Tubular‐interstitial interactions in proteinuric renal diseases

Abstract

SUMMARY: Progressive chronic renal disease of all types is characterized by a relatively uniform set of tubular (atrophy, hypertrophy, hyperplasia) and interstitial (inflammatory cell infiltration, fibrosis) pathological changes, the severity of which correlates well with the degree of proteinuria and the decline in glomerular filtration. Complex and redundant pathophysiological events underlie the relationship between proteinuria, tubular injury and interstitial damage, forming potential targets for therapy. The outcome of these events is also determined by additional factors not limited to proteinuric diseases, including tissue hypoxia, complement activation and mediators produced in response to glomerular damage. In response to proteinuria and these additional factors, tubular cells are activated to produce a large number of chemoattractants, proinflammatory and profibrotic cytokines and matrix proteins, which cause, at least in part, interstitial inflammation and fibrosis. In turn, soluble products of interstitial inflammatory cells (predominantly T lymphocytes and macrophages), dendritic cells and fibroblasts are at least partially responsible for altering the phenotype of tubular cells. Abnormal tubular‐interstitial interactions may also depend on direct cell contact rather than soluble mediators, as evidenced by up‐regulation of integrins and cell adhesion molecules. Myofibroblasts, a key cell in the production of interstitial fibrosis, may arise in response to the above mediators by trans‐differentiation of fibroblasts, perivascular cells and tubular cells. In addition, tubular cells have been shown to be capable of the induced expression of the signalling molecules necessary for them to behave as antigen‐presenting cells and thereby potentially initiate interstitial inflammation through the classic interactions of cognate immunity. It is probable that several, but not all, of this bewildering number of pathophysiological events are of prime importance to the development of tubulointerstitial damage in proteinuria. The immediate challenge for investigators is to define the relative importance of these events and, thus, the most appropriate targets for new treatments.