1.  Introduction

Rabbit Antithymocyte globulin (rATG) is a polyclonal antibody indicated for the treatment of acute rejection in renal transplant recipients [1]. Transplant centers across the nation are also utilizing this agent for induction therapy in kidney transplantation [2,3]. The approved FDA indication of 1.5 mg/kg/day for 4 to 7 days is supported by clinical trials that have shown rATG to be as effective as other induction agents in preventing acute rejection [4-7]. However, some studies report that the use of rATG is associated with several adverse effects, including an increased risk of infectious complications, a grave concern for kidney transplant recipients [4-6]. While the tradeoff between the benefit and the risk is yet to be established, evidence suggests that the immunosuppressive benefit of rATG may outweigh risks of infection when administered to patients with high immunologic risk, such as kidney transplant recipients with Delayed Graft Function (DGF) [8-11].

DGF is defined as a post-transplant complication that requires dialysis within one week following kidney transplantation. Its occurrence is associated with inferior graft outcomes and increased risk of graft rejection [9,12]. Immediate initiation of calcineurin inhibitors post-transplant may prolong renal transplant recovery from DGF because of its nephrotoxicity. Administration of rATG induction helps delay initiation of calcineurin inhibitors without increasing the risk of rejection post-transplant.

However, a study has suggested that doses of greater than 7 mg/kg of rATG for induction in the early postoperative period may be associated with an increased incidence of infectious episodes [13]. Therefore, there is a critical need to examine whether there exists an optimal cumulative dose of rATG induction that is effective for high risk renal transplant patients, as well as, minimizes infectious episodes without compromising allograft outcomes in renal transplant recipients with DGF. The purpose of this study is to compare outcomes of reduced dose versus standard dose rATG in deceased donor kidney transplant recipients with DGF.

2.       Methods

2.1    Study Design and Patients

The study design was a retrospective chart review of adult deceased donor kidney recipients who developed DGF following transplantation at Methodist University Hospital from January 1, 2005 to April 30, 2011. Patients were included if they received dialysis for the treatment of DGF within the first week after renal transplantation, (2) received rATG induction therapy preoperatively, and (3) had a minimum of one-year follow-up. Patients were excluded if (1) they received multiple transplants, such as simultaneous liver-kidney or kidney-pancreas, (2) experienced graft loss within the first week post-transplant.

2.2    Treatment Assignment

Patients receiving a cumulative rATG dose of < 7 mg/kg were placed in the reduced dose group while those receiving a cumulative dose of ≥ 7 mg/kg were in the high dose group. Induction with rATG was initiated according to the institution’s immuno suppression protocol. Based on the patient’s actual body weight at the time of transplant, rATG was given intra operatively using an Intravenous (IV) dose of 1.5 mg/kg. Postoperatively, patients received 3 to 6 additional doses of 1.5 mg/kg daily.

 For the first rATG dose, patients received methyl prednisolone 500 mg preoperatively followed by a steroid taper to a goal of prednisone 5 mg daily by 30 to 60 days post-transplant. Patients were also pre-medicated with acetaminophen 650 mg PO and diphenhydramine 25-50 mg PO/IV, 30 minutes prior to each infusion. After the first rATG dose, patients were premeditated with hydrocortisone 50-100 mg IV instead of methyl prednisolone.  Mycophenolate mofetil was started at 500 mg twice a day on the day of transplant and titrated to a goal of 2000 mg daily in divided doses as tolerated. Tacrolimus was started per transplant nephrologist’s preference. A trough level of 8-15 ng/mL was targeted for the first three months, 8 10 ng/mL for months 3 through 6, and 7-9 ng/mL for months 6-12. All patients received an antifungal, antiviral, and Pneumocystis jiroveci pneumonia prophylaxis following transplantation. Prophylactic medications were adjusted for renal function.

2.3  Measures of Study End Points

The primary endpoint consisted of renal outcomes measured by Serum Creatinine (SCr) and calculated estimated Glomerular Filtration Rate (eGFR) at 1, 3, 6, and 12 months. Estimated GFR (eGFR) was calculated using the abbreviated MDRD (Modification of Diet in Renal Disease) equation [14] Secondary endpoints included patient and graft survival at each time point, episodes of Biopsy-Proven Acute Rejection (BPAR), and infectious episodes of BK virus (BKV) and/or Cytomegalovirus (CMV) within the first-year post-transplant. Episodes of BPAR were further classified into T-cell vs. antibody mediated ones. Infectious episodes of BKV and/or CMV were determined by a positive Polymerase Chain Reaction (PCR).

2.4   Statistical Analysis

Endpoints were compared between treatment groups using the chi-square analysis for categorical data and the t-test for continuous data. The Grubbs tests were used to detect any significant outliers. Statistical significance was defined as a P value less than 0.05. SAS 9.4 (Cary, North Carolina) was used to perform the statistical test.

3.  Results

3.1   Description of Study Subjects

Of the 131 patients previously categorized as DGF, 41 were excluded because they did not receive dialysis for the treatment of DGF within the first week of transplant (Figure 1).

Five were excluded for graft loss within the first week post-transplant, 4 were lost to follow-up, and 3 did not receive rATG intra operatively. Of the 78 patients who met inclusion/exclusion criteria, 26 were in the reduced dose rATG group and 52 were in the standard dose rATG group. Baseline recipient characteristics were similar between groups (Table 1)

The population was predominantly male (65.4%) and African American (83.3%). The leading causes of renal failure were hypertension and diabetes (74.4% and 23.1%, respectively), and 14% of patients had received a previous kidney transplant. Donor and transplant characteristics were also similar between groups (Table 2), except the standard dose rATG group received significantly more standard criteria donor organs compared to the reduced dose rATG group (P = 0.043). The mean cumulative rATG dose (±SD) in the reduced dose group was 6.0 ± 0.9 mg/kg compared to 8.1 ± 0.9 mg/kg in the standard dose group. Maintenance immuno suppression upon discharge was also similar between groups.

3.2   Primary Outcomes

Renal outcomes were similar between groups at all the time points. Mean serum creatinine was similar between the reduced dose group and the standard dose rATG group upon discharge (8.68 vs. 9.06 mg/dL), at 1-month post-transplant (2.37 vs. 2.44 mg/dL), at 3 months post-transplant (1.86 vs. 1.9 mg/dL), at 6 months post-transplant (1.9 vs. 1.7 mg/dL), and at 12 months post-transplant (1.62 vs. 1.7 mg/dL), respectively (Figure 2). Calculated e GFR was also similar between the reduced dose group and the standard dose group upon discharge (8 vs. 8.61 mL/min/1.73 m2), at 1-month post-transplant (37.77 vs. 43.4 mL/min/1.73 m2), at 3 months post-transplant (50.96 vs. 51.42 mL/min/1.73 m2), at 6 months post-transplant (49.48 vs. 56.04 mL/min/1.73 m2), and at 12 months post-transplant (55.88 vs. 56.28 mL/min/1.73 m2), respectively (Figure 3).

3.3    Secondary Outcomes

Patient and graft survival were not significantly different between groups at all the time points (Table 3).

Although not significantly different, patient survival was lower in the standard dose group (96.1%) than it was in the reduced dose group (100%) at 12-months post-transplant. Further patients in the standard dose group, although not significantly different from those in the reduced dose group, began to experience graft loss at approximately 3 to 6 months post-transplant. Episodes of BPAR, both T-cell mediated and antibody mediated, did not differ significantly between both groups (Figure 4). Comparison of infections with BKV and CMV were also similar between the reduced and standard dose groups (Figure 5).

4.  Discussion

The primary goal of rATG induction is to prevent acute rejection and preserve graft function by delaying the use of calcineurin inhibitors. However, rATG exposure should be minimized to prevent infectious complications related to BKV and CMV [13]. Our study found no significant difference in primary renal outcome measures such as SCr and eGFR as well as in secondary outcome measures such as patient/graft survival, episodes of BPAR, and infections with BKV and CMV between the reduced dose group and the standard dose group. In other words, a cumulative rATG dose of < 7mg/kg was found to be as effective as that of ≥ 7 mg/kg based on 1-year allograft outcomes.

It is worthwhile to note that the risk of infection related to BKV or CMV was not significantly different between the two groups. This non-significant finding was rather unexpected because previous studies reported that higher doses (cumulative dose >7 mg/kg) of rATG induction increased the risk of post-transplant infections [4,6,7,13,15]. Unlike the previous studies, our population predominantly consisted of African-American patients (~83% of the study population). African-American ethnicity, considered a risk factor for acute rejection possibly due to hyper immune responsiveness [16].  Could have contributed to the similar incidence of infection that was identified between groups in this study

It is also worthwhile to note that baseline characteristics were similar between the two different dose groups except for donor criteria. The transplant center from which the study subjects were recruited expanded the criteria for acceptance of donor kidneys in order to increase its donor pool for kidney transplantation. A study reports that kidney transplant patients who have received the expanded-criteria donors display inferior graft outcomes when compared to those who have received standard-criteria donors [17] our study found similar graft outcomes despite the increased incidence of expanded-criteria donors in the reduced dose rATG group. Had the two dosing groups received the same criteria donor, the reduced dose group could have produced more favorable outcomes than the standard dose group.  Future studies need to compare cost-effectiveness between low vs. high dose rATG inductions. Our study found no significant differences in primary as well as in secondary outcome measures between two different dosing strategies.

This finding suggests that the reduced dosing strategy would be more cost-effective than the standard dosing one considering the current cost of rATG at $797.35 per 25mg vial [18]. The exact cost-effectiveness of the reduced dosing strategy should factor in all costs related to drug preparation, hospital length of stay, and readmissions for post-transplant complications. A well-designed cost effectiveness study will inform transplant centers of efficient resource allocations between different dosing strategies of rATG induction for kidney transplant patients with DGF. This study had two limitations related to study sample. First, the sample size was small (n= 78), and thus may not be enough patients included in the study to detect a significant difference between two different dosing strategies. However, significant differences were identified with the donor source and cumulative rATG dose between groups.  Secondly, prescribers could have assigned more high-risk patients to the standard dosing strategy than to the reduced dose one. However, it is important to note that baseline characteristics were not significantly different between two different dosing strategies except for donor source.

5.  Conclusions

The reduced dosing strategy of rATG induction which consisted of a mean cumulative dose of 6 mg/kg was as effective as the standard dosing strategy which consisted of a mean cumulative dose of 8 mg/kg based on 1- year outcomes for adult deceased donor kidney transplant recipients with DGF. The results of this study suggest that 6 mg/kg of rATG induction may be a feasible option for adult kidney transplant recipients with DGF.

Figure 1: Study Enrollment.

Figure 2: Comparison of Serum Creatinine Values between Reduced Dose rATG (N=26) and Standard Dose rATG (N=52) Induction Groups.

Figure 3: Comparison of e GFR Values between Reduced Dose rATG (N=26) and Standard Dose rATG (N=52) Induction Groups.

Figure 4: Comparison of Episodes of T-Cell and Antibody Mediated Acute Rejection between Reduced Dose rATG (N=26) And Standard Dose rATG (N=52) Induction Groups.

Figure 5: Comparison of Episodes of BK Virus and Cytomegalovirus Infections between Reduced Dose rATG (n=26) and Standard Dose rATG (n=52) Induction Groups.

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