The Pathophysiology of Endothelin in Complications After Solid Organ Transplantation: A Potential Novel Therapeutic Role for Endothelin Receptor Antagonists

Although short-term allograft survival after solid organ transplantation has improved during the past two decades, improvement in long-term graft survival has been less pronounced. Common complications after transplantation include chronic allograft rejection, nephrotoxicity from calcineurin inhibitors (CNIs), and systemic hypertension, which all impact posttransplantation morbidity and mortality. Endothelin (ET)-1, a potent endogenous vasoconstrictor, inducer of fibrosis, and vascular smooth muscle cell proliferation, may play a key role in both the development of CNI-induced nephrotoxicity and endothelial vasculopathy in chronic allograft rejection. ET-1 levels increase after isograft implantation, and ET-1 plays a key role in CNI-induced renal vasoconstriction, sodium retention, and hypertension. Preclinical studies have demonstrated that endothelin receptor antagonists (ERAs) can reduce or prevent CNI-induced hypertension after renal transplantation. In addition, ERAs can ameliorate CNI-induced renal vasoconstriction and improve proteinuria and preserve renal function in animal models of renal transplantation. ET-1 may also play a significant role in cardiac allograft vasculopathy, and in animal models, ERAs improve pulmonary function and ischemic-reperfusion injury in lung transplantation and hepatic function and structure in liver transplantation. Emerging pharmacokinetic data suggest that the selective ERA ambrisentan may be used safely in conjunction with the most commonly used immunosuppressive agents tacrolimus and mycophenolate, albeit with appropriate dose adjustment. The weight of available evidence pointing toward a potential beneficial role of ERAs in ameliorating common complications after solid organ transplantation must be balanced with potential toxicities of ERAs but suggests that a randomized clinical trial of ERAs in transplant patients is warranted.