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

Depleting Agents

The majority of induction therapies exert their action through the depletion of lymphocytes.[2,4,18] In general, these agents work by causing T-cell lysis or clearance, resulting in the depletion of circulating lymphocytes. Administration of depleting agents is often accompanied by an extensive release of cytokine as a response to cell destruction, and this may cause significant adverse events. Reconstitution of the immune system can take up to a year, and full recovery is questionable, especially in elderly patients.[4] Due to the nature of inducing immunosuppression, the use of depleting proteins is generally associated with an increased risk of infectious complications and malignancy beyond that of standard immunosuppression.

Antithymocyte Globulins

Pharmacology. Two antithymocyte globulins are used for induction therapy in the United States. Antithymocyte globulin preparations are prepared by immunizing either horses or rabbits with lymphoid tissue and then harvesting and stabilizing the resultant immune serums.[19] The use of antithymocyte globulins leads to the depletion of thymus-produced lymphocytes through an array of mechanisms (e.g., opsonization, phagocystosis, lysis, removal by the reticuloendothelial system), resulting in profound interference with both the cellular and humoral immune responses.

T-cell destruction by antithymocyte globulin (equine) occurs through complement-dependent lysis after the antibody preparation binds to a variety of cell-surface markers, including CD2, CD3, CD4, CD8, CD11a, and CD18.[19–21] Destruction of lymphocytes occurs systemically and within the thymus and spleen.[9,21]

Possible mechanisms by which antithymocyte globulin (rabbit) induces immunosuppression in vivo include T-cell clearance from the circulation and modulation of T-cell activation, homing, and cytotoxic activities.[19,22] In vitro, antithymocyte globulin (rabbit) mediates T-cell suppressive effects via inhibition of proliferative responses to several mitogens. Antithymocyte globulin (rabbit) is thought to induce T-cell depletion and modulation through multiple mechanisms, including Fc-receptor-mediated complement-dependent lysis, opsonization and phagocytosis by macrophages, and immunomodulation, leading to long-term depletion via apoptosis and antibody-dependent T-cell-mediated cytotoxicity.[22] Regardless of its mechanism, immune reconstitution after the administration of antithymocyte globulin (rabbit) may take several months.[9,19,22] One analysis found that T-cell recovery after depletion induced by antithymocyte globulin (rabbit) is associated with an expansion of cell subsets that are linked to suppressor function.[23] This mechanism promotes the functioning of immunoregulatory T cells, resulting in long-term immunosuppression.

Dosage. As an induction agent, antithymocyte globulin (equine) is administered at a dosage of 10–30 mg/kg i.v. for 4–14 days and is typically infused over four to six hours per dose.[2,9,19,21] Abbreviated courses of therapy are often preferred due to high costs and the multiple barriers related to outpatient administration (e.g., need for a high-flow vein, long infusion times).[20] To help combat these barriers, many centers that use antithymocyte globulin (equine) have adopted a 15-mg/kg/day dosing regimen, with discontinuation occurring once maintenance therapy has been optimized.[20]

Although antithymocyte globulin (rabbit) is not labeled for induction therapy, it is used for this purpose more than any other agent.[8,19] When used for induction, doses range from 1 to 4 mg/kg/day for 3–10 days after transplantation. The most common dosage strategy is 1.5 mg/kg/day for 3–5 days.[9,19,22] Regardless of the dosing strategy, the initial dose of an induction agent should be administered in the operating room before allograft perfusion to prevent ischemic reperfusion injury.[24] Dosing adjustments are recommended in patients with myelosuppression. For example, doses may be halved or administered at less frequent intervals if the platelet count drops to 50,000–75,000 platelets/mm3 or the white blood cell count drops to 2,000–3,000 cells/mm3. Discontinuation of the drug should be considered if these values drop below 50,000 platelets/mm3 or to <2,000 white blood cells/mm3.[22]

Adverse Effects. Short-term adverse effects of the antithymocyte globulins are generally related to either cytokine release or myelosuppression. The adverse effects related to cytokine release include fever (63% and 63%), chills (57% and 43%), headache (40% and 35%), nausea (37% and 28%), diarrhea (37% and 32%), malaise (13% and 4%), dizziness (9% and 25%), and pain (46% and 43%) from antithymocyte globulin (rabbit) and antithymocyte globulin (equine), respectively.[19] Premedication with antihistamines and acetaminophen is highly recommended to reduce the overall number and severity of these reactions. Myelosuppression, specifically leukopenia and thrombocytopenia, may occur in up to 30% of patients treated with either preparation.[19]

Anaphylactic reactions secondary to the administration of one of these antithymocyte globulins are rare but possible.[19] The manufacturer of antithymocyte globulin (equine) recommends a skin test to detect the potential for any allergic reactions before the initial dose is given. It should be noted that a negative result on a skin test does not translate to freedom from risk for a patient. There is currently no recommendation for skin testing before initiating antithymocyte globulin (rabbit). The strong recommendation for a skin test makes the use of antithymocyte globulin (equine) more difficult when compared with the other antibody preparations. After the initial dose of either preparation, the injection site should be monitored every 15 minutes for the first hour.[2,21] Special consideration should be given to those patients who have previously received an antithymocyte globulin or spent an excessive amount of time with horses or rabbits when considering the use of antithymocyte globulin (equine) or antithymocyte globulin (rabbit), respectively, due to the possibility of preformed antibodies to those specific animals.[25]

Clinical Efficacy. Brennan et al.[26] conducted an analysis of patients receiving antithymocyte globulin (rabbit) 1.5 mg/kg/day (n = 48) versus antithymocyte globulin (equine) 15 mg/kg/day (n = 24) as induction therapy for at least seven days, with the initial dose being administered during transplantation. A total of 72 patients were followed for 12 months while on maintenance cyclosporine microemulsion, prednisone, and either mycophenolate mofetil or azathioprine. At the end of one year, biopsy-proven acute rejection (BPAR) occurred in only 4% of patients treated with antithymocyte globulin (rabbit) and 25% of patients treated with antithymocyte globulin (equine) (p = 0.014). Graft survival at 12 months was 98% in the antithymocyte globulin (rabbit) group and 83% in the antithymocyte globulin (equine) group (p = 0.02). Leukopenia was noted to occur at a much higher rate (56%) in the antithymocyte globulin (rabbit) group compared with the antithymocyte globulin (equine) group (4%) (p < 0.0001). Despite its higher frequency of leukopenia, antithymocyte globulin (rabbit) was associated with lower overall rates of infection. More importantly, the frequency of cytomegalovirus (CMV) disease was also significantly lower with antithymocyte globulin (rabbit) versus antithymocyte globulin (equine) (12.5% versus 33.3%, p = 0.025).

Ten-year follow-up results from this study revealed that the composite endpoint of event-free survival remained higher for the antithymocyte globulin (rabbit) group compared with the antithymocyte globulin (equine) group (48% versus 29%, p = 0.011).[27] Further, acute rejection was more prevalent in the antithymocyte globulin (equine) group (42%) compared with the antithymocyte globulin (rabbit) group (42% versus 11%, p = 0.004). The risk of CMV disease remained lower in the antithymocyte globulin (rabbit) group (13% versus 33%, p = 0.056). There was no difference in the rates of posttransplantation malignancy at 10 years. The authors also evaluated quality-adjusted life years (QALYs) and noted that 0.53 QALY was gained from the use of antithymocyte globulin (rabbit). The original analysis, along with this lengthy follow-up, clearly demonstrated antithymocyte globulin (rabbit) as the antithymocyte globulin preparation of choice in renal transplant recipients.

Alemtuzumab

Pharmacology. Alemtuzumab is an anti-CD52, humanized, monoclonal antibody labeled for use in the treatment of B-cell chronic lymphocytic leukemia.[28,29] CD52 is present on virtually all B cells and T cells, as well as macrophages, NK cells, and some granulocytes. When the alemtuzumab antibody binds to CD52, it triggers an antibody-dependent lysis of these cells. The depletion of lymphocytes is so marked that it takes several months or up to one year postadministration for a patient's immune system to be fully reconstituted.[28,29]

Dosage. Currently, there is no consensus regarding the dosing of alemtuzumab for use in induction therapy. Doses of 20–30 mg on the day of transplantation and again on postoperative day 1 or 4 have been shown to be effective.[30–34] The use of a single intraoperative dose of 30 mg is being evaluated with the hypothesis that it will be both as efficacious and better tolerated than the previously studied regimens.[28,29]

Adverse Effects. Alemtuzumab's mechanism of depletion is so profound that its adverse-effect profile occurs frequently and with a high level of severity. Adverse effects associated with alemtuzumab use include neutropenia (70%), thrombocytopenia (52%), anemia (47%), nausea (54%), vomiting (41%), diarrhea (22%), headache (24%), dysesthesias (15%), dizziness (12%), and autoimmune hemolytic anemia (<5%).[19,28,29] These adverse effects warrant the administration of corticosteroids, acetaminophen, and an antihistamine infusion in an attempt to decrease both the number and severity of the events.

One potential concern of the profound immune depletion seen after alemtuzumab induction is the potential response associated with immune reconstitution. Although data are not available in the setting of renal transplantation, a study involving patients with multiple sclerosis demonstrated a profound IL-21-driven autoimmune response after lymphocyte depletion resulting from alemtuzumab.[35] Further characterization of the immune system after alemtuzumab use in renal transplant recipients is needed to understand the full impact of using this agent as induction therapy.

Clinical Efficacy The use of alemtuzumab as an induction agent has become an increasingly popular choice due to its overwhelming effects as a depleting antibody.[30,31,36–39] At this time, a few randomized controlled trials have evaluated its efficacy and safety. Vathsala et al.[40] completed the first such trial with 30 patients. Treatments included 20 mg of alemtuzumab on posttransplantation day 0 with maintenance immunosuppression consisting of low-dose cyclosporine (goal trough concentration, 90–110 ng/mL) (n = 20) versus high-dose cyclosporine (goal trough concentration, 180–225 ng/mL), azathioprine, and corticosteroids (n = 10). At the end of six months, there were no obvious differences in rates of graft and patient survival, BPAR, and treatment failure. Infectious complications were also similar.

Ciancio et al.[41] performed a randomized analysis of three separate treatment groups, with 30 patients in each group: (1) antithymocyte globulin (rabbit) 1 mg/kg/day for the first week postoperatively, (2) alemtuzumab 0.3 mg/kg on the day of surgery and four days later, and (3) daclizumab 1 mg/kg during surgery and every two weeks thereafter for five total doses. All patients in the antithymocyte globulin (rabbit) and daclizumab groups received tacrolimus (goal trough concentration, 8–10 ng/mL), mycophenolate mofetil 1 g twice daily, and long-term corticosteroid therapy. The alemtuzumab-treated group was maintained on tacrolimus (goal trough concentration, 4–7 ng/mL) and mycophenolate mofetil 500 mg twice daily and was tapered off steroids within a week after surgery. After 12 months, no differences in the rates of BPAR, patient and graft survival, infectious complications, and posttransplantation diabetes were observed.

A prospective, open-label analysis compared 8 patients treated with antithymocyte globulin (rabbit) and receiving a maintenance regimen of tacrolimus, mycophenolate mofetil, and corticosteroids with 11 alemtuzumab-treated patients receiving tacrolimus alone for maintenance of immunosuppression.[42] Antithymocyte globulin (rabbit) 1.5 mg/kg was administered daily for four days, with the first dose given before transplantation. Alemtuzumab-treated patients received a one-time alemtuzumab dose of 30 mg before kidney reperfusion. At 12 months, each group had similar rates of graft survival, BPAR, and infectious complications.

Muromonab-CD3

Muromonab-CD3, a murine monoclonal antibody with activity against the CD3 cell-surface antigen of T cells, received marketing approval in 1986 and was used extensively for the treatment of acute cellular rejection in renal transplantation.[43] This anti-CD3 antibody was the first biological agent used in clinical medicine and has been associated with significant and sometimes life-threatening adverse effects. The antibody's murine composition allows a recipient to produce antimouse antibodies and mount a substantial immune response to drug administration. Due to declining worldwide use and the expense associated with manufacturing muromonab-CD3, the manufacturer discontinued production of the agent. The current supply of muromonab-CD3 is expected to last through the end of 2010. Once these supplies have been exhausted, muromonab-CD3 will no longer be available for clinical use. Thus, the use of muromonab-CD3 in clinical practice is not discussed herein.

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