The authors have studied relationships of renal structure and function in more than 100 patients with insulin-dependent diabetes mellitus (IDDM), aged 13-55 years (mean, 30 years) with diabetes for 1-30 years (mean, 19 years). The authors confirmed the unique nature of the diabetic lesions that, in constellation, occur in no other disease. It was found that increased fractional mesangial volume (Vv Mes) is strongly associated with decreased glomerular filtration rate (GFR), proteinuria, and hypertension and that all patients with overt diabetic nephropathy have Vv Mes in excess of 0.35 micron 3/micron 3. This relationship results from constriction of the capillary lumen and filtration surface as a consequence of increased Vv Mes. Global glomerulosclerosis (scarring) is common in IDDM patients and appears related to arteriolar hyalinosis. Focal segmental glomerulosclerosis is a rare lesion in these patients. Having a single kidney (transplanted IDDM patients) is not associated with accelerated lesion development. The presence or absence of microalbuminuria (MA), per se, does not predict underlying glomerular structure, which may vary from the normal range to a level of pathology bordering on that regularly associated with overt nephropathy. However, when MA is associated with hypertension, or reduced GFR or both, urine albumin excretion (UAE) generally exceeds 40 mg/24 hr, and glomerular pathology is always present. The authors concluded that diabetic nephropathy is a unique renal disorder that cannot be caused by hemodynamic factors alone. The authors further conclude that MA becomes a predictor only when other features of overt nephropathy are already present and that serious diabetic glomerular lesions can be present in patients with normal UAE.