Kidney transplantation in adults: Induction immunosuppressive therapy

INTRODUCTION — Induction therapy is immunosuppressive therapy administered at the time of kidney transplantation to reduce the risk of allograft rejection. In general, induction strategies fall into one of two categories. The first relies upon high doses of conventional immunosuppressive agents, while the more commonly used strategy utilizes either T cell-depleting or interleukin (IL) 2 receptor-blocking antibodies in combination with lower doses of conventional agents.

This topic will review the approach to induction therapy in adults undergoing kidney transplantation. Maintenance immunosuppressive therapy for adult kidney transplant recipients is discussed separately. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)

GENERAL PRINCIPLES

Indications for induction therapy — Practically all kidney allograft recipients require immunosuppressive therapy to prevent rejection and loss of the allograft. For most patients undergoing kidney transplantation, we suggest induction therapy consisting of antibody therapy plus standard immunosuppressive therapy, rather than standard immunosuppressive therapy alone. The choice of antibody therapy depends upon an assessment of the patient's risk of acute rejection (algorithm 1). (See 'Assessment of immunologic risk' below.)

There are select patients to whom we do not administer antibody induction therapy:

●Recipients of two-haplotype-identical, living, related donor kidneys. These patients are at very low risk for acute rejection; thus, we do not administer antibody therapy as part of the induction regimen in this group.

●Recipients of a kidney transplant who have another functioning solid organ transplant such as a liver, lung, or heart and are currently being administered immunosuppressive agents [1]. Such patients generally do not get induction therapy, as they have been on long-term maintenance immunosuppression and are therefore at increased infection risk with lymphocyte depletion.

However, clinical practice varies worldwide and induction therapy is frequently center specific; at some transplant centers in other countries, induction therapy is not routinely administered.

Several randomized, controlled trials and meta-analyses have shown that induction therapy consisting of biologic antibodies plus standard immunosuppressive therapy, compared with standard immunosuppressive therapy alone, reduces the risk of kidney allograft rejection and may reduce the risk of short-term graft loss [2-4]. As examples:

●In a 2017 Cochrane systematic review that included 17 randomized trials (2044 kidney transplant recipients) comparing rabbit or horse antithymocyte globulin (ATG) with placebo or no treatment for induction therapy, ATG reduced the risk of acute rejection (relative risk [RR] 0.63, 95% CI 0.51-0.78) [4]. When used together with calcineurin inhibitor (CNI)-based maintenance immunosuppression, ATG possibly reduced the risk of death (RR 0.75, 95% CI 0.27-2.06 at 1 to 2 years and RR 0.94, 95% CI 0.11-7.81 at 5 years) and graft loss (RR 0.65, 95% CI 0.36-1.19 at 1 to 2 years), but these results were not statistically significant. However, ATG increased the risk of cytomegalovirus (CMV) infection (RR 1.55, 95% 1.24-1.95), leukopenia (RR 3.86, 95% CI 2.79-5.34), and thrombocytopenia (RR 2.41, 95% CI 1.61-3.61).

●In a 2010 Cochrane systematic review that included 32 randomized trials (5854 kidney transplant recipients) comparing an interleukin (IL) 2 receptor antagonist (basiliximab or daclizumab) with placebo for induction therapy, use of an IL-2 receptor antagonist reduced the risk of biopsy-proven acute rejection at one year (14 trials; RR 0.72, 95% CI 0.64-0.81) [3]. Treatment with an IL-2 receptor antagonist also reduced the risk of graft loss at one year (24 trials; RR 0.75, 95% CI 0.62-0.90) but not beyond this.

Standard immunosuppressive therapy is discussed elsewhere. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)

Types of antibody therapy — Available antibodies for induction therapy include the following:

●Antilymphocyte antibodies – Antilymphocyte antibodies include both polyclonal and monoclonal antibodies:

•Polyclonal antilymphocyte antibodies contain antibodies to a wide variety of human T cell surface antigens, including the major histocompatibility complex (MHC) antigens. Thymoglobulin is a polyclonal immunosuppressive agent that is generated in rabbits. Although there is no generic formulation, it is commonly referred to as rabbit antithymocyte globulin, or rATG. This may produce some confusion, as there are other rATGs, such as one produced by Fresenius. The immunogen for rATG-Thymoglobulin is human thymocytes, while, for rATG-Fresenius, the immunogen is a Jurkat T cell leukemia line. The preparations also differ in potency and efficacy. Another polyclonal antibody, ATGAM, is a purified gamma globulin solution obtained by immunization of horses with human thymocytes.

•Monoclonal antilymphocyte antibodies include alemtuzumab. Alemtuzumab is a humanized anti-CD52 panlymphocytic (both B and T cells) monoclonal antibody, the use of which is declining in the United States [5]. Alemtuzumab is not available in many countries in Europe.

●IL-2 receptor antagonists – Full T cell activation leads to the calcineurin-mediated stimulation of the transcription, translation, and secretion of IL-2, an essential autocrine growth factor that induces T cell proliferation. Thus, an attractive therapeutic option is the abrogation of IL-2 activity via the administration of anti-IL-2 receptor antibodies. The only IL-2 receptor antibody that is available is basiliximab.

●Anti-CD20 antibodies – Rituximab is an anti-CD20 monoclonal antibody that depletes CD20-positive B cells. It is approved for treatment of multiple conditions, but it has been used most commonly among transplant recipients for treatment of posttransplant lymphoproliferative disease and for desensitization for human leukocyte antigen (HLA)- and ABO-incompatible transplants and the treatment of antibody-meditated rejection. (See "Treatment and prevention of post-transplant lymphoproliferative disorders" and "Kidney transplantation in adults: HLA-incompatible transplantation" and "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection".)

ASSESSMENT OF IMMUNOLOGIC RISK — An important element of some approaches to induction protocols involves the attempt to identify patients at high risk of acute rejection. With this view, more aggressive immunosuppression is justified in patients at significantly increased risk of rejection (figure 1). Risk factors for acute rejection include the following [6]:

●One or more human leukocyte antigen (HLA) mismatches

●Younger recipient and older donor age

●Calculated panel reactive antibody (cPRA) greater than 20 percent

●Presence of a donor-specific antibody (DSA)

●Blood group incompatibility

●Delayed onset of graft function

●Cold ischemia time greater than 24 hours

Patients with one or more of the above risk factors are considered to be at high immunologic risk for acute rejection. Those who have none of the above risk factors are considered to be at low immunologic risk. (See 'Patients at high risk of rejection' below and 'Patients at low risk of rejection' below.)

APPROACH TO INDUCTION THERAPY

Patients at high risk of rejection — For patients at high immunologic risk of acute rejection (see 'Assessment of immunologic risk' above), we recommend induction therapy with rATG-Thymoglobulin rather than an interleukin (IL) 2 receptor antagonist (basiliximab) (algorithm 1). In patients who are unable to tolerate rATG-Thymoglobulin, such as those who are hypotensive, leukopenic, and/or thrombocytopenic at the time of transplant surgery, basiliximab is an alternative option. This approach is consistent with the 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines [6]. Dosing and administration of these agents are discussed below. (See 'Dosing and administration' below.)

In patients at increased risk for acute rejection, rATG-Thymoglobulin is more effective than basiliximab in preventing rejection [3,7-13]. The efficacy and safety of rATG-Thymoglobulin versus basiliximab in high-risk patients was best assessed in a multicenter trial that randomly assigned 278 first deceased-donor kidney transplant recipients to a five-day course of rATG-Thymoglobulin or two doses of basiliximab [7]. All patients received cyclosporine, mycophenolate mofetil, and prednisone for maintenance immunosuppression, as well as antiviral prophylaxis with ganciclovir.

●At one year, patients receiving rATG-Thymoglobulin had lower rates of acute rejection (16 versus 26 percent) and acute rejection requiring antibody treatment (1.4 versus 8 percent). Patient and graft survival were similar between the groups. Although serious adverse event rates were similar between the groups, patients treated with rATG-Thymoglobulin had a higher rate of infection (86 versus 75 percent) but a lower incidence of cytomegalovirus (CMV) disease (8 versus 18 percent).

●At five years, rates of acute rejection and acute rejection requiring antibody treatment remained lower among those treated with rATG-Thymoglobulin compared with basiliximab (16 versus 30 percent and 3 versus 12 percent, respectively) [10]. Patients treated with rATG-Thymoglobulin also had a lower composite endpoint of acute rejection, graft loss, and death at five years (39 versus 52 percent) and incidence of treated CMV infection (7 versus 17 percent); however, the incidence of malignancy did not differ. Thus, the relative benefits of rATG-Thymoglobulin were sustained over a five-year period after surgery.

Compared with rATG-Thymoglobulin, basiliximab may be associated with increased occurrence of de novo donor-specific antibodies (DSAs) and antibody-mediated rejection (ABMR). This was suggested by a study of 114 consecutive recipients of deceased-donor kidneys who had DSAs but a negative crossmatch at the time of transplantation [14]. At 36 months, compared with basiliximab, rATG-Thymoglobulin was associated with decreases in de novo DSA and ABMR. (See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection".)

Patients at low risk of rejection — For patients who are at low immunologic risk of acute rejection (see 'Assessment of immunologic risk' above), either an IL-2 receptor antagonist (basiliximab) or rATG-Thymoglobulin is a reasonable induction therapy agent (algorithm 1). Some experts prefer rATG-Thymoglobulin based upon data showing lower rates of biopsy-proven acute rejection at one year with rATG-Thymoglobulin [15]. Other experts prefer basiliximab based upon studies that have shown similar rates of acute rejection, patient and graft survival, and infection with rATG-Thymoglobulin and IL-2 receptor antibodies in low-risk patients. The 2009 KDIGO clinical practice guidelines recommend the use of IL-2 receptor antibodies as first-line induction therapy in patients not at high immunologic risk [6]. Dosing and administration of these agents are discussed below. (See 'Dosing and administration' below.)

Data from randomized trials and retrospective studies have shown that basiliximab and rATG-Thymoglobulin have similar rates of acute rejection, patient and graft survival, and infection in low-risk patients [9,16-19]. The best data come from a multicenter trial from Germany, in which 615 low-risk transplant recipients were randomly assigned to one of three different immunosuppressive regimens: basiliximab induction with long-term maintenance glucocorticoids, basiliximab induction with rapid glucocorticoid withdrawal (within eight days of transplantation), or rATG-Thymoglobulin induction with rapid glucocorticoid withdrawal [17]. All patients received low-dose extended-release tacrolimus capsules and mycophenolate mofetil as maintenance immunosuppression. At 12 months, rates of biopsy-proven acute rejection were similar among the rATG-Thymoglobulin and both basiliximab groups (10 versus 11 and 11 percent). In addition, there were no differences in patient or graft survival, graft function, infections, or malignancy. Similar findings were reported in two other smaller randomized trials, one of which also found comparable patient and graft survival between basiliximab and rATG-Thymoglobulin at five years [16,18,19].

Dosing and administration

rATG-Thymoglobulin — The optimal dosing strategy for rATG-Thymoglobulin is not known, and practice may vary between centers. Our approach is as follows:

●At our centers, the targeted cumulative dose for rATG-Thymoglobulin varies depending upon the patient's risk of rejection. For patients at high risk of rejection, we use higher doses of rATG-Thymoglobulin and target a cumulative dose of 5 to 6 mg/kg. For patients at low risk of rejection, we target a cumulative dose of 3 mg/kg. (See 'Assessment of immunologic risk' above.)

●We administer the initial dose of intravenous (IV) rATG-Thymoglobulin (1 to 2 mg/kg) intraoperatively, in combination with IV methylprednisolone (7 mg/kg). rATG-Thymoglobulin should not be given if, at presentation, the patient is hypotensive (systolic blood pressure <90 mmHg), the white blood cell (WBC) count is less than 2000/microL, or the platelet count is less than 75,000/microL. If rATG-Thymoglobulin cannot be given, we administer basiliximab. (See 'Basiliximab' below.)

●Following the initial intraoperative dose of rATG-Thymoglobulin, we administer 1 to 2 mg/kg of rATG-Thymoglobulin per day for the next one to two days (ie, a total of two to three doses), depending upon the targeted cumulative dose. The dose of rATG-Thymoglobulin is skipped if the WBC count falls to less than 2000/microL or the platelet count decreases to less than 75,000/microL. A half dose of rATG-Thymoglobulin is administered for a WBC between 2000 and 3000/microL or a platelet count between 75,000 and 100,000/microL. If a dose of rATG-Thymoglobulin is skipped due to cytopenia, some experts would withhold any further doses, even if the intended cumulative dose has not been given, with the rationale that the development of cytopenia indicates that the patient has received sufficient rATG-Thymoglobulin. Other experts would resume therapy within 24 hours of skipping a dose and administer the cumulative dose target, given concerns that administering doses lower than the cumulative dose target may increase the risk of rejection.

●This rATG-Thymoglobulin regimen is combined with maintenance immunosuppressive therapy, which begins preoperatively. Selection and initiation of a maintenance immunosuppressive regimen are described in detail elsewhere. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)

Support for intraoperative administration of rATG-Thymoglobulin comes from a trial of 58 deceased-donor transplant recipients who were randomly assigned to receive either intraoperative or postoperative rATG-Thymoglobulin therapy, with both groups receiving the same cumulative doses of the agent [20]. Intraoperative administration resulted in a lower incidence of delayed graft function (15 versus 36 percent) and a decreased posttransplantation length of hospital stay.

rATG-Thymoglobulin induction has been dosed from 1 to 6 mg/kg per dose, and the duration may range from 1 to 10 days; however, a more typical regimen is 1.5 mg/kg for three to five days [20-28].

The optimal cumulative dose for rATG-Thymoglobulin is unknown but is felt to total 3 to 6 mg/kg [23,26,28]. Total doses of 5.7 mg/kg, which are, on average, given as 1.5 mg/kg per day, have been shown to produce similar outcomes in high-risk recipients who received an average of 10.3 mg/kg [27]. Higher doses and prolonged duration of induction agents are thought to be associated with an increased risk of infection, serum sickness, and the potential development of lymphoma, while low doses that are <3 mg/kg may not effectively prevent acute rejection [20]. Some programs use lower doses for low-risk recipients of living-related-donor kidneys and higher doses for recipients of deceased-donor kidneys and others perceived to be at higher risk for rejection.

Basiliximab — Dosing and administration of basiliximab is as follows:

●We administer IV basiliximab 20 mg intraoperatively in combination with IV methylprednisolone (7 mg/kg), and 20 mg on postoperative day 4.

●Basiliximab is combined with maintenance immunosuppressive therapy, which begins preoperatively. Selection and initiation of a maintenance immunosuppressive regimen are described in detail elsewhere. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)

Special populations

Recipients of an HLA-incompatible kidney transplant — The approach to induction therapy in human leukocyte antigen (HLA)-incompatible kidney transplantation differs from that used in most HLA-compatible transplants. This is discussed in more detail elsewhere. (See "Kidney transplantation in adults: HLA-incompatible transplantation", section on 'Transplant immunosuppression'.)

Recipients of an ABO-incompatible kidney transplant — The optimal induction therapy in patients receiving a kidney transplant from an ABO-incompatible donor is not known. Such recipients of an ABO-incompatible donor kidney are considered to be at high immunologic risk for rejection and should be considered for rATG-Thymoglobulin as part of their induction immunosuppressive therapy. In addition to induction therapy, additional measures such as plasmapheresis and immunoabsorption are generally required to decrease circulating ABO antibody titers and reduce the risk of acute ABMR. ABO-incompatible transplantation is being performed less frequently given the increased emphasis on kidney paired donation. (See 'Assessment of immunologic risk' above and 'Patients at high risk of rejection' above and "Kidney transplantation in adults: Kidney paired donation" and "Kidney transplantation in adults: ABO-incompatible transplantation".)

Recipients with HIV — Transplant recipients with HIV, compared with those without HIV, have a higher risk of acute rejection and, therefore, would theoretically benefit from antibody induction therapy [29]. However, given the underlying immunosuppressed state of patients with HIV, prolonged lymphocyte depletion with antibody induction therapy could potentially increase their risk of developing opportunistic infections.

The use of induction immunosuppression in kidney transplant recipients with HIV remains controversial, and there is no uniform agreement among UpToDate authors and editors about the optimal approach in these patients. Some centers avoid the use of antibody induction therapy among transplant recipients with HIV. In centers that use antibody induction therapy, some use basiliximab (an IL-2 receptor antibody) based upon data from two studies of kidney transplant recipients with HIV that demonstrated an increased risk of infection among those treated with rATG-Thymoglobulin [30,31]. Other centers prefer to use rATG-Thymoglobulin given its superior efficacy in preventing acute rejection in recipients without HIV.

One study of 830 kidney transplant recipients with HIV compared clinical outcomes among patients treated with rATG-Thymoglobulin, an IL-2 receptor antibody, or no induction therapy [32]. Compared with no induction, induction with either rATG-Thymoglobulin or an IL-2 receptor antibody was associated with a decreased risk of delayed graft function (relative risk [RR] 0.66, 95% CI 0.51-0.84) and death-censored graft loss (hazard ratio [HR] 0.47, 95% CI 0.24-0.89). Antibody therapy did not significantly reduce the risk of biopsy-confirmed acute rejection. Notably, antibody induction therapy was not associated with an increased risk of infection.

INFREQUENTLY USED INDUCTION THERAPIES

Alemtuzumab — Alemtuzumab is a humanized anti-CD52 panlymphocytic (both B and T cells) monoclonal antibody that is approved for treatment of chronic lymphocytic leukemia. Alemtuzumab induction therapy is used in approximately 10 percent of kidney transplant recipients in the United States.

We do not routinely use alemtuzumab as induction therapy in most patients undergoing kidney transplantation. Although randomized trials comparing alemtuzumab with either rATG-Thymoglobulin or basiliximab have shown similar or lower rates of acute rejection [33-36], there are concerns that its benefits in reducing acute rejection may decrease over time [33]. Other long-term outcomes, including graft and patient survival and development of chronic allograft nephropathy, may also be worse in patients receiving alemtuzumab compared with rATG-Thymoglobulin and interleukin (IL) 2 receptor antagonists [34,37]. In addition, alemtuzumab is not readily available to all medical centers that perform kidney transplantation.

Some centers use alemtuzumab as induction therapy for recipients of a human leukocyte antigen (HLA)-incompatible kidney transplant following HLA desensitization, as discussed separately. (See "Kidney transplantation in adults: HLA-incompatible transplantation", section on 'Transplant immunosuppression'.)

Alemtuzumab is administered as a single intravenous (IV) dose of 30 mg at the time of transplantation.

Rituximab — Rituximab is an anti-CD20 monoclonal antibody that depletes CD20-positive B cells. We do not routinely use rituximab as induction therapy in most patients undergoing kidney transplantation, as rituximab does not appear to add benefit and may cause harm among recipients of HLA- and ABO-compatible allografts.

Two randomized trials have evaluated rituximab as induction therapy in kidney transplant recipients:

●In one trial that randomly assigned 136 kidney transplant recipients to induction therapy with single-dose rituximab (375 mg/m²) or placebo, rates of acute rejection, mortality, and bacterial or viral infection at six months were similar between the groups [38]. However, three-year mortality was higher among rituximab-treated patients (12 versus 0 percent); deaths were related to fungal pneumonia (n = 1), pulmonary carcinoma (n = 1), and myocardial infarction and/or cardiac arrest (n = 6) [39].

●In a second trial that randomly assigned 280 kidney transplant recipients to induction therapy with single-dose rituximab (375 mg/m²) or placebo, overall rates of acute rejection were comparable at six months posttransplantation [40]. However, among high-risk patients (defined as having a panel reactive antibody [PRA] >6 percent or retransplantation), rates of rejection were lower in those receiving rituximab (18 versus 38 percent). Rituximab-treated patients had a higher incidence of neutropenia (24 versus 2 percent), but the risk of infection and malignancy was the same between the groups at two years.

Rituximab has been used for desensitization for HLA- and ABO-incompatible transplants, as discussed elsewhere. (See "Kidney transplantation in adults: ABO-incompatible transplantation", section on 'Approach to ABOI transplantation' and "Kidney transplantation in adults: HLA-incompatible transplantation", section on 'Pretransplant HLA desensitization'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)

SUMMARY AND RECOMMENDATIONS

●General principles – Induction therapy is immunosuppressive therapy administered at the time of kidney transplantation to reduce the risk of allograft rejection. In general, induction strategies fall into one of two categories. The first relies upon high doses of conventional immunosuppressive agents, while the more commonly used strategy utilizes either T cell-depleting or interleukin (IL) 2 receptor-blocking antibodies in combination with lower doses of conventional agents. (See 'Introduction' above and 'Types of antibody therapy' above.)

●Indications for induction therapy – For most patients undergoing kidney transplantation, we suggest induction therapy consisting of antibody therapy plus standard immunosuppressive therapy, rather than standard immunosuppressive therapy alone (Grade 2B) (algorithm 1). Select patients to whom we do not administer antibody induction therapy include:

•Recipients of two-haplotype-identical, living, related allografts, given the decreased immunologic risk of acute rejection

•Recipients of a kidney transplant who have another functioning solid organ transplant (eg, liver, lung, or heart) and who are currently being administered immunosuppressive agents, as they have been on long-term maintenance immunosuppression and are therefore at increased infection risk with lymphocyte depletion

However, clinical practice varies worldwide and induction therapy is frequently center specific; at some transplant centers in other countries, induction therapy is not routinely administered. (See 'Indications for induction therapy' above.)

●Patients at high risk of rejection – For patients at high immunologic risk of acute rejection, we recommend induction therapy with rATG-Thymoglobulin rather than an IL-2 receptor antagonist (basiliximab) (Grade 1B). In patients who are unable to tolerate rATG-Thymoglobulin, such as those who are hypotensive, leukopenic, and/or thrombocytopenic at the time of transplant surgery, basiliximab is an alternative option. (See 'Patients at high risk of rejection' above and 'Dosing and administration' above.)

●Patients at low risk of rejection – For patients who are at low immunologic risk of acute rejection, either an IL-2 receptor antagonist (basiliximab) or rATG-Thymoglobulin is a reasonable induction therapy agent. Some experts prefer rATG-Thymoglobulin based upon data showing lower rates of biopsy-proven acute rejection at one year with rATG-Thymoglobulin. Other experts prefer basiliximab based upon studies that have shown similar rates of acute rejection, patient and graft survival, and infection with rATG-Thymoglobulin and IL-2 receptor antibodies in low-risk patients. (See 'Patients at low risk of rejection' above and 'Dosing and administration' above.)