Induction Therapy With Thymoglobulin After Heart Transplantation

CARDIAC REJECTION

Induction Therapy With Thymoglobulin After Heart Transplantation: Impact of Therapy Duration on Lymphocyte Depletion and Recovery, Rejection, and Cytomegalovirus Infection Rates Sorel Goland, MD, Lawrence S. C. Czer, MD, Bernice Coleman, PhD, Michele A. De Robertis, RN, James Mirocha, MS, Kaveh Zivari, BS, Ernst R. Schwarz, MD, PhD, Robert M. Kass, MD, and Alfredo Trento, MD Background: This retrospective single-center study compared lymphocyte depletion in 144 heart transplant recipients using 2 different induction protocols with Thymoglobulin (Genzyme Transplant, Cambridge, MA). Methods: Thymoglobulin (1.5 mg/kg) was given to 105 patients for 7 days (Thymo7) and 39 patients for 5 days (Thymo5). Results: Patient clinical characteristics were similar except that the Thymo7 group had a higher prevalence of women (33% vs 15%, p ⫽ 0.04), gender mismatch (35% vs 19%, p ⫽ 0.07), donor African American race (19% vs 2%, p ⫽ 0.008), older donor age (35 ⫾ 13 vs 31 ⫾ 12, p ⫽ 0.08), and higher pre-transplant creatinine (1.43 ⫾ 0.67 vs 1.25 ⫾ 0.48 mg/dl, p ⫽ 0.095). Seventy-five percent of the Thymo7 group reached target (absolute lymphocyte count ⱕ200) and 42% at 21 days (p ⫽ 0.002). Thymo7 patients had significantly lower rejection rates (ⱖ1B) within the first year (7% vs 22%, p ⫽ 0.02). No humoral rejection occurred. At 1 year, freedom from rejection was 93% in the Thymo7 group vs 80% in the Thymo5 group (p ⫽ 0.007), and cytomegalovirus disease (9% and 5%, p ⫽ 0.5) and bacterial infection (26% vs 32%, p ⫽ 0.5) were similar. One-year actuarial survival was 92% ⫾ 3% in the Thymo7 and 100% in the Thymo5 group (p ⫽ 0.07), and at 3 years, 85 ⫾ 4% and 90 ⫾ 6%, respectively (p ⫽ 0.4). Conclusions: Both Thymoglobulin regimens were well tolerated. The 7-day treatment led to more efficient and prolonged lymphocyte depletion and significantly less rejection at 1 year, without an increase in cytomegalovirus infection rate. J Heart Lung Transplant 2008;27:1115-21. Copyright © 2008 by the International Society for Heart and Lung Transplantation.

The effectiveness of cytolytic induction phase therapy after heart transplantation (HTx) continues to be debated.1 Historically, published reports have demonstrated favorable short-term outcomes with or without the use of induction therapy, which continues to fuel the debate on the cost-benefit of this treatment.2 Although induction therapy with anti-lymphocyte antibodies has failed to show advantages in patient survival, it is used in approximately 40% to 50% of patients undergoing HTx.

From the Divisions of Cardiology and Cardiothoracic Surgery, CedarsSinai Medical Center, and the University of California, Los Angeles School of Medicine, Los Angeles, California. Submitted January 1, 2008; revised May 17, 2008; accepted July 1, 2008. Reprint requests: Lawrence S. C. Czer, MD, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Rm 6215, Los Angeles, CA 90048. Telephone: 310-423-3851. Fax: 310-423-0127. E-mail: Lawrence.Czer@ cshs.org Copyright © 2008 by the International Society for Heart and Lung Transplantation. 1053-2498/08/$–see front matter. doi:10.1016/ j.healun.2008.07.002

An advantage of induction therapy is the avoidance of nephrotoxic calcineurin inhibitors early after surgery.3–5 The disadvantage of using these powerful immunosuppressants is the possibility of increased adverse events, including the incidence of infections in the early phase6 and malignancies in the long-term.7,8 No published reports, to our knowledge, have compared different regimens of polyclonal anti-thymocyte globulin (ATG) on cellular rejection. Moreover, the influence of Thymoglobulin (Genzyme Transplant, Cambridge, MA) on humoral rejection in patients after HTx has not been evaluated. Therefore, the purpose of this study was to review our center’s experience with Thymoglobulin, comparing 5-day or 7-day post-HTx induction strategies, and evaluate the effectiveness of lymphocyte depletion and recovery, rejection, and cytomegalovirus (CMV) disease rates. METHODS We have used Thymoglobulin induction therapy since 2000. A total of 144 HTx recipients received Thymo1115

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globulin (1.5 mg/kg): 105 for 7 days (Thymo7) and 39 for 5 days (Thymo5). The Thymo7 protocol was used in recipients at high risk for rejection (African American recipients, patients aged younger than 60 years, multiparous women, patients with panel reactive antibody ⬎ 10%, positive donor/recipient cross match, and multiorgan transplant recipients) as well as in patients with impaired renal function. Maintenance immunosuppressive therapy included cyclosporine or tacrolimus, azathioprine or mycophenolate mofetil, and prednisone. Cyclosporine was started after completion of Thymoglobulin (on day 5 or 7) with the aim of achieving a level of 200 to 300 ng/ml. Tacrolimus was used with the target of 10 to 20 ng/ml. Mycophenolate mofetil was used routinely since 2000 as part of the initial post-Htx regimen in most patients. Azathioprine was administered at 2 mg/kg daily and adjusted for the white blood cell and platelet counts. Methylprednisolone was first given at a dose of 125 mg every 8 hours for 3 to 5 doses. Prednisone was then initiated at 0.5 mg/kg daily and tapered to 0.1 mg/kg daily over 3 months. Specimens from the first 3 biopsies were routinely stained for immunoglobulin and complement. The postHtx surveillance protocol and pathology assessment has been described elsewhere.9 All patients in the 2 groups received the same CMV prophylaxis. Seropositive recipients (recipient CMV immunoglobulin [Ig] G positive; moderate risk) received intravenous (IV) ganciclovir for 2 weeks or while in the hospital (5 mg/kg daily and adjusted for renal function), then acyclovir for up to 6 months. Seronegative recipients (recipient CMV IgG negative) with seropositive donor (donor CMV IgG positive) or a donor who received blood products unscreened for CMV (high-risk) received ganciclovir for 2 weeks or while in the hospital (5 mg/kg IV daily, adjusted for renal function), then valganciclovir for up to 1 year after HTx, adjusted for renal function. Seronegative recipients (recipient CMV IgG negative) with a seronegative donor (donor CMV IgG negative) and no blood products (low risk) received acyclovir for up to 6 months after HTx. We repeated prophylaxis for any rejection episode requiring Solu-Medrol (Pharmacia & Upjohn division of Pfizer, New York, NY) or an increase in prednisone dosage. We obtained CMV polymerase chain reaction every 6 months after HTx. Results for continuous variables were presented as mean ⫾ standard deviation and for categoric variables as frequency (percentage). Categoric variables were compared across groups by chi-square or Fisher exact tests. Kaplan-Meier method was applied for the timerelated events of rejection or death. The log-rank test was used to compare survival across groups. All statistical tests were 2-sided, and a significance level

The Journal of Heart and Lung Transplantation October 2008

of 0.05 was used throughout. Statistical analyses were performed using the SAS 9.1 software (SAS Institute Inc, Cary, NC). RESULTS Clinical Characteristics The clinical characteristics (Table 1) in both groups were similar, with the exception of a higher prevalence of women (33% vs 15%, p ⫽ 0.04), gender mismatch (35% vs 19%, p ⫽ 0.07), recipient African American race (19% vs 2%, p ⫽ 0.008), older donor age (35 ⫾ 13 vs 31 ⫾ 12 years, p ⫽ 0.08) and higher baseline creatinine level (1.43 ⫾ 0.67 vs 1.25 ⫾ 0.48 mg/dl, p ⫽ 0.09) in the Thymo7 group. The D⫹/R⫺ CMV mismatch was 33% of patients within the Thymo5 group vs 8% in the Thymo7 group (p ⫽ 0.3). The mean total dose of Thymoglobulin was significantly lower in Thymo5 patients than in Thymo7 (442 ⫾ 124 vs 623 ⫾ 165 mg, p ⬍ 0.0001). The mean daily dose was 1.2 vs 1.1 mg/kg (p ⫽ 0.39), respectively. There was a trend toward a smaller number of patients who were taking prednisone at 1 year compared with Thymo5 (71% vs 75%, p ⫽ 0.09). Moreover, the mean dose of prednisone in patients who received prednisone at 1-year after HTx was significantly lower in the Thymo7 group (10 ⫾ 8 mg vs 15 ⫾ 12, p ⫽ 0.02). Cyclosporine was used in 66% of patients in the Thymo5 group vs 28% in the Thymo7 group (p ⬍ 0.0001), and the rest of the patients received tacrolimus. Effect on Lymphocyte Depletion and Recovery Lymphocyte count decreased rapidly in both groups but was more pronounced and persisted longer in the Thymo7 group (Figure 1). By 7 days, 62% of Thymo7 recipients reached the target, absolute lymphocyte count of 200 per ␮l, compared with 37% in the Thymo5 group (p ⫽ 0.009). Lymphocyte count recovery of 1000 per ␮l was achieved within 100 days in one-third of each group. The white blood cell count was significantly lower at 7 days in the Thymo7 group and remained similar after the first week (Figure 2). A decrease in the mean platelet count was found at 7 days and was similar in both groups (Figure 3). Effect on Creatinine Levels, Rejection, and Infection Rates The serum creatinine level at 7 days after HTx improved in both groups, from 1.25 to 1.02 mg/dl; (p ⬍ 0.001) in Thymo7 and from 1.43 to 1.09 mg/dl (p ⬍ 0.001) in Thymo5. Recipients treated with Thymo7 had significantly lower rejection rates (ⱖ1B) within the first year (7% vs 22%, p ⫽ 0.02). The 1-year freedom from rejection was 93% in the Thymo7 group and 80% in the Thymo5 group (p ⫽ 0.007; Figure 4). No humoral

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Table 1. Comparison of Baseline and Post-transplant Characteristicsa by Duration of Thymoglobulinb Treatment Characteristics Pre-op characteristics Recipient age, years Donor age, years Recipient female, % Donor female, % Gender mismatch, % African American recipient, % Ischemic cardiomyopathy UNOS status 1 Hypertension Diabetes mellitus Baseline creatinine, mg/dl Intra-op and post-op characteristics Ischemic time, min Re-op for bleeding Post-op creatinine, mg/dl Post-op peak creatinine, mg/dl Dialysis Mechanical ventilation ⱖ48 hours In-hospital infection Pneumonia Sternal infection Post-op infection ⱕ1 year Post-op hemodynamics, LV function Cardiac output at 1 year, liters/min PCWP at 1 year, mm Hg mPAP at 1year, mm Hg PVR at 1 year, WU TPG at 1 year mm Hg EF at 1 year, % EF at 3 years, %

Thymo5 (n ⫽ 39)

Thymo7 (n ⫽ 105)

p-valuec

56 ⫾ 12 31 ⫾ 11 15 15 20 2 19 (46) 13 (32) 17 (41) 2 (5) 1.25 ⫾ 0.48

56 ⫾ 11 35 ⫾ 12 32 34 35 19 46 (45) 36 (35) 42 (41) 1 (1) 1.43 ⫾ 0.67

0.3 0.08 0.04 0.02 0.08 0.008 0.9 0.9 ⬎0.9 0.2 0.09

142.4 ⫾ 43.1 6 (15) 1.02 ⫾ 0.63 1.6 ⫾ 0.6 1 (2) 7 (17) 12 (29) 0 (0) 2 (5) 13 (32)

155.0 ⫾ 45.1 13 (13) 1.09 ⫾ 0.55 2.1 ⫾ 1.3 17 (17) 25 (24) 32 (31) 5 (5) 2 (2) 27 (26)

0.1 0.8 0.2 0.07 0.02 0.4 ⬎0.9 0.3 0.3 0.5

5.4 ⫾ 1.1 12.6 ⫾ 5.5 23.8 ⫾ 7.1 2.7 ⫾ 1.2 11.2 ⫾ 3.3 60.5 ⫾ 7.3 61.3 ⫾ 3.2

5.80 ⫾ 1.4 13.1 ⫾ 5.1 22.5 ⫾ 6.8 1.7 ⫾ 0.9 9.4 ⫾ 4.3 61.0 ⫾ 8.1 62.3 ⫾ 7.0

0.2 0.7 0.5 0.09 0.06 0.8 0.8

EF, ejection fraction; LV, left ventricular; mPAP, mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; Thymo5, 5-day course of Thymoglobulin treatment; Thymo7, 7-day course of Thymoglobulin treatment; TPG- transpulmonary gradient; UNOS, United Network for Organ Sharing. a Continuous data are presented as the mean ⫾ standard deviation, and categoric data as number or percentage (%). b Genzyme Transplant, Cambridge, Massachusetts. c Comparison between the 2 groups.

rejection was found in either group. No significant difference in CMV disease rate within the first year was observed between the 2 groups (9% and 5%, p ⫽ 0.5). The in-hospital infection rates, including pneumonia and wound infection, were similar during the first year, as was the incidence of bacterial infection (32% vs 26%, p ⫽ 0.5; Table 1). Effect on Short-term and Intermediate-term Survival and Complications The 30-day mortality rate was similar in the Thymo7 and Thymo5 groups (2.9% vs 0%, p ⫽ 0.6). Survival estimates at 1 year were 92 ⫾ 3% in the Thymo7 and 100%

in the Thymo5 group (p ⫽ 0.07), and at 3 years, 85 ⫾ 4% in the Thymo7 and 90 ⫾ 6% in the Thymo5 groups (p ⫽ 0.4). Twenty-four patients died during a median follow-up of 2.8 years (range, 0 –5.8 years). There were 3 early deaths (1 within 30 days in the Thymo7 group; 2 from infection, and 1 from renal failure), and 21 during the later follow-up period. The causes of death were rejection in 1 (4%), cardiac in 5 (21%), infection in 4 (17%), malignancy in 1 (4 %), allograft vasculopathy in 5 (21%), renal failure in 2 (8%), and other causes in 6 (25%). Deaths in the Thymo7 group (n ⫽ 21) were caused by rejection in 1 patient, cardiac in 5, infection in 4, malignancy in 1, allograft vasculopathy in 3, renal

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Figure 1. Changes in the absolute lymphocyte count by Thymoglobulin (Genzyme Transplant, Cambridge, MA) treatment course. The p-values are for comparison between the 5-day (white bars) and 7-day course (black bars). ␮l, microliter.

failure in 2, and other causes in 5 patients. Causes of the 3 deaths in the Thymo5 group were allograft vasculopathy in 2 patients and other causes in 1. With regard to infection as a cause of death, no differences were found between the groups (p ⫽ 0.53). During follow-up, 7 of 144 (5%) patients were found to have malignancy: 2 had renal cell carcinoma, 3 had skin cancer, 1 had lymphoma, and 1 had resolved posttransplant lymphoproliferative disease. No significant differences were observed between the groups (p ⫽ 0.35). No serious side effects were observed; in 8% of patients unexplained fever during the first 72 hours could be attributed to Thymoglobulin treatment. There was no significant difference between Thymo5 and Thymo7 with regard to allograft vasculopathy (5% vs 9%, p ⬎ 0.9) at 3 years after HTx. A trend towards better rest hemodynamics (pulmonary vascular resistance and transpulmonary pressure gradient) at 1 year after HTx was obtained (Table 1) with Thymo 7.


Figure 3. Changes in the platelet count by Thymoglobulin (Genzyme Transplant, Cambridge, MA) treatment course. The p-values are for comparison between the 5-day (white bars) and 7-day (black bars) course. ␮l, microliter.

prevent allograft rejection. Induction immunotherapy with anti-lymphocyte antibodies includes the murine monoclonal antibody muromonab-CD3, ATG, and anti-interleukin-2 receptor antibodies. Retrospective studies have suggested that cytolytic therapy reduces the risk of early rejection10 –13 but has potential adverse effects, including increased incidence of infection and malignancy.7,8 Use of induction with the monoclonal antibody OKT3 has declined during the past several years because of poor tolerability. Moreover, the Randomized Multicenter Comparison of Basiliximab and Muromonab (OKT3) in Heart Transplantation (SIMCOR) study did not show differences in efficacy outcomes when OKT3 was compared with induction with the newer anti-CD25 antibody agent basiliximab.14 Polyclonal antibodies such as ATG have been used for a longer time, and the efficacy of ATG is thought to correlate with its ability to deplete T lymphocytes. The polyclonal nature of ATG results in important

DISCUSSION The growing success of HTx is closely related to improvements in immunosuppressive regimens that

Figure 2. Changes in the white blood cell (WBC) by Thymoglobulin (Genzyme Transplant, Cambridge, MA) treatment course. The p-values are for comparison between the 5-day (white bars) and 7-day (black bars) course. ␮l, microliter.

Figure 4. The Kaplan-Meier method was used to compare freedom from acute cellular rejection (ⱖ1B) within 1 year after heart transplantation in patients who received Thymoglobulin (Genzyme Transplant, Cambridge, MA) treatment for 5 days (Thymo5, solid line) and 7 days (Thymo7, dashed line), with p ⫽ 0.01 for the comparison between the groups.


varied effects on the immune system, such as T-cell depletion; T-cell activation and apoptosis; inducing apoptosis in B-cell lineages; interference with dendritic cell functional properties; and the induction of regulatory T cells and natural killer T cells. As a consequence, ATG might lead to inducing an immunologic tolerance that is purported to be the key to successful transplantation. Tolerance is now known to be assured by multiple subtypes of regulatory and suppressor T lymphocytes.15 Lopez et al16 reported for the first time that ATG, but not the anti-CD52 (alemtuzumab) or the interleukin-2R antagonists, causes rapid and sustained expansion of regulatory T cells when cultured with human peripheral blood lymphocytes. These promising results suggest that ATG may not only promote expansion/generation of regulatory T cells but may also be useful in the future for cellular therapy in autoimmunity and transplantation. The only large retrospective study, by Higgins et al,2 attempted to evaluate the impact of induction therapy in 6,553 post-HTx patients. No induction therapy was given to 65%, and 30% received induction with different agents, most with OKT-3.2 These authors have found that only recipients at high risk for rejection can benefit from induction therapy. The incidence of humoral rejection has not been reported. Moreover, Thymoglobulin has only been used in 1.2% of patients. No other studies have compared a Thymoglobulin regimen with a protocol not using induction. In this report, we described our experience with 2 induction regimens (5- or 7-day course) of Thymoglobulin. We found that patients on both regimens had similar survival. However, the 7-day treatment resulted in more efficient and prolonged lymphocyte depletion and had a favorable effect on renal function during hospitalization. The freedom from rejection at 1 year was better in recipients treated with Thymo7. No episodes of humoral rejection were observed with either of the regimens. The CMV infection and inhospital bacterial infection rates were low and similar in both groups. In addition, we found a trend toward a smaller number of patients who were taking prednisone at 1 year in the Thymo7 group compared with Thymo5 patients, and the mean dose of prednisone in patients who received prednisone at 1 year after HTx was significantly lower in the Thymo7 group. Reviewing our previous published data on OKT-3, we reported a high incidence of humoral rejection, in which 54 of 134 recipients (40%) had 1 episode of humoral rejection compared with the current study using Thymoglobulin, where no humoral rejection was documented by immunofluorescence.9 This has been supported by Casarez et al,17 who reported humoral rejection in 32% of allografts in a pediatric population

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without induction therapy. The absence of humoral rejection in our study may be attributed to the treatment with Thymoglobulin. The effect of newer agents for induction therapy on cellular rejection have been compared with ATG. Brennan et al18 prospectively compared short courses of Thymoglobulin and basiliximab in renal transplant recipients and showed a significantly lower incidence of acute cellular rejection and rejection that required treatment with an antibody in those treated with Thymoglobulin.18 In a randomized controlled trial of daclizumab vs ATG induction for lung transplantation, Mullen et al19 found no significant difference in the number of acute or chronic rejections between groups, with a trend toward a delay in time to first acute rejection with daclizumab therapy. Carlsen et al10 reported lower rejection rates with Thymoglobulin during the first 3 months compared with daclizumab, without long-term benefit after HTx. Recently, Falman et al20 demonstrated that rabbit ATG was more effective than basiliximab for prevention of rejection episodes after HTx. Both induction agents provided similar safety profile. Comparing Thymoglobulin with ATG-Fresenius,13 the use of both preparations has been found to result in low rejection rates in the first 3 months; however at 1 year, Thymoglobulin demonstrated some benefit, with 77% freedom from rejection. In the current study, we reported freedom from grade ⱖ1B rejection (93% with 7 days of Thymoglobulin and 80% with 5 days), although a higher dose (2.5 mg/kg/day) compared with our protocol (1.5 mg/kg/ day) has been used. A study by Schnetzler et al12 using higher doses of Thymoglobulin (2.5 to 3.5 mg/kg/day) showed similar freedom from rejection at 1 year of about 88%. Delgado et al3 have studied the safety and efficacy of basiliximab compared with Thymoglobulin with delayed initiation of cyclosporine in patients with renal dysfunction undergoing HTx. Cyclosporine immunosuppression was started on post-operative Day 5 in the basiliximab-treated patients but was started earlier (within 5 days) than our study with Thymoglobulin patients. Either strategy used to delay cyclosporine initiation resulted in similar benefit in renal function at 1 week (p ⫽ 0.069), 1 month (p ⫽ 0.39), or 6 months (p ⫽ 0.24) after HTx. The use of Thymoglobulin resulted in fewer episodes of cellular rejection within the 6-month follow-up period compared with basiliximab. In the current study improvement in renal function occurred in all patients after HTx, with some added benefit of Thymo7. Cytolytic therapy is considered to raise the incidence of malignancy in post-transplant patients.1,7,8 In a large series of 474 patients, Rinaldi et al21 examined the effect of immunosuppression on the development of

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cancer. All patients received triple-drug immunosuppression with cyclosporine, azathioprine, and steroids, and many received various prophylactic anti-lymphocyte therapies. Various cancers developed in 55 patients (11.6%). The malignancy rate in our study was 5%, and the relatively low incidence compared with the report by Zuckermann et al13 might be related to lower doses of Thymoglobulin induction. However, the follow-up was too short to determine the exact malignancy rates. Infection is another concern with induction therapy. Although the Thymo7 regimen led to more profound and prolonged immunosuppression, the CMV rates within the first year were similar (9% and 5%), as was the rate of in-hospital bacterial infection. The 1-year CMV rates were similar to those reported by Zuckermann et al13 and lower than those reported by Schnetzler et al.12 The effect of Thymoglobulin on lymphocyte depletion and recovery has only been addressed in one study.12 This group has demonstrated a similar trend in total lymphocyte count as well as platelets and white blood cells counts. In addition, lymphocyte recovery (⬎ 1000 per ␮l) in our study occurred earlier, at 6 months, compared with 8 months in the Schnetzler et al study.12 The longer lymphocyte depletion is likely attributable to the higher Thymoglobulin dose. Compared with ATG, Thymoglobulin has been found to have a more pronounced and persistent effect on several subsets of tested lymphocytes.12 Moreover, a faster lymphocyte recovery (8 weeks vs 8 months) was demonstrated with ATG. We found that Thymo7 resulted in a greater dose-dependent lymphocyte depletion compared with the Thymo5 regimen. Thus, the results suggest that lymphocyte depletion by Thymoglobulin is dose related and probably superior to ATG. Our study has some limitations. It was a retrospective, single-center study that compared the efficacy of 2 Thymoglobulin induction protocols in HTx recipients. The patient groups were not matched, and the groups were determined by clinical criteria of risk based on published data.22 Also lacking was a control group of patients who were not treated with induction strategies; therefore, the question whether the induction is needed at all cannot be addressed by this study. With regard to the trend to the lower survival in the Thymo7 group, because of the small sample size, a type II error cannot be ruled out. In conclusion, the 5-day and 7-day Thymoglobulin regimens were both well tolerated. The 7-day treatment led to more efficient and prolonged lymphocyte depletion and less rejection at 1 year, without an increase in the rate of CMV infection or incidence of in-hospital bacterial infection. There was no significant effect on survival. The benefit of Thymoglobulin


induction includes avoidance of calcineurin administration in the early post-operative period, improvement of renal function, and absence of humoral rejection. REFERENCES 1. Uber PA, Mehra MR. Induction therapy in heart transplantation: is there a role? J Heart Lung Transplant, 2007;26(3):205–9. 2. Higgins R, Kirklin JK, Brown RN, et al. To induce or not to induce: do patients at greatest risk for fatal rejection benefit from cytolytic induction therapy? J Heart Lung Transplant 2005;24(4): 392– 400. 3. Delgado DH, Miriuka SG, Cusimano RJ, Feindel C, Rao V, Ross HJ. Use of basiliximab and cyclosporine in heart transplant patients with pre-operative renal dysfunction. J Heart Lung Transplant 2005;24(2):166 –9. 4. Odim J, Wheat J, Laks H, et al. Peri-operative renal function and outcome after orthotopic heart transplantation. J Heart Lung Transplant 2006;25(2):162– 6. 5. Rosenberg PB, Vriesendorp AE, Drazner MH, et al. Induction therapy with basiliximab allows delayed initiation of cyclosporine and preserves renal function after cardiac transplantation. J Heart Lung Transplant 2005;24(9):1327–31. 6. Mattei MF, Redonnet M, Gandjbakhch I, et al. Lower risk of infectious deaths in cardiac transplant patients receiving basiliximab versus anti-thymocyte globulin as induction therapy. J Heart Lung Transplant 2007;26(7):693–9. 7. Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004; 4(2):222–30. 8. Garlicki M, Wierzbicki K, Przybylowski P, et al. The incidences of malignancy in heart transplant recipients. Ann Transplant 1998; 3(4):41–7. 9. Aleksic I, Freimark D, Blanche C, Czer LS, Trento A. Hemodynamics during humoral rejection events with total versus standard orthotopic heart transplantation. Ann Thorac Cardiovasc Surg 2004;10(5):285–9. 10. Carlsen J, Johansen M, Boesgaard S, et al. Induction therapy after cardiac transplantation: a comparison of anti-thymocyte globulin and daclizumab in the prevention of acute rejection. J Heart Lung Transplant 2005;24(3):296 –302. 11. De Santo LS, Romano G, Mastroianni C, et al. Role of immunosuppressive regimen on the incidence and characteristics of cytomegalovirus infection in heart transplantation: a single-center experience with preemptive therapy. Transplant Proc 2005; 37(6):2684 –7. 12. Schnetzler B, Leger P, Volp A, Dorent R, Pavie A, Gandjbakhch I. A prospective randomized controlled study on the efficacy and tolerance of two antilymphocytic globulins in the prevention of rejection in first-heart transplant recipients. Transpl Int 2002; 15(6):317–25. 13. Zuckermann AO, Grimm M, Czerny M, et al. Improved long-term results with thymoglobuline induction therapy after cardiac transplantation: a comparison of two different rabbit-antithymocyte globulines. Transplantation 2000;69(9):1890 – 8. 14. Segovia J, Rodriguez-Lambert JL, Crespo-Leiro MG, et al. A randomized multicenter comparison of basiliximab and muromonab (OKT3) in heart transplantation: SIMCOR study. Transplantation 2006;81(11):1542– 8. 15. Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia 2007;21(7):1387–94. 16. Lopez M, Clarkson MR, Albin M, Sayegh MH, Najafian N. J Am Soc Nephrol 2006;10:2844 –53.


17. Casarez TW, Perens G, Williams RJ, et al. Humoral rejection in pediatric orthotopic heart transplantation. J Heart Lung Transplant 2007;26(2):114 –9. 18. Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D. Thymoglobulin Induction Study Group. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med 2006;355(19):1967–77. 19. Mullen JC, Oreopoulos A, Dale LC, et al. Randomized controlled trial of Daclizumab vs Anti-thymocyte globulin induction for lung transplantation. J Heart Lung Transplant 2007; 26(5):504 –10.

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20. Flaman F, Zieroth S, Rao V, et al. Basiliximab versus rabbit anti-thymocyte globulin for induction in patients after heart transplantation. J Heart Lung Transplant 2006;25(11):1358 – 62. 21. Rinaldi M, Pellegrini C, D’Armini AM, et al. Neoplastic disease after heart transplantation: single center experience. Eur J Cardiothorac Surg 2001;19(5):696 –701. 22. Mehra MR, Uber PA, Scott RL, Park MH. Ethnic disparity in clinical outcome after heart transplantation is abrogated using tacrolimus and mycophenolate mofetil-based immunosuppression. Transplantation 2002;74(11):1568 –73.