Quantitative structural studies in native kidneys of IDDM patients have almost all been cross sectional, and little is known regarding the dynamics of progression of structural lesions in relation to clinical progression. It has been suggested that interstitial may be more important than glomerular changes in determining functional outcome. This study evaluated renal structure in sequential biopsies from IDDM patients with established renal lesions to determine whether glomerular, arteriolar and interstitial changes progress together and in concordance with measures of renal function. Eleven long-term IDDM patients [age 29 +/- 10 years, duration 17 +/- 7 years (mean +/- SD)] had renal function studies and kidney biopsies performed at two occasions 5.6 +/- 1.6 years apart. HbA1 as well as creatinine clearance (CCr) did not change over this time; albumin excretion rate (AER) increased from 12 (6 to 280) to 19 (5 to 2462) [median (range)] mg/24 hr (P < 0.03). AER increased in the three patients with abnormal albuminuria at first observation, and two normoalbuminuric patients became microalbuminuric. Blood pressure (BP) did not change; however, the number of patients on antihypertensive therapy increased from 1 to 5. All structural parameters were abnormal at first evaluation. Mesangial fractional volume [Vv(mes/glom)] and mean glomerular volume increased and the surface density of the peripheral glomerular basement membrane (GBM) decreased, while GBM width did not change over the five years of the study. Also, arteriolar hyalinosis lesions progressed, while the fractional volume of cortical interstitium [Vv(interstitium/cortex)] and the percent of globally sclerosed glomeruli did not change. The only structural change that correlated with the increasing AER was the change in Vv(mes/glom). Changes in structural parameters, AER or CCr did not significantly correlate with baseline BP or change in BP over the five years. Although based on a small number of patients, this study suggests that at the stage of disease where renal lesions are established and where some IDDM patients are in transition to microalbuminuria or early clinical nephropathy, continuing mesangial expansion is the central variable. Interstitial changes were not occurring over this time. Progressive interstitial expansion at the later stages of diabetic nephropathy may thus be consequent to advanced diabetic glomerular injury.