Use of Thymoglobulin® (antithymocyte immunoglobulin) in renal transplantation: practical guide

A combinação de imunossupressores faz parte do protocolo de tratamento de pacientes submetidos a um transplante renal (TR).1 O termo terapia de indução refere-se ao tratamento imunossupressor usado especificamente no período perioperatório, mas cujo efeito se prolonga no pós-transplante. Atualmente, as recomendações internacionais indicam o uso de agente biológico com anticorpos mono ou Guia prático para usar Thymoglobuline® (globulina antitimócito) em transplante renal

the transplant procedure.Current international recommendations on induction therapy for renal transplantation suggest the use of biological agents such as monoclonal and polyclonal antibodies against T cells. 1 Thymoglobuline ® , a rabbit anti-thymocyte globulin, is the most commonly used drug in induction therapy regimens offered to kidney transplant patients in the United States. 2 Interleukin-2 receptor antagonists (IL2-Ra) such as Basiliximab are also recommended. 1 In Brazil, Thymoglobuline ® was approved by the National Health Surveillance Agency (ANVISA) for use in the prevention and treatment of organ (kidney, liver, pancreas etc.) transplant patients facing acute rejection.Thymoglobuline ® is also used in the treatment of aplastic anemia and in cases of graft-versushost disease. 3lthough Thymoglobuline ® is broadly prescribed to kidney transplant patients, there is no clear favorite among treatment schemes or choice of route of infusion, dosage, duration, and ideal therapy start time.
This study aimed to assess the scientific evidence on the prescription of Thymoglobuline ® to kidney transplant patients in terms of route of administration, dosage, duration of treatment, and ideal therapy start time.

objectIve
This systematic review included studies in which Thymoglobuline ® was prescribed to kidney transplant patients on induction therapy or individuals treated for rejection, with the purpose of listing the recommended uses of Thymoglobuline ® in kidney transplantation scenarios.

Methods
An extensive search for papers using keywords "Thymoglobuline," "randomized," and "renal" was carried out in the EMBASE (Excerpta Medica Database), LILACS (Latin American and Caribbean Health Sciences), and MedLine (Medlars On Line) databases.The resulting references were considered for analysis and included in a literature review.
The review included randomized trials comparing anti-thymocyte globulin (ATG) to other drugs used in induction therapy and analyzing the efficacy of ATG administered at different times.
The search included every study published in English and enrolling adult patients carried out within a thirty-year period (1982-2012), in which the use of Thymoglobuline ® was assessed for its two indications: induction therapy and treatment of rejection.The following variables were analyzed: route of infusion, number of days of administration, time of first infusion, total dose infused, adverse events (leucopenia, delayed graft function, cytomegalovirus infection, and tumors), graft rejection rate, graft survival, and reversal rate of cases of rejection treated with Thymoglobuline ® .Papers in which Thymoglobuline ® was not analyzed, nonrandomized trials, and studies enrolling liver/ pancreas transplant patients were excluded, as described in Table 1.Two reviewers read the titles and abstracts of the references retrieved from the search.The papers were then independently assessed based on the inclusion criteria and data sets were extracted from the included studies.Two reviewers extracted the data from each included study independently.The first author's name and the year of publication were used to identify the studies.General data, methodological characteristics, and the variables considered in each study were collected.Only randomized trials were included in this review; some were openlabel and others were blind studies.All were intention-to-treat studies and groups were compared for at least one primary outcome.
Eight questions concerning the use of Thymoglobuline ® by kidney transplant patients were prepared, as seen below.The main aspects considered were: • Time of infusion;

results
The flowchart used to identify the included studies, as recommended by PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), 4 is shown in Figure 1.The first search yielded 103 studies, of which 26 met the inclusion criteria (randomized studies on the use of Thymoglobuline ® ).Nineteen discussed the use of the medication in induction therapy The recommendations over the use of Thymoglobuline ® in kidney transplant patients are outlined below in the form of the most frequently asked questions in clinical practice, according to experts.

Question 1A
What is the preferred route of infusion of Thymoglobuline ® for kidney transplant patients?

AnsweR:
Route of infusion: there is no direct comparison between different routes of infusion in the literature.Only five of the randomized trials [5][6][7][8][9] on the use of Thymoglobuline ® in induction therapy included in this review -adding up to 562 patients -described the route of infusion.Peripheral catheters were used in only one study 6 with 58 patients.Central catheters or arteriovenous fistulae were the devices of choice in the other studies.In the study in which patients were given peripheral devices, Thymoglobuline ® was administered intraoperatively or postoperatively; no adverse effects were reported.

Question 1b
What are the adverse events reported for kidney transplant patients given peripheral infusions of Thymoglobuline ® ?

AnsweR
A retrospective 10 study reported data from 244 peripheral infusions of ATG or basiliximab, with Thymoglobuline ® accounting for 152 infusions.None of the patients were given concurrent courses of heparin or hydrocortisone.Adverse events were mild and rare.Local pain was observed in four patients (2.6%), erythema in two (1.3%), and edema in one patient (0.7%).No cases of thrombosis or thrombophlebitis were described.Patients with adverse events were maintained on peripheral drug infusion.The authors of the study concluded this was a safe infusion route.regimens (Table 2) and seven in the treatment of cases of severe rejection (Tables 3 and 4).

recoMMendAtIon
Although some studies suggest peripheral infusions are safe, central catheters are preferred.When a central line cannot be used, infusions can be made through a large peripheral vein.

Question 2A
What dosage of Thymoglobuline ® should be given to patients on induction therapy?

AnsweR
The search yielded no randomized trials directly comparing different dosages of ATG.In the included studies, the dosage of Thymoglobuline ® ranged from 1-1.5 mg/kg/day (maximum of 2.5 mg/kg/day).Induction therapy was generally started on D0 (i.e., on the day of transplantation) and as long as on D10.Drug infusion took no less than four hours in most studies.The search yielded no randomized trials comparing different treatment lengths or different times of drug infusion.Two randomized studies reported the use of single-dose ATG. 11,12In one study 11 Thymoglobuline ® was infused preoperatively at a dosage of 4-5 mg/kg; in another study 12 a single dose of 9 mg/kg was infused intraoperatively.
The main adverse events reported in these studies are listed in Table 5.

recoMMendAtIon
The authors recommend the use of 1 mg to 1.5 mg of Thymoglobuline ® for four to six days, with the total cumulative dose ranging from 4 to 8 mg/ kg based on the patient's immune risk.

Question 2b
When should induction therapy be started?

AnsweR
The time at which patients were started on Thymoglobuline ® varied significantly between studies (Table 6).Only one randomized trial 6 compared intraoperative (prior to graft reperfusion) versus postoperative infusion.Patients given ATG during surgery had better outcomes in terms of DGF (Table 2).

recoMMendAtIon
The authors believe the first infusion should be started before graft reperfusion.

Question 3A
Does Thymoglobuline ® decrease the rates of acute rejection and delayed graft function of kidney transplant patients?

AnsweR
The use of ATG was associated with low acute rejection rates in most of the included studies (Table 2). 6,8,13,14Thymoglobuline ® was statistically superior to IL-2R antagonists in two studies. 8,13In three studies, 11,14,15 patients given a regimen of ATG combined with other immunosuppressants (including calcineurin inhibitors) had significantly lower acute rejection rates than controls not given Thymoglobuline ® .The efficacy of Thymoglobuline ® in terms of immune risk deserves careful analysis, once the definition of high immune risk was inconsistent among the included studies.Some studies attributed high immune risk to patients with peak panel reactive antibody (PRA) levels ≥ 30%, 8,13 whereas others considered levels ≥ 20% or > 25%. 7,16Brennan et al. 13 reported that Thymoglobuline ® was more effective than IL-2R antagonists in decreasing the rates of acute rejection in high-risk patients; high risk was assigned to patients at increased risk of rejection and DGF.In general, most of the studies included mildly sensitized or unsensitized patients.DGF rates were similar in most of the studies on the use of Thymoglobuline ® (Table 2).In three studies, Thymoglobuline ® was statistically superior to IL-2R antagonists in this indication. 8,12,17estion 4A Does ATG improve graft and patient survival after renal transplantation?

AnsweR
Thymoglobuline ® has not changed patient survival within the first or second year of renal transplantation 8,13,18 (Table 2) regardless of patient immune risk level.One study 15 described improved graft survival when Thymoglobuline ® was added to the immunosuppressive regimen.Low and high-risk patients (anti-HLA sensitization of any level was deemed as high immune risk) were included; the outcome was not assessed separately for each level of immune risk.

Question 5
How should other immunosuppressants be managed when ATG is used in induction therapy?

AnsweR
Triple-therapy immunosuppression (cyclosporine, mycophenolate mofetil/sodium, steroids) was prescribed in most of the studies assessing Thymoglobuline ® .A meta-analysis showed that reducing the use of steroids or discontinuing them altogether was not associated with increased mortality or graft loss when Thymoglobuline ® was used. 19he ideal dosage of other immunosuppressants used concomitantly with ATG has not been published the literature.ATG may delay the introduction of calcineurin inhibitors without negatively affecting rejection rates. 20The induction therapy in most immunosuppression minimization studies (calcineurin inhibitors and steroids) included Thymoglobuline ® , and none reported inferior outcomes.recoMMendAtIon Modified immunosuppression protocols with induction therapy vary significantly.There is no standard recommendation.

Question 6
How should patients treated with ATG be monitored?How should dosage be adjusted?

AnsweR
In most early studies, Thymoglobuline ® dosage was adjusted to maintain CD3+ counts below 20 cells/mm 3 .Another method used to monitor patients dictated that peripheral lymphocyte counts should be kept between 50-150 cells/ mm 3 .Thymoglobuline ® was tapered down or temporarily suspended in cases of leucopenia or thrombocytopenia. 21,22coMMendAtIon Monitor lymphocyte counts and consider the discontinuation/reduction of the drug when counts are below 100 cells/mm 3 .

Question 7
Is there a recommendation to monitor or offer prophylactic or preemptive therapy against cytomegalovirus infection?

AnsweR
Increased rates of CMV infection were observed in four studies 7,14,18,23 with Thymoglobuline ® (Table 5).In most studies, prophylactic therapy was prescribed to patients at increased risk of CMV infection (individuals with serologic evidence of exposure to CMV before renal transplantation; 21 or CMV-positive donors matched with CMV-negative recipients 13 ).The authors defined CMV infection as positive viremia detected by increased titers of IgG, and/or IgM-positive tests, and/or CMVpositive PCR tests.
The guidelines published by The Transplantation Society 24 consider the prescription of CMV prophylactic therapy for patients on ATG, and further recommends courses of ganciclovir or valganciclovir for a period of three months after renal transplantation in individuals at high risk of infection.
Among the medications used in prophylactic therapy against CMV, ganciclovir was superior to acyclovir 1 .Oral and intravenous ganciclovir were equally efficacious. 25ost studies included prescriptions of three grams per day (three doses of one gram) of oral ganciclovir or 450-900 mg/ day of valganciclovir for up to 90 days after transplantation. 1,13,26,27Randomized trials 28,29 and a meta-analysis of a systematic review of the literature 25 revealed that the incidence of CMV infection decreased when antiviral drugs were prescribed in courses of prophylactic or preemptive therapy.This decrease was associated with better graft survival. 1recoMMendAtIon Patients on Thymoglobuline ® should be assessed for CMV prophylactic or preemptive therapy.

Question 8
What is the role of ATG in the treatment of acute graft rejection?What is the recommended dosage and length of treatment?What about more severe cases of rejection (vascular and antibodymediated rejection)?

AnsweR
A systematic review 30 comparing Thymoglobuline ® versus steroids in the treatment of first episodes of acute rejection reported a trend toward reduced graft loss favoring Thymoglobuline ® .Since 2009, lymphocyte-depleting agents such as Thymoglobuline ® have been recommended for patients not responding to initial steroid therapy. 1 The mean dose of ATG prescribed in early studies for the treatment of acute rejection was 4 mg/kg/day for seven to ten days. 22,31,32In one study, 33 the patients prescribed a fixed dose of 200 mg/day on alternate days for ten days of Thymoglobuline ® had better outcomes than the group given methylprednisolone.[36][37][38] recoMMendAtIon There are no randomized studies on the use of Thymoglobuline ® in the treatment of individuals with severe rejection.However, consensus stipulates that more severe cases (vascular and antibody-mediated rejection) should be treated with lymphocyte-depleting agents. 30Dosages and routes of administration are the same used in induction therapy, but treatment time ranges between seven and ten days.

Figure 1 .
Figure 1.Flowchart used in the identification of studies.

Table 2
is a summary chart of the included studies and contains data on sample sizes, comparisons between groups, transplant types (live or deceased donor), and clinical outcomes.

tAble 2
RAndomized studies on the use of Anti-thymocyte globulin in the induction theRApy of kidney Cyclosporine + mycophenolate mofetil or azathioprine and prednisone; * Cyclosporine + azathioprine and steroids.Farney et al. 2008 5 looked into renal transplant data only.

tAble 3
RAndomized studies on the use of Anti-thymocyte globulin in the tReAtment of kidney tRAnsplAnt pAtients with Acute Rejection : anti-thymocyte globulin; NR: Not reported.* No difference in severity of acute renal failure between groups on first episode of acute rejection.Reduced occurrence seen in second and third episodes of rejection favoring ATG.** Dose adjusted based on T cell counts (50-150/mm 3 ).

tAble 5
RAtes of occuRRence of the mAin AdveRse effects obseRved in the included studies

tAble 6
detAils peRtAining to the Route of infusion of Anti-thymocyte globulin in induction theRApy descRibed in the included studies