Mean follow-up time was 37 months posttransplant. For the primary efficacy assessment of acute rejection, the acute rejection rate was 10% at 6 months and 11% at 12 months and was similar for both subgroups (3-dose arm: 10%, 10%; 4-dose arm: 9%, 11%; p=ns, Table 3). The majority of acute rejection episodes were steroid responsive. Of the patients who experienced acute rejection within the first year (n=9), two of 37 patients with PRA more than or equal to 80% experienced acute rejection, whereas two of 13 patients with a PRA 20% to 79% and one of eight African Americans with no other risk factors experienced acute rejection. Patient and graft survival at 1 year was 100% for each group. During the entire period of follow-up, graft survival was 92% and patient survival was 97%, with no differences between 3-dose or 4-dose cohorts. Additional analyses of the median length of hospital stay (LOS) and eGFR demonstrated that the LOS in the 3-dose group was shorter than the 4-dose group (LOS 3 days vs. 4 days, respectively, P=0.004) and the eGFR was significantly higher in the 3-dose rATG group at both 6 months and 1 year (at 6 months: 3-dose=64 mL/min vs. 4-dose=57 mL/min, P=0.03; at 1 year: 3-dose=63 mL/min vs. 4-dose=55 mL/min, P=0.03).
The rate of infectious complications was not statistically different between the subgroups (Table 3). At 1 year, the most common infections in the 3-dose group were bacterial infections (25.6%; upper respiratory/pneumonia n=3, urinary tract infection/pyelonephritis n=3, other=3), CMV disease (5.1%), and BKV viremia (5.1%). In the 4-dose group, the incidence of infection overall was similar and included bacterial infections (15.9%; upper respiratory/pneumonia n=1, urinary tract infection/pyelonephritis n=4, other=3), and BKV viremia (18.2%) with no patients experiencing CMV disease. The incidence of neutropenia within the first year was 7.2% overall and not significantly different between subgroups. Although there was a trend toward a lower frequency of BKV viremia in the 3-dose (4.5 mg/kg) group, this difference did not reach statistical significance (P=0.09). Of those patients with BK viremia, two patients in the 3-dose arm and one patient in the 4-dose arm developed biopsy-proven BKV nephropathy with graft dysfunction within the first year posttransplant; whereas two additional cases of BKV nephropathy occurred after the 12-month assessment in the 4-dose arm. When excluding patients with BK viremia from the analysis, eGFR differences persisted between the 3-dose and 4-dose arms (mean eGFR at 6 months: 3-dose=65 mL/min vs. 4-dose=58 mL/min, P=0.05; at 1 year: 3-dose=65 mL/min vs. 4-dose=55 mL/min, P=0.02).
This study is the first to report the efficacy of two defined low-exposure dosing regimens (3 or 4 consecutive days, 1.5 mg/kg/day rounded to the nearest 25 mg) of rATG as an induction agent in patients at increased immunologic risk of acute rejection and is the largest report of “lower-dose” (4.5 mg/kg total) rATG use in a subset of our patient population. The findings of low acute rejection rates and excellent patient and graft survival at 1 year with either approach support either strategy in this “high risk” group and provide a rationale for further studies to optimize rATG use.
Others have reported the efficacy of rATG at lower doses in patients with different risk profiles. A single-center report of 16 patients, all of whom were primary transplants with low PRA, examined the efficacy of 3.0 vs. 4.5 mg/kg total dose rATG for 3 days (15). No acute rejection was reported; interestingly, an analysis of peripheral T cell depletion showed that 4.5 mg/kg rATG resulted in more prolonged depletion of T cells at 1 and 6 months vs. 3.0 mg/kg. These findings were similar to a previous study of 58 low-immunologic risk patients at risk for delayed graft function, which demonstrated improved protection from acute rejection with intraoperative dosing and a total exposure of 4.6 mg/kg rATG (16). Finally, a prospective trial of 41 patients with risk factors for delayed graft function and acute rejection evaluated an intermittent rATG dosing strategy based on CD3+ lymphocyte depletion (17). The inclusion criteria were more heterogeneous within this trial than ours and included patients with simultaneous kidney pancreas transplants and patients at risk for delayed graft function exclusive of immunological risk factors for acute rejection. Despite these differences, the low acute rejection rate (12.2% of patients) achieved in this trial with a mean total cumulative dose of rATG of 4.2 mg/kg is comparable with our results. Together with our study, these studies suggest that a lower dosing range for rATG exists depending on indication and patient characteristics, which may be evaluated at intervals both pre- and posttransplantation.
Additional findings when comparing the 3-dose to 4-dose rATG subgroups are worthy of comment. Of secondary interest is the difference in median length of hospital stay between the 3-dose and 4-dose cohorts. Since the time of infusion of rATG often requires 4 to 6 hr after the first dose to avoid infusion-related side effects, a reduction in rATG total dose may permit a more rapid transition to an outpatient setting. This would be expected to result in a cost-savings by reducing both medication and hospital charges. However, because many facilities are capable of transitioning patients to an outpatient infusion center routinely, a strong relationship between dose reduction of rATG and cost savings related to early hospital discharge cannot be firmly stated. Differences in eGFR were noted between the 3- and 4-dose groups at both 6 and 12 months after transplant. One potential explanation for these findings was that the more frequent use of TAC/SRL/Pred in the 4-dose cohort may have resulted in a reduced eGFR due to enhanced CNI nephrotoxicity with this regimen compared with a TAC/MPA/Pred regimen (22–24), despite equivalent acute rejection rates. Although the differences in maintenance immunosuppression may have influenced eGFR differences, it is unlikely that this influenced the primary endpoint (the incidence of acute rejection), because acute rejection was not more prevalent with one antiproliferative agent than another (four patients taking MPA and five patients taking SRL had rejection). A final observation from this study was the trend to greater BK viremia in the 4-dose cohort. Given the differences in maintenance immunosuppression regimens, it is difficult to ascribe increased risk of BK viremia simply due to an additional 1.5 mg/kg dose of rATG. When excluding patients with BKV viremia from the eGFR comparison, the eGFR differences persisted between subgroups. Therefore, the eGFR findings cannot be attributed to a higher rate of renal dysfunction from BKV.
A number of limitations of our study should be considered. Despite the important finding of low acute rejection rates in both arms, the retrospective nature of the study does not permit determination of other variables that may be contributory when selecting patients for 3- vs. 4-dose therapy, and thus patients with unaccounted-for factors (e.g., a more rapid change in creatinine by day 3 or an uneventful postoperative course) may have influenced 3- vs. 4-dose therapy. Our results are limited to patients who did not develop delayed graft function (dialysis within 48 hr after transplant) because these patients would commonly remain on rATG for longer periods while calcineurin inhibitors were held to avoid additional nephrotoxicity in the early posttransplant period and would typically remain hospitalized for more prolonged periods. Given the immediate graft function in both groups and the lower serum creatinine values on day 2 in the 3-dose cohort, it is likely that the degree of immediate graft function contributed to medical decision-making regarding 3- vs. 4-dose strategies. Additionally, expanded criteria donors comprised a small percentage of deceased donors within this study, which limits the interpretation of this study for this subgroup. Reduced-dose rATG may indeed be reasonable in patients with expanded criteria donor kidneys or DGF as well. Our clinical practice during this era did not permit this assessment, and the study must be viewed within the context of these donor and recipient risk factors. We included African American race within our definition of increased immunologic risk, despite ongoing debate regarding its inclusion in the definition of “high risk” (25, 26). However, only eight of the 83 patients would have been excluded if this cohort were not considered at increased risk for acute rejection. We used a PRA cutoff of more than or equal to 20% for inclusion, a value that is variably applied to high-risk cohorts (2, 27). Despite these inclusion criteria, most patients were classified as high risk due to a previous transplant and had an elevated PRA more than or equal to 80%, and only 13 of 83 subjects would have been excluded from this study if the PRA threshold for inclusion were limited to PRA more than or equal to 80%. Using the more stringent definition of “immunologic high risk,” of the 62 patients with PRA more than or equal to 80% or who were retransplant recipients, the acute rejection rate was 8% at 1 year.
Despite these limitations, this report provides promising safety and efficacy data for the use of reduced dose rATG in high-risk renal transplant recipients. An additional economic benefit may exist with reduced dose rATG not only from medication cost savings but also a potential decrease in overall hospital costs. These data support the use of tailored rATG induction therapy for patients with elevated immunologic risk and immediate graft function and warrant further study in novel immunosuppression regimens and patient populations.
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