EXPERIMENTAL INSIGHTS INTO THE TUBULOINTERSTITIAL DISEASE ACCOMPANYING PRIMARY GLOMERULAR-LESIONS

Although chronic progressive tubulointerstitial (TI) disease plays a c ritical role in the outcome of patients with primary glomerular lesion s, the basic mechanisms that generate the TI damage remain unclear. Th is review focuses on recent insights into this process that originate primarily from studies of animal models of glomerular injury. The acut e phase, which is often clinically silent, is characterized by tubular epithelial cell injury and interstitial inflammation. Proposed mediat ors of tubular injury include antibodies, lysosomal enzymes, obstructi on, reactive oxygen metabolites, and complement. Damaged tubules may r egenerate or undergo necrosis or apoptosis. The identification of the molecular mediators of mononuclear cell recruitment to the interstitiu m is of current interest because of evidence that monocytes/macrophage s play a key role in progressive interstitial scarring through the rel ease of fibrosis-promoting cytokines, particularly transforming growth factor-beta 1 (TGF-beta 1). Events linked to the initiation of inters titial inflammation include the deposition of antibodies or immune com plexes along the tubular basement membranes, T cell-dependent mechanis ms, glomerular factors, and factors linked to proteinuria. Several mol ecules likely regulate the interstitial migration of Circulating monoc ytes, although the critical mediators are presently unknown. Candidate s include chemotactic factors such as intercrines, growth factors, com plement, 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 severa l candidate fibrogenic cytokines, to date, only TGF-beta 1 has been st udied in any detail. TGF-beta 1 is produced by interstitial inflammato ry cells and appears to trigger increased matrix production by perivas cular 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 vitr o. 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 inhibitor s. The existence of an intrarenal matrix-degrading enzyme cascade sugg ests that renal fibrosis may be reversible, at least to a limited exte nt. In summary, during the early stage of glomerular injury, numerous cellular and molecular mediators of acute interstitial disease are act ivated and ultimately converge on common pathways that lead to progres sive renal scarring.