Kidney Fibrosis: Origins and Interventions

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.

Conflict of interest statement

The authors declare no funding or conflicts of interest.

Figures

FIGURE 1.

Simplified diagram of renal fibrogenesis. Most injurious stimuli result in an inflammatory cascade characterized by recruitment and activation of inflammatory cells, as well as activation of damaged epithelial cells. All of these cell types produce not only proinflammatory but also profibrotic mediators that result in consecutive waves of epithelial dedifferentiation. Resident and recruited mesenchymal cells (fibrocytes, fibroblasts, pericytes) and possibly also epithelial cells (tubular and endothelial) transdifferentiate to become contractile myofibroblasts that produce ECM. When the injury is severe and/or persistent, eventually a point of no return may be reached beyond which fibrosis progresses on a local level even after resolution of injury. EndoMT, endothelial-to-mesenchymal transition; FGF, fibroblast growth factor.

FIGURE 2.

Canonical mediators and molecular pathways in renal fibrosis. Many injurious stimuli converge on the TGF-β pathway, which has context-dependent pleiotropic effects and interacts with several related pathways. AGEs, advanced glycation end products; BMP-7, bone morphogenetic protein 7; FzR, frizzled receptor; HGF, hepatocyte growth factor; HIF, hypoxia-inducible factor; ROS, reactive oxygen species.