免疫抑制剂他克莫司在肾脏移植的应用

目的：对免疫抑制剂他克莫司在肾脏移植应用的进展进行综述。方法：综述近年来他克莫司在肾脏移植应用的有关文献。结果：他克莫司具有极强的免疫抑制作用，可以降低移植肾早期急性排斥反应的发生率，但现有临床资料显示它并不能延长移植肾的中长期存活期。和环孢素相比，他克莫司治疗的病人高血压和高脂血症的发生率较低，但神经并发症和糖尿病发生率高。结论：他克莫司是一种有效的免疫抑制剂，可用于肾脏移植的基础治疗和转换治疗，为肾脏移植免疫抑制治疗方案的制定提供了选择余地。     

免疫抑制剂对合并或不合并移植后糖尿病肾移植患者自测健康的影响

目的:研究环孢素、他克莫司对合并或不合并移植后糖尿病肾移植患者自测健康的影响。方法:根据是否合并有移植后糖尿病和服用的主要免疫抑制剂,将门诊肾移植患者分为合并糖尿病组、不合并糖尿病组、环孢素组、他克莫司组,应用自测健康评定量表(SRHMS)进行调查。结果:合并有移植后糖尿病肾移植患者生理、心理、社会健康比不合并糖尿病组明显偏低,二者有显著性差异(P<0.01);环孢素、他克莫司对合并移植后糖尿病的肾移植患者生理、心理、社会健康的影响无显著性差异;他克莫司对不合并移植后糖尿病的肾移植患者生理健康的身体症状与器官功能维度、心理健康的正向情绪维度方面较环孢素组得分高,二者有显著性差异(P<0.05)。结论:移植后合并糖尿病明显影响肾移植患者的自测健康;对不合并移植后糖尿病肾移植患者,服用他克莫司的比服用环孢素的有更好的生理健康和心理健康。     

移植后糖尿病的相关基因多态性研究进展

移植后糖尿病(posttransplantation diabetes mellitus,PTDM)是肾移植术后常见的并发症,是导致慢性移植肾功能障碍、移植物失功的主要原因,明显降低移植物和患者的存活率,其发病率为2%～53%。高龄、急性排斥、黑色人种、糖尿病家族史、肥胖、丙肝和巨细胞病毒感染是PTDM发病的高危因素,免疫抑制剂如环孢素和他克莫司的应用是导致PTDM的重要危险因素。与2型糖尿病(T2DM)相似,胰岛素分泌缺陷和胰岛素抵抗是PT-     

造血干细胞移植患者中伏立康唑与环孢素及他克莫司的相互作用

目的 通过监测造血干细胞移植患者伏立康唑和免疫抑制剂（环孢素A、他克莫司）的稳态血药谷浓度,探讨伏立康唑与环孢素及他克莫司之间的作用。方法 回顾性分析2016年6月-12月于宁波市第一医院血液科住院治疗的造血干细胞移植患者的伏立康唑、环孢素A以及他克莫司的稳态血药浓度数据。结果 伏立康唑与环孢素A合用后,环孢素A稳态谷浓度升高41.55%（P<0.05）,伏立康唑稳态谷浓度下降23.31%;伏立康唑与他克莫司合用后,他克莫司稳态谷浓度升高17.52%,伏立康唑稳态谷浓度下降29.45%（P<0.05）。结论 伏立康唑联用环孢素A或他克莫司时,建议诊疗过程严密监测免疫抑制剂及伏立康唑的血药浓度,以便及时调整治疗药物剂量,保障安全、有效、合理用药。     

1例肺移植的干燥综合征患者联用奈玛特韦/利托那韦与环孢素、他克莫司导致肾功能损伤

1例76岁右单肺移植的干燥综合征男性患者在新冠病毒感染后使用奈玛特韦/利托那韦治疗,导致合并使用的免疫抑制剂环孢素和他克莫司全血药物谷浓度升高,引起血肌酐升高,后通过停用环孢素、调整他克莫司剂量使他克莫司浓度维持在治疗浓度,血肌酐水平较前改善,患者好转出院。此病例可为临床安全用药实践提供参考。     

他克莫司致器官移植后新发糖尿病的发病机制研究进展

器官移植术后新发糖尿病是实体器官移植后的一个主要并发症,通常导致住院率和死亡率的升高。免疫抑制剂常被认为是导致器官移植术后新发糖尿病的主要因素,包括糖皮质激素、钙调磷酸酶抑制剂等。其中,钙调磷酸酶抑制剂对血糖的影响最大。他克莫司是从链霉菌属中分离出的发酵产物,是一种强效免疫抑制性大环内酯类抗生素,现广泛用于实体器官移植的免疫抑制剂。他克莫司对细胞免疫有选择性抑制作用,主要通过抑制白介素-2的释放,全面抑制T淋巴细胞的作用。通过查阅了大量的国外文献,本文分别从三个方面综述了他克莫司引起高血糖的机制,包括影响β细胞存活和复制、影响胰岛素分泌、影响外周组织的胰岛素利用。     

环孢素和他克莫司对肾移植后发生糖尿病的影响研究

目的:探讨免疫抑制药对肾移植患者术后发生移植后糖尿病(PTDM)的影响。方法:回顾性调查496例使用环孢素(CsA组)和他克莫司(FK506组)的肾移植患者,分析其血糖变化和PTDM发病情况,并比较PTDM患者(PTDM组)和非PTDM患者(对照组)环孢素和他克莫司剂量、血浓度差异。结果:CsA组和FK506组PTDM发病率分别为23.0%(69/300)和28.9%(28/98),差异无统计学意义(P=0.280),但FK506组患者术后3,6,12个月的空腹血糖均明显高于CsA组(P<0.05)。PTDM组患者术后第1,3,6,12,24个月的环孢素剂量和术后第1,3,6个月的环孢素血浓度均明显高于对照组(P<0.05)。两组患者的他克莫司剂量和血浓度均无明显差异(P>0.05)。结论:肾移植患者术后服用大剂量环孢素和他克莫司是导致移植后糖尿病发生的重要因素。     

免疫抑制剂他克莫司及其在肾移植中的应用

他克莫司 ( tacrolimus,FK50 6 )商品名为普乐可复 ( Prograf) ,是日本藤泽药品工业公司从筑波链霉菌 ( streptomyces tssukubaensis) No9993的发酵液中提取的一种 2 3元环大环内酯类免疫抑制剂 ,其本身有较弱的抗真菌活性。目前已广泛用于器官移植以及贝赫切特综合征、变应性皮炎、类风湿性关节炎、牛皮癣、多发性硬化病、糖尿病等自身免疫性疾病的治疗。因其作用强 ,不良反应较环孢素 A( Cs A)少而正在取代 Cs A成为器官移植术后首选的免疫抑制剂[1] 。1　作用机制他克莫司的作用机制目前已基本明确 [2 ,3 ]。他克莫司进入细胞后先与…     

他克莫司致器官移植后新发糖尿病的发病机制研究进展

器官移植术后新发糖尿病是实体器官移植后的主要并发症之一,免疫抑制常被认为是导致器官移植术后新发糖尿病的主要因素,包括糖皮质激素、钙调磷酸酶抑制剂等。其中,钙调磷酸酶抑制剂对血糖的影响最大。他克莫司是从链霉菌属中分离出的发酵产物,是一种强效免疫抑制性大环内酯类抗生素,现广泛用于实体器官移植的免疫抑制剂。他克莫司对细胞免疫有选择性抑制作用,主要通过抑制白细胞介素-2的释放,全面抑制 T 淋巴细胞的作用。通过查阅文献,从三方面综述了他克莫司引起高血糖的机制,包括影响β细胞存活和复制、影响胰岛素分泌、影响外周组织的胰岛素利用。     

他克莫司滴眼液对高危角膜移植术后免疫排斥反应的影响观察

摘要：目的:观察他克莫司滴眼液在预防高危角膜移植术后免疫排斥反应中的作用。方法:眼科行高危角膜移植术患者98例(100眼)随机分为他克莫司组49例(50眼)、环孢素组49例(50眼)。他克莫司组术后局部应用0.1%他克莫司滴眼液环孢素组局部应用1%环孢素A滴眼液起始给药剂量均为1滴,qid,根据患者恢复情况调整剂量,连续给药12个月。分别于术后1 2,12个月时进行复查,记录免疫排斥反应发生情况,比较两组患者术后12个月的视力、眼压变化及眼部体征,包括角膜水肿、角膜基质混浊、角膜上皮缺损、角膜新生血管程度。结果:术后1个月,两组免疫排斥反应发生率比较差异无统计学意义(P>0.05),术后12个月,他克莫司组免疫排斥反应发生率(4.00%)明显低于环孢素组(26.00%)(P<0.05)。他克莫司组术后12个月的角膜水肿评分、角膜基质混浊评分、新生血管分布评分均优于环孢素组(P<0.05);两组最佳矫正视力比较,差异无统计学意义(P>0.05)。两组术后眼压升高例数与眼压范围比较差异均无统计学意义(P>0.05),未见其他相关并发症出现。他克莫司组的不良反应发生率低于环孢素组(P<0.05)。结论:0.1%他克莫司滴眼液用于高危角膜移植术后免疫排斥反应安全、有效,其短期预防作用与环孢素A滴眼液相当,长期预防作用优于环孢素A滴眼液。     

Analysis of common type 2 diabetes mellitus genetic risk factors in new-onset diabetes after transplantation in kidney transplant patients medicated with tacrolimus

Purpose

New-onset diabetes after transplantation (NODAT) is a major complication after kidney transplantation. The risk factors for NODAT include the use of calcineurin inhibitors as part of the immunosuppressive regimen, among which tacrolimus has the most pronounced diabetogenic effect. Both NODAT and type 2 diabetes mellitus (T2DM) share several risk factors. Recent studies have identified a number of common genetic variants associated with increased risk of T2DM. Here we report the results of our study on the potential effect of single nucleotide polymorphisms (SNPs) previously associated with T2DM on the risk of NODAT in kidney transplant patients medicated with tacrolimus.

Methods

Seven SNPs in six genes known to increase the risk of T2DM in Caucasians were genotyped by means of TaqMan assays in 235 kidney transplant patients medicated with tacrolimus: rs4402960 and rs1470579 in IGF2BP2; rs1111875 in HHEX; rs10811661 upstream of CDKN2A/B; rs13266634 in SLC30A8; rs1801282 in PPARG; rs5215 in KCNJ11. The TCF7L2 rs7903146 SNP was also included in the multivariate analysis.

Results

None of the analyzed SNPs was significantly associated with the risk of NODAT. However, the IGF2BP2 rs4402960 T allele was present significantly more frequently among patients diagnosed with NODAT more than 2?weeks after transplantation (p?=?0.048). Mean (± standard deviation) number of the analyzed alleles tended to be lower in patients without NODAT (6.19?±?1.71) than in NODAT patients (6.58?±?1.1.95; p?=?0.09) and significantly lower compared to late-onset NODAT patients (7.03?±?1.88; p?=?0.018). Multivariate analysis confirmed the significance of ‘diabetogenic’ allele number in late-onset NODAT development [odds ratio (OR) 1.37, 95?% confidence interval (CI) 1.05–1.78; p?=?0.017]. Additionally, individuals carrying >7 of the analyzed ‘diabetogenic’ alleles were at a significantly higher risk of NODAT (OR 2.17, 95 % CI 1.18–3.99; p?=?0.015).

Conclusions

Complex analysis of genotypes increasing the risk of diabetes may lead to the identification of NODAT susceptibility predictors.     

Tacrolimus: a further update of its pharmacology and therapeutic use in the management of organ transplantation

Tacrolimus (FK-506) is an immunosuppressant agent that acts by a variety of different mechanisms which include inhibition of calcineurin. It is used as a therapeutic alternative to cyclosporin, and therefore represents a cornerstone of immunosuppressive therapy in organ transplant recipients. Tacrolimus is now well established for primary immunosuppression in liver and kidney transplantation, and experience with its use in other types of solid organ transplantation, including heart, lung, pancreas and intestinal, as well as its use for the prevention of graft-versus-host disease in allogeneic bone marrow transplantation (BMT), is rapidly accumulating. Large randomised nonblind multicentre studies conducted in the US and Europe in both liver and kidney transplantation showed similar patient and graft survival rates between treatment groups (although rates were numerically higher with tacrolimus- versus cyclosporin-based immunosuppression in adults with liver transplants), and a consistent statistically significant advantage for tacrolimus with respect to acute rejection rate. Chronic rejection rates were also significantly lower with tacrolimus in a large randomised liver transplantation trial, and a trend towards a lower rate of chronic rejection was noted with tacrolimus in a large multicentre renal transplantation study. In general, a similar trend in overall efficacy has been demonstrated in a number of additional clinical trials comparing tacrolimus- with cyclosporin-based immunosuppression in various types of transplantation. One notable exception is in BMT, where a large randomised trial showed significantly better 2-year patient survival with cyclosporin over tacrolimus, which was primarily attributed to patients with advanced haematological malignancies at the time of (matched sibling donor) BMT. These survival results in BMT require further elucidation. Tacrolimus has also demonstrated efficacy in various types of transplantation as rescue therapy in patients who experience persistent acute rejection (or significant adverse effect's) with cyclosporin-based therapy, whereas cyclosporin has not demonstrated a similar capacity to reverse refractory acute rejection. A corticosteroid-sparing effect has been demonstrated in several studies with tacrolimus, which may be a particularly useful consideration in children receiving transplants. The differences in the tolerability profiles of tacrolimus and cyclosporin may well be an influential factor in selecting the optimal treatment for patients undergoing organ transplantation. Although both drugs have a similar degree of nephrotoxicity, cyclosporin has a higher incidence of significant hypertension, hypercholesterolaemia, hirsutism and gingival hyperplasia, while tacrolimus has a higher incidence of diabetes mellitus, some types of neurotoxicity (e.g. tremor, paraesthesia), diarrhoea and alopecia. Conclusion: Tacrolimus is an important therapeutic option for the optimal individualisation of immunosuppressive therapy in transplant recipients.     

他克莫司在932例肾移植患者中的应用

目的 :评价他克莫司 (FK506)用于肾移植患者免疫抑制治疗的效果与安全性。方法 :对肾移植术后应用FK506的932例患者的资料进行回顾性分析。结果 :肾移植术后即应用FK506的547例患者 ,急性排斥反应发生率低 ;由环孢素A (CsA)改用FK506的385例患者 ,大部分排斥反应缓解 ,肝功能改善。FK506的主要不良反应有血糖升高和神经系统毒性。结论 :FK506是一种强效免疫抑制剂 ,还可用于CsA不能逆转排斥反应的挽救治疗。     

他克莫司在932例肾移植患者中的应用评价

目的 :评价他克莫司 (FK506)用于肾移植患者免疫抑制治疗的效果与安全性。方法 :对肾移植术后应用FK506的932例患者的资料进行回顾性分析。结果 :肾移植术后即应用FK506的547例患者 ,急性排斥反应发生率低 ;由环孢素A (CsA)改用FK506的385例患者 ,大部分排斥反应缓解 ,肝功能改善。FK506的主要不良反应有血糖升高和神经系统毒性。结论 :FK506是一种强效免疫抑制剂 ,还可用于CsA不能逆转排斥反应的挽救治疗。     

The role of tacrolimus in renal transplantation

Tacrolimus gained FDA approval for use in liver transplantation in 1994 and, approximately 3 years later, was approved for the prevention of acute rejection in kidney transplantation. Over the last decade tacrolimus has become the calcineurin inhibitor of choice for the prevention of rejection in renal transplantation. The objective of this study was to provide a review and update of the literature on the use of tacrolimus in renal transplantation. Numerous clinical trials have shown tacrolimus to be superior to cyclosporine in the prevention of acute rejection and recent trials have demonstrated superiority of tacrolimus over cyclosporine in terms of allograft survival. Post-transplant diabetes remains more common with tacrolimus than cyclosporine, despite lower doses of both tacrolimus and corticosteroids. A novel once-daily dosage form of tacrolimus has recently been developed and is approved for use in Europe. Tacrolimus remains an important immunosuppressant for the prevention of acute rejection. The prolonged-release formulation may improve compliance and possibly long-term outcomes.     

Tacrolimus: a further update of its use in the management of organ transplantation

Extensive clinical use has confirmed that tacrolimus (Prograf) is a key option for immunosuppression after transplantation. In large, prospective, randomised, multicentre trials in adults and children receiving solid organ transplants, tacrolimus was at least as effective or provided better efficacy than cyclosporin microemulsion in terms of patient and graft survival, treatment failure rates and the incidence of biopsy-proven acute and corticosteroid-resistant rejection episodes. Notably, the lower incidence of rejection episodes after renal transplantation in tacrolimus recipients was reflected in improved cost effectiveness. In bone marrow transplant (BMT) recipients, the incidence of tacrolimus grade II-IV graft-versus-host disease was significantly lower with tacrolimus than cyclosporin treatment. Efficacy was maintained in renal and liver transplant recipients after total withdrawal of corticosteroid therapy from tacrolimus-based immunosuppression, with the incidence of acute rejection episodes at up to 2 years' follow-up being similar with or without corticosteroids. Tacrolimus provided effective rescue therapy in transplant recipients with persistent acute or chronic allograft rejection or drug-related toxicity associated with cyclosporin treatment. Typically, conversion to tacrolimus reversed rejection episodes and/or improved the tolerability profile, particularly in terms of reduced hyperlipidaemia. In lung transplant recipients with obliterative bronchiolitis, conversion to tacrolimus reduced the decline in and/or improved lung function in terms of forced expiratory volume in 1 second. Tolerability issues may be a factor when choosing a calcineurin inhibitor. Cyclosporin tends to be associated with a higher incidence of significant hypertension, hyperlipidaemia, hirsutism, gingivitis and gum hyperplasia, whereas the incidence of some types of neurotoxicity, disturbances in glucose metabolism, diarrhoea, pruritus and alopecia may be higher with tacrolimus treatment. Renal function, as assessed by serum creatinine levels and glomerular filtration rates, was better in tacrolimus than cyclosporin recipients at up to 5 years' follow-up. CONCLUSION: Recent well designed trials have consolidated the place of tacrolimus as an important choice for primary immunosuppression in solid organ transplantation and in BMT. Notably, in adults and children receiving transplants, tacrolimus-based primary immunosuppression was at least as effective or provided better efficacy than cyclosporin microemulsion treatment in terms of patient and graft survival, treatment failure and the incidence of acute and corticosteroid-resistant rejection episodes. The reduced incidence of rejection episodes in renal transplant recipients receiving tacrolimus translated into a better cost effectiveness relative to cyclosporin microemulsion treatment. The optimal immunosuppression regimen is ultimately dependent on balancing such factors as the efficacy of the individual drugs, their tolerability, potential for drug interactions and pharmacoeconomic issues.     

Tacrolimus once-daily formulation: in the prophylaxis of transplant rejection in renal or liver allograft recipients

Tacrolimus once-daily (OD) is a new oral formulation of the well established immunosuppressant tacrolimus. Tacrolimus OD provided equivalent steady-state systemic tacrolimus exposure to that achieved with standard oral tacrolimus twice daily in stable renal and liver transplant recipients. The two formulations also provided broadly similar steady-state systemic exposure in de novo renal and liver transplant recipients. In a large, randomised, nonblind, multicentre, three-armed, noninferiority trial in de novo renal transplant recipients, the efficacy failure rates (primary endpoint) [any patient who died, experienced graft failure, had a biopsy-confirmed acute rejection or was lost to follow-up] of tacrolimus OD (14.0%) and standard tacrolimus (15.1%) were noninferior to that of ciclosporin (cyclosporine) microemulsion (17.0%) at 1 year, when each was given in conjunction with corticosteroids, mycophenolate mofetil and basiliximab induction. Data from a pharmacokinetic study suggests that tacrolimus OD has similar efficacy to standard tacrolimus in de novo liver transplant recipients over 6 weeks of treatment. In noncomparative 2-year trials, tacrolimus OD was effective in stable renal and liver transplant recipients converted to tacrolimus OD from standard tacrolimus. The overall tolerability profile of tacrolimus OD appears to be similar to that of standard tacrolimus in de novo and stable renal and liver transplant patients.     

高龄患者肾移植126例临床分析

目的 :探讨高龄患者肾移植的临床特点及四联免疫抑制疗法对临床治疗效果的影响。方法 :分析 1990年 1月至 2 0 0 0年 12月 12 5 1例肾移植中 12 6例高龄患者临床资料 ,将术后使用免疫抑制剂为三联疗法 (CsA +Aza +激素 )的 5 5例作组Ⅰ ;而使用四联疗法 (CsA +MMF +激素 +抗T细胞单抗 )的 71例作为组Ⅱ ,组Ⅱ中 4 7例患者术后使用 2周Wu -T3抗排斥治疗 ,另 2 4例应用抗IL- 2R抗体预防急性排斥反应。将两组的术后并发症、急性排斥率及 1年人 /肾存活率相比较 ,并与本院同期非高龄患者相同指标比较。结果 :高龄患者肾移植后心脑血管并发症以及感染发生率均明显高于非高龄患者。组Ⅰ和组Ⅱ患者的术后并发症发生率分别为 74 5 5 %和 38 0 3% ;急性排斥发生率分别为 12 73%和 4 2 3% ;1年人 /肾存活率分别为 81 82 % /78 18%和 97 18% /95 77%。结论 :高龄患者肾移植术后较容易发生心脑血管并发症及感染 ,使用新的四联免疫抑制疗法能有效地降低心脑血管并发症、感染和急性排斥反应的发生率 ,1年人 /肾存活率亦明显提高。     

Administration of Antithymocyte Globulin (Rabbit) to Treat a Severe,Mixed Rejection Episode in a Pregnant Renal Transplant Recipient

Pregnancy in solid organ transplant recipients carries numerous risks to the mother such as increased risk of rejection, gestational diabetes mellitus, and preeclampsia. The developing fetus is subjected to risks such as birth defects, preterm delivery, and low birth weight. Typically, these risks can be managed through intensive, multidisciplinary prenatal care and a proper immunosuppressive regimen. In the setting of rejection, however, little data are available to suggest safe and effective treatment of acute cellular rejection, antibody‐mediated rejection, or mixed rejection episodes in the pregnant solid organ transplant recipient. We describe the first case, to our knowledge, in which antithymocyte globulin (rabbit) was used to successfully treat a pregnant renal transplant recipient who experienced a mixed rejection episode. A 22‐year‐old, African American woman with stage 6 chronic kidney disease received a deceased donor renal transplant after undergoing hemodialysis for 3 years. Her maintenance immunosuppressive regimen at the time of transplantation consisted of tacrolimus, prednisone, and mycophenolate mofetil. Despite counseling efforts on the importance of having a planned pregnancy after kidney transplantation so that her immunosuppressive medications could be optimized, the patient became pregnant 12 months later; her mycophenolate mofetil was changed to azathioprine to reduce the risk of fetal deformities or death. Three months later, the patient was admitted for biopsy of her transplanted kidney and was evaluated for possible kidney rejection. After confirmation of a mixed 1B acute cellular rejection and antibody‐mediated rejection episode, the patient decided to pursue resolution of her rejection episode and continue the pregnancy despite the potential risks to the fetus. She was treated with high‐dose corticosteroids, intravenous immunoglobulin, plasmapheresis, and antithymocyte globulin (rabbit). Twenty‐nine months after transplantation, the patient was induced and gave birth to a healthy baby boy. Our patient's case offers unique insight into the potential management of a rejection episode requiring aggressive immunosuppressive therapy. Although potent immunosuppressive therapies were successfully used in our patient, further studies are needed to make definitive recommendations regarding the use of such therapies for treatment of rejection episodes in pregnant solid organ transplant recipients. The risks and uncertainties of treating rejection episodes should always be discussed with and understood by the patient before an informed decision is made.