EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: We describe our experiences with, and compare the outcomes of, 2 groups of renal transplant patients treated with thymoglobulin or antithymocyte globulin-Fresenius as induction therapy at transplant to reduce the incidence of acute rejection and prevent delayed allograft function.

Materials and Methods: Twenty-four recipients of deceased-donor or living-donor kidney transplants received thymoglobulin, and 23 patients received antithymocyte globulin-Fresenius. Patient and graft survival and efficacy and safety were assessed at 3 months.

Results: The demographic characteristics of both groups were comparable, but the predominant donor type was significantly different. Incidence of complications, delayed graft function, and creatinine concentrations were comparable in both groups. At 3 months after the transplant, patient survival rate was 92% in the thymoglobulin group and 96% in the antithymocyte globulin-Fresenius group (P > .05), and death-censored graft survival rate for both groups was not significantly different. Average hematocrit and lymphocyte, neutrophil, and platelet counts were comparable in both groups at 3 months’ follow-up. Average white blood count at 1 month was significantly different between the groups: at 5.62 ± 2.45 × 10³ cells/mm³ in the thymoglobulin group and 7.85 ± 4.10 × 10³ cells/mm³ in the ATG-F group (P < .05).

Conclusions: Considering the study design limitations, we observed that our group of treated patients, safety, and efficacy of thymoglobulin and antithymocyte globulin-Fresenius were generally comparable.

Key words : Transplant, Kidney, Immunosuppression, ATG, Argentina

Transplanted organ survival is negatively affected by delayed graft function and acute rejection. Induction therapy at the time of transplant is used to reduce the incidence of acute rejection and prevent delayed allograft function.1 Moreover, lymphocyte-depleting antibodies may reduce exposure to calcineurin inhibitors and decrease nephrotoxicity.^2,3 These antibodies generally are administered to patients who have a high immunologic risk; their use in low-risk patients remains controversial. It has been suggested that although living-donor recipients are generally regarded to be at lower risk for rejection than deceased-donor recipients, living-donor recipients experience rejection more often because induction is not used often in this population.⁴

Antithymocyte globulin is one of the induction agents most widely used in renal transplant. Rabbit antithymocyte globulin is thought to deplete T cells within 24 hours of administration, thereby reducing expression of inflammatory cytokines and affecting adhesion molecule modulation and chemokine effector expression. These properties are extremely important in ischemia-reperfusion injury; rATG used before reperfusion may decrease the incidence of delayed-graft function, allow steroid withdrawal, and minimize exposure to calcineurin inhibitors.^5,6

Thymoglobulin and ATG-Fresenius (ATG-F) have different immunomodulatory potentials and characteristics. Thymoglobulin was developed with human thymocytes as the immunogen, whereas ATG-F was developed using Jurkat human cells to immunize rabbits.⁷ Studies comparing thymoglobulin and ATG-F are limited, and their results are dissimilar. This retrospective study sought to describe our experience using induction therapy with thymoglobulin and ATG-F, to compare the effectiveness and safety of these 2 agents, in 2 groups of renal transplant patients, treated with either drug at the Hospital Alemán in Buenos Aires, Argentina.

Materials and Methods

This observational retrospective cohort study of adult renal transplant patients receiving induction therapy with thymoglobulin or ATG-F (Fresenius) was conducted at the renal transplant unit at the Hospital Alemán in Buenos Aires, Argentina. We evaluated the respective influence of the 2 polyclonal ATGs on the occurrence of posttransplant outcomes. All protocols were approved by the ethics committee of the institution before the study began, and the protocols conformed with the ethical guidelines of the 1975 Helsinki Declaration. Informed consent was obtained from all patients.

Forty-seven recipients of deceased-donor or living-donor renal transplants were given, as is customary at the transplant center and recommended in the literature,⁸ personalized induction therapy according to the following parameters: age, type of donor, panel reactive antibodies, number of transplants, and cold ischemia time. From September 2009 to July 2011, twenty-four recipients of deceased-donor or living-donor kidney transplants received thymoglobulin; they comprised group 1. From August 2011 to July 2012, twenty-three patients received ATG-F; they comprised group 2.

Patients in group 1 received thymoglobulin (1 to 1.5 mg/kg/d for 5 to 7 days; mean cumulative dosage, 6.56 ± 0.75 mg/kg) while patients in group 2 received ATG-F (2 to 5 mg/kg/d for 5 to 7 days; mean cumulative dosage 19.74 ± 2.89 mg/kg). In both groups, infusion was started before the clamps were released, according to standard procedures. Methylprednisolone was used as follows: 500 mg perioperatively, 250 mg on day 1, and 125 mg on day 2. Oral prednisolone was used in cases in which oral therapy was tolerated, and the dosage was tapered to 20 mg on day 30. Subsequently, the dosage was reduced to 4 mg. In addition, 1440 mg of mycophenolate sodium was used daily in both groups. In groups 1 and 2, immunosuppressant maintenance therapy was begun on the last day of thymoglobulin or ATG-F therapy, consisting of tacrolimus at 0.1 to 0.2 mg/kg/d to achieve a blood concentration of 6 to 10 ng/mL during the first 3 months.

In cases of rejection up to Banff II, the therapy of choice was a 3-day intravenous course of methylprednisolone (500 mg). Steroid-resistant rejections, on the other hand, were treated with intravenous immunoglobulin at 400 mg/kg/d for 5 days.⁹ Cytomegalovirus prophylaxis consisted of 900 mg/d of valganciclovir for 3 to 6 months according to each patient’s pretransplant mismatch status. Pneumocystis carinii pneumonia prophylaxis was given regularly for 9 months with trimethoprim/sulfamethoxazole 1 tablet each day. Patients who showed signs of cytomegalovirus infection by polymerase chain reaction were treated with valganciclovir according to the standardized dosing schedule recommended by the manu facturer. Antibody-mediated acute rejection was treated with intravenous immunoglobulin (400 mg/kg/d) or plasmapheresis (7 sessions per day, every 2 days) and bortezomib (4 doses on days 1, 4, 7, and 11, after a diagnosis of rejection).

Patient and graft survival were assessed at month 3. Effectiveness was evaluated by assessing biopsy-proven acute cellular rejection, the incidence of antibody-mediated rejection according to the Banff 2007 classification system, and delayed-graft function, defined as the need for dialysis within the first week after transplant.

Follow-up data of all patients were obtained in the third month. Safety was assessed by comparing cytomegalovirus infections, pneumonia, nervous system disorders, lymphocele, malignancies, and hematologic parameters (eg, anemia, leukopenia, and thrombocytopenia). When the platelet and white blood cell (WBC) counts dropped to 80 000 and 2500 cells/mm³, the dosage of thymoglobulin or ATG-F was reduced by 50%. If the platelet or WBC count was below 50 000/mm³ or 2000 cells/mm³, thymoglobulin or ATG-F was discontinued.

Categoric variables are expressed as percentages. Continuous data are presented as the means ± SEM, or means and range. Variables were compared using the Wilcoxon rank-sum test, the Fisher exact test, the chi-square test, and t test, accordingly. Differences were regarded as significant at P < .05. All statistical analyses were performed using STATA 11 (StataCorp LP, College Station, TX, USA).

There was no significant difference regarding the demographic characteristics of both patient groups including recipient age, sex, and time on dialysis before transplant. The mean patient age was 46.95 ± 12.09 years for thymoglobulin and 49.35 ± 15.47 years for ATG-F. The predominant donor type in each group was significantly different. In the thymoglobulin group, 17 of the transplants were from deceased donors (71%), and 7 were from living donors (29%), compared with 22 from deceased donors (96%) and 1 from a living donor (4%) in the ATG-F group (P < .05). No significant differences were seen in any of the other characteristics of the donors and factors affecting the transplant (eg, donor age, cold ischemia time, proportion of expanded criteria, deceased donor, ≥ 3 HLA mismatches, proportion of retransplant, and cytomegalovirus serostatus; Table 1). Mean cumulative dosage of thymoglobulin was 6.56 ± 0.75 mg/kg and ATG-F, 19.74 ± 2.89 mg/kg.

The incidence of complications was comparable in both groups (thymoglobulin n=16 vs ATG-F n=15; P > .05). The most common complication in both groups was a urinary tract infection (thymoglobulin n=12 vs ATG-F n=11; P > .05). Delayed-graft function, defined as the need for dialysis within the first week after transplant, was seen in 13 patients in the thymoglobulin group (54%) and in 10 patients in the ATG-F group (43%; P > .05). Serum creatinine was not significantly different at 1 week, and 1 and 3 months in either group. The decrease in creatinine at month 3 compared with the baseline level was comparable in both groups: from 776.15 ± 345.64 to 157.35 ± 47.7 μmol/L (79.6% decrease) in the thymoglobulin group, and 736.37 ± 249.23 to 144.98 ± 71.60 μmol/L (80% decrease) in the ATG-F group (Table 2).

The incidence of acute cellular rejection proven by biopsy was 163% (n=4) in the thymoglobulin group and 17% (n=4) in the ATG-F group (P > .05); there were no cases of antibody-mediated rejection in the thymoglobulin group, whereas there was 1 case (4.2%) in the ATG-F group (P > .05) (Table 2). The survival rate at 3 months was 92% in the thymoglobulin group and 96% in the ATG-F group (P > .05). The death-censored graft survival rate at 3 months was 96% in the thymoglobulin group and 96% in the ATG-F group (P > .05; Table 2).

Regarding hematologic adverse events, the average hematocrit and lymphocyte, neutrophil, and platelet counts were comparable in both groups at the 3 months’ follow-up. However, the average WBC count at 1 month was significantly different between the groups, at 5.62 ± 2.45 × 10³ cells/mm³ in the thymoglobulin group and 7.85 ± 4.10 × 10³ cells/mm³ in the ATG-F group (P < .05; data not shown). In 2 cases in each group, dosages were reduced slightly within range, owing to the WBC count. Similarly, in 2 patients in the thymoglobulin group, drug dosage was reduced because the patients presented with a fever. Regarding other adverse events, we did not observe any cases of rash, serum sickness, blood pressure drop, or lymph node enlargement.

Induction therapy with T-cell–depleting agents is standard in renal transplant. In this retrospective cohort study, we found the incidences of delayed-graft function, acute cellular rejection, and antibody-mediated rejection were not significantly different in renal transplant recipients treated with thymoglobulin or ATG-F. The incidences of a urinary tract infection, cytomegalovirus infection, nervous system disorders, lymphocele, and malignancies between the groups did not differ. Moreover, comparable graft function, graft survival, and patient survival rates were observed between the 2 groups. None of the 7 living-donor grafts in the thymoglobulin group showed delayed-graft function, whereas the only living-donor graft in the ATG-F group exhibited delayed-graft function. Regarding hematologic outcomes, the only significant difference between the groups was the WBC count at month 1, which showed a more pronounced drop in the thymoglobulin group than it did in the ATG-F group. Although not significantly different, the higher mortality rate in the ATG-F group may be explained by its higher immunologic and medical risk. However, the ATG-F recommended dosage does not differ for high-risk transplant patients, and the sample size of our study was too small to conclude on this issue. Based on recommendations in the literature, safe and effective outcomes are possible with a dosage ≤ 1.5 mg/kg/d in the case of thymoglobulin⁵ and 4 to 6 mg/kg/d for ATG-F.¹⁰ In our study, the mean dosages of both drugs were within these values and those recommended by the manufacturers.

Two studies comparing induction therapy with thymoglobulin and ATG-F in renal transplant recipients showed different results: Schultz and associates¹⁰ found comparable and favorable results when either drug was used in combination with tacrolimus, mycophenolate mofetil, and prednisolone, whereas Ducloux and associates¹¹ reported thymoglobulin was associated with a significantly greater incidence of cytomegalovirus disease, malignancy, and death compared with ATG-F. Other studies, including randomized controlled trials comparing thymoglobulin; and (lymphocyte immune globulin, anti-thymocyte globulin [equine] sterile) solution, have favored thymoglobulin over (lymphocyte immune globulin, anti-thymocyte globulin [equine] sterile) in terms of efficacy and safety.^12-15 On the other hand, studies of ATG-F have reported mixed results.^2,16 Notwithstanding these contradictory findings, we could not find significant differences, except for the WBC count at month 1, between the 2 drugs. Even though the WBC count was lower in the thymoglobulin group than in the ATG-F group, this drop was not associated with a lower incidence of rejection or higher infection rates. Moreover, by month 3, the WBC counts were comparable in both groups. In addition to induction therapy with thymoglobulin or ATG-F, maintenance therapy with mycophenolate sodium, cytomegalovirus prophylaxis with valganciclovir, and Pneumocystis carinii pneumonia prophylaxis with sulfamethoxazole and trimethoprim may explain the decrease in WBCs.

The optimal dosage of thymoglobulin or ATG-F is still being studied. Each of these drugs used in our study was individually compared to a different drug or sets of drugs, in populations with diverse characteristics. This may explain the opposing results found in the literature. To better position thymoglobulin and ATG-F with respect to other agents and confirm whether one is superior to the other, it would be necessary to conduct randomized control trials or prospective comparative studies. Popow and associates¹² recently compared 4 batches of in vitro thymoglobulin and ATG-F and demonstrated that there was little variation between ATG lots of thymoglobulin and ATG-F, and that their clinical efficacy should not be expected to be different.

It has been reported that transplant centers often avoid using rATG in populations at low immunologic risk because of the cost burden.⁴ Therefore; it would be beneficial to further examine differences in clinical efficacy for both drugs and to evaluate the costs associated with choosing one drug over the other. In addition, further research is needed with longer follow-ups to assess such outcomes as malignancies and posttransplant lymphoproliferative disorder, and to investigate how these agents function through lymphocyte depletion. It is important to note that the short induction time in our study might have played a role in maintaining comparable lymphocyte counts in both groups.

We acknowledge the serious limitations of our study, including the small number of patients, the short follow-up, and the retrospective design that did not allow us to control for confounding variables and biases; for this reason, our objective was merely to describe our experience in the use of thymoglobulin and ATG-F as induction therapy in 47 renal transplant patients.

In conclusion, in patients at our transplant center, the safety and efficacy of thymoglobulin and ATG-F are generally comparable. Because these agents are used extensively in renal transplant, our preliminary findings should be confirmed by means of controlled trials to determine the most cost-effective strategy for induction therapy.

Volume: 11 Issue: 5 October 2013

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