Charge Selectivity of Proteinuria in Type I Diabetes Explored by Ig Subclass Clearance

Abstract

To investigate the role of protein charge in early diabetic proteinuria, the clearance of proteins differing in charge and/or size (anionic and cationic Igs, albumin) was evaluated in 98 insulin-dependent (type I) diabetic patients selected as a representative sample of the 418 patients attending our clinics. Of the patients, 12.9% were microalbuminuric and 4.8% were macroalbuminuric. Anionic and total IgG clearances were significantly increased in 30.6 and 12.2% of patients and were correlated with duration of disease. Anionic IgG4 clearances were increased in patients (9.2%) with normal IgG excretion, suggesting that charge-selectivity impairment is responsible for protein loss. Anionic Ig clearances were also higher in some patients (14.3%) with normal albumin clearance, probably as a result of different glomerular filtration and/or tubular reabsorption. The anionic-cationic IgG clearance ratio tended to increase in parallel with albumin clearance, but once above macroalbuminuric levels, it tended to fall again, indicating the concomitant presence of size-selectivity loss. The anionic IgG clearance and the anionic-cationic IgG ratio, in addition to albumin excretion, may be valuable in assessing early kidney protein charge-selectivity impairment and better characterizing normoalbuminuric patients and those in the preclinical stage of diabetic nephropathy.

Size and Charge Selectivity of the Glomerular Filter in Patients with Insulin-Dependent Diabetes mellitus: Urinary Immunoglobulins and Glycosaminoglycans

“…The increased albumin excretion rate observed in patients with diabetic nephropathy may be caused by an increase in either the effective small-pore radius, due to, e.g., reductions in small-pore charge selectivity, or the large-pore radius and number (and/or the production of ‘shunts’). If large pores are affected, the increased albumin excretion will be accompanied by an increased excretion of large molecules like IgG, as found previously [8, 9, 10, 11, 12, 13], and IgM, as found in the present study. A selective change in the negative charge of the GBM would result in an increased excretion of polyanionic macromolecules such as albumin through the small pores.…”

“…However, there will also be an increased transport of larger polyanions, such as IgG4, through large pores, since it was recently demonstrated that glomerular large pores are small enough, ∼85 Å in radius, to show charge-selective properties [14]. Increases in excretion of polyanions such as albumin (excreted mainly across small pores) and of IgG4 (filtered mainly across large pores) have been found also previously [8, 9, 10, 11, 12, 13, 26]. The relation between total IgG and IgG4 has been used to describe a selectivity index [8, 9, 10, 11, 12, 13]as a measure of loss of negative large-pore charge selectivity.…”

“…Increases in excretion of polyanions such as albumin (excreted mainly across small pores) and of IgG4 (filtered mainly across large pores) have been found also previously [8, 9, 10, 11, 12, 13, 26]. The relation between total IgG and IgG4 has been used to describe a selectivity index [8, 9, 10, 11, 12, 13]as a measure of loss of negative large-pore charge selectivity. We preferred to measure the ratio between IgG2 and IgG4, as these molecules are of identical size and, therefore, by size alone, should be excreted in equal amounts in the urine.…”

“…In contrast, there is a decrease or redistribution in negatively charged groups of GAGs [1, 2, 3, 4, 5, 28]in the GBM. Hypothetically, as mentioned above, this may lead to albuminuria [7, 13]and increased excretion of IgG4 [8, 9, 10, 11, 12, 13, 28]. The present GAG assay measures the urinary sulphated GAGs: chondroitinsulphate (50–60%), heparansulphate (15–25%), keratansulphate (18%), and dermatan sulphate (1%) [29].…”

“…With a loss of charge selectivity, negatively charged albumin and IgG4 [7]are excreted in increasing amounts. The ratio of total IgG to IgG4 has been used as a measure of charge selectivity [8, 9, 10, 11, 12, 13], even though most IgG is filtered across large (80–90 Å) pores in the glomerulus, where charge effects would be of less importance, than through small pores [14]. This ratio has been shown to decrease with progression of nephropathy.…”