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.

Renoprotective Effects of ETA Receptor Antagonists Therapy in Experimental Non-Diabetic Chronic Kidney Disease: Is There Still Hope for the Future?

“…The negative side effects of calcineurin inhibitors such as cyclosporine and tacrolimus are associated with the activation of both renin-angiotensin and endothelin systems (Hošková et al 2017). The mechanism underlying nephrotoxic effects of cyclosporine A (CSA) is connected with the induction of endothelin-converting enzyme by CSA resulting in ET-1 generation which leads to further renal hypoxia and ET-1 synthesis (Heyman et al 2018).…”

“…Originally, ET-1 was demonstrated to act through ET B receptors to promote natriuresis and diuresis, especially in response to increased salt load (Ahn et al 2004). In addition to many experimental studies, diuresis and natriuresis following ET-1 infusion has also been recently demonstrated in humans (Hunter et al 2017). Previous studies in rats with knockout of ET B receptors demonstrated salt-sensitive hypertension in these animals (Gariepy et al 2000).…”

Off‐label use of tacrolimus in children with glomerular disease: Effectiveness, safety and pharmacokinetics

“…Altogether, these processes can lead to endothelial dysfunction and contribute to the impairment of organ function, including kidney. 131 The early nephrotoxicity of tacrolimus is related to irrational drug use, especially when the dosage is too high or the plasma concentration is high. Undre et al believe that the risk of renal toxicity is greatly increased when the trough whole blood concentration of tacrolimus is greater than 20 ng/mL.…”

Brincidofovir as Salvage Therapy for Adenovirus Disease in Intestinal Transplant Recipients

“…Of note, we had previous experience with an intestinal transplant recipient who had adenovirus enteritis that was controlled with cidofovir for 3 weeks; however, acute kidney injury occurred and led to long‐term dialysis requirement. Given the fact that transplant recipients are commonly receiving a calcineurin inhibitor, which is also nephrotoxic, the risk of nephrotoxicity secondary to cidofovir use is higher . In our first patient, we initially started treatment with ribavirin due to literature demonstrating its efficacy in treating adenovirus disease and its favorable adverse effect profile compared with cidofovir .…”