Heterogeneity in renal structure has been described in type 2 diabetic patients with both microalbuminuria and proteinuria; in fact, only a subset of type 2 diabetic patients have the typical diabetic glomerulopathy. However, it is currently unknown whether abnormalities in albumin excretion rate (AER) have a different renal prognostic value depending on the underlying renal structure. Aims of this study were: 1) to study the course of renal function in type 2 diabetic patients with altered AER; 2) to evaluate the relationship between the course of glomerular filtration rate (GFR) and renal structure; and 3) to evaluate the relationship between the course of GFR and baseline AER levels, metabolic control, and blood pressure levels during a follow-up period of 4 years. A total of 108 type 2 diabetic patients, 74 with microalbuminuria (MA) and 34 with proteinuria (P), were recruited into a prospective study that encompassed: 1) a baseline kidney biopsy with morphometric measurements of glomerular parameters; 2) intensified antihypertensive treatment for an average 4-year period (blood pressure target <140/90 mmHg); and 3) determinations of GFR at baseline and every 6 months. Mean (+/- SD) GFR significantly decreased from baseline in both MA (-1.3+/-9.4 [95% CI -3.51 to +0.86], P < 0.05) and P (-3.0+/-13.0 ml x min(-1) x 1.73 m(-2) per year [-7.71 to +1.61], P < 0.01). However, the changes in GFR were quite heterogeneous. Thus, on the basis of percent GFR change per year from baseline (delta%GFR), both MA and P patients were defined as progressors or nonprogressors when they were below or above the median, respectively. Baseline parameters of glomerular structure had a strong influence on the course of GFR. Indeed, the odds ratios of being progressors significantly increased across the quartiles of baseline glomerular basement membrane (GBM) width and mesangial fractional volume [Vv(mes/glom)], being 2.71 and 2.85 higher, respectively, in the fourth quartile than in the first quartile (P < 0.01 for both). Conversely, nonprogressors outnumbered progressors in the first quartile of GBM width (odds ratio: 2.14, P < 0.05) and in the first quartile of Vv(mes/glom) (odds ratio: 2.28, P < 0.01). Baseline albumin excretion rate (AER) did not influence delta%GFR; in fact, the number of progressors did not increase across quartiles of baseline AER among either MA or P. Similarly, mean blood pressure levels during follow-up (and intensified antihypertensive therapy) did not affect the course of GFR: the number of progressors and nonprogressors did not change across quartiles of mean blood pressure. In contrast, HbA1c during follow-up had an impact on delta%GFR: the odds ratio for being a progressor increased across quartiles of HbA1c, particularly for the highest quartile (HbA1c >9.0%). In conclusion, the course of renal function is heterogeneous in type 2 diabetic patients with microalbuminuria or proteinuria. In fact, a subset of patients has a rapid decline in GFR over a 4-year follow-up period; these patients have more advanced diabetic glomerulopathy and worse metabolic control than the remaining patients, whose GFR remains stable. These two cohorts are otherwise undistinguishable as regards the degree of AER at baseline and tight blood pressure control. Kidney biopsy has an important prognostic role in these patients. Thus, tight blood pressure control, when not associated with satisfactory glycemic control, is unable to prevent rapid GFR decline in type 2 diabetic patients with typical diabetic glomerulopathy.