To define the earliest renal morphological changes in patients with type I diabetes, we studied renal function and morphometric analysis of renal biopsies in 59 patients with diabetes for 5-12 years and normal blood pressure, normal creatinine clearance (CCr), and negative dipstick urinary protein. Arteriolar hyalinization and intimal fibrous thickening were noted in 43%. Glomerular basement membrane thickness and fractional mesangial volume were increased in 51% and 56%, respectively. The pre-pubertal and post-pubertal years of diabetes were associated with similar degrees of renal structural changes, but during the pre-pubertal years normal urinary albumin excretion (UAE) was seen. Principal factor analysis of morphometric structural parameters yielded four clusters of variables: "glomerular size" correlated with patient age, CCr, and UAE; "peripheral capillary decrease" correlated with glycosylated hemoglobin, diastolic blood pressure, glomerular filtration rate, and UAE; "mesangial increase" correlated with UAE; and "interstitial scarring" correlated with diastolic blood pressure. This study provides unique documentation of renal structural abnormalities which precede clinically evident renal functional abnormalities and documents that these early structural abnormalities are present in the pre-pubertal years of diabetes as well as postpuberty, and are associated with each other in constellations that correspond to postulated mechanisms in diabetic nephropathy.