Charge selectivity and size selectivity were assessed by the clearance ratio of IgG and IgG4, which are the same in molecular weight but different in electronic charge. The subjects were 32 NIDDM patients, 14 males and 18 females, with normoalbuminuria (n=14), incipient nephropathy (n =12) and overt nephropathy (n=6). Timed urine samples were collected in the morning, during exercise of 1h walking, in the afternoon, and during overnight sleep. The urinary albumin excretion rate (AER) and serum and urinary concentrations ofβ2 microglobulin (βMG), IgG and IgG4 were measured and the selectivity index (SI) was calculated by the IgG/IgG4 clearance. The ratio AER was divided into normoalbuminuric (A0, AER <20), microalbuminuric (Al, AER 20-200), and macroalbuminuric (A2, AER > 200). IgG clearance was higher in A2 than in Al and A0. SI was significantly lower in Al than in A0, and was even lower in A2 than in Al. No difference was found in βMG clearance between the groups. Also there were no differences in AER and SI among different timed-urine samples. The study may indicate that loss of charge selectivity precedes loss of size selectivity in diabetic nephropathy.