Immunosuppression for pancreas transplantation with an emphasis on antibody induction strategies: review and perspective

Abstract

A review of recent literature was performed to identify trends and evaluate outcomes with respect to immunosuppression in pancreas transplantation (PTX). In the past decade, the majority of PTXs were performed with depleting antibody induction, particularly in the setting of either calcineurin inhibitor minimization, corticosteroid withdrawal or both. Maintenance immunosuppression consisted of predominantly tacrolimus (TAC)/mycophenolatemofetil, TAC/mycophenolic acid or TAC/sirolimus with or without corticosteroids. Depending on PTX category, donor and recipient risk factors, case mix and immunosuppressive regimen, the 1-year incidence of acute rejection has decreased to 5–20%. Current 1-year rates of immunological pancreas graft loss range between 1.8 and 6%. Depleting antibody induction and either TAC/mycophenolatemofetil or TAC/sirolimus maintenance therapy with early steroid withdrawal have become the mainstay of immunosuppression in PTX. However, the development of non-nephrotoxic, nondiabetogenic, and nongastrointestinal toxic regimens is highly desirable to improve quality of life in all solid organ transplant recipients.

Keywords::

• alemtuzumab
• antibody induction
• basiliximab
• calcineurin inhibitors
• diabetes mellitus
• mycophenolate
• rabbit antithymocyte globulin
• sirolimus
• steroid withdrawal
• tacrolimus

Financial & competing interests disclosure

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.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Currently available immunosuppressive agents are classified into three categories (induction, maintenance and antirejection therapy), and historically immunosuppressant selection was based exclusively on efficacy in the prevention of acute rejection.

• The vast majority (85–90%) of pancreas transplant (PTX) recipients receive antibody induction; 70% or more receive depleting T-cell antibody induction, usually with rabbit antithymocyte globulin.

• Although alemtuzumab induction may result in lower rates of acute rejection, no specific antibody induction strategy has been associated with improved intermediate-term outcomes in PTX.

• Nearly 80% receive maintenance immunosuppression with the tacrolimus/mycophenolatemofetil or mycophenolic acid combination; 40–50% undergo corticosteroid withdrawal without adverse consequences.

• Limited data with tacrolimus/sirolimus reveal excellent outcomes, whereas initial attempts with calcineurin inhibitor avoidance or minimization are less promising.

• Because most current immunosuppressive regimens are diabetogenic, a challenge in PTX is balancing the safety and efficacy of the requisite medications in order to achieve long-term euglycemia without the need for adjunctive antidiabetic therapies.

• Pancreas transplantation provides an excellent paradigm to study acute rejection because insulin-requiring diabetic patients represent a relatively homogeneous patient population who historically had a high rate of rejection because of variable drug absorption, the hierarchy of organ-specific immune reactivity and heightened immunological responsiveness from the presumed autoimmune etiology of diabetes.