Rabbit antithymocyte globulin as induction immunotherapy in pediatric heart transplantation

BACKGROUND: There is little published data on the use of antithymocyte globulins in children. This retrospective study describes the use of Thymoglobulin (Imtix, SangStat, Lyon, France) in pediatric cardiac transplantation over a 13-year period in a single center that adjusted the dose of Thymoglobulin according to platelet count monitoring and examines the short-term hematological effects as well as longer-term outcomes. METHODS: Data for all children who received a heart transplant at the H?pital Cardiologique at Lyon from 1984 to 2001 and who were given Thymoglobulin as part of their immunosuppressive protocol were extracted. The dose of Thymoglobulin given depended on baseline platelet count and was 2, 1.5, or 1 mg/kg per day over 5 days for the following platelet count groups: greater than 150,000/mm (normal group), 100 to 150,000/mm (mild thrombocytopenia group), and 50 to 100,000/mm (moderate thrombocytopenia group). RESULTS: Thirty children of median age 14.2 years were given a median cumulative dose of Thymoglobulin of 8 mg/kg per patient; the moderate thrombocytopenia subgroup was given significantly less (6.4 mg/kg) ( P=0.032). Immediate tolerability of Thymoglobulin was good, with no cases of first-dose syndrome, anaphylaxis, or serum sickness. The platelet count decreased at the start of therapy, but recovered after discontinuation, and did not give rise to clinical concern. Patients were followed up for a median of 6.3 years (7 days-15.5 years); actuarial survival was 90%, 86%, and 74.5%, respectively, at 1, 5, and 10 years. In the first year, 50% of patients suffered an episode of rejection. The overall incidence of infection in the month following transplantation was 40%. One lymphoma occurred at 5 months. CONCLUSIONS: The use of Thymoglobulin in pediatric heart-transplant patients as part of an immunosuppressive protocol, with dose adjustment according to platelet levels, has been shown to be effective in terms of rejection rate and patient survival and safe in terms of the incidence of infections and malignancy.     

Optimal perioperative immunosuppression in cardiac transplantation using rabbit antithymocyte globulin

A randomized trial of RATG (polyclonal) vs. OKT3 (monoclonal) antibody prophylaxis was carried out in 82 cardiac transplant recipients who, in addition, received baseline immunosuppression with cyclosporine, azathioprine and prednisone. One-year actuarial survival was comparable between groups (95% and 98%). The incidence of moderate or severe rejection within the first 30 days of transplant was over 7 times greater in patients receiving OKT3 vs. those receiving RATG. Patients receiving OKT3 were more likely to have repeated episodes of rejection and the mean time to rejection for patients receiving OKT3 was shorter (33 days) than for RATG patients (67 days). At 120 days, 52% of RATG patients were free of rejection while only 37% of the OKT3 patients were rejection-free. There was no difference in the incidence of major or minor bacterial or viral infection between groups. Patients receiving OKT3 showed a less-prolonged depression of the CD3 and CD4 T cell subsets than did those receiving RATG. Significant hemodynamic side-effects were seen after the first dose of OKT3 and there was a 5% incidence of aseptic meningitis associated with its use.     

Rabbit antithymocyte globulin as induction immunotherapy for pediatric deceased donor kidney transplantation

PURPOSE: There is scant literature describing the long-term outcome of the use of antithymocyte globulin induction immunotherapy in pediatric deceased donor kidney transplants. We retrospectively studied the long-term results and safety of antithymocyte globulin as induction immunotherapy in all children undergoing transplantation at our institution since 1991. MATERIALS AND METHODS: A total of 120 kidney transplants were performed in 95 patients 18 years or younger between January 1986 and December 1998. Patients were divided into 2 groups. The control group (63 patients) received cyclosporine, azathioprine and prednisolone, while the treatment group (59 patients) received rabbit antithymocyte globulin (RATG) induction immunotherapy for 6 to 10 days, combined with cyclosporine, azathioprine and prednisolone. RESULTS: Actuarial patient survival rates at 1, 3, 5 and 10 years were 96%, 95%, 95% and 90%, respectively. Actuarial graft survival rates at 1, 3, 5 and 10 years were 76%, 69%, 64% and 49%, respectively. The 1, 3, 5 and 10-year graft survival rates in the control group were 62%, 57%, 51% and 36%, respectively, compared to 90%, 82%, 79% and 69%, respectively, in the RATG group (p = 0.001). There was a significant difference in the incidence of graft loss secondary to acute cellular rejection between the control and RATG groups (19.7% vs 3.3%, p = 0.008). There was no difference in infectious complications between the control and RATG groups (13% vs 20%, p = 0.33), and there was no case of post-transplant lymphoproliferative disorder encountered in either group. CONCLUSIONS: The use of rabbit antithymocyte globulin in pediatric deceased donor kidney transplant recipients resulted in significant improvement in graft survival and was relatively safe.     

Rabbit antithymocyte globulin compared with basiliximab in kidney transplantation: a single-center study

Background

Induction therapy is used to reduce the incidence of acute rejection and to prevent or treat delayed graft function. We compared basiliximab with rabbit antithymocyte globulin (ATG) as induction therapies for kidney transplant recipients.

Methods

We retrospectively analyzed the clinical data from 514 patients who received ATG or basiliximab. The patients in the ATG group (n = 152) received ATG (1.5 mg/kg/d) for 5-7 days and those in the basiliximab group (n = 362) were given 2 doses of basiliximab (20 mg) on posttransplantation days 0 and 4. All patients received standard triple immunosuppressive therapy with calcineurin inhibitors, mycophenolate mofetil, and steroids.

Results

There were statistically significant differences in the incidences of delayed graft function, 1-year acute rejection rate, death-censored graft survival, and patient survival between the 2 groups, even though the ATG group had more kidney transplants from deceased donors, higher levels of panel reactive antibodies, and more retransplantations. The incidences of cytomegalovirus (CMV) infection and parvovirus infection in the ATG group were higher than those in the basiliximab group. However, there was no statistically significant difference in the incidence of CMV disease between the 2 groups.

Conclusions

ATG is safe and efficacious for use in kidney transplant recipients. Our results suggest that ATG should be considered for induction therapy in high-risk patients, such as those who have a kidney allograft from a deceased donor, high levels of panel reactive antibodies, and are undergoing retransplantation.     

One center's experience with antithymocyte globulin treatment for acute rejection in renal transplantation

Antithymocyte globulin (ATG) is a polyclonal antibody used in renal transplantation for prevention and treatment of acute rejection. In this study we have presented the outcomes of 23 cases treated with ATG due to steroid-resistant acute rejection episodes in 17 male and 6 female recipients. Sixteen transplantations were performed from cadaver donors and the other 7 from living-related donors. The mean recipient age was 31.9 ± 9 years and the mean donor age was 56.3 ± 10.8 years. ATG treatment was administered in doses of 3-5 mg/kg/d for 10 or 14 days. All patients received the same premedication before the ATG treatment; we did not encounter any ATG-related side effects. ATG doses were adjusted according to the T-lymphocyte levels. All recipients were followed up for infectious complications, for graft function, and for immunologic parameters of CD3 levels, CD4 levels, CD3/CD4 ratios, lymphocyte, and polymorphonuclear leukocyte numbers. According to the Banff criteria introduced in 1997, 4 patients displayed humoral rejection: 3 had type 3; 5 had type 2; and 11 had type 1 acute rejection episodes. Nine patients developed infectious complication during the follow-up. Three had pulmonary aspergillosis; 2 had cytomegalovirus infection; and 4 had bacterial infections. One patient who experienced aspergillosis died with a functioning graft, and the remaining 8 patients were treated successfully. Graft function improved in 19 (83%) cases. The other 4 patients returned to hemodialysis. Mean creatinine levels decreased from 4 ± 1.7 to 2.1 ± 0.2 mg/dL. We did not observe any relationship between the immunologic parameters and infectious complications. In conclusion, although ATG is a powerful drug to treat steroid-resistant acute rejection episodes, there was no precise way to monitor the intensity of immunosuppression to prevent infectious complications.     

Prophylactic therapy for rejection after cardiac transplantation. A comparison of rabbit antithymocyte globulin and OKT3

The value of prophylactic monoclonal or polyclonal antibody therapy early after cardiac transplantation is controversial. Between Jan. 1, 1987, and July 1, 1988, 32 consecutive patients underwent cardiac transplantation (cyclosporine, azathioprine, and prednisone maintenance therapy) with either early prophylactic rabbit antithymocyte globulin (n = 17) or monoclonal OKT3 (Ortho Diagnostic Systems, Inc., Raritan, N.J.) (10 days) (n = 15). Follow-up was through Sept. 1, 1988, for morbid events and through Jan. 1, 1989, for survival. All patients (100%) survived the study period (follow-up of 6 to 24 months). The efficacy of rabbit antithymocyte globulin and OKT3 prophylaxis was similar regarding median time (days) to first rejection (16 versus 21 days, p = 0.5), number of rejection episodes during first 2 months (1.5 versus 1.3 days, p = 0.8), and freedom from rejection at 2 months (18% versus 27%, p = 0.8). Early infections were slightly less common in the rabbit antithymocyte globulin group than the OKT3 group (median time to first infection: 318 versus 250 days, p = 0.5; freedom from rejection at 2 months: 82% versus 64%, p = 0.21), although differences were likely due to chance. Cytomegalovirus syndrome was common, with one case of cytomegalovirus pneumonia. T-cell markers during OKT3 treatment did not predict subsequent rejection (within 2 weeks after OKT3) as assessed by mean T3-lymphocyte count during OKT3 use (p = 0.3) or T3-lymphocyte count during the last 3 days of OKT3 use (p = 0.4). Inferences: (1) Prophylactic rabbit antithymocyte globulin or OKT3 with triple-drug immunosuppression yields excellent intermediate survival after heart transplantation. (2) These protocols for rabbit antithymocyte globulin and OKT3 provide similar protection against early rejection with a relatively low risk of early infection. (3) T-cell markers do not predict early rejection after OKT3.     

Pregnancy in patients with prosthetic cardiac valve. A 10-year experience

Pregnancy after valve replacement has been considered hazardous because of maternal and fetal complications secondary to anticoagulant medication, in addition to basic myocardial problems. Of 229 females aged 15-45 years with prosthetic valve replacement, 37 (including 34 with Bj?rk-Shiley valve and anticoagulants) subsequently had a total of 47 pregnancies. Fullterm delivery of a normal infant was achieved in 40 cases. There were three premature births, two spontaneous abortions, one stillbirth and one ectopic pregnancy. The fetal mortality was 8.5%. Valve thrombosis developed in two cases, but surgical treatment was successful. Oral anticoagulants (acenocoumarin and dipyridamole) were continued throughout pregnancy. Heparin was substituted before labour began, but discontinued after delivery, when effective oral anticoagulation was resumed. Our experience showed that pregnancy in women with mechanical heart valve prosthesis and continued oral intake of anticoagulants is safe and successful in most cases.     

Induction therapy in lung transplantation: initial single-center experience comparing daclizumab and antithymocyte globulin

Acute and chronic rejection remain unresolved problems after lung transplantation, despite heavy multidrug immunosuppression. Because acute rejection is associated with inferior outcomes in lung transplantation, we have routinely employed antithymocyte globulin (ATG) or daclizumab as adjuncts to reduce the incidence of rejection episodes. METHODS: We performed a controlled clinical trial of the two therapies to evaluate differences in postoperative rejection, infection, bronchiolitis obliterans syndrome (BOS) and host survival. Twenty-five consecutive lung transplant patients received ATG (n = 12; group 1) or daclizumab (n = 13; group 2) as an induction agent. The groups showed similar demographics and immunosuppression protocols, differ only in induction agent. RESULTS: No differences were observed in the immediate postoperative outcomes, such as length of hospitalization, ICU stay, or time on ventilator. There were no significant differences in the number of episodes of acute rejection, freedom from BOS, or infections. Freedom from acute rejection was significantly greater with daclizumab than with ATG (P = .037). The 1-year survival for group 1 was 67% and for group 2, 77% (P = .584). CONCLUSIONS: Daclizumab constitutes a safe and effective form of induction immunosuppressive therapy. Using a two-dose administration schedule, daclizumab prolonged the time without acute rejection compared to ATG. The differences in the incidence of infectious complications, acute rejection, or BOS as well as the short-term or long-term results were not significantly different. The results of the study justify the further use of daclizumab as an induction agent in patients following lung transplantation.     

Induction immunosuppression with rabbit antithymocyte globulin in pediatric liver transplantation.

Routine use of rabbit antithymocyte globulin (RATG) induction therapy remains controversial in pediatric liver transplantation. We reviewed our experience of 18 cadaveric liver transplants in 18 children over a span of 2 years. All patients received the same immunosuppression: perioperative steroid therapy with taper, 3 doses of RATG, and maintenance therapy of steroids and tacrolimus started on postoperative day 3. Mean follow-up was 2.2 +/- 0.2 years. End-stage liver disease was secondary to biliary atresia in 10 patients (56%) and metabolic disorders in 4 patients (22%). Graft and patient survival were 89%. Serum bilirubin was 1.2 mg/dL, 1.1 mg/dL, 0.5 mg/dL, and 0.5 mg/dL at 1, 3, 6, and 12 months, respectively. The 2 mortalities were secondary to multiple organ system failure. Overall rejection rate was 17% (3/18). Rejection episodes occurred at 4, 6, and 7 months. Two patients were treated with steroids; the third was treated with OKT3. No patient has developed posttransplant lymphoproliferative disease. Serum creatinine was 0.7 mg/dL, 0.6 mg/dL, 0.6 mg/dL, and 0.6 mg/dL at 1, 3, 6, and 12 months, respectively, among surviving patients. In conclusion, our data suggest that RATG induction with steroid and tacrolimus maintenance therapy is safe, easy to use, and effective in the prevention of rejection.     

Effect of antithymocyte globulin on islet of Langerhans transplantation.

Lewis rats were treated with streptozotocin to induce hyperglycemia and glycosuria (400-600 mg/dl). Transplantation of approximately 1,000 dissociated islets obtained from collagenase-treated pancreases from 4 donors will promptly correct induced diabetes. Functional survival of islet allografts is related to genetic disparity between donor and recipient strains. In the closely matched Fisher-to-Lewis combination, islets functioned for a mean of 4.2+/-1 days while in the AgB-incompatible Wistar/Furth-to-Lewis combination, islets functioned for a mean of only 2.1+/-0.5 days. Treatment of recipients with antithymocyte globulin (ATG) for 3 days extended islet survival to a mean of 11.8 +/- 1.9 days in the Wistar/Furth-to-Lewis combination and to as long as 184+/-87.5 days in the Fischer-to-Lewis combination. ATG may have a role in trials of clinical islet transplants.     

Specific absorbed antithymocyte globulin for incubation treatment in human marrow transplantation.

The experimental data show that absorption of ATG with liver-kidney homogenate and CLL and LCL cells stepwise removed the hemopoietic toxicity, whereas the specific activity against T lymphocytes remained. Although the mode of action of absorbed ATG could not be tested in the first clinical case, the successful experiments in rodents together with the fact that the incubation treatment was tolerated by the patient may provide a new way of preventing fatal GVH reactions in man.     

Rabbit antithymocyte globulin induction and sirolimus monotherapy supports prolonged islet allograft function in a nonhuman primate islet transplantation model

BACKGROUND: We reported that rabbit anti-thymocyte globulin (RATG) induction followed by maintenance immunosuppression with sirolimus supports human kidney allograft survival and asked if this combination would promote islet allograft survival in our primate model. METHODS: Using intra-arterial streptozotocin infusion, we rendered four cynomolgus primates diabetic with undetectable C-peptide levels. Animals were maintained on insulin therapy for at least 1 month, and then islets from mixed lymphocyte reaction mismatched primates were infused into the portal vein. Immediately before the islet allotransplant and for 6 additional days, primates were infused with RATG (20 mg/kg) and given a sirolimus dose to achieve a 24-hr trough level of 8 to 14 ng/mL. RESULTS: The regimen resulted in profound peripheral and lymph node lymphocyte depletion for up to 1 month. Repopulation was gradual thereafter. One primate remained insulin-independent for 169 days and rejected after a sirolimus-dose reduction. Two primates died on day 23 while insulin independent because of wound dehiscence, and a third died on day 30 with high sirolimus levels. Liver sections revealed well-vascularized islets with no signs of inflammation. CONCLUSION: Using a nonhuman primate islet transplant model, RATG plus sirolimus supports islet survival as long as proper sirolimus levels are maintained, but the therapy is limited by sirolimus toxicity. Our findings suggest that RATG is not toxic for islets and thus may be considered in future clinical trails while recognizing that sirolimus monotherapy, with its difficult-to-achieve therapeutic dosing, may not be sufficient to maintain long-term islet allograft function in an autoimmune environment.