本帖最後由 lsc0019 於 2009-6-29 23:10 編輯
作者：Alice McCarthy
出處：WebMD醫學新聞
June 12, 2009 (麻州波士頓) — 對於曾經接受腎臟移植且免疫風險低的病患，mycophenolate mofetil (MMF)與cyclosporine可以使其在良好耐受下提早停用類固醇。不過，維持較高的MMF治療劑量並無助於預防排斥。
此結果屬於OPERA試驗的一部份，該試驗檢視腎臟免疫抑制的類固醇最少化規範，發表於2009年美國移植研討會：美國移植外科醫師協會與美國移植協會聯合年會。
腎臟移植病患常用包括類固醇與MMF的藥物維持處方。隨著時間，希望停止類固醇以降低其相關副作用。
法國Limoges大學醫院腎臟科的Yannick Le Meur醫師向與會聽眾表示，及早停止類固醇是腎臟移植者類固醇最少化的一個有趣選項。不過，這可能讓病患面對較高的臨床或次臨床排斥風險。協定切片中有15%至30%的次臨床排斥，且與降低移植器官存活有關。
他也解釋，藉由一般的MMF起始劑量、每天2 g，許多病患，特別是那些接受cyclosporine者，MMF的活性代謝物、mycophenolic acid (MPA)不足。
在OPERA試驗中，所有病患在移植後接受1週的皮質類固醇治療。一組接著以每天3g的MMF治療(n= 126人)，最初10天，監測他們的MPA值，調整MMF劑量以維持濃度為40 mg/h/L。Le Meur醫師解釋，目標在監控MPA值與隨著時間調整而維持穩定濃度。另一組(n= 121人)接受固定劑量的MMF、2 g/天。所有病患在移植之後3到12個月接受切片。
【促進MPA曝露不會減少排斥】
Le Meur醫師表示，我們發現，較高的MMF起始劑量，和隨後的MPA治療藥物監控，以確保較高的MPA曝露，使80%的病患達到治療濃度。不過，3個月與1年時的次臨床急性排斥比率出乎意料的低，並未隨著MPA治療藥物監控改善。
研究者發現，調整劑量組與固定劑量組在移植後3個月時的次臨床急性排斥(SCAR)以及切片證實急性排斥(BPAR)比率相似(17.5% vs14.1%；P= .46)。
Le Meur醫師表示，根據在文獻上所見的BPAR與SCAR比率，我們預期在調整劑量組看到20%的排斥率、在固定劑量組看到40%的排斥率。在12個月時，調整劑量組與固定劑量組的整體排斥比率再度相似(38.9% vs 38.8；P= .99) 。
兩組在1年時未使用類固醇的病患約有68%。兩組的嚴重MMF相關副作用、白血球減少症(等級3和4)或嗜中性白血球減少症頻率沒有差異。
Le Meur醫師向Medscape Transplantation表示，我們最初設計一個研究，希望治療藥物的MPA監控有助於降低腎臟移植之後的排斥比率。我們在這個研究中顯示的是，藥物監控增加了腎臟移植的停用類固醇成功率。不幸的是，這是個負向結果的研究，目前，我們無法陳述它是否有幫助。
本段會議的共同主持人、芝加哥西北大學的John Friedewald醫師向Medscape Transplantation表示，這個試驗背後的問題是，透過監控的積極MMF劑量是否有助於cyclosporine/MMF處方的類固醇停用？排斥或副作用比率上沒有顯著差異。希望可以藉由更積極的MMF劑量控制而降低排斥率。沒有差異著實令人訝異。
另一名主持人、賓州大學腎臟移植專家Peter Reese醫師向Medscape Transplantation表示，不過，該研究在副作用的資料強度可能不足。因此不難令人想像，如果試驗樣本有兩倍之多，在副作用上可能有更大的差異。
Roche SAS支持本研究。 Le Meur醫師接受Roche SAS的顧問費用。Friedewald 醫師與 Reese醫師宣告沒有相關財務關係。
2009年美國移植研討會(ATC)：美國移植外科醫師協會(ASTS)與美國移植協會(AST)聯合年會：摘要521。發表於2009年6月2日。
ATC 2009: Optimized Mycophenolic Acid Does Not Appear to Reduce Kidney Rejection Rates
By Alice McCarthy
Medscape Medical News
June 12, 2009 (Boston, Massachusetts) — In patients who have undergone kidney transplantation and have low immunological risk, mycophenolate mofetil (MMF) with cyclosporine allows for early corticosteroid discontinuation with good tolerability. However, maintaining a higher therapeutic dose of MMF does not appear to be beneficial in preventing rejection.
The results, part of the OPERA trial, which tested steroid-minimization protocols in kidney immunosuppression, were presented here at American Transplant Congress 2009: The Joint Annual Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation.
A drug-maintenance regimen that includes steroids and MMF is common for kidney-graft recipients. Over time, steroid withdrawal is a desirable goal to reduce steroid-related adverse effects.
"Early steroid withdrawal is an interesting option for steroid minimization in renal transplantation," Yannick Le?Meur, MD, from the Department of Nephrology, Limoges University Hospital in France, told meeting attendees. "However, it may expose patients to a higher risk of clinical or subclinical rejections. Subclinical rejections have been reported in 15% to 30% of protocol biopsies and are associated with a reduced graft survival."
He also explained that with the usual starting dose of MMF of 2?g/day, a large proportion of patients, particularly those receiving cyclosporine, are underexposed to mycophenolic acid (MPA), the active metabolite of MMF.
In the OPERA trial, all patients received 1 week of corticosteroid therapy after transplantation. One group was then treated with an MMF dose of 3?g/day (n?= 126) for the first 10 days, and their MPA levels were monitored and MMF dose adjusted to maintain a level of 40?mg/h/L. "The goal was to monitor the MPA and adjust it over time to maintain a constant exposure," explained Dr. Le?Meur. Another group (n?= 121) received a fixed dose of MMF of 2?g/day. All patients had biopsies 3 to 12 months posttransplantation.
Enhanced MPA Exposure Did Not Reduce Rejection
"We found that the higher starting MMF dose followed by MPA therapeutic drug monitoring guarantees a higher MPA exposure, with 80% of the patients achieving therapeutic concentrations," said Dr. Le?Meur. "However, the rates of subclinical acute rejection at 3 months and 1 year were unexpectedly low?.?.?. and not improved by therapeutic drug monitoring of MPA."
Researchers found that rates of subclinical acute rejection (SCAR) and biopsy-proven acute rejection (BPAR) were similar between the adjusted- and fixed-dose groups at 3 months posttransplantation (17.5% vs14.1%; P?= .46).
"We expected to see rejection rates of about 20% in the adjusted-dose group [and] about 40% in the fixed-dose group, based on the rates of BPAR and SCAR we see in the literature," said Dr. Le?Meur. At 12 months, the overall rejection rates were again similar (38.9% vs 38.8; P?= .99) for the adjusted- and fixed-dose groups.
Approximately 68% of patients in both groups were steroid-free at 1 year. There were no differences between the groups in the frequency of severe MMF-related adverse events, leucopoenia (grade?3 and 4), or neutropenia.
"We first designed a study showing that therapeutic drug monitoring of MPA was effective in reducing the rate of acute rejection after renal transplantation," Dr. Le?Meur told Medscape Transplantation. "We would have liked to have shown in this study whether drug monitoring increases the success rate of steroid withdrawal in kidney transplantation. Unfortunately, this was a negative study, so at this point we cannot say whether it will be helpful."
"The question behind the trial concept is: Will more aggressive MMF dosing through monitoring allow for steroid withdrawal in a cyclosporine/MMF-based regime?" session comoderator John Friedewald, MD, from Northwestern University in Chicago, Illinois, told Medscape Transplantation. "There wasn't a significant difference in rejection episodes or adverse-event rates. The hope was that by more aggressively dosing MMF, you would have lower rejection rates. It was surprising that there was no difference."
"However, [the study] might have been underpowered in terms of the adverse-effects data," session comoderator Peter Reese, MD, a transplant nephrologist at the University of Pennsylvania, in Philadelphia, told Medscape Transplantation. "It makes you wonder whether, if the trial was twice as large, you would have seen larger differences in side effects."
The study was funded by Roche SAS. Dr. Le?Meur has received consulting fees from Roche SAS. Dr. Friedewald and Dr. Reese have disclosed no relevant financial relationships.
American Transplant Congress (ATC) 2009: The Joint Annual Meeting of the American Society of Transplant Surgeons (ASTS) and the American Society of Transplantation (AST): Abstract 521. Presented June 2, 2009. |
|
