title: Pathophysiological mechanisms of calcineurin inhibitor-induced nephrotoxicity and arterial hypertension.
abstract: Solid organ transplantation is an established treatment modality in patients with end-stage organ damage in cases where other therapeutic options fail. The long-term outcomes of solid organ transplant recipients have improved considerably since the introduction of the first calcineurin inhibitor (CNI) - cyclosporine. In 1984, the potent immunosuppressive properties of another CNI, tacrolimus, were discovered. The immunosuppressive effects of CNIs result from the inhibition of interleukin-2 synthesis and reduced proliferation of T cells due to calcineurin blockade. The considerable side effects that are associated with CNIs therapy include arterial hypertension and nephrotoxicity. The focus of this article was to review the available literature on the pathophysiological mechanisms of CNIs that induce chronic nephrotoxicity and arterial hypertension. CNIs lead to activation of the major vasoconstriction systems, such as the renin-angiotensin and endothelin systems, and increase sympathetic nerve activity. On the other hand, CNIs are known to inhibit NO synthesis and NO-mediated vasodilation and to increase free radical formation. Altogether, these processes cause endothelial dysfunction and contribute to the impairment of organ function. A better insight into the mechanisms underlying CNI nephrotoxicity could assist in developing more targeted therapies of arterial hypertension or preventing CNI nephrotoxicity in organ transplant recipients, including heart transplantation.
authors.affiliation: Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. lenka.hoskova@ikem.cz.
authors.forename: L
authors.initials: L
authors.lastname: Hošková
authors.forename: I
authors.initials: I
authors.lastname: Málek
authors.forename: L
authors.initials: L
authors.lastname: Kopkan
authors.forename: J
authors.initials: J
authors.lastname: Kautzner
mesh_terms: D000818:Animals; D065095:Calcineurin Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control*; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D007166:Immunosuppressive Agents / Q000009:adverse effects; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D017382:Reactive Oxygen Species