[L]) ACR 1.2-2.5 in males or 1.7-3.5 mg/mmol(-1) in females. Both groups demonstrated a higher prevalence for CAD as opposed to patients without MAU (24 vs 14%, respectively) [18].
According to certain studies, MAU is also associated with cardiac diseases and abnormalities, especially in terms of the connection between MAU and left ventricular (LV) hypertrophy and dysfunction, which has been proven to have a strong correlation [5,6,9]. In the LIFE study [5], LV hypertrophy (LVH) was assessed at baseline and 14 days after treatment by electrocardiogram (ECG) readings. The results showed that LVH was associated with a 1.6-fold higher prevalence of MAU and a 2.6-fold higher prevalence of MAU (both p<0.001). This relationship was independent of age, systolic and diastolic blood pressure, diabetes, gender, race, serum creatinine or smoking status, leading to the suggestion that cardiac damage and albuminuria occur in parallel.
In conclusion, even lower MAU thresholds (defined as MAU) should be used for implementation of more rigorous risk reduction strategies and more aggressive antihypertensive treatment for the purpose of reducing general cardiovascular risk. Also, studies have shown that even small increases in MAU indicate worsening CV disease, so the recommendation should be to perform this test in all hypertension patients and not only newly diagnosed patents, as suggested by Gerstein et al and Klausen et al [3,7]. Thus, it is probable that this test would also help in reducing the cost of treatment of CV disease worldwide, estimated in Europe to be around 169 billion euros annually, as evaluated by the European Heart Health Charter set up by the ESC and the European Heart Network.
Influence of antihypertensive medications on MAU
Although there are multiple clinical studies that prove that MAU is an important predictor and marker for CAD, there is still insufficient evidence of the role of treatment for MAU or whether decreasing its levels could result in a reduction of the risk for CAD.
Multiple clinical trials have shown that angiotensin-converting enzyme (ACE) inhibitors and аngiotensin II receptor blockers have a higher capability in reducing albuminuria in hypertensive patients, and their effects seem to be independent of their ability to lower BP [19,20].
The Prevention of REnal and Vascular ENdstage Disease Intervention Trial (PREVEND IT) is the only randomised trial so far to study the effect of albuminuria lowering in microalbuminuric, otherwise healthy individuals, who were not receiving antihypertensive or lipid-lowering agents. In this study, fosinopril reduced albuminuria by 26% (p<0.001) and was associated with a 40% reduction in the primary endpoint (a composite of CVD mortality and hospitalisation for non-fatal MI or myocardial ischaemia, heart failure, peripheral vascular disease, or cerebrovascular accident – p =0.098) compared with placebo. A 90% reduction (p =0.03) in cerebrovascular events was observed in the group treated with fosinopril [21]. In the LIFE substudy [22], 8,206 hypertensive patients with electrocardiographic evidence of LVH were randomised to either losartan or atenolol and observed for a median of 4.8 years. The treatment with losartan resulted in a greater reduction in albuminuria compared with the beta-blocker therapy, despite equivalent decreases in blood pressure. Moreover, losartan had a better result in reducing the incidence of the primary composite endpoint (non-fatal myocardial infarction and stroke and CV death).
Dihydropyridine (DHP) calcium antagonists (DHPCAs), on the other hand, have failed to reduce proteinuria in patients with type 2 diabetes [23]. Multiple studies have provided evidence that DHPCAs may cause an increase in albuminuria [16], particularly in treatment-resistant hypertension [24]. However, more studies are needed to confirm these results. On the other hand, non-DHP calcium channel blockers (CCBs) have been proven to have a therapeutic effect on MAU in type 2 diabetes [23].
Measurements of MAU and erroneous calculations
Albuminuria can appear due to a transient increase in glomerular capillary permeability. It can be found in certain states such as vigorous exercise, fever, decompensated heart failure, urinary tract infection, postural changes or sleep apnoea. The urine albumin:creatinine ratio should not be measured if these conditions are present. Due to day-to-day variations, three-month confirmation of MAU presence is advised. The storage process and time do not influence MAU tests [1]. Assay techniques used for albuminuria include the StatLIA Assay Report (RIA), enzyme‐linked immunoabsorbent assay (ELISA) and high‐performance liquid chromatography (HPLC).
Studies have demonstrated that the best results are found with early morning urine samples [25]. Timed urine samples can be efficient in predicting MAU, but their collection by patients can be erroneous. In these cases, it is advised to calculate MAU along with creatininuria measurement [25]. Qualitative measurement of spot urine samples can give high levels of false positive/negative results and depend on the volume of excreted urine influenced by fluid intake and physical activity. Dipstick urinalysis also has many false positive values and needs repeated testing. Blood pressure, sodium intake, protein intake, and hyperglycaemia could be factors for low sensitivity and specificity of the daytime urine samples [25]. This of course should not preclude effective and precise evaluation of the presence of MAU in all hypertensive patients and spot urine samples for MAU measurement are thought to be most easily performed in everyday practice and are recommended once annually.
Conclusion
Evaluating the presence of MAU is a low-cost, easily accomplished test that can help in making an adequate risk assessment of hypertensive patients for the purpose of optimising BP therapy and setting individual and adequate BP targets. By implementing more aggressive BP controls, healthy lifestyle changes and effective antihypertensive management, MAU can indirectly help in the reduction of CVD risk in patients, serving not just as a predictor for CVD, but also as a target for therapy.
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