**3. Which induction agent?**

According to the annual report from SRTR 2009, 83% of transplant recipients received induction agents at the time of kidney transplant. The majority of patients received a T-cell depleting agent, 58%, and 21.2% received an IL-2 receptor blocking agent.

How agents are used in practice is dependent on a number of factors which range from center specific protocols to tailored immunosuppression based on recipient factors. The risks and benefits of each agent must be assessed in every patient individually based on the individuals' immunologic risk and susceptibility to infectious complications. Induction agents clearly possess different mechanisms of action that will have different effects on modulating cellular and humoral immune responses. It may be more advantageous to use more potent induction therapies such as the lymphocyte depleting agents, in those recipients at higher risk for rejection. On the other hand, utilizing such agents may be of concern in recipients with chronic infections such as hepatitis B and/or C or HIV. [7-10]

Caucasian, and those receiving living donor kidneys. When compared to lymphocyte deplet‐

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Utilizing data from the United Network For Organ Sharing Data Registry, a recent study examining a large cohort of HIV recipients demonstrated higher risk of DGF and death censored graft loss with IL-2 receptor agents.[12] HIV patients also have higher rates of acute rejection with one recent study reporting a 31% incidence at one year.[7] Questions remain as to whether this is driven in part by choosing a less potent induction agent such as Simulect or issues with achieving therapeutic levels and/or avoiding toxic levels of maintenance drugs that interact with many anti-retroviral HIV medications. Thymo‐ globulin has been used in HIV recipients but can lower the CD4+ cell count dramatically, with recovery occurring as far out as two years. [13] Thymoglobulin use in HIV has also been associated with increased risk of infections requiring hospitalizations. Clearly, more studies are needed to weigh the risks and benefits of IL-2 receptor blockers on long-term

A study by Terasaki et al analyzed the various induction immunosuppression strategies used across centers in the United States [3]. From 2003 onwards, the majority of centers were utilizing Simulect, rATG or Alemtuzumab. According to the OPTN database, recipients who received alemtuzumab had the lowest risk of graft failure, followed by rATG and basiliximab. However, the benefit of one induction agent over the other is not entirely clear because conclusions from small single center studies and retrospective studies utilizing database reviews are often mixed. In addition, studies may be difficult to evaluate secondary to different

Larger randomized trials and multicenter trials have been conducted and generally dem‐ onstrate that cell-depleting agents are generally more efficacious than IL2RA induction. [3] In a randomized controlled trial, rATG was superior to IL2RA in preventing acute re‐ jection in recipients with high-immunologic risk, and with standard criteria donor kid‐ neys. Two prospective randomized trials demonstrated rATG was superior to basiliximab in preventing biopsy proven acute rejection in standard criteria donor kidney recipients. When comparing Alemtuzumab to rATG, studies are mixed. In a separate single center randomized trial comparing alemtuzumab with rATG induction, Farney et al have shown that alemtuzumab is superior to rATG in preventing biopsy proven acute rejec‐ tion.[14] However, in a larger randomized multicenter study (INTAC), Hanaway et al compared induction therapy with alemtuzumab to conventional induction (basiliximab or rATG). At one year post transplant, the incidence of biopsy proven acute rejection was lower in the alemtuzumab arm compared to basiliximab induction in low immunologic risk recipients. However in the high immunologic risk recipients, alemtuzumab was as

ing agents, clinical trials suggest more acute rejection episodes with IL-2RA. [11]

graft function and post-transplant infectious complications.

**4. Comparison of induction agents; clinical trials**

maintenance regimens that are used after induction.

efficacious but not superior to rATG.


**Table 1.** Immunosuppressive agents

Lymphocyte depleting agents such as rATG and Alemtuzumab primarily differ in their ability to deplete specific types of leukocytes. rATG contains polyclonal antibodies directed at thymic antigens and is more T-cell directed, and has little direct effect on B-cell depletion. Alemtuzu‐ mab contains a specific monoclonal antibody against CD52 which is expressed by both T and B cells as well as antigen presenting cells (APCs). The effect of Alemtuzumab mechanistically is directed at disabling several arms of the immune response, such as cell mediated (T-cell re‐ sponses) and humorally mediated (B-cells) responses, as well as affecting antigen presenting cells.

Existing studies however, fail to show greater efficacy of Alemtuzumab compared to rATG in clinical trials. However, case series and other small trials speak of the benefit of utilizing Alemtuzumab in refractory rejection, and in instances of mixed rejection where an agent with activity against both cell mediated and humoral responses are required. Finally, both Alem‐ tuzumab and rATG are agents of choice in patients that are considered higher risk such as African American race, repeat renal transplant, and sensitized patients with high panel reactivity to multiple HLA antigens.

The IL-2 receptor blocker, Basiliximab (Simulect), provides an option for induction therapy in those recipients with history of chronic infections with hepatitis B and or C and HIV, as Simulect is associated with less infectious complications post-transplant compared to lym‐ phocyte depleting agents. Less immunosuppression is also an attractive option for those patients who may not require potent induction therapy, such as recipients that are older, Caucasian, and those receiving living donor kidneys. When compared to lymphocyte deplet‐ ing agents, clinical trials suggest more acute rejection episodes with IL-2RA. [11]

Utilizing data from the United Network For Organ Sharing Data Registry, a recent study examining a large cohort of HIV recipients demonstrated higher risk of DGF and death censored graft loss with IL-2 receptor agents.[12] HIV patients also have higher rates of acute rejection with one recent study reporting a 31% incidence at one year.[7] Questions remain as to whether this is driven in part by choosing a less potent induction agent such as Simulect or issues with achieving therapeutic levels and/or avoiding toxic levels of maintenance drugs that interact with many anti-retroviral HIV medications. Thymo‐ globulin has been used in HIV recipients but can lower the CD4+ cell count dramatically, with recovery occurring as far out as two years. [13] Thymoglobulin use in HIV has also been associated with increased risk of infections requiring hospitalizations. Clearly, more studies are needed to weigh the risks and benefits of IL-2 receptor blockers on long-term graft function and post-transplant infectious complications.
