**5. Induction agents in sensitized patients**

**Rituximab (Rituxan)** is used in the following clinical scenarios; 1) ABO incompatible or positive cross match transplantation, 2) treatment of antibody mediated rejection and 3) desensitization by decreasing titers of preformed alloantibodies prior to transplantation. [15-17] It is an anti-CD20 monoclonal antibody directed against the CD20 antigen present on naive B-cell lymphocytes. It creates a rapid and sustained depletion of circulating naive B cells for approximately 6 months. Because of its specific activity against B-cells, Rituxan is used to target the humoral arm of the immune response by limiting B-cell activity and antibody production. Although widely used in transplantation, the efficacy of this drug when compared with other newer agents in treating humoral responses and decreasing alloantibody produc‐ tion remains to be seen.

introduction of calcineurin inhibitors (CNI) together with anti-proliferative agents like mycophenolate mofetil has resulted in major improvements in acute rejection rates and short term graft survival over the last three decades in kidney transplant recipients. However, long term graft outcomes have not improved dramatically, partly because of nephrotoxicities associated with the long term use of these drugs. In the year 2009, the initial maintenance regimen for 81% of kidney transplant recipients included tacrolimus and mycophenolate mofetil, per SRTR report, 2009. At one year post transplantation, 72.1% of the kidney transplant recipients remained on tacrolimus and mycophenolate moefetil and only 5.3% were receiving cyclosporine and mycophenolate mofetil. See Table 1 for common maintenance agents.

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Although the majority of US centers utilize CNI in combination with mycophenolate moefetil for maintenance, different dosing strategies for CNI, as well as new agents are being explored. A recently FDA approved medication for use in renal transplant, Belatacept, may have a promising role in widescale maintenance immunosuppression in the future. The basic pharmacology, clinical uses, major drug interactions and toxicity profiles of commonly used

Since their introduction in the 1970s, CNI have been the fundamental agents used for main‐ tenance immunosuppression in solid organ transplantation. They played a revolutionary role in transplantation by dramatically reducing the incidence of acute rejection episodes and prolonging allograft survival post-transplant. Cyclosporine and tacrolimus are the available CNI preparations with both having a unique role in maintenance. Currently, tacrolimus is more widely used compared to cyclosporine primarily because there is less nephrotoxicity associated with tacrolimus. Based on recent SRTR reporting, the use of cyclosporine has declined from 66.3% in 1998 to 5.7% in 2009. Notably the use of tacrolimus has increased from

The target protein of both tacrolimus and cyclosporine is CNI which is a calcium-dependent phosphatase. This enzyme is ubiquitously expressed and associates with calmodulin to form an active enzyme complex that dephosphorylates and activates the transcription factor, nuclear factor of activated T cells (NFAT), after T-cell receptor signaling. Dephosphorylated NFAT can then translocate to the nucleus and initiate transcription of several key cytokine genes (e.g., IL-2, IL-4, TNF- and IFN-γ). Blockade of calcineurin leads to decreased NFAT activity and transcription of critical cytokines affecting T cell function, activation and prolif‐ eration. Both these drugs bind to cytoplasmic proteins to mediate their action. Cyclosporin

Recommended starting dose for tacrolimus is 0.15-0.30 mg/kg, while that of cyclosporine is 6-10 mg/kg. For both drugs, total dose is administered in two divided doses. Intravenous

and new maintenance agents will be discussed in this section.

binds to cyclophilin, while tacrolimus binds to FKBP-12.

**6.1. Calcineurin inhibitors**

25.9% to 87.8%.

**6.3. Clinical use**

**6.2. Mechanism of action of CNI**

**Eculizumab,** is an anti C5 antibody which leads to terminal complement blockade and pre‐ vents formation of the membrane attack complex. Eculizumab protects allografts from comple‐ ment mediated injury which occurs when pathogenic alloantibodies directed against donor allograft tissue activate complement. Although not widely used yet, the Mayo Clinic published an open label study demonstrating that blockade of terminal complement decreases antibody mediated rejection in sensitized patients and allows for positive crossmatch transplantation to occur. Eculizumab reduced antibody mediated rejection (AMR) to 7.7% compared to historical control groups where the incidence of AMR was 30-40% in the first few months.[18] Compared to long-standing protocols widely used for sensitized patients (e.g, plasmapharesis, IVIG and Rituximab), Eculizumab looks more promising in decreasing AMR rates.

**Bortezomib,** is a proteasome inhibitor that has specific activity against high affinity antibody producing plasma cells (PC), and induces apoptosis of circulating PC (a small percentage of the PC population) but in addition is able to effect PC that remain in survival niches such as the bone marrow and spleen.[19] Besides affecting the humoral arm, Bortezomib has multiple effects on immune cell function. Proteosome inhibition prevents the function of NFκB, an important transcription factor that transcribes multiple genes important for immune cell function and disrupts the regulation of cell cycle proteins, cell survival signals and expression of adhesion molecules.[20, 21] In transplantation it is used to treat refractory antibody mediated rejection as well as to reduce the burden of preformed alloantibodies to facilitate transplantation of highly sensitized individuals. Studies and case series evaluating the use of Bortezomib for desensitization and treatment of acute rejection have been mixed.[22-25] Although used by some centers, it has not been widely adopted into practice.
