title: Sirolimus-induced thrombotic microangiopathy is associated with decreased expression of vascular endothelial growth factor in kidneys.
abstract: The aim of this study was to examine the clinical characteristics, the histological features and the renal expression of vascular endothelial growth factor (VEGF) of five patients with sirolimus-associated thrombotic microangiopathy (TMA). Sirolimus-induced TMA occurs preferentially in kidneys with concomitant endothelial injury: it was observed in three patients with acute cellular rejection on calcineurin inhibitor-free regimen, in one patient with chronic graft rejection on a calcineurin inhibitor-free protocol and in one patient with chronic calcineurin inhibitor nephrotoxicity. We found that renal VEGF expression during sirolimus-induced TMA was significantly lower than VEGF expression in normal transplanted kidneys (p < 0.01). Decreased expression of VEGF seems to be a consequence of sirolimus treatment since (i) analysis of two biopsies performed after the switch of sirolimus to calcineurin inhibitor showed reappearance of VEGF expression, (ii) no decreased expression of VEGF was found in five kidneys with classical TMA and, (iii) an increased expression of VEGF was observed in seven kidneys with acute cellular rejection on a sirolimus-free immunosuppressive regimen (p < 0.01). The potential role of sirolimus-induced downregulation of VEGF as a predisposing factor to the development of TMA is discussed.
authors.affiliation: Pol Bouin Laboratory, University of Reims, Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Sartelet
authors.forename: Olivier
authors.initials: O
authors.lastname: Toupance
authors.forename: Marianne
authors.initials: M
authors.lastname: Lorenzato
authors.forename: Fouad
authors.initials: F
authors.lastname: Fadel
authors.forename: Laure Hélène
authors.initials: LH
authors.lastname: Noel
authors.forename: Eymeric
authors.initials: E
authors.lastname: Lagonotte
authors.forename: Philippe
authors.initials: P
authors.lastname: Birembaut
authors.forename: Jacques
authors.initials: J
authors.lastname: Chanard
authors.forename: Philippe
authors.initials: P
authors.lastname: Rieu
mesh_terms: D000328:Adult; D001706:Biopsy; D065095:Calcineurin Inhibitors; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D006084:Graft Rejection; D006801:Humans; D019044:Image Cytometry; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism; D016030:Kidney Transplantation / Q000379:methods; D008297:Male; D008875:Middle Aged; D012079:Renal Circulation; D020123:Sirolimus / Q000494:pharmacology*; D013927:Thrombosis / Q000139:chemically induced*; D014652:Vascular Diseases / Q000139:chemically induced*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D042461:Vascular Endothelial Growth Factor A; D020123:Sirolimus