Editorial [ Has the Time Come for a New Definition of Microalbuminuria? ]

Microalbuminuria (MA) is an independent predictor of cardiovascular (CV) morbidity and mortality and for endstage renal disease in patients with diabetes mellitus (DM) or hypertension [1-6]. Furthermore, there is a relationship between albuminuria and CV risk regardless of the presence of DM or hypertension [7-12]. It is well established that MA is associated with proliferative diabetic retinopathy [13]. In subjects without MA or DM, those with increased waist circumference (WC) or metabolic syndrome (MetS) are more likely to develop MA after a 6-year follow-up compared with those with a normal WC or no MetS [14]. In a cohort with type 1 DM, MetS and its components predicted risk but MA was the best single predictor of coronary heart disease (CHD), renal failure and diabetes-related death [15]. The Third National Health and Nutrition Examination Survey reported MA in 6.1% of men and 9.7% of women in the general population in the USA [16]. MA prevalence was 28.8% in patients with previously diagnosed type 1 or 2 DM, 16.0% in those with hypertension and 5.1% in those without DM, hypertension, cardiovascular disease or elevated serum creatinine levels. European studies report a 5% to 7% prevalence of MA in the general population [9, 10]. An increase in urinary albumin excretion (UAE) in “newly-detected hyperglycaemics” was reported in 1961 [17]. However, the term MA was introduced [18,19] to describe a UAE below the detection limit of a standard dipstick, but at a level that was predictive of overt nephropathy in patients with type 1 DM [20]. Currently, MA is defined as UAE between 20 and 200 mg/g (2.5-25 mg/mmol) in men and 30-300 mg/g (3.5-35 mg/mmol) in women, using the urinary albumin-to-creatinine ratio (UACR) in a random urine sample, 30-300 mg/day, if measured in a 24h urine collection or 20-200 μg/min, if measured in a timed (e.g. 4h or overnight) urine collection [21]. Any urinary albumin value below these limits is considered as normal UAE [22]. Because MA is initially intermittent, 2 or 3 specimens should be assessed within a 3-6 month period before considering a patient as having MA [22]. A post-hoc analysis of the Heart Outcomes Prevention Evaluation (HOPE) trial, which included patients with a history of CV disease or DM and at least one vascular risk factor, showed that MA increased the adjusted relative risk (RR) by 1.83 for major CV events, 2.09 for all-cause death and 3.23 for hospitalization for congestive heart failure, with similar RRs for participants with or without DM [8]. For every 0.4 mg/mmol increase in UACR, the adjusted hazard of major CV events increased by 5.9%. The results of the HOPE trial show that any degree of albuminuria is a risk factor for CV events regardless of the presence of DM. This risk increases with the UACR, starting well below the MA cut-off. Similar results were obtained from a post-hoc analysis of the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, which included patients with hypertension and left ventricular hypertrophy [23]. Among nondiabetic patients, for every 10-fold increase in UACR, the hazard ratios (HR) for the composite endpoint increased by 57%, for CV mortality by 97.7%, for all cause mortality by 75.2%, for stroke by 51% and for myocardial infarction by 45% (p<0.001 for all comparisons). Ratios were similar in diabetic patients, although for myocardial infarction the trend was weaker and not significant. This study showed a prognostic value for UACR at a level below the current definition of MA, whereas the risk for the composite CV endpoint increased continuously as albuminuria increased. A positive dose-response relationship between increasing UAE and mortality was found in 40,548 inhabitants of Groningen, the Netherlands [10]. After adjustment for other wellrecognized CV risk factors, a higher UAE increased the risk of both CV and non-CV death, with a significantly higher rise for CV mortality than for non-CV mortality (p=0.014). A 2-fold increase in UAE was associated with a RR of 1.29 for CV mortality and 1.12 for non-CV mortality. This relationship was already apparent at levels of albuminuria currently considered as normal. In middle-aged nonhypertensive, nondiabetic individuals, those with UACR greater than or equal to the sex-specific median (≥3.9 mg/g for men, ≥7.5 mg/g for women) experi enced a nearly 3-fold risk of CV disease (adjusted HR 2.92, p<0.001) and a borderline significantly increased risk of death (adjusted HR 1.75, p=0.08) compared with those with UACR below the median [11]. MA is associated with lowgrade systemic inflammation [24, 25] and endothelial dysfunction [26-28]. Therefore, it is not surprising that UAE predicts the development of CV events.