Risk of serious opportunistic infections after solid organ transplantation: interleukin-2 receptor antagonists versus polyclonal antibodies. A meta-analysis.

Expert Review of Anti-infective Therapy

ISSN: 1478-7210 (Print) 1744-8336 (Online) Journal homepage: http://www.tandfonline.com/loi/ierz20

Risk of serious opportunistic infections after solid organ transplantation: interleukin-2 receptor antagonists versus polyclonal antibodies. A metaanalysis Andre C Kalil, Marius C Florescu, Wendy Grant, Clifford Miles, Michael Morris, R Brian Stevens, Alan N Langnas & Diana F Florescu To cite this article: Andre C Kalil, Marius C Florescu, Wendy Grant, Clifford Miles, Michael Morris, R Brian Stevens, Alan N Langnas & Diana F Florescu (2014) Risk of serious opportunistic infections after solid organ transplantation: interleukin-2 receptor antagonists versus polyclonal antibodies. A meta-analysis, Expert Review of Anti-infective Therapy, 12:7, 881-896 To link to this article: http://dx.doi.org/10.1586/14787210.2014.917046

View supplementary material

Published online: 29 May 2014.

Submit your article to this journal

Article views: 42

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierz20 Download by: [University of California, San Diego]

Date: 12 September 2015, At: 14:14

Downloaded by [University of California, San Diego] at 14:14 12 September 2015

Original Research

Risk of serious opportunistic infections after solid organ transplantation: interleukin-2 receptor antagonists versus polyclonal antibodies. A meta-analysis Expert Rev. Anti Infect. Ther. 12(7), 881–896 (2014)

Andre C Kalil*1, Marius C Florescu2, Wendy Grant3, Clifford Miles2, Michael Morris3, R Brian Stevens4, Alan N Langnas3 and Diana F Florescu1,3 1 Infectious Diseases Division, University of Nebraska Medical Center, Omaha, NE, USA 2 Nephrology Division, University of Nebraska Medical Center, Omaha, NE, USA 3 Transplant Surgery Division, University of Nebraska Medical Center, Omaha, NE, USA 4 Transplant Surgery Division, Wright State University, Dayton, OH, USA *Author for correspondence: Tel.: +1 402 559 8650 [email protected]

informahealthcare.com

Background: We aimed to evaluate and quantify the risk of serious opportunistic infections after induction with polyclonal antibodies versus IL-2 receptor antagonists (IL-2RAs) in randomized clinical trials. Methods: PRISMA guidelines were followed and random-effects models were performed. Results: 70 randomized clinical trials (10,106 patients) were selected: 36 polyclonal antibodies (n = 3377), and 34 IL-2RAs (n = 6729). Compared to controls, polyclonal antibodies showed higher risk of serious opportunistic infections (OR: 1.93, 95% CI: 1.34–2.80; p < 0.0001); IL-2RAs were associated with lower risk of serious opportunistic infections (OR: 0.80, 95% CI: 0.68–0.94; p = 0.009). Polyclonal antibodies were associated with higher risk of bacterial (OR: 1.58, 95% CI: 1.00–2.50; p = 0.049) and viral infections (OR: 2.37, 95% CI: 1.60–3.49; p < 0.0001), while IL-2RAs were associated with lower risk of cytomegalovirus (CMV) disease (OR: 0.73, 95% CI: 0.56–0.97; p = 0.032). Adjusted indirect comparison: compared to polyclonal antibodies, IL-2RAs were associated with lower risk of serious opportunistic infections (OR: 0.41, 95% CI: 0.34–0.49; p < 0.0001), bacterial infections (OR: 0.51, 95% CI: 0.39–0.67; p < 0.0001) and CMV disease (OR: 0.58, 95% CI: 0.34–0.98; p = 0.043). Results remained consistent across allografts. Conclusion: The risk of serious opportunistic infections, bacterial infections and CMV disease were all significantly decreased with IL-2RAs compared to polyclonal antibodies. KEYWORDS: IL-2 receptor antagonists • induction • infection • polyclonal antibodies

Antibody induction therapy has transformed the field of transplantation in the past two decades. Several randomized trials have demonstrated that induction with antibodies decreases the incidence of early acute allograft rejection, delays the onset of acute rejection beyond the critical perioperative period and increases longterm graft survival [1,2]. These agents are often used in patients with delayed graft function to decrease the doses of nephrotoxic maintenance immunosuppressants without increasing the risk of rejection as the organ recovers from ischemia-reperfusion injury [3,3–7]. They seem to be particularly beneficial in improving the

10.1586/14787210.2014.917046

outcomes of patients at high risk of acute rejection such as African-American recipients, highly sensitized patients or patients undergoing retransplantation [8–10]. The frequency of induction antibody use varies not only between different centers around the world but also among different surgical departments within a given center. After the introduction of antibodies for induction therapy in solid organ transplantation (SOT), their use significantly changed over time for different transplanted organs. Meier-Kriesche et al. reported that polyclonal antibodies are most frequently administered for kidney and pancreas

2014 Informa UK Ltd

ISSN 1478-7210

881


Original Research

Kalil, Florescu, Grant et al.

transplantation, while IL-2 receptor antagonists (IL-2RAs) are mainly used for heart–lung, heart, lung and liver transplantations [2]. The preference of antibody for induction has changed from muromomab-CD3 and horse antithymocyte globulins (ATG) to rabbit ATG and monoclonal IL-2RAs [2]. Data comparing the efficacy and safety of polyclonal (depleting) antibodies with IL-2RAs (nondepleting) are very limited. Few small studies suggested that basiliximab and daclizumab have relatively similar efficacy in preventing acute rejection [11–15]. Trials comparing rejection rate, graft and patient survival after administration of polyclonal antibodies versus IL-2RAs have had mixed results [16–23]. No studies published to date have had the statistical power to evaluate the effects of polyclonal antibodies and IL-2RAs on the risk of serious infections after transplantation. The principal aim of our study was to evaluate and quantify the risk of serious opportunistic infections with the use of induction immunosuppression with polyclonal antibodies versus IL-2RAs after SOT. Results

A total of 70 randomized trials (n = 10,106 patients) were selected: 36 studies (n = 3377) [3,24–58] for the polyclonal antibody analysis and 34 studies (n = 6729) [7,59–90] for the IL-2RA analysis. TABLE 1 describes the characteristics of the studies. Polyclonal antibodies versus control (direct comparison) Risk of opportunistic infections

The risk of all serious opportunistic infections (n = 3142) was significantly increased for polyclonal antibodies compared to controls (OR: 1.93; 95% CI: 1.34–2.80; p < 0.0001, I2 = 71%) (FIGURE 1). The risk of serious opportunistic infections was evaluated by each allograft type: heart (n = 32): OR: 4.68 (95% CI: 1.04–21.04; p = 0.044, I2 = 0%); kidney (n = 2778): OR: 2.08 (95% CI: 1.51–2.86; p < 0.0001, I2 = 59%); kidney–pancreas (n = 100): OR: 3.63 (95% CI: 0.02– 613.81; p = 0.62, I2 = 82%); liver (n = 188): OR: 0.35 (95% CI: 0.16–0.76; p = 0.008, I2 = 28%); and lung (n = 44): OR: 7.88 (95% CI: 0.86–72.12; p = 0.068, I2 = 0%). The analysis was also performed by specific polyclonal antibody type: horse antithymocyte (n = 270): OR: 2.17 (95% CI: 1.19–3.94; p = 0.011, I2 = 0%); horse antilymphocyte (n = 1355): OR: 2.66 (95% CI: 1.46–4.84; p = 0.039, I2 = 75%); rabbit antithymocyte (n = 1287): OR: 1.79 (95% CI: 1.03–3.13; p = 0.039, I2 = 67%); and unknown antilymphocyte (n = 230): OR: 0.60 (95% CI: 0.08–4.28; p = 0.610, I2 = 76%). When the overall analysis was stratified by the type of infection, we found the following results: bacterial infections (n = 1958): OR: 1.58 (95% CI: 1.00–2.50; p = 0.049, I2 = 75%) (SUPPLEMENTARY FIGURE 1 [supplementary material can be found online at www.informahealthcare.com/suppl/ 14787210.2014.917046_suppl.doc]); fungal infections (n = 1552): OR: 1.06 (95% CI: 0.66–1.70; p = 0.803, I2 = 45%); viral infections (n = 1542): OR: 2.37 (95% CI: 1.60–3.49; p < 0.0001, I2 = 61%) (SUPPLEMENTARY FIGURE 2); CMV infection (n = 1724): OR: 2.13 (95% CI: 1.66–2.74; p < 0.0001, I2 = 0%) (FIGURE 2); and CMV disease (n = 780): OR: 1.26 (95% CI: 0.78–2.03; p = 0.351, I2 = 0%) (SUPPLEMENTARY FIGURE 3). Risk of 882

infections evaluated by the type of maintenance immunosuppression did not change the above results. Risk of allograft rejection & allograft loss

Compared to controls, the risk of acute allograft rejection was decreased with the use of induction with polyclonal antibodies (n = 3377): OR: 0.73 (95% CI: 0.55–0.97; p = 0.032, I2 = 79%) (SUPPLEMENTARY FIGURE 4). These results were unchanged by adjustment for allograft type. There was no difference between groups regarding the risk of graft loss (n = 3543): OR: 0.86 (95% CI: 0.71–1.04; p = 0.118, I2 = 0) and allograft loss with censoring for death (n = 2402): OR: 0.78 (95% CI: 0.58–1.04; p = 0.091; I2 = 30%). Risk of death

The risk of all-cause mortality between polyclonal antibodies and controls was (n = 3377): OR: 0.90 (95% CI: 0.71–1.14; p = 0.391, I2 = 0%) and the risk of infection-related mortality between polyclonal antibodies and controls was (n = 2240): OR: 1.33 (95% CI: 0.89–1.99; p = 0.166, I2 = 0%). Sensitivity analysis

Sensitivity analysis evaluated the changes in the overall risk of serious opportunistic infections by adjusting for the length of follow-up of each study (n = 3142): OR: 1.84 (95% CI: 1.43– 2.37; p < 0.0001, I2 = 71%) and also for the quality of each study based on the Jadad score (n = 3142): OR: 2.11 (95% CI: 1.52–2.93; p < 0.0001; I2 = 70%). Meta-regression on the number of antibody doses & total cumulative dosage

The number of doses of rabbit antibodies ranged from 1 to 10. The higher the number of rabbit antibody doses, the higher the risk of serious infections (slope: 0.1494; intercept: 0.567; p = 0.0001) (SUPPLEMENTARY FIGURE 5). The number of doses of horse antibodies ranged from 7 to 35. The number of horse antibody doses did not change the risk of infection (slope: 0.013; intercept: 0.703; p = 0.69). No significant changes on the risk of opportunistic infections were observed with different total cumulative doses of either rabbit or horse antibodies. IL-2 receptor antagonist versus control (direct comparison) Risk of opportunistic infections

The risk of all serious opportunistic infections (n = 5648) was significantly decreased for IL-2RAs compared to controls (OR: 0.80, 95% CI: 0.68–0.94; p = 0.009, I2 = 42%) (FIGURE 3). The risk of serious opportunistic infections was evaluated by each allograft type: heart (n = 434): OR: 0.84 (95% CI: 0.57–1.25; p = 0.478, I2 = 0%); kidney (n = 3353): OR: 0.88 (95% CI: 0.71–1.09; p = 0.247, I2 = 38%); kidney–pancreas (n = 185): OR: 0.35 (95% CI: 0.19–0.66; p = 0.001, I2 = 0%); and liver (n = 1338): OR: 0.69 (95% CI: 0.53–0.90; p = 0.006, I2 = 0%). The analysis was also performed by specific IL-2RAs: basiliximab (n = 1771): OR: 0.83 (95% CI: 0.66–1.06; p = 0.137, I2 = 1%) and daclizumab (n = 3877): OR: 0.78 (95% CI: 0.61–0.99; Expert Rev. Anti Infect. Ther. 12(7), (2014)


115

32

110

173

22

50

371

50

50

53

119

40

Banhegyi et al. (1991)

Barnhart et al. (1985)

Belitsky et al. (1991)

Bell et al. (1983)

Bogetti et al. (2005)

Cantarovich et al. (1998)

Charpentier et al. (2002)

Chatterjee et al. (1976)

Cosimi et al. (1976)

Diethelm et al. (1979)

Eason et al. (2003)

Jakobsen et al. (1977)

45.7/44.6

NA/NA

NA/NA

48.5/51

NA/NA

44.7/44.5

43/39

52/53

NA/NA

NA/NA

41/38

49.7/47.3

Mean age (years) Treatment/ control

Kidney

Liver

Kidney

Kidney

Kidney

Kidney

Kidney– pancreas

Liver

Kidney

Kidney

Heart

Kidney

Allograft type

Steroids Steroids

TAC/MMF TAC/MMF/steroids

AZA/steroids AZA/steroids



AZA/TAC/steroids CsA/AZA/steroids AZA/TAC/steroids

CsA/AZA/steroids CsA/AZA/steroids

CsA/TAC/steroids CsA/TAC/steroids



CsA/steroids Steroids

CsA/steroids CsA/steroids

Immunosuppression Treatment/control

ALG: Antilymphocyte globulin; ATG: Antithymocyte globulins; CMV: Cytomegalovirus.

Sample size

Study (year)

Table 1. Characteristics of the studies included in meta-analysis.

No induction

No induction

No induction

No induction

No induction

No induction

No induction

No induction

Placebo

No induction

NA

No induction

Control

Horse antilymphocyte antibody

Rabbit antithymocyte antibody

Horse antithymocyte antibody





Antithymocyte antibody





Treatment

Graft survival and graft function

Patient and graft survival, rejection and treatment required to reverse rejection, incidence of infectious complications

Effectiveness of ALG on rejection, graft survival and patient death

Graft and patient survival

Efficacy of horse ATG in patient and graft survival

Incidence and time to first acute rejection episode confirmed by biopsy

Acute renal rejection and the number of clinically suspected pancreas acute rejection episodes at 1 year

Ability of thymoglobulin to protect against ischemia reperfusion injury in liver transplant recipients

ALG to prevent rejection, improve graft survival

Effectiveness of sequential quadruple therapy with ALG compared with triple therapy

NA

Advantages and disadvantages of ATG induction therapy

Outcome measure


2

1

2

1

2

3

3

1

4

1

1

2

Jadad scale

[34]

[33]

[32]

[31]

[30]

[29]

[28]

[3]

[27]

[26]

[25]

[24]

Ref.

Risk of infections & induction therapy

Original Research

883

884

100

120

58

311

Koga et al. (2004)

Langrehr et al. (2001)

Hesse et al. (1986)

Mourad et al. (2001)

NA/NA

45/46

34.9/35

43.2/42.8

NA/NA

NA/NA

40/37

36.4/36

34.7/30.9

47.5/44.7

42.8/36.1

47/49


Kidney

Liver

Kidney

Kidney

Kidney

Liver

Kidney

Kidney

Kidney

Kidney

Kidney

Liver

Allograft type

AZA/steroids CsA/steroids

AZA/TAC/steroids TAC/steroids

Steroids CsA/AZA/steroids

AZA/TAC/steroids AZA/TAC/steroids

CsA/steroids CsA/AZA/steroids

AZA/TAC TAC


CsA/AZA or MMF/steroids CsA/AZA or MMF/steroids

Steroids Steroids



CsA/AZA/steroids Steroids



67

68

Khosroshahi et al. (2008)

Novick et al. (1986)

49

Kreis et al. (1981)

120

100

Kasiske et al. (1997)

Neuhaus et al. (2000)

35

Kahn et al. (2000)

230

121

Jonas et al. (1995)

Najarian et al. (1985)

Sample size

Study (year)

No induction

NA

No induction

No induction

No induction

No induction

No induction

No induction

No induction

No induction

No induction

No induction

Control

Table 1. Characteristics of the studies included in meta-analysis (cont.).


Antilymphocyte antibody




Antilymphocyte antibody







Treatment

Effect of cyclosporine on initial function of cadaver renal allografts after extended preservation

Graft and patient survival after induction with azathioprine and ALG

Patient and graft survival rates at 1 and 2 years

Efficacy and safety of induction treatment with ATG, followed by tacrolimus therapy

Graft survival at 3, 6 and 12 months

Effectiveness and safety of quadruple therapy (Tac, steroids, AZA, ALG) vs dual therapy (AZA, steroids) induction for liver transplant

Induction therapy with antilymphocyte antibodies improves long-term renal allograft survival

Reduction of acute rejection

Effectiveness of ATG in prolonging kidney graft survival and to assess the possibility of ATG dose determination by T-cell count

Acute rejection and delayed graft function in patients treated with cyclosporine and diltiazem vs ATG

Impact of ATG on duration of acute tubular necrosis and rejection

Tacrolimus as primary immunosuppression after liver transplantation

Outcome measure


1

1

2

3

1

1

2

1

2

1

2

1

Jadad scale

[46]

[45]

[44]

[43]

[42]

[41]

[40]

[39]

[38]

[37]

[36]

[35]

Ref.

Original Research Kalil, Florescu, Grant et al.

Expert Rev. Anti Infect. Ther. 12(7), (2014)


56

44

79

79

85

80

121

182

246

179

89

50

381

340

Novick et al. (1983)

Palmer et al. (1999)

Samsel et al. (2001)

Samsel et al. (2008)

Sansom et al. (1976)

Sheashaa et al. (2008)

Slakey et al. (1993)

Sutherland et al. (1984)

Sutherland et al. (1985)

Taylor et al. (1976)

Thibaudin et al. (1998)

Wadstrom et al. (1995)

Neuhaus et al. (2002)

Ponticelli et al. (2001)

44.2/44.2

49/50.2

40.3/39.4

47/46

NA/NA

NA/NA

NA/NA

47.4/47.3

30.3/31.7

36.3/36

43/40

43.4/41.2

47/51

36/40


Kidney

Liver

Kidney– pancreas

Kidney

Kidney

Kidney

Kidney

Kidney

Kidney

Kidney

Kidney

Kidney

Lung

Kidney

Allograft type




CsA/steroids CsA/AZA/steroids

Steroids Steroids




Steroids Steroids

Steroids Steroids

CsA/AZA/MMF/steroids CsA/AZA/MMF/steroids






Sample size

Study (year)

Placebo

Placebo

No induction

No induction

No induction

No induction

No induction

No induction

No induction

No induction

NA

No induction

No induction

Placebo

Control


Basiliximab

Basiliximab













Treatment

First episode of acute rejection during the first 6 months

Biopsy-proven acute rejection at 6 months, death, graft loss

Advantages and disadvantages of quadruple therapy (adding ATG)

Efficacy of ATG induction in sensitized kidney recipients

Effect of ALG on graft survival

Graft function and survival rates

Graft function and survival rates

To evaluate the role of prophylactic ALG for first-time adult cadaver transplants with immediate graft function

Graft and patient survival

Graft survival and graft function

Incidence of acute rejection

Onset and incidence of acute rejection and complications

Efficacy of thymoglobulin induction therapy in lung transplantation

Impact on delayed onset of rejection and number of rejection episodes

Outcome measure


3

5

1

1

2

2

2

2

1

1

3

1

2

4

Jadad scale

[60]

[59]

[58]

[57]

[56]

[55]

[54]

[53]

[52]

[51]

[50]

[49]

[48]

[47]

Ref.


Original Research

885

886

56

192

72

376

Mehra et al. (2005)

Grenda et al. (2006)

Spada et al. (2006)

Nashan et al. (1999)

49.4/49.6

32.9/32.5

39.8/40.6

49/48

2.9/2.8

11.5/11.3

56.5/53.4

44.9/46.2

45.8/47.9

50/45

43.2/43.9

45.4/45.9


Liver

Kidney

Kidney

Kidney

Liver

Kidney

Heart

Kidney

Kidney

Kidney

Kidney

Kidney

Allograft type

TAC/steroids TAC/steroids




TAC TAC/steroids

TAC/AZA/steroids TAC/AZA/steroids

CsA/MMF/steroids CsA/MMF/steroids


CsA CsA


TAC/steroids TAC/MMF TAC/MMF/steroids




99

346

Kahan et al. (1999)

Schmeding et al. (2007)

108

Parrott et al. (2005)

100

56

Tan et al. (2005)

Sheashaa et al. (2005)

451

Vitko et al. (2005)

71

123

Lawen et al. (2003)

Folkmane et al. (2001)

Sample size

Study (year)

No induction

No induction

No induction

Placebo

No induction

No induction

Placebo

Placebo

Placebo

No induction

No induction

Placebo

Control


Basiliximab

Basiliximab

Basiliximab

Basiliximab

Basiliximab

Basiliximab

Basiliximab

Basiliximab

Basiliximab

Basiliximab

Basiliximab

Basiliximab

Treatment

Long-term effect of basiliximab on rejection and graft survival

Long-term effect of basiliximab on graft and patient survival, biopsyproven rejection

Incidence of acute rejection at 1 year and CMV infection

Incidence of acute rejection at 6 months

Occurrence of first rejection episode

Incidence of and time to first biopsyproven acute rejection

Safety and tolerability of basiliximab

Incidence of acute rejection episodes

Requirement of additional immunosuppressive agents at 12 months

Efficacy and safety of basiliximab as induction therapy for prevention of acute allograft rejection among sensitized kidney recipients

Efficacy and safety of rapid corticosteroid withdrawal from TAC monotherapy after basiliximab administration and from TAC/MMF regimen without antibody induction compared with standard triple regimen TAC/MMF/steroids

Tolerability of basiliximab, adverse events related to immunosuppression

Outcome measure


1

1

1

5

2

3

5

3

5

1

3

4

Jadad scale

[72]

[71]

[70]

[69]

[68]

[67]

[66]

[65]

[64]

[63]

[62]

[61]

Ref.

Original Research Kalil, Florescu, Grant et al.



434

148

260

70

51

698

185

81

364

538

54

39

100

Hershberger et al. (2005)

Yoshida et al. (2005)

Vincenti et al. (1998)

Lietz et al. (2003)

Wilson et al. (2005)

Boillot et al. (2005)

Stratta et al. (2003)

Heffron et al. (2003)

ter Meulen et al. (2004)

Rostaing et al. (2005)

Asberg et al. (2006)

Kato et al. (2005)

Ahsan et al. (2002)

47/47

52/50

57/58.2

46.7/45.5

48/49

6.6/5.3

40/39

50.9/51

53/47

52.8/48.2

47/47

53/52.4

52.4/53.1


Kidney

Liver

Kidney

Kidney

Kidney

Liver

Kidney– pancreas

Liver

Kidney

Heart

Kidney

Liver

Heart

Allograft type

TAC/MMF/steroids TAC/MMF/steroids

TAC/MMF/steroids TAC/MMF

CsA/MMF/steroids MMF/steroids





TAC TAC/steroids








Sample size

Study (year)

No induction

No induction

No induction

No induction

No induction

No induction

No induction

No induction

No induction

No induction

Placebo

No induction

Placebo

Control


Daclizumab

Daclizumab

Daclizumab

Daclizumab

Daclizumab

Daclizumab

Daclizumab

Daclizumab

Daclizumab

Daclizumab

Daclizumab

Daclizumab

Daclizumab

Treatment

Incidence of biopsy-proven acute rejection during the first 6 months

Rejection in steroid-free induction and preemptive antiviral therapy for liver recipients with HCV

Difference in GFR at 12 months

Incidence and time to first biopsyconfirmed acute rejection episode

Incidence of a first biopsy-proven acute rejection within 12 months after transplantation

Daclizumab to spare TAC for 7 days with respect to efficacy and renal function

Incidence of presumed or biopsyproven kidney or pancreas ejection, graft loss or death within the first 6 months

Incidence and time to first biopsyconfirmed acute rejection episode at 3 months

Immediate graft function

Effect of daclizumab induction on high-grade allograft rejection

Incidence of biopsy-confirmed acute rejection within the first 6 months

Renal function indicated by MDRD

Effect on severe cellular rejection, hemodynamic compromise, death, second transplantation

Outcome measure


1

2

2

3

3

1

1

2

1

2

2

2

2

Jadad scale

[84]

[83]

[82]

[81]

[80]

[79]

[78]

[77]

[7]

[76]

[75]

[74]

[73]

Ref.


Original Research

887

p = 0.04, I2 = 54%). When the overall analysis was stratified by the type of infection, we found the following results: bacterial infections (n = 1962): OR: 0.81 (95% CI: 0.57–1.13; p = 0.210, I2 = 57%) (SUPPLEMENTARY FIGURE 6); fungal infections (n = 3542): OR: 0.93 (95% CI: 0.70– 1.22; p = 0.583, I2 = 36%); viral infections (n = 4641): OR: 0.76 (95% CI: 0.60–0.95; p = 0.017, I2 = 52%) (SUPPLEMENTARY FIGURE 7); CMV infection (n = 4795): OR: 0.79 (95% CI: 0.59– 1.06; p = 0.121, I2 = 61%) (FIGURE 4); and CMV disease (n = 2356): OR: 0.73 (95% CI: 0.55– 0.97; p = 0.032, I2 = 0%) (SUPPLEMENTARY FIGURE 8). Risk of infections evaluated by the type of maintenance immunosuppression did not change the above results.

2

3

Effect on biopsy-proven acute rejection at 24 weeks

Effect of lower levels and delayed introduction of TAC on renal function

[90]

1 Cardiovascular end points

[89]

3 Impact on immunosuppression and rejection rate

[88]

1 Impact on acute rejection

[87]

3 Effect of induction on HCV-positive liver recipients

[86]

3 Number of patients who had biopsyproven acute rejections within the first 6 months

[85]

Jadad scale Outcome measure

[69]


888

54/54 157

338

Otero et al. (2009)

Neuberger et al. (2009)

55/54

57.1/47.6 54 Gelens et al. (2006)

Compared to controls, the risk of acute allograft rejection was decreased with the use of IL-2RAs (n = 6729): OR: 0.65 (95% CI: 0.52–0.82; p = 0.0003, I2 = 71%) (SUPPLEMENTARY FIGURE 9). These results remained unchanged after adjustment for allograft type. There was no difference between groups regarding the risk of graft loss (n = 5606): OR: 0.97 (95% CI: 0.81–1.16; p = 0.724, I2 = 0%) and allograft loss with censoring for death (n = 2987): OR: 1.10 (95% CI: 0.82–1.47; p = 0.533, I2 = 0%). Risk of death


Daclizumab No induction MMF/TAC/steroids MMF/TAC/steroids Liver

Daclizumab No induction TAC/MMF TAC/steroids Liver

Daclizumab No induction MMF TAC TAC/MMF Kidney

Daclizumab No induction CsA/MMF/steroids CsA/MMF/steroids CsA/MMF/steroids 535 Ekberg et al. (2007)

35.4/35.9 118 Ji et al. (2007)

47.2/47.6

Kidney

Daclizumab No induction CsA/MMF/steroids CsA/MMF/steroids Kidney

Daclizumab No induction MMF/TAC TAC/steroids MMF/TAC/steroids 306 Klintmalm et al. (2007)

44/46 273 Nashan et al. (1999)

51.5/51.4

Liver

Daclizumab Placebo CsA/steroids CsA/steroids Kidney

Treatment Immunosuppression Treatment/control Sample size Study (year)


Allograft type

Control

Risk of allograft rejection & allograft loss



Ref.

Original Research

The risk of death between IL-2RAs and controls was not different (n = 6729): OR: 1.03 (95% CI: 0.82–1.30; p = 0.817, I2 = 0%) and the risk of infection-related mortality between IL-2RAs and controls was (n = 5503): OR: 0.96 (95% CI: 0.63–1.45; p = 0.849, I2 = 2%). Sensitivity analysis

Sensitivity analysis evaluated if adjusting for the length of follow-up or quality of each study could have changed the overall risk of serious opportunistic infections: the results remained consistent for the follow-up analysis (n = 5310): OR: 0.83 (95% CI: 0.71–0.97; p = 0.017, I2 = 42%) and for the study quality (Jadad score) analysis (n = 5310): OR: 0.85 (95% CI: 0.73–0.98; p = 0.03, I2 = 41%). Meta-regression on the number of IL-2RA doses

This analysis was not performed for the IL-2RA trials because the number of doses for each antagonist was the same among trials. Expert Rev. Anti Infect. Ther. 12(7), (2014)



Study name

Eason J et al., (2001) [33] Palmer S et al., (1999) [48] Cantarovich D et al., (1999) [28] Barnhart G et al., (1985) [25] Mourad G et al., (2001) [43] Thibaudin D et al., (1998) [57] Najarian J et al., (1985) [44] Slakey D et al., (1993) [53] Kasiske B et al., (1997) [37] Kreis H et al., (1981) [38] Langrehr J et al., (2001) [41] Wadstrom J et al., (1995) [58] Banhegyi C et al., (1991) [24] Belitsky P et al., (1991) [26] Charpentier B et al., (2003) [29] Bell P et al., (1983) [27] Taylor H et al., (1976) [56] Hesse U et al., (1986) [42] Turcotte J et al., (1973) [105] Sutherland D et al., (1984) [54] Sutherland D et al., (1985) [55] Cosimi A et al., (1976) [31] Samsel R et al., (2008) [50] Sheashaa H et al., (2008) [52]

Statistics for each study

Events/total

Odds ratio

Lower limit

Upper limit

p-value

PolyAb.

Control

0.56 7.88 47.22 4.68 3.02 20.07 144.51 1.41 1.73 1.79 0.25 0.25 1.51 1.92 2.14 1.37 2.27 11.04 2.63 1.71 1.96 3.30 0.93 0.50 1.93

0.20 0.86 2.59 1.04 1.81 1.11 8.77 0.66 0.61 0.49 0.11 0.01 0.72 0.34 1.37 0.57 1.20 4.45 0.94 0.95 1.11 0.60 0.37 0.19 1.34

1.63 72.12 860.51 21.04 5.02 363.14 2380.44 3.01 4.91 6.53 0.57 6.48 3.18 10.97 3.33 3.52 4.29 27.44 7.37 3.08 3.46 18.26 2.35 1.30 2.80

0.290 0.068 0.009 0.044 0.000 0.042 0.001 0.371 0.301 0.379 0.001 0.405 0.274 0.461 0.001 0.484 0.011 0.000 0.067 0.074 0.020 0.171 0.876 0.155 0.000

8/34 21/22 25/25 9/14 123/153 47/47 109/109 23/61 11/50 19/24 30/59 21/22 34/55 4/57 138/184 13/86 65/87 40/107 28/36 54/90 40/115 6/26 26/40 10/40 904/1543

12/34 16/22 13/25 5/18 91/158 35/42 73/121 18/60 7/50 17/25 49/61 28/28 31/60 2/53 108/185 10/87 52/92 6/117 20/35 43/92 28/131 2/24 26/39 16/40 708/1599

Original Research

Odds ratio and 95% Cl

0.1 0.2 0.5 1 Favors polyclonal Ab

2 5 Favors control

10

Figure 1. Polyclonal antibody versus control for the risk of serious opportunistic infections.

IL-2 receptor antagonist versus polyclonal antibodies (adjusted indirect comparison) Risk of serious infections

Induction with IL-2RAs was associated with a 59% reduction in the risk of serious opportunistic infections compared to polyclonal antibodies (OR: 0.41, 95% CI: 0.34–0.49;

Study name

Statistics for each study Odds Lower Upper ratio limit limit

Cantarovich D et al., (1998) [28] Mourad G et al., (2001) [43] Najarian J et al., (1985) [44] Thibaudin D et al., (1998) [57] Langrehr J et al., (2001) [41] Wadstrom J et al., (1995) [58] Charpentier B et al., (2003) [29] Hesse U et al., (1986) [42] Neuhaus P et al., (2000) [45] Samsel R et al., (2008) [50] Sheashaa H et al., (2008) [52]

2.25 2.01 3.80 2.17 1.28 1.00 2.09 5.28 3.12 2.54 0.73 2.13

0.73 1.19 1.80 0.93 0.52 0.33 1.25 1.11 1.19 0.71 0.15 1.66

6.98 3.39 8.03 5.06 3.15 3.06 3.47 25.02 8.22 9.07 3.49 2.74

p < 0.0001). The risk of bacterial infections (OR: 0.51, 95% CI: 0.39–0.67; p < 0.0001), CMV infection (OR: 0.37, 95% CI: 0.28–0.49; p < 0.0001) and CMV disease (OR: 0.58, 95% CI: 0.34–0.98; p = 0.0429) were all significantly reduced with IL-2RAs treatment. No difference was noted in the rate of fungal infections.

Events/total

p-value

PolyAb.

Control

0.160 0.009 0.000 0.074 0.584 1.000 0.005 0.036 0.021 0.151 0.693 0.000

15/25 49/153 30/109 28/47 13/59 11/22 52/186 9/107 17/59 9/40 3/40 236/847

10/25 30/158 11/121 17/42 11/61 14/28 29/185 2/117 7/61 4/39 4/40 139/877


0.1 0.2 0.5 1 Favors polyclonal Ab

2 5 Favors control

10

Figure 2. Polyclonal antibody versus control for the risk of cytomegalovirus infections.


889

Original Research


Study name

Hershberger R et al., (2005) [73] Yoshida E et al., (2005) [74] Vincenti F et al., (1998) [75] Wilson C et al., (2005) [4] Boillot O et al., (2005) [77] Stratta R et al., (2003) [78] Meulen C et al., (2004) [80] Rostaing L et al., (2005) [81] Asberg A et al., (2006) [82] Kato T et al., (2005) [83] Ahsan N et al., (2002) [84] Kirkman R et al., (1991) [106] Nashan B et al., (1999) [69] Ji S et al., (2007) [86] Neuhaus P et al., (2002) [59] Ponticelli C et al., (2001) [60] Lawen J et al., (2003) [61] Kahan B et al., (1999) [65] Spada M et al., (2006) [68] Sheashaa H et al., (2005) [71] Ekberg H et al., (2007) [87] Folkmane I et al., (2001) [70] Neuberger J et al., (2009) [90]


Statistics for each study Odds ratio

Lower limit

Upper limit

0.84 0.91 0.84 37.84 0.66 0.35 1.21 0.92 0.06 0.35 0.48 0.03 1.11 0.77 0.81 0.99 0.71 1.06 0.38 0.44 0.81 0.95 0.94 0.80

0.57 0.47 0.51 2.08 0.45 0.19 0.79 0.64 0.00 0.07 0.16 0.00 0.65 0.30 0.48 0.63 0.33 0.66 0.14 0.18 1.56 0.28 0.58 0.68

1.25 1.75 1.37 688.33 0.96 0.66 1.84 1.33 1.13 1.62 1.43 0.56 1.91 1.94 1.37 1.55 1.51 1.72 1.02 1.10 1.16 3.18 1.53 0.94

p-value

Events/total IL-2ra


Control

71/216 0.403 80/218 41/72 0.780 45/76 50/126 0.478 59/134 25/25 0.014 15/26 57/351 0.030 79/347 49/107 0.001 55/78 0.384 118/186 105/178 0.672 77/260 87/278 0.060 21/27 27/27 0.179 3/19 7/20 0.189 6/50 11/50 0.018 29/40 40/40 0.697 105/140 97/133 10/60 0.575 12/58 0.433 151/188 161/193 0.966 110/168 113/172 37/59 0.372 45/64 0.806 129/173 127/173 0.056 26/36 18/36 10/50 0.078 18/50 136/362 0.249 74/173 18/23 0.930 38/48 0.804 45/169 43/169 0.009 1314/2907 1366/2741 0.1

0.2 0.5 Favors IL-2 RA

1

2 5 Favors control

10

Figure 3. IL-2 receptor antagonist versus control for the risk of serious opportunistic infections.

Risk of allograft rejection and allograft loss

Risk of death

No significant differences for the risk of allograft rejection or loss were found between the two types of induction therapy.

No significant differences between the two types of induction were found for the risk of death.

Study name

Statistics for each study Odds ratio

Hershberger R et al., (2005) [73] Vincenti F et al., (1998) [75] Boillot O et al., (2005) [77] Asberg A et al., (2006) [82] Ahsan N et al., (2002) [84] Kirkman R et al., (1991) [106] Nashan B et al., (1999) [69] Neuhaus P et al., (2002) [59] Ponticelli C et al., (2001) [60] Lawen J et al., (2003) [61] Kahan B et al., (1999) [65] Grenda R et al., (2006) [67] Nashan B et al., (1997) [69] Folkmane I et al., (2001) [70] Ekberg H et al., (2007) [87] Garcia R et al., (2007) [107] Vitco S et al., (2005) [62]

0.78 1.16 0.41 1.26 5.44 1.18 0.66 1.12 1.23 0.68 0.73 3.46 0.70 1.25 0.29 2.18 0.52 0.79

Lower limit 0.49 0.53 0.23 0.33 0.61 0.38 0.37 0.50 0.68 0.26 0.34 0.70 0.44 0.35 0.20 0.22 0.26 0.59

Upper limit 1.24 2.51 0.74 4.75 48.40 3.63 1.18 2.52 2.20 1.80 1.60 17.11 1.13 4.51 0.43 21.76 1.02 1.06

Events/total

p-value

IL-2ra

Control

0.292 0.709 0.003 0.736 0.128 0.775 0.162 0.784 0.492 0.437 0.432 0.128 0.148 0.733 0.000 0.508 0.056 0.121

43/216 15/126 18/351 6/27 5/50 8/40 25/140 13/188 29/168 8/59 12/173 7/99 39/190 19/23 104/362 3/54 12/153 366/2419

50/207 14/134 40/347 5/27 1/50 7/40 33/133 12/193 25/172 12/64 16/173 2/93 50/186 38/48 100/173 1/38 42/298 448/2376


0.1

0.2 0.5 Favors IL-2 RA

1

2 5 Favors control

10

Figure 4. IL-2 receptor antagonist versus control for the risk of cytomegalovirus infections.

890



Publication bias

No bias was found by the two different methods: Egger’s regression: intercept = 0.671, standard error = 0.838; p = 0.43 and Begg and Mazumdar’s rank correlation: Tau = 0.137; p = 0.345.


Discussion

The direct comparison of polyclonal antibodies with controls showed a significant increase in the risk of serious opportunistic infections, while IL-2RAs were associated with a significant decrease in the risk of serious opportunistic infections. Polyclonal antibodies were associated with a significant higher risk of bacterial and viral infections (including CMV infection), but not fungal infections, while IL-2RAs were associated with a lower risk of bacterial, fungal and viral infections. These results remained consistent when the analysis was performed for the different types of polyclonal antibodies and IL-2RAs. Similarly, our findings were unchanged after adjusting for length of the study follow-up, type of maintenance immunosuppression and the quality of the included studies. The lower rate of infections with IL-2RAs compared to controls was an unexpected finding, but possible explanations include the requirement of lower maintenance immunosuppression levels after induction with IL-2RA, or trial enrollment of patients with lower risk of serious infections (unlikely due to the randomized design of all included trials). On the other hand, the lower rate of infections with IL-2RAs compared to polyclonal antibodies may be explained by the more profound long-term immunosuppression provided by polyclonal antibodies. Polyclonal antibodies were significantly associated with a 93% increase in all serious opportunistic infections, 58% increase in bacterial infections, 137% increase in all viral infections and 113% increase in CMV infection. If we translate these findings into more clinically oriented measures such as the number needed to treat to increase infections, only seven patients will need to be treated with polyclonal antibodies to cause one more serious opportunistic infection. On the other hand, compared with controls, IL-2RAs were significantly associated with a 20% decrease in all serious opportunistic infections, 24% decrease in all viral infections and 27% reduction in CMV disease. Correspondingly, we could use the number needed to treat to prevent infections, and demonstrate that 15 patients will need to be treated with IL-2RAs to prevent one more serious opportunistic infection. The adjusted indirect comparison demonstrated that there was a statistical lower risk of all types of infections, except for fungal infections, with the use of IL-2RAs compared to polyclonal antibodies. Of note, the risk of opportunistic infections was higher with polyclonal antibodies, independent of the specific type of antibodies (horse antithymocyte, horse antilymphocyte, rabbit antithymocyte or unknown). However, the fact that the risk of infections decreased with the lower number of doses of rabbit polyclonal antibodies, with no differences with cumulative doses, was an intriguing finding that merits further evaluation. The mechanism of action of polyclonal antibodies is poorly understood; it is explained mainly on the correlation between informahealthcare.com

Original Research

in vitro activities of the antibodies with their in vivo immunosuppressive efficacy [91]. ATG and antilymphocyte globulin are polyclonal immunoglobulins, a mixture of antibody with different specificities prepared by immunization of horses or rabbits with human thymocytes, and, respectively, lymphocytes or T cell lines [91–93]. Polyclonal antibodies are not interchangeable. The effect on cell depletion and risk of infections depend on the specificity of the sera for human cells (immunogens and animal used for antibodies preparation), method of production, lot-to-lot variation and the dosing strategy (number of doses, total dose and duration) [91–95]. The immunogens might be more important than the species of animal used for production regarding the potency of the antibodies; it seems that the Jurkat cultured cell line (Fresenius) is less immunogenic than the human thymocytes and cultured lymphoblasts [93]. These differences would explain the wide range of doses used in clinical trials, and their different effects on similar end points (rejection and/or mortality). Hence, differences in trial end points should be interpreted with caution, taking into consideration not only the methods of production and lot variation but also the flow cytometry analysis to compare the potency of different products. More recent clinical studies showed that immunosuppression could be achieved without lymphocyte depletion, just by interfering with functional lymphocyte surface molecules such as IL-2RAs. Since IL-2 is involved in the clonal expansion of activated lymphocytes (differentiation and proliferation), development of antibodies to target high-affinity IL-2 receptors on activated T cells made sense. IL-2R is composed of three chains: the a-chain (CD25) is not capable of signaling but able to stabilize the other chains, and the b- and g-chains are phosphorylated after binding to the a-chain triggering signal transduction; the association of all three chains is required for high-affinity binding of IL-2 and intracellular signaling; T cells express the a-chain (CD25) only after activation [96–99]. IL-2RAs interfere with IL-2 signaling by inhibiting the association and subsequently the phosphorylation of the b- and g-chains of IL-2R, but have no effect on cell viability and do not modulate the surface expression of the IL-2R chains [96]. The consequence is a blunting of the immune response to any antigenic challenge (alloantigens, bacterial, viral or fungal antigens). Basiliximab is a chimeric antibody containing a human constant region and a murine variable region, while daclizumab is a humanized antibody with only CDR regions of murine origin [100]. Daclizumab has already been commercially discontinued. Both polyclonal antibodies and IL-2RA induction therapies caused a similar decrease in the risk of allograft rejection compared with controls in the direct comparison, independent of the type of allograft. No difference between polyclonal antibodies and IL-2RAs compared with controls was observed regarding the risk of death, risk of infection-related mortality and risk of graft loss, even when graft loss was censored for death. The adjusted indirect comparison demonstrated similar risk of allograft rejection, allograft loss and risk of death. These results are in concordance with the analysis of the USA Renal Data System database, which showed that patient and graft survival was 891


Original Research


similar using either rabbit ATG or IL-2 receptor inhibitors in kidney transplant recipients in the tacrolimus era [19]. Several limitations of our study need to be recognized: First, not all trials provided a systematic reporting of viral, bacterial and fungal infections, so underreporting of infections may have occurred. Second, adjusted indirect comparison might not reflect the direct comparison. However, because the controls for the studies were similar, and the results remained consistent in the subset group and after adjustments for several variables, we believe that our findings are a reliable reflection of the impact of these two induction therapies on the rate of serious infections. Last, the studies on polyclonal antibodies had higher heterogeneity than the IL-2RAs studies. This could be explained by differences in study design or definitions used for the main variable. In addition, studies on polyclonal antibodies spanned for several years, so the heterogeneity could also be due to secular changes on transplantation techniques and immunosuppression. In conclusion, we found that induction therapy with polyclonal antibodies was associated with significantly more serious opportunistic infections (especially bacterial and viral, including CMV) than with IL-2RAs, while both therapies demonstrated similar efficacy in decreasing allograft rejection. Our study brings important and novel information, as most of the previously published studies focused mainly on rejection rate and graft outcomes. Our results indicate that safety according to risk of serious opportunistic infections should be taken into consideration when choosing antibody preparations for induction therapy.

Study selection

Inclusion criteria: All randomized studies that evaluated polyclonal antibodies or IL-2RAs against a control arm (no induction therapy or placebo) as induction therapy for SOT. Exclusion criteria: Trials that used polyclonal antibodies or IL-2RAs as part of their control arm regimens; trials that evaluated monoclonal antibodies such as alemtuzumab and OKT3; trials in which the antibodies were used to treat rejection; trials in which the control group received active therapy and review articles. Data extraction

The following variables were collected: authors, publication year; study design; type of allograft; gender; age; sample size; type of induction therapy; maintenance immunosuppressive regimen; bacterial, fungal and viral infections, CMV infection and CMV disease; length of follow-up; acute rejection rate; allograft loss and mortality. Definitions

Serious opportunistic infections: bacterial, fungal, viral and CMV infections as defined by the original studies. Rejection: biopsy-proven acute allograft rejection reported up to 12 months. Mortality: death reported up to 12 months. Primary objective

The principal aim of this study was prospectively defined as: to quantify the risk of serious opportunistic infections with the use of induction immunosuppression with polyclonal antibodies versus IL-2RAs after SOT.

Material & methods Literature search

Statistical analysis

The PRISMA guidelines for conducting and reporting systematic literature review were followed. The literature search was based on MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic through January 2013. Available abstracts from the American Transplantation Congress and the Infectious Disease Society of America were searched. No language restrictions were applied. The keywords used were thymoglobulin, rabbit antithymocyte globulin, rabbit polyclonal sera, thymoglobulin, ATG, horse antithymocyte globulin, horse polyclonal sera, antithymocyte globulin, antilymphocyte globulin, ALG, interleukin-2, IL-2RAs, basiliximab, simulect, daclizumab, zenapax, transcriptional activator of CDR genes (Lo-Tac-1, anti-Tac), transplant and randomized. Only randomized controlled trials that evaluated polyclonal antibodies, basiliximab and daclizumab for induction in SOT recipients were included. Two investigators (AK and DF) independently evaluated the previously published studies to identify those that met the inclusion/exclusion criteria, and disagreements were resolved by consensus. We assessed the method and concealment of randomization, the reported blinding to the allocation of the intervention, the reporting of the patients who withdrew or dropped out from the study and the quality of the trials by the Jadad scale.

The odds ratios were adjusted by the DerSimonian and Laird method, the I-squared method was used to assess the inconsistencies and the Q statistic method was used to assess the statistical heterogeneity [101]. All data were pooled by the random-effects model. A meta-regression was performed to evaluate the influence of the dose of antibodies on the risk of developing serious infections. The PRISMA Guidelines for meta-analysis were followed and the software used was Comprehensive Meta-analysis Version 2 (Biostat, Englewood, NJ 2011). The adjusted indirect treatment effect was performed by the Bucher method [102]. This method has been validated by Song et al. [103] and was used to evaluate the differences in the risk of serious infections between the polyclonal antibodies and the IL-2RAs. The Jadad score was calculated to evaluate the quality of studies and the QUOROM criteria for the search methodology (SUPPLEMENTARY FIGURE 10 & FIGURE 11). Egger’s regression and Begg and Mazumdar’s methods were used to evaluate publication bias [104].

892

Acknowledgement

The authors thank Ms. Ashley Calhoon and Ms. Elaine Litton for the excellent preparation of this manuscript. Expert Rev. Anti Infect. Ther. 12(7), (2014)


Financial & competing interests disclosure

W Grant has received research grants from Genzyme and B Stevens has received research grants from Genzyme and consulting honoraria from Sanofi-Aventis. The authors have no other relevant affiliations or financial

Original Research

involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • Antibody induction therapy has transformed the field of transplantation in the past two decades. • The frequency of induction antibody use varies not only between different centers around the world but also among different surgical departments within a given center. • The preference of antibody for induction has shifted from muromomab-CD3 and horse antithymocyte globulins to rabbit antithymocyte


globulins and IL-2 receptor antagonists (IL-2RAs). • Previously published studies have not had the statistical power to evaluate the effects of polyclonal antibodies and IL-2RAs on the risk of serious infections after transplantation. • We aimed to evaluate and quantify the risk of serious opportunistic infections after induction with polyclonal antibodies versus IL-2RAs in randomized clinical trials through the meta-analytic methodology. • Polyclonal antibodies showed significantly twofold higher risk of serious opportunistic infections, while IL-2RAs were associated with significant 20% lower risk of serious opportunistic infections. • Polyclonal antibodies were also associated with significantly higher risk of viral infections, whereas IL-2RAs were associated with significantly lower risk of cytomegalovirus (CMV) disease. • The risk of serious opportunistic infections, bacterial infections and CMV disease were all significantly decreased with IL-2RAs compared to polyclonal antibodies.

non-heart-beating kidney transplants. Br J Surg 2005;92:681-7

References 1.

2.

3.

Szczech LA, Berlin JA, Aradhye S, et al. Effect of anti-lymphocyte induction therapy on renal allograft survival: a meta-analysis. J Am Soc Nephrol 8:1771-7 Meier-Kriesche H.U, Li S, Gruessner RW, et al. Immunosuppression: evolution in practice and trends, 1994-2004. Am J Transplant 2006;6:1111-31 Bogetti D, Sankary HN, Jarzembowski TM, et al. Thymoglobulin induction protects liver allografts from ischemia/reperfusion injury. Clin Transplant 2005;19:507-11

4.

Wilson C, Brook NR, Gok MA, et al. Evaluation of daclizumab to reduce delayed graft function in non-heart-beating renal transplantation: a prospective, randomized trial. Transplant Proc 2005;37:1774-5

5.

Sellers MT, McGuire BM, Haustein SV, et al. Two-dose daclizumab induction therapy in 209 liver transplants: a single-center analysis. Transplantation 2004;78:1212-17

6.

7.

Zhang R, Haverich A, Struber M, et al. Delayed onset of cardiac allograft vasculopathy by induction therapy using anti-thymocyte globulin. J Heart Lung Transplant 2008;27:603-9 Wilson CH, Brook NR, Gok MA, et al. Randomized clinical trial of daclizumab induction and delayed introduction of tacrolimus for recipients of


8.

Belitsky P, MacDonald AS, Lawen J, et al. Use of rabbit anti-thymocyte globulin for induction immunosuppression in high-risk kidney transplant recipients. Transplant Proc 1997;29:16S-7S

9.

Gaston RS, Hudson SL, Deierhoi MH, et al. Improved survival of primary cadaveric renal allografts in blacks with quadruple immunosuppression. Transplantation 1992;53:103-9

10.

11.

12.

13.

Augustine JJ, Poggio ED, Heeger PS, Hricik DE. Preferential benefit of antibody induction therapy in kidney recipients with high pretransplant frequencies of donor-reactive interferon-gamma enzyme-linked immunosorbent spots. Transplantation 2008;86:529-34 Adu D, Cockwell P, Ives NJ, et al. Interleukin-2 receptor monoclonal antibodies in renal transplantation: meta-analysis of randomised trials. BMJ 2003;326:789 Grego K, Arnol M, Bren AF, et al. Basiliximab versus daclizumab combined with triple immunosuppression in deceased donor renal graft recipients. Transplant Proc 2007;39:3093-7 Pham K, Kraft K, Thielke J, et al. Limited-dose Daclizumab versus Basiliximab: a comparison of cost and

efficacy in preventing acute rejection. Transplant Proc 2005;37:899-902 14.

Vega O, Cardenas G, Correa-Rotter R, et al. Basiliximab vs. limited-dose daclizumab (2 mg/kg) administered in single or two separated doses in kidney transplantation. Rev Invest Clin 2008;60: 82-6

15.

Nair MP, Nampoory MR, Johny KV, et al. Induction immunosuppression with interleukin-2 receptor antibodies (basiliximab and daclizumab) in renal transplant recipients. Transplant Proc 2001;33:2767-9

16.

Martins L, Henriques AC, Dias L, et al. Anti-interleukin 2-receptor antibodies: a comparative study with polyclonal antibodies in kidney transplantation: preliminary results. Transplant Proc 2000;32:2623-5

17.

Nampoory MR, Abdulhalim M, Johny KV, et al. Bolus anti-thymocyte globulin induction in renal transplant recipients: a comparison with conventional ATG or anti-interleukin-2 receptor antibody induction. Transplant Proc 2002;34: 2916-19

18.

Brennan DC, Daller JA, Lake KD, et al. Thymoglobulin Induction Study Group. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med 2006;355:1967-77

893

Original Research 19.

20.


21.

22.


Jindal RM, Das NP, Neff RT, et al. Outcomes in African-Americans vs. Caucasians using thymoglobulin or interleukin-2 receptor inhibitor induction: analysis of USRDS database. Am J Nephrol 2009;29:501-8 Al Najjar A, Etienne I, Le Pogamp P, et al. Long-term results of monoclonal anti-Il2-receptor antibody versus polyclonal antilymphocyte antibodies as induction therapy in renal transplantation. Transplant Proc 2006;38:2298-9 Haririan A, Morawski K, Sillix DH, et al. Induction therapy with basiliximab versus Thymoglobulin in African-American kidney transplant recipients. Transplantation 2005;79:716-21 Knight RJ, Kerman RH, Schoenberg L, et al. The selective use of basiliximab versus thymoglobulin in combination with sirolimus for cadaveric renal transplant recipients at low risk versus high risk for delayed graft function. Transplantation 2004;78:904-10

23.

Noel C, Abramowicz D, Durand D, et al. Daclizumab versus antithymocyte globulin in high-immunological-risk renal transplant recipients. J Am Soc Nephrol 2009;20: 1385-92

24.

Banhegyi C, Rockenschaub S, Muhlbacher F, et al. Preliminary results of a prospective randomized clinical trial comparing cyclosporine A to antithymocyte globulin immunosuppressive induction therapy in kidney transplantation. Transplant Proc 1991;23:2207-8

25.

26.

27.

28.

Barnhart GR, Goldman MH, Hastillo A, et al. Comparison of immunosuppression therapy following heart transplantation: pretransfusion/azathioprine/ATG/prednisone versus cyclosporine/prednisone. J Heart Transplant 1985;4:381-4 Belitsky P, MacDonald AS, Cohen AD, et al. Comparison of antilymphocyte globulin and continuous i.v. cyclosporine A as induction immunosuppression for cadaver kidney transplants: a prospective randomized study. Transplant Proc 1991;23:999-1000 Bell PR, Blamey RW, Briggs JD, et al. Medical research council trial of antilymphocyte globulin in renal transplantation. A multicenter randomized double-blind placebo controlled clinical investigation. Transplantation 1983;35: 539-45 Cantarovich D, Karam G, Giral-Classe M, et al. Randomized comparison of triple therapy and antithymocyte globulin induction treatment after simultaneous

894

pancreas-kidney transplantation. Kidney Int 1998;54:1351-6 29.

Charpentier B; European Tacrolimus vs Microemulsified Cyclosporin Study Group. A three arm study comparing immediate tacrolimus therapy with ATG induction therapy followed by either tacrolimus or cyclosporine in adult renal transplant recipients. Transplant Proc 2002;34:1625-6

30.

Chatterjee SN. Antithymocyte globulin in renal transplant recipients. Report of a prospective randomized controlled trial. Arch Surg 1976;111:680-3

31.

Cosimi AB, Wortis HH, Delmonico FL, Russell PS. Randomized clinical trial of antithymocyte globulin in cadaver renal allograft recipients: importance of T cell monitoring. Surgery 1976;80:155-63

32.

Diethelm AG, Blackstone E, Whelchel JD, et al. The adjunctive value of equine antithymocyte membrane globulin in a randomized study of patients undergoing cadaveric renal transplantation. Transplant Proc 1979;11:27-30

33.

Eason JD, Nair S, Cohen AJ, et al. Steroid-free liver transplantation using rabbit antithymocyte globulin and early tacrolimus monotherapy. Transplantation 2003;75: 1396-9

34.

Jakobsen A, Sodal G, Flatmark A, Thorsby E. Antilymphocyte globulin in cadaveric renal transplantation – a controlled trial. Scand J Urol Nephrol Suppl 1977(42):94-6

35.

Jonas S, Kling N, Bechstein WO, et al. Rejection episodes after liver transplantation during primary immunosuppression with FK506 or a cyclosporine-based regimen: a controlled, prospective, randomized trial. Clin Transplant 1995;9:406-14

36.

37.

38.

39.

Kahn D, Botha JF, Pascoe MD, et al. Withdrawal of cyclosporine in renal transplant recipients with acute tubular necrosis improves renal function. Transpl Int 2000;13(Suppl 1):S82-3 Kasiske BL, Johnson HJ, Goerdt PJ, et al. A randomized trial comparing cyclosporine induction with sequential therapy in renal transplant recipients. Am J Kidney Dis 1997;30:639-45 Kreis H, Mansouri R, Descamps JM, et al. Antithymocyte globulin in cadaver kidney transplantation: a randomized trial based on T-cell monitoring. Kidney Int 1981;19: 438-44 Khosroshahi HT, Tubbs RS, Shoja MM, et al. Effect of prophylaxis with low-dose anti-thymocyte globulin on prevention of

acute kidney allograft rejection. Transplant Proc 2008;40:137-9 40.

Koga A, Moreso FJ, Seron D, et al. Beneficial effect of concomitant induction with antilymphoblast globulin, cyclosporine, and steroids on long-term renal allograft outcome. Transplant Proc 2004;36:1305-7

41.

Langrehr JM, Klupp J, Junge G, et al. Quadruple versus dual tacrolimus-based induction after liver transplantation: a prospective, randomized trial. Transplant Proc 2001;33:2330-1

42.

Hesse UJ, Fryd DS, Chatterjee SN, et al. Pulmonary infections. The Minnesota randomized prospective trial of cyclosporine vs azathioprine-antilymphocyte globulin for immunosuppression in renal allograft recipients. Arch Surg 1986;121:1056-60

43.

Mourad G, Garrigue V, Squifflet JP, et al. Induction versus noninduction in renal transplant recipients with tacrolimus-based immunosuppression. Transplantation 2001;72:1050-5

44.

Najarian JS, Fryd DS, Strand M, et al. A single institution, randomized, prospective trial of cyclosporin versus azathioprine-antilymphocyte globulin for immunosuppression in renal allograft recipients. Ann Surg 1985;201:142-57

45.

Neuhaus P, Klupp J, Langrehr MJ, et al. Quadruple tacrolimus-based induction therapy including azathioprine and ALG does not significantly improve outcome after liver transplantation when compared with standard induction with tacrolimus and steroids: results of a prospective, randomized trial. Transplantation 2000;69:2343-53

46.

Novick AC, Hwei HH, Steinmuller D, et al. Detrimental effect of cyclosporine on initial function of cadaver renal allografts following extended preservation. Results of a randomized prospective study. Transplantation 1986;42:154-8

47.

Novick AC, Braun WE, Steinmuller D, et al. A controlled randomized double-blind study of antilymphoblast globulin in cadaver renal transplantation. Transplantation 1983;35:175-9

48.

Palmer SM, Miralles AP, Lawrence CM, et al. Rabbit antithymocyte globulin decreases acute rejection after lung transplantation: results of a randomized, prospective study. Chest 1999;116:127-33

49.

Samsel R, Rowinski W, Chmura A, et al. Perioperative administration of single, high-dose of ATG-Fresenius-S as an induction immunosuppressive therapy in cadaveric renal transplantation: preliminary results. Transplant Proc 2001;33:2952-4



50.

51.


52.

53.

Samsel R, Pliszczynski J, Chmura A, et al. Safety and efficacy of high dose ATG bolus administration on revascularization in kidney graft patients – long term results. Ann Transplant 2008;13:32-9 Sansom JR, Barnes AD, Hall CL. A randomized prospective clinical trial of antilymphocyte globulin in 100 cadaveric renal transplants. Postgrad Med J 1976;52: 75-8

Slakey DP, Johnson CP, Callaluce RD, et al. A prospective randomized comparison of quadruple versus triple therapy for first cadaver transplants with immediate function. Transplantation 1993;56:827-31 Sutherland DE, Goetz FC, Najarian JS. One hundred pancreas transplants at a single institution. Ann Surg 1984;200: 414-40

55.

Sutherland DE, Fryd DS, Strand MH, et al. Results of the Minnesota randomized prospective trial of cyclosporine versus azathioprine-antilymphocyte globulin for immunosuppression in renal allograft recipients. Am J Kidney Dis 1985;5:318-27

57.

58.

59.

60.

62.

Sheashaa HA, Hamdy AF, Bakr MA, et al. Long-term evaluation of single bolus high dose ATG induction therapy for prophylaxis of rejection in live donor kidney transplantation. Int Urol Nephrol 2008;40: 515-20

54.

56.

61.

Taylor HE, Ackman CF, Horowitz I. Canadian clinical trial of antilymphocyte globulin in human cadaver renal transplantation. Can Med Assoc J 1976;115:1205-8

63.

Vitko S, Klinger M, Salmela K, et al. Two corticosteroid-free regimens-tacrolimus monotherapy after basiliximab administration and tacrolimus/ mycophenolate mofetil-in comparison with a standard triple regimen in renal transplantation: results of the Atlas study. Transplantation 2005;80:1734-41 Tan J, Yang S, Wu W. Basiliximab (Simulect) reduces acute rejection among sensitized kidney allograft recipients. Transplant Proc 2005;37:903-5

64.

Parrott NR, Hammad AQ, Watson CJ, et al. Multicenter, randomized study of the effectiveness of basiliximab in avoiding addition of steroids to cyclosporine a monotherapy in renal transplant recipients. Transplantation 2005;79:344-8

65.

Kahan BD, Rajagopalan PR, Hall M. Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-interleukin-2-receptor monoclonal antibody. United States Simulect Renal Study Group. Transplantation 1999;67:276-84

66.

Thibaudin D, Alamartine E, de Filippis JP, et al. 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: 711-15

67.

Wadstrom J, Brekke B, Wramner L, et al. Triple versus quadruple induction immunosuppression in pancreas transplantation. Transplant Proc 1995;27: 1317-18

68.

Neuhaus P, Clavien PA, Kittur D, et al. Improved treatment response with basiliximab immunoprophylaxis after liver transplantation: results from a double-blind randomized placebo-controlled trial. Liver Transpl 2002;8:132-42

69.

Ponticelli C, Yussim A, Cambi V, et al. A randomized, double-blind trial of basiliximab immunoprophylaxis plus triple therapy in kidney transplant recipients. Transplantation 2001;72:1261-7

70.


Lawen JG, Davies EA, Mourad G, et al. Randomized double-blind study of immunoprophylaxis with basiliximab, a chimeric anti-interleukin-2 receptor monoclonal antibody, in combination with mycophenolate mofetil-containing triple therapy in renal transplantation. Transplantation 2003;75:37-43

Mehra MR, Zucker MJ, Wagoner L, et al. A multicenter, prospective, randomized, double-blind trial of basiliximab in heart transplantation. J Heart Lung Transplant 2005;24:1297-304 Grenda R, Watson A, Vondrak K, et al. A prospective, randomized, multicenter trial of tacrolimus-based therapy with or without basiliximab in pediatric renal transplantation. Am J Transplant 2006;6: 1666-72 Spada M, Petz W, Betani A, et al. Randomized trial of basiliximab induction versus steroid therapy in pediatric liver allograft recipients under tacrolimus immunosuppression. Am J Transplant 2006;6:1913-21 Nashan B, Light S, Hardie IR, et al. Reduction of acute renal allograft rejection by daclizumab. Daclizumab Double Therapy Study Group. Transplantation 1999;67:110-15 Folkmane I, Bicans J, Amerika D, et al. Low rate of acute rejection and cytomegalovirus infection in kidney

Original Research

transplant recipients with basiliximab. Transplant Proc 2001;33:3209-10 71.

Sheashaa HA, Bakr MA, Ismail AM, et al. Long-term evaluation of basiliximab induction therapy in live donor kidney transplantation: a five-year prospective randomized study. Am J Nephrol 2005;25: 221-5

72.

Schmeding M, Sauer IM, Kiessling A, et al. Influence of basiliximab induction therapy on long term outcome after liver transplantation, a prospectively randomised trial. Ann Transplant 2007;12:15-21

73.

Hershberger RE, Starling RC, Eisen HJ, et al. Daclizumab to prevent rejection after cardiac transplantation. N Engl J Med 2005;352:2705-13

74.

Yoshida EM, Marotta PJ, Greig PD, et al. Evaluation of renal function in liver transplant recipients receiving daclizumab (Zenapax), mycophenolate mofetil, and a delayed, low-dose tacrolimus regimen vs. a standard-dose tacrolimus and mycophenolate mofetil regimen: a multicenter randomized clinical trial. Liver Transpl 2005;11:1064-72

75.

Vincenti F, Kirkman R, Light S, et al. Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. Daclizumab Triple Therapy Study Group. N Engl J Med 1998;338:161-5

76.

Lietz K, John R, Beniaminovitz A, et al. Interleukin-2 receptor blockade in cardiac transplantation: influence of HLA-DR locus incompatibility on treatment efficacy. Transplantation 2003;75:781-7

77.

Boillot O, Mayer DA, Boudjema K, et al. Corticosteroid-free immunosuppression with tacrolimus following induction with daclizumab: a large randomized clinical study. Liver Transpl 2005;11:61-7

78.

Stratta RJ, Alloway RR, Lo A, Hodge E. Two-dose daclizumab regimen in simultaneous kidney-pancreas transplant recipients: primary endpoint analysis of a multicenter, randomized study. Transplantation 2003;75:1260-6

79.

Heffron TG, Pillen T, Smallwood GA, et al. Pediatric liver transplantation with daclizumab induction. Transplantation 2003;75:2040-3

80.

ter Meulen CG, van Riemsdijkl, Hene RJ, et al. Steroid-withdrawal at 3 days after renal transplantation with anti-IL-2 receptor alpha therapy: a prospective, randomized, multicenter study. Am J Transplant 2004;4: 803-10

895

Original Research 81.

82.


83.

84.

85.

86.

87.

88.

89.


Rostaing L, Cantarovich D, Mourad G, et al. Corticosteroid-free immunosuppression with tacrolimus, mycophenolate mofetil, and daclizumab induction in renal transplantation. Transplantation 2005;79:807-14 Asberg A, Midtvedt K, Line PD, et al. Calcineurin inhibitor avoidance with daclizumab, mycophenolate mofetil, and prednisolone in DR-matched de novo kidney transplant recipients. Transplantation 2006;82:62-8 Kato T, Yoshida H, Sadfar K, et al. Steroid-free induction and preemptive antiviral therapy for liver transplant recipients with hepatitis C: a preliminary report from a prospective randomized study. Transplant Proc 2005;37:1217-19 Ahsan N, Holman MJ, Jarowenko MV, et al. Limited dose monoclonal IL-2R antibody induction protocol after primary kidney transplantation. Am J Transplant 2002;2:568-73 Klintmalm GB, Washburn WK, Rudich SM, et al. Corticosteroid-free immunosuppression with daclizumab in HCV(+) liver transplant recipients: 1-year interim results of the HCV-3 study. Liver Transpl 2007;13:1521-31 Ji SM, Li LS, Cheng Z, et al. A single-dose daclizumab induction protocol in renal allograft recipients: a Chinese single center experience. Transplant Proc 2007;39: 1396-401 Ekberg H, Grinyo J, Nashan B, et al. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR Study. Am J Transplant 2007;7:560-70 Gelens MA, Christiaans MH, van Heurn EL, et al. High rejection rate during calcineurin inhibitor-free and early steroid withdrawal immunosuppression in renal transplantation. Transplantation 2006;82:1221-3 Otero A, Varo E, de Urbina JO, et al. A prospective randomized open study in

896

liver transplant recipients: daclizumab, mycophenolate mofetil, and tacrolimus versus tacrolimus and steroids. Liver Transpl 2009;15:1542-52 90.

91.

92.

93.

94.

95.

96.

97.

98.

domains is required for signalling. Nature 1994;369:330-3 99.

Minami Y, Kono T, Miyazaki T, Taniguchi T. The IL-2 receptor complex: its structure, function, and target genes. Annu Rev Immunol 1993;11:245-68

100.

Binder M, Vogtle FN, Michelfelder S, et al. Identification of their epitope reveals the structural basis for the mechanism of action of the immunosuppressive antibodies basiliximab and daclizumab. Cancer Res 2007;67:3518-23

101.

DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7: 177-88

102.

Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol 1997;50:683-91

103.

Raefsky EL, Gascon P, Gratwohl A, et al. Biological and immunological characterization of ATG and ALG. Blood 1986;68:712-19

Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ 2003;326:472

104.

Issa NC, Fishman JA. Infectious complications of antilymphocyte therapies in solid organ transplantation. Clin Infect Dis 2009;48:772-86

Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50: 1088-101

105.

Turcotte JG, Feduska NJ, Haines RF, et al. Antithymocyte globulin in renal transplant krecipients. A clinical trial. Arch Surg 1993;106(4):484-88

106.

Kirkman RL, Shapiro ME, Carpenter CB, et al. A randomized prospective trial of antiTac monoclonal antibody in human renal transplantation. Transplantation 1991;51(1): 107-13

107.

Garcia R, Machado PG, Felipe CR, et al. Exploratory calcineurin inhibitor-free regimens in living-related kidney transplant recipients. Braz J Med Biol Res 2007;40(4): 457-65

Neuberger JM, Mamelok RD, Neuhaus P, et al. Delayed introduction of reduced-dose tacrolimus, and renal function in liver transplantation: the ‘ReSpECT’ study. Am J Transplant 2009;9:327-36 Bonnefoy-Berard N, Vincent C, Revillard JP. Antibodies against functional leukocyte surface molecules in polyclonal antilymphocyte and antithymocyte globulins. Transplantation 1991;51:669-73 Rebellato LM, Gross U, Verbanac KM, Thomas JM. A comprehensive definition of the major antibody specificities in polyclonal rabbit antithymocyte globulin. Transplantation 1994;57:685-94 Bourdage JS, Hamlin DM. Comparative polyclonal antithymocyte globulin and antilymphocyte/antilymphoblast globulin anti-CD antigen analysis by flow cytometry. Transplantation 1995;59:1194-200

Goebel J, Stevens E, Forrest K, Roszman TL. Daclizumab (Zenapax) inhibits early interleukin-2 receptor signal transduction events. Transpl Immunol 2000;8:153-9 Nelson BH, Lord JD, Greenberg PD. Cytoplasmic domains of the interleukin-2 receptor beta and gamma chains mediate the signal for T-cell proliferation. Nature 1994;369:333-6 Nakamura Y, Russell SM, Mess SA, et al. Heterodimerization of the IL-2 receptor beta- and gamma-chain cytoplasmic


Bloodstream infections after solid-organ transplantation.

Transfusion transmitted infections in solid organ transplantation.

Risk of myeloid neoplasms after solid organ transplantation.

Cytomegalovirus infections in solid organ transplantation: a review.

Nutrition management after pediatric solid organ transplantation.

Solid organ transplantation: hypogammaglobulinaemia and infectious complications after solid organ transplantation.

Nosocomial infections within the first month of solid organ transplantation.

Non-tuberculous mycobacterial infections after solid organ transplantation: a survival analysis.

Role of MICA antibodies in solid organ transplantation.

Antiphospholipid syndrome, antiphospholipid antibodies and solid organ transplantation.

Emergency abdominal surgery after solid organ transplantation: a systematic review.

Everolimus and Malignancy after Solid Organ Transplantation: A Clinical Update.

Risk for transmission of Naegleria fowleri from solid organ transplantation.

Re: Cumulative incidence of cancer after solid organ transplantation.

Long-term outcomes of children after solid organ transplantation.

Pregnancy and reproductive health after solid organ transplantation.

Cardiovascular complications after transplantation: treatment options in solid organ recipients.

Herpes simplex virus hepatitis after solid organ transplantation in adults.

Tuberculosis in Solid Organ Transplantation.

Macrophages in solid organ transplantation.

Immunizations following solid-organ transplantation.

Sarcopenia in solid organ transplantation.

Suture versus staples for skin closure after cesarean: a metaanalysis.

Neurological complications of solid organ transplantation.