Journal of the American Society of Nephrology, Vol 5, 1273-1287, Copyright © 1994 by American Society of Nephrology

REVIEWS

Experimental insights into the tubulointerstitial disease accompanying primary glomerular lesions

AA Eddy

Although chronic progressive tubulointerstitial (TI) disease plays a critical role in the outcome of patients with primary glomerular lesions, the basic mechanisms that generate the TI damage remain unclear. This review focuses on recent insights into this process that originate primarily from studies of animal models of glomerular injury. The acute phase, which is often clinically silent, is characterized by tubular epithelial cell injury and interstitial inflammation. Proposed mediators of tubular injury include antibodies, lysosomal enzymes, obstruction, reactive oxygen metabolites, and complement. Damaged tubules may regenerate or undergo necrosis or apoptosis. The identification of the molecular mediators of mononuclear cell recruitment to the interstitium is of current interest because of evidence that monocytes/macrophages play a key role in progressive interstitial scarring through the release of fibrosis-promoting cytokines, particularly transforming growth factor-beta 1 (TGF-beta 1). Events linked to the initiation of interstitial inflammation include the deposition of antibodies or immune complexes along the tubular basement membranes, T cell-dependent mechanisms, glomerular factors, and factors linked to proteinuria. Several molecules likely regulate the interstitial migration of circulating monocytes, although the critical mediators are presently unknown. Candidates include chemotactic factors such as intercrines, growth factors, complement, lipid factors, osteopontin, and monocyte adhesion molecules (beta 1 integrins, beta 2 integrins, and L-selectins). The hallmark of the chronic phase of TI damage is interstitial fibrosis. Of the several candidate fibrogenic cytokines, to date, only TGF-beta 1 has been studied in any detail. TGF-beta 1 is produced by interstitial inflammatory cells and appears to trigger increased matrix production by perivascular and interstitial fibroblasts. Awaiting clarification is the role of tubular cells in vivo as a source of fibrogenic cytokines or as a site of increased matrix synthesis, activities they do perform in vitro. Preliminary studies suggest that interstitial fibrosis may also be due in part to the failure of matrix degradation by metalloproteinases and plasmin as a result of the overexpression of the enzyme inhibitors. The existence of an intrarenal matrix-degrading enzyme cascade suggests that renal fibrosis may be reversible, at least to a limited extent. In summary, during the early stage of glomerular injury, numerous cellular and molecular mediators of acute interstitial disease are activated and ultimately converge on common pathways that lead to progressive renal scarring.

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