肝移植后因药物不良反应暂停及转换钙调磷酸酶抑制剂的单中心经验

目的 研究肝移植术后暂停及转换钙调磷酸酶抑制剂(CNI)对控制感染和改善受损肾功能的作用.方法 回顾性分析单中心施行的947例原位肝移植的资料,分为2个阶段,第1阶段(2002年1月至2007年12月)有234例肝移植术后发生感染的患者,第2阶段(2008年1月至2010年12月)有101例.2个阶段共有329例受者因CNI肾毒性而造成肾功能损害,其中将CNI转换为SRL者40例(转换组),其余289例采取CNI减量+吗替麦考酚酯(MMF)加量方案(减量组).结果 肝移植术后存活超过1、3和5年者CNI的应用率分别为95.8%、95.3%和97.5%.第2阶段共有17例受者短期停用免疫抑制剂,停药的主要原因是细菌(部分合并真菌)感染(88.2%);2个阶段共有48例患者将CNI转换为SRL,换药主要原因是肾功能损害(83.3%).第2阶段感染患者中短期暂停CNI者15例,占14.9%(15/101),CNI暂停后感染控制的有效率为73.3%(11/15),排斥反应发生率为6.7%(1/15).第2阶段感染患者的累积存活率明显高于第1阶段(P＜0.05).转换组CNI转换前肾小球滤过率为(0.82±0.24)ml/s,CNI转换后6周时为(1.28±0.31)ml/s,6个月时为(1.36±0.32)ml/s,转换后6周和6个月时高于转换前(P＜0.05).CNI调整后6个月时,转换组患者存活率为85.0%,减量组为83.7%(P＞0.05).结论 肝移植术后患者发生感染及肾功能损害时可采取CNI减量甚至短时间停用CNI,或转换使用SRL,此方案是安全、有效的.

Abstract：

Objective To report the results of a single-center, retrospective study on the effect of calcineurin inhibitors (CNI) withdraw for controlling infections and conversion to sirolimus (SRL)for ameliorating renal dysfunction. Methods A total of 947 liver transplant cases from 2002 to 2010were divided into two eras (Jan. 2002 to Dec. 2007 and Jan. 2008 to Dec. 2010). There were 234cases of infections after liver transplantation (LT) in the first era and 101 cases in the second era. And of 329 cases of CNI-related renal dysfunction after LT in two eras, 40 cases (converting group) had converted CNI to SRL, while 289 cases (reducing group) adopted protocol of CNI reducing and mycophenolate mofetil (MMF) raising. Results CNI-based IS took up 95.8 %, 95. 3 %, 97. 5 % of the IS protocols with recipient survival time longer than 1, 3, and 5 years. The primary cause for CNI withdraw was infection (88. 2 %, 15/17) in the second era, and renal dysfunction for conversion to SRL in the two eras (83. 3 %, 40/48). In the second era, 14. 9% (15/101) of the cases of infections after LT experienced CNI withdraw. Of the 15 patients, 11 had effectively controlled the infection (77. 3 %) while rejection rate was 6. 7 % (1/15). The cumulative survival rate of the second era was significantly higher than the first era (P＜0. 05). The glomerular filtration rate (GFR) of converting group at 6th week and 6th month was statistically elevated as compared with that before conversion,respectively (1.28 ± 0. 31, 1.36 ± 0. 32 mL/s vs. 0. 82 ± 0. 24 mL/s, P＜0. 05). Six months after CNI adjustments, survival rate of converting group and reducing group was 85. 0% and 83. 7 %,respectively (P＞0. 05). Conclusion Reducing or even short-term withdraw of CNI may allow the better control of infections after LT, and the conversion from CNI to SRL can ameliorate the CNIrelated nephrotoxicity. These individually tailored IS protocols will benefit the long term survival for LT.     

肝移植后因药物不良反应暂停及转换钙调磷酸酶抑制剂的单中心经验

Objective To report the results of a single-center, retrospective study on the effect of calcineurin inhibitors (CNI) withdraw for controlling infections and conversion to sirolimus (SRL)for ameliorating renal dysfunction. Methods A total of 947 liver transplant cases from 2002 to 2010were divided into two eras (Jan. 2002 to Dec. 2007 and Jan. 2008 to Dec. 2010). There were 234cases of infections after liver transplantation (LT) in the first era and 101 cases in the second era. And of 329 cases of CNI-related renal dysfunction after LT in two eras, 40 cases (converting group) had converted CNI to SRL, while 289 cases (reducing group) adopted protocol of CNI reducing and mycophenolate mofetil (MMF) raising. Results CNI-based IS took up 95.8 %, 95. 3 %, 97. 5 % of the IS protocols with recipient survival time longer than 1, 3, and 5 years. The primary cause for CNI withdraw was infection (88. 2 %, 15/17) in the second era, and renal dysfunction for conversion to SRL in the two eras (83. 3 %, 40/48). In the second era, 14. 9% (15/101) of the cases of infections after LT experienced CNI withdraw. Of the 15 patients, 11 had effectively controlled the infection (77. 3 %) while rejection rate was 6. 7 % (1/15). The cumulative survival rate of the second era was significantly higher than the first era (P＜0. 05). The glomerular filtration rate (GFR) of converting group at 6th week and 6th month was statistically elevated as compared with that before conversion,respectively (1.28 ± 0. 31, 1.36 ± 0. 32 mL/s vs. 0. 82 ± 0. 24 mL/s, P＜0. 05). Six months after CNI adjustments, survival rate of converting group and reducing group was 85. 0% and 83. 7 %,respectively (P＞0. 05). Conclusion Reducing or even short-term withdraw of CNI may allow the better control of infections after LT, and the conversion from CNI to SRL can ameliorate the CNIrelated nephrotoxicity. These individually tailored IS protocols will benefit the long term survival for LT.     

肝移植后因药物不良反应暂停及转换钙调磷酸酶抑制剂的单中心经验

Objective To report the results of a single-center, retrospective study on the effect of calcineurin inhibitors (CNI) withdraw for controlling infections and conversion to sirolimus (SRL)for ameliorating renal dysfunction. Methods A total of 947 liver transplant cases from 2002 to 2010were divided into two eras (Jan. 2002 to Dec. 2007 and Jan. 2008 to Dec. 2010). There were 234cases of infections after liver transplantation (LT) in the first era and 101 cases in the second era. And of 329 cases of CNI-related renal dysfunction after LT in two eras, 40 cases (converting group) had converted CNI to SRL, while 289 cases (reducing group) adopted protocol of CNI reducing and mycophenolate mofetil (MMF) raising. Results CNI-based IS took up 95.8 %, 95. 3 %, 97. 5 % of the IS protocols with recipient survival time longer than 1, 3, and 5 years. The primary cause for CNI withdraw was infection (88. 2 %, 15/17) in the second era, and renal dysfunction for conversion to SRL in the two eras (83. 3 %, 40/48). In the second era, 14. 9% (15/101) of the cases of infections after LT experienced CNI withdraw. Of the 15 patients, 11 had effectively controlled the infection (77. 3 %) while rejection rate was 6. 7 % (1/15). The cumulative survival rate of the second era was significantly higher than the first era (P＜0. 05). The glomerular filtration rate (GFR) of converting group at 6th week and 6th month was statistically elevated as compared with that before conversion,respectively (1.28 ± 0. 31, 1.36 ± 0. 32 mL/s vs. 0. 82 ± 0. 24 mL/s, P＜0. 05). Six months after CNI adjustments, survival rate of converting group and reducing group was 85. 0% and 83. 7 %,respectively (P＞0. 05). Conclusion Reducing or even short-term withdraw of CNI may allow the better control of infections after LT, and the conversion from CNI to SRL can ameliorate the CNIrelated nephrotoxicity. These individually tailored IS protocols will benefit the long term survival for LT.     

钙调磷酸酶抑制剂转换为西罗莫司治疗慢性移植物肾病的疗效研究

探讨钙调磷酸酶抑制剂(CNI)转换为西罗莫司治疗慢性移植物肾病(chronic allograft nephropathy,CAN)的疗效及不良反应.方法 回顾性研究对象为2005年1月至2010年12月在西安交通大学医学院第一附属医院肾移植科随访的95例肾移植后并发CAN患者,术后均接受CNI为主的免疫抑制剂方案.所有患者均签署知情同意书,符合医学伦理学规定.患者确诊CAN后将CNI转换为西罗莫司.记录西罗莫司的维持剂量及血药浓度水平,了解转换治疗后血清肌酐(Scr)的变化,根据转换前Scr水平高低分为两组,Scr≥266 μmol/L为Scr高水平组(22例),Scr<266 μmol/L为Scr低水平组(73例);比较两组转换治疗后Scr变化幅度的差异;了解转换治疗的不良反应.结果 95例患者的随访时间6~48个月,西罗莫司的维持剂量为0.5~4 mg/d(中位数为1.5 mg/d),血药浓度为1.3~12 ng/ml(中位数为5.4 ng/ml).Scr低水平组转换治疗效果明显高于Scr高水平组(P<0.05).95例患者均未发生急性排斥反应.新发或蛋白尿加重32例(34%),新发或高脂血症加重25例(26%),1例患者发生肺部感染,经对症治疗后均治愈或缓解.结论 CNI类药物转换为西罗莫司治疗CAN是安全有效的,转换前Scr水平较低者的治疗效果优于转换前Scr水平较高者,转换后的主要并发症是蛋白尿和高脂血症.     

肝移植术后根据肝活检结果转换西罗莫司治疗:附12例报告

目的 探讨肝移植术后西罗莫司转换治疗后的有效性与安全性.方法 对12例肝移植术后完全停用钙调磷酸酶抑制剂(calcineurin Inhibitor,CNI)改用西罗莫司治疗至少1个月以上的病人进行随访,观察转换治疗后排斥反应的发生及CNI相关肾功能损害和肝功能恢复情况.结果 12例肝移植病人术后平均11个月开始西罗莫司转换治疗,治疗时间平均为14个月,平均随访时间为37个月.采用西罗莫司转换治后,12例中有6例肝穿证实未出现排斥反应.发生CNI相关肾损害的7例中有5例肾功能恢复正常,但有1例反而引起蛋白尿.反复肝功能异常的4例没有改善.结论 我们的小样本临床资料表明,对于某些经过选择的肝移植病人,例如合并CNI相关性肾损害者,可以尝试在肝穿活检指导下进行西罗莫司转换治疗.     

钙调磷酸酶抑制剂胰岛毒性作用的机制及临床意义

本文就钙调磷酸酶抑制剂引起胰岛毒性作用的机制予以综述,并着重探讨了钙调磷酸酶 抑制剂在肾移植、胰岛移植中的应用及前景。     

钙调磷酸酶抑制剂胰岛毒性作用的机制及临床意义

本文就钙调磷酸酶抑制剂引起胰岛毒性作用的机制予以综述，并着重探讨了钙调磷酸酶抑制剂在肾移植、胰岛移植中的应用及前景。     

肝移植受者单用霉酚酸类药物远期疗效评价

目的探讨肝移植受者术后单用霉酚酸(mycophenolic acid,MPA)类药物的远期疗效。方法回顾性分析2002年9月至2021年8月期间解放军总医院第三医学中心30例肝移植受者临床资料,上述病例从钙调磷酸酶抑制剂(calcineurin inhibitor,CNI)方案因肾毒性转换为单药霉酚酸类药物免CNI类方案,并对转换前后肝功能、肾功能以及其不良反应进行对比分析,随访周期为2年。结果转换后1年与转换后2年的肌酐(creatinine,Cr)水平分别为(83.5±24.3)μmol/L(、74.2±15.9)μmol/L。估算的肾小球滤过率(estimated glomerular filtration rate,e GFR)分别为(77.7±9.1)ml/min、(86.1±6.5)ml/min。与转换前比较,Cr水平明显降低(P<0.05),e GFR水平得到明显提高(P<0.05)。丙氨酸转氨酶(alanine aminotransferase,ALT)、天冬氨酸转氨酶(aspartate aminotransferase,AST)、总胆红素(total bilirubin,TBil)水平前后无明显变化(均P>0.05)。结论肝移植远期的受者霉酚酸类药物单药维持,其安全性值得肯定,无明显不良反应,且其肾功能水平可从免CNI抗排斥方案中获益。     

钙调磷酸酶抑制剂肾毒性致移植肾损伤1例并文献复习

钙调磷酸酶抑制剂(calcineurin inhibitor,CNI)、霉酚酸类药物和类固醇的联合用药是肾移植术后免疫抑制标准方案[1].是因为基于CNI的免疫抑制方案对预防排斥反应、提高短期移植肾存活率及移植物功能有确定疗效[2].然而,CNI的使用会增加肾毒性,这是导致慢性移植物肾病(chronic allogra...     

西罗莫司替代钙调磷酸酶抑制剂方案治疗肾移植后“爬行肌酐”患者的疗效观察（附28例报告）

目的探讨采用西罗莫司替代钙调磷酸酶抑制剂（CNI）方案治疗肾移植后＂爬行肌酐＂患者的临床疗效。方法具有＂爬行肌酐＂表现的28例患者中,术后采用以环孢素（CsA）为主的三联免疫抑制方案20例,采用以他克莫司（FK506）为主的三联免疫抑制方案8例。患者确诊后即停用CsA或FK506,24h后给予西罗莫司,初始剂量6mg,维持剂量为2mg/d,以后根据西罗莫司的血药浓度来调整剂量,使其血药谷浓度维持在5～9μg/L,药物替代前后麦考酚吗乙酯（MMF）及肾上腺皮质激素（激素）的用量不变。随访6个月,定期观察移植物肾功能,记录排斥反应的发生情况,并监测血常规、血糖、血脂、肝功能等指标。结果移植物肾功能明显改善16例,患者的血清肌酐（Scr）由替代前（205±20）μmo1/L降为替代后的（153±18）μmo1/L,内生肌酐清除率（Ccr）由（51±3）ml/min升高为（56±3）ml/min（均为P〈0.05）;移植物肾功能维持稳定8例,移植物肾功能继续恶化2例。治疗中,1例发生急性排斥反应,移植肾失功并恢复血液透析,1例西罗莫司替代后出现明显骨髓抑制而放弃替代治疗,恢复替代前的免疫抑制方案。结论西罗莫司替代CNI治疗肾移植后＂爬行肌酐＂患者是一种比较安全并有效的方法,可明显改善移植物肾功能,但会使患者血脂升高。     

西罗莫司替换钙调磷酸酶抑制剂治疗老年亲属供肾移植受者移植肾功能减退的疗效

目的 观察西罗莫司替换钙调磷酸酶抑制剂(CNI)治疗老年亲属供肾移植受者移植肾功能减退的临床效果.方法 选择病理检查证实为CNI药物肾毒性(11例)和慢性移植肾肾病(chronic allograft nephropathy,CAN)(13例)并出现慢性移植肾功能减退的24例老年亲属供肾肾移植受者,将原有免疫抑制方案环...     

Results of 4-year analysis of conversion from calcineurin inhibitors to mTOR inhibitors in renal transplant patients: single-center experience

In this retrospective study, 83 patients were accepted. Mammalian target of rapamycin (mTOR) group consisting of 37 patients were converted from calcineurin inhibitors (CNI), and the control group included 46 patients (initially CNI-receiving patients). As a control-match of each mTOR inhibitor patient, the succeeding patient with transplantation who continued CNI therapy was chosen. All patients received CNI, MMF, and prednisolone as an immunosuppressive therapy initially. In comparison of two groups, there was no significant difference between sex, donor organ source, donor organ ischemia time, or mismatches. However, mean age between groups was significantly different (mTOR group: 48.3 ± 12, CNI group: 38.6 ± 11, p < 0.001). Decision of conversion to mTOR inhibitors in 30 patients was made by biopsy. The reasons for conversion were determined as CNI nephrotoxicity in 15 patients, chronic allograft nephropathy in 15 patients, malignancy in 6 patients, and renal artery stenosis in 1 patient. Basal glomerular filtration rates (GFRs) were markedly lower in mTOR group than in CNI group (38.8 mL/min vs. 72.7 mL/min). At the end of 48-month follow-ups, GFR increased from 38 mL/min to 54 mL/min in mTOR group; however, it decreased to 53 mL/min from 72 mL/min in CNI group. There was no difference left between the two groups in GFR after 4-year follow-up. Hyperlipidemia was higher in mTOR group. Acute rejection rates were similar. Cytomegalovirus (CMV) disease was more prevalent in CNI group. Graft failure developed due to secondary reasons, causing mortality in both groups. We suggest that conversion to mTOR inhibitors maintains and improves graft functions well.     

Natural inhibitors of cholinesterases: implications for adverse drug reactions

Purpose

Acetylchomesterase and butyrylcholinesterase are two closely related enzymes important in the metabolism of acetylcholine and anaesthetic drugs, including succinylcholine. mvacunum. and cocaine. The sdanaceous glycoalkaloids (SGAs) are naturally occurring steroids in potatoes and related plants that inhibitboth acetylcholinesterase and butyrylcholinesterase. There are many clinical examples of direct SGA toxicity due to cholinesterase inhibition. The aim of thus study was to review the hypotheses that (I) SGAs may be the evolutionary driving force for atypical butyrytcholinesterase alletes and that (2) SGAs may adversely influence the actions of anaesthetic drugs that are metabolized by acetyicholinesterase and butyrylcholinesterase.

Source

The information was obtained by Medicine search and consultation with experts in the study of SGAs and cholinesterases.

Principal finding

The SGAs inhibrt both acetyicholinesterase and butyrylcholinesterase in numerousin vitro andin vivo experiments. Although accurate assays of SGA levels are difficult, published data indicate human serum SGA concentrations at least ten-fold lower than required to inhibit acetyicholinesterase and butyrylcholinesterasein vitro. However, we review evidence that suggests the detary ingestion of SGAs can initiate a cholinergic syndrome in humans. This syndrome appears to occur at SGA levels lower than those which interfere with anaesthetic drug catabolism. The world distribution of solanaceous plants parallels the distribution of atypical alleles of butyrylcholinesterase and may explain the genetic diversity of the butyrylcholinesterase gene.

Conclusion

Correlative evidence suggests that dietary SGAs may be the driving force for atypical butyrylcholinesterase alleles. In addition. SGAs may influence the metabolism of anaesthetic drugs and this hypothesis warrants experimental investigation.     

Evolution of proteinuria after conversion from calcineurin inhibitors (CNI) to sirolimus (SRL) in renal transplant patients: a multicenter study

Conversion from calcineurin inhibitors (CNI) to sirolimus (SRL) has become an option in patients with chronic allograft nephropathy or other conditions. However, in some cases an increase of proteinuria has been reported after such therapeutic intervention. The aim of this study was to characterize the clinical course of this so far unexplained proteinuria after conversion. We performed a retrospective analysis evaluating 94 renal transplant patients from various Spanish centers. Proteinuria (629 determinations) and clinical developments were analyzed between 6 months before and 6 months after conversion. Patients were divided into three groups according to mean proteinuria before conversion (group A: <300 mg/d; group B: 300 to 2000 mg/d; and group C: >2 g/d). The mean proteinuria level was 1.69 g/24 h (n = 312 determinations) before and 2.36 g/24 h after conversion (n = 317 determinations; P = .006), which corresponds to an overall increase of 25% (1.55 to 1.69 g/24 h considering only determinations of 1 month before and 1 month after conversion; P = NS). We could not detect any clear correlation between proteinuria and serum creatinine nor between changes of proteinuria and changes of serum creatinine. A variance analysis for repeated measures showed an increase in proteinuria compared to the preconversion values (P = .003), and when the three groups of preconversion proteinuria were evaluated separately it could be observed that this change in the evolution of proteinuria was almost completely dependent of an increase in the group C (preconversion proteinuria greater than 2 g/d; P = .03), whereas in the other two groups changes were almost irrelevant. Finally, the switch to SRL in renal transplant recipients is followed by an increase in the level of proteinuria predominantly dependent of an increase in patients with high levels of preconversion proteinuria, whereas it seems to be irrelevant in patients without or with light or moderate proteinuria. These results suggest that this might not be a direct effect of SRL.