The course of renal disease attributable to non-insulin-dependent diabetes mellitus (NIDDM) has been characterized extensively in the Pima Indians of Arizona. Studies in this population indicate that the glomerular filtration rate often increases at the onset of NIDDM and remains elevated as long as normal urinary albumin excretion (< 30 mg albumin/g creatinine) or microalbuminuria (30-299 mg albumin/g creatinine) persist. After the development of macroalbuminuria (> or = 300 mg albumin/g creatinine), the glomerular filtration rate declines at least as rapidly as reported in subjects with insulin-dependent diabetes. Morphologic examination of kidney tissue reveals extensive glomerular sclerosis, mesangial expansion, and widening of epithelial cell foot processes and the glomerular basement membrane in the subjects with macroalbuminuria, but not in those with normo- or microalbuminuria. These findings suggest that substantial structural damage to the kidney occurs at or about the time that macroalbuminuria develops, and the decline in glomerular function in those with macroalbuminuria is due to a loss of ultrafiltration surface area and a reduction in glomerular hydraulic permeability.