The spectrum of albuminuria as a predictor of cardiorenal outcomes

Hypertension is the leading cause of significant cardiovascular morbidity and mortality and leads to the progressive impairment of kidney function ultimately contributing to the development of end-stage renal disease [1]. Additionally, impairment of kidney function alone (i.e., estimated glomerular filtration rate [GFR] <60 ml/min) carries increased risk for occurrence of cardiovascular events [2]. Hypertension is present in more than 75 million people in the USA alone, with only 64% of them being controlled as recommended by current practice guidelines [3,101]. The high rates of death secondary to cardiovascular causes as well as the increasing incidence of chronic kidney disease (CKD) has prompted the American Heart Association (AHA) to set a goal of improving cardiovascular health in the general population by 20% by 2020 [3,101,102]. Therefore, timely recognition of increased risk for cardiovascular morbidity is essential for early intervention and prevention. High albuminuria, formally known as microalbuminuria, was considered a sign of early kidney disease in the 1990s; however, over the past decade it has been recognized as an important risk marker for cardiovascular outcomes and risk [4,5]. Indeed, the addition of albuminuria to predictive models for coronary heart disease improves their accuracy [6]. Albuminuria has been noted to significantly affect cardiovascular risk even at very low levels [7]. The level of albumin in urine helps define whether injury and inflammation is present at a vascular (i.e., endothelial dysfunction) or kidney level (i.e., podocyte membrane). Increased oxidant stress and related decreases in nitric oxide (NO) production in the vascular bed are associated with high albuminuria levels (i.e., <200 mg/day). Higher levels indicate not only vascular injury and inflammation, but also significant podocyte damage and tubular protein absorption translating into the presence of nephropathy [8,9]. The current concept therefore is that albuminuria is associated with a continuum of risk, with low levels indicating high cardiovascular risk and higher levels indicating both higher cardiovascular risk and the presence of CKD [10]. The most common pathologic conditions related to the development of albuminuria are diabetes mellitus, hypertension, lipid abnormalities and obesity [11,12]. In particular, poor glycemic and hypertensive control correlates with development of and progressive increases in albuminuria. It is, however, important to note that low levels of albuminuria represent a disease marker and not a contributing cause of the disease. Therefore, assessing and determining the occurrence of albuminuria and factors contributing to it will enable timely detection of a vascular inflammatory process that is related to poor control of a cardiovascular risk factor that Albuminuria is a consequence of vascular inflammation and injury but also podocyte dysfunction and damage. In respect to current practice, albuminuria levels of <29 mg/g are considered normal, between 30–299 mg/g high and >300 mg/g very high, with lower levels representing disease markers rather than disease cause. This concept refers to albuminuria as a continuum that reflects high cardiovascular risk at lower levels and high kidney disease risk at levels of >200 mg/day. Assessment of urinary albumin could therefore help with timely detection and improvement of vascular inflammatory process, with spot albumin:creatinine ratio currently being used for this purpose. The most common comorbidities related to albuminuria are diabetes mellitus with hyperinsulinemia, hypertension, dyslipidemia and obesity. Control of these risk factors is essential for patients with high levels of albuminuria. However, the therapeutic intervention for very high albuminuria is aimed at cardiovascular and renal risk reduction by improving blood pressure control to <130/80 mmHg and favors the use of renin angiotensin aldosterone system blockers as an initial approach.