多瘤病毒相关性肾病

病史摘要病史患者男性,29岁,“肾移植术后11个月,血肌酐升高1月余”于2007-05-24入院。患者于2006-06-23因慢性肾功能衰竭尿毒症期行同种异体肾移植术。手术过程顺利,术后血肌酐(SCr)恢复正常,先后以环孢素(CsA) 霉酚酸酯(MMF) 泼尼松(Pred)或普乐可复(FK506) MMF Pred抗排斥治     

不同免疫抑制方案对肾移植术后糖尿病发病率的影响

为探讨不同免疫抑制方案对肾移植术后糖尿病(PTDM)发病率的影响，根据不同免疫抑制方案把429例肾移植患者分为三组，定期监测患者用药情况、生化指标、环孢素A(CsA)浓度、FK506浓度，随访时间至少6个月。结果：PTDM发病率为强的松 CsA 硫唑嘌呤(1组)11．8％，强的松 霉酚酸酯(MMF) CsA(2组)6．4％，强的松 MMF FK506(3组)4．2％，三组之间存在显著差异，2组排斥反应率和平均激素用量明显低于1组。认为肾移植术后不同免疫抑制方案下PTDM的发病率不同，小剂量CsA或FK506联合MMF的免疫抑制方案可以降低PTDM的发生。     

肾移植术后肝功能异常的临床分析

目的探讨肾移植术后免疫抑制剂治疗引起肝损害的临床特点和防治措施。方法对24例肾移植术后出现肝功能异常的病例进行临床资料的回顾性分析。发生肝功能损害时,停用环孢菌素A(CsA)、硫唑嘌呤(Aza),采用他克莫司(FK506)、霉酚酸酯(MMF)和泼尼松三联用药,常规保肝及利胆治疗。结果24例肾移植患者肾功能全部恢复正常,未发生急性排斥反应,治疗8~12周后,全部患者肝功能恢复正常。结论FK506和MMF用于肾移植术后早期出现肝功能损害的患者是安全的。     

肾移植术后“爬行肌酐”患者使用他克莫司替换环孢素A疗效观察

目的观察他克莫司（FK506）替换环孢素A（CsA）逆转肾移植术后“爬行肌酐”的可行性。方法24例肾移植患者术后均采用以CsA为主的三联免疫抑制方案，出现“爬行肌酐”后用FK506替换CsA。观察替换前后的移植肾功能变化，同时监测血压、抗高血压药物分值（AHS值）、血糖和血脂的变化，随访12个月。结果“爬行肌酐”患者采用FK506替换CsA后，移植肾功能较替换前明显好转，血肌酐下降明显（P〈0．05）；同时降低了血脂水平，并减少降脂药物及抗高血压药物的使用。结论肾移植术后“爬行肌酐”患者采用FK506替换CsA的治疗方案可以有效地改善或者稳定移植肾的功能。     

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。     

他克莫司作为急性加速性排斥反应补救治疗的临床观察--附5例报道

目的：探讨他克莫司(FK506)治疗急性加速性排斥反应(AAR)的疗效及副作用。方法：5例患者在肾移植术后5天内经移植肾活检发现均存在血管内膜炎、小管炎及小球炎。将患者环孢素A(CsA)切换为FK506，并给予行连续性静脉．静脉血液滤过(CVVH)。结果：FK506起始剂量为1．5mg/(kg．d)，调整剂量，使FK506谷值浓度维持在5～15ng／ml之间。在给予：FK506治疗10～19天后患者血肌酐(SCr)开始下降，治疗20～39天后SCr降至正常或稳定在134～157μmol／L之间。患者少尿过程中均给予CBP治疗，无一例出现心衰、肺水肿及电解质紊乱。3例患者分别在间隔6、6、2个月后行重复活检术，组织学结果提示肾小球炎、间质小管炎及血管内膜炎较前有明显好转。结论：FK506联合CVVH治疗能有效逆转移植肾AAR。     

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。     

环孢素A切换成他克莫司对慢性移植肾肾病患者血脂的影响

目的:探讨以他克莫司(FK506)切换环孢素A(CsA)对慢性移植肾肾病(CAN)患者血脂和移植肾功能的影响。　方法:选择我院接受尸肾移植、移植时间在 1年以上,经临床和移植肾活检证实为CAN的患者 50例,男 41例,女 9例,平均年龄(36 .7±12 .7)岁,均采用CsA 硫唑嘌呤 (Aza)或霉酚酸酯 (MMF) 强的松免疫抑制方案治疗。根据是否将CsA切换为FK506将入选病例分为两组:一组继续采用原方案治疗 (CsA组,n=28);另一组切换为FK506 Aza/MMF 强的松方案治疗(FK506组,n=22)。观察两组 12个月时的血脂 [包括总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白(LDL)、高密度脂蛋白 (HDL) ]和肾功能的变化。　结果:观察 12个月时:①FK506组血TC、TG、LDL均显著低于CsA组[分别为 (5 ..2±0 75)mmol/Lvs(6 .6±1 .4)mmol/L,P<0 01; (1. 9±0 .86)mmol/Lvs(3. 0±1 .4 )mmol/L,P<0 .01; ( 3 .0±0 .72 ) mmol/Lvs( 3. 7±0. 93 ) mmol/L,P<0 01 ];②FK506组平均血肌酐水平显著低于CsA组 [ ( 210 .2 ± 65. 02 )μmol/Lvs( 150. 8 ± 54. 56 )μmol/L,P<0. 01 ],FK506的移植肾失功率显著低于CsA组(P<0 .05);③FK506组尿蛋白水平显著低于CsA组 [ (0. 9±0. 6)g/24hvs(1 1±0. 8)g/24h,P<0 .01) ],血清白蛋白水平高于CsA组[ (49±10 .2)g/Lvs(     

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。     

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.     

FK506和环孢素A对肾移植患者血脂的影响

目的研讨FK506和环孢素A(CsA)对肾移植术后患者脂质代谢的影响。方法对我们近三年以FK506或CsA为主要免疫抑制剂的肾移植患者术后1年血脂变化进行统计及初步分析,明确两组患者脂质代谢的不同之处。结果CsA组(198例)术后患者血脂增高的比例明显高于FK506(36例,17.17％ vs 2.78％,P＜0.05)且CsA组血脂增高患者的手术前、后血脂水平亦有明显差异(4.3±1.2mmol／L vs 4.9±1.6mmol／L,P＜0.01)。结论肾移植患者术后应用FK506比CsA可以有效降低高脂血症的发病率。     

肾移植受者FK506治疗窗浓度的临床观察

目的：寻求适合国人肾移植受者ＦＫ５０６理想治疗窗浓度范围。方法：应用ＥＬＩＡ法测定口服ＦＫ５０６ １２ｈ后全血谷浓度。结果：统计资料显示，术后第１个月应为１２～１８μｇ／Ｌ，第２～３个月为８～１３μｇ／Ｌ；第４个月后为５～８μｇ／Ｌ。结论：此浓度范围既能达到满意的免疫抑制效果，又有减少排斥反应和ＦＫ５０６肾毒性。     

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。     

Mycophenolate mofetil and FK506 have different effects on kidney allograft fibrosis in rats that underwent chronic allograft nephropathy

ABSTRACT: BACKGROUND: Tacrolimus (FK506) is associated with renal fibrosis in long-term use. Mycophenolatemofetil (MMF) can also inhibit or attenuate the progression of renal fibrosis. This study aimed to determine the different effects of FK506 and MMF on fibrosis-associated genes in the kidney in rats that underwent chronic allograft nephropathy (CAN). METHODS: Fisher (F344) kidneys were orthotopically transplanted into Lewis rat recipients. All recipients were given Cyclosporin A (CsA) 10 mg/kg-1.d-1 x 10 day and were then randomly divided into three oral treatment groups (n = 9 in each group): (1) the vehicle group was given vehicle orally; (2) the FK506 group was given 0.15 mg/kg-1.d-1 FK506; and (3) the MMF group was given 20 mg/kg-1.d-1 MMF. At 4, 8, and 12 weeks post-transplantation, serum creatinine (SCr), collagen deposition, Connective tissue growth factor (CTGF), alpha smooth muscle actin (alpha-SMA) and E-cadherin expressions were determined and hematoxylin-eosin (HE) and Periodic acid-Schiff (PAS) stains were performed. RESULTS: Renal function progressively deteriorated and showed typical CAN morphology in the vehicle and FK506 groups, while SCr and inflammatory infiltration (Banff score) showed a significant decrease in the MMF group after 8 weeks post-transplantation compared with those in the other groups (p < 0.05). Furthermore, expression levels of CTGF and alpha-SMA in the MMF group were significantly reduced, and the down-regulated expression of E-cadherin was abated (p < 0.05). CONCLUSIONS: MMF showed favorable effects on renal interstitial fibrosis, thus efficiently retarding the progression of CAN.     

Cyclosporin a and fk-506 in inhibition of rat ito cell activation in vitro

Ito cells are the primary matrix-producing cells in the liver. In hepatic fibrosis in vivo or culture on plastic, these cells undergo activation, a process characterized by cell proliferation, fibrogenesis, and smooth muscle α-actin expression. The cytosolic-binding proteins of cyclosporin A (CsA) and FK506 accelerate folding of various proteins including collagen and become inactivated by binding to those agents. CsA is shown to inhibit collagen synthesis in cultured fibroblasts. These findings prompted us to examine the effect of cyclosporin A and FK506 on Ito cell activation. CsA and FK506 reduced DNA synthesis in a dose-related manner, to 26% and 45% of controls at 5 μmol/L, respectively, without affecting total protein synthesis. CsA reduced collagen synthesis in a dose-related manner, to 70% of controls at 5 μmol/ L without affecting noncollagenous protein synthesis, whereas FK506 changed neither collagen synthesis nor noncollagenous protein synthesis. Moreover, smooth muscle α-actin expression was reduced by 0.5 μmol/L CsA, but not by FK506. CsA merits consideration for the therapy of hepatic fibrosis. FK506 may also be a candidate for such therapy through inhibitory action on Ito cell proliferation.     

环孢霉素A治疗Ⅴ型狼疮性肾炎的研究

目的Ⅴ型狼疮性肾炎(WHO分型LN-V型)主要表现为蛋白尿或肾病综合征,本文分析环孢霉素A(CsA)对LN-V型的疗效。方法分析16例经肾活检明确诊断为LN-V型患者CsA治疗的近期及远期的治疗反应。16例患者治疗前均处于肾病综合征状态。治疗方法CsA 5 mg／(kg·d)诱导治疗3个月,以后每月减1mg／(kg·d)直至2mg／(kg·d)维持,CsA治疗同时采用强的松维持。总疗程12～24月,随访时间18月～4年。结果诱导期CsA平均血药谷浓度为185±30.8μg／L。经CsA治疗3个月后,4例(25％)缓解,6例(37.5％)部分缓解。治疗6个月,平均尿蛋白为0.3±0.4g／24h,血清白蛋白为40.7±4.9g／L。12例(75％)缓解,3例(18.7％)部分缓解,1例(6.3％)无效,总有效率达93.7％。8例伴有镜下血尿者有6例血尿消失,血清学指标也有所改善。CsA停药两年后有5例(41.7％)复发。CsA治疗1月内81.2％患者(13／16)血尿素氮和肌酐有一过性升高。其它副作用有血压升高(6／16),少数患者出现多毛及齿龈增生。3例重复肾活检未见条索状间质纤维化或典型CsA导致的小动脉病变。结论本研究证实CsA治疗降低V型LN蛋白尿短期内疗效肯定,且CsA≤5mg／(kg·d)用于肾功能正常LN患者未出现严重肾毒性。但停用CsA后复发率高。CsA治疗V型LN的长期疗效及安全性有待严格的临床对照研究和随访。     

Conversion to mycophenolate mofetil for modulating recurrent hepatitis C in liver transplant recipients

BACKGROUND: The aim of this study was to analyze the influence of cyclosporine A (CsA) taper in conjunction with mycophenolate mofetil (MMF) therapy on recurrent hepatitis C virus (HCV) in liver transplant patients. PATIENTS AND METHODS: Nineteen liver recipients with serologically and morphologically confirmed recurrent HCV were included in this study. After MMF introduction up to a maximum dose of 2000 mg/day, CsA dose was significantly tapered. In the control group immunosuppression remained unchanged. Allograft function and morphology, viral loads, and renal function were analyzed continuously. RESULTS: MMF treatment was well tolerated without risk of rejection. Allograft fibrosis progressed in 6 patients of the MMF group (66.6%) and none (0%) of the controls at 12-month biopsy (P=0.005). Moreover, aminotransferases and viral loads increased slightly in the MMF-treated patients. Renal function improved significantly (serum creatinine: 239.3+/-90.2 micromol/L vs. 175.8+/-46.0 micromol/L; P=0.008) in the treatment group, while deteriorating (serum creatinine: 156.8+/-44.6 micromol/L vs. 214.8+/-120.1 micromol/L; P=0.06) in the controls. CONCLUSION: MMF introduction allows a safe CsA taper in HCV-positive liver transplant patients and results in significant improvement of renal function. However, there seems to be a risk of marked progression of HCV-induced allograft injury.     

Secretory defects induced by immunosuppressive agents on human pancreatic beta-cells

Despite the considerable interest for islet and pancreas transplantation, remarkably little is known about the direct effects of immunosuppressive drugs on human β-cell function. We measured different insulin secretory parameters and insulin gene expression of human islets cultured for 5 days in the presence of mycophenolate mofetil (MMF), cyclosporin A (CsA), tacrolimus (FK506) or a mixture of 3 cytokines. Basal insulin release after exposure to cytokines and FK506 was significantly higher than in control islets. Responsiveness to an acute glucose stimulus did not differ significantly between control and treated islets. However, absolute incremental insulin responses (Δ-AUCs) of islets exposed to cytokines or FK506 were significantly higher compared to islets exposed to CsA or MMF, mainly because of the higher basal release. Indeed, maximal over basal release (stimulation index, SI) tended to be lower in islets exposed to FK506 than in control islets. Insulin gene expression was significantly reduced only in islets exposed to CsA. FK506 was, among those tested, the immunosuppressive drug that most profoundly altered the normal insulin secretory pattern of human β-cells, whereas CsA was the only inhibiting insulin gene expression. Although the abnormalities induced by the immunosoppressive drugs utilized in this study were modest, these in vitro data are consistent with the reported in vivo diabetogenicity of CsA and FK506 and point to MMF as the ideal immunosuppressive agent from a pancreatic β-cell point of view. Received: 26 November 2001 / Accepted in revised form: 19 June 2002 Correspondence to A.M. Davalli     

Cyclosporine A, FK-506, 40-O-[2-hydroxyethyl]rapamycin and mycophenolate mofetil inhibit proliferation of human intrahepatic biliary epithelial cells in vitro

AIM: To investigate the effect of cyclosporine A (CsA),FK-506, and mycophenolate mofetil (MMF) and 40-0-[2-hydroxyethyl]rapamycin (RAD) on proliferation of human intrahepatic biliary epithelial cells (BECs)in vitro.METHODS: BECs were isolated from six human liver tissuespecimens with the immunomagnetic separation method and treated with different concentrations of CsA, FK-506, RAD, and MMF in vitro. Proliferation of the cells was measured by MTT assay at 24 and 48 h after treatment, respectively. One-way analysis of variance was used to analyze the results. Expression of CK 19in BECs was monitored by flow cytometry and Western blot.RESULTS: Six lines of BECs were established. They survived for 4-18 wk in vitro. Flow cytometry analysis showed that these cells always expressed CK19. CsA,FK-506, RAD, and MMF inhibited proliferation of BECs in a dose-dependent manner. The lowest concentration of CsA, FK-506, RAD, and MMF to inhibit proliferation of BECs (P＜0.05) was 500, 100, 0.25, and 100 μg/L,respectively. However, the expression of CK19 by BECs was not changed.CONCLUSION: CsA, FK-506, RAD, and MMF have an antiproliferative effect on human intrahepatic BECs in vitro, while RAD has the strongest growth-inhibitory effect. Their possible effects on liver regeneration and bile duct injury in transplant patients should be further investigated.     

骁悉对移植肾免疫抑制作用的临床研究

目的；研究骁悉（ＭＭＦ）对移植肾的免疫抑制作用，观察基副作用与毒性反应，方法；选择（ａ）３５例免疫抑制药物初次服用者，（ｂ）１８例药物性肝中毒者；（ｃ）８例常规免疫抑制治疗方案下出现急性排斥反应（ＡＲ），经治疗逆转后使用ＭＭＦ者，（ｄ）９例术后远期出现慢性排斥（ＣＲ）接受ＭＭＦ治疗者，结果：（ａ）５．７１％出现ＡＲ；（ｂ）肝功能逐步恢复，无ＡＲ；（ｃ）未发生二次急性排斥反应；（ｄ）蛋白尿减轻，肾工