Calcineurin and mammalian target of rapamycin inhibitors
The calcineurin inhibitors cyclosporine and tacrolimus are often implicated in TA-TMA after both HSCT and solid-organ transplantation.17,24,25 Endothelial injury is related to direct cytotoxic damage, platelet aggregation, elevated VWF and thrombomodulin, altered complement regulator proteins, and decreased production of prostacyclin and nitric oxide (NO).26–28 In recipients of kidney transplants, calcineurin inhibitor-induced TMA has been associated with endothelial damage from tissue ischemia at the time of transplantation.24 It is conceivable that a similar mechanism could lead to TA-TMA in the context of HSCT, whereby endothelial damage could occur secondary to infections, high-dose chemotherapy, or cytokines released during engraftment.
The recent use of both tacrolimus and sirolimus for GVHD prophylaxis in a phase 2 study was shown to increase the risk of TA-TMA, especially in patients receiving busulfan and cyclophosphamide.29 However, others have noted that, although the addition of sirolimus increased the risk for TA-TMA, patients receiving sirolimus had a more favorable renal and survival outcome than patients receiving only calcineurin inhibitors.30 Sirolimus may lead to TA-TMA by preventing repair of injured endothelium and by decreasing local VEGF production.26 Some have cautioned that the combination of calcineurin inhibitors with sirolimus or everolimus necessitates especially close monitoring for TA-TMA.24,31
In light of these findings, there is increased interest in analyzing the role of VEGF and NO in protecting the endothelium. In the kidney, VEGF is produced by podocytes, which induces glomerular endothelial cells to maintain the urinary filtration barrier. The antiangiogenic agent bevacizumab, used in cancer therapy, causes TMA by binding VEGF.20 In patients who received a HSC transplant, higher VEGF levels are associated with less endothelial injury, better survival, and less severe GVHD.32,33 NO prevents cytokine-induced endothelial damage by decreasing the release of P-selectins and VWF.26 In TA-TMA, free hemoglobin from excessive hemolysis may bind NO, perpetuating further endo-thelial injury.27