In recent years a number of reports have emerged implicating reduced kidney function as an independent risk factor for cardiovascular (CV) disease. Many studies demonstrated an excess CV risk in patients with moderate to severe renal insufficiency. Recent studies, however, indicate that in subjects with mild renal dysfunction and even renal function within 'normal' ranges the risk for development of CV disease is increased also. In hypertensive subjects it was shown that creatinine levels that are usually considered within high normal ranges (serum creatinine level 105-115 µmol/l) already predict CV outcome. In the large Valsartan in Acute Myocardial Infarction Trial (VALIANT, n=14,527) every 10 units reduction of the glomerular filtration rate (GFR) below 81 ml/min/1.73 m2 was associated with a 10% increase in relative risk of death or nonfatal CV complications. Therefore, it has been suggested that the presence of classic risk factors (like hypertension and diabetes), and probably some nonconventional risk factors (like C-reactive protein and homocysteine levels), predict the progression of renal disease. Synergism exists when these risk factors perpetuate renal disease, and progressive renal decline increases the potency of the risk factors. This, however, may not necessary be true for a decreased renal function within the 'normal' ranges.

In addition, several prospective studies have shown a relation between CV outcome and (micro)albuminuria. For type II diabetes these data have been confirmed several times now. But also for non-diabetic subjects there is increasing evidence for independent association between the presence of (micro)albuminuria and a poor CV outcome. To date, microalbuminuria has been observed in approximately 7% of the normal population and up to 40% of hypertensive subject, with increasing prevalence with age. In a population-based cohort from the MONICA study, in which subject without ischemic heart disease (IHD), renal disease, or diabetes mellitus were included, microalbuminuria was not only an independent predictor for IHD, but also doubled the risk associated with other established risk factors. In recent years, several studies showed that any degree of proteinuria, even at levels below the threshold for microalbuminuria, is associated with an excess CV risk in patients at high risk of CV events, but also in the general population, as was shown convincingly in the Prevention of Renal and Vascular End stage Disease (PREVEND) study, a large prospective study in the north of the Netherlands. Interestingly, risk continuously increases without threshold or plateau level for urine albumin-creatinine ratio (UACR).

Taking the aforementioned data together, it is clear that, as soon as renal function exhibits even minor derangements, a rise in CV risk occurs. The major question is whether mild changes in renal function are simply a marker of generalized vascular damage, or whether they contribute in a causative way to aggravate the risk and precipitate events.

As in diabetic kidney disease the pathogenic mechanisms leading to increased risk associated with microalbuminuria are still unknown. Microalbuminuria may be a marker of generalized endothelial dysfunction true increased transvascular escape of albumin, and thus a marker (not a pathogenetic mechanism) of increased susceptibility to the atherogenetic effect of other risk factors. Otherwise, microalbuminuria may be a marker of inflammatory status, but may also, by a still unexplained mechanism, reflect a greater severity of target organ damage of the kidney.