title: Increased risk of thrombotic microangiopathy in patients receiving a cyclosporin-sirolimus combination.
abstract: A single-center cohort study of kidney and kidney-pancreas recipients was conducted to evaluate the association between new immunosuppressive regimens and risk of thrombotic microangiopathy (TMA). From January 1st,1996 to December 31, 2002, 368 patients received a kidney or kidney-pancreas transplant at our center. Four immunosuppressive regimens were evaluated as potential risk factors of TMA: cyclosporin + mycophenolate mofetil (CsA + MMF), cyclosporin + sirolimus (CsA + SRL), tacrolimus + myophenolate mofetil (FK + MMF), and tacrolimus + sirolimus (FK + SRL). Thirteen patients developed biopsy-proven TMA in the absence of vascular rejection. The incidence of TMA was significantly different in the four immunosuppressive regimens studied (p < 0.001). The incidence of TMA was highest in the CsA + SRL group (20.7%). The relative risk of TMA was 16.1 [95% confidence interval (CI): 4.3-60.8] for patients in the CsA + SRL group as compared with those in the FK + MMF group. We also investigated in vitro the pathophysiological basis of this association. The CsA-SRL combination was found to be the only regimen that concomitantly displayed pro-necrotic and anti-angiogenic activities on arterial endothelial cells. We propose that this combination concurs to development of TMA through dual activities on endothelial cell death and repair.
authors.affiliation: CHUM, Notre-Dame Hospital, Nephrology and Transplantation, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Marie-Chantal
authors.initials: MC
authors.lastname: Fortin
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Raymond
authors.forename: François
authors.initials: F
authors.lastname: Madore
authors.forename: Jo-Ann
authors.initials: JA
authors.lastname: Fugère
authors.forename: Michel
authors.initials: M
authors.lastname: Pâquet
authors.forename: Gilles
authors.initials: G
authors.lastname: St-Louis
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Hébert
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D017209:Apoptosis; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D016572:Cyclosporine / Q000009:adverse effects*; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects; D006084:Graft Rejection / Q000188:drug therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007668:Kidney / Q000098:blood supply*; D016030:Kidney Transplantation; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives*; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000139:chemically induced*; D016035:Pancreas Transplantation; D012307:Risk Factors; D020123:Sirolimus / Q000009:adverse effects*; D013927:Thrombosis / Q000139:chemically induced* / Q000628:therapy
chemical_list: D020533:Angiogenesis Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D020123:Sirolimus