In patients with renal diseases, proteinuria is a major determinant of progressive renal failure, probably by causing tubular cell injury. Little is known on extent and site of tubular cell injury in patients with proteinuria. Glutathione S transferases (GST) are cytosolic enzymes. The alpha isoform is present only in proximal tubular cells, whereas the pi isoform is confined to distal tubular cells. We have studied the urinary excretion of both isoenzymes in 56 (38 male and 18 female) patients with glomerular diseases and proteinuria. The mean age was 45 +/- (SD) 16 years, the median creatinine clearance was 80 (range 27-159) ml/min, and the median albuminuria was 4.2 (range 0.7-16.9) g/10 mmol creatinine. The excretions of both GST alpha (median 35.9 ng/10 mmol creatinine) and GST pi (median 24.8 ng/10 mmol creatinine) were elevated as compared with control values (upper limits 10 and 12 ng/10 mmol creatinine, respectively). The urinary excretion of GST pi, but not that of GST alpha, was inversely correlated with the creatinine clearance. The highest levels of GST alpha were found in patients with a well-preserved renal function, whereas highest levels of GST pi were found in patients with renal failure. In a small number of patients we performed immunofluorescent studies of renal tissue. An increased urinary excretion of GST alpha correlated with brush border damage and decreased staining of proximal tubules for that isoenzyme. Our data suggest that in patients with proteinuria initial injury is apparent at the proximal tubules. Measurements of GST alpha and GST pi appear useful to study longitudinal timing and site of proteinuria-induced tubular cell injury.