在移植肾功能稳定的受者中主动撤除环孢素A的临床研究

目的 研究在移植肾功能稳定的受者中主动撤除环孢素A(CSA)对急性排斥反应发生率及肾功能的影响.方法 选择35例肾功能稳定的肾移植受者,其中尸体肾移植23例,亲属活体肾移植12例.除2例为再次肾移植外,其余均为初次肾移植.分别在肾移植术后6个月～6年时停用CsA,平均为术后(13.3±9.1)个月.撤除CsA后免疫抑制方案为:霉酚酸酯(MMF)+西罗莫司(SRL)+泼尼松(Pred).撤除CsA前有9例做了移植肾穿刺活检,8例测定了抗HLA抗体.结果 对35例受者随访6个月～4.5年,平均14.8个月.撤除CsA前、后血肌酐平均值分别为(88.1±15.5)μmol/L和(92.3±23.7)/μmol/L(P0.05).撤除CsA后,有2例经活检证实发生急性排斥反应,治疗后均逆转;CsA所致的毒副作用,如牙龈增生、糖耐量异常和多毛症等明显改善.9例移植肾活检中,有3例肾功能正常的受者已出现轻度慢性移植肾肾病表现.抗HLA抗体检测中,7例阴性者在撤除CsA前、后肾功能无明显变化.1例抗HLA抗体呈强阳性者在撤除CsA后进展为慢性移植肾肾病,恢复血液透析.结论 对移植肾功能稳定的受者在移植6个月后撤除CsA,转换为"霉酚酸酯+西罗莫司+泼尼松"的免疫抑制方案是安全的,不增加急性排斥反应风险;撤除CsA有利于消除一些与其相关的毒副作用;对抗HLA抗体呈强阳性者.撤除CsA后很难改变肾功能的进展.     

他克莫司与环孢素A在高致敏肾移植受者中的应用比较

目的 观察和比较高致敏肾移植受者应用他克莫司(FK506)与环孢素A(CsA)的有效性和安全性.方法 根据术后免疫抑制方案的不同,将147例高致敏肾移植受者(其中术前群体反应性抗体＞50%的首次肾移植受者59例,2次肾移植受者88例)分为FK506组(53例)和CsA组(94例),两组的免疫抑制方案分别为FK506(或CsA)+霉酚酸酯+泼尼松.观察并分析两组受者术后移植肾存活率、血肌酐水平以及并发症的发生率.结果 FK506组术后1、3和5年的移植肾存活率(86.8%、82.3%和75.3%)略高于CsA组(81.9%、75.4%和66.9%),但差异无统计学意义(P＞0.05);FK506组术后1年时血肌酐水平为(100.72±15.88)μmol/L,CsA组为(117.29±11.77)μmol/L,两组比较,差异有统计学意义(P＜0.01);FK506组与CsA组相比,术后急性排斥反应、慢性排斥反应、肝功能损害、高血压和高血脂的发生率显著降低(P＜0.05),而高血糖的发生率明显升高(P＜0.01),两组移植肾功能延迟恢复和感染的发生率无明显差异(P＞0.05).结论 FK506与CsA相比,能有效降低高致敏受者肾移植术后急、慢性排斥反应的发生率,减少术后并发症的发生,提高移植肾的长期存活率,对高致敏肾移植受者是非常有效和安全的.     

再次肾移植受者和移植肾长期预后影响因素分析

目的探究再次肾移植受者和移植肾存活情况及长期预后影响因素。 方法回顾性分析1991年1月1日至2017年12月31日于浙江大学医学院附属第一医院肾脏病中心接受肾移植受者临床资料。共纳入再次肾移植受者37例,首次肾移植受者5 374例。根据再次肾移植受者移植肾存活时间长短,将其分为长期存活组(19例,>5年)和短期存活组(18例,≤5年)。采用成组t检验比较长期和短期存活组供受者年龄、首次与再次肾移植间隔时间、HLA错配数和再次移植供肾冷/热缺血时间。采用卡方检验比较长期和短期存活组受者性别、再次移植供肾类型、再次移植前后群体反应性抗体阳性比例、首次移植失功移植肾切除比例、再次移植前免疫诱导比例及再次移植后移植肾功能延迟恢复(DGF)和急性排斥反应发生比例。采用Kaplan-Meier法分析再次和首次肾移植受者/移植肾1、5和10年存活率。采用Cox比例风险模型分析影响再次肾移植术后移植肾长期存活影响因素。P<0.05为差异有统计学意义。 结果截至2018年3月1日,37例再次肾移植受者中位随访时间为152个月(11～323个月),2例死亡,18例发生移植肾失功,17例移植肾功能稳定。5 374例首次肾移植受者中位随访时间为108.9个月(0.1～350.0个月),459例死亡,1 343例发生移植肾失功。再次移植组受者/移植肾1、5和10年存活率分别为86%/81%、86%/62%和82%/36%,首次移植组受者/移植肾1、5和10年存活率分别为99%/98%、93%/89%和88%/80%。再次移植组移植肾1、5和10年存活率均低于首次移植组(χ²＝60.816、25.110和43.900,P均<0.05);再次移植组受者1年存活率低于首次移植组,差异有统计学意义(χ²＝40.409,P<0.05)。长期和短期存活组受者再次移植后移植肾DGF和急性排斥反应发生比例差异均有统计学意义(χ²＝4.039和4.748,P均<0.05)。Cox回归分析结果示DGF和急性排斥反应是影响再次肾移植受者移植肾长期存活的独立危险因素,差异有统计学意义(RR＝4.317和4.571,P均<0.05)。 结论再次肾移植受者移植肾存活率低于首次肾移植受者,DGF和急性排斥反应是影响再次移植受者移植肾存活的独立危险因素。     

环孢素A血药浓度监测的临床意义

目的：探讨环孢素A(CsA)血药谷值浓度监测的临床意义。方法：对269例同种肾移植受者术后4081次CsA血药谷值浓度进行了分析。结果：随着移植肾存活时间的延长,CsA治疗浓度水平呈逐渐下降趋势。排斥反应发生时及排斥反应前两周内,CsA浓度不仅低下,而且有一持续约2周的显著下降过程,平均降幅达31％。术后一周内急性排斥反应的发生与CsA浓度关系不大。过高的CsA浓度则与肾中毒’反应有关。CsA治疗浓度与发生排斥反应时的浓度及肾中毒浓度均有一定程度的重叠。结论：认为术后CsA理想的治疗窗浓度应为：术后第1月内为300-450ng／ml,3月内为250～400ng／ml,半年内为200～350ng／ml,以后CsA浓度最好维持在150～250ng／ml。     

白细胞介素6mRNA在移植肾中的表达及意义

目的 探讨肾移植急性排斥反应时白细胞介素6(IL-6)产生的主要来源,并为初步阐明肾移植急性排斥反应的分子学发病机制提供实验依据。方法 采用3＇IL-6寡核苷酸探针,运用原位杂交技术观察IL-6mRNA在移植肾中的表达。结果 (1)在急性排斥反应时,移植肾各部位表达IL-6mRNA明显增多,较环孢素A(CsA)中毒、稳定期移植肾及正常人均有显著升高。(2)在急性排斥反应时,肾小管上皮细胞表达IL-6mRNA强度较肾小球细胞、血管内皮细胞及间质细胞均有明显升高。(3)CsA中毒患者肾脏IL-6mRNA表达较稳定期移植肾及正常对照无明显增多。结论 肾移植急性排斥反应时,移植肾细胞可直接产生IL-6,移植肾中IL-6异常激活与表达同肾移植急性排斥反应的发生机制有密切的关系;肾小管表达IL-6的异常增多和活化揭示了肾小管上皮细胞在肾移植急性排斥反应的发病机理中具有重要意义。     

肾移植术后中远期急性排斥反应临床研究

目的探讨肾移植术后中远期移植肾急性排斥反应(AR)发生影响因素及移植肾生存情况。 方法回顾性分析浙江大学医学院附属第一医院肾脏病中心2018年1月至2019年12月因血清肌酐水平升高而接受移植肾病理活检并确诊移植肾AR受者临床资料,共纳入43例受者,其中急性抗体排斥反应组17例,急性T细胞排斥反应组26例;同时纳入同期(2周内)肾移植且移植肾功能正常的39例受者为对照组。正态分布计量资料比较采用配对t检验或单因素方差分析。计数资料比较采用χ²检验或Fisher确切概率法。采用Kaplan-Meier进行生存分析,并采用log-rank进行比较。P<0.05为差异有统计学意义。 结果急性抗体排斥反应组HLA-A错配2个比例(4/17)高于对照组(1/39),差异有统计学意义(P＝0.026)。急性抗体排斥反应组和急性T细胞排斥反应组AR发生时和末次血清肌酐和估算肾小球滤过率(eGFR)均高于AR发生前(P均<0.05);急性抗体排斥反应组和急性T细胞排斥反应组AR发生时和末次血清肌酐和eGFR均高于对照组(P均<0.05);急性抗体排斥反应组进入慢性肾脏病(CKD)-4期受者比例低于急性T细胞排斥反应组(χ²＝5.73,P<0.05);急性T细胞排斥反应组进入CKD-4期受者比例以及急性抗体排斥反应组移植肾失功比例均高于对照组(χ²＝17.727和9.882,P均<0.05)。AR发生时急性抗体排斥反应组和急性T细胞排斥反应组受者均接受PRA检测,前者PRA-Ⅰ和PRA-Ⅱ阳性比例分别为41.2%(7/17)和88.2%(15/17),均高于后者[11.5%(3/26)和26.9%(7/26)],差异均有统计学意义(P＝0.042,P<0.001)。急性抗体排斥反应组、急性T细胞排斥反应组及对照组术后分别有13、24和38例受者应用他克莫司。发生AR时,急性抗体排斥反应组他克莫司血药浓度[(3.72±0.76)ng/mL]与急性T细胞排斥反应组[(3.37±0.86)ng/mL]均低于对照组[(5.73±1.25)ng/mL],差异均有统计学意义(P均<0.05);急性抗体排斥反应组与急性T细胞排斥反应组他克莫司血药浓度均低于发生AR前[(6.27±1.18)和(6.33±1.63)ng/mL],差异均有统计学意义(t＝7.120和6.216,P均<0.05)。急性抗体排斥反应组4例受者应用以环孢素为基础的免疫抑制方案,其中3例术后33、36和55个月环孢素血浓度分别为112.4、138.3和7.0 ng/mL,均低于要求血药浓度。急性T细胞排斥反应组2例应用环孢素受者术后16和177个月环孢素血药浓度分别为43.2和24.6 ng/mL,均低于要求血药浓度。随访至2021年6月30日,急性抗体排斥反应组移植肾生存率低于对照组(χ²＝8.738,P<0.05)。 结论HLA-A位点错配及他克莫司低血药浓度是肾移植术后中远期诱发AR的重要原因。急性抗体介导排斥反应是移植肾生存重要影响因素。     

声触诊组织定量技术诊断不同时期移植肾急性排斥反应的临床价值

目的  探讨声触诊组织定量(VTQ)技术在诊断不同时期移植肾急性排斥反应中的临床价值。方法  回顾性分析170例肾移植受者的临床资料。根据受者行VTQ检查的时间以及肾移植术后急性排斥反应的发生情况, 将肾移植术后4周内和术后4周后的受者分为肾功能正常组(41例和51例)、急性排斥反应组(22例和56例)。比较肾移植术后不同时期肾功能正常组和急性排斥反应组的临床超声参数情况; 分析超声参数在肾移植术后不同时期急性排斥反应中的诊断价值。结果  肾移植术后4周内, 急性排斥反应组的阻力指数(RI)和剪切波速度(SWV)均明显高于肾功能正常组(均为P < 0.001);术后4周后, 急性排斥反应组SWV明显高于肾功能正常组(P < 0.001)。术后4周内, RI、SWV诊断急性排斥反应的曲线下面积(AUC)分别为0.729、0.803;术后4周后, RI、SWV诊断急性排斥反应的AUC分别为0.478、0.794, SWV的诊断价值高于RI(P < 0.05)。术后4周内SWV诊断急性排斥反应的截断值高于术后4周后。结论  VTQ技术能有效辅助诊断不同时期移植肾急性排斥反应。     

肾移植受者将环孢素A转换为他克莫司治疗的三年疗效分析

目的 评价肾移植受者将环孢素A(CsA)转换为他克莫司(Tac)治疗的有效性和安全性。方法 回顾将CsA转换为Tac治疗的97例肾移植受者的资料,转换治疗的原因分别为慢性移植肾肾病62例,难治性排斥反应21例,肝功能异常8例,齿龈增生、多毛6例。观察转换治疗后3年内的肾功能、肝功能、血脂、血压、血糖、急性排斥发生率、人/肾存活率以及药物不良反应等指标。结果 与转换前相比较,慢性移植肾肾病及难治性排斥反应患者转换治疗1年后肾功能明显好转(P＜0.01),患者第2、3年肾功能稳定。转换治疗后,肝功能异常者的肝功能明显改善,齿龈增生和多毛患者的症状也明显改善。97例转换治疗后第1年的人/肾存活率分别为100％和97.9％,第3年为100％和92.8％,患者血浆胆固醇、低密度脂蛋白、甘油三酯和血压均下降(P＜0.05)。转换治疗后,13例需用药物控制血糖(13.4％),另发生腹泻和食欲不振2例(2.1％),震颤5例(5.2％)。观察期内患者均未发生严重肺部感染和肿瘤。结论 使用CsA行免疫抑制治疗的肾移植受者发生相关并发症后转换为Tac治疗是安全和有效的。     

丙型肝炎病毒感染对肾移植受者排斥反应及人/肾存活率的影响

目的 研究丙型肝炎病毒(HCV)感染是否影响移植肾急性和慢性排斥反应的发生率,以及受者和移植肾的存活率.方法 对1992年6月至2004年6月所行肾移植的495例受者进行了随访,其中术前HCV抗体阳性受者27例(HCV阳性组),随机抽取HCV抗体阴性受者27例作为对照组,行组间配对研究,分析HCV感染状态对肾移植受者急性和慢性排斥反应发生率以及人/肾存活率的影响.结果 HCV阳性组受者急性排斥反应的发生率显著高于对照组(19.14%和6.38%,P<0.01),HCV阳性组慢性排斥反应的发生率也明显高于对照组(23.40%和12.76%,P<0.01),对照组肾移植后1、3、5年人/肾存活率显著高于HCV阳性组,差异有统计学意义(P<0.01).结论 HCV感染可以明显增加肾移植受者急性和慢性排斥反应的发生率,降低人/肾存活率.     

致敏患者经双滤过法血浆分离方案预处理后行肾移植的临床效果分析

目的 分析致敏患者经双滤过法血浆分离(DFPP)方案预处理,并联合使用抗CD25单抗诱导治疗后行肾移植的临床效果和安全性.方法 回顾性分析2000年11至2012年1月45例致敏受者在肾移植前经DFPP方案预处理,并联合使用抗CD25单抗诱导治疗后接受肾移植的临床资料.所有受者预处理前的群体反应性抗体(PRA)水平均大于20％,为(56.5±19.9)％,预处理后PRA水平降至(18.9±19.1)％.受者与供者的HLA抗原错配数为(2.1±0.7)个,术前2次供、受者淋巴细胞毒交叉配型试验均为阴性.所有受者术后至少随访1年,观察术后1年受者和移植肾存活率,以及排斥反应和肺部感染的发生情况.结果 随访期间,无受者死亡,有2例受者发生移植肾功能丧失,术后1年受者存活率为100％(45/45),移植肾存活率为95.6％ (43/45).术中肾血管开放后1例发生超急性排斥反应,发生率为2.2％,受者在切除移植肾后恢复血液透析;术后发生急性排斥反应12例,发生率为26.7％(12/45),经甲泼尼龙和(或)ATG冲击治疗后,11例完全逆转,1例出现移植肾功能丧失而恢复血液透析.术后肺部感染发生率为8.9％(4/45),经抗感染治疗后均好转,未发生重症肺部感染.结论 肾移植前采用DFPP 预处理,并联合使用抗CD25单抗诱导治疗安全有效,能使致敏受者获得良好的肾移植效果.     

The effect of sevelamer on the pharmacokinetics of cyclosporin A and mycophenolate mofetil after renal transplantation.

BACKGROUND: After renal transplantation, patients with insufficient graft function may require phosphate binders. It is still unknown if sevelamer, a new calcium-free phosphate binder, interferes with the uptake of immunosuppressants. We studied its effects on the pharmacokinetics of cyclosporin A (CsA) and mycophenolate mofetil. METHODS: We examined 10 adults and eight children with stable renal graft function and stable CsA trough levels. A 12 h pharmacokinetic profile (10 observation points) was conducted without sevelamer, after a single dose and after 4 days of treatment with it. CsA levels were measured with both a monoclonal antibody assay (CEDIA) and a polyclonal antibody assay (FPIA), mycophenolic acid (MPA) levels by EMIT assay and CsA metabolites AM1, AM9 and AM4N by a modified HPLC method. RESULTS: Sevelamer had no significant effect on CsA kinetics [area under the curve (AUC), peak concentration (C(max)), time of C(max)]. The AUC of AM1 was decreased by 30% and C(max) by 25% after 4 days of sevelamer intake. MPA levels were significantly reduced by a mean of 25% of the AUC (P<0.05) and by 30% of the C(max) after a single dose of sevelamer. CONCLUSIONS: A single sevelamer dose reduces the C(max) and the AUC of MPA. Its intake for several days does not significantly influence CsA kinetics.     

Therapeutic drug monitoring of cyclosporine Neoral in de novo Chinese cardiac transplant recipients treated with an everolimus-cyclosporine immunosuppressive regimen

This study determined cyclosporine Neoral (CsA) pharmacokinetics and the accuracy of a limited sampling strategy to predict the 12-hour CsA area-under-the-curve (AUC) to provide a practical method for more accurate therapeutic drug monitor of CsA among de novo Chinese heart transplant recipients treated with an everolimus-CsA immunosuppressive regimen. METHODS: Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after oral administration of CsA in six de novo heart recipients receiving a CsA, everolimus, and methylprenisolone immunosuppressive regimen after rabbit antithymoglobulin sequential immuno-induction. We analyzed the pharmacokinetics of the first dose (PK-1) and steady state dose (PK-2) at 1 month after transplantation. The accuracy of a single-point sampling method to predict the AUC was generated by linear regression analyses. RESULTS: The t(max) and dose-normalized C(max) of PK-1 and PK-2 were similar. The correlations in single-point blood levels of PK-1 to predict the AUC(0-infinity) were much lower than the corresponding sampling times in PK-2. In PK-2 study, C4 had the best correlation (r(2) = 0.913, P = .003) to predict AUC(0-12). In addition, the trough concentrations, C(0) (r(2) = 0.875, P = .006) and C(12) (r(2) = 0.783, P = .02) also showed good correlations. C2 had insufficient correlation to predict AUC(0-infinity) in PK-1 or AUC(0-12) in the PK-2 study. In conclusion, the absorption of CsA was similar during PK-1 and PK-2. At steady dose, C4 had the best single-point correlation to predict AUC(0-12). Trough blood levels may be more practical in clinical use to monitor CsA.     

Cinacalcet's effect on the pharmacokinetics of tacrolimus, cyclosporine and mycophenolate in renal transplant recipients.

BACKGROUND: The calcimimetic drug cinacalcet offers a novel therapeutic option to treat post-transplant hypercalcemia and hyperparathyroidism; however, the interaction with calcineurin inhibitors and mycophenolate has not been evaluated. METHODS: In the present study the effects of cinacalcet on the pharmacokinetics of cyclosporine A (CsA), tacrolimus (Tac) and mycophenolate were investigated in 14 renal transplant recipients with stable renal function (mean creatinine 126.4 +/- 45.3 micromol/L). The patients were treated with either CsA (n = 8) or Tac (n = 6) in combination with mycophenolate/azathioprine and steroids. Twelve-hour pharmacokinetic investigations to measure CsA and its six main metabolites, Tac and mycophenolate concentrations were performed before and after 1-week treatment with 30 mg cinacalcet once daily. RESULTS: Cinacalcet treatment induced a significant 14.3 +/- 12.1% decrease in Tac AUC(0-12) (P = 0.039). Tac C(max), T(max) and T(1/2) also tended to decrease. The pharmacokinetics of CsA and mycophenolate were not significantly affected by concomitant treatment with cinacalcet. However, the secondary CsA metabolite, AM19, showed a significant increase of 9.0 +/- 9.5% during cinacalcet treatment (P = 0.040). Renal function decreased significantly from 78 +/- 11 to 72 +/- 12 mL/min (P = 0.019) and correlated with the increased levels of metabolite AM19 in the CsA group. Renal function was unchanged in the Tac group. CONCLUSION: Cinacalcet treatment showed a moderate effect on the Tac, but not CsA or mycophenolate, pharmacokinetics after 1-week concomitant treatment. This interaction appears to have minor clinical relevance. However, it is advisable to monitor renal function in CsA-treated patients due to the observed decrease in renal function.     

Cyclosporine pharmacokinetics in anti-HCV+ patients

BACKGROUND: Cyclosporine (CsA) is a widely used immunosuppressive agent in kidney transplant patients. In Brazil, around 30% of patients awaiting kidney transplantation carry anti-HCV antibodies. Previous observations suggest altered CsA pharmacokinetics in these patients. METHODS: We conducted two pharmacokinetic studies. In the pre-transplant (pre-Tx) study, we examined 22 dialysis patients on chronic hemodialysis awaiting transplantation, 11 anti-HCV+ [seven polymerase chain reaction (PCR)-positive] matched against 11 controls. In the post-transplant (post-Tx) study, we enrolled 24 kidney allograft recipients - 10 anti-HCV+ (six PCR-positive), and 14 controls. In the first study, all patients received an 8-mg/kg dose of CsA microemulsion (ME). Secondly, the dosage was indicated by the patient's medical team. Pharmacokinetic parameters were calculated from 13 blood samples (0-12 h postdose) by fluorescence polarization immunoassay with specific monoclonal antibodies. RESULTS: In both studies, maximum concentration (C(max)), minimum concentration (C(min)) and area under the CsA time-concentration curve from 0 to 12 h (AUC(0-12)) were higher for anti-HCV+ patients than for controls, but significantly so only for AUC(0-12) in the pre-Tx study (42%; p < 0.05). When PCR-positive patients were compared with controls, differences were amplified. In the pre-Tx study, differences were 58%, 69%, and 91% higher in PCR-positive patients for C(max) (p = 0.05), AUC(0-12) (p < 0.01), and C(min) (p < 0.01), respectively. In the post-Tx study, results were 50% (p < 0.01) and 32% (p < 0.01) higher in PCR-positive patients for C(max) and AUC(0-12), respectively. In the pre-Tx study, the impact of viremia was significantly higher in female patients. CsA trough levels remained higher along the first year post-transplantation in viremic patients. CONCLUSIONS: Anti-HCV+ patients, especially those with viremia, present altered CsA pharmacokinetics, with higher peak levels and drug exposure than controls.     

Pharmacokinetics and pharmacodynamics in renal transplant recipients under treatment with cyclosporine and Myfortic

INTRODUCTION: Efficacious prophylaxis of acute rejection episodes (ARE) requires adequate exposure to each component of the immunosuppressive treatment from the first days after renal transplantation. The aim of the present study was to evaluate the correlation between cyclosporine (CsA) and mycophenolic acid (MPA) exposure based upon pharmacokinetics (PK) and pharmacodynamics (PD) and 6-month biopsy-proven acute rejection (BPAR) episodes and chronic allograft nephropathy on 6 month protocol biopsies. PATIENTS AND METHODS: We examined twenty-two first or second de novo renal transplant recipients treated with steroids, Sandimmune Neoral (CsA) and Myfortic (720 mg twice a day). PK (C0, C2, and AUC(0-12h)) for both drugs were determined on days 7, 90, and 180. Calcineurin activity, interleukin-2 and interferon-gamma synthesis as well as %CEM were tested at days 7 and 180. CsA dosages were adjusted by C2 monitoring. Collected data included: BPAR during the first 6 months and Banff histological parameters on the 6-month protocol biopsies. RESULTS: Eighteen of 22 patients completed 1 year follow-up under treatment. The 6-month BPAR was 18% (4/22). Six-month protocol biopsies in 50% of 14 recipients showed chronic allograft nephropathy 1. At day 7, CsA C2 and AUC median values were 138 ng/mL and 6377 ng x h/mL, while C0 MPA was 1.0 microg/mL and AUC = 23.9 microg x h/mL. CsA C2 medians at 3 and 6 months were 1468 and 1720 ng/mL. MPA-AUC reached therapeutic targets at 3 months (32.3 microg x h/mL) and was 48.3 microg x h/mL at 6 months. Patients with BPAR showed lower CsA AUC (P = .06) and a significantly lower baseline inhibition of calcineurin activity (P < .005) than patients with no BPAR. An increase in mesangial matrix in 6-month protocol biopsies correlated with higher CsA C2 (P = .01). All biomarkers evaluated were significantly inhibited compared with the standard population. CONCLUSIONS: When Myfortic is administered together with CsA, it is advisable to begin with higher doses (720 mg x 3 days) to reach adequate PK targets and improve BPAR rates. To prevent chronic allograft nephropathy, lower CsA C2 should be targeted from 3 months.     

Impact of cyclosporin A pharmacokinetics on the presence of side effects in pediatric renal transplantation

Cyclosporin A (CsA) is a potent immunosuppressant that has many side effects, including hypertrichosis, gingival hyperplasia, and tremor. To evaluate whether there is a relationship between the CsA-pharmacokinetics (PK) and these side effects, their presence and intensity were observed in 46 renal transplanted children/adolescents during two regular visits, and the occurrence of the side effects was correlated with CsA-PK. CsA doses had been unchanged for at least 6 mo. CsA blood concentrations were measured at time 0, and 1, 2, and 4 h after the CsA morning dose. An abbreviated area under the curve (AUC) was calculated using C0, C2, and C4. Hypertrichosis positively correlated with C2, C4, Cmax, and AUC. An AUC > or = 4158 ng/ml per h was the best predictor for the presence of hypertrichosis. Tremor was also positively correlated with C2, Cmax, and AUC. A Cmax > or = 878 ng/ml was the best predictor for the appearance of tremor. These values of Cmax and AUC are within the therapeutic range of CsA as demonstrated by the studies of calcineurin inhibition by CsA. Gingival hyperplasia was not associated with any of the CsA-PK studied parameters. However, it was associated with the concomitant use of nifedipine. These data show that there is a correlation between the CsA side effects and its pharmacokinetics and that it is possible to decrease the incidence and intensity of such side effects by monitoring the CsA-PK parameters, providing they are under or at the proposed cutoff levels. Nifedipine should also be avoided to reduce the presence of gingival hyperplasia.     

The influence of calcineurin inhibitors on mycophenolic acid pharmacokinetics

Despite the fact that concentrations of mycophenolic acid (MPA) are not routinely measured, accumulating data suggest the usefulness of this monitoring to optimize therapy. The aim of this study was to assess the influence of CsA and tacrolimus on MPA pharmacokinetics. Concentrations of MPA were measured using HPLC. An assay was performed before dose (the C(0)), as well as at 40 minutes and 1, 2, 4, 6, 8, 10, 12 hours after administration of mycophenolate mofetil (MMF). MPA profiles were assessed in 51 patients receiving tacrolimus at a dose of 1.0 g/d and prednisone as well as in 97 patients receiving CsA (2.0 g/d) and prednisone. Significant correlations of MPA levels with serum albumin and GFR were observed in both groups. Women presented with higher levels of MPA than men. C(0) MPA level among the tacrolimus group were significantly higher than those in CsA group: 3.18 +/- 2.21 microg/mL versus 1.68 +/- 1.03 microg/mL (P 相似文献   

The pharmacokinetics and tolerability of an intravenous infusion of the new hydroxyethyl starch 130/0.4 (6%, 500 mL) in mild-to-severe renal impairment

Hydroxyethyl starches (HES) are almost exclusively excreted glomerularly, in part after hydrolysis by amylase. HES 130/0.4 (Voluven; Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany) was developed to improve pharmacokinetics whereas preserving the efficacy of volume effect. We studied the dependency of pharmacokinetics of HES 130/0.4 on renal function. Nineteen volunteers with stable, non-anuric renal dysfunction, ranging from almost normal creatinine clearance (CL(cr)) to severe renal impairment (mean CL(cr): 50.6 mL. min(-1). 1.73 m(-2)), were given a single infusion of 500 mL 6% HES 130/0.4 over 30 min. HES plasma concentrations were determined until 72 h, urinary excretion until 72-96 h. CL(cr) had been obtained at least twice before and twice after dosing. Standard pharmacokinetic calculations and regression analysis were performed. Area under the time concentration curve (AUC(0-inf)) clearly depended on renal function comparing subjects with CL(cr) < 50 with those with CL(cr) > or =50 (ratio 1.73). Peak concentration (C(max), 4.34 mg/mL) as well as terminal half-life (16.1 h, model independent) were not affected by renal impairment. At CL(cr) > or =30, 59% of the drug could be retrieved in urine, versus 51% at CL(cr) 15-<30. The mean molecular weight of HES in plasma was 62,704 d at 30 min, showing lower values with increased renal impairment (P = 0.04). Pre-dose amylase concentrations inversely correlated with baseline CL(cr). Residual HES plasma concentrations after 24 h were small in all subjects (< or =0.6 mg/mL). We conclude that HES 130/0.4 (500 mL 6%) can be safely administered to patients even with severe renal impairment, as long as urine flow is preserved, without plasma accumulation. IMPLICATIONS: Dependency of the pharmacokinetics of hydroxyethyl starch 130/0.4 on renal function was studied. The area under the time concentration curve increased moderately with more severe renal dysfunction; however, small plasma concentrations were observed after 24 h. Terminal half-life and peak concentration remained unaffected by renal impairment.     

Immunopathologic patterns of cyclosporine deposition associated with nephrotoxicity in renal allograft biopsies

Using antibody directed against cyclosporine (CsA-Ab) in an avidin-biotin-complex immunoperoxidase technique on routine formalin-fixed tissue specimens, 46 renal biopsies from CsA-treated renal allograft recipients and 23 biopsies from non-CsA-treated patients were examined to identify staining patterns potentially associated with CsA nephrotoxicity (CsA-NT). All specimens were examined independently in a masked fashion by two pathologists for the intensity of (CsA-Ab) specific staining for each of the four distinct patterns identified: diffuse interstitial staining (DIS, 0-3+); fine granular staining of tubular epithelium (FGS, 0-3+); coarse granular staining of tubular epithelium (CGS, 0-3+); and dark cellular staining of mononuclear inflammatory cells (DCS, 0-3+). Based on standard clinical criteria all CsA-treated patients were categorized according to the degree of CsA nephrotoxicity (grades 1-4). Significant differences in the intensity of CsA-Ab labeling were found for three of the four immunohistologic grading patterns (DIS, FGS, DCS). For the DIS and FGS patterns, cases with clinical evidence of moderate-severe CsA-NT (grades 3 and 4) had significantly higher average staining than either the slight-mild CsA-NT cases (grade 1 and 2) or the control cases (grade 0). The DCS pattern demonstrated significantly more staining in the moderate-severe CsA-NT cases than in the controls. The sum of individual scores for the DIS, FGS, and DCS immunohistologic pattern (CsA index) was also significantly higher in the moderate-severe CsA-NT cases (3.57 +/- 0.44) than in either the controls (1.73 +/- 0.23, P less than 0.05) or the slight-mild CsA-NT cases (1.98 +/- 0.27, P less than 0.05), demonstrating a specificity of 78% for identifying moderate-severe CsA nephrotoxicity. The extent of infiltration by Leu 2 (CD8; T cytotoxic-suppressor phenotype) positive cells was not significantly different between the moderate-severe versus the slight-mild CsA-NT outcome groups. However, when CsA index values were used in combination with the intensity of Leu-2-positive cell infiltrates to predict CsA-NT (CsA-treated patients with high CsA-Ab staining as well as low levels of Leu-2-positive infiltrate) the specificity for identifying moderate-severe CsA-NT was 96%. These results suggest that CsA labeling of renal allograft biopsies may be useful for identifying CsA-NT, especially when considered with the nature of inflammatory cell infiltration.     

A prospective cross-over study comparing the pharmacokinetics of cyclosporine A and its metabolites after oral versus short-time intravenous cyclosporine A administration in pre-heart transplant patients

Sometimes intravenous administration of cyclosporine (CsA) is essential before oral administration is possible. There are only a few reports available on the interindividual variability of CsA metabolism and different metabolite pattern depending on intravenous versus oral administration of CsA in heart transplant (HTx) patients. For effective inhibition of calcineurin we used a short infusion reaching peak concentrations after 2 hours. In a prospective cross-over study we compared the pharmacokinetics of CsA and its metabolites after oral (2.0 mg/kg body weight) versus intravenous (0.7 mg/kg body weight; 2-hour infusion) CsA administration (single test dose) in 7 pre-HTx patients. The pharmacokinetic parameters of CsA and its metabolites were analyzed using high-pressure liquid chromatography. The pharmacokinetic parameter area under the concentration time curve (AUC(0-infinity)) of CsA after intravenous administration was significantly lower (2903 ng*h*mL(-1)) than that after oral administration (4344 ng*h*mL(-1); P=.01). Peak concentrations, time to peak concentration, and terminal elimination half life were not significantly different. Short-time infusion of CsA resulted in a significant decrease in the AUC of the metabolites AM1 (3-fold), AM9 (10-fold), and AM1c (3-fold). A 2-hour infusion of CsA is just as effective as oral administration and the reduced amount of metabolites is advantageous for the patient.