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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 16  |  Issue : 3  |  Page : 303-308

Comparison of efficacy and safety between rabbit anti-thymocyte globulin and anti-T lymphocyte globulin in kidney only transplantation: A retrospective observational study


Department of Nephrology, KG Hospital and Post Graduate Medical Institute and Research Centre, Coimbatore, Tamil Nadu, India

Date of Submission13-Aug-2021
Date of Acceptance06-Sep-2022
Date of Web Publication30-Sep-2022

Correspondence Address:
Dr. S Sakthi Selva Kumar
145/52, Ayyankulam Street, Tiruvannamalai - 606 601, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_76_21

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  Abstract 


Introduction: The two formulations of antihuman thymocyte immunoglobulin that are used as T-cell depleting induction agents in renal transplantation are anti-thymocyte globulins (ATG) thymoglobulin and (antiT-lymphocyte globulin [ATLG]-Grafalon-formerly ATG-Fresenius). Very few trials have compared these two formulations. In this retrospective study, we compared the incidence of infections, rejections, graft survival, mortality, and lymphocyte profile of ATG and ATLG. Materials and Methods: This was a single-center retrospective study of 127 consecutive kidney-alone transplant recipients from January 2014 to June 2019. Patients received 3 mg/kg of ATG or 4 mg/kg single dose of ATLG. CD 3 counts were done on day 3 of the transplant. Most of the recipients received standard triple immunosuppression of tacrolimus, mycophenolate mofetil, and prednisolone. Results: Fifty-eight patients received ATG and 69 patients received ATLG. Baseline demographics were similar between the two groups. Death-censored graft survival (99%) (P = 0.258) and biopsy-proven acute rejection (BPAR) (32% vs. 29%, P = 0.128) were similar in both groups. Graft survival was better in ATLG group (92.7% vs. 87.5% P = 0.020). Bacterial infections (41.1% vs. 27.6%, P = 0.03) and sepsis-related mortality (11.54% vs. 4.34% P = 0.02) were significantly higher in the ATG group. Conclusion: ATLG, when used as an induction agent, was associated with a lesser rate of bacterial infections and sepsis-related mortality, but better graft survival as compared to ATG but has comparable BPAR, death-censored graft survival, and viral/fungal infections.

Keywords: Grafalon, induction, thymoglobulin


How to cite this article:
Kumar S S, Veerappan I, Sethuraman R, Chakravarthy T, Siddharth VA, Rajagopal A. Comparison of efficacy and safety between rabbit anti-thymocyte globulin and anti-T lymphocyte globulin in kidney only transplantation: A retrospective observational study. Indian J Transplant 2022;16:303-8

How to cite this URL:
Kumar S S, Veerappan I, Sethuraman R, Chakravarthy T, Siddharth VA, Rajagopal A. Comparison of efficacy and safety between rabbit anti-thymocyte globulin and anti-T lymphocyte globulin in kidney only transplantation: A retrospective observational study. Indian J Transplant [serial online] 2022 [cited 2022 Nov 27];16:303-8. Available from: https://www.ijtonline.in/text.asp?2022/16/3/303/357617




  Introduction Top


Anti-thymocyte globulins (ATG) are polyclonal T-lymphocyte-depleting agents that are potent immunosuppressive agents, used to prevent and treat rejections in high-risk kidney transplant recipients.[1] They act by antibody-dependent cell-mediated cytotoxicity, activation-induced cell death, and complement-dependent cytotoxicity (CDC).[2] The two formulations are thymoglobulin (ATG), produced by immunizing with human thymocytes and anti-T-lymphocyte globulin (ATLG), (formerly known as ATG-Fresenius or ATG-F) produced by immunizing rabbits with human Jurkat T-cell line.[3] They have quantitative differences between their antibody concentrations against different antigens, small differences in their antigen profile,[4] and different antigen specificity. ATG contains antibodies against many T-cell and B-cell antigens, including cluster differentiation (CD) CD2, CD3, CD4, CD8, CD11, CD18, CD20, CD25, CD40, CD44, human leukocyte antigen DR (HLA-DR), and HLA Class I,[5] whereas the antibody profile of ATLG is mainly against CD28, CD29, CD45, CD49, CD98, and CD147[6] with greater selectivity for activated T-cells. Both of them can cause malignancy and severe infections. There are very few studies,[7],[8],[9] comparing these two formulations including a recent Indian study by Jha et al.[10] Our study compares the efficacy and safety of these formulations by analyzing the graft outcomes, rejections, infections, and CD3 counts of recipients.


  Materials and Methods Top


This was a single-center retrospective study utilizing our institutional electronic medical record system (which was internal board/ethics committee approved) to identify all 127 recipients from January 2014 to June 2019 who received either ATG or ATLG induction. Consecutive sampling was done. Donors and recipients underwent HLA typing (A, B, and DRB1), CDC, and flow cross match. Positive CDC cross-match was a contraindication for transplant and none of the patients underwent HLA desensitization pretransplant. Those who had positive flow crossmatch underwent a single antigen bead to identify HLA antibodies. All recipients regardless of their immunological risk status received induction. Patients who received interleukin-2 (IL-2) induction were not included. ABO-incompatible recipients, who underwent desensitization according to institutional protocol, were also included in our study. No patients with both ABOI and HLA incompatibility underwent transplant. No pediatric patients underwent renal transplantation during the study.

Immunosuppressive protocols

As per our institutional protocol, all renal transplant recipients (including live or deceased) received the first dose of depleting agents on the day of the transplant. ATG was given at a single dose of 2 mg/kg on the day of transplant. While ATLG given was 4 mg/kg IV as a single dose on the day of the transplant. The first dose for both formulations was given intraoperatively, preclamp release, before reperfusion of the allograft. All the patients also received 500 mg IV methylprednisolone intraoperatively followed by the same dose on day 1 and day 2, respectively. CD3 counts (expected target is <200 cells/mm3) on postoperative day 3 were done to evaluate the efficacy of the induction therapy, but none of the patients received an additional dose of the r-ATG/ATG-F. Maintenance immunosuppression included calcineurin inhibitors, tacrolimus (TAC) (0.15 mg/kg) or cyclosporine (5 mg/kg) and anti-proliferative agent, mycophenolate mofetil (MMF) (30 mg/kg) with oral prednisolone (initially initiated at 20 mg/day on day 3 then was tapered to 2.5–5 mg/day at around 4 weeks' posttransplant. All patients received antibiotic (trimethoprim + sulfamethoxazole) prophylaxis for 6 months and antiviral (valganciclovir) prophylaxis were given for 3 months.

Patients who underwent ABO incompatible renal transplant (ABOiRT) received single dose of rituximab at a dose of 100 mg at 2 weeks before the intended date of transplant, respectively. Two weeks after receiving the last dose of rituximab, baseline ABO titers were recorded and oral TAC/MMF was started as per the above-mentioned doses. Plasmapheresis with 100 mg/kg IVIG (postplasmapheresis) was started at this point. Alternate day plasmapheresis was continued till A/B antibody titer of <1:8 was achieved. At this point, the transplant was done. Posttransplant course till discharge was similar as above mentioned.

Patients were followed up weekly twice for the 1st month, weekly once for the 2nd month, once in 2 weeks for the 3rd month, and monthly once thereafter for 1 year. Baseline hemogram and renal function tests and TAC/cyclosporine levels were measured at visits.

Target trough levels for TAC/cyclosporine were 10–12 and 200–400 ng/ml for the 1st month, 8–10 and 125–275 ng/ml for months 2–3, 6–8, and 10–150 ng/ml for months 4–6 and 4–6 ng/ml and 75–150 ng/ml thereafter, respectively. After 1 year, patients were followed up once in 2 months.

All the rejection episodes were biopsy-proven and were classified as per the Banff criteria.[11] Acute cellular (T-cell) rejections were treated with intravenous methylprednisolone at a dose of 500 mg/day for 3 days, with the escalation of maintenance immunosuppressant doses and for steroid-resistant rejection, r-ATG was given (1–1.5 mg/kg daily for 5–7 days). Acute antibody-mediated (B-cell) rejections were treated with therapeutic plasma exchange, after every plasma exchange a dose of intravenous immunoglobulin (100 mg/kg), and rituximab exchange (375 mg/m2/dose to maintain a CD19 count of 0).

Primary endpoints

  1. One-year graft survival
  2. Death-censored graft survival at the end of 1 year.


Secondary endpoints

  1. Efficacy as analyzed by CD3 counts at day 3 of transplant and biopsy-proven acute rejections
  2. Safety as analyzed by severe allergic reactions, hematological side effects (leukopenia <3000 cells/μL and thrombocytopenia <50000 cells/μL), infections, probability of infection occurrence, and sepsis-related mortality.


Statistical analysis

The probability of infections was identified with binary logistics regression. Efficacy of the formulations was analyzed with odd's ratio. The association between the categorical factors and groups was tested using the Chi-square test. P <0.05 was considered statistically significant. Univariate analysis was conducted for each factor assumed to be related to the group. Multivariate logistic regression was used to assess the adjusted effect of the factors that are statistically significant at a 10% level of significance from the univariate analysis and clinically significant were included in the model. Data were reported as mean values ± standard deviation.

Declaration of patient consent

Consent was obtained for participation in the study and for publication of clinical details and images. Patients understand that their names and initials would not be published, and all standard protocols will be followed to conceal their identity.

Ethics statement

Indian Council of Medical Research/Good Clinical Practice guidelines were followed. Patients were enrolled for the study after clearance from the Institutional Ethics Committee.(ECR/213/Inst/TN/2013/RR-16). The study was performed according to the guidelines in Declaration of Helsinki.


  Results Top


During the study, a total of 135 renal transplants were done. Out of which 58 patients who received ATG and 69 patients who received ATLG as the induction agent (n = 127) were included in the study. Both living and deceased donor transplants were done during the study. Baseline demographics are shown in [Table 1] which were comparable including ABOiRT.
Table 1: Demographics and baseline characteristics

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Deceased donor transplants were more in ATG group (36 vs. 24), whereas live donor transplants (24 vs. 45) were more in ATLG group (P = 0.01). The maintenance immunosuppressants were similar in the two groups. TAC/CSA levels and mycophenolic acid area under the curve levels were similar with no statistically significant difference, as shown in [Table 2]. ATLG group achieved better prednisolone tapering (28 vs. 45) as compared to the ATG group (P = 0.04).
Table 2: Maintenance immunosuppressive therapy during follow-up

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One-year graft survival was more in ATLG group (92.7% vs. 87.5% P = 0.04). Death-censored graft survival was similar (99%) in both groups.

None of the patients developed severe allergic reactions, leukopenia, or thrombocytopenia. Bacterial infections (41.1% vs. 27.6%, P = 0.02) and sepsis-related mortality (11.54% vs. 4.34% P = 0.02) were significantly higher in the ATG group as compared to ATLG group, as shown in [Table 3]. Probability of infection occurrence was more in ATG (41.1% vs. 27.6% P = 0.02). Single-point mean CD3 level on the 3rd day (211.3 ± 243.8) versus (163.2 ± 156.0), although this difference is statistically insignificant (P = 0.328).
Table 3: Patient and graft outcomes showing the efficacy and safety of the formulations

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The variables considered did not have any effect on the significant differences between the two groups that persisted in respect to graft survival and infections, analyzed using multivariable Cox logistic regression, as shown in [Table 4]. Banff score is provided in [Table 5].
Table 4: Multivariate logistic regression assessing the variables

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Table 5: Banff scores for acute rejections

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  Discussion Top


Studies have shown that depleting agents were superior compared to IL-2 receptor antagonist in preventing BPAR.[12] Because of the polyclonal natures of ATGs, this functional beneficial effect may not be related directly to T-cell depletion.[13],[14] There have been very few studies comparing these two agents[7],[8],[9] including a recent one from India[9] which showed a different outcome from our study.

There were significantly fewer deceased donors in ATLG group as compared to ATG group (24 vs. 36 P < 0.001). Due to the risk of delayed graft function (DGF) in deceased donor transplants, the dose reduction was gradual in ATG group.

A retrospective analysis by Chen et al.[8] suggested ATG may reduce the duration of DGF and acute rejection rate after deceased donor transplant. However, DGF was more in ATG (19.1%) than ATLG group (25.4%) in that study.

In another retrospective study by Jha et al.,[9] ATLG was associated with a significantly higher rate of BPARs as compared to ATG, although with comparable short-term patient and death censored graft survival, graft function, and infection rates. A prospective study by Burkhalter et al.[10] showed that BPAR was comparable between the two groups. A meta-analysis by Song et al.[7] and a study by Kuypers et al.[15] on simultaneous pancreas-kidney transplantation revealed comparable results between ATG and ATLG with regard to acute rejection. Our analysis revealed comparable BPAR (32% vs. 29%; P = 0.128). None of the patients had DGF.

Infections are always of concern in patients receiving depleting antibodies. Studies by Ducloux et al.[16] and Norrby and Olausson[17] have demonstrated that viral infections, especially cytomegalovirus (CMV) infection, occur earlier and have a higher incidence in patients receiving ATG as compared to ATLG.[16],[17] However, we did not find any difference in CMV infection between the two groups. In the meta-analysis by Song et al.,[7] ATG was associated with a higher risk of infections including CMV infections. In a study by Burkhalter et al.[10] and in a study by Jha et al.,[9] infection rates were comparable between groups. In our study, bacterial infection rates were more in the ATG group (43% vs. 30% P = 0.02) with the probability of infection occurrence was more in ATG group (41.1% vs. 27.6% P value = 0.03).

However, we did not find any difference in CMV/BKV infection or sepsis-related mortality between the two groups. Infections are closely related to the absolute lymphocyte counts and duration of T-cell depletion postinduction.[18],[19] Single dosing of ATLG and comparatively less long-term immune-inhibitory potential, resulted in quicker lymphocyte, CD4, and CD8 T-cell recovery,[18] which may have contributed to fewer infections. Of note, all our patients received prophylaxis with valganciclovir and cotrimoxazole for months and 6 months, respectively, regardless of induction modality which can explain the almost nil incidence of CMV and nil incidence of BKV infection.

Antitumor effects have been mainly attributed to the activity of CD4+ T-helper 1 cells, CD8+ cytotoxic T-cells, and natural-killer cells. Studies have shown a higher incidence of posttransplant malignancy in patients receiving t-cell-depleting formulations,[7],[16] especially more often and earlier in ATG recipients.[16],[20] ATG with broader cell markers targets expressed by various immune cells may explain the predisposition to malignancies.[21] However, in our study, none of the patients in either group developed posttransplant malignancy, although our mean follow-up period was only 24 months and studies have shown malignancies developing in transplant recipient on longer follow-up periods.[21]

In a randomized controlled trial by Burkhalter et al.,[10] the patient survival was comparable between the groups.[9] In a trial by Ducloux et al.,[16] the ATG group had more mortality. In a meta-analysis by Song et al.,[7] ATLG was superior to ATG in preventing patient mortality. In a study by Ourahma et al.,[22] the rate of graft loss was lower among the patients treated with ATLG than ATG. One-year survival and death-censored graft survival in our study were comparable between the two groups.


  Conclusion Top


ATLG when used as an induction agent has significantly reduced bacterial infections, sepsis-related mortality, and improved graft survival as compared to ATG. However, BPAR, death-censored graft survival, and viral/fungal infections were comparable.

Limitations

The study's limitations have been acknowledged by us. Data collection was retrospective and had a small sample size. The follow-up period was only 24 months. The patient data collection was only limited during the OP/IP visits and only laboratory values were evaluated. This could have led to missed periods of over or under-immunosuppression in either group or an under-representation of adverse events. Although we have regulated for all baseline transplants and demographic characteristics of the patients that can be statistically different between our groups, the possibility of the presence of residual confounding factors such as native kidney and disease is still present. Our study was retrospective and samples were taken chronologically, i.e. patients received ATG from 2014 to 2016 and patients received ATLG from 2017 to 2019. The decision to switch formulation was based on multiple clinical and economic reasons and idea for the retrospective evaluation was followed subsequently to validate the same. We also acknowledge the difference in outcome could be due to difference in deceased vs live transplant patients in ATG/ATLG groups.

Future directions

Further comparison of these two formulations with larger sample sizes, randomized, blinded, and prospective analysis longer follow-up is needed to evaluate the other differences. Prospective trials are required. Notably, a recent prospective, multi-center, noninterventional study (NCT03996278) has been initiated recently to compare the efficacy and safety of ATG versus ATLG, which may provide more evidence for clinical practice in future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Tanriover B, Jaikaransingh V, MacConmara MP, Parekh JR, Levea SL, Ariyamuthu VK, et al. Acute rejection rates and graft outcomes according to induction regimen among recipients of kidneys from deceased donors treated with tacrolimus and mycophenolate. Clin J Am Soc Nephrol 2016;11:1650-61.  Back to cited text no. 1
    
2.
Genestier L, Fournel S, Flacher M, Assossou O, Revillard JP, Bonnefoy-Berard N. Induction of Fas (Apo-1, CD 95)-mediated apoptosis of activated lymphocytes by polyclonal antithymocyte globulins. Blood 1998;91:2360-8.  Back to cited text no. 2
    
3.
Padiyar A, Augustine JJ, Hricik DE. Induction antibody therapy in kidney transplantation. Am J Kidney Dis 2009;54:935-44.  Back to cited text no. 3
    
4.
Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia 2007;21:1387-94.  Back to cited text no. 4
    
5.
Bonnefoy-Bérard N, Vincent C, Revillard JP. Antibodies against functional leukocyte surface molecules in polyclonal antilymphocyte and antithymocyte globulins. Transplantation 1991;51:669-73.  Back to cited text no. 5
    
6.
Bourdage JS, Hamlin DM. Comparative polyclonal antithymocyte globulin and antilymphocyte/antilymphoblast globulin anti-CD antigen analysis by flow cytometry. Transplantation 1995;59:1194-200.  Back to cited text no. 6
    
7.
Song T, Yin S, Li X, Jiang Y, Lin T. Thymoglobulin vs. ATG-Fresenius as induction therapy in kidney transplantation: A bayesian network meta-analysis of randomized controlled trials. Front Immunol 2020;11:457.  Back to cited text no. 7
    
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Chen GD, Lai XQ, Ko DS, Qiu J, Wang CX, Han M, et al. Comparison of efficacy and safety between rabbit anti-thymocyte globulin and anti-T lymphocyte globulin in kidney transplantation from donation after cardiac death: A retrospective cohort study. Nephrology (Carlton) 2015;20:539-43.  Back to cited text no. 8
    
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Jha PK, Rana A, Kher A, Bansal SB, Sethi S, Nandwani A, et al. Grafalon® vs. thymoglobulin® as an induction agent in renal transplantation – A retrospective study. Indian J Nephrol 2021;31:336-40.  Back to cited text no. 9
  [Full text]  
10.
Burkhalter F, Schaub S, Bucher C, Gürke L, Bachmann A, Hopfer H, et al. A comparison of two types of rabbit antithymocyte globulin induction therapy in immunological high-risk kidney recipients: A prospective randomized control study. PLoS One 2016;11:e0165233.  Back to cited text no. 10
    
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Mengel M, Sis B, Haas M, Colvin RB, Halloran PF, Racusen LC, et al. Banff 2011 meeting report: New concepts in antibody – Mediated rejection. Am J Transplant 2012;12:563-70.  Back to cited text no. 11
    
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Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D. Thymoglobulin induction study G. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med 2006;355:1967-77.  Back to cited text no. 12
    
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LaCorcia G, Swistak M, Lawendowski C, Duan S, Weeden T, Nahill S, et al. Polyclonal rabbit antithymocyte globulin exhibits consistent immunosuppressive capabilities beyond cell depletion. Transplantation 2009;87:966-74.  Back to cited text no. 13
    
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Kuypers DR, Malaise J, Claes K, Evenepoel P, Maes B, Coosemans W, et al. Secondary effects of immunosuppressive drugs after simultaneous pancreas-kidney transplantation. Nephrol Dial Transplant 2005;20 Suppl 2:ii33-9, ii62.  Back to cited text no. 14
    
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Schnetzler B, Leger P, Völp A, Dorent R, Pavie A, Gandjbakhch I. A prospective randomized controlled study on the efficacy and tolerance of two antilymphocytic globulins in the prevention of rejection in first-heart transplant recipients. Transpl Int 2002;15:317-25.  Back to cited text no. 15
    
16.
Ducloux D, Kazory A, Challier B, Coutet J, Bresson-Vautrin C, Motte G, et al. Long-term toxicity of antithymocyte globulin induction may vary with choice of agent: A single-center retrospective study. Transplantation 2004;77:1029-33.  Back to cited text no. 16
    
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Norrby J, Olausson M. A randomized clinical trial using ATG Fresenius or ATG Merieux as induction therapy in kidney transplantation. Transplant Proc 1997;29:3135-6.  Back to cited text no. 17
    
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Stevens RB, Foster KW, Miles CD, Lane JT, Kalil AC, Florescu DF, et al. A randomized 2×2 factorial trial, part 1: Single-dose rabbit antithymocyte globulin induction may improve renal transplantation outcomes. Transplantation 2015;99:197-209.  Back to cited text no. 18
    
19.
Ducloux D, Courivaud C, Bamoulid J, Vivet B, Chabroux A, Deschamps M, et al. Prolonged CD4 T cell lymphopenia increases morbidity and mortality after renal transplantation. J Am Soc Nephrol 2010;21:868-75.  Back to cited text no. 19
    
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Opelz G, Naujokat C, Daniel V, Terness P, Döhler B. Disassociation between risk of graft loss and risk of non-Hodgkin lymphoma with induction agents in renal transplant recipients. Transplantation 2006;81:1227-33.  Back to cited text no. 20
    
21.
Michallet MC, Preville X, Flacher M, Fournel S, Genestier L, Revillard JP. Functional antibodies to leukocyte adhesion molecules in antithymocyte globulins. Transplantation 2003;75:657-62.  Back to cited text no. 21
    
22.
Ourahma S, Talon D, Barrou B, Sylla C, Mouquet C, Luciani J, et al. A prospective study on efficacy and tolerance of antithymocyte globulin Fresenius versus thymoglobuline Merieux after renal transplantation. Transplant Proc 1997;29:2427.  Back to cited text no. 22
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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