title: Differential expression of tissue factor (TF) in calcineurin inhibitor-induced nephrotoxicity and rejection--implications for development of a possible diagnostic marker.
abstract: Deposition of fibrin in the form of fibrinoid necrosis is a common feature of severe acute renal allograft rejection. The role of the coagulation system and its initiator tissue factor (TF) during this process is, however, still poorly understood. In this study, we analyzed the expression of TF in 88 renal transplants afflicted with different forms of rejection and calcineurin inhibitor-induced nephrotoxicity, to see whether there was differential expression of this protein. TF immunoreactivity was evaluated semiquantitatively in six different renal structures: the podocytes, Bowman epithelium, the endothelium of the glomeruli, the brush border of tubular cells, the thin ascending loop of Henle, and small arteries/arterioles. The TF expression of normal renal tissue (n=6) was restricted to the glomerular podocytes and Bowman epithelium, and to some extent the ascending loop of Henle. Renal allografts undergoing acute rejection (AR) of grades I-III, (n=13, n=17 and n=12, respectively) did not show any altered TF expression in the glomeruli or vascular endothelium. In the ascending loop of Henle, a reduced expression could be seen (ARI, p=0.015; and ARII, p=0.043). TF staining of the brush border of renal transplants undergoing acute cyclosporin A (CsA) nephrotoxicity (n=18) was significantly higher than in normal kidneys (p=0.0003), as well as in transplants undergoing various degrees of acute rejection (ARI, p=0.027; ARII, p=0.0012; and ARIII, p=0.0001). Tubular brush border-expressed TF was also evident in 10 of 15 allografts suffering from chronic CsA nephrotoxicity, compared to 4 out of 13 cases with chronic allograft vasculopathy (CAV), but the increase was not statistically significant relative to normal kidneys. The majority of the grafts afflicted with either of the two chronic conditions displayed a TF-positive arterial endothelium (CAV, p=0.0034; and chronic CsA nephrotoxicity, p=0.0026) relative to controls. In conclusion, these results indicate that vascular TF expression is not altered during acute rejection, but may be of importance in chronic allograft nephropathy. Furthermore, TF immunoreactivity in the tubular brush border may be specific to acute CsA nephrotoxicity and might be used as a biomarker for this condition. Further studies are required to evaluate the possible role of brush border-expressed TF in the pathogenesis of CsA nephrotoxicity.
authors.affiliation: Department of Nephrology and Transplantation, Lund University, Malmö University Hospital, S-205 02 Malmö, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Osterholm
authors.forename: B
authors.initials: B
authors.lastname: Veress
authors.forename: M
authors.initials: M
authors.lastname: Simanaitis
authors.forename: U
authors.initials: U
authors.lastname: Hedner
authors.forename: H
authors.initials: H
authors.lastname: Ekberg
mesh_terms: D000208:Acute Disease; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001777:Blood Coagulation / Q000276:immunology; D065095:Calcineurin Inhibitors; D002908:Chronic Disease; D016572:Cyclosporine / Q000009:adverse effects; D006084:Graft Rejection / Q000175:diagnosis* / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D007678:Kidney Glomerulus / Q000098:blood supply / Q000378:metabolism; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology; D011817:Rabbits; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: D015415:Biomarkers; D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D013925:Thromboplastin