Tacrolimus-Induced Hypertension

Abstract

See related article, pp 1167–1175 Hypertension associated with solid-organ transplantation is of major clinical importance, because the degree of posttransplant hypertension has been shown to correlate with reductions in graft viability and survival.1,–,3 Effective blood pressure control with antihypertensives has been shown to enhance graft survival and reduce the risk of future cardiovascular disease and events in transplant recipients.3 The etiology of posttransplant hypertension is varied; however, hypertension produced by immunosuppressant therapy is an important cause of posttransplant-related hypertension. Tacrolimus (FK506) and cyclosporine A are 2 common immunosuppressants that have been shown to affect blood pressure. Thus, elucidation of mechanisms that contribute to posttransplant hypertension has major clinical implications. In general, the type of immune response evoked by a particular set of antigens, such as that associated with organ transplantation, depends on the expansion of specific T-lymphocyte (T-cell) subsets, as well as the duration of antigen exposure, which, in the case of organ transplantation, is life long. Tacrolimus and cyclosporine A limit the immune response via inhibition of calcineurin activity, through similar but slightly different mechanisms. With tacrolimus, the mechanism of calcineurin inhibition involves tacrolimus binding to its cytosolic binding partner, the ubiquitously expressed immunophilin FKBP12. Tacrolimus/FKBP12, along with calcium and calmodulin, forms a complex with calcineurin, thereby inhibiting calcineurin's phosphatase activity. Calcineurin signaling has been shown to regulate expression of a number of cytokines, including interleukin (IL)-2, IL-3, IL-4, and interferon-γ, as well as expression of the IL-2 receptor, which have been implicated in T-cell activation.4 For example, reducing IL-2 signaling with tacrolimus is important in limiting the immune response, because IL-2 promotes the expansion of cytotoxic T cells and has been shown to play an important role in immunologic memory. In this issue of Hypertension , Chiasson et al5 report …