Kidney Fibrosis: Origins and Interventions

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Abstract

All causes of renal allograft injury, when severe and/or sustained, can result in chronic histological damage of which interstitial fibrosis and tubular atrophy are dominant features. Unless a specific disease process can be identified, what drives interstitial fibrosis and tubular atrophy progression in individual patients is often unclear. In general, clinicopathological factors known to predict and drive allograft fibrosis include graft quality, inflammation (whether “nonspecific” or related to a specific diagnosis), infections, such as polyomavirus-associated nephropathy, calcineurin inhibitors (CNI), and genetic factors. The incidence and severity of chronic histological damage have decreased substantially over the last 3 decades, but it is difficult to disentangle what effects individual innovations (eg, better matching and preservation techniques, lower CNI dosing, BK viremia screening) may have had. There is little evidence that CNI-sparing/minimization strategies, steroid minimization or renin-angiotensin-aldosterone system blockade result in better preservation of intermediate-term histology. Treatment of subclinical rejections has only proven beneficial to histological and functional outcome in studies in which the rate of subclinical rejection in the first 3 months was greater than 10% to 15%. Potential novel antifibrotic strategies include antagonists of transforming growth factor-β, connective tissue growth factor, several tyrosine kinase ligands (epidermal growth factor, platelet-derived growth factor, vascular endothelial growth factor), endothelin and inhibitors of chemotaxis. Although many of these drugs are mainly being developed and marketed for oncological indications and diseases, such as idiopathic pulmonary fibrosis, a number may hold promise in the treatment of diabetic nephropathy, which could eventually lead to applications in renal transplantation.

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