There is much debate over the origins of fibroblast-type cells that accumulate in interstitial fibrosis. A controversial hypothesis, supported by data from animal and cell-culture studies, is that fibroblast-type cells can derive from tubular epithelial cells by a process of epithelial-mesenchymal transdifferentiation. However, to date, no evidence supports this postulate in human glomerulonephritis. This study sought to provide evidence that tubular epithelial cells can undergo phenotypic change toward a fibroblast-like cell in human glomerulonephritis. One hundred twenty-seven open renal biopsy specimens from patients with minimal change disease (MCD), immunoglobulin A (IgA) nephropathy, and rapidly progressive glomerulonephritis (RPGN) were examined for tubular phenotypic change by two-color immunohistochemistry using the criteria of de novo expression of [alpha ]-smooth muscle actin ([alpha ]-SMA), a myofibroblast marker; loss of the epithelial marker cytokeratin; and collagen production. In normal human kidney and MCD, tubular epithelial cells expressed cytokeratin with no evidence of [alpha ]-SMA staining. However, in 36 of 90 cases of IgA nephropathy and 9 of 18 cases of RPGN, small numbers of tubular epithelial cells in areas of fibrosis showed de novo [alpha ]-SMA expression, accounting for 0.4% [plusmn] 0.2% (IgA nephropathy) and 3.8% [plusmn] 1.5% (RPGN) of cortical tubules. An intermediate stage of phenotypic change was observed in some cuboidal epithelial cells that expressed both cytokeratin and [alpha ]-SMA. Tubules containing [alpha ]-SMA-positive ([alpha ]-SMA⁺) cells also stained for collagen types I and III, suggesting that tubular cells undergoing phenotypic change have an active role in the fibrotic process. There also was a marked increase in transforming growth factor-[beta ]1 (TGF-[beta ]1) tubular expression in areas with interstitial fibrosis, including tubules with phenotypic change. There was a highly significant correlation between tubular [alpha ]-SMA expression and interstitial fibrosis, interstitial [alpha ]-SMA⁺ myofibroblast accumulation, deposition of collagen types I and III, tubular TGF-[beta ]1 expression, and renal dysfunction. In conclusion, this study provides evidence that tubular epithelial cells can undergo phenotypic change toward a myofibroblast-like phenotype on the basis of de novo [alpha ]-SMA expression, loss of cytokeratin, and de novo collagen staining. These data, although not conclusive, provide the first support for the hypothesis that transdifferentiation of tubular epithelial cells has a role in progressive renal fibrosis in human glomerulonephritis. [copy ] 2001 by the National Kidney Foundation, Inc.