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CLINICAL TRANSPLANTATION

A three-arm study comparing immediate tacrolimus therapy with antithymocyte globulin induction therapy followed by tacrolimus or cyclosporine A in adult renal transplant recipients1

Charpentier, Bernard2 32; Rostaing, Lionel3; Berthoux, Francois4; Lang, Philippe5; Civati, Giovanni6; Touraine, Jean-Louis7; Squifflet, Jean-Paul8; Vialtel, Paul9; Abramowicz, Daniel10; Mourad, Georges11; Wolf, Philippe12; Cassuto, Elisabeth13; Moulin, Bruno14; Rifle, Gerard15; Pruna, André16; Merville, Pierre17; Mignon, Françoise18; Legendre, Christophe19; Le Pogamp, Patrick20; Lebranchu, Yvon21; Toupance, Olivier22; Hurault de Ligny, Bruno23; Touchard, Guy24; Olmer, Michel25; Purgus, Raj25; Pouteil-Noble, Claire26; Glotz, Denis27; Bourbigot, Bernard28; Leski, Michel29; Wauters, Jean-Pierre30; Kessler, Michèle31

Author Information
doi: 10.1097/01.TP.0000056635.59888.EF
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Abstract

Induction therapy with antithymocyte globulin (ATG) prevents early acute rejection by inhibiting T-cell function (1). Furthermore, the use of induction therapy allows the delayed administration of potentially nephrotoxic immunosuppressive agents (2–5). Sequential treatment protocols were therefore developed in which ATG induction was administered after transplantation and the primary immunosuppressant was given once renal function was established (2,4,5). In a recent study in renal transplant patients, it was demonstrated that ATG induction with tacrolimus-based triple therapy resulted in a lower incidence of acute rejection compared with immediate tacrolimus triple therapy without induction (5). In the induction arm of the study, however, there was a significant increase in hematologic adverse events and cytomegalovirus (CMV) infection.

Tacrolimus-based therapies have consistently proved superior to cyclosporine A (CsA)-based therapies (standard and microemulsion formulation) in renal transplantation with respect to the prevention of acute rejection (6–8). In an earlier comparative study in the United States (8) in which the standard formulation of CsA was used and patients were randomized to immunosuppressive treatment after antibody induction (OKT3 or ATGAM), tacrolimus was more efficacious than CsA with respect to a reduction in the incidence of acute rejections (30.7% vs. 46.4%, P =0.001). However, the efficacy and safety of ATG induction has not been explored in comparative trials using the more recent microemulsion formulation of CsA. Therefore, the efficacy and safety of immediate tacrolimus triple therapy, tacrolimus triple therapy with ATG induction, and microemulsion CsA triple therapy with ATG induction in adult renal transplantation patients was investigated.

METHODS

Patients

This was a 6-month, open-label, randomized, multicenter, prospective, parallel-group study conducted in 30 centers in France, Belgium, Switzerland, and Italy. Patients were men or women 18 years of age and older, and were undergoing a first kidney allograft transplantation or retransplantation from cadaveric donors. A negative pregnancy test was required and effective birth control practice was essential for women of childbearing age. Patients were eligible for entry if the donor was 60 years or younger and the patient was not older than 65 years and human immunodeficiency virus-negative; had no evidence of drug addiction; had no previous or current malignancy; and had no known hypersensitivity or incompatibility with tacrolimus, CsA, macrolides, polyoxyethylene hydrogenated castor oil, steroids, or azathioprine.

Patients were excluded from the study if they received an ABO-incompatible graft, had received another solid organ transplant or required multiple organ transplantation, had a positive T-cell crossmatch on their most recent serum specimen, required immunosuppressive drug therapy for other reasons than transplantation, or had systemic infections requiring therapy at the time of transplantation. Patients were also excluded if they exhibited significant thrombocytopenia (<50,000 thrombocytes/μL) or if they had elevated liver enzymes (greater than three times the upper limit of the normal range) at study entry.

Trial Design

The patients were randomized to one of three treatment groups: (1) tacrolimus (Prograf; Fujisawa GmbH, Munich, Germany)-based triple therapy without induction (Tac triple), (2) ATG (Thymoglobuline, formerly Institut Merieux, now Imtix Sangstat, Lyon, France) induction followed by tacrolimus-based triple therapy (ATG-Tac), and (3) ATG induction followed by CsA microemulsion (Neoral; Novartis AG, Basel, Switzerland)-based triple therapy (ATG-CsA). Triple therapy comprised the baseline immunosuppressant with azathioprine and corticosteroids. Administration of azathioprine and corticosteroids was initiated on the day of transplantation (day 0) in all groups.

In the Tac triple group, the first tacrolimus dose was administered as soon as possible after transplantation and randomization. Administration was oral as capsules, or by nasogastric tube. If clinically indicated, tacrolimus could be given intravenously (initial dose, 0.06 mg/kg/day); patients were converted to oral therapy as soon as practicable. The initial oral dose of tacrolimus was 0.30 mg/kg/day in two divided doses and subsequent adjustments to dosing were made on the basis of maintenance of the recommended whole-blood trough levels. Whole-blood trough levels were maintained as follows: 10 to 20 ng/mL from day 1 to day 42 and 5 to 15 ng/mL from day 43 to day 180.

ATG induction therapy was commenced within 12 hr of closure of the abdominal wall. The initial dose was 1.25 mg/kg, and subsequent doses from day 1 to day 10 were adjusted according to the clinical condition of the patient. ATG administration was discontinued on day 11, but only if trough concentrations of tacrolimus and CsA were within the recommended range.

For patients in the ATG-Tac group, the first dose of tacrolimus was administered on day 9 after transplantation, and adjustments to the tacrolimus dosage were as for the Tac triple group. In the ATG-CsA group, the first dose of CsA was administered on day 9 after transplantation. The initial dose for CsA was 8 mg/kg/day taken in two divided doses. If the patient was not able to take oral medication (capsules or solution), an appropriate dose of CsA was given intravenously. Subsequent doses were adjusted to maintain whole-blood trough levels of 150 to 300 ng/mL from day 9 to day 42 and 100 to 200 ng/mL from day 43 to day 180.

Methylprednisolone was administered intravenously to all three treatment groups at 500 mg on day 0 and 125 mg on day 1. Prednisolone equivalent was administered orally at 20 mg from day 2 to day 14, at 15 mg on day 15 to day 28, at 10 mg from day 29 to day 90, and at 10 mg or less from day 91 to day 180. Azathioprine was administered to all three treatment groups intravenously at 2 mg/kg on day 0 and orally at 1 to 2 mg/kg on day 1 to day 90; thereafter, azathioprine dosing could be discontinued.

Tacrolimus and CsA whole-blood trough levels were assessed three times per week during hospitalization and at weeks 1, 2, and 3; months 2, 3, and 6; and at withdrawal and as clinically indicated. The trough tacrolimus concentrations were measured using a microparticle enzyme immunoassay (IMx analysis II, Abbott Diagnostics, Abbott Park, Illinois). The CsA concentration was determined by immunoassay using monoclonal antibodies or high-performance liquid chromatography.

This study was undertaken in accordance with the Declaration of Helsinki (48th General Assembly, Somerset West, Republic of South Africa, October 1996) and all subsequent updates and was approved by the appropriate ethics committees. Written informed consent was obtained from all participants. At each center, randomization was performed intraoperatively, or at the latest 12 hr after transplantation using sealed envelopes provided by the Data Operations Department of Fujisawa GmbH. Each center was allocated a unique sequence of patient numbers, and patients were allocated the consecutive center specific patient number. After opening the sealed envelope, the investigator was provided with the patient’s study number and the treatment group to which the patient was randomized.

Efficacy and Safety Assessments

All visits were calculated from the date of surgery or reperfusion (day 0); at days 1, 7, 14, and 21; and at months 2, 3, and 6. Blood pressure, weight, and routine laboratory assessments were all performed at baseline. After surgery, graft and patient survival were assessed on a continuous basis. Patients were observed for signs of rejection (e.g., increase in serum creatinine, fever, tenderness of the graft, reduced urine output) on an ongoing basis. At each visit, blood and urine samples were obtained for laboratory evaluation. Vital signs were recorded at all visits. Periods of dialysis dependence and periods of hospitalization, between visits, were recorded, as were details of concomitant immunosuppressive therapy and general medication.

In case of a clinically apparent rejection, a renal biopsy specimen was taken and was thereafter classified by the local histopathologist according to the Banff 93 criteria (9). Acute rejection episodes were treated with an increased dosage of corticosteroids; if the rejection failed to respond, antibody therapy was initiated according to local practice. Rejections were therefore classified as “corticosteroid-sensitive” or “corticosteroid-resistant.” The latter category comprised rejections that required antibody treatment, addition of mycophenolate mofetil, or a switch of the baseline immunosuppressant.

The primary efficacy endpoint of the study was the incidence and time to biopsy-confirmed acute rejection (Banff 93, grades I, II, and III). Secondary efficacy endpoints included the incidence of clinically apparent rejection, the number of corticosteroid-resistant rejections, the severity of the histopathology of the rejections, the number of days hospitalized, and the number of days on dialysis.

Adverse events were recorded on an ongoing basis. All serious adverse events (death or life-threatening events and those causing persistent significant disability or incapacity, hospitalization or prolongation of hospitalization, congenital abnormality, cancer, and overdose) were reported to the sponsor within 24 hr of their occurrence to allow for notification of the health authorities.

Statistical Analysis

The sample size was determined on the basis of an estimated incidence of acute rejection in the first 6 months posttransplantation of 25% for patients receiving tacrolimus-based therapy. Allowing for a dropout rate of 12.5%, it was estimated that a total of 555 patients (185 patients in each treatment group) would be required to detect a difference of 15% between the treatment groups with a power of 75%. The intent-to-treat population included all randomized patients who received at least one dose of study medication and was used for all analyses for both efficacy and safety. For the incidence of and time to first acute rejection episode confirmed by biopsy, the Kaplan-Meier procedure (10) was used to estimate the survival rates by treatment group. The generalized Wilcoxon test was used to test equality across the three treatment groups, and if the generalized Wilcoxon test showed significance at the P <0.05 level, the two-tailed generalized Wilcoxon test was performed to assess the significance of differences between treatment groups. Ninety-five percent confidence intervals for rejection-free rates at month 6 were calculated for each treatment and for all treatment differences using Greenwood’s formula. Fisher’s exact test was used to compare differences in adverse events. Corticosteroid usage was summarized and the cumulative dose of corticosteroids up to month 6 was compared between treatment groups using the Kruskal-Wallis test, as was the cumulative dose of azathioprine.

RESULTS

Patients

In total, 568 patients were recruited and randomized to receive treatment: 188 in the Tac triple group, 190 in the ATG-Tac group, and 190 in the ATG-CsA group. In all, 13 patients were excluded from the intent-to-treat population (three in the Tac triple group, four in the ATG-Tac group, and six in the ATG-CsA group) because they did not receive a transplant, study medication, or induction therapy (Table 1). Of the intent-to-treat population, a total of 88 patients withdrew during the study (Tac triple, n=22; AGT-Tac, n=28; ATG-CsA, n=38). The most common adverse events associated with premature discontinuation of the study in the three treatment groups, Tac triple, ATG-Tac, and ATG-CsA, respectively, were hemolytic uremic syndrome (three, two, and six patients), drug-induced nephrotoxicity (two, four, and three patients), increased serum creatinine level (two, three, and four patients), diabetes mellitus (two, three, and zero patients), and acute tubular necrosis (three, zero, and zero patients). A total of 13 patients (five, three, and five patients, respectively) died during the study or after withdrawal (Table 1).

T1-21
Table 1:
Disposition of patients

The treatment groups were well balanced with regard to demographic characteristics and in terms of primary diagnoses (Table 2). In all treatment groups, there were more male than female patients, and in the Tac triple and ATG-Tac groups there were fewer patients who had undergone at least one previous transplant compared with the ATG-CsA group (P =0.03). Mean cold ischemia times were similar for each group, as was the CMV status of the recipient and donor. There were no significant differences between values for human leukocyte antigen mismatch. The number of patients with a panel reactive antibody (PRA) grade of greater than 50% was small overall but significantly higher in the ATG-CsA group than in the other two groups (P =0.044) (Table 2). There were no substantial differences between the treatment groups with regard to medical history and current secondary diagnoses.

T2-21
Table 2:
Patient demographics and baseline characteristics

Treatment Compliance and Study Drug Exposure

Values for dosages administered and whole-blood trough concentrations are given in Table 3. In the Tac triple group, the mean daily dose at week 1 was 0.22 mg/kg, and by month 6 the mean daily dose had been reduced to 0.12 mg/kg. The mean whole-blood trough levels of tacrolimus in the Tac triple group fell gradually from 19.8 ng/mL at week 1 to 10.1 ng/mL at month 6. In the ATG-Tac group, the mean daily dose of tacrolimus during week 2 was 0.24 mg/kg, and by month 6 the mean daily dose had been reduced to 0.12 mg/kg. The whole-blood trough concentrations of tacrolimus had fallen from 17.9 ng/mL at week 2 to 9.9 ng/mL at month 6. The mean daily dose of CsA in the ATG-CsA group was 6.4 mg/kg during week 2, and during month 6 the mean daily dose had been reduced to 3.9 mg/kg. The mean CsA whole-blood trough concentration was 228.7 ng/mL during week 2. The maximum concentration of 256.3 ng/mL was observed during week 3 (mean daily dose, 5.9 mg/kg). During month 6, CsA concentrations had fallen to a mean value of 165.4 ng/mL. The concentrations of both immunosuppressive agents were within the recommended ranges for this study and similar to those observed in other studies (7,11,12).

T3-21
Table 3:
Tacrolimus and CsA daily oral doses and whole-blood concentrations (relative to day of skin closure)

By month 6, the total cumulative daily corticosteroid doses (mean±SD) were 61.5±31.2 mg/kg (Tac triple), 59.2±42.4 mg/kg (ATG-Tac), and 59.9±33.6 mg/kg (ATG-CsA). There were no significant differences between the groups (P =0.494). The mean daily dose of azathioprine was consistently higher in the Tac triple group than in the ATG-Tac and ATG-CsA groups throughout the study, and differences between the treatment groups emerged in terms of the cumulative dose (mean±SD) at month 6: Tac triple, 223.5±89.3 mg/kg; ATG-Tac, 166.6±90.2 mg/kg; and ATG/CsA, 148.8±98 mg/kg (P <0.001).

Efficacy

Clinical signs and symptoms of acute rejection were present in 61 patients (33.0%) in the Tac triple group, 42 patients (22.6%) in the ATG-Tac group, and 68 patients (37.0%) in the ATG-CsA group (Table 4). The incidence of clinically apparent rejection in the Tac triple group was significantly higher than for ATG-Tac (P =0.003); the incidence for ATG-Tac was significantly lower than for ATG-CsA (P =0.004). The incidences of corticosteroid-resistant rejection in the Tac triple group (8.1%) and in the ATG-Tac group (7.0%) were significantly lower than for ATG-CsA (18.5%, P =0.002). Although at baseline the numbers of patients with PRA greater than 50% were significantly different between groups (3, 6, and 12 patients, respectively), the incidence of clinical acute rejection in each of the treatment groups was not significantly changed when data for these patients were excluded (32.9%, 22.2%, and 36.0%, respectively).

T4-21
Table 4:
Frequency of acute rejection

Of the clinically diagnosed rejection episodes, 90.2% (Tac triple), 92.9% (ATG-Tac), and 85.3% (ATG-CsA) were investigated by core needle biopsy for confirmation of acute rejection. A total of 47 patients (25.4%) in the Tac triple group experienced biopsy-confirmed acute rejection compared with 28 patients (15.1%) in the ATG-Tac group and 39 patients (21.2%) in the ATG-CsA group (Table 4). Differences between all treatment groups over 6 months for the patients free from biopsy-confirmed acute rejection were significant (P =0.011). The incidence of biopsy-confirmed acute rejection was significantly higher for Tac triple compared with ATG-Tac (P =0.004). The incidence in the ATG-Tac group was lower than observed in the ATG-CsA group, but the difference was not statistically significant (P =0.117). The incidences of corticosteroid-resistant acute rejection confirmed by biopsy in the Tac triple group was 7.0% compared with 4.8% for ATG-Tac and 10.9% for ATG-CsA. The difference between the ATG-Tac group and the ATG-CsA group was statistically significant (P =0.038).

By month 6, the estimated rate of patients free from biopsy-confirmed acute rejection in the Tac triple group was 74.3% (95% confidence interval [CI], 67.9%–80.7%) as compared with 84.6% in the ATG-Tac group (95% CI, 79.3%–90.0%) and 78.7% for the ATG-CsA group (95% CI, 72.5%–84.9%) (P =0.011). As shown in Figure 1, the onset of rejection events was delayed in the induction groups, with a median time to onset of the first biopsy-proven acute rejection of 12 days in the Tac triple group, 19.5 days in the ATG-Tac group, and 29 days posttransplant in the ATG-CsA group.

F1-21
Figure 1:
Kaplan-Meier analysis of the incidence and time to first biopsy-proven acute rejection over 6 months. The estimated rates of patients free from biopsy-proven acute rejection were 74.3% (Tac triple), 84.6% (ATG-Tac), and 78.7% (ATG-CsA) (over all groups, P =0.011; ATG-Tac vs. ATG-CsA, P =0.177). The median time to onset of the first biopsy-proven acute rejection was 12 days in the Tac triple group, 19.5 days in the ATG-Tac group, and 29 days posttransplant in the ATG-CsA group.

The majority of acute rejections in all three groups were mild according to the Banff 93 criteria (Table 5). There were no significant differences between groups for the mild (Banff I) category, but when considering the moderate and severe categories together (Banff II and III), it was apparent that the histologic severity was significantly lower in the ATG-Tac group compared with the ATG-CsA group (P =0.023).

T5-21
Table 5:
Histologic grades of biopsy-confirmed acute rejectionsa

Safety

Patient survival.

In total, 13 patients died during the study or after withdrawal (Table 1). The majority died of infections, sepsis, and multiple organ failure (four, zero, and two patients in the Tac triple, ATG-TAC, and ATG-CsA groups, respectively). Cardiovascular events were responsible for the death of three patients (one patient in each group) and two patients (one in the ATG-Tac group and one in the ATG-CsA group) died from noninfectious pulmonary events. One patient in the ATG-Tac group died of unknown causes and one in the ATG-CsA group committed suicide. Patient survival rates over the 6-month study using Kaplan-Meier estimates were similar in the three groups: 97.0% for Tac triple, 98.4% for ATG-Tac and 97.0% for ATG-CsA (P =0.788).

Graft survival, graft function, and hospitalization.

In the Tac triple group, 10 grafts were lost compared with 7 graft losses in the ATG-Tac group and 16 graft losses in the ATG-CsA group. The most common reasons for graft loss were death with a functioning graft, rejection, and thrombosis of the renal artery or vein (Table 6). Graft survival rates over the 6-month study using Kaplan-Meier estimates were slightly higher in the groups receiving tacrolimus but not significantly so, with 93.2% for Tac triple, 95.2% for ATG-Tac, and 90.8% for ATG-CsA (P =0.23). Graft function in terms of mean serum creatinine (±SD) was similar for the three treatment groups and, at month 6, mean values for the Tac triple, ATG-Tac, and ATG-CsA treatment groups were 134.0±68.7, 132.5±39.0, and 134.0±47.6 μM, respectively.

T6-21
Table 6:
Reasons for graft loss

The number of patients requiring dialysis during the study period was similar in the three groups, with 25.9% for Tac triple, 19.9% for ATG-Tac, and 25.5% for ATG-CsA. The number of days on dialysis (median) was also similar between groups: Tac triple, 7.5 days (range, 1–94 days); ATG-Tac, 4.0 days (range, 1–73 days); and ATG-CsA, 6.0 days (range, 1–47 days). The incidence of never functioning grafts was low overall: two, three, and two patients in the Tac triple, ATG-Tac, and ATG-CsA groups, respectively. The mean total number of days in hospital for each of the treatment groups was 29.2±17.9 days for Tac triple, 31.5±18.5 days for ATG-Tac, and 31.1±18.4 days for ATG-CsA, and there were no statistically significant differences between the groups.

Adverse events.

Adverse events were reported for nearly all patients: 179 patients (96.8%) in the Tac triple group, 182 patients (97.8%) in the ATG-Tac group, and 182 patients (98.9%) in the ATG-CsA group. The five most frequently observed adverse events that were not significantly different between the three groups, Tac triple, ATG-Tac, and ATG-CsA, respectively, were anemia (24.9%, 30.6%, and 26.6%), urinary tract infection (26.5%, 26.9%, and 23.9%), hypertension (18.4%, 17.7%, and 24.5%), acute tubular necrosis (ATN) (17.8%, 17.2%, and 13.6%), and increased creatinine (11.9%, 15.1%, and 17.4%). The diagnosis of ATN was made on the basis of biopsy findings. In three patients in the Tac triple group, ATN led to withdrawal from the study.

The adverse events that were significantly different between groups are shown in Table 7. In the groups receiving ATG induction, there was a significantly greater incidence of leukopenia, thrombocytopenia, serum sickness, fever, and CMV infection than in the Tac triple group. More than 80% of all cases of leukopenia and all cases of thrombocytopenia occurred in the first 7 days after transplantation, and the duration of these adverse events rarely exceeded a week. Neither leukopenia nor thrombocytopenia led to withdrawal from the study in any patient.

T7-21
Table 7:
Incidence of adverse events for which there were significant differences between groups

In addition to the significantly higher incidence of CMV infection (P =0.012) (Table 7), the frequency of bacterial infections (37.8%, 41.4%, and 41.3%) was also higher in the groups receiving ATG induction but not significantly so. Fungal (6.5%, 4.8%, and 6.0%) and protozoal (1.1%, 2.2%, and 0.0%) infections were reported with similar incidences in all groups. However, significant differences were apparent for all infections: 58.4% of patients receiving Tac triple recorded infection events compared with 67.7% in the ATG-Tac group and 75.0% in the ATG-CsA group (P =0.003). There was a significantly greater incidence of tremor in the patients receiving Tac triple and ATG-Tac than in the ATG-CsA patient group; conversely, there was a significantly greater incidence of hypercholesteremia in the ATG-CsA group. In patients without preexisting glucose metabolism disorders, the incidence of those with new-onset diabetes mellitus (i.e., insulin treatment for >30 consecutive days) in the three treatment groups, Tac triple, ATG-Tac, and ATG-CsA, was 7 of 173 (4.0%), 13 of 177 (7.3%), and 2 of 177 (1.1%), respectively (P =0.014).

One of the main concerns of antibody induction is the occurrence of malignancies. In the course of the study, seven malignant events were reported, one in the Tac triple group (Kaposi’s sarcoma), two in the ATG-Tac group (lymphoma, cancer in the transplanted kidney), and four in the ATG-CsA group (two lymphomas, one case of Epstein-Barr virus-related pre-posttransplant lymphoproliferative disorder, and one prostate cancer).

DISCUSSION

Overall, this European, multicenter, 6-month study comparing the therapeutic outcomes and safety of tacrolimus-based and CsA microemulsion-based triple therapies with ATG induction or immediate tacrolimus triple therapy has shown advantages for tacrolimus. Close assessment of the data indicated that the differences in therapeutic outcomes could not be explained by any disparity in the baseline data of the patient or donor population.

Clinical signs and symptoms of acute rejection were significantly different between the treatment groups. ATG-Tac was significantly more effective than ATG-CsA (P =0.004) and also more effective than Tac triple (P =0.003) in the prevention of acute rejection. However, the difference in the incidence of biopsy-proven acute rejection in the ATG-Tac group (15.1%) and in the ATG-CsA group (21.2%) did not reach statistical significance (P =0.177). This may in part be explained by the different number of biopsies performed: in the ATG-Tac group, 92.9% of all clinically apparent rejection episodes were investigated by biopsy, whereas in the ATG-CsA group, only 85.3% of clinically diagnosed rejections underwent biopsy. As a consequence, there may have been an underreporting of rejection events in the ATG-CsA arm. The incidence of biopsy-confirmed corticosteroid-resistant acute rejection was significantly lower in the ATG-Tac group compared with ATG-CsA group (P =0.038). Furthermore, there were significantly more Banff II and III acute rejections in the ATG-CsA group than in the ATG-Tac group (P =0.023). This difference between the treatment groups was not because of the unbalanced distribution of highly sensitized patients at study start. When all patients with PRA grades of 50% and higher were excluded from the analysis of histologic grades, the difference remained significant: there were 8 of 180 patients in the ATG-Tac group with histologic grades of Banff II or III compared with 20 of 172 patients in the ATG-CsA group (P <0.05).

Exposure to immunosuppressive medication was similar in all three groups, and the recommended dosages and trough level ranges were followed. Tacrolimus whole-blood trough levels remained within the target ranges and were similar to those observed in other studies (6,7). Also, for CsA, the dosages given and the trough levels obtained were within the ranges used in other studies (7,11,12). There was no difference in the total corticosteroid dose between the three groups. The cumulative daily azathioprine dose was significantly higher in the Tac triple group than in the ATG induction groups (P <0.001).

ATG induction is considered to be of particular benefit to immunized patients who are assumed to be more prone to acute rejection (4,13). The number of patients with PRA values above 50% was small in this study (21 in total). The incidence of rejection in highly immunized patients was one of three patients (33%) in the Tac triple group, two of six patients (33%) in the ATG-Tac group, and 6 of 12 patients (50%) in the ATG-CsA group.

The significantly lower incidence of acute rejection in the ATG-Tac group compared with Tac triple confirms the results of a previous study (5) in which tacrolimus-ATG was significantly (P =0.001) more effective than tacrolimus without induction. In addition, the incidence of biopsy-proven acute rejections was similar between the studies: 30.4% and 15.2% for Tac triple and ATG-tacrolimus, respectively, compared with the values of 25.4% and 15.1%, respectively, reported in this study.

The improved clinical outcome with ATG-tacrolimus versus ATG-CsA with respect to the incidence and severity of acute rejection is in agreement with the therapeutic outcome reported in a number of comparative studies in the absence of induction (6,7) and also confirms the results of the previous study in the United States in which induction was used (8). In that study, however, induction was by either OKT3 or ATGAM, the standard formulation of CsA was used, and tacrolimus and CsA were administered when renal function was fully established. In both the American study (8) and the European study reported here, acute rejections were more severe in the induction-CsA group. It is notable that in both the current study and in previous studies patient survival and graft survival were not influenced by induction. However, a reduction in the rate and incidence of acute rejection is considered to be of particular clinical relevance, because acute rejection is a significant risk factor for chronic rejection (3,14–17).

Patient and graft survival rates were similar in all groups 6 months after transplantation. Graft function recovered quickly in all three groups; however, the induction groups seem to have reached normal serum creatinine levels more rapidly. At study end, the mean serum creatinine values were similar in the three groups, with 134.0 μM for Tac triple, 132.5 μM for ATG-Tac, and 134.0 μM for ATG-CsA.

The incidence of adverse events and their severity was typical for tacrolimus and CsA and, as expected (3,6–8), it was found that new-onset diabetes occurred more frequently with tacrolimus, whereas hypercholesteremia was more common in the CsA group. The ATG induction therapy, however, irrespective of the primary immunosuppressive agent, was associated with increased side effects in terms of infection, serum sickness, fever, and leukopenia. These observations are similar to those reported by others for the use of induction therapy, and it has also been suggested that there may be an increased risk of malignancies (2,3,5).

CONCLUSION

This study has shown that induction therapy combined with tacrolimus-based immunosuppression is associated with lower rates of acute rejection than found with a combination of ATG induction and CsA-based therapy. Induction therapy was also associated with an increased incidence of hematologic disorders and infections, particularly CMV. Thus, there seems to be a balance in the use of induction therapy: lower rates of acute rejection are achieved, but the occurrence of severe side effects has to be taken into account.

Acknowledgment.

The authors thank T. Schindler, Ph.D., for expert editorial help.

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