*Purpose: Transplant glomerulopathy (TG) has been proposed to be a component of chronic antibody-mediated rejection (CAMR). However, a substantial number of patients with TG do not have positive C4d staining or DSA, indicating that a non-alloantibody-mediated process may be involved in the development of TG and called isolated TG. We compared histopathological features, the incidence of the development of endothelial-to-mesenchymal transition (EndoMT) and the outcome of patients that displayed TG with or without C4d expression and DSA.

*Methods: A total of 156 patients were included in the study. Of these, 76 (48.7%) had isolated TG (Group 1), and 80 (51.3%) had CAMR (Group 2). The intensity of interstitial, glomerular and peritubular capillary (PTC) leukocyte and macrophage infiltration was graded. CD31, VEGF, paxillin, α-SMA, and Smad2 expression in glomeruli and PTCs were studied to show the development of EndoMT. Tubulointerstitial TNF-α and TGF-β expression were examined. Follow-up biopsies were analyzed for the development of diffuse interstitial fibrosis (IF), and glomerulosclerosis (GS) (> 30% of glomeruli).

*Results: Patients with isolated TG displayed a lower degree of leukocyte and macrophage infiltration in the interstitium, glomeruli, and PTCs compared to group 2 patients (p<.001). Both in glomeruli and PTCs, the expression of α-SMA, paxillin, and Smad2 were found to be higher, and the expression of VEGF and CD31 were found to be lower in group 2 than in group 1 (p<.001), meaning the development of EndoMT was higher in group 2 than Group 1. The degree of both PTC and glomerular α-SMA, paxillin and Smad2 expression increases with the increasing degree of tubulointerstitial TGF-β and TNF-α expression (p<.001). The development of diffuse IF and GS during follow-up was found to be higher in group 2 than group 1 (p<.001). Overall the 3- and 5-year graft survival was 92%, and 82% respectively for Group 1 patients while it was 74%, and 45% respectively for Group 2 (p<.001).

*Conclusions: Our results showed that compared to patients with CAMR, patients with isolated TG had a lesser degree of allograft inflammation, a lower incidence of EndoMT with lower development of fibrosis and a better outcome. Endothelial activation during CAMR may induce EndoMT throughout glomeruli and PTCs. Thus, the EndoMT process plays an essential role in the fibrosis process through the TGF-β/Smad signaling pathways in allografts with an endothelial injury.

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