The Pima Indians of Arizona not only have a much higher incidence of nephropathy due to type 2 diabetes than Caucasians, but they also lose their renal function at an accelerated rate after they develop diabetic nephropathy. This rapid loss of renal function occurs despite a younger age of onset of nephropathy and lower blood pressures and lipid levels, all of which would seem to predict a slower rate of progression of nephropathy. These findings suggest that other factors contribute to the rapid progression of renal disease in this population. In particular, glomerulomegaly in this population may contribute to the high rate of glomerular filtration rate (GFR) loss during the terminal, clinically manifest phase of nephropathy, because of the greater incremental loss of single-nephron GFR (SNGFR) with each nephron lost to sclerosis. In nine Pima Indians with type 2 diabetic nephropathy who underwent renal biopsy followed by serial iothalamate clearances for up to ten years, we examined the relationship between glomerular tuft volume at initial biopsy and the rate of GFR loss during the terminal phase. By multivariate analysis, significant independent effects of both glomerular volume (P=0.006) and podocyte density (P=0.043) were evident in these individuals. The effect of glomerular volume may result from a greater loss of intrinsic filtration capacity with each glomerulus lost, while the effect of podocyte density may reflect the destabilizing influence of "podocyte insufficiency" on the glomerular tuft. Similar factors may play a role in the rapid loss of GFR associated with progressive glomerular diseases in other indigenous populations in whom glomerulomegaly and glomerulopenia coexist.