*2.6.2. Side effects*

agent" is used to describe the immunosuppressive drugs that are used, or were developed for use, in combination with a calcineurin inhibitor to enhance the potency of the immunosup‐ pressive protocol, as measured by a decreased incidence of acute rejection episodes [46].

Azathioprine inhibits purine metabolism. Following exposure to nucleophiles such as glutathione, azathioprine is cleaved to 6-mercaptopurine, which in turn is converted to additional metabolites that inhibit *de novo* purine synthesis. 6-thio-IMP, a fraudulent nucleo‐ tide, is converted to 6-thio-GMP and finally to 6-thio-GTP, which is incorporated into DNA. Cell proliferation is thereby inhibited, impairing a variety of lymphocyte functions. Azathio‐ prine appears to be a more potent immunosuppressive agent than 6-mercaptopurine, which may reflect differences in drug uptake or pharmacokinetic differences in the resulting

The major side effect of azathioprine is bone marrow suppression, including leukopenia (common), and thrombocytopenia (less common). Other important adverse effects include increased susceptibility to infections (especially varicella and herpes simplex viruses) and

There are two anti–IL-2R preparations for use in clinical transplantation: daclizumab and basiliximab. These are used for prophylaxis of acute organ rejection in adult patients. Basilix‐ imab is considered a chimeric antibody, because it consists of approximately 70% human and 30% murine proteins. This agent has low immunogenicity potential due to the incorporation of human protein sequences. Daclizumab consists of 90% human and 10% murine components. The effectiveness of daclizumab is comparable to that of basiliximab, with an adverse-effect

Basiliximab binds with high affinity to the alpha subunit of the IL-2 receptor, also known as CD25, where it acts as a receptor antagonist. The antagonistic effect on the IL-2 receptor prevents T-cell activation and subsequent proliferation without causing lysis or cell destruc‐ tion. Daclizumab, like basiliximab, is a nondepleting monoclonal antibody that acts as an antagonist at the CD25 subunit of T cells and received marketing approval in 1997 for induction therapy in renal transplant recipients. In Phase III trials, the half-life of daclizumab was 20 days, resulting in saturation of the IL-2Rα on circulating lymphocytes for up to 120 days after transplantation. In these trials, daclizumab was used with maintenance immunosuppression regimens (CsA, azathioprine, and steroids; CsA and steroids). Subsequently, daclizumab was successfully used with a maintenance triple-therapy regimen—either with CsA or TRL, steroids, and MMF substituting for azathioprine. In the Phase III trials, the half-life of basilix‐

*2.5.1. Mechanism of action*

316 Current Issues and Future Direction in Kidney Transplantation

metabolites [1,45].

*2.5.2. Side effects*

hepatotoxicity [1].

*2.6.1. Mechanism of action*

**2.6. Anti-IL-2 receptor (Anti-CD25) antibodies**

profile comparable to that seen with placebo [1,46].

No cytokine-release syndrome has been observed with these antibodies, but anaphylactic reactions can occur. Although lymphoproliferative disorders and opportunistic infections may occur, as with the depleting antilymphocyte agents, the incidence ascribed to anti-CD25 treatment appears remarkably low. No significant drug interactions with anti–IL-2-receptor antibodies have been described [46,47].
