Surgically removed perfusion-fixed human kidneys with chronic renal disease (hydronephrosis) were studied by electron microscopy in order to determine whether there is a quantitative relationship between ultrastructural changes in proximal tubules in atrophy and changes in the surrounding cortical interstitium. Morphometric techniques were applied to montages of electron micrographs each covering several tubular profiles in the cortical labyrinth and to montages representing cross-sections of individual proximal convoluted tubules at a higher magnification. In order to enable a quantification of the spatial relations between individual tubular cross-sections and adjacent peritubular capillaries a tubulo-capillary index (TCI) was defined. This index was based on the mean distances between individual tubular cross-sections and adjacent peritubular capillaries and on the fraction of tubular circumference facing capillaries. Normal tissue from similarly fixed human nephrectomy specimens, which had been removed mainly because of neoplastic disorders, served as control material. In the hydronephrotic kidneys the relative volume of cortical interstitium (excluding capillaries) covered a range from 19.2-70.3%. Inverse correlations were demonstrated between the relative volume of cortical interstitium and various structural variables of proximal convoluted tubules, including tubular wall volume, the volume of mitochondria and the surface area of basolateral membranes. The TCI showed positive correlations with these tubular variables. No significant correlation was found between the volume fractions of cortical interstitium and capillaries. Finally, it was found that an increase in the volume fraction of the cortical interstitium from 16.2% in controls to 24.7% in cortical areas of hydronephrotic kidneys was associated with a 40-50% reduction in the volume of mitochondria and in the surface area of basolateral membranes in proximal tubules. The results are consistent with a pathogenic interrelationship between tubular and interstitial changes. An important factor in this relationship might be disturbed topographic associations between tubules and blood capillaries caused by the increase in cortical interstitium. The results further show that even slight increases in the cortical interstitial volume are associated with significant quantitative changes in tubular fine structure suggesting impaired tubular functions.