Calcineurin inhibitors in liver transplantation – still champions or threatened by serious competitors?

Abstract

Current strategies for immunosuppression in liver transplant (LT) recipients include the design of protocols targeting a more individualized approach to reduce risk factors such as renal failure, cardiovascular complications and malignancies. Renal injury in LT recipients may be often multifactorial and is associated with increased risk of post-transplant morbidity and mortality. The quest for low toxicity immunosuppressive regimens has been challenging and resulted in CNI minimization protocols or CNI withdrawal and conversion to mycophenolate mofetil (MMF) and/or mammalian target of rapamycin inhibitor-based immunosuppressive regimens. Use of antibody induction to delay CNI administration may be an option in particular in immunocompromized, critically ill patients with high MELD scores. Protocols including MMF introduction and concomitant CNI minimization have the potential to recover renal function even in the medium and long term after LT. We review on hot topics in the prevention and management of acute and chronic renal injury in LT patients. For this purpose, we present and critically discuss results from immunosuppressive studies published in the current literature or presented at recent LT meetings.Prevention and treatment of side effects of immunosuppressive drugs, namely calcineurin inhibitors (CNI), have gained an important role in the liver transplant (LT) setting. CNI are deemed to be associated with acute and chronic nephrotoxicity, de novo malignancies and cardiovascular or metabolic complications (1-3). In addition, causes of structural renal damage before and after LT may include chronic liver diseases associated with concomitant kidney injury (e.g. glomerulonephritis in viral hepatitis) and cardiovascular risk factors (arterial hypertension, diabetes).In acute CNI-induced nephrotoxicity, vasoconstriction in the afferent arterioles followed by a decrease in renal blood flow and reduced urinary excretion plays an essential role (Fig. 1) (4). Vasoconstriction is caused by an imbalance in the release of vasodilatory factors (prostaglandin E2, nitric oxide) and vasoconstrictive factors (thromboxane A2, endothelin 1, angiotensin II) and activation of the sympathetic nervous system. Renal function usually improves upon CNI cessation, whereas prolonged CNI-induced vasoconstriction may cause histological damage.

New‐onset diabetes after liver transplantation and its impact on complications and patient survival

“…Cyclosporine A and FK506 are both CNIs with similar mechanisms of action . Studies have confirmed the toxic effect of CNIs on β ‐cells, as these agents can lead to β ‐cell apoptosis or dysfunction.…”

“…Cyclosporine A and FK506 are both CNIs with similar mechanisms of action. 48,49 Studies have confirmed the toxic effect of CNIs on β-cells, [50][51][52] as these agents can lead to β-cell apoptosis or dysfunction. It has been reported that MMF and RAP do not cause diabetes and that RAP administered for the treatment of AR after liver transplantation can relieve insulin dependence.…”

Mycophenolate mofetil therapy for severe immune thrombocytopenia

“…Mycophenolate mofetil is an antiproliferative immunosuppressant. It is a prodrug and is metabolized to mycophenolic acid in its active form (Franklin & Morris, 1994;Wang et al, 2013;Dall'Era, 2011;Aliabadi et al, 2012;Beckebaum et al, 2013). It is in the same class as azathioprine, though more selective in action and is often used as a steroid-sparing agent, particularly in autoimmune diseases and transplantation medicine to prevent graft rejection.…”

Review on immunosuppression in liver transplantation

“…This "steroidfree" strategy may be especially beneficial for patients with hepatitis C patients and for those with diabetes and hypertension. Antibody induction along with delayed CNI introduction can be used to preserve renal function in LT recipients and reduce renal dysfunction in those with impairment [24] . Overall, no significant increase in adverse side effects was observed in solid transplant recipients receiving antibody induction [23,25] .…”