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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2016  |  Volume : 27  |  Issue : 4  |  Page : 665-670
Effects of induction therapy with alemtuzumab versus antithymocyte globulin among highly sensitized kidney transplant candidates


1 Shiraz Organ Transplant Center, Shiraz University of Medical Sciences, Shiraz, Iran
2 Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
3 Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

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Date of Web Publication5-Jul-2016
 

   Abstract 

We retrospectively compared induction therapy utilizing alemtuzumab and antithymoglobulin (ATG) in high-risk kidney transplant recipients in our center. Two hundred and fifty-one patients underwent kidney transplantation between 2009 and 2012. The high-risk patients were defined as those who had two or more times kidney transplantation and/or more than 30% panel reactive antibody. We studied 130 high-risk kidney transplant candidate; 58 (44.6%) patients received induction immunosuppressive therapy with alemtuzumab, and 72 (55.4%) with ATG. Delayed graft function developed in 11 patients receiving alemtuzumab, against the 27 patients who receiving ATG (P = 0.021). Acute cellular rejection episodes were observed in five patients in the alemtuzumab group and 19 patients in the ATG group (P = 0.009). There were three graft failures in the alemtuzumab group and eight graft failures in the ATG group due to rejection episodes. We found immunosuppressive induction therapy with alemtuzumab a significantly less incidence of acute rejection and delayed graft function than induction therapy with ATG in the high-risk kidney transplant recipients.

How to cite this article:
Shamsaeefar A, Roozbeh J, Khajerezae S, Nikeghbalian S, Kazemi K, Motazedian N, Geramizadeh B, Malekhosseini SA. Effects of induction therapy with alemtuzumab versus antithymocyte globulin among highly sensitized kidney transplant candidates. Saudi J Kidney Dis Transpl 2016;27:665-70

How to cite this URL:
Shamsaeefar A, Roozbeh J, Khajerezae S, Nikeghbalian S, Kazemi K, Motazedian N, Geramizadeh B, Malekhosseini SA. Effects of induction therapy with alemtuzumab versus antithymocyte globulin among highly sensitized kidney transplant candidates. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2021 Oct 19];27:665-70. Available from: https://www.sjkdt.org/text.asp?2016/27/4/665/185221

   Introduction Top


Currently available immunosuppressive therapy following kidney transplantation has developed extensively over the past few years; however, acute rejection remains one of the most important causes of graft loss. Acute rejection episodes not only lead to chronic graft dysfunction and loss but also play a vital role in determining short and long-term survival of kidney transplant patients. [1]

Induction therapy is designed to reduce the frequency and severity of acute rejection during the early post-transplant period at the expense of generalized immunosuppression. The therapy has become an essential part of kidney transplant in order to optimize outcomes, especially patients with risk of poor short-term outcomes. Currently, immunosuppressive agents used in induction therapy are monoclonal antibodies such as muromonabCD3, daclizumab, basiliximab, alemtuzumab, or polyclonal antibodies such as antithymoglobulin (ATG). [2]

ATG is an immunosuppressive agent that is generated by immunization of rabbits with human thymocytes; therefore, commonly referred to as rabbit ATG (rATG) and it is approved for prevention and treatment of acute rejection in kidney transplant recipients, tolerance induction, regimens to lower the incidence of post-transplant renal insufficiency, and minimization protocols of steroids and calcineurin inhibitors. A large number of clinical experience has proven the efficiency of rATG for preventing rejection in various solid organ allografts and the use has expanded from high-risk patients to include a range of low to high immunological risks. [3],[4],[5]

Alemtuzumab (Campath-1H) a anti-CD52 monoclonal antibody that FDA approved as a third-line agent for the treatment of chronic lymphocytic leukemia. [6]

A study of Campath-1H proved its efficacy and safety in the setting of steroid-resistant rejection, with only two doses of 30 mg, patient survival was 95% and graft survival was 73.5%. [7] Adverse effects of alemtuzumab including infection complications, extended lymphocyte depletion, immunological disease, and unusual forms of rejection have been reviewed. [8],[9]

There is no optimal choice of antibody used in induction regimen for such clinical settings, which may be due to studies carried on patients with different immunological risks and diversity of immunosuppressive regimens already tested. Thus, a broader evaluation of patient immunological status, concomitant morbidities, cost analysis, and also maintenance immunosuppression agents is required to guide the clinician on most appropriate induction strategy.

The aim of the present study was to compare the induction therapy utilizing alemtuzumab versus ATG in high-risk kidney transplant patients in our center.


   Materials and Methods Top


Two hundred and fifty-one adult patients underwent kidney transplantation at Nemazee Hospital, Shiraz Organ Transplant Center from 2009 to 2012. Of this data base, we retrospectively studied the induction immunosuppressive therapy in the high-risk kidney transplant recipients. The high-risk patients were defined as those who had two or more times kidney transplantation and/or more than 30% panel reactive antibody. Exclusion criteria were: multiorgan transplant, hepatitis positivity, cancer, death due to unrelated causes, previous antilymphocyte globulin, or orthoclone monoclonal anti-CD3 antibody, and use of more than one class of antibody induction. In total, 130 high-risk kidney transplant recipients were included in this study, 58 (44.6%) patients received alemtuzumab (Genzyme, Bayer Schering Pharma; USA), and 72 (55.4%) patients received ATG (Genzyme Polyclonals, S.A.S. Marcy L'Etoile; France). The patients were matched for age, sex, primary diagnosis, and donor type before induction therapy.

Alemtuzumab was administered intravenously in two doses, 20 mg each, preoperatively. ATG was also administered intravenously in a single dose of 1mg per kg preoperatively and then 1 mg/kg, starting on post-transplant day 1, and subsequent doses daily for three days. The maintenance regimen for all patients composed of a therapeutic protocol with three immunosuppressive agents, calcineurin inhibitor (CNI), mycophenolate mofetil, and steroids. CNI included either cyclosporine initiated with a dose of 5.0 mg/kg/d or tacrolimus with a dose 0.1 mg/kg/d, and then the doses were titrated according to blood level and patients and grafts conditions. Mycophenolate mofetil was used in a dose of 1500-2000 mg/d. Prednisone was initiated with a dose of 30 mg/d on day 4 after the three doses of methylprednisolone (1 g/day) and then titrated in a declined dose of 5 mg/d each month until a maintenance dose was achieved.

The data collection form included demographic information, drug history, and underlying diseases. Follow-up records were used to identify cases of early complications, including delayed graft function, primary nonfunction, acute rejection, infection, leukopenia, and elevated creatinine level besides tissue survival and patient survival.

Patients were followed at nephrology clinic weekly for four weeks after discharge from hospital and then monthly for six months, followed by visits every three months after transplantation. Additional information was also available in archives of our transplant research center to determine the incidence of infection with BK polyomavirus, and cytomegalovirus (CMV).

This study was done according to the principle of Declaration of Istanbul and the WHO principles on tissue and organ donation. Our study also was approved by the Ethics Committee of Shiraz University of Medical Sciences.


   Statistical analysis Top


Statistical analysis was performed using Statistical Package for the Social Sciences version (SPSS) software version 18 (SPSS, Inc., Chicago, IL, USA). Categorical variables related to demographics, acute rejection, incidence of infection and delayed graft function, graft loss, and patient survival were compared between the two groups using Chi-square test or Fisher's exact test. Statistical significance was considered as P <0.05.


   Results Top


The 130 study patients included (61.5 %) eighty men and fifty women (38.5 %) with an average age of 38.0 ± 14.0 years. The characteristics of both groups are summarized in [Table 1].
Table 1: Characteristic of the antithymoglubin (ATG) and alemtuzumab-treated groups.

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The incidence of acute rejection was lower in the alemtuzumab group (n = 5, 8.6%) compared with the ATG group (n = 19, 26.4%) (P = 0.009). All patients with acute rejection were treated with metheyprednisolone. Delayed graft function developed in 11 (19%) patients who received alemtuzumab versus 27 (37.5%) patients who received ATG (P = 0.021).

Compared with the patients who received alemtuzumab (n = 3, 5.3%) those who received ATG (n = 8, 11.1%) had higher graft failures due to multiple rejection episodes (P = 0.0.345). Four (6.9%) patients in the alemtuzumab group and seven (9.7%) patients in the ATG group died during the follow-up (P = 0.754).

The incidence of viral infections episodes in the ATG group [CMV n = 6 (8.3%) and BK virus n = 8 (11.1%)] was lower than alemtuzumab group [CMV n = 8 (13.8%) and BK virus n = 9 (15.5%)]. However, there were no significant difference between the two treatment groups in the incidence of viral infections (CMV and BK virus) (P = 0.318, P = 0.459), respectively.

The incidence of leukopenia was four (6.2%) in the patients in the ATG group as compared with 8 (33.3%) in the alemtuzumab group, (P<0.001). Serum creatinine level rose in 16 (24.6%) patients in the ATG group and nine (16.7%) patients in the alemtuzumab group (P= 0.289, [Table 1]).


   Discussion Top


The use of induction therapy in kidney transplantation has decreased the rates of acute rejection in short-term. However, the benefits are minimized by unchanged graft and patient survival rates. [10]

Our study showed that the incidence of biopsy-confirmed acute rejection and delay graft function was significantly higher in patients in the ATG group compared with those in the alemtuzumab group. Our results also showed that there was lower incidence of leukopenia in the ATG-treated group compared with alemtuzumab group [Table 2].
Table 2: Risks of postkidney transplant complication, antithymoglobulin (ATG) versus alemtuzumabtreated groups.

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A study of kidney transplants of older donors demonstrated that the use of ATG or alemtuzumab for induction regimen resulted in graft rejection incidence of <20%. [4]

A comparative study of ATG and alemtuzumab showed similar efficacy and safety of both agents with a considerably lower cost of alemtuzumab. [11]

A systematic review identified nine studies that compared the effect of alemtuzumab and ATG on patients and grafts survival and overall acute rejection rates, revealed similar results for both agents over two years of follow-up. However, three-year follow-up of the same study showed a lower rate of infection among patients who received alemtuzumab. [12] Similarly, a meta-analysis of ten randomized controlled trials on the effects of both agents showed no significance difference in the incidence of biopsy-proven acute rejection, graft loss, DGF, and patient survival. [13] However, a randomized trial on a group of 98 transplanted patients reports acute rejection occurred in nine (20%) of patients who received ATG and in none (0%) of patients who received alemtuzumab. Furthermore, the study reported a mean cost of $1474 for the alemtuzumab therapy and $4996 for the rATG therapy. [14]

The first randomized trial comparing the three common antibody induction agents (alemtuzumab, daclizumab, and ATG) in kidney transplants demonstrated that patients in alemtuzumab group had slightly lower GFR after one month, however, at one year, there was no difference from the other two groups. Further analysis revealed that 80% of the alemtuzumab-treated patients remained steroid-free after one-year of follow-up. The overall rate of adverse events was similar among the induction agents. The study concluded similar efficacy of all the three agents. [15]

Hanaway et al compared alemtuzumab induction with ATG in 139 high-risk patients. The study concluded there was no significant difference between two treatment groups in terms of the rates of biopsy-confirmed acute rejection, severe rejection, or rejection in which patients required antibodies by 36 months, and patient and graft survival. In addition, the mean total lymphocyte count dropped to <10% of baseline within the 1 st week following kidney transplantation in the patients in both treatment groups. In the alemtuzumab group, the rate of efficacy was 76% compared with 70% in the ATG group (P = 0.42). Efficacy is defined as a presence of no pathological rejection on biopsy, loss of graft, or death within three years of kidney transplant. The rate of infection with CMV and BK virus was the same between the treatment groups at three years of follow-up. [16]

Short-term effects of antilymphocyte antibodies include an increased risk of cardiovascular and death from infection and long-term effects are associated with an increased risk of cancer. These effects should be considered in any risk/benefit analysis of the use of these agents for induction therapy in kidney transplant recipients. [17]

The choice of induction immunosuppressive regimen still remains elusive. [18]

In our study, the incidence of acute rejection was less in patients who received alemtuzumab than ATG, but in patients and grafts, survival was not significantly different between the two groups. Leucopenia was more observed in alemtuzumab-treated group but the incidence of infection was similar in both groups in our study.

Our study had two limitations: the first one was the retrospective nature of study, so no conclusive inferences could be extracted from the analysis. The second one is short time of follow-up, therefore, further prospective randomized studies are warranted to evaluate late antibody mediated rejection in patients treated with alemtuzumab.

Patient and donor immunological status could be a determinant factor of therapy duration. Therefore, one solution in minimizing complications of therapy is to adjust the immunosuppressive regimen according to each patient's immunological status.


   Conclusion Top


We conclude beneficial immunosuppressive induction therapy with alemtuzumab due to significantly less incidence of acute rejection and delayed graft function than induction therapy with ATG in the high-risk kidney transplant recipients.


   Acknowledgment Top


The authors would like to thank Nadia Motazedian for her invaluable assistance in editing this article.

Conflict of interest: None declared.

 
   References Top

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Wang W, Yin H, Li XB, et al. A retrospective comparison of the efficacy and safety in kidney transplant recipients with basiliximab and antithymocyte globulin. Chin Med J (Engl) 2012; 125:1135-40.  Back to cited text no. 1
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Gabardi S, Martin ST, Roberts KL, Grafals M. Induction immunosuppressive therapies in renal transplantation. Am J Health Syst Pharm 2011; 68:211-8.  Back to cited text no. 2
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Harrison JJ, Hamandi B, Li Y, Famure O, Kim SJ. Timing of rabbit antithymocyte globulin induction therapy in kidney transplantation: An observational cohort study. Transplant Res 2014; 3:1.  Back to cited text no. 3
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Grinyó JM, Cruzado JM, Bestard O, Vidal Castiñeira JR, Torras J. Immunosuppression in the era of biological agents. Adv Exp Med Biol 2012; 741:60-72.  Back to cited text no. 4
    
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Gaber AO, Monaco AP, Russell JA, Lebranchu Y, Mohty M. Rabbit antithymocyte globulin (thymoglobulin): 25 years and new frontiers in solid organ transplantation and haematology. Drugs 2010;70:691-732.  Back to cited text no. 5
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Modjtahedi H. Monoclonal antibodies as therapeutic agents: advances and challenges. IJI 2005;2(1):3-20.  Back to cited text no. 6
    
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Mahmud N, Klipa D, Ahsan N. Antibody immunosuppressive therapy in solid-organ transplant: Part I. MAbs 2010;2:148-56.  Back to cited text no. 7
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Hardinger KL, Brennan DC, Klein CL. Selection of induction therapy in kidney transplantation. Transplant International. 2013; 26(7):662-72.  Back to cited text no. 8
    
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Chouhan KK, Zhang R. Antibody induction therapy in adult kidney transplantation: A controversy continues. World J Transplant 2012; 2:19-26.  Back to cited text no. 9
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Afaneh C, Aull MJ, Schubl S, Leeser DB, Kapur S. Induction Therapy: A Modern Review of Kidney Transplantation Agents. J Transplant Technol Res 2011:S4-001.  Back to cited text no. 10
    
11.
Sampaio EL, Freitas TV, Galante NZ, et al. Alemtuzumab induction in kidney transplant recipients. J Bras Nefrol 2010; 32:89-97.  Back to cited text no. 11
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Hao WJ, Zong HT, Cui YS, Zhang Y. The efficacy and safety of alemtuzumab and daclizumab versus antithymocyte globulin during organ transplantation: A meta-analysis. Transplant Proc 2012; 44:2955-60.  Back to cited text no. 12
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Morgan RD, O'Callaghan JM, Knight SR, Morris PJ. Alemtuzumab induction therapy in kidney transplantation: A systematic review and meta-analysis. Transplantation 2012; 93:1179-88.  Back to cited text no. 13
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Farney A, Sundberg A, Moore P, et al. A randomized trial of alemtuzumab vs. antithymocyte globulin induction in renal and pancreas transplantation. Clin Transplant 2008; 22:41-9.  Back to cited text no. 14
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Ciancio G, Burke GW 3rd. Alemtuzumab (Campath-1H) in kidney transplantation. Am J Transplant 2008; 8:15-20.  Back to cited text no. 15
    
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Hanaway MJ, Woodle ES, Mulgaonkar S, et al. Alemtuzumab induction in renal transplantation. N Engl J Med 2011; 364:1909-19.  Back to cited text no. 16
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Meier-Kriesche HU, Arndorfer JA, Kaplan B. Association of antibody induction with short-and long-term cause-specific mortality in renal transplant recipients. J Am Soc Nephrol 2002;13:769-72.  Back to cited text no. 17
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Bakr MA, Nagib AM, Donia AF. Induction immunosuppressive therapy in kidney transplantation. Exp Clin Transplant 2014; 12 Suppl 1:60-9.  Back to cited text no. 18
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Correspondence Address:
Nasrin Motazedian
Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz
Iran
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DOI: 10.4103/1319-2442.185221

PMID: 27424681

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