Rabbit Antithymocyte Globulin or Basiliximab for Induction Therapy?
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《新英格兰医药杂志》
In this issue of the Journal, Brennan et al.1 compare the safety and efficacy of two induction therapies commonly used in kidney transplantation: rabbit antithymocyte globulin and basiliximab. Induction refers to the administration of an intensive immunosuppressive regimen during the perioperative period. The rationale behind this approach is that the risk of acute rejection is greatest in the first weeks or months after transplantation. Induction therapies often involve the use of polyclonal or monoclonal antibodies to achieve rapid and profound early immunosuppression. Polyclonal antibodies used for this purpose include those against thymocytes (e.g., commercially available rabbit or equine preparations); monoclonal antibodies include basiliximab (a chimeric human–murine anti-CD25 or anti–interleukin-2 receptor antibody), daclizumab (a humanized anti–interleukin-2 receptor antibody), OKT3 (muromonab-CD3, a mouse anti-CD3 antibody), and alemtuzumab (an anti-CD52 antibody targeting both B and T cells).
From 2000 to 2004, 63.6% of kidney-transplant recipients received antibody-induction therapy.2 Historically, however, antibody-based induction has gone in and out of favor, depending on the efficacy of the available maintenance therapy, the perceived risk of the course of induction therapy itself, and the goal of the treatment. In the early era of renal transplantation, the 1960s to 1970s, immunosuppressive options were limited to the use of azathioprine and prednisone. Graft loss within 1 year was all too frequent — occurring in approximately half of recipients — mainly owing to rejection.3 Antilymphocyte globulin (produced in horses, sheep, goats, and rabbits) was used clinically in the 1970s, but there was controversy over its efficacy, production, and standardization.4 Some transplantation programs produced a "homegrown" product, depending on local staff to immunize the animals and process the resulting antilymphocyte globulin.
The introduction of cyclosporine use into clinical transplantation in the early 1980s was a major advance. Rejection rates dropped, and graft survival at 1 year reached 72.0 to 89.5%.5 In 1985, OKT3 was introduced. Its immunosuppressive efficacy was undermined by its potential side effects, which included adverse reactions to the initial doses and cancer.6 Since cyclosporine was being widely used, resulting in far better graft survival than was seen with azathioprine and prednisone, many centers decided that the risks associated with OKT3 induction therapy outweighed its benefits. Both the use of OKT3 and the enthusiasm for induction therapy in general declined. Then, in the late 1990s, interest in antibody-based induction therapy rebounded with the development of anti–interleukin-2 receptor antibodies, which held promise as induction therapy without toxic effects. Nevertheless, many programs avoided induction, unless the transplant was considered to carry a high risk of acute rejection.
Besides reducing the risk of early rejection, antibody-based induction therapy makes it possible to delay the introduction of specific immunosuppressive agents (particularly the calcineurin inhibitors, which are nephrotoxic). Safely postponing the use of these agents is desirable when there is a risk of delayed allograft function, especially since calcineurin inhibitors may delay recovery.7 Kidneys with a high risk of delayed function include those from deceased donors with prolonged cold-ischemia times, donors without a heartbeat, older donors, and donors with acute renal failure at the time of death8,9 — the types of kidneys studied by Brennan et al.
Delayed graft function has been associated with decreased long-term graft survival.8 With an ever-increasing gap between the supply of and demand for transplantable kidneys and few solutions in sight, the use of kidneys that carry a high risk of delayed function will increase. As of October 6, 2006, there were 70,497 people on the waiting list for a kidney from a deceased donor in the United States.2 For those registered in 2001, the median waiting time is 1176 days, and it is no doubt increasing for those registered more recently.2 Since transplantation of a kidney (even from a "marginal" donor) portends a survival advantage as compared with continued dialysis,10 the trend toward using available kidneys (even if they are less than perfect) is reasonable. We must therefore define strategies that will maximize the outcome of transplantation with these kidneys.
That is what Brennan et al. set out to do. In a multicenter study, they compared the 12-month outcomes for kidney-transplant recipients at high risk for delayed graft function or acute rejection who were randomly assigned to receive either a 5-day course of antithymocyte globulin or two doses of basiliximab. The introduction of cyclosporine was delayed in this trial. At 12 months, recipients in the antithymocyte globulin group had fewer episodes of biopsy-proven acute rejection, and the episodes were less severe (fewer required antibody treatment) than those in the basiliximab group.
Why, then, were there no significant differences between the two groups with respect to the primary end point (a composite of acute rejection, delayed graft function, graft loss, and death) or specifically with regard to graft loss as well as graft function? Perhaps 12 months of follow-up is too short to detect a significant difference or a different end point would have been a better indicator of efficacy and safety. Would the results of kidney biopsies at 12 months have been a more sensitive measure of graft status than serum creatinine levels, potentially revealing fibrosis or subclinical but destructive episodes of rejection?
Perhaps neither longer follow-up nor another end point would have made a difference and this study exemplifies the two-headed monster that is immunosuppression. On the one hand, immunosuppression may be less than sufficient and lead to rejection, as seen in the basiliximab group. On the other hand, immunosuppression may be more than sufficient and lead to cancer and infection. Though not significant, the incidence of cancer tended to be higher in the antithymocyte globulin group than in the basiliximab group, a trend that could increase over time. And although the incidence of infection with cytomegalovirus (CMV) was lower in the antithymocyte globulin group than in the basiliximab group, the incidence of infection with viruses other than CMV was higher in the antithymocyte group. If the non-CMV viruses included BK virus (a polyomavirus that causes nephropathy reminiscent of acute cellular rejection),11 then the increased incidence of infection with non-CMV viruses in the antithymocyte globulin group could account for the similar kidney function and incidence of graft loss at 12 months in the two groups.
The prospective nature of this study is a strength. However, even a well-designed, adequately powered study will not provide all the answers or end the debate about induction therapy. Transplantation is a rapidly evolving field. By the time a clinical question is articulated and studied, that question is likely to have changed. To some extent, that is the case with the study by Brennan et al., which used a cyclosporine-based immunosuppressive regimen. In 2004, only 21% of institutions in the United States were using cyclosporine as the calcineurin inhibitor of choice, whereas 72% were using tacrolimus.2 The immunosuppressive regimen used by Brennan et al. also included prednisone. Many centers now use corticosteroid-free regimens. Can the results of Brennan et al. be applied to centers using tacrolimus regimens or prednisone-free regimens? About half of all transplantation centers in the United States use the antibody-based induction therapies evaluated in this study; 25.7% of patients receiving kidneys between 2000 and 2004 were given antithymocyte globulin and 24.2% were given basiliximab.2 However, other induction strategies are used as well. During the 2000–2004 period, 2.3% of all kidney-transplant recipients were given alemtuzumab for induction, and among those who were on corticosteroid-free regimens, 10% received it.2
Despite anticipated changes in immunosuppressive regimens, the study by Brennan et al. shows that induction with antithymocyte globulin (as compared with basiliximab) helps win an important battle — reducing the incidence and severity of clinically significant acute cellular rejection. However, at least in the short term, winning that battle does not mean winning the war. Graft survival and function were not altered at 12 months, but for long-term survival and function, only time will tell. For now, some centers may switch to antithymocyte globulin, but both treatments — antithymocyte globulin and basiliximab — will continue to have their supporters.
Dr. Josephson reports having received consulting fees from Ideon, lecture fees from a continuing-medical-education company sponsored by Roche, and grant support from Wyeth. No other potential conflict of interest relevant to this article was reported.
Source Information
From the University of Chicago, Chicago.
References
Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med 2006;355:1967-1977.
2005 Annual report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: transplant data 1995-2004. Rockville, MD: Health Resources and Services Administration, 2006.
Levey AS. The improving prognosis after kidney transplantation: new strategies to overcome immunologic rejection. Arch Intern Med 1984;144:2382-2387.
Guttmann RD. Renal transplantation. N Engl J Med 1979;301:1038-1048.
Cohen DJ, Loertscher R, Rubin MF, Tilney NL, Carpenter CB, Strom TB. Cyclosporine: a new immunosuppressive agent for organ transplantation. Ann Intern Med 1984;101:667-682.
Swinnen LJ, Costanzo-Nordin MR, Fisher SG, et al. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med 1990;323:1723-1728.
Canafax DM, Torres A, Fryd DS, et al. The effects of delayed function on recipients of cadaver renal allografts: a study of 158 patients randomized to cyclosporine or ALG-azathioprine. Transplantation 1986;41:177-181.
Ojo AO, Wolfe RA, Held PJ, Port FK, Schmouder RL. Delayed graft function: risk factors and implications for renal allograft survival. Transplantation 1997;63:968-974.
Wijnen RM, Booster MH, Stubenitsky BM, de Boer J, Heineman E, Kootstra G. Outcome of transplantation of non-heart-beating donor kidneys. Lancet 1995;345:1067-1070.
Ojo AO, Hanson JA, Meier-Kriesche H, et al. Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant candidates. J Am Soc Nephrol 2001;12:589-597.
Hirsch HH. Polyomavirus BK nephropathy: a (re-)emerging complication in renal transplantation. Am J Transplant 2002;2:25-30.(Michelle A. Josephson, M.)
From 2000 to 2004, 63.6% of kidney-transplant recipients received antibody-induction therapy.2 Historically, however, antibody-based induction has gone in and out of favor, depending on the efficacy of the available maintenance therapy, the perceived risk of the course of induction therapy itself, and the goal of the treatment. In the early era of renal transplantation, the 1960s to 1970s, immunosuppressive options were limited to the use of azathioprine and prednisone. Graft loss within 1 year was all too frequent — occurring in approximately half of recipients — mainly owing to rejection.3 Antilymphocyte globulin (produced in horses, sheep, goats, and rabbits) was used clinically in the 1970s, but there was controversy over its efficacy, production, and standardization.4 Some transplantation programs produced a "homegrown" product, depending on local staff to immunize the animals and process the resulting antilymphocyte globulin.
The introduction of cyclosporine use into clinical transplantation in the early 1980s was a major advance. Rejection rates dropped, and graft survival at 1 year reached 72.0 to 89.5%.5 In 1985, OKT3 was introduced. Its immunosuppressive efficacy was undermined by its potential side effects, which included adverse reactions to the initial doses and cancer.6 Since cyclosporine was being widely used, resulting in far better graft survival than was seen with azathioprine and prednisone, many centers decided that the risks associated with OKT3 induction therapy outweighed its benefits. Both the use of OKT3 and the enthusiasm for induction therapy in general declined. Then, in the late 1990s, interest in antibody-based induction therapy rebounded with the development of anti–interleukin-2 receptor antibodies, which held promise as induction therapy without toxic effects. Nevertheless, many programs avoided induction, unless the transplant was considered to carry a high risk of acute rejection.
Besides reducing the risk of early rejection, antibody-based induction therapy makes it possible to delay the introduction of specific immunosuppressive agents (particularly the calcineurin inhibitors, which are nephrotoxic). Safely postponing the use of these agents is desirable when there is a risk of delayed allograft function, especially since calcineurin inhibitors may delay recovery.7 Kidneys with a high risk of delayed function include those from deceased donors with prolonged cold-ischemia times, donors without a heartbeat, older donors, and donors with acute renal failure at the time of death8,9 — the types of kidneys studied by Brennan et al.
Delayed graft function has been associated with decreased long-term graft survival.8 With an ever-increasing gap between the supply of and demand for transplantable kidneys and few solutions in sight, the use of kidneys that carry a high risk of delayed function will increase. As of October 6, 2006, there were 70,497 people on the waiting list for a kidney from a deceased donor in the United States.2 For those registered in 2001, the median waiting time is 1176 days, and it is no doubt increasing for those registered more recently.2 Since transplantation of a kidney (even from a "marginal" donor) portends a survival advantage as compared with continued dialysis,10 the trend toward using available kidneys (even if they are less than perfect) is reasonable. We must therefore define strategies that will maximize the outcome of transplantation with these kidneys.
That is what Brennan et al. set out to do. In a multicenter study, they compared the 12-month outcomes for kidney-transplant recipients at high risk for delayed graft function or acute rejection who were randomly assigned to receive either a 5-day course of antithymocyte globulin or two doses of basiliximab. The introduction of cyclosporine was delayed in this trial. At 12 months, recipients in the antithymocyte globulin group had fewer episodes of biopsy-proven acute rejection, and the episodes were less severe (fewer required antibody treatment) than those in the basiliximab group.
Why, then, were there no significant differences between the two groups with respect to the primary end point (a composite of acute rejection, delayed graft function, graft loss, and death) or specifically with regard to graft loss as well as graft function? Perhaps 12 months of follow-up is too short to detect a significant difference or a different end point would have been a better indicator of efficacy and safety. Would the results of kidney biopsies at 12 months have been a more sensitive measure of graft status than serum creatinine levels, potentially revealing fibrosis or subclinical but destructive episodes of rejection?
Perhaps neither longer follow-up nor another end point would have made a difference and this study exemplifies the two-headed monster that is immunosuppression. On the one hand, immunosuppression may be less than sufficient and lead to rejection, as seen in the basiliximab group. On the other hand, immunosuppression may be more than sufficient and lead to cancer and infection. Though not significant, the incidence of cancer tended to be higher in the antithymocyte globulin group than in the basiliximab group, a trend that could increase over time. And although the incidence of infection with cytomegalovirus (CMV) was lower in the antithymocyte globulin group than in the basiliximab group, the incidence of infection with viruses other than CMV was higher in the antithymocyte group. If the non-CMV viruses included BK virus (a polyomavirus that causes nephropathy reminiscent of acute cellular rejection),11 then the increased incidence of infection with non-CMV viruses in the antithymocyte globulin group could account for the similar kidney function and incidence of graft loss at 12 months in the two groups.
The prospective nature of this study is a strength. However, even a well-designed, adequately powered study will not provide all the answers or end the debate about induction therapy. Transplantation is a rapidly evolving field. By the time a clinical question is articulated and studied, that question is likely to have changed. To some extent, that is the case with the study by Brennan et al., which used a cyclosporine-based immunosuppressive regimen. In 2004, only 21% of institutions in the United States were using cyclosporine as the calcineurin inhibitor of choice, whereas 72% were using tacrolimus.2 The immunosuppressive regimen used by Brennan et al. also included prednisone. Many centers now use corticosteroid-free regimens. Can the results of Brennan et al. be applied to centers using tacrolimus regimens or prednisone-free regimens? About half of all transplantation centers in the United States use the antibody-based induction therapies evaluated in this study; 25.7% of patients receiving kidneys between 2000 and 2004 were given antithymocyte globulin and 24.2% were given basiliximab.2 However, other induction strategies are used as well. During the 2000–2004 period, 2.3% of all kidney-transplant recipients were given alemtuzumab for induction, and among those who were on corticosteroid-free regimens, 10% received it.2
Despite anticipated changes in immunosuppressive regimens, the study by Brennan et al. shows that induction with antithymocyte globulin (as compared with basiliximab) helps win an important battle — reducing the incidence and severity of clinically significant acute cellular rejection. However, at least in the short term, winning that battle does not mean winning the war. Graft survival and function were not altered at 12 months, but for long-term survival and function, only time will tell. For now, some centers may switch to antithymocyte globulin, but both treatments — antithymocyte globulin and basiliximab — will continue to have their supporters.
Dr. Josephson reports having received consulting fees from Ideon, lecture fees from a continuing-medical-education company sponsored by Roche, and grant support from Wyeth. No other potential conflict of interest relevant to this article was reported.
Source Information
From the University of Chicago, Chicago.
References
Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med 2006;355:1967-1977.
2005 Annual report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: transplant data 1995-2004. Rockville, MD: Health Resources and Services Administration, 2006.
Levey AS. The improving prognosis after kidney transplantation: new strategies to overcome immunologic rejection. Arch Intern Med 1984;144:2382-2387.
Guttmann RD. Renal transplantation. N Engl J Med 1979;301:1038-1048.
Cohen DJ, Loertscher R, Rubin MF, Tilney NL, Carpenter CB, Strom TB. Cyclosporine: a new immunosuppressive agent for organ transplantation. Ann Intern Med 1984;101:667-682.
Swinnen LJ, Costanzo-Nordin MR, Fisher SG, et al. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med 1990;323:1723-1728.
Canafax DM, Torres A, Fryd DS, et al. The effects of delayed function on recipients of cadaver renal allografts: a study of 158 patients randomized to cyclosporine or ALG-azathioprine. Transplantation 1986;41:177-181.
Ojo AO, Wolfe RA, Held PJ, Port FK, Schmouder RL. Delayed graft function: risk factors and implications for renal allograft survival. Transplantation 1997;63:968-974.
Wijnen RM, Booster MH, Stubenitsky BM, de Boer J, Heineman E, Kootstra G. Outcome of transplantation of non-heart-beating donor kidneys. Lancet 1995;345:1067-1070.
Ojo AO, Hanson JA, Meier-Kriesche H, et al. Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant candidates. J Am Soc Nephrol 2001;12:589-597.
Hirsch HH. Polyomavirus BK nephropathy: a (re-)emerging complication in renal transplantation. Am J Transplant 2002;2:25-30.(Michelle A. Josephson, M.)