Induction Immunosuppressive Therapies in Renal Transplantation

Steven Gabardi, Pharm.D., BCPS; Spencer T. Martin, Pharm.D., BCPS; Keri L. Roberts, Pharm.D.; Monica Grafals, M.D.

Disclosures

Am J Health Syst Pharm. 2011;68(3):211-218. 

In This Article

Abstract and Introduction

Abstract

Purpose. Induction immunosuppressive therapies for patients undergoing renal transplantation are reviewed.
Summary. The goal of induction therapy is to prevent acute rejection during the early posttransplantation period by providing a high degree of immunosuppression at the time of transplantation. Induction therapy is often considered essential to optimize outcomes, particularly in patients at high risk for poor short-term outcomes. All of the induction immunosuppressive agents currently used are biological agents and are either monoclonal (muromonab-CD3, daclizumab, basiliximab, alemtuzumab) or polyclonal (antithymocyte globulin [equine] or antithymocyte globulin [rabbit]) antibodies. Although antithymocyte globulin (rabbit) is not labeled for induction therapy, it is used for this purpose more than any other agent. Basiliximab is not considered as potent an immunosuppressive agent but has a much more favorable adverse-effect profile compared with antithymocyte globulin (rabbit) and is most commonly used in patients at low risk for acute rejection. Rituximab is being studied for use as induction therapy but to date has not demonstrated any significant benefits over placebo. While head-to-head data are available comparing most induction agents, the final decision on the most appropriate induction therapy for a transplant recipient is highly dependent on preexisting medical conditions, donor characteristics, and the maintenance immunosuppressive regimen to be used.
Conclusion. No standard induction immunosuppressive regimen exists for patients undergoing renal transplantation. Antithymocyte globulin (rabbit) is the most commonly used agent, whereas basiliximab appears safer. The choice of regimen depends on the preferences of clinicians and institutions.

Introduction

Renal transplantation is the treatment of choice for patients with end-stage renal disease. Short-term outcomes (e.g., acute rejection rate, one-year graft survival) of solid organ transplantation have dramatically improved over the past several decades, in large part due to improvements in immunosuppression and medical care posttransplantation. Despite the improvements in transplantation-related outcomes, this treatment is limited by the availability of suitable organ donors. Currently, roughly 86,000 patients in the United States are awaiting a renal transplant.[1] In 2009, about 10,400 kidneys from deceased donors and 6,600 kidneys from living donors were transplanted.[1]

The goal of transplant pharmacotherapy is immunosuppression with resultant long-term allograft and patient survival while minimizing the complications of this immunosuppression (e.g., infectious complications, malignancy). Immunosuppressive regimens typically comprise multiple medications that act on different targets of the immune system. In general, clinical immunosuppression consists of three distinct stages: induction therapy, maintenance therapy, and treatment of an established acute rejection episode.

The introduction of highly potent and selective agents for the initiation of immunosuppression has reduced the frequency of acute rejection.[2] However, acute rejection is still a concern in transplantation and remains an important risk factor for the development of chronic rejection. Subclinical acute rejection has received a large amount of attention and could be an important determinant of outcomes in renal transplant recipients.[3] Induction immunosuppressive therapies play an important role in these patients.

The goal of induction therapy is to prevent acute rejection during the early posttransplantation period by providing a high degree of immunosuppression at the time of transplant surgery.[2,4–7] This type of therapy is initiated intraoperatively or immediately postoperatively and is concluded within the first week or two after transplantation. The rationale behind the increased use of induction therapy is multifactorial. Induction therapy is not a mandatory stage of immunosuppression in transplant recipients; however, it is often considered essential to optimize outcomes, particularly in high-risk individuals, such as highly sensitized patients, recipients with a history of transplantation, and those receiving a calcineurin inhibitor (CNI) (i.e., cyclosporine or tacrolimus) or corticosteroid minimization or withdrawal regimens.[2,4–7]

The rate of induction therapy with biological agents continued a nine-year trend of increasing use in renal transplantation and was 74% in 2004–05.[8] However, there is no universal consensus on the optimal agent for induction therapy after renal transplantation. In 2005, antithymocyte globulin (rabbit) was the most frequently used induction agent in the United States, used in 39% of renal transplant recipients. In contrast, interleukin-2 (IL-2) receptor antibodies were used in 28% (basiliximab = 16%, daclizumab = 12%), alemtuzumab in 9%, and antithymocyte globulin (equine) or muromonab-CD3 in <2% of all transplant recipients who received induction therapy.[8,9]

A number of trials involving renal transplant recipients have demonstrated significant reductions in the frequency of acute rejection and improved one-year graft survival when certain biological agents were used for induction therapy.[2,4,5,7,10–16] Due to their potent effects on controlling enhanced alloimmune responses, these agents are often considered vital in patients at high risk for poor short-term outcomes, such as patients with preformed antibodies, a history of organ transplantation, multiple human leukocyte antigen mismatches, or transplanted organs with a prolonged cold-ischemic time or from expanded-criteria donors. Induction therapy in renal transplant recipients also plays a vital role in the prevention of CNI-induced nephro-toxicity immediately after transplant surgery.[2] By using induction therapy, initiation of CNI therapy can often be delayed until the graft regains some functioning.[2,17,18] However, the improved short-term outcomes inferred from induction therapies include a degree of risk. By using these highly potent immunosuppressive agents, the body loses much of its innate ability to mount an immune response, thereby increasing the risk of infectious complications and malignancy.[2,18] Some of these agents are also associated with several serious short-term adverse events.

The following review of induction therapy is not meant to provide specific recommendations in clinical practice. This article summarizes the available literature for practicing pharmacists to help them better understand the available induction immunosuppressive agents. Before considering any induction therapy for a renal transplant recipient, a clinician should recognize that allograft function and survival are reliant on multiple patient-specific and pharmacologic factors, including maintenance immunosuppression protocols, recipient and donor ages, race, sex, weight, transplant function immediately after surgery, and the degree of immunologic risk before transplantation.

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