Pathogenesis of tubulointerstitial fibrosis in chronic allograft dysfunction

Abstract

The term chronic allograft nephropathy (CAN) was originally coined in 1991 to replace chronic rejection which was used too generalized. However, the revised Banff classification, published in 2007, eliminated the term CAN again because it was felt that the term was used too broadly and prevented the search for the underlying cause. Interstitial fibrosis and tubular atrophy are integral parts of chronic allograft dysfunction and represent in the new classification a separate entity with or without the identification of a specific etiology. Myofibroblasts are the key, albeit not exclusive, effector cells in renal fibrogenesis resulting in upregulated extracellular matrix synthesis and eventually in interstitial fibrosis. These cells are formed mainly by stimulation of resident interstitial fibroblasts but also by differentiation processes of periadventitial cells, bone marrow derived cells and by a process entitled epithelial mesenchymal transition (EMT) of tubular epithelial cells. EMT has been described by many groups to be of high prevalence in renal allograft dysfunction contributing to matrix accumulation and renal function deterioration. This is of particular interest because immunosuppressive therapy has differential effects on EMT with calcineurin inhibitors in particular inducing the process. Moreover, specific therapies inhibiting EMT have been applied in experimental studies although the effects of their application in chronic allograft dysfunction remain to be studied. At the same time, immunosuppression may interfere with physiologic clearance of myofibroblasts by apoptosis, explaining in part the high prevalence of interstitial fibrosis in allograft biopsies. The Fas system has been identified to be mainly responsible for this physiologic apoptosis in non-renal scarring models; however, its relevance for renal fibrosis and particular fibrosis in renal allograft dysfunction remains to be determined. These findings point to a cautious and individualized use of immunosuppressive therapy in patients with allografts and particular those with chronic allograft dysfunction not because of rejection processes. Protocols using CNI-free immunosuppression are interesting options to prevent fibrosis in chronic allograft dysfunction.

Correction of Postkidney Transplant Anemia Reduces Progression of Allograft Nephropathy

“…[30][31][32] Taking into account the role of calcineurin inhibitors in the progression of chronic allograft nephropathy and their importance in mediating the epithelial to mesenchymal transition, one can speculate that the nephroprotective effects of epoetin-b may be at least partly caused by the inhibition of calcineurin inhibitor-induced epithelial to mesenchymal transition by RHuEPO. Thus, correcting tissue hypoxia by raising Hb levels adds to the tissue protective effects of RHuEPO.…”

Fas/Fas Ligand pathways gene polymorphisms in pediatric renal allograft rejection

“…Recently, there are many investigations in the pathogenesis of renal graft rejection, one of the most evident investigation is the protein molecules that participate in various stages of apoptosis. Fas/Fas Ligand (FasL) interaction seems to play a key role in AR and chronic allograft nephropathy (CAN) [6]. Apo-1/Fas, (CD95 and TNFRSF6), is a trans-membrane protein and its major function might be the induction of apoptosis in cells expressing it after ligation by its legend.…”

Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype

“…It would be interesting to investigate whether infection with cytomegalovirus, which constitutes a risk factor for BO, can induce EMT. In the chronic rejection of the kidney, immunosuppressive treatments have been described to be involved in EMT [169].…”