两剂激素联合两剂达利珠单抗及他克莫司的免疫抑制方案在肝移植中的应用

目的 探讨两剂激素联合两剂达利珠单抗及他克莫司(FK506)的免疫抑制方案在肝移植中应用的安全性及有效性.方法 中山大学附属第一医院器官移植中心2006年9月至2008年3月共实施成人肝移植74例,排除3例血型不合、4例围手术期死亡外,余67例纳人本研究,其中男性54例,女性13例,年龄28～66岁,平均(46.9±8.7)岁.将67例成人肝移植患者随机分为两组:传统免疫抑制方案(激素3个月撤离)组(n=35)和两剂激素免疫抑制方案组(n=32),比较两组术后代谢并发症、感染(含细菌、真菌及巨细胞病毒感染)及排斥反应的发生率的差异.结果 两组患者的术后早期高血糖发生率,高血糖患者使用胰岛素的平均剂量,随访期内糖尿病、高血压及感染的发生率的差异有统计学意义(P<0.05);术后早期高血压发生率及随访期内排斥反应的发生率和高脂血症发生率无明显差异(P0.05).结论 两剂激素的免疫抑制方案是安全有效的,其不增加急性排斥反应的发生率,并可显著减少长期使用激素引起的各种不良反应及并发症的发生.     

小剂量兔抗人胸腺细胞免疫球蛋白和赛尼哌在肾移植诱导治疗中的应用效果

目的比较小剂量兔抗人胸腺细胞免疫球蛋白（ATG，即复宁）和赛尼哌在肾移植诱导治疗中的应用效果。方法150例尸体肾移植患者分3组，小剂量即复宁组72例（总剂量2．1～3．0mg／kg），赛尼哌组15例（50mg第1、14天各1次），未接受诱导治疗的肾移植受者63例作为对照组。随访6个门，比较3组患者急性排斥反应、DGF发生率和并发肺部感染率。结果即复宁组、赛尼哌组和对照组6个月内发生急性排斥反应分别为4例（5．5％）、1例（6．7％）、10例（15．9％），发生DGF分别为3例（4．2％）．0例、8例（12．7％），并发肺部感染分别为4例（5．1％）、1例（6．7％）、3例（4．8％），发生白细胞减少分别3例（4．2％）、1例（6．7％）、5例（7．9％），发生血小板减少分别2例（2．8％）、1例（6．7％）、5例（7．9％）。结论早期应用小剂最即复宁和赛尼哌是肾移植诱导治疗的合适选择。     

Multicenter survey of daclizumab induction in simultaneous kidney-pancreas transplant recipients.

We report an experience with 71 simultaneous kidney-pancreas transplant (SKPT) recipients receiving daclizumab induction in combination with tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. The mean follow-up time was 5.9+/-2.5 (SD) months (range 0.5-11 months). The study population included 47 males (65%) and 24 females (35%) with a mean age of 40+/-8 years. The mean pretransplant duration of diabetes and dialysis were 25+/-8 and 1.5+/-0.9 years (34 hemodialysis, 16 peritoneal dialysis), respectively. Mean HLA match was 1.2+/-1.5, with one patient receiving a second transplant. The mean cold ischemic times for the kidney and the pancreas were 15+/-5 and 16+/-4 hr, respectively. Six-month patient, kidney, and pancreas graft survival and rejection rates were 97, 96, 93, and 35%, respectively. There were two deaths, one due to fungal infection and the other due to a cardiac event. There were three kidney graft losses, two immunological, and one death with function. Of the five pancreas graft losses, two were due to infection, one immunological, one thrombosis, and one death with function. The patient population was then stratified according to the number of daclizumab doses: 4-5 doses (n=45) or 1-3 doses (n=26). There were no differences in patient and kidney graft survival rates, 98 vs. 96%, and 92 vs. 92%, respectively. However, there was a trend toward improved pancreas graft survival in the group receiving 4-5 doses (96%) compared with 1-3 doses (85%), P=0.07. Although more patients receiving 1-3 doses had rejection (54%) than patients receiving 4-5 doses (24%), there was no dose response relationship between the total number of doses or the adjusted total mg/kg dose and time to rejection. All patients with functioning grafts have good renal and pancreas allograft function at 6 and 12 months. The overall incidence of major infection was 27% and there were no differences in the incidence of infection between the two groups. No major adverse events were attributed to daclizumab use. In conclusion, excellent short-term outcomes were noted in this retrospective, multicenter survey of initial experience with daclizumab induction in combination with TAC, MMF, and steroids in SKPT recipients. Optimal dosing strategies for SKPT recipients remain to be determined.     

Antithymocyte globulin induction therapy in hepatitis c-positive liver transplant recipients

It is unclear whether antithymocyte globulin (ATG) induction therapy in hepatitis C-positive (HCVpositive) liver transplant recipients influences the risk of developing recurrent HCV disease. Multiple acute rejection episodes and high-dose steroids and/or OKT3 used to treat acute rejection increase the risk of graft loss from HCV. We studied the impact of ATG induction on graft and patient survival in HCVpositive liver transplants performed since 1990. Recipients who died or lost their grafts within 1 month of transplantation were excluded. Second, third, and fourth grafts were excluded, as were patients with stage III or IV hepatocellular carcinoma. There were 443 cadaveric liver transplants in adult recipients, of whom 142 (32%) were HCV positive. The incidence of biopsy-proven acute rejection was less in patients who received ATG induction, 34.2% (ATG induction) versus 66.6% (no ATG induction) (P = .01). ATG induction did not influence the risk of graft loss from HCV-related disease (P ≤ .75). When only HCV-related graft loss was considered, 10-year graft survival for HCV-positive recipients was 74% (ATG induction) versus 68.2% (no ATG induction). Whether ATG induction was given or not had no significant impact on either overall graft survival (P = .39) or patient survival (P = .11) in HCVpositive recipients. Presented at the Fifth Biennial Meeting of the American Hepato-Pancreato-Biliary Association, Fort Lauderdale, Florida, April 14–17, 2005     

他克莫司缓释胶囊对肝移植术后稳定期受者安全性和临床疗效评估

目的通过他克莫司缓释胶囊（MR4）的Ⅲ期临床试验（MR4LTxCN02）评价MR4在肝移植术后稳定期受者中的安全性和临床疗效。方法受试者随机分配入MR4或他克莫司（FK506）组,MR4组药物剂量按1：1进行药物转换,每日口服1次;FK506组维持每12h服药1次至试验结束。在为期3个月的临床试验阶段,随访了受试者生命体征、不良事件、血常规、尿常规、肝功能、血糖、血脂及FK506的谷值浓度。随访结果采用SAS8．0统计软件进行了Fisher精确卡方检验及t检验分析。结果MR4组按1：1药物转换后与FK506组具有同等的安全性和临床疗效。与FK506组比较,MR4组具有感冒、上呼吸道感染症状减少倾向,没有增加不良事件或不良反应的发生率。转换药物后的剂量和血药浓度与换药前未发生显著变化;药代动力学检测结果表明,MR4具备缓释剂型的药代动力学特征,并与FK506具有良好的生物等效性。结论MR4与FK506具有同等的安全性和临床疗效,同时简化了服药次数,在提高受者长期依从性以及术后生活质量方面具有较大的优势。     

Two-dose daclizumab induction therapy in 209 liver transplants: a single-center analysis

BACKGROUND: Patient and graft survival after liver transplantation are adversely affected by early posttransplant renal dysfunction. Therefore, our immunosuppressive strategies should be as "renal sparing" as possible. This is the largest published series to date using daclizumab induction therapy in a renal-sparing regimen. METHODS: This is a retrospective, nonrandomized study comparing 209 adult liver transplants with daclizumab induction to 115 transplants with no induction. RESULTS: Patient and graft survival were similar, despite higher pretransplant acuity of illness and older age in the induction group. Acute rejection within the first 6 months occurred less commonly in the induction group (25.4% vs. 39.1%, P=0.01), despite significantly delayed initiation and lower doses of a calcineurin inhibitor. Mycophenolate mofetil was used more commonly in induction patients, but the efficacy of daclizumab in preventing rejection was independent of this. Patients with a pretransplant creatinine concentration 1.5 mg/dL or less had less rejection if they received induction. Renal function worsened in noninduction patients but showed sustained improvement throughout follow-up in induction patients with a pretransplant creatinine concentration greater than 1.5 mg/dL. Induction therapy provided better rejection prophylaxis among those requiring temporary calcineurin inhibitor cessation because of renal dysfunction. The incidences of histologic hepatitis C recurrence and cytomegalovirus infection were similar in each group. CONCLUSIONS: Liver recipients with and without pretransplant renal dysfunction have less acute rejection with daclizumab induction therapy. This is not associated with an increased risk of over-immunosuppression. Sustained renal improvement in recipients with pretransplant renal dysfunction is possible with daclizumab induction.     

Sinus bradycardia associated with daclizumab in liver transplant recipients: report of 3 cases

Daclizumab is a commonly used immunosuppressive agent for prophylaxis of solid organ rejection. Although rare, the cardiovascular adverse effects of daclizumab include sinus tachycardia, hypotension, and hypertension. Here, we report 3 patients who developed significant and prolonged sinus bradycardia after receiving daclizumab following orthotopic liver transplant. Daclizumab should be considered a possible cause of bradycardia following its administration in orthotopic liver transplant.     

Pharmacokinetics,pharmacodynamics, and immunodynamics of daclizumab in a two-dose regimen in liver transplantation

BACKGROUND: The humanized anti-interleukin 2 receptor (IL-2R) monoclonal antibody daclizumab (Zenapax) has been shown to be safe and effective for preventing acute allograft rejection in renal transplantation. The aim of this study was to evaluate pharmacokinetics and pharmacodynamics of daclizumab in a two-dose regimen (1.5 mg/kg total) after liver transplantation. METHODS: Twenty-eight patients were enrolled in this study. Patients were evaluated for outcome, postoperative blood and ascites loss, serum levels of daclizumab, and corresponding changes in peripheral blood. Patients were also checked for development of anti-daclizumab antibodies. RESULTS: CD25+ cells in patients' blood were significantly reduced for 28 days after daclizumab application. Elimination half-life of the antibody was 99 hr with a total body clearance of 57 ml/hr. Blood loss was not statistically significant and loss of ascites was weakly correlated to the monoclonal antibody clearance. One episode of mild acute rejection occurred. Although there was no significant decrease in absolute counts of CD3+, CD4+, and CD8+ lymphocytes, we were not able to show constant coating of IL-2Ralpha with daclizumab. IL-2Ralpha was not detectable on cell surface with two different antibodies and IL-2Rbeta was clearly reduced. Low titers of neutralizing anti-daclizumab antibodies in 3 of 13 patients were not of clinical significance and without influence on the pharmacokinetics. CONCLUSIONS: A two-dose regimen with daclizumab in liver transplantation leads to effective blockade of the IL-2Ralpha for at least 14 days after transplantation. Daclizumab seems to affect not only IL-2Ralpha but also IL-2Rbeta and may lead to an impairment of other cytokine pathways, such as the IL-15 pathway.     

Alternative therapy use in liver transplant recipients

BACKGROUND: The extent of use of alternative therapies and the psychosocial variables predictive of their use have not been well defined in liver transplant recipients. OBJECTIVE: To determine types of alternative therapies used by liver transplant recipients and to assess psychosocial, behavioral, and quality of life variables associated with the use of alternative therapies in these patients. METHODS: Assessment of types of alternative therapies used, demographic characteristics, satisfaction with social support, coping styles, sense of personal control (mastery), quality of life, and health beliefs in 32 liver transplant recipients. RESULTS: Overall, 34.4% of the liver transplant recipients used a form of alternative therapy. Herbal products were used by 45% of the alternative therapy users and included milk thistle (silymarin), eclipta, and green beet leaf-all considered "hepatic tonics". Alternative therapy users tended to have greater problem-focused coping skills than nonusers (P = .08). Nineteen percent of the patients incurred annual out-of-pocket expense of at least dollars 100 for alternative therapies. Patients incurring out-of-pocket expenses reported better overall health (P = .02), were more likely to be employed (P = .025), and had higher mastery scores (P = .01). CONCLUSIONS: Use of alternative therapies is common after liver transplantation. Herbal products used by liver transplant recipients are disease specific; that is, they claim to promote liver health.     

A comparison of daclizumab to ATGAM induction in simultaneous pancreas-kidney transplant recipients on triple maintenance immunosuppression

Daclizumab (DAC) is a molecularly engineered humanized IgGa monoclonal Ab directed against the alpha chain of the interleukin‐2 receptor (IL2R). Inhibiting the amplification of the immune response by blocking IL2R can reduce the frequency of acute rejection without the attendant risk of infection.
The purpose of this retrospective study was to compare DAC to anti‐thymocyte (ATGAM) induction in 24 simultaneous pancreas–kidney (SPK) transplants performed between September 1995 and September 1998. The primary endpoints were the incidence within 6 months post‐transplant of: 1) biopsy‐proven acute rejection; and 2) infection. The two groups (DAC, n=12; ATGAM, n=12) were matched on age, race, ESRD, number of HLA mismatches, PRA level, and cold ischemia time. DAC (1 mg/kg) was given on the day of transplant, then every other week (a total of five doses); ATGAM (15 mg/kg) was given on post‐transplant day 1, then daily for 7–10 d. Immunosuppressive therapy consisted of cyclosporine (Neoral®– 8–10 mg/kg/d) or Prograf® (0.16–0.2 mg/kg/d), mycophenolate mofetil (CellCept®– 2–3 g/d) and steroids.
Of the 12 DAC patients, 3 patients (25%) had biopsy‐proven acute rejection versus 8/12 (67%) of the ATGAM patients. The time to acute rejection was significantly different by group (DAC=110 d; ATGAM=26 d). There was a reduction in the number of patients receiving antilymphocyte drugs for moderate to severe rejection (DAC=2/12; ATGAM=4/12), with 2 of the 4 ATGAM patients experiencing more than two episodes of biopsy‐proven rejection. There was an increase in infection by group (DAC=4/12; ATGAM=7/12): total of three septic infections occurred in the ATGAM group opposed to none in the DAC group. Patient, pancreas, kidney 6‐month survival rates were 100% for both groups.
We conclude that DAC induction coupled with triple immunosuppressive therapy reduces the incidence of rejection in SPK transplant patients. The time to acute rejection was prolonged in the DAC group compared with the ATGAM group without the attendant risks of rejection.     

Long-term efficacy and safety of mycophenolate mofetil in liver transplant recipients with calcineurin inhibitor-induced renal dysfunction

Long-term survival after orthotopic liver transplantation (OLT) is mainly influenced by adverse events caused by immunosuppression. Several studies have shown the efficacy of mycophenolate mofetil (MMF) in improving calcineurin inhibitor (CI)-induced nephrotoxicity with concomitant reduction or withdrawal of CI. In this prospective study we assessed the long-term effect and safety of MMF. Thirty-two OLT recipients with significant renal impairment due to either cyclosporine A (n=25) or tacrolimus (n=7) were enrolled in this study. CIs were reduced stepwise by at least 70%. Mean serum creatinine had decreased from 2.63±0.39 to 1.74±0.34 mg/dl after 1 month, and this improvement was maintained within a follow-up period of 4.8±0.6 (range 3.1–6.0) years, without major immunological or non-immunological side effects. Of all participants, 88% showed a significant reduction, and 41% even a normalization, in their serum creatinine level. In addition, MMF conversion, within 6 months of OLT, appears to be crucial in order to improve or even normalize renal function. This study demonstrates the long-term efficacy and safety of MMF in OLT recipients with CI-induced nephropathy.This work was supported by Verein zur Förderung der Forschung in Gastroenterologie und Hepatologie an der Universität Innsbruck     

Efficacy and safety of basiliximab with a tacrolimus-based regimen in liver transplant recipients

BACKGROUND: Induction with monoclonal antibodies for prevention of acute cellular rejection (ACR) may avoid many of the adverse events associated with polyclonal antibodies. Basiliximab, a chimeric monoclonal antibody directed against the alpha-chain of the interleukin 2 receptor (CD25), has been extensively evaluated as an induction therapy for kidney transplant recipients, more frequently in combination with a cyclosporine-based regimen. In this study, we assessed the efficacy and safety of basiliximab in combination with a tacrolimus-based regimen after liver transplantation. METHODS: Fifty consecutive liver transplants (47 cadaveric donors; 3 living donors) were analyzed. All patients received two 20-mg doses of basiliximab (days 0 and 4 after transplantation) followed by tacrolimus (0.15 mg/kg/day; 10-15 ng/mL target trough levels) and a tapered dose regimen of steroids. Follow-up ranged from 404 to 1,364 days after transplantation (mean 799.89 days, SD+/-257.37; median 796 days). RESULTS: A total of 88% of patients remained rejection-free during follow-up with an actuarial rejection-free probability of 75% within 3 months. The actuarial patient survival rate at 3 years was 88%, and the graft survival rate was 75%. Twelve (24%) patients experienced one episode of sepsis, requiring temporary reduction of immunosuppressive therapy. There were no immediate side effects associated with basiliximab and no evidence of cytomegalovirus infection or posttransplant lymphoproliferative disorder. CONCLUSIONS: Basiliximab in combination with a tacrolimus-based immunosuppressive regimen is effective in reducing episodes of ACR and increasing ACR-free survival after liver transplantation. In addition, basiliximab does not increase the incidence of adverse effects or infections.