Microalbuminaria and the risk of atherosclerosis. Clinical epidemiological and physiological investigations.

Abstract Microalbuminuria, i.e., slightly elevated albumin excretion in the urine, is considered a novel atheroslerotic risk factor. This supposition is based partly on two preliminary minor studies, partly on the current knowledge within the fields of diabetes mellitus and arterial hypertension. The aims of the present series of studies were 1) to examine whether a relationship exists between microalbuminuria and atherosclerotic cardiovascular disease in the general population, and 2) to illuminate possible pathophysiological mechanisms underlying this association. The studies were performed as sub-studies of the Copenhagen City Heart Study and the Monica Population Study. In the 3rd Copenhagen City Heart Study a cross-sectional analysis comprising 2,613 individuals without diabetes mellitus or renal- or urinary tract disease revealed a positive association between overnight urinary albumin excretion rate and a history of acute myocardial infarction. This association was independent of age, sex, conventional atherosclerotic risk factors, and glomerular filtration rate. Participants with a urinary albumin excretion rate exceeding the upper decile (7 micrograms/min) in the entire study population had a higher frequency of previous acute myocardial infarction than the others. In order to assess the time sequence of the observed association, this population will be followed prospectively. In the 1st Monica Population Study in Copenhagen County, 2,085 individuals without diabetes, mellitus, cardiovascular disease, or renal or urinary tract disease were followed for 10 years. Participants with a urinary albumin/creatinine concentration ratio exceeding the upper decile (0.65, mg/mmol) in the entire study population had a relative risk of 2.3 for developing ischaemic heart disease as compared to participants with a lower urinary albumin/creatinine concentration ratio. This predictive effect was independent of age, sex, and conventional atherosclerotic risk, factors, but it was not known whether participants with a urinary albumin/creatinine concentration ratio above the upper decile had severe subclinical atherosclerosis already at entrance to the study. A group of individuals with persistent microalbuminuria, and an age- and sex-matched control group with persistent normoalbuminuria underwent a clinical physiological and biochemical investigation program. None had developed clinically present atherosclerotic cardiovascular disease. Microalbuminuria was defined as a urinary albumin excretion rate exceeding the upper decile in the entire study population, normoalbuminuria as a lower urinary albumin excretion rate. Measurements of glomerular filtration rate and tubular function made it unlikely that the difference in urinary albumin excretion between the two study groups was due to local renal conditions exclusively, although reductions in both glomerular charge selectivity and size selectivity were observed in the microalbuminuric individuals. Individuals with persistent microalbuminuria had increased systemic transvascular albumin leakage to a level similar to that seen among individuals with severe clinical atherosclerosis. This could be explained neither by differences in blood pressure or concentration of plasma lipoproteins, both of which were more atherogenic in the microalbuminuric individuals, nor by differences in plasma volume or albumin concentration, antropometric factors, insulin sensitivity, or smoking habits. It is hypothesized that the systemic transvascular leakiness may also include lipoproteins, thus allowing for an increased lipid insudation into the vessel walls. The leakiness might be due to haemodynamic factors or structural or functional perturbations of the endothelium or the intracellular matrix beneath. Although endothelial dysfunction could not be demonstrated in the present studies, future research will focus on these possibilities.