In the natural history of diabetic nephropathy there is a progressive impairment of protein permselectivity. The early increased excretion of anionic proteins may be explained by the initial loss of charge selectivity of the filtration filter. In comparison to other immunoglobulin subclasses, IgG4 has the same molecular weight but an acid isoelectric point: its possible selective urinary elimination could indicate a charge selectivity impairment in the preclinical stage of diabetic nephropathy. To verify this hypothesis, 53 Type 1 diabetic patients, grouped according to their albumin excretion rate (AER) (23 showed an AER less than 35 micrograms/min, Group I; 19 between 35-200 micrograms/min, Group II; 11 an AER greater than 200 micrograms/min, Group III), and 20 normal subjects were tested for urinary IgG4, total IgG, and other nephrological and metabolic parameters. Urinary IgG4 and IgG were detected with solid phase methods (ELISA and RIA respectively) developed in our laboratory. Urinary total IgG values were significantly higher in Group III in comparison with Group I and II and with normal subjects. Urinary IgG4 values were significantly increased in Group III, as well as in Group II, in comparison with Group I and normal controls. IgG4/IgG ratio values were significantly increased in both Groups II and III in comparison with Group I and control subjects. Whereas IgG values were within the normal range in Group II, IgG4 values were clearly elevated, thus demonstrating a selective elimination of this acid, medium-sized protein. Urinary IgG4 could be an additional parameter to characterize more precisely and subgroup microalbuminuric patients.