Markers of Endothelial-to-Mesenchymal Transition

Abstract

Antibody-mediated rejection (ABMR) is a leading cause of allograft loss. Treatment efficacy depends on accurate diagnosis at an early stage. However, sensitive and reliable markers of antibody-endothelium interaction during ABMR are not available for routine use. Using immunohistochemistry, we retrospectively studied the diagnostic value of three markers of endothelial-to-mesenchymal transition (EndMT), fascin1, vimentin, and heat shock protein 47, for ABMR in 53 renal transplant biopsy specimens, including 20 ABMR specimens, 24 cell-mediated rejection specimens, and nine normal grafts. We validated our results in an independent set of 74 unselected biopsy specimens. Endothelial cells of the peritubular capillaries in grafts with ABMR expressed fascin1, vimentin, and heat shock protein 47 strongly, whereas those from normal renal grafts did not. The level of EndMT marker expression was significantly associated with current ABMR criteria, including capillaritis, glomerulitis, peritubular capillary C4d deposition, and donor-specific antibodies. These markers allowed us to identify C4d-negative ABMR and to predict late occurrence of disease. EndMT markers were more specific than capillaritis for the diagnosis and prognosis of ABMR and predicted late (up to 4 years after biopsy) renal graft dysfunction and proteinuria. In the independent set of 74 renal graft biopsy specimens, the EndMT markers for the diagnosis of ABMR had a sensitivity of 100% and a specificity of 85%. Fascin1 expression in peritubular capillaries was also induced in a rat model of ABMR. In conclusion, EndMT markers are a sensitive and reliable diagnostic tool for detecting endothelial activation during ABMR and predicting late loss of allograft function.

Early Antibody-Mediated Kidney Transplant Rejection Associated With Anti-Vimentin Antibodies: A Case Report

“…The implantation biopsy specimen demonstrated no tubular vimentin expression that increased significantly in proximal tubules by postoperative day 2. Because IRI increases vimentin expression of tubular epithelial and endothelial cells, [5][6][7][8] we speculate that the confluence of vimentin exposed by IRI and constitutive vimentin expression, in the setting of pre-existing AVAs, triggered an acute AMR in our patient. Notably, treatment with antithymocyte globulin/ plasmapheresis/intravenous immunoglobulin resulted in clinical and histopathologic improvement with a concurrent decrease in tubular vimentin expression on follow-up biopsies.…”

“…4,10,16,17 Global production of vimentin throughout the kidney and its exposure to the immune system increase in response to apoptosis and endothelial injury, such as occurs during peritransplantation IRI or after rejection. [5][6][7][8] AVA is associated with focal proximal tubular vimentin expression and subclinical rejection by 21 days after kidney transplantation in rhesus monkeys. 18 In kidney transplantation in humans, increased AVA titers and IgG AVAs may be associated with the development of transplant glomerulopathy and interstitial fibrosis/tubular atrophy.…”

“…Peritubular capillary and glomerular vimentin expression have been described during AMR, with endothelial localization confirmed by CD34 staining. 7,8 This expression is associated with cold ischemic time and delayed graft function. 7 We identified constitutive vimentin expression in peritubular capillaries and podocytes, but not glomerular endothelium, which was present at implantation and postoperative day 2.…”

“…Ischemia-reperfusion injury (IRI) can increase the surface expression of vimentin in apoptotic renal tubular epithelial and endothelial cells, providing a plausible mechanism for exposure of donorspecific antigenic targets to cause anti-vimentin AMR. [5][6][7][8] Notably, all traditional measures of alloreactivity defined this recipient as "low-risk" for immune memory, demonstrating the need for improved understanding of individual immunologic risk.…”

Histopathological findings in transplanted kidneys

“…We previously reported that PV-1 and caveolin-1 expression were a distinct feature of chronic rejection-induced transplant glomerulopathy and capillaropathy, respectively [37][38][39]. More recent data showed that three markers of endothelial-tomesenchymal transition (EndMT), fascin1, vimentin, and heat shock protein 47 provide a sensitive and reliable diagnostic tool for detecting endothelial activation during ABMR [40].…”