FK 506 primary immunosuppression following emergency liver transplantation for fulminant hepatic failure

Abstract The efficacy and safety of an FK 506-compared to a cyclosporin A based immunosuppression regimen was examined in liver recipients who underwent transplantation for fulminant hepatic failure in the European FK 506 liver study. A consistent trend towards improved patient and graft survival noted in the FK 506-treated patients was apparent from the first postoperative week (e. g. patient survival: day 7, 95.5% vs. 82.1% and month 6, 72.7% vs. 60.7%). Acute (in particular intractable) rejection was less frequent in the FK 506 group (e. g. cumulative intractable rejection rate at 6 months, 6.2% vs. 22.6%). In a single centre (Kings College Hospital), 17 patients were studied in more detail. The FK 506 treatment group had improved graft function, lower steroid requirments and episodes of infection. Accompanying these benefits, apache 111 and TISS scores were lower in this group in the early posttransplant period. Intensive care discharge was earlier and both treatment groups experienced similar toxicity.     

Patient and graft survival in the European Multicentre Liver Study - FK 506 vs cyclosporin A

Abstract A prospective randomised study was conducted to evaluate the efficacy and safety of FK 506 administered with corticosteroids compared with a cyclosporin A-based immunosuppressive regimen in patients undergoing primary liver transplantation. 545 patients were recruited in eight European centres, of whom 267 were randomised to FK 506 therapy and 273 to cyclosporin A-based therapy. The estimated Kaplan-Meier patient and graft survival figures of 82.9% and 77.5% respectively in the FK 506 group were higher than the comparable figures in the cyclosporin A group (77.5% and 72.6%, respectively). These differences did not reach statistical significance. Retransplantation rates, time to first rejection episode and number of rejection episodes were all lower ( P < 0.001) in the FK 506 group. The infection rates were comparable between the two groups. During the study, the dose of FK 506 was reduced; this did not compromise efficacy and reduced the associated toxicity. FK 506 provides effective immunosuppression in patients undergoing primary liver transplantation and is associated with a lower incidence of rejection.     

Single-center experience with primary orthotopic liver transplantation with FK 506 immunosuppression.

OBJECTIVE: The efficacy for primary orthotopic liver transplantation of a new immunosuppressive agent, FK 506 (tacrolimus, Prograf, Fujisawa USA, Deerfield, IL), was determined. SUMMARY BACKGROUND DATA: After 3 years of preclinical research, a clinical trial of FK 506 for orthotopic liver transplantation was begun in February 1989, first as a rescue therapy for patients with intractable rejection with conventional immunosuppression, then as a primary drug. METHODS: Between August 1989 and December 1993, 1391 recipients (1188 adult and 203 pediatric) of primary liver allografts were treated with FK 506 from the outset. Results from these patients were analyzed and compared with those of 1212 historical control patients (971 adult and 241 pediatric) given cyclosporine-based immunosuppression. RESULTS: Actuarial survival at 4 years was 86.2% with FK 506 versus 65.5% with cyclosporine in the pediatric patients (p < 0.0000) and 71.4% versus 65.5% in the adults (p < 0.0005). The need for retransplantation was reduced significantly for FK 506 patients. Four-year graft survival was 77.0% with FK 506 versus 48.4% with cyclosporine in the pediatric patients (p < 0.0000), and 61.9% with FK 506 versus 51.4% with cyclosporine in the adult recipients (p < 0.0000). Regression analysis revealed that reduction in mortality or graft loss from uncontrollable rejection, sepsis, technical failure, and recurrent original liver disease were responsible for the improved results with FK 506 therapy. CONCLUSIONS: FK 506 is a potent and superior immunosuppressive agent for orthotopic liver transplantation.     

FK506与CsA在肾移植术后抗排斥的临床应用

目的 比较他克莫司(FK506)与环孢素A(CsA)预防肾移植术后排斥反应的效果和安全性。方法 肾移植患者53例分成两组,FK506组为28例,CsA组为25例。其中CsA组因肝功能损害3例,难治性急性排斥反应1例而改换成FK506。FK506起始用0.2mg·kg~(-1)·d~(-1),CsA起始用6mg·kg~(-1)·d~(-1),同时分别联合应用MMF0.75g,每日2次口服,以及术后三天大剂量甲基强的松龙(MP)静滴,第三天改强的松口服,所有病例均严密观察并行血、尿等生化分析。结果 FK506组移植肾功能好,平均7.5天脱酐水平降至平均99.5μmol/L,2例出现排斥反应,经MP连续3d冲击后治愈。CsA组19例移植肾功能良好,6例出现急性排斥,其中3例经MP连续3d冲击后治愈,2例应用OKT3后急性排斥逆转,1例术后3d出现急性排斥经MP与OKT3治疗后改换成FK506,另3例肝损害呈进行性转氨酶升高改换成FK506。FK506组有血糖升高6例(18.8%),高血压5例(15.6％),感染7例(21.9％)。CsA组血糖升高2例(9.5％),高血压5例(23.8％),感染4例(19.0%)。结论肾移植术后应用FK506疗效确切,能有效防治难治性排斥的发生、发展,降低急性排斥的发生率,特别是在乙肝抗原阳性、肝功能受损者比CsA优越。     

Corticosteroids and concomitant medication in the European multicentre study of FK 506 and cyclosporin in primary liver transplantation

Abstract The steroid-paring effect and the use of concomitant medication during the treatment of liver transplant patients with the novel immunosuppressant FK 506 were evaluated within the European multicentre, randomized, parallel-group study in liver transplantation. Patients undergoing primary liver transplantation were randomized to treatment with FK 506 ( n = 267) or with a cyclosporin-based immunosuppressive regimen ( n = 273). The total cumulative steroid usage was significantly reduced in the FK 506 treatment group, which is likely to have resulted from the lower incidence of acute rejection in these patients. The number of patients receiving antidiabetic, diuretic and antihypertensive therapy did not differ between the two treatment groups, even though the incidence of diabetes mellitus and oliguria was significantly higher in the FK 506 group. It can, therefore, be assumed that in a number of such cases the severity of these events was very mild necessitating no specific therapy.     

肾移植术后应用他克莫司的临床观察

目的 观察他克莫司（ＦＫ５０６）作为免疫抑制剂的有效性和安全性。方法 将首次接受同种异体肾移植的３５例患者随机分为２组,一组给予他克莫司,硫唑嘌呤（或霉酚酸酯）和泼尼松（ＦＫ５０６组）,另一组给予环孢素Ａ、硫唑嘌呤（或霉酚酸酯）及泼尼松（ＣｓＡ组）,观察２个组的免疫抑制效果及药物的副作用。结果 ＣｓＡ组和ＦＫ５０６组的人／肾１年存活率分别为１００．０％／９３／３％和９５．０％／９５．０％;两组肝和     

FK506 conversion for intractable rejection of the liver allograft

Twenty-seven liver transplant recipients with intractable, biopsy-proven, acute or chronic rejection (defined as vanishing bile duct syndrome) were conerted from cyclosporin to FK506. Successful conversion was achieved in 9 of 15 patients with acute rejection and in 6 of 12 patients with vanishing bile duct syndrome. A normal bilirubin was achieved more quickly in those with acute rejection (within 1 moth) than in those with chronic rejection (within 3 months). A preconversion total bilirubin of less than 12 mg/dl was considered significant with regard to a successful outcome (P=0.002). Graft survival was 66.7% and patient survival 73% in the case of acute rejection, and 50% and 66.7%, respectively, in the case of chronic rejection. Nephrotoxicity, neurotoxicity, and gastroitestinal side effects were the most serious complications of FK506 conversion. Six of ten patients had a drop in GFR that was 50% or greater a minimum of 1 month of FK506 exposure. The mean maintenance dose of FK506 to maintain FK506 serum levels of 0.5–1.5 ng/ml was 0.07 mg/kg per 12 h for adults (half the recommended dose), compared to 0.15 mg/kg per 12 h for pediatric patients. This study demonstrates that FK506 can be used successfully to convert patients with intractable acute and chronic rejection. Careful adjustments of FK506 dosages and levels are required to minimize side effects.     

Prolonged survival of rat hindlimb allografts following short-course FK506 and mycophenolate mofetil combination therapy

The immunosuppressive effect of combined therapy using FK506 and mycophenolate mofetil (MMF) was studied in rat limb allotransplantation. Dark Agouti rat donor hindlimbs were orthotopically transplanted into Lewis rat recipients. In total, 38 models of transplantation were performed and divided into 8 groups that were treated individually or in combination with FK506 + MMF therapy. Animals were immunosuppressed for 28 days and then observed for up to 140 days. Graft rejection was evaluated both macroscopically and histologically. Survival times for rat limb allotransplants receiving combination FK506 + MMF therapy were significantly longer than with FK506 or MMF monotherapy, and this was achieved without serious side effects. A histopathological study demonstrated a significantly lower level of rejection with FK506 + MMF combination treatment compared to groups receiving FK506 or MMF monotherapy. Combined FK506 + MMF treatment can prolong the survival of rat limb allografts.     

移植肝的急性排斥反应

目的 分析供、受者年龄,受者性别,术前原发疾病,肝,肾功能以及免疫抑制剂的使用对移植肝的急性排斥反应产生的影响。方法 对玛丽医院从１９９１年１０月至１９９８年９月发生移植急性排斥反应的所有病例进行回顾性分析。结果 ８１例患者做了８３例次肝移植,共发生急性排斥反应７０例次,发生率为５３％。经过统计学分析,发现使用普乐可复（ＦＫ５０６）的受者,急性排斥反应的发生率较使用环孢素Ａ和硫唑嘌呤组为低,供,受     

肝移植术后糖尿病的诊治策略

目的探讨肝移植术后糖尿病(PTDM)的临床特征和诊治措施。方法回顾性分析我院自2003年10月到2008年8月的58例PTDM患者的临床资料。70.7%(41/58)的患者予胰岛素治疗,激素组23例口服激素的PTDM患者中有15例激素减量或停用;FK506组16例使用单药他克莫司(FK506)免疫抑制方案的PTDM患者,转换为霉酚酸酯(MMF)或西罗莫司(RPM)为主的免疫抑制方案,随访3个月,观察改变免疫抑制方案对PTDM的影响。结果 89.7%(52/58)的PTDM患者临床症状不典型,激素组有5例患者空腹血糖正常,出现糖尿病逆转;11例患者胰岛素用量显著降低或停用,无一例发生急性排斥反应。FK506组有2例患者糖尿病逆转,10例患者胰岛素用量显著降低或停用,1例患者发生急性排斥反应,在FK506加量后排斥反应得以控制。结论肝移植术后PTDM的临床症状不典型,胰岛素治疗占主体。减低激素和FK506用量,转换MMF或RPM为主的免疫抑制方案,可能是防治PTDM的有效手段。     

肝移植术后患者应用免疫抑制剂的单中心经验总结(附1400例分析)

目的总结对肝移植术后患者应用免疫抑制剂的经验,探讨个体化治疗的可行性。方法回顾分析2002年4月至2010年8月单中心1400例肝移植患者的临床资料。术后免疫抑制治疗方案的制定按时间发展经历了3个阶段:(1)第1阶段(2002年4月至2004年12月)311例患者采用传统免疫抑制治疗方案;(2)第2阶段(2005年1月至2007年12月)618例患者采用部分传统免疫抑制剂减量的方案;(3)第3阶段(2008年1月至2010年8月)471例患者采用个体化免疫抑制治疗方案。再按术前终末期肝病模型(modelforend-stageliverdisease,MELD)评分及肿瘤是否超出米兰标准分为常规组、超米兰标准组和重症组。收集3个阶段肝移植患者的生存情况,绘制生存曲线。观察第3阶段3组患者的排斥反应发生情况,了解免疫抑制剂其他不良反应及药物替换情况。结果第1、第2、第3阶段患者生存率呈逐渐升高趋势。第3阶段采用个体化治疗,3组的免疫抑制剂用量不同,但3组间免疫排斥反应发生率差异无统计学意义(均为P>0.05)。第3阶段共将12例患者的他克莫司(FK506)转换为环孢素(CsA),32例患者因肾功能损害将FK506转换为小剂量FK506+麦考酚吗乙酯(MMF)或西罗莫司,病情得以缓解。因肿瘤因素或肾功能异常应用单独应用西罗莫司27例,3例因为高脂血症或口腔溃疡不能耐受西罗莫司。结论肝移植术后免疫抑制剂的个体化治疗是可行的,可减少免疫抑制剂的用量,又不增加排斥反应发生率,有利于提高患者生存率。     

再次肝移植手术临床病例分析:附六例

目的 探讨影响再次肝移植预后的因素及再次移植手术问题.方法 回顾性总结2000年7月至2006年4月北京大学第三医院完成的6例再次肝移植病例临床资料,分析再次肝移植的原因、手术方法及病人转归.结果 6例再次肝移植的原因中:移植肝肝癌复发1例,乙型肝炎复发1例,慢性排斥反应2例,肝动脉血栓形成1例,药物性肝损害1例;再次肝移植时间距第一次肝移植平均(12.9±10.0)个月;术中出血平均(14 050±8 215)m1;平均手术时间(12.7±2.0)h.围手术期死亡3例.结论 再次肝移植病人术前一般情况差,手术风险大,正确把握手术时机及手术适应证,术中精细操作,减少出血,手术后采取个体化免疫抑制剂治疗方案等是提高再次肝移植病人存活率的关键因素.     

Conversion of liver allograft recipients from cyclosporine to FK506 immunosuppressive therapy--a clinicopathologic study of 96 patients.

The effect of conversion from cyclosporine-steroid immunosuppression to the new agent FK506 was studied in 96 liver allograft recipients who were experiencing graft dysfunction or cyclosporine toxicity. Patients were stratified according to the cause of graft dysfunction that ultimately led to conversion to FK506. Response to FK506 introduction was monitored pathologically and biochemically. The outcome of a switch from CsA to FK506 was highly favorable in patients experiencing acute and the early stages of chronic rejection, despite optimal conventional therapy. Patients with later stages of chronic rejection did not respond to conversion to FK506 and most eventually lost their liver grafts in this process. Patients in whom we had difficulty separating chronic rejection from chronic persistent or low-grade chronic active hepatitis were mostly unaffected by conversion to FK506. Active hepatitis was a poor indication for conversion, because most of the patients experienced graft failure or died from liver failure. As a group, there was no statistically significant change in renal function 180 days after conversion to FK506. These findings expand the experience with FK506 in human liver allograft recipients.     

FK506 rescues peripheral nerve allografts in acute rejection

This study investigated the ability of the immunosuppressant FK506 to reverse nerve allograft rejection in progress. Eighty-four Buffalo rats received posterior tibial nerve grafts from either Lewis or Buffalo donor animals. Allografts were left untreated for either 7, 10, or 14 days before receiving daily subcutaneous FK506 injections (2 mg/kg). Time-matched control animals received either an isograft, an allograft with continuous FK506, or an allograft with no postoperative FK506 therapy. All animals underwent weekly evaluation of nerve function by walking track analysis. Experimental group animals were sacrificed either immediately prior to initiation of FK506 therapy (days 7, 10, or 14), after 2 weeks of immunosuppressive treatment, or 8 weeks postsurgery. Histomorphometric analysis, consisting of measurements of total number of nerve fibers, neural density, and percent of neural debris, demonstrated a statistically significant increase in regeneration in the isograft group relative to the untreated allograft group within 28 days of transplantation. Grafts harvested from animals receiving 2 weeks of FK506 after 7 or 10 days of rejection were histomorphometrically similar to time-matched isografts. By contrast, grafts from animals receiving 2 weeks of FK506 following 14 days without therapy resembled untreated allografts and demonstrated significant histomorphometric differences from isografts at the corresponding time point. Analysis of walking track data confirmed that relative to untreated allografts, functional recovery was hastened in animals receiving an isograft, or allograft treated with FK506. This study demonstrated that when started within 10 days of graft placement, FK506 could reverse nerve allograft rejection in rats evaluated following 2 weeks of treatment.     

Steroid withdrawal 3 months after liver transplantation - does FK 506 confer any advantage over cyclosporin?

Abstract Eighty-one liver recipients were randomised to FK 506 Or cyclosporin (CyA) and azathioprine (AzA), both in combination with steroids. Twenty-even FK 506 and 29 CyA/AzA patients continued in the trial 3 months after transplantation. Steroids were ceased in 23 (85%) FK 506 patients and in 27 (93%) CyA patients. After steroid withdrawal, 2 FK 506 and 4 CyA patients were excluded from the study, all for reasons other than rejection. The median follow-up was 16 months for the FK 506, and 19 months for CyA group. There were no acute rejection episodes or graft losses in the FK 506 group. None of the CyA patients lost their graft but three (13%) had episodes of acute rejection requiring steroids to be recommenced in two cases. There was no evidence of chronic rejection in any of the annual review biopsies in either group. Our results suggested no advantage of FK 506 over CyA in its steroid-paring effect.     

FK 506 versus cyclosporin in the prevention of renal allograft rejection — European pilot study: six-week results

FK 506 was compared with cyclosporin in a randomised trial in good-risk cadaveric renal transplant recipients. The objective was to evaluate whether oral FK 506 dosing was viable and whether blood concentrations in the range 10–20 ng/ml would prove to be practical. Thirty-one adult patients were randomised to FK 506 and 16 to cyclosporin. Both groups received an identical regimen of azathioprine and corticosteroids. Serum creatinine concentrations decreased rapidly in both groups with mean values below 200 mol/l within 2 weeks. One graft in the cyclosporin group was lost due to renal vein thrombosis. During the 6-week study period, 19.4% of patients on FK 506 and 31.3% on cyclosporin experienced acute rejection. One patient in each group experienced corticosteroidresistant rejection that responded to anti-lymphocyte therapy. Infections were reported in 51.6% of the FK 506 group compared with 37.5% of the cyclosporin group. The spectrum of adverse events was similar in both groups. However, minor neurological disorders were more common in the FK 506 group (54.8% versus 6.3%) whereas hypertension was less common (48.8% versus 75.0%). The results indicate that oral FK 506 rapidly achieves therapeutic blood concentrations and is an effective immunosuppressant for the initial treatment of renal allograft recipients.     

Liver, kidney, and thoracic organ transplantation under FK 506.

The new immunosuppressive drug FK 506 was used from the outset with low doses of prednisone to treat 120 recipients of primary liver grafts and 20 more patients undergoing liver retransplantation. The patient survival rate after 2 to 8 months in the primary liver transplantation series is 93.3%, with original graft survival of 87.5%. Of the 20 patients in the hepatic retransplant series, 17 (85%) are living. Almost all of the surviving patients have good liver function. In addition 11 hearts, 2 double lungs, and a heart-lung have been transplanted under FK 506, with survival of all 14 patients. With all of the organ systems so far tested, including the kidney (which has been reported elsewhere), rejection usually has been controlled without additional drugs and with lower average steroid doses than in the past. Nephrotoxicity has been observed, but not to an alarming degree, and there has been a notable absence of hypertension. There is a suggestion that serum cholesterol may be lowered by FK 506, but this is unproved. Although the adverse reactions of FK 506 and the immunosuppressive mechanisms resemble those of cyclosporine, our preliminary observations suggest that FK 506 may have a more advantageous therapeutic index.     

肝移植后采用巴利昔单抗进行免疫诱导治疗

目的 探讨肝移植后采用巴利昔单抗进行免疫诱导治疗预防急性排斥反应的有效性和安全性.方法 160例肝移植患者中,47例术后给予两剂巴利昔单抗(20 mg/剂)进行免疫诱导治疗(研究组),另外113例为对照组,不使用巴利昔单抗.所有患者术后均采用他克莫司、霉酚酸酯和糖皮质激素预防排斥反应.结果 术后1年内,研究组的急性排斥反应发生率为8.5%(4/47),对照组为22.1%(25/113),二者间的差异有统计学意义(P＜0.05);研究组排斥反应活动指数平均为4,对照组为6,两组间的差异无统计学意义(P＞0.05).研究组术后感染发生率为31.9 %(15/47),对照组为26.5%(30/113),两组间的差异无统计学意义(P＞0.05).研究组患者及移植肝1年存活率分别为95.7%和95.7%,对照组分别为96.5%和94.7%,两组间的差异均无统计学意义(P＞0.05).两组间其它不良反应发生率的差异也无统计学意义.结论 在以他克莫司为基础的免疫抑制治疗方案中,采用巴利昔单抗进行诱导治疗可明显降低肝移植后急性排斥反应发生率,且不增加感染和其它不良反应发生率.     

Primary immunosuppression regimen of rapid steroid withdrawal after living related liver transplantation: a single-center experience

AIM: Corticosteroids have been considered the mainstay of immunosuppressive therapy after liver transplantation. However, the side effects of long-term steroid use such as diabetes, infections, and bone disease, including growth retardation in children, are serious problems. Our immunosuppression regimen includes FK506 and steroid withdrawal by 30 days after transplantation. The aim of this study was to determine the outcomes of liver transplant, using this immunosuppressive regimen. PATIENTS: Fifteen primary liver transplant recipients were performed between January 1994 and May 2003 and data were reviewed retrospectively. Eight pediatric and four adult recipients, who had survived more than 3 months after transplantation, were included in this sample. The immunosuppressive regimen consisted of FK 506 (Prograf), initially at doses of 0.03 mg/kg, with dose adjustments to achieve daily trough levels of approximately 10 to 12 ng/mL, and predonisone, initially at 4 mg/kg/d, with a taper and cessation by 30 days when the graft was stable. RESULTS: All recipients were successfully withdrawn by 30 days. Acute rejection episodes occurred in three patients, no patient was diagnosed with chronic rejection. The acute rejection-free rate at 5 year was 74.1%. No recipient had diabetes, serious infections or bone disease. CONCLUSION: Our primary immunosuppressive regimen of rapid steroid withdrawal is safe with regard to acute and chronic rejection with benefits upon steroid-related side effects.     

肾移植术后长期应用他克莫司的临床观察

目的　探讨肾移植术后长期应用他克莫司 (FK5 0 6 )的临床疗效和安全性。方法　对肾移植术后符合入选条件的 12 6例服用FK5 0 6和 10 9例服用环孢素A(CsA)的患者进行为期 3年的随访。详细记录了患者的服药剂量、FK5 0 6和CsA谷值浓度 ,观察排斥反应、毒副反应发生率 ,计算人 /肾存活率。结果　FK5 0 6组和CsA组 1、3年人 /肾存活率分别为 :98.4 % / 96 .8%、95 .2 % / 90 .5 %和 97.2 % / 96 .3%、94 .4 % / 89.0 % ;急性排斥反应发生率分别为 :13.5 %和 19.3% (P <0 .0 5 ) ;慢性排斥反应发生率分别为 :3.2 %和 8.3% (P <0 .0 5 ) ;糖代谢紊乱发生率分别为 :16 .7%和 9.2 % (P<0 .0 5 ) ;神经精神毒性分别为 :14 .3%和 12 .0 % ;肝功能损害分别为 :6 .3%和 10 .1% (P <0 .0 5 ) ;肾功能损害分别为 :3.2 %和 8.3% (P <0 .0 5 ) ;脱发分别为 :5 .6 %和 0 (P <0 .0 5 ) ;感染分别为 :7.1%和 6 .4 %。结论　FK5 0 6长期使用疗效确切 ,毒副反应发生率较低。