Conversion to Combined Mycophenolate Mofetil and Low-Dose Calcineurin Inhibitor Therapy for Renal Dysfunction in Liver Transplant Patients: Never Too Late?

Abstract

A progressively increasing life expectancy after liver transplantation (LT) leads to previously underestimated long-term complications, in particular renal damage as well as metabolic and cardiovascular disease [1]. Although the etiology of kidney damage in LT patients may be multifactorial, calcineurin-inhibitor (CNI)-induced nephrotoxicity significantly contributes to the development of renal dysfunction after LT [2]. CNIs may cause acute and chronic nephrotoxicity, with the latter usually being associated with structural changes in the kidney [3]. Acute nephrotoxicity comprises vascular effects such as vasoconstriction of the afferent arterioles, an increased secretion of vasoconstrictor factors including endothelin and thromboxane, activation of the renin-angiotensin system (RAS), and reduction of vasodilatation factors such as nitric oxide, prostacyclin and prostaglandin E2. Acute CNI-induced nephrotoxicity may further lead to tubular damage and/or dysfunction and thrombotic microangiopathy. Chronic CNI-related nephrotoxicity including arteriolar hyalinosis, tubular atrophy, interstitial fibrosis, and glomerular sclerosis is observed in most LT recipients with long-term CNI therapy [2]. Chronic CNI-related renal damage is thought to be a consequence of both CNI-induced hemodynamic changes and direct toxic effects on renal tubular epithelium. Despite the fact that chronic CNI-related nephrotoxicity is associated with parenchymal damage, various clinical studies have shown that CNI dose reduction or discontinuation results in an improvement of renal function in the majority of LT patients, thus suggesting a partly dose-dependent nephrotoxic effect and reversible functional kidney impairment [4]. In addition, CNI reduction or withdrawal is also associated with decreased cardiovascular risk in LT patients [5].