Glomerular permselectivity at the onset of nephropathy in type 2 diabetes mellitus

The development of microalbuminuria in individuals with type 2 diabetes mel litus is associated with a 10-fold increase in the risk of progression to o vert nephropathy and eventual end-stage renal failure, The present study re ports long-term (up to 8 yr) follow-up of 43 Pima Indians with type 2 diabe tes detected on screening to have microalbuminuria. The natural history of albuminuria in these individuals included progression to overt proteinuria (urinary albumin excretion greater than or equal to 300 mg/d) in half of th e participants by 7 yr of follow-up. The size selectivity of the glomerular barrier was also investigated using dextran sieving and pore theory. Where as a comparison group of macroalbuminuric Pima Indians had an excess of lar ge pores that, served as a macromolecular "shunt," individuals with microal buminuria had a shunt size no different from long-term diabetic, normoalbum inuric control subjects. An abrupt transition from little or no relationshi p to a highly significant and positive relationship between increasing albu minuria and shunt size occurred at an albumin-to-creatinine ratio of approx imately 3000 mg/g. Shunt size in macroalbuminuric individuals correlated wi th the extent of foot process broadening. Podocyte foot processes in microa lbuminuric participants were not different from those in control subjects. In conclusion, although microalbuminuria in type 2 diabetic Pima Indians of ten heralds progressive glomerular injury, it is not the result of defects in the size permselectivity of the glomerular barrier but rather of changes in either glomerular charge selectivity or tubular handling of filtered pr oteins or of a combination of these two factors.