钙神经素抑制剂在肾移植中的应用与进展

环孢素A(CsA)和他克莫司(FK506)属于钙神经素抑制剂(calcineuri inhibitor,CNI),均可以抑制钙神经素的活性,破坏在T细胞活化方面有重要作用的细胞因子如IL-2、IL-4等基因的表达,从而阻断T细胞活化,减少急性排斥反应.然而与CNI治疗相关的肾毒性及肾外的不良反应对移植物的生存产生不良影响,所以近年来临床医学家在研究积极减轻这些药物毒性的新的免疫抑制方案.     

神经钙素抑制剂在肝移植术后慢性肾功能衰竭发生、发展中的合理应用(文献综述)

肝移植术后 ,神经钙素抑制剂长期的剂量依赖性肾毒性是慢性肾功能衰竭发生的主要原因 ,神经钙素抑制剂在术后慢性肾功能衰竭发生、发展中的合理应用具有重要的临床意义。     

阿仑单抗诱导后钙神经蛋白抑制剂单药治疗方案在肾移植中的应用:一项系统评价研究

目的  探讨阿仑单抗诱导后钙神经蛋白抑制剂单药治疗(AiCNIm)方案应用于肾移植术后免疫抑制的有效性和安全性。方法  应用计算机检索Pubmed、Embase、Web of science、Cochrance library及中国知网(CNKI)等数据库, 查找1980年至2014年12月31日发表的有关AiCNIm方案(AiCNIm组)和常规三联方案(Triple组)进行肾移植术后免疫抑制的随机对照临床研究。采用Rev Man 5.2软件进行Meta分析。结果  共纳入5项随机对照研究, 421例肾移植受者。随访6~12个月结果显示, 与Triple组相比, AiCNIm组的急性排斥反应或穿刺活检证实的排斥反应发生率更低[相对风险系数(RR)=0.59, 95%可信区间(CI)0.40~0.89], 但两组在移植肾失功(RR=0.85, 95%CI0.38~1.87)、受者死亡(RR=0.89, 95%CI0.30~2.67)、感染(RR=1.03, 95%CI0.91~1.17)和移植后新发糖尿病(RR=0.62, 95%CI0.29~1.30)方面比较, 差异无统计学意义(均为P>0.05)。结论  基于现有证据, 肾移植术后应用阿仑单抗诱导后用钙神经蛋白抑制剂单药治疗, 短期免疫抑制效果好且安全。     

神经钙黏素和上皮钙黏素在肝细胞癌中的表达及其临床意义

目的目的探讨神经钙黏素和上皮钙黏素在肝细胞癌中的表达及其与临床病理参数的关系。方法采用免疫组织化学方法对38例肝细胞癌组织标本进行检测。结果肝癌组织中上皮钙黏素表达阳性率为39．5％，神经钙黏素表达阳性率57．9％，两者具有显著负相关性（P〈0.05）。上皮钙黏素表达下调和神经钙黏素表达上调与肝癌包膜的完整性和侵袭表型显著相关（P〈0．05），而与肿瘤分化、肿瘤直径、门静脉癌栓、卫星灶等无关（P〉0．05）。结论上皮钙黏素表达下调和神经钙黏素表达上调均与肝细胞癌侵袭转移相关，联合检测两个指标有助于判断肝细胞癌的生物学特性。     

神经钙黏素和上皮钙黏素在肝细胞癌中的表达及其临床意义

目的目的探讨神经钙黏素和上皮钙黏素在肝细胞癌中的表达及其与临床病理参数的关系。方法采用免疫组织化学方法对38例肝细胞癌组织标本进行检测。结果肝癌组织中上皮钙黏素表达阳性率为39.5%,神经钙黏素表达阳性率57.9%,两者具有显著负相关性(P<0.05)。上皮钙黏素表达下调和神经钙黏素表达上调与肝癌包膜的完整性和侵袭表型显著相关(P<0.05),而与肿瘤分化、肿瘤直径、门静脉癌栓、卫星灶等无关(P>0.05)。结论上皮钙黏素表达下调和神经钙黏素表达上调均与肝细胞癌侵袭转移相关,联合检测两个指标有助于判断肝细胞癌的生物学特性。     

血管紧张素转换酶抑制剂在肾移植中应用进展

近些年来实验和临床研究表明，血管紧张素转换酶抑制剂对于肾移植术后所出现的肾移植后高血压，蛋白尿，红细胞增多症以及慢性排斥反应等都有独特的功效。     

血管紧张素转换酶抑制剂在肾移植中应用进展

近些年来实验和临床研究表明 ,血管紧张素转换酶抑制剂对于肾移植术后所出现的肾移植后高血压 ,蛋白尿 ,红细胞增多症以及慢性排斥反应等都有独特的功效     

基因芯片在肾移植中的应用进展

基因芯片是一种综合了寡核苷酸高密度空间合成技术的核酸分子杂交分析技术,可同 时、快速、高效、高通量分析生物信息。本文综述了基因芯片在肾移植组织配型、移植免疫机制、移植术 后感染的诊断以及敏感药物筛选、抗排斥药物作用机制方面的研究进展。     

Prevention of calcineurin inhibitor nephrotoxicity in renal transplantation

Calcineurin inhibitors (CNI) cyclosporine (Csa) and tacrolimus (Tac) are now first intention immunosuppressive drugs in renal transplantation. However, although these treatments are effective for preventing allograft rejection, they are nephrotoxic: they can cause chronic renal dysfunction and degradation of renal graft function [Nankivell BJ, et al. The natural history of chronic allograft nephropathy. N Engl J Med. 2003 Dec 11;349(24):2326-33]. In view of these undesirable effects, several strategies have been developed to minimize or even avoid their use. These strategies are reviewed and discussed in this paper.     

Simultaneous corticosteroid avoidance and calcineurin inhibitor minimization in renal transplantation

Steroids and calcineurin inhibitors (CNI) have been mainstays of immunosuppression but both have numerous side effects that are associated with substantial morbidity and mortality. This study was carried out to determine if steroids can be eliminated with early discontinuation of cyclosporine A (CsA) and later discontinuation of mycophenolate mofetil (MMF). Ninety-six patients with kidney transplants were entered into four subgroups of two pilot studies. All patients received Thymoglobulin induction, rapamycin (RAPA), and the immunonutrients arginine and an oil containing omega-3 fatty acids. Mycophenolate mofetil was started in standard doses and discontinued by 2 years. CsA was given in reduced doses for either 4, 6, or 12 months. Follow-up was 12-36 months. Thirteen first rejection episodes occurred during the first year (14%). Combining all patients, 86% were rejection-free at 1 year, 80% at 2 years and 79% at 3 years. No kidney has been lost to acute rejection. Ninety percent of the 84 patients at risk at the end of the study were steroid-free and 87% were off CNI. Fifty-seven percent of 54 patients with a functioning kidney at 3 years were receiving monotherapy with RAPA. We conclude that this therapeutic strategy is worthy of a prospective multi-center clinical trial.     

Lifetime cost-effectiveness of calcineurin inhibitor withdrawal after de novo renal transplantation

After renal transplantation, immunosuppressive regimens associated with high short-term survival rates are not necessarily associated with high long-term survival rates, suggesting that regimens may need to be optimized over time. Calcineurin inhibitor (CNI) withdrawal from a sirolimus-based immunosuppressive regimen may maximize the likelihood of long-term graft and patient survival by minimizing CNI-associated nephrotoxicity. In this study, a lifetime Markov model was created to compare the cost-effectiveness of a sirolimus-based CNI withdrawal regimen (sirolimus plus steroids) with other common CNI-containing regimens in adult de novo renal transplantation patients. Long-term graft survival was estimated by renal function and data from published studies and the US transplant registry, including short- and long-term outcomes, utility weights, and health-state costs were incorporated. Drug costs were based on average daily consumption and wholesale acquisition costs. The model suggests that treatment with sirolimus plus steroids is more efficacious and less costly than regimens consisting of a CNI, mycophenolate mofetil, and steroids; therefore, CNI withdrawal not only shows potential for long-term clinical benefits but also is expected to be cost-saving over a patient's life compared with the most commonly prescribed CNI-containing regimens.     

Safety and efficacy of a calcineurin inhibitor avoidance regimen in pediatric renal transplantation

Thirty-four children were entered into a pilot trial of calcineurin inhibitor avoidance after living-donor kidney transplantation, the CN-01 study. Patients were treated with anti-CD25 mAb, prednisone, mycophenolate mofetil, and sirolimus. Twenty patients were maintained on the protocol for up to 3 yr of follow-up. One enrolled patient did not receive the transplant because of a donor problem, eight terminated because of one or more rejection episodes, four terminated because of adverse events, and one was lost to follow-up. Two grafts were lost, one as a result of chronic rejection and the other as a result of posttransplantation lymphoproliferative disorder. There were no deaths. The 6- and 12-mo acute rejection rates were 21.8 and 31.5%, respectively. GFR were stable throughout the course of the study, with a slight downward trend by 6 mo after transplantation followed by a slight upward trend to a mean of 70 ml/min thereafter. Early surveillance graft biopsies frequently showed focal interstitial mononuclear cellular infiltrates without overt vasculitis or tubulitis, but these infiltrates disappeared without treatment. Anti-HLA class I and II antibodies were detected in three patients before transplantation, and all three had acute rejections, including the two patients who lost their grafts. De novo anti-HLA Ab production occurred in only one patient after transplantation. There were two episodes of Epstein Barr virus-related posttransplantation lymphoproliferative disorder, one of which developed after the patient had been terminated from the study. It is concluded that calcineurin inhibitor-free immunosuppression can be safe and effective in pediatric living-donor renal transplantation. However, further modifications that are designed to lessen early rejection rates and decrease complications should be tested before this approach is used routinely.     

Abatacept as rescue immunosuppression after calcineurin inhibitor treatment failure in renal transplantation

A majority of kidney transplant recipients receive calcineurin inhibitor‐based immunosuppression. However, some do not tolerate calcineurin inhibitors and require other immunosuppressive strategies. Until recently, alternative approaches have been associated with inferior outcomes, but recent methods have effectively utilized belatacept in calcineurin inhibitor‐intolerant patients. Though promising, belatacept uptake has been limited by higher acute rejection rates, unavailability due to production shortages, and logistical challenges as a result of intravenous infusion requirements. Interestingly, its predecessor abatacept is clinically available in subcutaneous formulation to treat autoimmune disorders but has not been used in clinical transplantation. Here we report on a series of 9 calcineurin inhibitor‐intolerant transplant recipients converted to abatacept early after transplant as rescue immunosuppression during periods of belatacept unavailability. Retrospective review revealed successful allograft salvage and 100% patient and graft survival (median 115 months) after conversion to abatacept. Patients received abatacept for a median duration of 82 months with stable, long‐term renal allograft function, a single cellular rejection episode, and no clinically apparent protective immunity concerns. Hence our findings suggest that future clinical studies utilizing abatacept either de novo or as conversion therapy in transplant recipients should be considered.     

Comparison of sirolimus-based calcineurin inhibitor-sparing and calcineurin inhibitor-free regimens in cadaveric renal transplantation

INTRODUCTION: This study examines the efficacy and toxicity of sirolimus used as primary immunosuppression in combination with reduced dose tacrolimus (calcineurin inhibitor [CI]-sparing regimen) or mycophenolate mofetil (CI-free regimen) in high-risk cadaveric renal transplantation. METHODS: Seventy subjects were treated in a quadruple sequential protocol in which 41 were treated with a CI-sparing regimen and 29 were treated with a CI-free regimen. The efficacy and toxicity profiles of these regimens were prospectively monitored and compared. RESULTS: The study consisted of African Americans (71%), cadaveric donors (100%), donors aged more than 50 years (30%), and patients with delayed graft function (47%). At 1 year, patient survival, graft survival, and incidence of biopsy-proven acute rejection were 98%, 80%, and 10%, respectively, in the CI-sparing group and 100%, 89%, and 7%, respectively, in the CI-free group. Three-month protocol biopsies were performed in 41% (17/41) and 67% (20/29) of the subjects in the CI-sparing and CI-free groups, respectively. Subclinical rejection was detected in 6% (1/17) and 15% (3/20) of the subjects in the CI-sparing and CI-free groups, respectively. Histologic evidence of chronic allograft nephropathy was more prevalent in the CI-sparing group. At 1 year, the mean estimated creatinine clearance was higher in the CI-free group than in the CI-sparing group (72.4 +/-20.0 mL/min vs. 50.5 +/-20.8 mL/min, P <0.01). The two regimens had similar toxicity profiles (hospital readmission, infection, wound complications, and metabolic complications). CONCLUSIONS: Both sirolimus-based CI-sparing and CI-free regimens are safe and effective in a population with high immunologic risk. The CI-free regimen is associated with better renal function at 1 year post-transplant. Long-term follow-up will aid in determining the risk and benefit ratio of these regimens.     

Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation

BACKGROUND: The adoption of calcineurin inhibitors (CNI) as the mainstay of immunosuppression has resuited in a significant decrease of acute rejection and improvement of short-term graft survival. However, because of the irreversible nephrotoxicity associated with the chronic use of the CNI, the magnitude of the improvement of long-term graft survival has been more modest. Therefore, an effective immunosuppression regimen that does not rely on CNI may result in improvement of long-term outcome and simplification of the management of transplant recipients. METHODS: Ninety-eight patients of primary cadaver or living donor kidneys at low immunologic risk were enrolled in a CNI avoidance study. The immunosuppression regimen consisted of daclizumab, a humanized monoclonal antibody that binds to the alpha chain of the interleukin-2 receptor (IL-2Ralpha), administered for a total of five doses at biweekly intervals; 3 gm/day mycophenolate mofetil for the first 6 month and 2 gm thereafter; and conventional corticosteroid therapy. Patients who underwent rejection episodes could be started on CNI. The primary efficacy end-point was biopsy-proven rejection during the first 6 months posttransplant. RESULTS: Biopsy-proven rejection was diagnosed in 48% of patients during the first 6 months after transplantation. The majority of rejection episodes were Banff grade I and IIA and were fully reversed with corticosteroid therapy. The median time to the first biopsy-proven rejection among patients who experienced this event during the first 6 months was 39 days. In 22 patients with delayed graft function, the proportion of patients with biopsy-proven rejection was 50% at 6 months. However in the first 2 weeks posttransplant, only 1 of 22 patients with delayed graft function developed biopsy-proven rejection. At 1 year, patient survival was 97% and graft survival was 96%. Only two grafts were lost secondary to rejection. At 1-year posttransplant, 62% of patients had received CNI for more than 7 days. At 1-year posttransplant, the mean serum creatinine in the nonrejectors with no CNI use was 113 micromol/L (95%, confidence interval [CI], 100.7 to 125.3 micromol/L) and in the rejectors or patients with CNI use (more than 7 days) was 154 micromol/L (95% CI, 135.0 to 173.0 micromol/L). In selected patients with rejection, analysis of circulating and intragraft lymphocytes revealed complete IL-2Ralpha saturation. CONCLUSIONS: This CNI avoidance study in immunologic low-risk patients, while only partially successful in preventing acute rejection, provided benefits to a sizable minority of patients who have not required chronic CNI therapy. However, wide acceptance of a CNI-sparing immunosuppression regimen may require a lower rate of acute rejection, possibly through the addition of a non-nephrotoxic dose of CNI. However, because complete IL-2Ralpha blockade was present during rejection, it can be assumed that alternative pathways, such as IL-15, may be responsible for the rejection; thus, the incorporation of non-nephrotoxic immunosuppressive agents, such as sirolimus, may provide a more strategic approach.