- Email: [email protected]
Immunosuppression use in renal transplantation from Asian transplant centers: A preliminary report from the Asian Transplant Registry
Immunosuppression Use in Renal Transplantation From Asian Transplant Centers: A Preliminary Report From the Asian Transplant Registry A. Vathsala, for the Asian Transplant Registry ABSTRACT Since the first renal transplant (RTx) in 1956 in Asia in Japan, over 100,000 RTx have been performed in over 300 centers across the region. A survey was conducted to evaluate immunosuppression (IS) use among Asian RTx. Briefly, directors of RTx centers were surveyed regarding IS use for RTx performed at their centers in 2001 for (1) induction therapy, (2) maintenance IS therapy at hospital discharge, (3) antirejection treatment (REJ) to 1 year post-RTx, and (4) maintenance IS therapy to 1 year post-RTx. Categories and types of IS included in the survey were polyclonal antilymphocyte antibodies (PAB), OKT3, IL2 receptor antibodies (IL2RAb), corticosteroids (CS), cyclosporine (CyA), tacrolimus (Tac), azathioprine (Aza), mycophenolate mofetil (MMF), Mizoribine (Miz), Sirolimus (Sir), and other agents. Though only 17 RTx centers in Asia responded to the survey, a wide variation in IS use was demonstrated. In the 334 living and 85 cadavericRTx among whom actual usage was reported, induction therapy was used in only 18.4% of Asian RTx (14.1%, IL2RAb; 4.3%, PAB), in contrast to the 59.3% reported as using induction IS among RTx from the UNOS database in the same year. For maintenance therapy at hospital discharge, 87.1% of Asian RTx received CyA-based IS while only 12.4% received Tac-based therapy. This is in contrast to the 55.3% use of Tac for new RTx in the United States. Generic CyA has widespread use in Asia with over 29.9% on CyA using generic versus the Neoral formulation. Azathioprine is still the predominant antimetabolite in use in Asian RTx, with MMF being used in only 33.6% of patients, in contrast to its 77% usage in the United States. Usage of Tac and MMF for maintenance therapy was significantly higher among cadavericRTx (P ⬍ .005). Corticosteroids were used in 51.1% of REJ episodes while PAB or OKT3 were used in 31.9% and 17% of REJ episodes, respectively. As these results may be skewed due to participation of few centers in the survey, greater participation will ensure more accurate evaluation of immunosuppression use in Asia for de novo RTx.
T
HE FIRST RENAL transplant (RTx) was performed in Asia by Kusonoki and Inoue at Niigata University, Japan.1 Since then, over 105,000 RTx have been performed across over 310 transplant centers in Asia.2– 4 While in the early 1990s, approximately 5000 RTx were performed annually at Asian renal transplant centers, these numbers have increased and approximately 12,650 RTx were reported to have been performed in 2001 to the Asian Transplant Registry. The present study evaluated immunosuppression (IS) use among RTx performed in Asian transplant centers in 2001.
PATIENTS AND METHODS Briefly, directors of Asian transplant centers were surveyed regarding use of various IS during different phases post-RTx for transplants performed at their centers in 2001. The survey included IS From the Department of Renal Medicine, Singapore General Hospital, Singapore. Address reprint requests to Dr A. Vathsala, Co-Chairman, Asian Transplant Registry, C/O Department of Renal Medicine, Singapore General Hospital, Outram Road, Singapore 169608. E-Mail: [email protected]
0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.08.132
© 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1868
Transplantation Proceedings, 36, 1868 –1870 (2004)
IMMUNOSUPPRESSION USE IN ASIA
1869
used during induction therapy starting within the first 3 days post-RTx, those used at time of hospital discharge and during the first posttransplant year, and those used for treatment of rejection. Agents potentially used for induction therapy included polyclonal antilymphocyte antibodies (PAB) such as antilymphocyte and antithymocyte globulins and monoclonal preparations such as OKT3 and interleukin-2 receptor antibodies (IL2RAb; Basiliximab, Daclizumab). For evaluation of agents used for maintenance therapy, use of corticosteroids (CS), calcineurin inhibitors (CNI), including Neoral and generic cyclosporine (CyA) and tacrolimus (Tac), antimetabolites such as azathioprine (Aza), mycophenolate mofetil (MMF), mizoribine (Miz), and Sirolimus were surveyed at hospital discharge and 1 year post-RTx. Use of CS, PAB, OKT3, and IL2RAb for treatment of rejection was likewise surveyed.
RESULTS
Seventeen Asian RTx centers responded to the survey; these included those from Brunei, Hong Kong, India, Indonesia, Japan, Korea, Lebanon, Pakistan, Philippines, Thailand, Taiwan, and Singapore. Overall, 704 RTx were performed at these centers in 2001, of which 131 (18.6%) were cadaveric (CadRTx) while the remainder were living related or unrelated donor (LiveRTx). Of these, 11 centers reported actual usage among 419 RTx; the remaining six centers reported only estimated usage of various IS among the 285 RTx performed at their centers (⬍20% vs approximately 50% vs ⱖ80%). Despite the small number of centers responding to the survey in this preliminary report, there was a wide variation in IS use. Thirteen of 17 centers reported usage of either IL2RAb or PAB for induction therapy. Nevertheless, actual usage was low, with only 18.4% receiving any induction therapy and the majority receiving IL2RAb (Table 1), none reported the use of OKT3 for induction therapy. There were no significant differences in usage of induction therapy for LiveRTx versus CadRTx. Among agents used for maintenance therapy at hospital discharge, CS was used in all Asian centers surveyed
and for the majority (Table 1). However, there was a wide variation in CNI usage among Asian transplant centers. Whereas 13 centers used CyA for the majority of its patients, two centers used Tac for the majority. In terms of actual usage, the majority (87.1%) used CyA as the maintenance IS at hospital discharge; nevertheless, in comparison to Live-RTx, a significantly larger proportion of CadRTx used Tac as the maintenance CNI at hospital discharge (21.2% vs 10.2%, CadTx vs LiveTx P ⫽ .008). Among centers using CyA, generic CyA, such as Consupren, was used at two centers. Overall, 29.9% of Asian RTx (36.3% of Live-RTx) used generic CyA over that of Neoral CyA; there was no usage of generic CyA among CadRTx in the survey. While Aza was the most common antimetabolite used among Asian RTx, the proportion was significantly higher among Live-RTx than CadRTx (62.9% vs 27.1%, Live-Tx vs CadTx; P ⫽ .000). Correspondingly, a significantly larger proportion of CadRTx used MMF for maintenance IS at hospital discharge (Table 1). Mizoribine was available as an alternate antimetabolite at four centers; however, information on its actual usage was not available. Sirolimus was used in only 3 of 17 centers surveyed and actual usage was less than 5% among Asian RTx. Maintenance IS at 1 year post-RTx was similar to that at hospital discharge; as less than 10% of RTx switched from either CyA to FK or from Aza to MMF in the first year, these minor changes are not reported in this preliminary report. The incidence of rejection during the first year was not reported in this survey; nevertheless, 70 antirejection treatments for Live-RTx and 24 treatments for CadRTx were reported. Among both LiveTx and CadRTx; CS was the most common agent used (48.6% and 58.3% respectively, overall 51.1%); PAB and OKT3 were used for treatment in 31.9% and 17% of REJ episodes, respectively. No use of IL2RAb in the treatment of rejection was reported among Asian RTx.
Table 1. Immunosuppressant Use Among Asian Renal Transplant Recipients Immunosuppressant
Induction therapy Any antibody preparation Polyclonal antilymphocyte antibodies IL2 receptor antibodies Maintenance therapy at hospital discharge Corticosteroids Calcineurin inhibitors† Cyclosporine Tacrolimus Antimetabolites‡ Azathioprine Mycophenolate mofetil Mizoribine Sirolimus
No. of centers (n ⫽ 17)
Living donor (n ⫽ 334)*
Cadaveric donor (n ⫽ 85)*
All (n ⫽ 419)*
13 (76.5%) 6 (35.3%) 12 (70.6%)
57 (17.1%) 16 (4.8%) 41 (12.3%)
20 (23.5%) 2 (2.3%) 18 (21.2%)
77 (18.4%) 18 (4.3%) 59 (14.1%)
17 (100%)
330 (98.8%)
82 (96.5%)
412 (98.3%)
16 (94.1%) 1 (5.9%)
300 (89.8%) 34 (10.2%)
65 (76.5%) 18 (21.2%)
365 (87.1%) 52 (12.4%)
14 (82.4%) 16 (94.1%) 4 (23.5%) 7 (41.2%)
210 (62.9%) 91 (27.2%) — 11 (3.3%)
23 (27.1%) 37 (43.5%) — 9 (10.6%)
233 (61.2%) 128 (33.6%) — 20 (4.8%)
*Includes only centers reporting actual usage. † P ⫽ .008, usage of cyclosporine vs tacrolimus among Live-RTx vs CadRTx. ‡ P ⬍ .000, usage of azathioprine vs mycophenolate mofetil among Live-RTx vs CadRTx.
1870
DISCUSSION
The preliminary results of this survey demonstrate a wide variation in IS usage among Asian RTx. Nevertheless, induction therapy predominately with IL2RAb, was used in only 18.4% of Asian RTx, a percentage lower than the 59.3% recorded for the same year for RTx reported to the United Network for Organ Sharing (UNOS).5 Corticosteroids and CNI constituted maintenance IS therapy in the vast majority of Asian RTx at hospital discharge and at 1 year post-RTx. Cyclosporine was used in 87.1% of Asian RTx, a proportion higher than the 38.7% reported from the UNOS database. Tacrolimus usage was correspondingly lower at 12.4% among Asian RTx, in comparison to its use in 55.3% of American RTx. Among the antimetabolites, Aza was used in 61.2% of Asian RTx, remarkably different from the 4.4% usage among patients reported to the UNOS database. Correspondingly, use of MMF was lower among Asian RTx at 33.6%, in contrast to its 77% use among American RTx. Of note, however, was the use of both Tac and MMF in larger proportions of CadRTx (21.2% and 43.5% respectively), in comparison to Live-RTx, likely due to anticipated higher risks for rejection in the former. As
VATHSALA
among patients reported to the UNOS database, CS was the mainstay of antirejection therapy among Asian RTx. While IS use in the United States has been suggested to have entered a new era over the last decade with decreasing use of CyA and increasing use of Tac and MMF, IS use among surveyed Asian RTx in 2001 is still predominately CyA-based. Though all of the newer IS are available in Asia, funding policies for these IS may be the critical factor determining use. Not withstanding these results, it is noted that only 17 of the over 300 Asian RTx centers have been included in this survey. It is hoped that future analyses will have greater participation from more RTx centers so that the Asian experience can be summarized. REFERENCES 1. Ota K, Teraoka S, Kawai T: Transplant Proc 27:1463, 1995 2. Ota K, Teraoka S, Takahashi K, et al: Transplant Proc 26:2457, 1994 3. Ota K: Transplant Proc 31:205, 1999 4. Ota K: Transplant Proc 33:1989, 2001 5. Transplant Statistics: Annual Report: Immunosuppression Practice and Trends. Organ Procurement and Transplantation Network. United Network for Organ Sharing, 2003
T
HE FIRST RENAL transplant (RTx) was performed in Asia by Kusonoki and Inoue at Niigata University, Japan.1 Since then, over 105,000 RTx have been performed across over 310 transplant centers in Asia.2– 4 While in the early 1990s, approximately 5000 RTx were performed annually at Asian renal transplant centers, these numbers have increased and approximately 12,650 RTx were reported to have been performed in 2001 to the Asian Transplant Registry. The present study evaluated immunosuppression (IS) use among RTx performed in Asian transplant centers in 2001.
PATIENTS AND METHODS Briefly, directors of Asian transplant centers were surveyed regarding use of various IS during different phases post-RTx for transplants performed at their centers in 2001. The survey included IS From the Department of Renal Medicine, Singapore General Hospital, Singapore. Address reprint requests to Dr A. Vathsala, Co-Chairman, Asian Transplant Registry, C/O Department of Renal Medicine, Singapore General Hospital, Outram Road, Singapore 169608. E-Mail: [email protected]
0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.08.132
© 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1868
Transplantation Proceedings, 36, 1868 –1870 (2004)
IMMUNOSUPPRESSION USE IN ASIA
1869
used during induction therapy starting within the first 3 days post-RTx, those used at time of hospital discharge and during the first posttransplant year, and those used for treatment of rejection. Agents potentially used for induction therapy included polyclonal antilymphocyte antibodies (PAB) such as antilymphocyte and antithymocyte globulins and monoclonal preparations such as OKT3 and interleukin-2 receptor antibodies (IL2RAb; Basiliximab, Daclizumab). For evaluation of agents used for maintenance therapy, use of corticosteroids (CS), calcineurin inhibitors (CNI), including Neoral and generic cyclosporine (CyA) and tacrolimus (Tac), antimetabolites such as azathioprine (Aza), mycophenolate mofetil (MMF), mizoribine (Miz), and Sirolimus were surveyed at hospital discharge and 1 year post-RTx. Use of CS, PAB, OKT3, and IL2RAb for treatment of rejection was likewise surveyed.
RESULTS
Seventeen Asian RTx centers responded to the survey; these included those from Brunei, Hong Kong, India, Indonesia, Japan, Korea, Lebanon, Pakistan, Philippines, Thailand, Taiwan, and Singapore. Overall, 704 RTx were performed at these centers in 2001, of which 131 (18.6%) were cadaveric (CadRTx) while the remainder were living related or unrelated donor (LiveRTx). Of these, 11 centers reported actual usage among 419 RTx; the remaining six centers reported only estimated usage of various IS among the 285 RTx performed at their centers (⬍20% vs approximately 50% vs ⱖ80%). Despite the small number of centers responding to the survey in this preliminary report, there was a wide variation in IS use. Thirteen of 17 centers reported usage of either IL2RAb or PAB for induction therapy. Nevertheless, actual usage was low, with only 18.4% receiving any induction therapy and the majority receiving IL2RAb (Table 1), none reported the use of OKT3 for induction therapy. There were no significant differences in usage of induction therapy for LiveRTx versus CadRTx. Among agents used for maintenance therapy at hospital discharge, CS was used in all Asian centers surveyed
and for the majority (Table 1). However, there was a wide variation in CNI usage among Asian transplant centers. Whereas 13 centers used CyA for the majority of its patients, two centers used Tac for the majority. In terms of actual usage, the majority (87.1%) used CyA as the maintenance IS at hospital discharge; nevertheless, in comparison to Live-RTx, a significantly larger proportion of CadRTx used Tac as the maintenance CNI at hospital discharge (21.2% vs 10.2%, CadTx vs LiveTx P ⫽ .008). Among centers using CyA, generic CyA, such as Consupren, was used at two centers. Overall, 29.9% of Asian RTx (36.3% of Live-RTx) used generic CyA over that of Neoral CyA; there was no usage of generic CyA among CadRTx in the survey. While Aza was the most common antimetabolite used among Asian RTx, the proportion was significantly higher among Live-RTx than CadRTx (62.9% vs 27.1%, Live-Tx vs CadTx; P ⫽ .000). Correspondingly, a significantly larger proportion of CadRTx used MMF for maintenance IS at hospital discharge (Table 1). Mizoribine was available as an alternate antimetabolite at four centers; however, information on its actual usage was not available. Sirolimus was used in only 3 of 17 centers surveyed and actual usage was less than 5% among Asian RTx. Maintenance IS at 1 year post-RTx was similar to that at hospital discharge; as less than 10% of RTx switched from either CyA to FK or from Aza to MMF in the first year, these minor changes are not reported in this preliminary report. The incidence of rejection during the first year was not reported in this survey; nevertheless, 70 antirejection treatments for Live-RTx and 24 treatments for CadRTx were reported. Among both LiveTx and CadRTx; CS was the most common agent used (48.6% and 58.3% respectively, overall 51.1%); PAB and OKT3 were used for treatment in 31.9% and 17% of REJ episodes, respectively. No use of IL2RAb in the treatment of rejection was reported among Asian RTx.
Table 1. Immunosuppressant Use Among Asian Renal Transplant Recipients Immunosuppressant
Induction therapy Any antibody preparation Polyclonal antilymphocyte antibodies IL2 receptor antibodies Maintenance therapy at hospital discharge Corticosteroids Calcineurin inhibitors† Cyclosporine Tacrolimus Antimetabolites‡ Azathioprine Mycophenolate mofetil Mizoribine Sirolimus
No. of centers (n ⫽ 17)
Living donor (n ⫽ 334)*
Cadaveric donor (n ⫽ 85)*
All (n ⫽ 419)*
13 (76.5%) 6 (35.3%) 12 (70.6%)
57 (17.1%) 16 (4.8%) 41 (12.3%)
20 (23.5%) 2 (2.3%) 18 (21.2%)
77 (18.4%) 18 (4.3%) 59 (14.1%)
17 (100%)
330 (98.8%)
82 (96.5%)
412 (98.3%)
16 (94.1%) 1 (5.9%)
300 (89.8%) 34 (10.2%)
65 (76.5%) 18 (21.2%)
365 (87.1%) 52 (12.4%)
14 (82.4%) 16 (94.1%) 4 (23.5%) 7 (41.2%)
210 (62.9%) 91 (27.2%) — 11 (3.3%)
23 (27.1%) 37 (43.5%) — 9 (10.6%)
233 (61.2%) 128 (33.6%) — 20 (4.8%)
*Includes only centers reporting actual usage. † P ⫽ .008, usage of cyclosporine vs tacrolimus among Live-RTx vs CadRTx. ‡ P ⬍ .000, usage of azathioprine vs mycophenolate mofetil among Live-RTx vs CadRTx.
1870
DISCUSSION
The preliminary results of this survey demonstrate a wide variation in IS usage among Asian RTx. Nevertheless, induction therapy predominately with IL2RAb, was used in only 18.4% of Asian RTx, a percentage lower than the 59.3% recorded for the same year for RTx reported to the United Network for Organ Sharing (UNOS).5 Corticosteroids and CNI constituted maintenance IS therapy in the vast majority of Asian RTx at hospital discharge and at 1 year post-RTx. Cyclosporine was used in 87.1% of Asian RTx, a proportion higher than the 38.7% reported from the UNOS database. Tacrolimus usage was correspondingly lower at 12.4% among Asian RTx, in comparison to its use in 55.3% of American RTx. Among the antimetabolites, Aza was used in 61.2% of Asian RTx, remarkably different from the 4.4% usage among patients reported to the UNOS database. Correspondingly, use of MMF was lower among Asian RTx at 33.6%, in contrast to its 77% use among American RTx. Of note, however, was the use of both Tac and MMF in larger proportions of CadRTx (21.2% and 43.5% respectively), in comparison to Live-RTx, likely due to anticipated higher risks for rejection in the former. As
VATHSALA
among patients reported to the UNOS database, CS was the mainstay of antirejection therapy among Asian RTx. While IS use in the United States has been suggested to have entered a new era over the last decade with decreasing use of CyA and increasing use of Tac and MMF, IS use among surveyed Asian RTx in 2001 is still predominately CyA-based. Though all of the newer IS are available in Asia, funding policies for these IS may be the critical factor determining use. Not withstanding these results, it is noted that only 17 of the over 300 Asian RTx centers have been included in this survey. It is hoped that future analyses will have greater participation from more RTx centers so that the Asian experience can be summarized. REFERENCES 1. Ota K, Teraoka S, Kawai T: Transplant Proc 27:1463, 1995 2. Ota K, Teraoka S, Takahashi K, et al: Transplant Proc 26:2457, 1994 3. Ota K: Transplant Proc 31:205, 1999 4. Ota K: Transplant Proc 33:1989, 2001 5. Transplant Statistics: Annual Report: Immunosuppression Practice and Trends. Organ Procurement and Transplantation Network. United Network for Organ Sharing, 2003