Epithelial-to-Mesenchymal Transition Predicts Cyclosporine Nephrotoxicity in Renal Transplant Recipients

Abstract

Maintenance immunosuppression with cyclosporine A (CsA) can cause nephrotoxicity in renal transplant recipients. Identifying patients at increased risk for CsA nephrotoxicity may allow interventions to prolong graft survival. Here, we studied the effect of early CsA withdrawal or maintenance among 96 kidney recipients at risk for interstitial fibrosis and tubular atrophy (IF/TA) on the basis of tubular expression of vimentin and ␤-catenin in a protocol biopsy performed 3 months after transplant. In this retrospective analysis of biopsies collected during a randomized trial of early withdrawal of CsA or mycophenolate mofetil, the semiquantitative score of early phenotypic changes suggestive of epithelial-to-mesenchymal transition (EMT) progressed with time among those maintained on a CsA-containing regimen. EMT-positive grafts displayed a significantly higher IF/TA score and greater progression of the IF/TA score at 12 months (P ϭ 0.001 and 0.008, respectively). EMT-positive grafts exposed to CsA also had a greater decrease in estimated GFR compared with EMT-negative grafts exposed to CsA and EMT-positive grafts withdrawn from CsA exposure. Multivariable analysis revealed that the presence of EMT was an independent risk factor for a 10% decline in graft function up to 4 years posttransplant (odds ratio 4.49; 95% confidence interval 1.02 to 19.9). Collectively, these data demonstrate that changes consistent with EMT are strong prognostic biomarkers in renal transplant recipients exposed to CsA.

Markers of Endothelial-to-Mesenchymal Transition

“…Grafts with a score $2 (10% or more of PTC cells were strongly stained by any one of the three markers) were considered EndMT-positive. This cutoff was defined before any statistical analysis, based on our experience with EMT markers, [30][31][32][33] and the level of EndMT marker expression observed in normal kidneys. The Kendall's coefficient of concordance for EndMT score between different readings by one recorder was 0.97 (P,0.001), and between two recorders was 0.86 (P=0.001).…”

TMBIM6 (transmembrane BAX inhibitor motif containing 6) enhances autophagy and reduces renal dysfunction in a cyclosporine A-induced nephrotoxicity model

“…[52][53][54][55] Significant alterations of autophagy 19,56 have been reported in CsA-associated nephrotoxicity. CsA-induced renal injury is frequently observed in renal tubular structure including proximal tubules.…”

Activation of Hypoxia-Inducible Factor by Cobalt Is Associated with the Attenuation of Tissue Injury and Apoptosis in Cyclosporine-Induced Nephropathy

“…CIN also presents inflammatory changes, including macrophage or monocyte infiltration into the injured kidney areas (Carlos et al 2010;Park et al 2010). In addition, CsA induces epithelial-mesenchymal transition in the kidney (McMorrow et al 2005;Park et al 2010;Hazzan et al 2011). However, the precise underlying mechanism of CIN remains undefined.…”