老年患者肾移植术后他克莫司应用体会

老年患者肾移植以往采用环孢素治疗，但其影响老年血脂代谢，而新型免疫抑制药他克莫司对血脂代谢影响甚微。我院2000年9月应用他克莫司，本文对比观察老年和成年患者他克莫司用药情况。     

他克莫司替换环孢素A治疗肾移植后肝、肾功能损害的临床观察

19例用环孢素A(CsA)并相继出现肝和(或)肾功能损害的肾移植患者，用他克莫司(FK506)替换CsA治疗，取得了明显疗效，平均随访观察6个月，疗效稳定。     

他克莫司延缓移植性肾病进展的临床观察

目的:观察他克莫司(FK506)与霉酚酸酯(MMF)联合应用延缓移植性肾病肾功能进展的疗效。方法:选择肾移植术后肾功能异常,并经移植肾活检病理证实为慢性移植性肾病患者46例,将原环孢素A(CsA)切换为FK506,同时联合MMF和激素。FK506起始剂量0·08mg/(kg·d),MMF1.5g/d,监测切换12个月后血清肌酐、肾小球滤过率(GFR)[ml/(min·1·73m2)]、24h尿蛋白定量(g)变化。结果:切换为FK506治疗12个月后,平均血清肌酐由(293±45)μmol/L降至(198±24)μmol/L(P<0·05)。GFR由(39·77±2·35)ml/(min·1·73m2)提高至(49·87±3·17)ml/(min·1·73m2),24h尿蛋白定量由(4·8±0·8)g降至(1·9±0·7)g(P<0·05)。副作用包括高血糖(6例)、震颤(8例)、腹泻(4例)、白细胞减少(2例)、带状疱疹(1例)、骨痛(1例)。结论:FK506可以有效延缓移植肾病进展。     

CYP3A5基因型对肾移植术后他克莫司血药浓度及疗效的影响

目的:CYP3A5基因型影响他克莫司(FK506)血药浓度,本文分析CYP3A5基因型对肾移植术后排斥反应和毒性及不良反应的影响. 方法:67例肾移植术后采用FK506 霉酚酸酯 泼尼松免疫抑制方案,FK506初始剂量均为0.15 mg/(kg·d),1周后根据目标浓度调整FK506剂量.按CYP3A5基因型*1/*1型(n=16)、*1/*3型(n=22)和*3/*3型(n=29)将患者分为三组,比较12月内三组FK506药物剂量和浓度以及血药浓度/剂量比、急性排斥反应和毒性及不良反应发生率. 结果:肾移植术后7天和1月时三组患者药物浓度统计学差异明显(P＜0.01),3、6、12月无统计学差异;术后7天、1月、3月、6月、12月*3/*3型患者FK506血药浓度/剂量比显著高于*1/*3型和*1/*1型(P＜0.01);3个月内*1/*1型(43.8%)急性排斥反应的比例显著高于*1/*3型(9.1%)和*3/*3型(6.9%)(P＜0.01),3～12月分别为0%、4.5%、6.9%(P＞0.05).术后3个月内*3/*3型组高血糖、神经及肾毒性等不良反应显著高于*1/*1型. 结论:由于CYP3A5基因多态型的影响,*1/*1型组在肾移植早期难以达到有效FK506目标血药浓度,使该组3个月内的急性排斥反应发生率明显升高,不合适采用目前FK506的初始剂量方案作为早期的抗排斥反应方案;*3/*3型组FK506血药浓度明显升高,使术后3个月内该组毒性及不良反应发生率也明显升高.因此,以CYP3A5基因多态性作为FK506的剂量调整依据较为合理,可以使不同CYP3A5基因型的肾移植患者在术后早期迅速达到6～10 ng/ml的目标治疗浓度,既使*1/*1型患者早期急性排斥反应的发生率下降,又能使*3/*3型患者的药物不良反应减少.     

他克莫司与环孢素A对肾移植患者霉酚酸酯血药浓度影响的比较

目的:观察肾移植患者他克莫司(FK506)联用霉酚酸酯(MMF)方案和环孢素A(CsA)联用MMF方案术后6月血浆霉酚酸(MPA)浓度的变化,对比两组之间MPA浓度和MMF剂量的差别。方法:51例首次肾移植患者根据免疫抑制方案分为FK506组(n=20)和CsA组(n=31),两组MMF使用方法相同。采用高效液相色谱法测定MPA浓度,用MPA药物曲线下面积(MPAAUC0~12)反映MPA浓度,测定移植术后15天、30天、3月和6月MPAAUC0~12。结果:与CsA组相比,FK506组MPAAUC0~12在15天和1月时较高[15天:(56·0±21·1)vs(33·2±8·9)mg/L·h;1月:[(54·0±12·5)vs(38·5±12·9)mg/L·h,P=0·01],而MMF剂量无明显差别;3月和6月时两组之间MPAAUC0~12无差别,但FK506组MMF剂量较CsA组低[3月:(1·10±0·29)g/dvs(1·27±0·25)g/d,P<0·05,6月:(1·02±0·18)g/dvs(1·22±0·10)g/d,P<0·05]。两组在4个时间点上体重,血红蛋白、血清肌酐和白蛋白水平均无差别。结论:FK506与CsA相比,联用同样剂量的MMF在术后1月内其MPA浓度较高,而术后3月起可减低MMF剂量而达到同样的MPA浓度,提示在临床实践中要注意MMF剂量个体化。     

他克莫司联合霉酚酸酯治疗肾移植术后早期难治性急性体液性排斥的疗效

目的:前瞻性观察他克莫司(FK506)联合霉酚酸酯(MMF)作为肾移植术后急性体液性排斥(AHR)的挽救治疗的有效性,为中国肾移植受者AHR的救治寻找一个可行的方案。方法:160例肾移植受者,根据临床表现、组织学特征、移植肾组织C4d染色符合AHR诊断标准者11例,所有患者在排斥发生时均立即应用FK506联合MMF治疗,除激素冲击外,所有患者均不接受免疫吸附、血浆置换等其他治疗方案,需要透析的患者给予连续性血液净化(CBP)治疗。结果:11例符合AHR的诊断,均表现为急剧的移植肾功能下降,治疗上无一例对冲击治疗有反应,所有患者移植肾组织肾小管周围毛细血管(PTC)部位均有弥漫的C4d沉积,接受FK506联合MMF治疗初期,所有患者仍表现为移植肾功能的进行性减退,其中10例接受了CBP治疗,在治疗4～26(16.19±6.16)天后,11例患者均出现尿量增多,移植肾功能逐渐恢复正常,平均随访12.8个月,移植肾功能均保持稳定。结论:在中国人中,FK506联合MMF能够有效逆转肾移植术后早期发生的难治性AHR,并且副作用少,经济安全,是适合中国人特点的一种治疗方案。     

肾移植患者他克莫司血药浓度的影响因素

目的:研究除CYP3A5基因背景外,影响他克莫司(FK506)血药浓度的临床因素,为更合理的应用免疫抑制剂提供帮助。方法:观察肾移植术后常规使用FK506 霉酚酸酯 强的松三联免疫抑制治疗的CYP3A5*3/*3型患者共93例,记录术后7天(±2天)、1个月、3个月、6个月和10~12个月时的FK506全血谷浓度,并记录当天(术后1个月至1年的时间点可放宽至隔日)的各项临床观察指标,包括性别、年龄、体重、FK506剂量、激素剂量、血红蛋白、血清总胆红素、谷丙转氨酶、肌酐、白蛋白、总胆固醇、三酰甘油、葡萄糖等。采用单因素回归的方法分析各项临床指标对FK506血药浓度的影响。结果:FK506的血药浓度随术后时间逐渐降低,浓度/剂量比随着术后时间的延长逐渐升高,CYP3A5*3/*3型患者术后7天、1个月、3个月、6个月和10~12个月时浓度/剂量比分别为(103.0±47.1)、(117.0±76.7)、(150.1±86.6)、(138.5±47.3)、(181.0±159.1)(ng.ml)/(mg.kg)。除术后时间外,性别、年龄、血红蛋白、谷丙转氨酶、胆红素、血肌酐水平以及激素用量等因素也在术后不同时间段对FK506的体内吸收、代谢具有一定影响。女性患者的浓度/剂量比在术后7天显著低于男性患者[(108.1±44.6)vs(84.3±37.2)(ng.ml)/(mg.kg),P<0.05],而老年患者高于年轻患者(术后7天、1个月及3个月分别r=0.27,0.26,0.29,P<0.01)。激素用量也显著影响FK506血药浓度,在术后前半年激素用量与浓度/剂量比呈现显著的负相关关系(术后1、3、6个月分别r=-0.31,-0.35,-0.25,P=0.002,0.0005,0.03)。血红蛋白、谷丙转氨酶、胆红素、血肌酐水平等与浓度/剂量比呈现出一定的正相关关系。结论:在肾移植术后,FK506的药代动力学随时间而改变,根据各种临床因素对FK506血药浓度的影响,合理使用药物,有利于移植后成功的免疫抑制治疗。     

他克莫司治疗移植肾慢性排斥的初步临床观察

目的：探讨他克莫司（FK506）、环孢素A（CsA)治疗移植肾慢性排斥（CR)的可行性及安全性。方法：40例同种异体肾移植患者肾功能减退经病理证实为CR，随机分为CsA切我为FK506组20例、继续使用CsA组20例。观察各组移植肾功能、肾小球滤过率、蛋白尿、血压、血脂变化及急性排斥（AR）发生率，治疗后随访12个月。结果：追踪12个月，FK506组16例移植肾功能稳定（80％）；3例行血液透析治疗，1例死亡，人存活率95％。CsA组15例移植肾功能稳定，3例行血液透析治疗，逆转成功率75％；2例死亡，人存活率90％。结论：FK506可以延缓慢性移植物失功。FK506的使用是安全和有效的。     

他克莫司在移植肾功能延迟恢复患者中的临床应用

目的:探讨他克莫司(FK506)在移植肾功能延迟恢复(DGF)患者中的临床应用价值与合理用药方案.方法:17例DGF患者临床结合移植肾病理确立诊断.肾移植术后早期均接受三联(FK506 MMF Pred)免疫抑制药物治疗至少3个月.不用任何生物制剂诱导治疗,观察临床疗效及副作用.结果:17例患者无一例死亡或摘除移植肾.15例在术后第2～3天开始血液透析(HD)/连续性血液净化(CBP)治疗,2例在术后第5天开始HD/CBP.HD/CBP治疗2～15次后,10例在术后7天内停止,7例在术后7天后仍需CBP治疗,最长1例在术后第18天停止透析.FK506治疗后8～17天患者尿量开始明显增多,SCr开始明显下降.17例患者诊断DGF时SCr水平在489～1028μmol/L,14例在治疗后8～17天降至＜200μmol/L,另3例中2例SCr分别在术后第24天,28天降至＜200μmol/L.副作用主要是腹泻(3例),血糖升高(1例)及手颤,肢体麻木(4例),但未出现CMV等严重感染病例.结论:FK506 MMF Pred三联免疫抑制治疗方案治疗肾移植DGF安全有效,可作为肾移植术后DGF患者的过渡治疗方法之一.     

肝移植病人术后他克莫司剂量的个体化调整

目的了解肝移植后肝脏功能和血药浓度的共同检测对指导个体化抗排异减量的意义。方法动态随访检测15例肝移植病人肝功能与他克莫司（FK506）血药浓度,根据检测结果进行FK506剂量的个体化调整。结果15例病人在联合检测行FK506个体化的减量过程中均获得成功。结论肝移植病人术后,通过肝脏功能和FK506血药浓度的共同检测,可以指导抗排异药物达到合理、有效、个体化的调整使用,值得临床推广。     

Optimal blood concentration of cyclosporine among Iranian kidney transplant recipients

Introduction. Clinical information concerning cyclosporine dose reduction in Iranian kidney transplant recipients is limited. There are data in Asian, Caucasian, and Iranian ethnic kidney transplant recipients that recommend the trough level (C0) and 2-hour postdose level (C2) of cyclosporine may be different. Our aim was to determine therapeutic levels of C0 and C2 at different time after transplantation among Iranian transplant patients. Materials and Methods. Blood concentrations of cyclosporine were assessed in 4419 samples of kidney transplant recipients between 2008 and 2010. The patients were divided into 3 groups according to the time of laboratory studies (< 3 months, 4 to 12 months, and > 1 year after transplantation). Both univariable and multivariable analyses were performed to determine the correlation between cyclosporine blood levels and serum creatinine. Results. A total of 1270 kidney transplant patients with 4419 blood samples enrolled. The mean age of the donor was 28 ± 6 years (range, 6 to 64 years) and 82.6% were men and 17.4% were women. In the subset of patients with serum creatinine values of at least 1.6 mg/dL for men and 1.4 mg/dL for women, we determined C0 and C2 levels between therapeutic and undertherapeutic creatinine ranges at 3 different time interval after transplantation, as follows: the first 3 months, 230 ng/mL to 240 ng/mL and 725 ng/mL to 775 ng/mL; 4 to 12 months, 135 ng/mL to 156 ng/mL and 535 ng/mL to 612 ng/mL; and after 1 year, 95 ng/mL to 120 ng/mL and 420 ng/mL to 479 ng/mL for C0 and C2, respectively. Conclusions. The present study suggests that the cyclosporine levels for Iranian kidney transplant patients are lower compared to the recommended levels in western countries.     

Conversion of twice-daily to once-daily tacrolimus is safe in stable adult living donor liver transplant recipients

BACKGROUND: Once-daily extended-release tacrolimus(Tac-OD) has been introduced as a useful therapeutic option to increase patient adherence to immunosuppressive therapy. This study aimed to evaluate the safety, efficacy and immunosuppressant adherence of conversion from twice-daily tacrolimus(Tac-BID) to Tac-OD in stable adult living donor liver transplant(LDLT) recipients in a single institution.METHODS: Between February and May 2013, Tac-BID was converted to Tac-OD in recipients followed up for at least 12 months after transplantation and without previous rejection episodes. The switching policy was based on a dose ratio of 1:1 with dose adjustment target trough levels at 3-5 ng/m L. Tacrolimus trough levels, laboratory parameters, metabolic disorders, and adverse events were assessed.RESULTS: A total of 229 patients were enrolled in the study. The median age at conversion was 53 years(range 31-73). The median transplant duration was 35.3 months(range 12.0-95.4). During a median follow-up of 13.5 months after conversion, 9 patients returned to Tac-BID because of adverse events. No acute rejection episodes were observed. Of 214 patients still on Tac-OD at 12 months, 12(5.6%) received a reduced dose and 95(44.4%) required an increased dose over baseline. Overall adherence was 82.2% at the end of follow-up.CONCLUSION: The conversion from Tac-BID to Tac-OD with similar target trough levels after conversion is safe and effective for long-term stable LDLT patients.     

Conversion of cyclosporine A to tacrolimus following heart transplantation

BACKGROUND: Cyclosporine A (CyA) is ususally the immunosuppressive drug of choice in organ transplantation; however, some side effects have limited its use. Tacrolimus is a novel immunosuppressive drug that is more potent than CyA, and has been used as a rescue agent following heart transplantation when the use of CyA is undesirable or inefficient. PATIENTS AND METHODS: Since 1996, 14 heart transplant recipients under CyA were switched to tacrolimus therapy, for refractory rejection or intolerance, to conventional immunosuppression. RESULTS: After a mean of 35+/-7 months of treatment, tacrolimus was substituted for CyA therapy. The reason for substitution was refractory rejection in six patients, gingival hypertrophy in five patients, hypertrichosis in one patient, severe arterial hypertension in one patient and hepatotoxicity in one patient. Five patients underwent a successful rescue therapy and one patient died of refractory rejection despite the use of tacrolimus. All patients with CyA side effects recovered with tacrolimus. After conversion from CyA to tacrolimus, the number of episodes of acute rejection decreased from a mean of 0.42+/-0.17 to 0.14+/-0.09 episodes/patient/month under CyA and tacrolimus therapy (P=0.11), respectively. The mean dose of prednisone was 0.18+/-0.06 mg/kg/day before compared with 0.06+/-0.01 mg/kg/day after conversion from CyA to tacrolimus (P=0.09). Creatinine serum levels averaged 124+/-7 mmol/L under CyA treatment compared with 113+/-7 mmol/L with tacrolimus therapy (P=0.002). CONCLUSION: In patients with refractory rejections or intolerance to CyA after heart transplantation, conversion to tacrolimus-based immunosuppression is safe and effective.     

Changes in lipid metabolism and effect of simvastatin in renal transplant recipients induced by cyclosporine or tacrolimus

Hyperlipidemia is frequently developed following renal transplantation and results in worsening of the patient's prognosis. In study 1, the effects of immunosuppressants, cyclosporine (CsA) and tacrolimus on serum lipids were compared in-patients undergoing renal transplantation. The study included 32 cases of renal transplantation recipients who randomized to the CsA treatment group (15 patients) and the tacrolimus group (17 patients). Before and 1 month after the transplantation, we assessed the serum lipid levels, apolipoprotein levels, the concentrations of cholesterol in the respective lipoprotein fractions and the enzyme activities related to lipid-metabolism. The serum lipid levels in both groups were significantly increased at 1 month after renal transplantation. In the CsA group, there were significant increases in cholesterol contents in very-low-density lipoprotein (VLDL), LDL2 and HDL2 fractions, whereas, in the tacrolimus group, cholesterol content was increased in VLDL and HDL2 fractions. In study 2, 1 month after renal transplantation, 19 patients with hypercholesterolemia (total cholesterol (TC) >200 mg/dl) and hypertriglyceridemia (triglyceride (TG) >150 mg/dl) were treated with simvastatin 5-10 mg/day for 6 months. Simvastatin treatment significantly decreased serum TC (240+/-29-200+/-22 mg/dl, P<0.001), low-density lipoprotein cholesterol (LDL-C; 114+/-20-99+/-17 mg/dl, P<0.05) and TG levels (217+/-103-130+/-38 mg/dl, P<0.01). In addition, there were significant decreases in very-low-density lipoprotein cholesterol (VLDL-C; 53+/-20-34+/-15 mg/dl, P<0.001). The Cmax and AUC of simvastatin were increased about eight-fold, when simvastatin was given in combination with CsA. In contrast, no significant changes in simvastatin levels were observed when combination with tacrolimus. Although simvastatin levels were increased with CsA, there were no abnormal changes in renal and liver functions, creatinine phosphokinase (CPK) levels or in incidence of adverse effects.     

Coronary endothelial vasomotor function and vascular remodeling in heart transplant recipients randomized for tacrolimus or cyclosporine immunosuppression.

OBJECTIVES: This study aimed to compare changes in coronary endothelial function, systemic endothelin-1 (ET-1) levels, and vascular remodeling in heart transplant recipients randomized to cyclosporin A (CyA) or tacrolimus (Tac) immunosuppression. BACKGROUND: Functional endothelial abnormalities and intimal thickening are sensitive measures of early cardiac allograft vasculopathy (CAV). METHODS: The randomized, prospective study was performed in two groups of 22 patients, maintained on Tac or CyA and mycophenolate mofetil immunosuppression, 1 and 12 months after heart transplantation. We investigated epicardial luminal diameter, coronary blood flow velocity, and ET-1 plasma levels at 1 and 12 months after transplantation. Structural coronary alterations were determined using intravascular ultrasound. RESULTS: Epicardial vasomotor function at baseline and during follow-up was comparable between the groups. Deterioration of microvascular endothelial function during follow-up was significantly enhanced in the CyA versus Tac group (p < 0.05). Circulating ET-1 concentration increased in the CyA group but significantly decreased over time in the Tac group (CyA +17% vs. Tac -25%; p < 0.05). The time-dependent increase in mean intimal area was significantly enhanced in the CyA versus Tac group, whereas the vessel area significantly increased during follow-up in the Tac compared with the CyA group. CONCLUSIONS: Epicardial endothelial function is comparable between CyA- and Tac-treated patients. Microvascular endothelial function deteriorates more in CyA-treated patients, a finding that correlates with enhanced ET-1 concentration and an increased intimal area during follow-up. The mean vessel area in the Tac group increased over time, indicating positive vascular remodeling. Tac is superior to CyA with respect to microvascular endothelial function, intimal thickening, and vascular remodeling.