Glomerular permselectivity in early stages of overt diabetic nephropathy

Background. Impairment of glomerular size selectivity has been demonstrated by the dextran-sieving technique in nephropathic diabetics with heavy, but not mild proteinuria. The purpose of the present study was to determine wh ether such a barrier defect could be demonstrated with mild proteinuria by substituting Ficoll 70, a polysucrose, for dextran as a probe of the filtra tion barrier. Methods. Differential solute clearances were performed in 12 individuals wi th early diabetic nephropathy on two occasions: after 60 days of treatment with losartan 50 mg daily or a placebo. An uncharged preparation of nonreab sorbable Ficoll 70 was infused along with inulin. Fractional clearance (the ta) of Ficoll of discrete size was determined after separating molecules in urine and plasma in narrow 2 Angstrom fractions over a 20 to 60 Angstrom r adius interval by size exclusion high-performance liquid chromatography (HP LC). A hydrodynamic theory of hindered ficoll transport through water-fille d pores was used to characterize the pore size distribution of the glomerul ar barrier. Results. The theta for Ficoll molecules with radii >50 Angstrom was selecti vely enhanced in placebo-treated diabetic nephropathy versus corresponding theta in healthy control subjects (N = 12). Computations revealed a lower d istribution of glomerular pores that was unaltered in nephropathic diabetic s. However, an upper distribution of large, shunt-like pores was more promi nent, exceeding healthy controls by one order of magnitude in diabetic neph ropathy (P = 0.01). A trend to lower theta for Ficoll in the 56 to 60 Angst rom radius range during losartan therapy is computed to have lowered the fr action of shunted filtrate by 26 to 44%, depending on whether glomerular pr essure declined. The corresponding reduction in theta for endogenous albumi n, IgG, and IgG(4) was by 19 to 23% (P < 0.05). Conclusion. Our findings suggest that shunt-like defects, partially reversi ble by angiotensin II blockade, are present early in the course of diabetic nephropathy. We estimate that such defects can account for immunoglobulinu ria in this disorder. Additional impairment of either charge- or shape-sele ctivity must be invoked to explain the observed level of albuminuria, howev er.