Recent studies in experimental glomerular disease suggest that proteinuria may be involved in the pathogenesis of accompanying tubulointerstitial (TI) lesions. To investigate whether there is a relationship between proteinuria and TI damage in membranous glomerulonephritis, 78 biopsy specimens with no or mild vascular disease and 10% or less obsolete glomeruli were examined and evaluated quantitatively., Extent of TI damage was represented by the TI index (TII) obtained for each biopsy specimen by dividing the morphometrically measured area of cortical damage by the total cortical area and multiplying the result by 1,000, The TII increased with stage of glomerular disease, but only the difference between stages 3 and 1 was significant (P < 0.016). The TII showed significant individual correlation with 24-hour urinary protein (r = 0.435, P < 0.0001), serum albumin (r = -0.327, P = 0.0045), and percent of glomeruli with visceral epithelial cell protein absorption droplets (r = 0.419, P = 0.0001), but not with age, serum creatinine, or percent obsolete glomeruli, With multivariate analysis TII correlated significantly with urinary protein (r = 0.286, P = 0.0146) and percent glomeruli with visceral epithelial cell protein droplets (r = 0.304, P = 0.0058), The results are consistent with the hypothesis that proteinuria is involved in the development of TI injury in glomerular disease. (C) 1995 by the National Kidney Foundation, Inc.