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

Abstract

The combination of immunosuppressive drugs is part of the treatment regimen of patients undergoing kidney transplantation (RT). Thymoglobulin^®, a rabbit immunoglobulin directed against human thymocytes, is the most commonly agent used for induction therapy in RT in the US. In Brazil, Thymoglobulin^® is approved by ANVISA for the use in patients who underwent kidney transplantation and despite being widely used, there are controversies regarding the drug administration. We prepared a systematic review of the literature, evaluating studies that used Thymoglobulin^® for induction and for acute rejection treatment in patients undergoing RT. The review used the computadorized databases of EMBASE, LILACS and MedLine. Data were extracted from the studies concerning general features, methodological characteristics and variables analyzed in each study. From the results, a practical guide was prepared analyzing various aspects on the use of Thymoglobulin^® in patients submitted to RT.

Keywords:
antilymphocyte serum; immunoglobulins, intravenous; kidney transplantation

Resumo

A combinação de imunossupressores faz parte do protocolo de tratamento de pacientes submetidos a um transplante renal (TR). A Thymoglobuline^®, imunoglobulina policlonal de coelho dirigida contra timócitos humanos, é o agente mais usado como terapia de indução no TR nos Estados Unidos. No Brasil, a Thymoglobuline^® está aprovada para uso em pacientes que foram submetidos a transplante e, apesar de ser amplamente utilizada, ainda existem controvérsias em relação ao seu modo de uso. Realizamos uma revisão sistemática da literatura avaliando os estudos que utilizaram a Thymoglobuline^® na indução e no tratamento de rejeição em pacientes submetidos ao TR. A revisão utilizou os bancos de dados computadorizados da EMBASE, LILACS e MedLine e dos trabalhos selecionados foram extraídas informações sobre os dados gerais dos pacientes, as características metodológicas e as variáveis analisadas em cada estudo. Dos resultados obtidos, desenvolvemos um guia prático sobre o uso de Thymoglobuline^® em pacientes transplantados renais.

Palavras-chave:
imunoglobulinas intravenosas; soro antilinfocitário; transplante de rim

Introduction

Combined immunosuppressant therapy is commonly used in the protocols developed for kidney transplant patients.¹ The term induction therapy refers to immunosuppressive treatment prescribed specifically in the perioperative period, with effects extending until after 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-versus-host disease.³

Although 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, non-randomized 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 open-label and others were blind studies. All were intention-to-treat studies and groups were compared for at least one primary outcome.

Table 1
Characteristics od reviewed and excluded studies

Study	Reasons for exclusion
Chaparro et al. 200939	Not randomized
Díaz et al. 200840	Not randomized
Kuypers et al.200541	Kidney/pancreas transplants
Mehrabi et al. 200742	Not randomized
Agha et al. 200243	Not randomized
Moura et al. 200644	Not randomized
Nicoluzzi et al. 201045	Pancreas transplants
Sampaio et al. 201046	Not randomized
Sancho et al. 200647	Not randomized
Laftavi et al. 201148	Not randomized
Anil Kumar et al. 200849	Did not assess anti-thymocyte globulin
Ciancio et al. 200850	Did not assess anti-thymocyte globulin
Buchler et al. 200751	Did not assess anti-thymocyte globulin
Aoun et al. 200752	Kidney/pancreas transplants
Bogetti et al. 200553	Liver transplants
Hardinger et al. 200554	Did not assess anti-thymocyte globulin
Lo et al. 200455	Did not assess anti-thymocyte globulin
Stegall et al. 200356	Did not assess anti-thymocyte globulin
Kim et al. 201257	Not randomized
LaMattina et al. 201258	Not randomized
Ciancio et al. 201159	Did not assess anti-thymocyte globulin
Hourmant et al. 199460	Not randomized
Martin et al. 201161	Not randomized
Thielke et al. 200562	Not randomized
Ulrich et al. 201163	Not randomized

Eight questions concerning the use of Thymoglobuline^® by kidney transplant patients were prepared, as seen below. The main aspects considered were:

• Time of infusion;

• Total dose infused;

• Route of infusion;

• Prevention and treatment of acute rejection; the cases of acute rejection included in this study were confirmed by biopsy;

• Delayed graft function (DGF), defined as need for dialysis within the first week of transplantation;

• Graft and patient survival;

• Management of leucopenia;

• Prevalence and prevention of cytomegalovirus (CMV) infection; the authors defined CMV infection as positive viremia detected by increased titers of IgG, and/or IgM-positive tests, and/or CMV-positive PCR tests;

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.

Figure 1
Flowchart used in the identification of studies.

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 regimens (Table 2) and seven in the treatment of cases of severe rejection (Tables 3 and 4).

Table 2
Randomized studies on the use of anti-thymocyte globulin in the induction therapy of kidney transplant patients

	Type of study	Comparison	N	Acute rejection rate	Chronic injury rate	Delayed graft function	Survival (+ 6-12 months)	Graft survival (+ 6-12 months)	Graft loss rate
Ciancio et al. 201064	RCT, live donors	ATG vs. Alemtuzumab vs. Daclizumab	13	0 (0%)	0 (0%)	2 (15.3%)	NR	NR	0 (0%)
			13	1 (769%)	3 (23.%)	0 (0%)			0 (0%)
			12	1 (8.33%)	0 (0%)	0 (0%)			0 (0%)
					p = 0.01
Brennan et al. 199 921	RCT,deceased donors	ATG vs. Atgam	48	2 (4.2%)	NR	1/72 (1%)	47 (98%)	47 (98%)	0 (0%)
							23 (96%)	20 (83%)	3 (13%)
			24	6 (25%)			p = 0.606	p = 0.020
				p = 0.014
Brennan et al. 200613	RCT,deceased donors	ATG vs. Basiliximab	141	22 (15.6%)	NR	57 (40.4%)	135 (95.7%)	128 (90.8%)	13 (9.2%)
							131 (95.6%)	123 (89.8%)	14 (10.2%)
			137	35 (25.5%)	NR	61 (45.5%)	p = 0.90		p = 0.68
				p = 0.02		p = 0.54
Noëlet al. 20098	RCT,deceased donors	ATG vs. Daclizumab	113	17 (15%)	NR	35 (31.5%)	108 (95.6%)	93 (82.3%)	20 (177%)
							110 (96.5%)	98 (86.0%)	16 (14%)
			114	31 (27.2%)		50 (44.6%)	p = 0.75	p = 0.47	p = 0.47
				p = 0.016		p = 0.044
Mourad et al. 200423	RCT deceased or live donors	ATG vs. Basiliximab	53	5 (9.4%)	NR	16 (30%)	51 (98.1%)	50 (96.2%)	2 (3.8%)
							52 (98.1%)	50 (94.2%)	2 (3.9%)
			52	5 (9.6%)		15 (28%)
Abou-Ayache et al. 200826	RCT,deceased donors	ATG vs. Daclizumab	55	8 (14.5%)	NR	20 (36%)	54 (98%)	52 (95%)	NR
							53 (98%)	51 (94%)
			54	9 (16.7%)		17 (32%)
				p = NS
Ciancio et al. 2005/200827,65	RCT,deceased donors	ATG vs. Alemtuzumab vs. Daclizumab	30	6 (17%)	5 (14%)	4 (13.3%)	25 (85%)	24 (81%)	1 (3.33%)
							26 (88%)	22 (74%)	6 (20%)
			30	7 (24%)	11 (37%)	2 (6.7%)	25 (85%)	24 (82%)	1 (3.33%)
							p = 0.89	p = 0.66
			30	7 (25%)	3 (11%)	2 (6.7%)
					p = 0.02	p = 0.58
Khosroshahi et al. 200811	RCT, live donors	Immunosuppression # vs. Immunosuppression # + ATG	37	12 (32.4%)	NR	NR	NR	NR	0 (0%)
									1 (3.22%)
			31	4 (12.9%)
				p = 0.05
Farney et al. 20085	RCT, deceased or live donors	ATG vs. Alemtuzumab	45	9 (20%)	NR	8 (18%)	NR	43 (96%)	NR
								30 (94%)
			32	0 (0%)		5 (16%)		p = NS
				p = 0.007		p = NS
Hernandez et al. 200718	RCT,deceased donors	ATG + Cyclosporine + Azathioprine vs. Basiliximab + Cyclosporine + MMF vs. Basiliximab + Tacrolimus + MMFBasiliximabe + Tacrolimus + MMF	80	12 (15%)	NR	22 (27.5%)	80 (100%)	73 (91%)	NR
							79 (98.7%)	72 (90%)
			80	11 (13.8%)		26 (32.5%)	78 (97.5%)	65 (82%)
			80	13 (16.3%)		32 (40%)
				p = NS
Thomas et al. 200716	RCT,deceased donors	Alemtuzumab + Tacrolimus Tacrolimus vs. ATG + Tacrolimus + MMF + steroids	11	2 (18.2%)	NR	NR	11 (100%)	9 (85.7%)	1 (9%)
							7 (87.5%)	7 (87.5%)	2 (25%)
			10	3 (37.5%)				p = NS
Goggins et al. 20036	RCT,deceased donors	ATG IO vs. ATG PO	27	1 (3.6%)	NR	4 (14.8%)	27 (100%)	27 (100%)	NR
							31 (100%)	31 (100%)
			31	5 (16%)		11 (35.5%)
				p = 0.11		p < 0.05
Lebranchu et al. 20027	RCT,deceased donors	Basiliximab + Cyclosporine vs. ATG + Cyclosporine	50	4 (8%)	NR	9 (18%)	49 (98%)	47 (94%)	2 (4%)
							50 (100%)	48 (96%)	0
			50	4 (8%)		11 (22%)
Charpentier et al. 200314	RCTdeceased donors	Tacrolimus vs. ATG + Tacrolimus vs. ATG + Cyclosporine	185	47 (25.4%)	NR	NR	180 (97%)	172 (93.2%)	10 (5.4%)
				28 (15.1%)			183 (98.4%)	177 (95.2%)	7 (3.76%)
			186	39 (21.2%)			179 (97%)	167 (90.8%)	16 (8.69%)
				p = 0.004					p = 0.23
			184
Thibaudin et al. 199815	RCT, deceased and live donors	RCT, deceased and live donors	42	27 (64%)	NR	14 (33%)	NR	32 (76%)	12 (28.5%)
				18 (38%)				42 (89%)	5 (10.63%)
			47	p = 0.02		13 (28%)		p = 0.04
						p = NS
Kyllonen et al. 200712	RCT,deceased donors	ATG vs. Basiliximab vs. Immunosuppression *	53	6 (11.3%)	NR	3 (5.7%)	53 (100%)	52 (98.1%)	1 (1.88%)
				0 (0%)			58 (100%)	56 (96.6%)	1 (1.72%)
			58	NR		14 (24.1%)	42 (95.4%)	41 (93.2%)	4 (9.09%)
			44		7 (15.9%)
					p < 0.025
Soulillou et al. 19909	RCT,deceased donors	ATG vs. 33B3.1	50	5 (10%)	15 (30%)	NR	48 (96%)	42 (85%)	8 (16%)
				7 (14.5%)			48 (96%)	42 (85%)	7 (14%)
			50	p = NS	16 (32%)
Shidban et al. 200317	RCT,deceased donors	ATG vs. Basiliximab	50	4 (8%)	NR	22 (44%)	NR	NR	NR
				3 (12%)
			25	p = NS		19 (76%)
						p = 0.01
Tullius et al. 200366	RCT,deceased donors	ATG vs. Basiliximab	62	22 (35%)	NR	NR	62 (100%)	NR	2 (3.22%)
			62	20 (32%) p = NS			58 (93.5%)		6 (9.6%)

• ATG: anti-thymocyte globulin; Atqam (equine anti-thymocyte globulin); MMF: mycophenolate mofetil; IO: intraoperative; PO: postoperative.
• ^#
  Cyclosporine + mycophenolate mofetil or azathioprine and prednisone;
• ^*
  Cyclosporine + azathioprine and steroids. Farney et al. 2008⁵ 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

	Comparison	N	Rejection reversal rate
Hoitsma et al. 198231	ATG (4 mg/kg per day and additional doses of 2-7 mg/kg)**vs. steroids	20	18 (90%)
		20	15 (75%)
Hilbrands et al.199633	ATG (200 mg in alternate days for ten days) vs. methylprednisolone	19	16 (84%)
		17	9 (53%)
Theodorakis et al. 199832	ATG (4 mg/kg per day for seven days) vs .methylprednisolone	25	NR*
		25
Baldi et al. 200022	ATG (4 mg/kg per day for ten days) vs. OKT3	28	21 (75%)
		28	14 (50%)
			p = 0.05

• ATG: 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/mm³).

Table 4
Randomized studies on the use of anti-thymocyte globulin in the treatment of kidney transplant patients with steroid resistant rejection

	Comparison	N	Rejection reversal rate	Graft survival rate (30-90 days)	Recurrent rejection rate (90 days)
Gaber et al. 1998/	ATG 7-14 days (1.5 mg/kg/day) vs. Atgam	82	72 (88%)	77 (94%)	14 (17%)
Tesi et al. 1997/		81	61 (76%)	73 (90%)	29 (36%)
Schroeder et al. 199934-36			p = 0.027	p = 0.17	p = 0.011
Mariat et al. 199837	ATG	31	97%	1 (3%)	28%
	< 40 kg = 25 mg/day	29	87%	3 (10%)	38%
	40 - 75Kg = 50 mg/day
	> 75 kg = 75 mg/day vs. OKT3		p = NS	p = NS	p = NS
Midtvedt et al. 200338	ATG	27	20 (74%)	26 (96.2%)	12 (44%)
	D1 (2 mg/kg) administered again 1 mg/kg if needed vs. OKT3	28	22 (78.5%)	26 (92.8%)	14 (50%)
			p = NS	p = NS	p = NS

• ATG: anti-thymocyte globulin; NR: not reported; NS: not significant; Atgam (equine anti-thymocyte globulin - eATG).

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.

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^5-9 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 study⁶ 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 retrospective¹⁰ 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.

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.^11,12 In one study¹¹ Thymoglobuline^® was infused preoperatively at a dosage of 4-5 mg/kg; in another study¹² a single dose of 9 mg/kg was infused intraoperatively. The main adverse events reported in these studies are listed in Table 5.

Table 5
Rates of occurrence of the main adverse effects observed in the included studies

	N	Treatment	Leucopenia(approx.1month)	Cytomegalovirus(infection)	Tumor
Ciancio et al. 201064	13	ATG	0 (0%)	0 (0%)	0 (0%)
	13	Alemtuzumab	6 (46.2%)	0 (0%)	1 (769%)
	12	Daclizumab	0 (0%)	0 (0%)	0 (0%)
			(p = 0.0002)
Brennan et al. 199921	48	ATG	27 (56%)	6 (12.5%)	0 (0%)
	24	Atgam	1 (4%)	8 (33%)	1 (4%)
			p = NS	p = 0.056
Brennan et al. 200613	141	ATG	47 (33.3%)	11 (78%)	5 (3.5%)
	137	Basiliximab	20 (14.6%)	24 (175%)	1 (0.7%)
			p < 0.001	p = 0.02	p = 0.21
Noëlet al. 20098	113	ATG	9 (796%)	21 (18.6%)	1 (0.9%)
	114	Daclizumab	5 (4.38%)	12 (10.5%)	0 (0%)
			p = 0.36	p = 0.093	p = NS
Mourad et al. 200423	53	ATG	27 (51%)	22 (41.5%)	NR
	52	Basiliximab	10 (19.2%)	11 (21.2%)
			p = 0.0007	p = 0.025
Abou-Ayache et al. 200826	55	ATG	NR	19 (68%)	0 (0%)
	54	Daclizumab		18 (83%)	0 (0%)
Ciancio et al. 2005/200827,65	30	ATG	NR	1 (3.33%)	0 (0%)
	30	Alemtuzumab		2 (6.66%)	0 (0%)
	30	Daclizumabe		0 (0%)	1 (3.33%)
Khosroshahi et al. 200811	37	Immunosuppression #	NS	NR	NR
	31	Immunosuppression #
		+ ATG
Farney et al. 20085	45	ATG	NR	2 (4.44%)	NR
	32	Alemtuzumab		1 (3.12%)
				p = NS
Hernandez et al. 200718	80	ATG + Cyclosporine + Azathioprine	NR	33 (41%)	3 (3.75%)
	80	Basiliximab + Cyclosporine + MMF		16 (20%)	2 (2.5%)
	80	Basiliximab + Tacrolimus + MMF		20 (25%)	2 (2.5%)
				p = 0.008
Thomas et al. 200716			p < 0.05
	11	Alemtuzumab + Tacrolimus	in favor of	NR	0 (0%)
			Alemtuzumab
	10	ATG + Tacrolimus + MMF + steroids			0 (0%)
Goggins et al. 20036	27	ATG IO	NR	1 (3.7%)	NR
	31	ATG PO		2 (6.5%)
				p = NS
Lebranchu et al. 20027	50	Basiliximab + cyclosporine	0 (0%)	6 (12%)	0 (0%)
	50	ATG + cyclosporine	5 (10%)	19 (38%)	0 (0%)
			p < 0.03	p = 0.005
Charpentier et al. 200314	185	Tacrolimus	16 (8.6%)	29 (15.7%)	1 (0.54%)
	186	ATG +	72 (38.7%)	45 (24.2%)	2 (1.07%)
	184	Tacrolimus	64 (34.8%)	52 (28.3%)	4 (2.17%)
		ATG + cyclosporine	p < 0.001	p = 0.012
Thibaudin et al. 199815	42	Immunosuppression *	7 (17%)	17 (40%)	NR
	47	Immunosuppression * + ATG	20 (43%)	28 (59%)
			p = 0.007	p = NS
Kyllonen et al. 200712	53	ATG vs. Basiliximab vs. Immunosuppression*	NR	9 (17%)	2 (3.77%)
	58			9 (16%)	0 (0%)
	44			5 (11%)	1 (2.27%)
				p = NS	p = NS
Soulillou et al. 19909	50	ATG vs. 33B3.1	> in the ATG arm	9 (18%)	NR
	50			10 (20%)
			p < 0.005
Theodorakis et al. 199832	25	ATG vs. methylprednisolone	NR	NS	NR
	25
Baldiet al. 200022	28	ATG vs. OKT3	4 (14.2%)	2 (71%)	2 (714%)
	28		3 (10.7%)	3 (10.7%)	0 (0%)
			p = NS	p = NS
Mariat et al. 199837	31	ATG vs. OKT3	NR	12 (39%)	0 (0%)
	29			13 (45%)	2 (7%)
Midtvedt et al. 200338	27	ATG vs. OKT3	NR	14 (51.8%)	NR
	28			11 (39.2%)
				p = NS
Hoitsma et al. 198231	20	ATG vs. steroids	NR	NS	NR
	20
Tullius et al. 200366	62	ATG vs. Basiliximab	NR	7 (11.3%)	NR
	62			2 (3.22%)
				p = NS

• NR: not reported; NS: not significant; Atgam (equine anti-thymocyte globulin (eATG); MMF: mycophenolate mofetil; IO: Intraoperative; PO: Postoperative;
• ^#
  Cyclosporine + mycophenolate mofetil or azathioprine and prednisone;
• ^*
  Cyclosporine + azathioprine and steroids.

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 trial⁶ compared intraoperative (prior to graft reperfusion) versus postoperative infusion. Patients given ATG during surgery had better outcomes in terms of DGF (Table 2).

Table 6
Details pertaining to the route of infusion of anti-thymocyte globulin in induction therapy described in the included studies

	Route of infusion	Days of infusion	Time of first anti-thymocyte globulin infusion	Dose mg/kg/day (total ATG dose)
Ciancio et al. 201064	NR	D0 to D7	After surgery	1 mg/kg/day (7 doses)
Brennan et al. 199921	NR	D0 to D6	During surgery (before graft reperfusion)	1.5 mg/kg/day (6 doses)
Brennan et al. 200613	NR	D0 to D4	During surgery (before graft reperfusion)	1.5 mg/kg/day (75mg/kg)
Noëlet al. 20098	Central catheter	D0 to D7	During surgery (before graft reperfusion)	1.25 mg/kg/day
Mourad et al. 200423	NR	NR	NR	1 mg/kg/day DO and D1 and adjusted based on CD3 + (mean of 5.4 infusions)
Abou-Ayache et al. 200826	NR	D0 to D9	After surgery	1-1.5mg/kg/day (< 9 doses, mean of 6.5 days)
Ciancio et al. 2005/200827,65	NR	7 days	After surgery	1 mg/kg/day (x 7 doses)
Khosroshahi et al. 200811	NR	D0	Before surgery (12h hours before the procedure)	4-5 mg/kg
Farney et al. 20085	Central catheter	D0, D2, D4, D6, etc.	During surgery	1.5 mg/kg/day (< 7 doses + 5 mg/kg)
Hernandez et al. 200718	NR	7 days	NR	1-1.5 mg/kg/day (7 days)
Thomas et al. 200716	NR	D0 to D4	Before surgery	1.5 mg/kg/day (x4)
Goggins et al. 20036	Mostly peripheral catheters	D0 to D6	During or after surgery	1 mg/kg (< 6 doses)
Lebranchu et al. 20027	AV fistula or central catheter	D1 to D10	After surgery (24 hours after transplantation)	1-1.5 mg/kg/day (6-10 days; no more than 1O days)
Charpentier et al. 200314	NR	D1 to D10	After surgery (< 12 hours after transplantation)	1.25 mg/kg and adjusted based on clinical status
Thibaudin et al. 199815	NR	D0 to D10	During surgery (before graft reperfusion)	1.25 mg/kg/day DO and adjusted based on CD 2+ and CD3+
Kyllonen et al. 200712	NR	D0	During surgery (before graft reperfusion)	9 mg/kg single dose
Soulillou et al. 19909	AV fistula or central catheter	D0to D14	After surgery	1.5 mg/kg/day (maximum of 2.5 mg/kg)
Shidban et al. 200317	NR	D0 to D5	NR	1.5 mg/kg/day for 5 days under 100 mg/day);
Tullius et al. 200366	Tullius	NR	NR	9 mg/kg perioperatorio

• NR: Not reported.

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).^6,8,13,14 Thymoglobuline^® was statistically superior to IL-2R antagonists in two studies.^8,13 In 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%.^7,16 Brennan 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.^8,12,17

Question 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 study¹⁵ 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.¹⁹

The 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.²⁰ The 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/mm³. Another method used to monitor patients dictated that peripheral lymphocyte counts should be kept between 50-150 cells/ mm³. Thymoglobuline^® was tapered down or temporarily suspended in cases of leucopenia or thrombocytopenia.^21,22

Recommendation

Monitor lymphocyte counts and consider the discontinuation/reduction of the drug when counts are below 100 cells/mm³.

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 recipients¹³). The authors defined CMV infection as positive viremia detected by increased titers of IgG, and/or IgM-positive tests, and/or CMV-positive PCR tests.

The guidelines published by The Transplantation Society²⁴ 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 acyclovir¹. Oral and intravenous ganciclovir were equally efficacious.²⁵

Most 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.^1,13,26,27 Randomized trials^28,29 and a meta-analysis of a systematic review of the literature²⁵ 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.¹

Recommendation

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 antibody-mediated rejection)?

Answer

A systematic review³⁰ 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.^22,31,32 In 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. The dosage most commonly prescribed to patients with steroid-resistant acute rejection was 1.5 to 2 mg/kg/day.^34-38

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.³⁰ Dosages and routes of administration are the same used in induction therapy, but treatment time ranges between seven and ten days.

Acknowledgements

This study was supported by Sanofi. The authors would like to thank company Evidências for the aid provided with references and methods.

REFERÊNCIAS

• ¹
  Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9:S1-155.
• ²
  Gaber AO, Knight RJ, Patel S, Gaber LW. A review of the evidence for use of thymoglobulin induction in renal transplantation. Transplant Proc 2010;42:1395-400. PMID: 20620442 DOI: http://dx.doi.org/10.1016/j.transproceed.2010.04.019
  » http://dx.doi.org/10.1016/j.transproceed.2010.04.019
• ³
  Thymoglobuline. São Paulo, 2014. Bula do remédio [Acesso 20 Mar 2015]. Disponível em: http://www.anvisa.gov.br/datavisa/fila_bula/index.asp
  » http://www.anvisa.gov.br/datavisa/fila_bula/index.asp
• ⁴
  Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 2009;151:W65-94. PMID: 19622512 DOI:http://dx.doi.org/10.1016/j.jclinepi.2009.06.006
  » http://dx.doi.org/10.1016/j.jclinepi.2009.06.006
• ⁵
  Farney A, Sundberg A, Moore P, Hartmann E, Rogers J, Doares W, et al. A randomized trial of alemtuzumab vs. anti-thymocyte globulin induction in renal and pancreas transplantation. Clin Transplant 2008;22:41-9.
• ⁶
  Goggins WC, Pascual MA, Powelson JA, Magee C, Tolkoff-Rubin N, Farrell ML, et al. A prospective, randomized, clinical trial of intraoperative versus postoperative Thymoglobulin in adult cadaveric renal transplant recipients. Transplantation 2003;76:798-802. PMID: 14501856 DOI:http://dx.doi.org/10.1097/01.TP.0000081042.67285.91
  » http://dx.doi.org/10.1097/01.TP.0000081042.67285.91
• ⁷
  Lebranchu Y, Bridoux F, Büchler M, Le Meur Y, Etienne I, Toupance O, et al. Immunoprophylaxis with basiliximab compared with antithymocyte globulin in renal transplant patients receiving MMF-containing triple therapy. Am J Transplant 2002;2:48-56. DOI: http://dx.doi.org/10.1034/j.1600-6143.2002.020109.x
  » http://dx.doi.org/10.1034/j.1600-6143.2002.020109.x
• ⁸
  Noël C, Abramowicz D, Durand D, Mourad G, Lang P, Kessler M, et al. Daclizumab versus antithymocyte globulin in high-immunological-risk renal transplant recipients. J Am Soc Nephrol 2009;20:1385-92. DOI: http://dx.doi.org/10.1681/ASN.2008101037
  » http://dx.doi.org/10.1681/ASN.2008101037
• ⁹
  Soulillou JP, Cantarovich D, Le Mauff B, Giral M, Robillard N, Hourmant M, et al. Randomized controlled trial of a monoclonal antibody against the interleukin-2 receptor (33B3.1) as compared with rabbit antithymocyte globulin for prophylaxis against rejection of renal allografts. N Engl J Med 1990;322:1175-82. PMID: 2157982 DOI: http://dx.doi.org/10.1056/NEJM199004263221702
  » http://dx.doi.org/10.1056/NEJM199004263221702
• ¹⁰
  Erickson AL, Roberts K, Malek SK, Chandraker AK, Tullius SG, Gabardi S. Analysis of infusion-site reactions in renal transplant recipients receiving peripherally administered rabbit antithymocyte globulin as compared with basiliximab. Transpl Int 2010;23:636-40. DOI: http://dx.doi.org/10.1111/j.1432-2277.2009.01042.x
  » http://dx.doi.org/10.1111/j.1432-2277.2009.01042.x
• ¹¹
  Khosroshahi HT, Tubbs RS, Shoja MM, Ghafari A, Noshad H, Ardalan MR. Effect of prophylaxis with low-dose anti-thymocyte globulin on prevention of acute kidney allograft rejection. Transplant Proc 2008;40:137-9. PMID: 18261569 DOI: http://dx.doi.org/10.1016/j.transproceed.2007.12.016
  » http://dx.doi.org/10.1016/j.transproceed.2007.12.016
• ¹²
  Kyllonen LE, Eklund BH, Pesonen EJ, Salmela KT. Single bolus antithymocyte globulin versus basiliximab induction in kidney transplantation with cyclosporine triple immunosuppression: efficacy and safety. Transplantation 2007;84:75-82. PMID: 17627241 DOI:http://dx.doi.org/10.1097/01.tp.0000268084.64888.f3
  » http://dx.doi.org/10.1097/01.tp.0000268084.64888.f3
• ¹³
  Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D; Thymoglobulin Induction Study Group. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med 2006;355:1967-77. DOI: http://dx.doi.org/10.1056/NEJMoa060068
  » http://dx.doi.org/10.1056/NEJMoa060068
• ¹⁴
  Charpentier B, Rostaing L, Berthoux F, Lang P, Civati G, Touraine JL, et al. A three-arm study comparing immediate tacrolimus therapy with antithymocyte globulin induction therapy followed by tacrolimus or cyclosporine A in adult renal transplant recipients. Transplantation 2003;75:844-51. DOI: http://dx.doi.org/10.1097/01.TP.0000056635.59888.EF
  » http://dx.doi.org/10.1097/01.TP.0000056635.59888.EF
• ¹⁵
  Thibaudin D, Alamartine E, de Filippis JP, Diab N, Laurent B, Berthoux F. Advantage of antithymocyte globulin induction in sensitized kidney recipients: a randomized prospective study comparing induction with and without antithymocyte globulin. Nephrol Dial Transplant 1998;13:711-5. PMID:9550651
• ¹⁶
  Thomas PG, Woodside KJ, Lappin JA, Vaidya S, Rajaraman S, Gugliuzza KK. Alemtuzumab (Campath 1H) induction with tacrolimus monotherapy is safe for high immunological risk renal transplantation. Transplantation 2007;83:1509-12. PMID: 17565326 DOI:http://dx.doi.org/10.1097/01.tp.0000263344.53000.a1
  » http://dx.doi.org/10.1097/01.tp.0000263344.53000.a1
• ¹⁷
  Shidban H, Sabawi M, Puhawan M, Aswad S, Mendez RG, Mendez R. A prospective, randomized, phase IV comparative trial of Thymoglobulin(r) versus Simulect(r) for the prevention of delayed graft function and acute allograft rejection in renal transplant recipients. Am J Transplant 2003;3:352.
• ¹⁸
  Hernández D, Miquel R, Porrini E, Fernández A, González-Posada JM, Hortal L, et al. Randomized controlled study comparing reduced calcineurin inhibitors exposure versus standard cyclosporine-based immunosuppression. Transplantation 2007;84:706-14. PMID: 17893603 DOI:http://dx.doi.org/10.1097/01.tp.0000282872.17024.b7
  » http://dx.doi.org/10.1097/01.tp.0000282872.17024.b7
• ¹⁹
  Pascual J, Zamora J, Galeano C, Royuela A, Quereda C. Steroid avoidance or withdrawal for kidney transplant recipients. Cochrane Database Syst Rev 2009;21:CD005632. PMID: 19160257
• ²⁰
  Naujokat C, Berges C, Fuchs D, Sadeghi M, Opelz G, Daniel V. Antithymocyte globulins suppress dendritic cell function by multiple mechanisms. Transplantation 2007;83:485-97. PMID: 17318082 DOI: http://dx.doi.org/10.1097/01.tp.0000251975.81281.22
  » http://dx.doi.org/10.1097/01.tp.0000251975.81281.22
• ²¹
  Brennan DC, Flavin K, Lowell JA, Howard TK, Shenoy S, Burgess S, et al. A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients. Transplantation 1999;67:1011-8. PMID: 10221486 DOI:http://dx.doi.org/10.1097/00007890-199904150-00013
  » http://dx.doi.org/10.1097/00007890-199904150-00013
• ²²
  Baldi A, Malaise J, Mourad M, Squifflet JP. A prospective randomized study comparing poly-ATG to mono-OKT3 clonal antibodies for the first rejection therapy after kidney transplantation: long-term results. Transplant Proc 2000;32:429-31. PMID: 10715467 DOI: http://dx.doi.org/10.1016/S0041-1345(00)00838-1
  » http://dx.doi.org/10.1016/S0041-1345(00)00838-1
• ²³
  Mourad G, Rostaing L, Legendre C, Garrigue V, Thervet E, Durand D. Sequential protocols using basiliximab versus antithymocyte globulins in renal-transplant patients receiving mycophenolate mofetil and steroids. Transplantation 2004;78:584-90. PMID: 15446319 DOI:http://dx.doi.org/10.1097/01.TP.0000129812.68794.CC
  » http://dx.doi.org/10.1097/01.TP.0000129812.68794.CC
• ²⁴
  Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Snydman DR, et al.; Transplantation Society International CMV Consensus Group. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation 2010;89:779-95. PMID:20224515 DOI: http://dx.doi.org/10.1097/TP.0b013e3181cee42f
  » http://dx.doi.org/10.1097/TP.0b013e3181cee42f
• ²⁵
  Hodson EM, Barclay PG, Craig JC, Jones C, Kable K, Strippoli GF, et al. Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev 2005;19:CD003774. PMID: 16235341
• ²⁶
  Abou-Ayache R, Büchler M, Lepogamp P, Westeel PF, Le Meur Y, Etienne I, et al. CMV infections after two doses of daclizumab versus thymoglobulin in renal transplant patients receiving mycophenolate mofetil, steroids and delayed cyclosporine A. Nephrol Dial Transplant 2008;23:2024-32. DOI: http://dx.doi.org/10.1093/ndt/gfm873
  » http://dx.doi.org/10.1093/ndt/gfm873
• ²⁷
  Ciancio G, Burke GW, Gaynor JJ, Carreno MR, Cirocco RE, Mathew JM, et al. A randomized trial of three renal transplant induction antibodies: early comparison of tacrolimus, mycophenolate mofetil, and steroid dosing, and newer immune-monitoring. Transplantation 2005;80:457-65. PMID: 16123718 DOI: http://dx.doi.org/10.1097/01.tp.0000165847.05787.08
  » http://dx.doi.org/10.1097/01.tp.0000165847.05787.08
• ²⁸
  Kudlacz E, Perry B, Sawyer P, Conklyn M, McCurdy S, Brissette W, et al. The novel JAK-3 inhibitor CP-690550 is a potent immunosuppressive agent in various murine models. Am J Transplant 2004;4:51-7. DOI: http://dx.doi.org/10.1046/j.1600-6143.2003.00281.x
  » http://dx.doi.org/10.1046/j.1600-6143.2003.00281.x
• ²⁹
  Strippoli GF, Hodson EM, Jones C, Craig JC. Preemptive treatment for cytomegalovirus viremia to prevent cytomegalovirus disease in solid organ transplant recipients. Transplantation 2006;81:139-45. PMID: 16436954 DOI: http://dx.doi.org/10.1097/01.tp.0000183970.71366.da
  » http://dx.doi.org/10.1097/01.tp.0000183970.71366.da
• ³⁰
  Webster AC, Pankhurst T, Rinaldi F, Chapman JR, Craig JC. Monoclonal and polyclonal antibody therapy for treating acute rejection in kidney transplant recipients: a systematic review of randomized trial data. Transplantation 2006;81:953-65. PMID: 16612264 DOI:http://dx.doi.org/10.1097/01.tp.0000215178.72344.9d
  » http://dx.doi.org/10.1097/01.tp.0000215178.72344.9d
• ³¹
  Hoitsma AJ, Reekers P, Kreeftenberg JG, van Lier HJ, Capel PJ, Koene RA. Treatment of acute rejection of cadaveric renal allografts with rabbit antithymocyte globulin. Transplantation 1982;33:12-6. PMID: 7039017 DOI: http://dx.doi.org/10.1097/00007890-198201000-00003
  » http://dx.doi.org/10.1097/00007890-198201000-00003
• ³²
  Theodorakis J, Schneeberger H, Illner WD, Stangl M, Zanker B, Land W. Aggressive treatment of the first acute rejection episode using first-line anti-lymphocytic preparation reduces further acute rejection episodes after human kidney transplantation. Transpl Int 1998;11:S86-9. DOI:http://dx.doi.org/10.1111/j.1432-2277.1998.tb01203.x
  » http://dx.doi.org/10.1111/j.1432-2277.1998.tb01203.x
• ³³
  Hilbrands LB, Hoitsma AJ, Koene RA. Methylpredenisolone versus ATG as initial treatment for acute rejections after renal transplantation [abstract of European Dialysis and Transplant Association-European Renal Association (ERA-EDTA)]. Nephrol Dial Transplant 1996;11:1675.
• ³⁴
  Gaber AO, First MR, Tesi RJ, Gaston RS, Mendez R, Mulloy LL, et al. Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation. Transplantation 1998;66:29-37. PMID:9679818 DOI: http://dx.doi.org/10.1097/00007890-199807150-00005
  » http://dx.doi.org/10.1097/00007890-199807150-00005
• ³⁵
  Tesi RJ, Kano JM, Horn HR, Schroeder T. Thymoglobulin reverses acute renal allograft rejection better than ATGAM--a double-blinded randomized clinical trial. Transplant Proc 1997;29:21S-23S. PMID: 9366922 DOI: http://dx.doi.org/10.1016/S0041-1345(97)80005-X
  » http://dx.doi.org/10.1016/S0041-1345(97)80005-X
• ³⁶
  Schroeder TJ, Moore LW, Gaber LW, Gaber AO, First MR. The US multicenter double-blind, randomized, phase III trial of thymoglobulin versus atgam in the treatment of acute graft rejection episodes following renal transplantation: rationale for study design. Transplant Proc 1999;31:1S-6S. DOI:http://dx.doi.org/10.1016/S0041-1345(99)00092-5
  » http://dx.doi.org/10.1016/S0041-1345(99)00092-5
• ³⁷
  Mariat C, Alamartine E, Diab N, de Filippis JP, Laurent B, Berthoux F. A randomized prospective study comparing low-dose OKT3 to low-dose ATG for the treatment of acute steroid-resistant rejection episodes in kidney transplant recipients. Transpl Int 1998;11:231-6.
• ³⁸
  Midtvedt K, Fauchald P, Lien B, Hartmann A, Albrechtsen D, Bjerkely BL, et al. Individualized T cell monitored administration of ATG versus OKT3 in steroid-resistant kidney graft rejection. Clin Transplant 2003;17:69-74. DOI: http://dx.doi.org/10.1034/j.1399-0012.2003.02105.x
  » http://dx.doi.org/10.1034/j.1399-0012.2003.02105.x
• ³⁹
  Chaparro A, Monteverde M, Ibañez J, Adragna M, Lopez L, Briones L, et al. Trasplante renal 1988 - 2008. Med Infant 2009;16:118-25.
• ⁴⁰
  Díaz JM, Cabera C, Facundo C, Guirado L, Maderuelo A, Silva I, et al. Evolución de los pacientes trasplantados con riñones procedentes de donantes en asistolia. Actas Fund Puigvert 2008;27:127-30.
• ⁴¹
  Kuypers DR, Malaise J, Claes K, Evenepoel P, Maes B, Coosemans W, et al.; Euro-SPK Study Group. Secondary effects of immunosuppressive drugs after simultaneous pancreas-kidney transplantation. Nephrol Dial Transplant 2005;20:33-9.
• ⁴²
  Mehrabi A, Mood ZhA, Sadeghi M, Schmied BM, Müller SA, Welsch T, et al. Thymoglobulin and ischemia reperfusion injury in kidney and liver transplantation. Nephrol Dial Transplant 2007;22:viii54-viii60. DOI: http://dx.doi.org/10.1093/ndt/gfm651
  » http://dx.doi.org/10.1093/ndt/gfm651
• ⁴³
  Agha IA, Rueda J, Alvarez A, Singer GG, Miller BW, Flavin K, et al. Short course induction immunosuppression with thymoglobulin for renal transplant recipients. Transplantation 2002;73:473-5. DOI: http://dx.doi.org/10.1097/00007890-200202150-00025
  » http://dx.doi.org/10.1097/00007890-200202150-00025
• ⁴⁴
  Moura LRR, Pereira MG, Durão M, Tomato EJ, Matos ACC, Wroclawski ER, et al. Imunoglobulina antitimócito como terapia de indução: proteção contra a lesão de isquemia e reperfusão. Einstein (São Paulo) 2006;4:315-20.
• ⁴⁵
  Nicoluzzi JE, Silveira F, Silveira FP, Macri M. Experience with 100 pancreas transplants. Rev Col Bras Cir 2010;37:102-5. DOI:http://dx.doi.org/10.1590/S0100-69912010000200006
  » http://dx.doi.org/10.1590/S0100-69912010000200006
• ⁴⁶
  Sampaio ELM, Freitas TVD, Galante NZ, Park SI, Harada KM, Haolla FAB, et al. Terapia de indução com alentuzumabe em receptores de transplante renal. J Bras Nefrol 2010;32:91-9. DOI: http://dx.doi.org/10.1590/S0101-28002010000100015
  » http://dx.doi.org/10.1590/S0101-28002010000100015
• ⁴⁷
  Sancho A, Gavela E, Crespo JF, Górriz JL, Ávila A, Núñez A, et al. Renal transplantation with positive cross-matching test. Nefrologia 2006;26:261-6.
• ⁴⁸
  Laftavi MR, Patel S, Soliman MR, Alnimri M, Kohli R, Said M, et al. Low-dose thymoglobulin use in elderly renal transplant recipients is safe and effective induction therapy. Transplant Proc 2011;43:466-8. PMID: 21440735 DOI: http://dx.doi.org/10.1016/j.transproceed.2011.01.039
  » http://dx.doi.org/10.1016/j.transproceed.2011.01.039
• ⁴⁹
  Anil Kumar MS, Irfan Saeed M, Ranganna K, Malat G, Sustento-Reodica N, Kumar AM, et al. Comparison of four different immunosuppression protocols without long-term steroid therapy in kidney recipients monitored by surveillance biopsy: five-year outcomes. Transpl Immunol 2008;20:32-42. DOI: http://dx.doi.org/10.1016/j.trim.2008.08.005
  » http://dx.doi.org/10.1016/j.trim.2008.08.005
• ⁵⁰
  Ciancio G, Burke GW, Gaynor JJ, Roth D, Sageshima J, Kupin W, et al. Randomized trial of mycophenolate mofetil versus enteric-coated mycophenolate sodium in primary renal transplant recipients given tacrolimus and daclizumab/thymoglobulin: one year follow-up. Transplantation 2008;86:67-74.
• ⁵¹
  Büchler M, Caillard S, Barbier S, Thervet E, Toupance O, Mazouz H, et al.; SPIESSER Group. Sirolimus versus cyclosporine in kidney recipients receiving thymoglobulin, mycophenolate mofetil and a 6-month course of steroids. Am J Transplant 2007;7:2522-31. DOI:http://dx.doi.org/10.1111/j.1600-6143.2007.01976.x
  » http://dx.doi.org/10.1111/j.1600-6143.2007.01976.x
• ⁵²
  Aoun M, Eschewege P, Hamoudi Y, Beaudreuil S, Duranteau J, Cheisson G, et al. Very early steroid withdrawal in simultaneous pancreas-kidney transplants. Nephrol Dial Transplant 2007;22:899-905. DOI: http://dx.doi.org/10.1093/ndt/gfl660
  » http://dx.doi.org/10.1093/ndt/gfl660
• ⁵³
  Bogetti D, Sankary HN, Jarzembowski TM, Manzelli A, Knight PS, Thielke J, et al. Thymoglobulin induction protects liver allografts from ischemia/reperfusion injury. Clin Transplant 2005;19:507-11. DOI: http://dx.doi.org/10.1111/j.1399-0012.2005.00375.x
  » http://dx.doi.org/10.1111/j.1399-0012.2005.00375.x
• ⁵⁴
  Hardinger KL, Bohl DL, Schnitzler MA, Lockwood M, Storch GA, Brennan DC. A randomized, prospective, pharmacoeconomic trial of tacrolimus versus cyclosporine in combination with thymoglobulin in renal transplant recipients. Transplantation 2005;80:41-6. PMID: 16003231 DOI:http://dx.doi.org/10.1097/01.TP.0000162980.68628.5A
  » http://dx.doi.org/10.1097/01.TP.0000162980.68628.5A
• ⁵⁵
  Lo A, Egidi MF, Gaber LW, Shokouh-Amiri MH, Nazakatgoo N, Fisher JS, et al. Observations regarding the use of sirolimus and tacrolimus in high-risk cadaveric renal transplantation. Clin Transplant 2004;18:53-61. DOI: http://dx.doi.org/10.1111/j.1399-0012.2004.00116.x
  » http://dx.doi.org/10.1111/j.1399-0012.2004.00116.x
• ⁵⁶
  Stegall MD, Larson TS, Prieto M, Gloor J, Textor S, Nyberg S, et al. Kidney transplantation without calcineurin inhibitors using sirolimus. Transplant Proc 2003;35:125S-7S. DOI: http://dx.doi.org/10.1016/S0041-1345(03)00226-4
  » http://dx.doi.org/10.1016/S0041-1345(03)00226-4
• ⁵⁷
  Kim JM, Jang HR, Ko JS, Kwon CH, Kwak MS, Hur WS, et al. Comparison between thymoglobulin and ATGAM as an induction agent in adult kidney transplantation: a single-center experience. Transplant Proc 2012;44:171-4. DOI: http://dx.doi.org/10.1016/j.transproceed.2011.11.061
  » http://dx.doi.org/10.1016/j.transproceed.2011.11.061
• ⁵⁸
  LaMattina JC, Mezrich JD, Hofmann RM, Foley DP, D'Alessandro AM, Sollinger HW, et al. Alemtuzumab as compared to alternative contemporary induction regimens. Transpl Int 2012;25:518-26. DOI: http://dx.doi.org/10.1111/j.1432-2277.2012.01448.x
  » http://dx.doi.org/10.1111/j.1432-2277.2012.01448.x
• ⁵⁹
  Ciancio G, Gaynor JJ, Sageshima J, Guerra G, Zarak A, Roth D, et al. Randomized trial of dual antibody induction therapy with steroid avoidance in renal transplantation. Transplantation 2011;92:1348-57. PMID: 22027927 DOI: http://dx.doi.org/10.1097/TP.0b013e3182384b21
  » http://dx.doi.org/10.1097/TP.0b013e3182384b21
• ⁶⁰
  Hourmant M, Le Mauff B, Cantarovich D, Dantal J, Baatard R, Denis M, et al. Prevention of acute rejection episodes with an anti-interleukin 2 receptor monoclonal antibody. II. Results after a second kidney transplantation. Transplantation 1994;57:204-7. PMID: 8310508 DOI:http://dx.doi.org/10.1097/00007890-199401001-00008
  » http://dx.doi.org/10.1097/00007890-199401001-00008
• ⁶¹
  Martin ST, Roberts KL, Malek SK, Tullius SG, Vadivel N, De Serres S, et al. Induction treatment with rabbit antithymocyte globulin versus basiliximab in renal transplant recipients with planned early steroid withdrawal. Pharmacotherapy 2011;31:566-73. DOI: http://dx.doi.org/10.1592/phco.31.6.566
  » http://dx.doi.org/10.1592/phco.31.6.566
• ⁶²
  Thielke J, DeChristopher PJ, Sankary H, Oberholzer J, Testa G, Benedetti E. Highly successful living donor kidney transplantation after conversion to negative of a previously positive flow-cytometry cross-match by pretransplant plasmapheresis. Transplant Proc 2005;37:643-4. PMID: 15848486 DOI:http://dx.doi.org/10.1016/j.transproceed.2004.12.063
  » http://dx.doi.org/10.1016/j.transproceed.2004.12.063
• ⁶³
  Ulrich F, Niedzwiecki S, Pascher A, Kohler S, Weiss S, Fikatas P, et al. Long-term outcome of ATG vs. Basiliximab induction. Eur J Clin Invest 2011;41:971-8. DOI: http://dx.doi.org/10.1111/j.1365-2362.2011.02490.x
  » http://dx.doi.org/10.1111/j.1365-2362.2011.02490.x
• ⁶⁴
  Ciancio G, Gaynor JJ, Roth D, Kupin W, Hanson L, Tueros L, et al. Randomized trial of thymoglobulin versus alemtuzumab (with lower dose maintenance immunosuppression) versus daclizumab in living donor renal transplantation. Transplant Proc 2010;42:3503-6. PMID: 21094804 DOI:http://dx.doi.org/10.1016/j.transproceed.2010.08.045
  » http://dx.doi.org/10.1016/j.transproceed.2010.08.045
• ⁶⁵
  Ciancio G, Burke GW, Gaynor JJ, Roth D, Kupin W, Rosen A, et al. A randomized trial of thymoglobulin vs. alemtuzumab (with lower dose maintenance immunosuppression) vs. daclizumab in renal transplantation at 24 months of follow-up. Clin Transplant 2008;22:200-10. DOI:http://dx.doi.org/10.1111/j.1399-0012.2007.00774.x
  » http://dx.doi.org/10.1111/j.1399-0012.2007.00774.x
• ⁶⁶
  Tullius SG, Pratschke J, Strobelt V, Kahl A, Reinke P, May G, et al. ATG versus basiliximab induction therapy in renal allograft recipients receiving a dual immunosuppressive regimen: one-year results. Transplant Proc 2003;35:2100-1. DOI: http://dx.doi.org/10.1016/S0041-1345(03)00679-1
  » http://dx.doi.org/10.1016/S0041-1345(03)00679-1

• Erratum

  The paper "Use of Thymoglobulin® (antithymocyte immunoglobulin) in renal transplantation: practical guide", published on the April of 2015 issue of the Brazilian Journal of Nephrology [J Bras Nefrol. 2015; 37: 228-240], has been changed, where the author’s affiliation, Luciane Deboni, was misquoted, and the her correct affiliation is: São José Municipal Hospital.

Publication Dates

• Publication in this collection
  Apr-Jun 2015

History

• Received
  05 June 2014
• Accepted
  12 Jan 2015