Increased Risk of Thrombotic Microangiopathy in Patients Receiving a Cyclosporin–Sirolimus Combination

Abstract

A single-center cohort study of kidney and kidneypancreas 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.

Sirolimus‐Induced Thrombotic Microangiopathy is Associated with Decreased Expression of Vascular Endothelial Growth Factor in Kidneys

“…The recent introduction of sirolimus (rapamycin, Rapamune ® ) has provided an important evolution in transplantation therapeutics, because this immunosuppressive agent lacks the nephrotoxic profile of the calcineurin inhibitors (1,2). However, data from recent clinical trials suggest that sirolimus may be associated with a high rate of thrombotic microangiopathy (TMA) compared with other immunosuppressive agents (3)(4)(5)(6)(7)(8). The incidence of de novo TMA in renal transplantation recipients was 4.9 episodes per 1000 person-years in a historical cohort study of 15 870 patients in the United States Renal Data System (USRDS) (9).…”

Clinical characteristics of thrombotic microangiopathy following ABO incompatible living donor liver transplantation

“…28 As for the cases of ABO-incompatible transplants, the amount of immunosuppressive agent inevitably tends to be "over-dosed" to regulate the hyperimmunological state. In particular, CPA showed a close association with the incidence of TMA, compared with other additional immunosuppressive agents, including azathioprine and mizoribine.…”

Transplant-Associated Thrombotic Microangiopathy in Childhood

“…Cyclosporine and most probably tacrolimus show direct toxicity to endothelium (40)(41)(42)(43)(44)(45) and addition of sirolimus to calcinorin inhibitors potentializes these toxic effects (46)(47)(48).…”