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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 21  |  Issue : 3  |  Page : 115-123

Induction agents and their role in low-immunological-risk kidney transplant recipients: A Review


1 Department of Nephrology and Kidney Transplantation, University of Toronto, Toronto, Canada
2 Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool; Department of Transplantation Surgery, Royal Liverpool University Hospital, Liverpool, United Kingdom
3 Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool; Department of Transplantation Surgery, Sheffield Teaching Hospital, Sheffield, United Kingdom

Date of Submission10-Apr-2021
Date of Acceptance23-Apr-2021
Date of Web Publication09-Aug-2021

Correspondence Address:
Dr. Ahmed M Halawa
MEd (Higher Education), FRCS, FRCS (Gen), Department of Transplantation Surgery, Sheffield Teaching Hospital, Sheffield S5 7 AU
United Kingdom
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jesnt.jesnt_12_21

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  Abstract 


Induction agents are widely used at the time of kidney transplantation to decrease the risk of rejection. While there is a strong immunological rationale supporting the use of induction immunosuppression, the clinical evidence demonstrating benefit in low-immunological-risk recipients in addition to current effective maintenance immunosuppression is less robust, especially in terms of improvement in long-term graft survival. This review aims to shed light on the immunological basis of use of induction immunosuppression, available options of induction agents and the current evidence and recommendation for their use in low-immunological-risk kidney transplant recipients.

Keywords: IL-2 receptor antibody, induction, low immunological risk, lymphocyte-depleting antibodies, monoclonal antibodies, polyclonal antibodies


How to cite this article:
Sathyan S, Sharma A, Halawa AM. Induction agents and their role in low-immunological-risk kidney transplant recipients: A Review. J Egypt Soc Nephrol Transplant 2021;21:115-23

How to cite this URL:
Sathyan S, Sharma A, Halawa AM. Induction agents and their role in low-immunological-risk kidney transplant recipients: A Review. J Egypt Soc Nephrol Transplant [serial online] 2021 [cited 2021 Oct 17];21:115-23. Available from: http://www.jesnt.eg.net/text.asp?2021/21/3/115/323528




  Introduction Top


One of the biggest challenges in organ transplantation is the prevention of allograft rejection without increasing the complications of immunosuppression. There has been progressive improvement in short-term graft survival in kidney transplant recipients over the last few decades, which is primarily related to introduction of newer immunosuppressant agents and immunosuppression protocols [1],[2],[3]. Induction agents have become an integral part of these immunosuppression protocols.

After the first successful kidney transplantation by Murray and colleagues in 1954 between HLA identical twins, it took a few more years to overcome the immunological barrier to carry out successful transplantation between HLA non-identical individuals using immunosuppressive agents [4]. In the absence of immunosuppression, a strong alloimmune response is inevitable, resulting in inflammation and graft dysfunction, followed by graft loss.


  The three-signal model of alloimmune response Top


Alloimmune response involves activation of recipient T- lymphocytes by both donor and recipient antigen-presenting cells, through different pathways. In the direct pathway of allorecognition, dendritic cells from the donor allograft migrate to recipient secondary lymphoid tissue, where the donor major histocompatibility complex (MHC) molecule along with other peptides on its surface are recognized by the recipient T-lymphocytes. In the indirect pathway, the recipient dendritic cells process alloantigen and present it along with self-MHC on its surface to T-lymphocytes [5],[6]. In a more recently described semi-direct pathway, recipient dendritic cells uptake donor MHCs and present it to T-lymphocytes [5],[7] ([Figure 1]).
Figure 1 Types of allorecognition [5].

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Signal 1 of alloimmune response involves the binding of the MHC molecule on the surface of an antigen-presenting cell (mostly a dendritic cell), along with the alloantigen bound to it, to the T cell receptor (TCR)- CD3 complex on the surface of the T-lymphocyte. In addition to Signal 1, T-lymphocyte activation requires co-stimulation, which involves engaging of CD 80 (B7-1) and CD 86 (B7-2) on an antigen-presenting cell with CD 28 on the T-lymphocyte. This step is called Signal 2. These two signals result in transduction of three intracellular downstream pathways, namely, (1) the calcium–calcineurin pathway, which leads to the production of transcription factor nuclear factor of activated T cells, (2) the mitogen-activated protein kinase pathway resulting in activation of protein 1 synthesis and (3) the protein kinase C–nuclear factor kB (NFkB) pathway, with the production of NFkB [6],[8]. These transcription factors increase the expression of interleukin-2 (IL-2), IL-2 receptor alpha-chain (CD-25) and CD 154. The activation of the 1L-2 receptor on the T-lymphocyte by IL-2 results in downstream signaling through the phosphoinositide-3-kinase (PI-3K) pathway and the molecular target of rapamycin pathway forms Signal 3. The outcome of Signal 3 is T-lymphocyte proliferation due to cell cycle acceleration [8].

The proliferating effector T-lymphocytes cause parenchymal damage through direct cytotoxicity as well as through cytokine-mediated response, manifesting as tubulitis, interstitial inflammation and arteritis, characteristic of cell-mediated rejection [8]. Activation of B-lymphocytes gives rise to alloantibody production and antibody-mediated rejection.


  Immunological basis for the requirement of induction immunosuppression Top


It is generally accepted that there is a requirement of more intense immunosuppression in the initial period following transplantation to prevent allograft rejection. Induction agents are polyclonal or monoclonal agents, which are administered before, during or immediately after transplantation to prevent or modulate T-lymphocyte response when encountered with the alloantigen [9].

A combination of factors predisposes to a higher risk of rejection during the early period after transplantation, necessitating increased intensity of immunosuppression. The endothelial damage suffered during the surgical handling of the organ as well as ischemia–reperfusion injury sustained during the process increase the intensity of antigen presentation and decreases the threshold of T-lymphocyte activation. In addition, T-lymphocytes have the inherent ability to mount a robust immune response when presented with alloantigen, due to a high allospecific T-lymphocyte precursor frequency. This precursor frequency is further increased and the activation threshold is lowered, in the context of sensitization due to pregnancy, blood transfusion or previous transplantation [10]. Also, the activation of T-lymphocytes through the direct pathway by donor antigen-presenting cells is powerful, but short lasting, and wanes off with increasing duration post-transplant [7] ([Figure 2]).
Figure 2 Factors determining the requirement of induction immunosuppression [10].

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In view of a potentially more robust alloimmune response and risk of rejection in the early post-transplant period, induction agents became an integral part of the immunosuppression repertoire. Phases of immunosuppression have traditionally been divided into the following: (1) The induction phase, which is the peri-transplant period, when one or more induction agents are administered, while maintenance immunosuppressive medications reach target concentration levels to be effective in preventing rejection. (2) The early maintenance phase 3–6 months post-transplant when higher doses or levels of maintenance immunosuppressive agents are sustained to prevent rejection. (3) The late maintenance phase, more than 3-6 months post-transplant, when the maintenance immunosuppression is reduced to long-term levels, with the aim of balancing prevention of rejection with minimizing long-term complications of immunosuppression. In totality, the goal of immunosuppression is longer patient and graft survival, and improved quality of life with maximum cost-effectiveness [11].


  Induction immunosuppressive agents Top


Induction agents are broadly classified into lymphocyte-depleting and lymphocyte-non-depleting agents and into polyclonal and monoclonal agents. Depleting agents in general act by causing destruction of lymphocytes, while non-depleting agents block specific receptors on lymphocytes, preventing their activation and thereby prevent mounting of an immune response [9].

Classification and mechanism of action of induction agents

Lymphocyte-depleting agents

Polyclonal antibodies: Anti-thymocyte globulins (ATG) are polyclonal antibodies that are derived from rabbit (Thymoglobulin) or horse (ATGAM) sera by injecting them with human thymocytes. ATG binds non-specifically to a number of molecules on the surface of lymphocytes such as CD2, CD3, CD4, CD8, CD11a and CD18, resulting in complement-mediated cell destruction [12]. Because of its high potency and significant adverse-effect profile, both short term (fever, chills, cytokine release, leukopenia and thrombocytopenia) and long term (increased infections, cytomegalovirus (CMV), post-transplant lymphoproliferative disorder (PTLD)), it is usually reserved for use as an induction agent in recipients with high immunological risk [12].

Monoclonal antibodies: Monomurab or OKT3 was the first monoclonal antibody used clinically as an induction agent. It is a murine monoclonal antibody against CD3, part of the T-cell receptor complex on the surface of the T-lymphocyte. The interaction between OKT3 and CD3 results in cell lysis. The associated side effect of cytokine release and first-dose effect, along with treatment failure due to development of anti OKT3 antibodies, have led to its discontinuation from clinical use [12].

Alemtuzumab is a humanized monoclonal antibody against CD52. CD52 is present on the surface of T as well as B-lymphocytes, monocytes and NK cells. Therefore, induction with alemtuzumab results in antibody-dependent lysis of these cells [12]. It is used mainly as an induction agent in high-immunological-risk recipients as an alternative to thymoglobulin based on availability and center preference.

Rituximab is a chimeric monoclonal antibody against CD20. By binding to CD20 on the surface of B-lymphocytes, rituximab triggers lysis of B-lymphocytes [12]. This mechanism enables rituximab to be used for induction in special circumstances like desensitization before HLA incompatible transplant and ABO incompatible transplant [13].

Lymphocyte-non-depleting agents

Daclizumab and basiliximab are monoclonal antibodies against the alpha chain of the IL-2 receptor (CD25). While daclizumab is humanized, basiliximab is a chimeric antibody. The variable region of basiliximab is murine, while the constant region is comprised of human immunoglobulin amino acid sequences [14]. As a result, basiliximab has lower immunogenicity compared with fully murine antibodies like OKT3. CD25 is expressed on the surface of activated lymphocytes. By blocking CD25, they prevent the activation and proliferation of T-lymphocytes without causing lysis [12],[14]. The longer half-life of basiliximab of 7–14 days, with prolonged saturation of IL-2 receptors for up to 6 weeks, makes it the preferred IL-2 receptor antagonist to daclizumab, which requires the administration of five doses over 8 weeks [15],[16],[17].

Choice of induction agent

An induction agent is used at the time of both living and deceased donor kidney transplant, with the exception of a small minority. As per the OPTN/SRTR Annual Report 2020, in the year 2018, less than 10 percent of all kidney transplant recipients did not receive any specific induction agent at the time of transplant. Depleting agents were the most commonly used induction agents. There has been an increasing trend in the use of any induction agent and specifically depleting agents as the choice of induction agents in the US from 2008 to 2018 [18] ([Figure 3]).
Figure 3 Trend of induction agent use in adult kidney transplant recipients in USA [18].

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Kidney Disease: Improving Global Outcomes [16] as well as The Renal Association of British Transplant Society (BTS) [11] recommend use of a biological induction agent for all kidney transplant recipients. Both these associations recommend use of the IL-2 receptor antagonist as the first-line induction agent for all kidney transplant recipients, except those with high immunological risk [11],[19].

Therefore, the first step in making a decision on the induction agent depends on the stratification of immunological risk ([Table 1]).
Table 1 Immunological risk stratification [11]

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Evidence for use of an induction agent in low-immunological-risk recipients

IL-2 receptor antibody versus no induction

Acute rejection: A number of RCTs have demonstrated the efficacy of the IL-2 receptor antibody in reducing acute rejection [20],[21],[22]. In these trials, the incidence of acute rejection was decreased by 28–37% with the IL-2 receptor antibody compared with placebo, in the initial 6 months post transplantation. However, in these trials, even in the treatment group, the incidence of acute rejection was high, at around 25–30%. Steroid-resistant acute rejections were also significantly lower in the treatment group. The maintenance immunosuppression regimen used in these trials was either double (cyclosporine with steroid) or triple therapy (cyclosporine, azathioprine and steroid) [20],[21],[22]. In another RCT with cyclosporine, mycophenolate and steroid as the maintenance regimen, there was a trend toward a decrease in acute rejection at 6 months post-transplant (15.3 vs. 26.6%), but this did not reach statistical significance [23]. A meta-analysis of 17 randomized trials showed that acute rejection episodes were significantly lower by 34% at 6 months and by 33% at 1 year with the IL-2 receptor antibody compared with the placebo. The number needed to treat to prevent one rejection episode was seven [24]. A systematic review, which included 32 studies comparing the IL-2 receptor antibody with placebo, revealed that there was a significant 28% reduced risk of acute rejection at 1-year post transplant [25]. According to this review, nine kidney transplant recipients will need to be treated with IL-2 receptor antibody induction to prevent one acute rejection episode [25]. A more recent meta-analysis comparing IL-2 receptor antibody induction versus no induction in low-immunological-risk kidney transplant recipients, including only those on tacrolimus-based maintenance immunosuppression (7 trials, around 30000 patients), showed no significant difference in acute rejection episodes at 1 year post-transplant [26]. Low immunological risk was defined as 0–1 HLA-DR mismatches, panel reactive antibody less than 20% and no or only one previous transplant. The authors concluded that this result was likely related to already low rejection rates with tacrolimus compared with previous cyclosporine-based maintenance immunosuppression. However, they also noted that the results might also have been influenced by a smaller number of extended-criteria donor transplants (<10%) in the included studies, a subgroup who might still have benefited from induction [26].

Graft survival: The evidence to support use of IL-2 receptor antibody induction in terms of effect on graft survival is even less robust. Randomized-controlled trials that included recipients on cyclosporine-based maintenance immunosuppression did not show any difference in graft survival at 1 year, compared with placebo [20],[21],[22],[23]. Graft survival at 1 year and 3 years was not different with IL-2 receptor antibody induction or placebo in a meta-analysis carried out in 2004 [24]. In the 2017 meta-analysis including patients who were receiving tacrolimus as the calcineurin inhibitor (CNI), there was no difference in patient or graft survival [26]. In the NIH CTOT2 study, de novo donor-specific antibody development was lower with IL-2 receptor antibody induction compared with placebo, but with no benefit in terms of graft survival [27],[28].

Tolerability: Both basiliximab and daclizumab were well tolerated, with no significant adverse events associated with the administration of medication compared with placebo [20],[22],[23].

Infection: There was no difference in the incidence of infection with IL-2 receptor antibody induction compared with placebo [20],[22]. In a meta-analysis, which included information from 7 trials about CMV infection, there was no difference at 1 year [24]. In the Cochrane systematic review, CMV disease was significantly lower by 19% with IL-2 receptor antibody induction [25].

Malignancy: While there was no difference in malignancy and PTLD between IL-2 receptor antibody induction and no induction in a meta-analysis [24], analysis of eight trials with information about malignancies in the Cochrane systematic review revealed that there was a 64% reduction in early malignancy with the former [25].

Cost-effectiveness: Compared with no induction, IL-2 receptor antibody induction was found to be more effective and less costly, based on data from a meta-analysis of randomized-controlled trials and large registries [29]. According to this study, the cost saved per patient over 20 years was around $ 80000, irrespective of risk profile, when the cost benefit of improved quality-adjusted life years was analyzed [29]. Cost-effectiveness analysis of different induction strategies in deceased donor kidney transplants in United States showed that the strategy of ‘no induction’ was least cost-effective in both low- and high-risk groups, but depleting agents were more cost-effective compared with IL-r receptor antibody induction, with thymoglobulin being the most cost-effective in both risk groups [30].

ATG versus no induction

Limited randomized trials comparing ATG induction with placebo in low-immunological-risk recipients have shown significantly reduced acute rejection episodes with ATG [31],[32],[33]. However, relatively high rejection rates were seen even in the ATG group (15–-37%) over 6-12 months with the maintenance immunosuppression regimen of double therapy (cyclosporine/tacrolimus with steroid) or triple therapy (cyclosporine/tacrolimus with azathioprine and steroid). There was a significantly higher incidence of fever, serum sickness, leukopenia, thrombocytopenia and CMV infection with ATG [31],[32]. In a Cochrane systematic review analyzing data from studies comparing ATG with no induction in intermediate-risk kidney transplant recipients, ATG reduced the risk of acute rejection by 39%, but did not have significant benefit in terms of patient or graft survival [9]. There was a significant increase in CMV infection, leukopenia and thrombocytopenia with ATG, but no significant increase in malignancy and PTLD [9]. However, other studies have shown associations between the use of ATG induction with increased risk of malignancies, especially PTLD [34],[35]. Cost-effectiveness analysis of induction immunosuppression in deceased donor kidney transplant recipients in United States revealed that ATG induction was more cost-effective than no induction [30].

ATG versus IL-2 receptor antibody induction

There is limited evidence in terms of randomized-controlled trials comparing ATG and IL-2 receptor antibody induction in low-immunological-risk recipients. One single-center trial that randomized racially and immunologically diverse living and deceased kidney transplant recipients to basiliximab/ daclizumab or thymoglobulin induction, with both groups receiving tacrolimus, mycophenolate and steroid maintenance, did not show any difference in acute rejection or graft function at one year [36]. Analysis of large registry data showed a lower acute rejection rate with an antilymphocyte agent compared with the IL-2 receptor antagonist, but there was a trend toward lower graft survival in recipients who received an antilymphocyte agent. The latter finding could be confounded by indications to receive an antilymphocyte agent since these were non-randomized registry data. The authors also noted much lower cost with basiliximab compared with the course of thymoglobulin induction [37]. According to the 2010 Cochrane systematic review, which included 18 studies comparing ATG with IL-2 receptor antagonist induction for all immunological risk groups, irrespective of the maintenance immunosuppressive regimen, there was a lower biopsy-proven acute rejection rate, but higher serum creatinine levels, malignancy and CMV disease with ATG [25].

Alemtuzumab versus IL-2 receptor antibody induction

Randomized-controlled trials comparing alemtuzumab and IL-2 receptor antagonist induction in low-immunological-risk kidney transplant recipients, but with early steroid withdrawal [38] or steroid-free maintenance immunosuppression [39],[40] along with tacrolimus and mycophenolate, showed lower rates of acute rejection with alemtuzumab, but with a trend toward higher late acute rejections [38] and graft failure [40]. In a recent retrospective single-center analysis of induction agents in low-immunological-risk recipients, defined as a negative virtual crossmatch pretransplant, alemtuzumab with early steroid withdrawal was associated with higher de-novo DSA at 1 year, compared with basiliximab or ATG, with no increase in graft failure, although limited by lack of long-term follow-up [41].

Rituximab as an induction agent

Rituximab induction was not associated with a decrease in biopsy-proven acute rejection compared with placebo in low-immunological-risk recipients at 6 months. Rituximab was well tolerated, with no increase in infection or malignancy [42]. The ReMIND trial is an ongoing trial, which is evaluating the effect of rituximab in addition to tacrolimus, mycophenolate and either early steroid withdrawal or continuing steroid on estimated GFR at 1 year as the primary outcome and biopsy-proven acute rejection, graft and patient survival as secondary outcomes. As of now, there is limited evidence to support the use of rituximab as induction in kidney transplant recipients.

Special situations

Based on available evidence obtained from clinical trials and meta-analysis, the IL-2 receptor antagonist is the preferred induction agent in low-immunological-risk kidney transplant recipient in view of efficacy, safety profile and cost-effectiveness [11],[19],[25],[29]. In some situations, though, this cohort may benefit from the use of lymphocyte-depleting agents.

Steroid-free or early steroid withdrawal

Both alemtuzumab and ATG have been compared with the IL-2 receptor antagonist as preferred induction along with steroid-free or withdrawal maintenance regimen. Analysis of large living donor transplant registry data showed that among recipients who were not on steroids, alemtuzumab and ATG were associated with lower acute rejections. However, alemtuzumab, but not ATG, was associated with higher graft loss [40]. As mentioned earlier, alemtuzumab was associated with lower acute rejection, but with a tendency for higher late rejection compared with basiliximab in a randomized-controlled trial including recipients on early steroid withdrawal [38].

CNI monotherapy and CNI minimization

Alemtuzumab induction was associated with a lower acute rejection rate, when administered along with tacrolimus monotherapy, compared with no induction with standard maintenance immunosuppression with tacrolimus, mycophenolate and steroid in living donor transplant recipients, but with no difference in graft failure [43]. A similar study in deceased donor kidney transplant recipients did not reveal any difference between the two groups in terms of acute rejection, patient or graft survival [44].

Even though evidence is limited, lymphocyte-depleting agents may be preferable in the context of these unconventional maintenance regimens such as steroid avoidance, early steroid withdrawal, CNI avoidance or monotherapy. BTS Renal association guidelines suggest a lymphocyte-depleting agent as the preferred induction immunosuppression in low-immunological-risk recipients planned for steroid or CNI avoidance [11].

Factors influencing the choice of the induction agent for low-immunological-risk recipients

The choice of the induction agent at the time of kidney transplant is influenced by a number of recipient and donor factors, which determine the immunological risk as well as the anticipated adverse effects of the agent, balancing the risks and benefits. The planned maintenance immunosuppression also has a significant influence on this decision-making [12]. The variety of options with respect to available immunosuppressant medications enables different combinations of induction and maintenance agents.

There is lack of strong evidence to recommend one or the other induction agent in specific situations. Evolution of more effective maintenance immunosuppression over the past few decades has made it difficult to compare the efficacy of different induction agents since the primary outcome studied is the incidence of acute rejection. With the current standard regimen of tacrolimus, mycophenolate and steroid, the acute rejection rates are already low, so that a large number of patients need to be recruited to have adequate power to detect a difference [3]. As a result, there is variation in the practice with respect to the choice of induction agent between countries. While in the US, depleting agents, mainly thymoglobulin, are the most commonly used induction agents (more than 70% of all transplant recipients in 2018 as per OPTN/SRTR data) [18], IL-2 receptor antagonists are the preferred agents in UK and Australia. In Australia, 77% of the kidney transplant recipients received IL-2 receptor antibody induction, with polyclonal antibody only in 12% [45]. Apart from this, preference of individual transplant center based on local experience also plays a significant role in the decision. The choice of an induction agent in the low–intermediate-immunological-risk group often depends on the treating transplant physician’s perception of immunological risk versus the risk of complications like infection (e.g. CMV mismatch) or malignancy (e.g., Epstein–Barr Virus mismatch, previous PTLD), thereby introducing heterogeneity not only on a patient-to-patient basis but among treating transplant physicians. This difference in practice is especially evident in the case of donation after cardiac death donor kidneys, especially those who are also extended criteria who are considered to be at high risk of delayed graft function and are administered induction with a lymphocyte-depleting agent by some transplant nephrologists due to the anticipated higher risk of rejection; others prefer basiliximab with a low threshold for graft biopsy for early detection of rejection post-transplant in the presence of delayed graft function.


  Conclusions Top


Even though induction agents have become an integral part of immunosuppression, the evidence to support any specific induction choice along with the current maintenance immunosuppression regimen in low-immunological-risk recipients remains weak. Hence, there is an unmet need for better evidence to enable translation to improved practice of induction immunosuppression. There is a need to develop a scoring system to stratify the immunological risk on a linear scale, rather than into ambiguous broad categories, taking into consideration the various recipient and donor factors, and allotting specific risk scores to each parameter. This would enable prediction of anticipated rejection risk as well as graft failure for individual recipients based on their risk score as well as the effect of different interventions including induction in modifying the risk. This will also facilitate the interpretation of data from different centers.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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