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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2014  |  Volume : 25  |  Issue : 1  |  Page : 9-15
Anti-thymocyte globulin versus basiliximab induction in renal transplant recipients: Long-term outcome


1 Department of Biochemistry and Immunology, Transimmun, Transplantation Immunology and Research Center, Hyderabad, India
2 Department of Nephrology and Transplantation Unit, Krishna Institute of Medical Sciences, Hyderabad, India
3 Department of Nephrology and Transplantation Unit, Mahavir Hospital and Research Center; Department of Nephrology and Transplantation Unit, Krishna Institute of Medical Sciences, Hyderabad, India

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Date of Web Publication7-Jan-2014
 

   Abstract 

Although basiliximab and rabbit anti-thymocyte globulin (ATG) are effective in delaying and reducing the incidence of acute rejection (AR) thus improving short-term graft survival, their impact on long-term graft survival has not been well established in renal transplant recipients. To evaluate the long-term efficacy after induction therapy with ATG/basiliximab in renal transplant recipients, we studied retrospectively 86 renal transplant recipients of living donor renal transplantation from 2003 to 2006; of them, 42 patients received induction with ATG three doses of 50 mg, 25 mg, 25 mg/day on 0, 1 and 2 post-operative days (POD) and 44 age-matched patients received induction with basiliximab (20 mg/day on 0 and 4 PODs). All the patients received tacrolimus, mycophenolate mofetil and corticosteroids as maintenance immunosuppressive therapy. Demographic characteristics were similar between both groups. Patient survival at 5 years was 90.5% in the ATG group and 84.1% in the basiliximab group, while graft survival was 83.4% and 77.3%, respectively. The incidence of acute rejection was 14.2% and 18.1% in the ATG and the basiliximab groups, respectively. The estimated mean glomerular filtration rates at 5 years post-transplantation was 52.1 mL/min and 49.1 mL/min and the mean serum creatinine levels were 1.55 ± 0.37 and 1.66 ± 0.51 mg/dL in the ATG and basiliximab groups, respectively. A low incidence of tuberculosis and cytomegalovirus (CMV) was observed in the ATG group. There were no significant differences between the two groups, and both induction regimens assured a safe and effective treatment and were associated with similar excellent long-term patient and graft survival.

How to cite this article:
Kesiraju S, Paritala P, Rao Ch UM, Athmakuri SM, Reddy V S, Sahariah S. Anti-thymocyte globulin versus basiliximab induction in renal transplant recipients: Long-term outcome. Saudi J Kidney Dis Transpl 2014;25:9-15

How to cite this URL:
Kesiraju S, Paritala P, Rao Ch UM, Athmakuri SM, Reddy V S, Sahariah S. Anti-thymocyte globulin versus basiliximab induction in renal transplant recipients: Long-term outcome. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2014 Nov 28];25:9-15. Available from: http://www.sjkdt.org/text.asp?2014/25/1/9/124459

   Introduction Top


In recent years, there has been a significant improvement in the short-term outcome following renal transplantation; however, improvement has not been shown in the long-term graft survival. Hence, the primary concern has been shifted to long-term outcomes with emphasis on fewer complications. Short-term allograft survival has been achieved by using various immunosuppressive protocols; nevertheless, the incidence of acute rejection (AR) and delayed graft function (DGF) early in the post-transplantation period have a negative impact in achieving long-term outcome. Many studies have shown that early graft function is a predictor of the long-term graft survival. [1],[2] Induction therapy is administered at the time of transplantation to lower the incidence of AR or to prevent DGF and to improve the long-term allograft survival. Currently, 60-80% of the kidney transplant patients receive induction therapy with either rabbit anti-thymocyte globulin (ATG), a lymphocyte-depleting polyclonal antibody, shown to reduce the severity of the early post-transplant adverse events by triggering B-cell and plasma cell apoptosis by multiple pathways [3],[4] or non-lymphocyte-depleting monoclonal antibodies such as basiliximab or declizumab.

ATG is usually administered intravenously as a series of divided doses during the first week of post-transplantation or in a single bolus dose of 9 mg/kg body weight of ATG, which lowers the incidence of AR and DGF by reducing the lymphocyte counts. Basiliximab is a commonly used chimeric monoclonal antibody that targets IL-2 receptors. The convenient two-dose prophylaxis is facilitated by its high-affinity binding to the α-subunit of the IL-2 receptor and its long half-life.

The main aim of the induction therapy is to avoid early rejection so as to improve the short- and long-term graft survival. However, patients are exposed to increased risk of infectious complications and post-transplant lymphoproliferative disorders due to over immunosuppression. [6] Earlier studies established the safety and tolerability of both ATG and basiliximab induction. [7]

The aim of our study was to compare the safety and efficacy of low-dose ATG and basiliximab in live donor renal transplant recipients receiving triple-immunosuppressive maintenance therapy over a period of 5 years.


   Materials and Methods Top


Renal transplant data were collected for the patients with live related and unrelated donor transplants performed at KIMS and Mahavir hospitals, Hyderabad, India, from March 2003 to March 2006 receiving either ATG or basiliximab induction therapy. Of the 241 patients who received kidney transplants during that period, 86 patients were included in the study. We enrolled in the study all HLA non-identical living related and unrelated voluntary donor renal transplant recipients aged between 18 and 61 years and whose PRA levels were below 30%, whereas patients who did not receive induction therapy were excluded from the study. All the deceased donors who received induction were also excluded from the study.

Forty-two patients received 50 mg of ATG (Thymo; Genzyme, USA) intra-operatively before releasing the clamps and 25 mg on Days 1 and 2 post operatively, and 44 patients received the first dose of 20 mg of basiliximab (Simulect, Novartis Pharmaceuticals, Basel, Switzerland) before the graft reperfusion, followed by a second dose of 20 mg on Day 4 post-operatively.

Maintenance oral immunosuppression consisted of prednisolone starting on Day 0 (125 mg IV and tapered to 10 mg orally at 15 days post-transplantation), Mycophenolate mofetil (MMF) 500 - 1000 mg twice daily and tacrolimus 6 - 8 mg/day adjusted accordingly based on the trough levels (12-15 ng/mL) in both the groups. Early after transplantation the trough levels were maintained at 12 - 15 ng/mL up to one month and, later, the levels were maintained at 5 - 10 ng/mL up to six months post-transplant and thereafter the levels were maintained at 5.0 ng/mL.

All the recipients received oral valgancyclovir for three months and cotrimoxozole for six months post-transplantation.

Assessment of patients and graft survival and anti-rejections were the primary efficacy end points. Complete follow-up was obtained for all the patients except two in the basiliximab group who died in the first three months post-transplantation. Laboratory analysis of hematological, biochemical and pathological investigations were measured at baseline, 0, 3, 7, 14 and 30 days and then monthly up to six months and annually up to five years. CD counts were performed using a four-color flow cytometric method. Leucopenia was defined as a white blood cell count below 2500/mm 3 and thrombocytopenia as a platelet count below 80,000/ mm 3 . Leukopenia was treated if the white blood cell count dropped below 2500 mm 3 and thrombocytopenia was treated if the platelet count was less than 100 × 10 3 /mm 3 . [8]

Diagnosis of CMV and tuberculosis was carried out by an enzyme-linked immunosorbant assay (ELISA) and polymerase chain reaction (PCR)-based methods. Acute rejections were diagnosed either clinically or with biopsies. All the episodes were confirmed by biopsy in both groups of patients and described according to the Banff criteria. [9] Acute rejection episodes were treated with intravenous courses of methyl prednisolone (500-1000 mg) for three to five days. The safety was assessed by the adverse events associated with the treatment drug, including frequencies of infections.


   Statistical Analysis Top


Data were presented as percentages, means and standard deviations. Categorical variables were summarized as percentages. Graft survival and acute rejection rates were determined using Kaplan-Meier estimates. P-value less than 0.05 was set as an indicator of statistical significance.


   Results Top


Patients' and donors' demographic characteristics are outlined in [Table 1]. There were no significant differences in the demographic features among both groups, and the baseline characters and the reasons for end-stage renal disease requiring transplantation were also similar. Donor age (mean 35.7 ± 8.9, 36.2 ± 10.4) and HLA mismatches in the ATG and basiliximab groups were comparable.
Table 1: Demographic characters between the two groups.

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The mean WBC and platelet counts (data not shown) were comparable in both groups. The mean WBC count was 6.9 ± 1.3 × 10 3 and 7.1 × 1.6 × 10 3 mm 3 in the ATG and basiliximab groups, respectively, (P = 0.389) at 30-day post-transplant, and the counts were comparable during the follow-up period and ranged from 4.3 to 7.1 × 10 3 mm 3 in both groups. There was a sharp fall of platelet count observed on Day 3 post-transplant in both groups and recovered by Day 14 post-transplant. The mean platelet count was 251 ± 21 and 246 ± 29 × 10 3 mm 3 on day 30 post-transplant, in ATG vs Basiliximab respectively. The CD counts were dropped within 48-72 h after induction in both groups, and recovered after two weeks post-transplantation, and the CD4/CD8 ratio was 1.86 ± 0.99, 1.95 ± 1.07 before induction and remained at 1.02 ± 0.64, 0.96 ± 0.72 at 30 days in the ATG and basiliximab groups, respectively. The pre-transplant lymphocyte counts were within the normal range. There was a sharp drop of CD counts by 85-90% in both the groups immediate post-induction. The average CD4/CD8 ratio on Day 3 was 0.47 and 0.31 (P = 0.62), respectively, in the ATG and basiliximab groups, and decreased in both groups and remained significantly low during the first 30 days post-transplant even though the ATG dose (total 100 mg) administered was very low. Adverse events were comparable in both groups throughout the study period [Table 2].
Table 2: Frequency of adverse events during five years of follow-up.

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The patient survival rates at five years were 90.5% in the ATG group and 84.1% in the basiliximab group, with no statistical significance [Figure 1]. The graft loss was 16.6% and 22.7% in the ATG and basiliximab groups, respectively, and the majority was due to death [Figure 2]. The reasons for death included pneumonia, myocardial infarction and fungal meningitis. The graft loss due to death was 9.5% and 15.9% in the ATG and the basiliximab groups, respectively. Mortality due to infections was comparable in both groups [Table 3]. Acute rejection episodes were comparable in both groups [Table 4].
Figure 1: Kaplan–Meier curve for time to death.

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Figure 2: Kaplan–Meier curve for time to transplant failure.

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Table 3: Reasons for death in antithymocyte globulin (ATG) vs basiliximab.

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Table 4: Efficacy end points at five years.

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The renal graft function improved rapidly in the ATG group and the mean serum creatinine was normal at the end of the first week (1.41 mg/dL) vs 2.13 mg/dL in the basiliximab group (P = 0.05). The means of the serum creatinine levels at one year were 1.36 ± 0.61 and 1.51 ± 0.59 mg/dL (P = 0.26) in the ATG and basiliximab groups, respectively. At five years, the means of the serum creatinine levels were 1.55 ± 0.37 and 1.66 ± 0.51 mg/dL in the ATG and basiliximab groups, respectively. The renal function measured by urinary creatinine clearance was not significantly different between both groups from the 1 st year post transplantation to the 5 th year [Figure 3].
Figure 3: Five-year follow-up of creatinine clearance in the antithymocyte globulin (ATG) and basiliximab groups

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   Discussion Top


Induction therapy prevents the early AR episodes, which may help in improving the long-term outcome in renal transplantation. Several studies have shown that the renal allograft half-life was longer in patients who never had AR episodes. [10]

There were several reports using different induction regimens to improve the early graft function, thereby improving the short- and long-term graft survival. Hence, in the present study, we compared the safety and efficacy of low-dose ATG with a standard dose of basiliximab. In this study, we observed no signifi­cant differences between the two study groups in number of AR episodes, patient survival and graft survival. We did not find any delayed graft function in either group as it could be due to the fact that all the patients received kidneys from live donors and are considered as a low-risk group for AR and DGF. We observed rapid improvement in the renal function in the ATG group within one week post-transplantation than in the basiliximab group. The reason could not be explained by any observed recipient factors or differences in the cold ischemia times. However, the mean baseline creatinine levels were slightly higher in the basiliximab group.

Brennan et al, [11] in a high-risk patient study group, observed a significantly higher rate of infections and adverse events such as leucopenia in the ATG group patients who received 7.5 mg/kg in divided doses when compared with the standard dose basiliximab group. A recent study by Ulrich et al [12] compared the long-term outcome of ATG (single bolus 9 mg/kg) and a standard dose of basiliximab with double immunosuppression therapy in deceased donor renal transplantation. It concluded that the rate of ARs was slightly higher in the ATG group (ns) and the adverse events and the infection rates were also significantly higher in that group. In our study, the incidence of AR was slightly lower in the ATG group, which was not statistically significant when compared with the basiliximab group.

The rate of infection and mortality due to infection were comparable in both groups [Table 3]. The incidence of adverse events such as anemia, leucopenia and thrombocytopenia were comparable in both groups; however, these were slightly higher in the ATG group. We found that there was a decrease of the CD4 counts (data not shown) past the 5 th week post-transplantation, whereas CD3 counts' recovery was earlier in the basiliximab group with a lower infection rate than in the ATG group [Table 2].

Lymphocyte depletion occurred within three days post-transplant, with slower recovery giving an additional immunological benefit and, thus, providing long-term graft survival in both groups. A multicenter study [13] evaluated 50 low-risk patients on a triple-drug regimen and compared the ATG and the basiliximab induction and found no significant difference in the AR episodes between both groups. Cytomegalovirus (CMV) disease was 12% and 6% (not significant) with no anti-viral prophylaxis. In our study, the incidence of CMV was 2.3% and 2.27% in the ATG and the basiliximab groups, respectively, and this may be due to the prophylaxis and pre-emptive measures. All the patients received prophylaxis against CMV disease for the first three months and were monitored at regular intervals (once in three months for the first one year) using polymerase chain reaction qualitative CMV test from whole blood.

Even though there was no statistical difference in the mortality rate between both our study groups, mortality was slightly higher in the basiliximab group. The reason for the higher rate of mortality in the basiliximab group could not be discerned.

In summary, our study suggests that both induction regimens with ATG and basiliximab in live kidney transplantation offered a safe and effective treatment and were associated with excellent long-term patient and graft survival. Low-dose ATG has been found to be safe, equally effective and less costly as compared with the standard dose of ATG (6 mg/kg). This will significantly reduce the cost of induction therapy.

 
   References Top

1.Mizutani K, Terasaki P. Serum creatinine as a predictor of transplant survival and death. Clin Transpl 2004:345-56.  Back to cited text no. 1
[PUBMED]    
2.Salvadori M, Rosati A, Bock A, et al. Estimated one year glomerular filtration rate is the best predictor of long-term graft function following renal transplantation. Transplantation 2006;81:202-6.  Back to cited text no. 2
[PUBMED]    
3.Zand MS, Vo T, Huggins J, et al. Polyclonal rabbit antithymocyte globulin triggers B- cell and plasma cell apoptosis by multiple pathways. Tranplantation 2005;79:1507-15.  Back to cited text no. 3
    
4.Beiras-fernandez A, Chappel D, Hammer C, Thein E. Influence of poly clonal antithymocyte globulins upon ischemia -reperfusion injury in a non-human primate model. Transpl Immunol 2006;15:273-9.  Back to cited text no. 4
    
5.Yussim A, Shapira Z. Single bolus high dose ATG for prophylaxis of rejection in renal transplantation- A prospective, randomized study. Transplant Int 2000;13(Suppl 1):S293-4.  Back to cited text no. 5
    
6.Meier-Kriesche HU, Arndorfer JA, Kaplan B. Association of antibody induction with short - and long term cause specific mortality in renal transplant recipients. Am Soc Nephrol 2002; 13:769-72.  Back to cited text no. 6
    
7.Amlot PL, Rawlings E, Fernando ON, et al. Prolonged action of a chimeric interleukin 2 receptor (CD25) monoclonal antibody used in cadaveric renal transplantation. Transplantation 1995;60:748-56.  Back to cited text no. 7
[PUBMED]    
8.Wong W, Agrawal N, Pascual M, et al. Comparison of two doses of thymoglobulin used as a short course for induction in kidney transplantation. Transpl Int 2006;19:629-35.  Back to cited text no. 8
[PUBMED]    
9.Racusen LC, Solez K, Colvin RB, et al. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999; 55:713-23  Back to cited text no. 9
    
10.Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med 2000;342:605-12.  Back to cited text no. 10
[PUBMED]    
11.Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D; Thymoglobulin Induction Study Group. Antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med 2006;335:1967-77.  Back to cited text no. 11
    
12.Ulrich F, Niedzwiecki S, Pascher A, et al. Long term outcome of ATG vs Basiliximab induction. Eur J of Clin Invest 2011;41:971-8.   Back to cited text no. 12
    
13.Lebranchu Y, Bridoux F, Büchler M, et al. Imunoprophylaxis with basiliximab compared with anti thymocyte globulin in renal transplant patients receiving MMF containing triple therapy. AM J Transplant 2002;2:48-56.  Back to cited text no. 13
    

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Correspondence Address:
Sailaja Kesiraju
Department of Biochemistry and Immunology, Transimmun, Krishna Institute of Medical Sciences, Hyderabad
India
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PMID: 24434376

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