肝移植术后长期存活慢性肾功能损害受者的免疫抑制方案个体化应用

目的探讨肝移植术后长期存活慢性肾功能损害受者应用个体化免疫抑制方案的疗效。方法选择18岁以上、肝移植术后2年以上、入组前采用以他克莫司(FK506)为基础免疫抑制方案、肝功能正常而肾功能损害的受者,共32例。根据免疫功能评分和白细胞计数制定个体化免疫抑制方案,以FK06用量最小化为原则,转换为麦考酚吗乙酯(MMF)或西罗莫司,并调整其用量。调整后至少每个月随访1次,进行肝功能、肾功能、血常规检查和免疫功能评估。结果 32例受者经个体化免疫抑制方案治疗,随访(24.3±7.6)个月,个体化治疗后各时段的肾小球滤过率(GFR)均较此前有明显提高(均为P<0.01),以调整用药后1个月最明显。无发生排斥反应。结论根据免疫功能评分和白细胞计数制定个体化免疫方案,使FK506用量最小化,可以有效改善肝移植术后长期存活的受者的肾功能,并不增加排斥反应的发生率。     

个体化免疫抑制治疗的理论与实践

新型免疫抑制剂在降低急性排斥反应发生率的同时,也因其狭窄的治疗指数以及药代动力学、药效动力学的个体差异而导致的药物毒性,很大程度上影响了移植物以及受者的长期存活。免疫抑制个体化治疗的概念产生于需要尽量减少药物的不良反应的同时又要优化这些药物的疗效。因中毒剂量与有效剂量之间的差距很小,故免疫抑制个体化治疗非常重要,并且越来越受到移植界的重视。基因多态性可影响药物的药代动力学和药效学特性,所以器官移植受者对药物的反应可能会因个体间基因多态性而有所不同。因此,个体化治疗就是以每个受者的信息为基础决定治疗策略,根据受者的基因组成、表达变化以及药物的治疗效果、不良反应等不同个性,对每个受者进行最适宜的治疗。     

药物基因组学:优化器官移植受者免疫抑制治疗的新策略

对于治疗指数(TI)异常狭窄的免疫抑制剂来说，如何在治疗效能和毒副作用两个方面取得平衡，一直是一个难题。尽管治疗药物监测(TDM)已经广泛应用于临床，但其本身的局限性使得免疫抑制剂的个体化用药至今依然举步维艰。基因组时代的来临催生了药物基因组学，这是一门寻找药物治疗与个体遗传背景差异之间关系的科学。本文将其在器官移植受者免疫抑制治疗方面的研究现状及应用前景做一简要综述。     

新型免疫抑制剂在肾移植中的应用

近年来,各种新型免疫抑制剂(immunosuppressant)不断地被开发和应用,使得临床医师们有了更大的空间来探索新的免疫抑制方案,做到合理而精确的个体化用药(individual-ized medication),降低药物的不良反应,达到更好的免疫抑制效果,提高肾移植患者长期存活率.本文就肾移植中新型免疫抑制剂的应用进展进行探讨.     

中国肝癌肝移植临床实践指南（2014版）

肝移植是被全世界认可的治疗终末期肝病的有效手段之一.目前,肝移植在全国范围内已得到广泛开展,亟待相关临床实践指南来指导全国肝移植工作更规范、有效、安全地开展.中华医学会器官移植学分会、中华医学会外科学分会移植学组及中国医师协会器官移植医师分会组织专家制订了《中国肝癌肝移植临床实践指南（2014版）》,重点阐述肝移植受者选择标准、术前降期治疗、受者抗病毒治疗、受者免疫抑制剂应用、术后肿瘤复发的防治5部分内容.米兰标准是肝癌肝移植受者选择的参考基准,而杭州标准是对米兰标准局限于肿瘤形态学的巨大突破.肝癌肝移植术前肿瘤降期治疗可使不满足肝癌肝移植受者选择标准的患者能够被纳入移植标准,获得肝移植机会.对于乙型病毒性肝炎肝癌肝移植受者行抗病毒治疗,有助于降低移植术后乙型病毒性肝炎复发率,提高受者长期生存率.目前主张个体化的低剂量免疫抑制方案以达到最大限度保护移植肝脏功能,同时减轻其毒副作用,减少移植后肝癌复发.肝癌肝移植术后复发的防治可采用手术、TACE、局部消融以及放射免疫、靶向治疗、系统性化疗等手段,为受者制订个体化治疗方案.     

中国肝移植受者代谢病管理专家共识(2015版)

肝移植受者是罹患代谢病的高危人群。肝移植术后代谢病的发生与免疫抑制剂、心血管疾病、肾病、感染等关系密切,在很大程度上影响受者的长期存活。中国医师协会器官移植医师分会、中华医学会外科学分会器官移植学组、中华医学会器官移植学分会肝移植学组组织专家制定了《中国肝移植受者代谢病管理专家共识(2015版)》,旨在为中国肝移植受者术后代谢病的防治提供建议,以期改善受者的长期生存。代谢病以肥胖症、糖尿病、高血压病、高脂血症为典型特征。代谢病的防治应以改变饮食习惯和生活方式为基础,调整免疫抑制方案,并适当使用药物治疗。建议在保证移植肝功能的前提下将相关可能导致代谢病的免疫抑制剂减量,含霉酚酸酯的无激素及钙调神经磷酸酶抑制剂最小化方案对减少肝移植术后代谢病的发生有益。     

肾移植受者新发恶性肿瘤后免疫抑制方案的调整

目的总结肾移植后新发恶性肿瘤患者免疫抑制治疗方案的调整经验。方法分析1978年1月至2011年6月期间3279例肾移植受者中67例新发恶性肿瘤患者的临床资料。结果术后新发恶性肿瘤中,泌尿生殖系统恶性肿瘤最为常见（56.7%）。予以外科手术与免疫抑制剂减至半量或将钙调磷酸酶抑制剂转换为雷帕霉素相结合的个体化治疗方案。5年患者存活率为30%。结论对于移植后新发肿瘤患者,宜采取外科手术与免疫抑制剂减量或换药相结合的个体化治疗方案。     

肾移植免疫抑制剂的新进展

九十年代以来 ,随着移植免疫学、免疫药理学等相关学科的飞速发展 ,人们开发出一些新型免疫抑制药物用于肾移植。动物实验及某些Ⅲ期临床实验已证明这些免疫抑制剂能显著降低肾移植后急性排斥反应发生率 ,其中一些药物尚有防治慢性排斥反应的作用 ,而且感染和恶性肿瘤的发病率未见升高。这些作用机制不同的新型免疫抑制剂为临床医生提供了组合不同免疫抑制剂的全新方案 ,将阻断不同免疫激活途径的药物有选择地联合起来 ,并且尽量使药物间的毒副作用不重叠 ,使每个药物的用量都可以减少到低于毒性水平。这样的免疫抑制治疗也使得治疗的个体化…     

细胞增殖信号传递抑制剂在心脏移植中的应用进展(续)

三、细胞增殖信号传递抑制剂（PSI）在心脏移植中的应用进展 1．预防和治疗急性排斥反应：器官移植后急性排斥反应是导致移植物功能丧失以及影响长期存活的重要因素。目前，评价一种免疫抑制剂效果的最主要的指标是看其对急性排斥反应的抑制程度（有效性）及药物对受者的毒副作用大小（安全性）。西罗莫司作为心脏移植术后免疫抑制方案中的基础用药，急性排斥反应发生率比硫唑嘌呤明显降低。     

中国器官移植术后结核病临床诊疗指南(2016版)

<正>结核病是实体器官移植(solid organ transplantation,SOT)术后一种较为少见但后果严重的感染性疾病,SOT受者结核病患病率明显高于正常人群。由于免疫抑制剂的长期使用,抗结核药物肝肾毒性及其与免疫抑制剂相互的代谢干扰,使得SOT受者临床抗结核治疗复杂性明显增加,致死率明显高于非移植结核病患者。随着器官移植受者以及结核病患病人数的增加,需要建立规范的诊疗程序和治疗指导原则,以便合理制定化学治疗和免疫抑制方案,     

Reduction of Plasma Fibrinogen, Immunoglobulin G, and Immunoglobulin M Concentrations by Immunoadsorption Therapy with Tryptophan and Phenylalanine Adsorbents

Abstract Immunoadsorption (1A) therapy with tryptophan (TR-350) or phenylalanine (PH-350) adsorbents has been used to reduce the concentration of serum antibodies in human lymphocyte antigen (HLA)-immunized patients. Other forms of plasma purification have been reported to reduce the level of fibrinogen, which affects the blood properties. In this study we investigated the effects of IA therapy using both adsorbents on plasma fibrinogen and immunoglobulins G and M in 13 patients (8 patients were treated with TR-350, and 5 patients were treated with PH-350). During each session 1 plasma volume (2.8 ± 0.4 L of plasma) was processed through the immunocolumn and then returned to the patient together with the blood cells. Compared with the pretreatment values, the plasma fibrinogen, IgG, and IgM concentrations were significantly reduced after IA therapy (p < 0.01 for TR-350; p < 0.04 for PH-350). There was a positive correlation between the degree of reduction of plasma proteins and the number of IA treatments given. A nonpara-metric test (Wilcoxon's signed-rank test or the Mann-Whitney test) was used for statistical analysis. We conclude from our study that IA therapy effectively lowers the plasma levels of fibrinogen, IgG, and IgM and thus can be considered a valuable alternative to other blood purification methods.     

Is the recovery profile of mivacurium independent of the rate of decay of its plasma concentration in patients with normal plasma cholinesterase activity?

Background: The duration of action of muscle relaxants is poorly correlated to the rate of decay of their plasma concentration. The plasma concentration of mivacurium may rapidly decrease below its active concentration because of the extensive hydrolysis of mivacurium. By inflating a tourniquet on one upper limb for 3 min after the administration of atracurium, mivacurium or vecuronium, we studied the influence of the initial decline of their plasma concentration on their effect. Methods: In 50 patients anaesthetised with thiopental, isoflurane and fentanyl, the effect of bolus doses of 0.15 or 0.25 mg . kg^?1 mivacurium (MIV 15, MIV 25), 0.3 or 0.5 mg . kg^?1 atracurium (ATR 30, ATR 50) and 0.06 or 0.1 mg . kg^?1 vecuronium (VEC 06, VEC 10) were measured on both arms (evoked response of the adductor pollicis to train-of-four stimulation every 12 s), a tourniquet being applied on one arm just before and during 3 min after the muscle relaxant bolus. Results: Tourniquet inflation of 3 min almost abolished the neuromuscular effect of mivacurium. In the vecuronium groups and in the ATR 50 group, tourniquet inflation did not modify the maximum degree of depression of the twitch response. Also, the duration of action of vecuronium was unaffected by the tourniquet. In the ATR 30 group, times to return of the twitch response to 25% (duration 25%) and 75% (duration 75%) of control response were significantly shorter in the cuffed arm, 23 min vs 27 min, and 41 min vs 45 min, respectively. In the ATR 50 group, only duration 25% was significantly shorter in the cuffed arm (41 min vs 45 min). Conclusion: The results suggest that the rate of decline of the plasma concentration of mivacurium is so rapid, that a very low and almost clinically ineffective concentration is present as soon as 3 min after its administration. The results also indicate that the recovery from a mivacurium-induced neuromuscular blockade is not influenced by the rate of decay of its plasma concentration in patients with genotypically normal plasma cholinesterase.     

Membranes in Artificial Organs

Abstract: Membrane processes play a pivotal and enabling role in modern replacement therapy for acute and chronic organ failure and in the management of immunologic diseases. In fact, virtually all contemporary extracorporeal blood purification methods employ membrane devices, and the next generation of artificial organs and tissue engineering therapies are almost certain to be similarly grounded in membrane technology. In this short essay, we comment on the similarities and differences among synthetic membranes and their natural counterparts and also provide a critical overview of the demographics and technology of hemodialysis, hemofiltration, apheresis, oxygenation, and emerging membrane technologies and applications.     

The multiply injured child

Blunt trauma is the principal cause of childhood death in many developed countries. This review outlines the differences between adults and children with respect to resuscitation and treatment of orthopaedic injuries in a child with polytrauma. Recent advances in techniques of fracture stabilization are reported.     

Dilemma of Membrane Biocompatibility and Reuse

Abstract: Numerous articles have been published on the multiple use of dialyzers and on the effect of different reprocessing chemicals and techniques on the dialyzer biocompatibility and performance. The results often appear contradictory, especially those comparing standard biocompatibility parameters. Despite this confusion, a discerning review of the published works allows certain limited conclusions to be drawn. Reprocessing of used hemodialyzers changes the biocompatibility profile of a dialyzer as defined by the parameters complement activation. leukopenia, and cytokine release. The effect of reprocessing depends on the chemicals and reprocessing technique applied and also on the type of membrane polymer being subjected to the reprocessing procedure. Reports of pyrogenic reactions indicate that the flux of the membrane also influences how suitable it is for safe reuse. An increased risk of allergic and pyrogenic reactions appears to be associated with dialyzer reuse. Furthermore, there has been a lack of investigations into the immunologic effect of the layer of adsorbed and chemically altered proteins that remains on the inner surface of reprocessed dialyzers. We conclude that the clinical benefit of dialyzer reuse cannot be generally accepted from a biocompatibility point of view.     

The analgesic effect of racemic ketamine in patients with chronic ischemic pain due to lower extremity arteriosclerosis obliterans

Background : Ketamine in sub-dissociative doses has been shown to have analgesic and phantom-Limb pain, where conventional treatment has often failed. Chronic ischemic pain due to lower extremity arteriosclerosis obliterans often responds poorly to analgesics, and the pain-generating mechanisms are not well understood.
Methods : Eight patients with rest pain in the lower extremity due to arteriosclerosis obliterans were given sub-dissociative doses of 0.15, 0.30, or 0.45 mg/kg racemic ketamine and morphine 10 mg as a 5-min infusion on four separate days in a cross-over, double-blind, randomised protocol. Plasma levels of (S)- and (R)-ketamine and their nor-metabolites were analysed with an enantioselective high-performance liquid chromatography (HPLC) method. Pain levels were evaluated with a visual analogue scale (VAS).
Results : Individual pain levels were highly variable during and after all the infusions but the pooled pain levels showed a dose-dependent analgesic effect of ketamine with a transient but complete pain relief in all patients at the highest dose (0.45 mg/ kg). Side-effects, mainly disturbed cognition and perception, were pronounced and dose-dependent. Morphine 10 mg had an analgesic peak at 20 min and 5/8 patients had complete pain relief. The remaining 3 patients also had high baseline pain scores, indicating a higher analgesic potency for the 0.30 and 0.45 mg/ kg ketamine doses than for morphine 10 mg.
Conclusion : We have demonstrated a potent dose-dependent analgesic effect of racemic ketamine in clinical ischemic pain. Due to a narrow therapeutic window, this analgesic effect is probably best utilised in combination with other analgesics.     

Intravenous endotoxin does not increase tissue extravasation of albumin in rats

Background : It is unclear whether activation of the inducible nitric oxide synthase (iNOS) increases or decreases the extravasation of plasma.
Methods : Chloralose anaesthetised male Wistar rats received E. coli lipopolysacharide (LPS), 3 mg kg^-1 i.v., or the corresponding volume of saline, 3 or 5 h before the end of the experiment. Mean arterial pressure (MAP) and heart rate (HR) were recorded. Tissue clearance of radio-labelled albumin, during the last 2 h of each experiment, was determined by a double-isotope method. In separate animals, the serum concentration of nitrite and nitrate was determined, 5 h after LPS or the solvent.
Main Results : LPS initially decreased MAP and lastingly increased HR. In the 3-h LPS animals (n=8), tissue plasma clearance was lower in the heart and calf muscle and increased only in diaphragm, compared to corresponding control animals (n=8). In the 5-h LPS rats, clearance was lowered (n=8) in the entire gastrointestinal tract and in testes, compared to controls (n=8). The serum nitrite/nitrate concentration was higher in animals given LPS (n=6) than in controls (n=6).
Conclusion : After LPS, tissue clearance of albumin was not increased in any major tissue, in spite of increased serum levels of NO end products. Apparently, after activation of iNOS, the augmented release of NO is not necessarily associated with increased albumin extravasation.     

Adrenaline markedly improves thoracic epidural analgesia produced by a low-dose infusion of bupivacaine, fentanyl and adrenaline after major surgery: A randomised, double-blind, cross-over study with and without adrenaline

Background: Basic pharmacological research indicates that there are synergistic antinociceptive effects at the spinal cord level between adrenaline, fentanyl and bupivacaine. Our clinical experience with such a mixture in a thoracic epidural infusion after major surgery confirms this. The objectives of the present study were to evaluate the effects on postoperative pain intensity, pain relief and side effects when removing adrenaline from this triple epidural mixture. Methods: A prospective, randomised, double-blind, cross-over study was carried out in 24 patients after major thoracic or abdominal surgery. Patients with only mild pain when coughing during a titrated thoracic epidural infusion of about 10 ml · h^?1 of bupivacaine 1 mg · ml^?1, fentanyl 2 μg · ml^?1, and adrenaline 2 μg · ml^?1 were included. On the 1^st and 2^nd postoperative days each patient was given a double-blind epidural infusion, at the same rate, with or without adrenaline. The effect was observed for 4 h or until pain when coughing became unacceptable in spite of a rescue analgesic procedure. Rescue analgesia consisted of up to two epidural bolus injections per hour and i.v. morphine if necessary. All patients received rectal paracetamol 1 g, every 8 h. Fentanyl serum concentrations were measured with a radioimmunoassay technique at the start and end of each study period. Main outcome measures were extent of sensory blockade and pain intensity at rest and when coughing, evaluated by a visual analogue scale, a verbal categorical rating scale, the Prince Henry Hospital pain score, and an overall quality of pain relief score. Results: The number of hypaesthetic dermatomal segments decreased (P <0.001) and pain intensity at rest and when coughing increased (P <0.001) when adrenaline was omitted from the triple epidural mixture. This change started within the first hour after removing adrenaline. After 3 h pain intensity when coughing had increased to unacceptable levels in spite of rescue analgesia (epidural bolus injections and i.v. morphine). Within 15–20 min after restarting the triple epidural mixture with adrenaline, pain intensity was again reduced to mild pain when coughing. Serum concentration of fentanyl doubled from 0.22 to 0.45 ng · ml^?1 (P <0.01), and there was more sedation during the period without adrenaline. Conclusions: Adrenaline increases sensory block and improves the pain-relieving effect of a mixture of bupivacaine and fentanyl infused epidurally at a thoracic level after major thoracic or abdominal surgery. Serum fentanyl concentrations doubled and sedation increased when adrenaline was removed from the epidural infusion, indicating more rapid vascular absorption and systemic effects of fentanyl.