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of both hypertension [11] and coronary heart disease The concept of microalbuminuria was introduced more [12] among the non-diabetic parents of patients with than 30 years ago when it became possible to measure nephropathy. With regard to NIDDM, it has been concentrations of urinary albumin below the level of reported that non-diabetic relatives of NIDDM detection of a urinary protein dipstick [1]. By the early patients with microalbuminuria have an elevated albu1980s, microalbuminuria had been shown to predict min excretion rate [13]. These observations have been the development of nephropathy in insulin-dependent taken to imply that a common predisposition, possibly diabetic (IDDM) patients [2], leading to the view that of genetic origin, may underlie both the familial clusthe excretion of increased amounts of urinary albumin tering of microalbuminuria and its link to cardiovasin these patients was an early manifestation of the cular disease. pathophysiological process which, as a final conRecent studies, however, have suggested a substansequence, led to renal failure. tial heterogeneity in the phenotypic characteristics of Microalbuminuria also predicts dipstick-positive microalbuminuric diabetic patients. These findings proteinuria and nephropathy in patients with nonraise the possibility of a more diverse aetiology of insulin-dependent diabetes (NIDDM) [3], but in these microalbuminuria, which in turn challenges current patients its major prognostic significance is for thinking about the nature of its link with cardiovasincreased cardiovascular risk [4]. More recent observacular disease. We propose that microalbuminuria in tions have extended the concept of microalbuminuria diabetes is heterogeneous with respect to clinical feaas a risk marker for cardiovascular disease to subjects tures and renal histology. We suggest that this heterowithout diabetes, in whom an elevated albumin excregeneity has conceptual, prognostic and therapeutic tion rate has been shown to predict a mortality up to implications, and so is of clinical importance. 24 times that of normoalbuminuric subjects [5]. Furthermore, in IDDM patients, both dipstick-positive proteinuria [6 ] and microalbuminuria [7,8] are markers Microalbuminuria—the evidence for phenotypical of cardiovascular risk. Various abnormalities of cardioand histological heterogeneity vascular risk factors have been found in both diabetic and non-diabetic subjects with microalbuminuria, In both IDDM and NIDDM, microalbuminuria clusincluding hypertension, dyslipidaemia, procoagulant ters with hypertension, severe retinopathy and atherochanges in clotting factors and insulin resistance [9], sclerotic cardiovascular disease. Microalbuminuria is but even in combination these seem unlikely to explain associated with dysfunction of the vascular endothethe excess cardiovascular risk. lium, which may underlie this clustering [14–16 ]. The common links of microalbuminuria and proNevertheless, there is increasing evidence of heterogenteinuria to cardiovascular disease in subjects both with eity among these relationships [14,15,17–20]. and without diabetes have led to the concept of a The EURODIAB IDDM Complications Study has single disease entity. This view has been supported by investigated the associations of microalbuminuria with other clinical and biochemical characteristics in a Correspondence and offprint requests to: Dr C. D. A. Stehouwer, Europe-wide study of >3000 IDDM patients [17,18]. Department of Internal Medicine, Academisch Ziekenhuis Vrije The albumin excretion rate correlated significantly with Universiteit, De Boelelaan 1117, 1081 HV Amsterdam, The

How heterogeneous is microalbuminuria in diabetes mellitus? The case for 'benign' and 'malignant' microalbuminuria