An update on chemical pharmacotherapy options for the prevention of kidney transplant rejection with a focus on costimulation blockade

ABSTRACT

Introduction: The introduction of calcineurin inhibitors (CNI) has greatly improved graft survival in the past three decades. However, long-term graft survival is still limited due to chronic allograft injury and side-effects of immunosuppressive medication.

Areas covered: The present overview gives an update on pharmacotherapeutic strategies after kidney transplantation. The main focus is on CNI-sparing regimens using co-stimulatory blockade and on new substances on the horizone.

Expert opinion: CNI sparing regimens are well-established. Complete CNI avoidance after kidney transplantation was often associated with impaired graft survival until the approval of the co-stimulation blocker belatacept for de novo immunosuppression after kidney transplantation. Concerns still exist with respect to severe T-cell-mediated rejection episodes in the early phase after transplantation. Thus, a triple drug regimen with CNI, mycophenolic acid and steroids still represents the gold-standard of immunosuppressive therapy. Alternative substances expand the possibilities of tailoring individual immunosuppression for different indications such as biopsy-proven CNI toxicity, polyoma virus BK nephropathy or CNI-triggered thrombotic microangiopathy. However, a change of the immunosuppressive therapy must always be balanced against each patient´s individual immunological risk in order to address the importance of chronic antibody-mediated rejection driven by donor specific antibodies (DSA).

KEYWORDS:

• Kidney transplantation
• immunosuppressive regimens
• calcineurin inhibitors
• belatacept
• mammalian target of rapamycin inhibitors
• chronic antibody-mediated rejection

Article highlights

• Graft survival is limited due to chronic allograft injury and cardiovascular mortality both influenced by immunosuppression with CNI-therapy.

• CNI withdrawal or minimization is often associated with higher rejection rates and the induction of donor-specific antibodies. Thus CNI minimization is only an option in selected patients in late maintenance therapy after transplantation, e.g. in case of CNI-mediated nephrotoxicity.

• De novo CNI-free immunosuppression became feasible with the introduction of co-stimulatory blockade with belatacept which was approved in combination with mycophenolic acid and corticosteroids.

• Uncertainty remains concerning early acute rejections, studies testing belatacept versus tacrolimus are pending.

• Other substances that target the co-stimulatory signal (CD40 or CD28) are currently being tested.

• Recently published data provide evidence for the safe withdrawal of steroids early after transplantation with tacrolimus as primary immunosuppression. However, long-term data and data on the development of donor-specific antibodies are currently not available.

• Different once-a day formations of tacrolimus, Advagraf® and Envarsus®, provide immunosuppression with similar efficacy and safety to the traditional twice-a day formulation Prograf®.

• Changing immunosuppression must always be balanced against each individual immunological risk, especially concerning the development of donor-specific antibodies.

This box summarizes key points contained in the article.

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.

Additional information

Funding

This paper was not funded.