An update on the safety of tacrolimus in kidney transplant recipients, with a focus on tacrolimus minimization

ABSTRACT

Introduction: Tacrolimus-based immunosuppression remains the immunosuppressive drug of choice in kidney transplantation.

Areas covered: Its safety profile is closely linked to its pharmacokinetic properties. A narrow therapeutic range allows to limit under- and over-immunosuppression consequences. Minimization of tacrolimus exposure, using appropriate companion drugs, leads to the best renal outcomes in the long term. Also, reducing tacrolimus exposure variability helps in reducing tacrolimus toxicity. The novel concept of tacrolimus concentration-to-dose ratio (C/D ratio) associates with renal outcomes as well and provides some new possible improvements on tacrolimus safety, possibly by identifying kidney transplant recipient subpopulations at higher risk of tacrolimus toxicity. Similarly, the incidence of new-onset diabetes after transplantation (NODAT), a major side-effect of tacrolimus, can also be reduced by optimizing tacrolimus exposure. In this review, the authors summarize the safety profile of tacrolimus when optimizing mean tacrolimus exposure, tacrolimus exposure variability and tacrolimus C/D ratio. The impact of these adjustments on nephrotoxicity and NODAT is reviewed. Using such prescription optimization, tacrolimus’ safety profile is positive.

Expert opinion: Tacrolimus-based immunosuppression remains a valid option for kidney transplant recipients, and might even improve by individualizing prescriptions, the next frontier in transplant immunosuppression.

KEYWORDS:

• Kidney transplantation
• tacrolimus
• nephrotoxicity
• tacrolimus minimization
• new onset of diabetes after transplantation (NODAT)

Article highlights

• Tacrolimus, a calcineurin inhibitor, is the cornerstone of immunosuppression after organ transplantation.

• Tacrolimus has surpassed cyclosporine, another calcineurin inhibitor.

• In maintenance kidney transplant patients tacrolimus is associated with either MPA or with everolimus, with or without low doses of steroids.

• It is not possible to wean-off tacrolimus since such attempts have been rapidly stopped because they were associated with increased risk of dnDSA formation and acute rejection occurrence.

• Tacrolimus minimization, i.e. sustained trough levels below 3-5 ng/mL in association with MPA are detrimental with regards to allograft function/survival; conversely, it is possible to minimize tacrolimus exposure provided MPA is replaced by everolimus.

• Tacrolimus is potentially nephrotoxic; however, this is nowadays less frequent since trough levels between 5 and 8 ng/mL are targeted in the long-run. Tacrolimus intra-patient variability should also be considered when choosing target trough levels.

• Tacrolimus therapy is associated with a significant prevalence of NODAT, the latter being favored by higher tacrolimus trough levels, concomitant steroid therapy, or other non-modifiable factors. However, these non-modifiable factors are important to identify pretransplant in order to use low doses of tacrolimus in association with everolimus instead of full doses of tacrolimus plus MPA.

• Tacrolimus exposure recognizes a high intra-patient variability; this high IPV when present is associated with significantly poorer allograft function, poorer graft survival, and more chronic antibody-mediated rejections. IPV is significantly higher in African-Americans and in CYP3A5 expressers.

• Improvements in tacrolimus administration can be guided by the tacrolimus concentration-to-dose ratio, whose values can help target patients at higher risk of tacrolimus toxicity. Together with new tacrolimus formulations, a better tacrolimus safety profile might even be achieved.

This box summarizes key points contained in the article.

Declaration of interest

L Rostaing received travel grants from Chiesi, and honoraria from Chiesi, BMS, Novartis, and Sanofi. P Malvezzi received honoraria from Neovii and Chiesi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.