Pharmacotherapeutic options for the prevention of kidney transplant rejection: the evidence to date

ABSTRACT

Introduction

Although early rejection episodes are successfully controlled, the problem of unrecognized production of de novo anti-HLA antibodies and associated chronic rejection still persists.

Areas covered

In addition to the standard induction and maintenance therapy, we present a couple of new drugs as induction (Alemtuzumab), CNI-free protocol (Belatacept, Sirolimus, and Everolimus), and maintenance treatment in transplant patients with various types of malignancies (T cell-targeted immunomodulators blocking the immune checkpoints CTLA-4 and PD1/PDL1) and TMA (aHUS)—eculizumab and IL6 receptor antagonists in antibody-mediated rejection (AMR).

Expert opinion

There are a couple of issues still preventing improvement in kidney transplant long-term outcomes with current and anticipated future immunosuppression: patients more susceptible to infection and CNI nephrotoxicity in kidneys obtained from elderly donors and highly sensitized patients with limited chances to get appropriate kidney and a higher risk for late AMR. A lower rate of CMV/BK virus infections has been observed in everolimus-treated patients. Belatacept use has been justified only in EBV-seropositive kidney transplants due to the increased risk of PTLD. Eculizumab upon recurrence of aHUS is a sole cost-effective option. A new IL-6 blocking drug (clazakizumab/tocilizumab) is a promising option for prevention/treatment of AMR. Clinical experience in tailoring immunosuppression for improving as long as possible graft and patient survival is inevitable.

KEYWORDS:

• Kidney transplantation
• calcineurin inhibitors
• belatacept
• everolimus
• sirolimus
• eculizumab
• clazakizumab
• tocilizumab

Article highlights

• Long-term graft survival is influenced by the development of CAN because of CNI nephrotoxicity and development of DSA, while patient survival may be associated with an increased infection risk.

• HLA-sensitized patients at high risk for AMR will benefit from the standard DES protocol and new anti-IL6 receptor therapy (tocilizumab or clazakizumab).

• With the EMA conditional approval for desensitization in highly sensitized (with positive XM) KTRs of a DD, imlifidase becomes a life-saving agent. Its rapid effect on DSA degradation makes it a promising drug also for resistant AMR in combination with other agents that suppress antibody production.

• CNI-free regimen with belatacept has limited use because of its inconclusive results from RCTs and high annual cost, but has found its place within the standard immunosuppressive protocols only in EBV-seropositive KTRs due to the increased risk of PTLD.

• Everolimus showed better allograft function compared to the CsA group with similar graft loss, mortality, SAE, and neoplasms, but with more frequent proteinuria and lower GFR.

• Graft function in low TAC/EVR combination is noninferior to standTAC/MPA, while viral infections with CMV and BKV are less frequent.

• An early or late mTORi initiation is an adopted strategy in malignant KTRs compared to standardized CNI-free protocols.

• Eculizumab upon recurrence of aHUS may be viewed as a sole cost-effective option in view of the high cost of treatment.

• Treatment cost is an objective limitation for use of the new drugs. Patent expiration and development of biosimilars and generics will certainly help for their availability in low- and middle-income countries as well.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosure

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