Tacrolimus: 20 years of use in adult kidney transplantation. What we should know about its nephrotoxicity

Abstract

Tacrolimus (or FK506), a calcineurin inhibitor (CNI) introduced in field of transplantation in the 1990s, is the cornerstone of most immunosuppressive regi mens in solid organ transplantation. Its use has revolutionized the future of kidney transplantation (KT) and has been associated with better graft survival, a lower in cidence of rejection, and improved drug tolerance with fewer side effects compared to cyclosporine. However, its monitoring remains complicated and underexposure increases the risk of rejection, whereas overexposure increases the risk of adverse effects, primarily nephrotoxicity, neurotoxicity, infections, malignancies, diabetes, and gastrointestinal complaints. Tacrolimus nephrotoxicity can be nonreversible and can lead to kidney graft loss, and its diagnosis is therefore best made with reference to the clinical context and after exclusion of other causes of graft dysfunction. Many factors contribute to its development including: systemic levels of tacrolimus; local renal exposure to tacrolimus; exposure to metabolites of tacrolimus; local susceptibil ity factors for CNI nephrotoxicity independent of systemic or local tacrolimus levels, such as the age of a kidney; local renal P-glycoprotein, local intestinal and hepatic cytochrome P450A3, and renin angiotensin system activation. The aim of this review is to describe the pharmacokinetics, pharmacodynamics, and mechanisms of acute and chronic tacrolimus nephrotoxicity in adult KT. K E Y W O R D Sacute,

Comparison of clinical outcome of induction immunosuppressive therapy with thymoglobulin and standard therapy in kidney transplantation; a randomized double-blind clinical trial

“…Until 2014, more than 32 000 kidney transplants have been performed and added 2500-2700 cases annually (10)(11)(12)(13). One of the important issues is that the success rate of the transplant depends entirely on receiving immunosuppressive therapies.…”

Complement Components in the Diagnosis and Treatment after Kidney Transplantation—Is There a Missing Link?

“…Acute calcineurin inhibitor nephrotoxicity is dose-dependent and reversible after dose reduction. It occurs early after initiation of treatment and has been associated with vasoconstriction of the afferent and efferent glomerular arterioles, endothelial dysfunction, and resulting reduction in renal blood flow [ 68 ]. The association of calcineurin inhibitors with thrombotic microangiopathy has been reviewed above.…”

“…The association of calcineurin inhibitors with thrombotic microangiopathy has been reviewed above. Chronic calcineurin inhibitor-induced nephrotoxicity was long believed to be an important cause of late graft failure; however, newer studies underscore the impact of chronic antibody-mediated rejection (which may actually be associated with non-compliance and low immunosuppressive drug concentrations) [ 68 ]. The histopathologic features attributed to chronic calcineurin inhibitor nephrotoxicity (arteriolar hyalinosis, interstitial fibrosis and tubular atrophy, focal segmental or global glomerular sclerosis) are not specific, and the mechanisms underlying these changes are not clear [ 68 ].…”

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“…Sredinom 1970-ih godina jednogodišnje preživljenje je iznosilo oko 60 % u starijih od 35 godina. Postotak jednogodišnjeg preživljenja 1990-ih značajno se popravio i iznosio je oko 90 % 8,9 . Preživljenja u KBC-u Osijek u skladu su s ovakvim suvremenim ishodima.…”