Albuminuria is the first clinical event in the development of diabetic nephropathy. We assessed glomerular charge- and size selectivity in 51 patients with Type 1 (insulin-dependent) diabetes mellitus of juvenile onset and 11 healthy individuals. Patients were allocated to five groups. The urinary albumin excretion rate was normal in group D1; 30-100 mg/24 h in group D2; 101-300 mg/24 h in group D3 and greater than 300 mg/24 h in groups D4 and D5. Group D5 had elevated serum creatinine (above 110 mumol/l). Glomerular filtration rate and renal plasma flow were determined by constant infusion techniques and tubular protein reabsorption by excretion of beta 2-microglobulin. Charge selectivity was estimated from the IgG/IgG4 selectivity index. Size selectivity was measured by dextran clearance. Dextran was measured by refractive index detection after fractionation (2 A fractions in the range 26-64 A) by size exclusion chromatography. IgG/IgG4 selectivity index was significantly decreased in patients with albuminuria (p < 0.001). The drop in IgG/IgG4 selectivity index was found in patients with minimal albuminuria (D2) and was not accompanied by any changes in tubular function or glomerular haemodynamics. Size selectivity was significantly altered only in patients with the most advanced nephropathy (D5) as reflected by an increase in the clearance of 62 A dextran (p < 0.04). We conclude that loss of glomerular charge selectivity precedes or accompanies the formation of new glomerular macromolecular pathways in the development of diabetic nephropathy.