基于SVR的他克莫司血药浓度的预测模型

为了准确预测肾移植患者服用他克莫司之后的血药浓度,本研究利用LIBSVM软件包建立了以性别、年龄、体重、移植天数、相关生化指标、药剂量等作为输入因子的支持向量机回归预测模型.同时结合收集整理的服用他克莫司的肾移植患者相关数据进行实验,最终结果显示支持向量回归预测模型的精确度能达到75.00%,表明支持向量机回归模型在血药浓度上能取得良好的预测效果,有很好的应用前景.     

他克莫司对肾移植受者外周血NK和NKT细胞比例的影响及临床意义

他克莫司(Tacrolimus)是一种强效免疫抑制剂,现已广泛应用于肾脏、肝脏及心脏移植,有效减低了排异反应的发生,提高了移植受者的存活率.但是他克莫司个体药代动力学差异大,不同个体对其血药浓度的敏感性及耐受性有差异,故单纯依靠血药浓度监测不能有效反映移植受者的免疫状态.因此如何了解移植受者的免疫状态,指导免疫抑制剂的个体化应用,在免疫抑制不足及免疫过度之间寻找平衡,成为困扰移植医生的问题.NK细胞(natrural killer cell)是天然免疫系统的主要效应细胞.     

他克莫司血药浓度的方法学评价

评价德灵公司均相酶法他克莫司（Tacrolimus）试剂盒检测他克莫司血药浓度的可靠性。用本方法在日立7600分析仪上对其检测他克莫司血药浓度的精密度、线性、回收率、相关性等指标进行评价。本方法的评价表明,在他克莫司质控浓度为5.0ng/mL和15.0ng/mL时,批内变异系数分别为14.17%、10.66%,批间变异系数分别为12.56%、9.92%。平均回收率95.98%,在1.5~30ng/mL范围内,线性良好。与微粒子酶联免疫吸附法测定相关性良好（r=0.93）。结论：该方法操作简便、快速、准确,多通道检测,适用于临床上对肝肾移植患者他克莫司药物谷值浓度的监测。     

肾移植受者CYP3A5基因多态性对他克莫司血药浓度及疗效的影响*

背景：关于欧美人群中CYP3A5基因与他克莫司血药浓度之间关系已有报道,然而这些研究的数据多来自于移植后1个   月~1年,缺乏移植后早期的资料。 目的：探讨CYP3A 基因多态性与肾移植受者他克莫司血药浓度的关系,分析CYP3A5基因型对肾移植后排斥反应和毒性及不良反应的影响。 方法：按CYP3A5基因多态性将45例采用他克莫司+霉酚酸酯+泼尼松三联免疫抑制方案的肾移植患者分为*1/*1型组(11例)、*1/*3型组(15例)和*3/*3型组(19例),他克莫司初始剂量均为0.15 mg/(kg•d),1周后根据目标浓度调整他克莫司剂量。 结果与结论：术后7 d,1个月,3个月* 3/* 3型组他克莫司血药浓度/剂量比显著高于* 1/*3型组和*1/*1型组(P < 0.05) ;3个月内*1/*1型组急性排斥反应的比例显著高于*1/*3型组和*3/*3型组(P < 0.05)。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型组。结果可见*1/*1基因型患者在肾移植早期难以达到有效目标血药浓度,使该组3个月内的急性排斥反应发生率明显升高,不合适采用目前他克莫司的初始剂量方案作为早期的抗排斥反应方案;*3/*3基因型患者他克莫司血药浓度明显升高,使3个月内毒性及不良反应发生率也明显升高。因此,根据CYP3A5 基因多态性作为他克莫司个体化用药的依据,既能使* 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,提高肾移植的临床效果。      

肾移植后吗替麦考酚酯联合低剂量他克莫司加皮质激素的应用

背景：足量吗替麦考酚酯联合低剂量他克莫司和皮质激素可能是目前针对肾移植受者的理想治疗方案,该方案因其具有低肾毒性以及较少的不良反应和较强的免疫抑制作用已在临床上开始逐渐普及。 目的：以吗替麦考酚酯联合标准剂量他克莫司加皮质激素为对照,评估吗替麦考酚酯联合低剂量他克莫司加皮质激素在肾移植患者中的疗效和安全性。 方法：210例首次接受单一器官同种异体移植的肾移植成人受者被随机分配到他克莫司标准剂量组(n=104)和他克莫司低剂量组(n=106),并接受12个月的治疗。主要疗效指标包括肾移植后第12个月慢性移植物损伤指数(CADI)以及肾小球滤过率;次要疗效指标主要包括急性排斥反应发生率、治疗失败率以及患者和移植肾的存活率等;同时对新发移植后糖尿病,新发高血压,新发高血脂等安全性指标进行评价。 结果与结论：两组绝大多数患者使用了足量的吗替麦考酚酯(1.5 g/d及以上)。在他克莫司剂量方面,他克莫司标准剂量组大多数受试者的实际血药浓度水平偏低,与低剂量组的实际血药浓度水平类似,由此反映了吗替麦考酚酯联合低剂量他克莫司和皮质激素方案已广泛为目前临床医师接受和使用。因此,两组也表现出类似的疗效和安全性：他克莫司标准剂量组和低剂量组肾移植后12个月肾脏病理改变的平均CADI评分分别为1.82分和2.13分(P=0.081 3),平均肾小球滤过率分别为77.08 mL/min和       80.12 mL/min(P=0.794 9),急性排斥反应发生率分别为2.6%和5.2%(P=0.681 2),患者和移植肾存活率分别高达100%和99.1%(P=1.000 0)。在安全性方面,他克莫司标准剂量组和低剂量组新发移植后糖尿病的比例分别为2.9%和1.9%,新发高血脂的比例分别为2.9%和3.8%。结果显示在吗替麦考酚酯联合他克莫司和皮质激素的肾移植免疫抑制治疗方案中,足量吗替麦考酚酯的使用,可以减少他克莫司的剂量,在保持较强的免疫抑制作用即成功地降低急性排斥反应发生率的同时,显著减少他克莫司所致的肾毒性、高血脂和新发糖尿病等不良反应,较好地达到了疗效和毒性间的平衡。     

肾移植后他克莫司与五酯胶囊合用致高血钾症1例

背景：肾移植患者由于免疫抑制剂的药物肝毒性,肝功能异常发生率高,对临床出现肝功能异常者,需护肝治疗。但合用护肝药必须监测免疫抑制剂浓度。 目的：探讨肾移植患者他克莫司与五酯胶囊合用对他克莫司浓度及血生化的的影响。 方法：回顾性分析1例以他克莫司为免疫抑制剂的肾移植患者加服及停用五酯胶囊时他克莫司浓度及肾功能、血生化变化。患者因“慢性肾小球肾炎,慢性肾功能不全”于1998-06起行血液透析治疗。2000-08行同种异体尸体肾移植,移植后免服他克莫司+吗替麦考酚酯+泼尼松。移植后4个月患者出现肝功能异常,加用联苯双酯。2010-07-25患者停用联苯双酯,改服五酯胶囊。2010-07-29患者停用五酯胶囊。 结果与结论：服用他克莫司的肾移植受者,合用五酯胶囊,他克莫司血浓度显著升高。由5.3 ng/L升至24.7 ng/L,并合并高血钾症,停用五酯胶囊1周,他克莫司浓度由24.7 ng/L降至6.1 ng/L,血钾由6.4 mmol/L降至4.6 mmol/L。提示移植肾功能稳定的肾移植受者,在加用五酯胶囊,必须严密监测他克莫司血浓度及肝肾功能、电解质,及时调整他克莫司用量,保护移植肾功能。     

肾移植后不同免疫抑制剂抗排斥反应的临床应用及不良反应

背景：如何利用免疫抑制剂之间的协同作用,发挥最佳疗效是肾移植后抗排斥反应的关键所在,如何做到个体化用药,提高疗效避免不良反应的发生显得尤为重要。 目的：评价不同免疫抑制剂对肾移植受者和移植肾存活的影响,以便更好地避免药物不良反应。 方法：应用计算机检索1999-01/2009-10 CNKI数据库相关文献,检索词为“免疫抑制剂,肾移植,排斥反应”。选择文章内容与肾移植免疫抑制剂有关者,同一领域文献则选择近期发表或发表在权威杂志文章,入选25篇文献进行综述。 结果与结论：任何一种免疫抑制剂在发挥免疫抑制作用时都会伴有一定毒副作用,临床上应尽量避免不良反应发生。联合用药抗排斥反应已达成共识,事实证明无论采用何种联合方式,均有单一用药无可替代的优势。如何利用免疫抑制药之间的协同作用,发挥最佳疗效是临床关键所在,医生应严密监测患者血药浓度,做到个体化用药,尽可能降低肾移植后排斥反应发生率。关键词：免疫抑制剂;肾移植;排斥反应;环孢素A;吗替麦考酚酯;他克莫司 doi:10.3969/j.issn.1673-8225.2012.18.032      

他克莫司用于治疗口腔扁平苔癣的疗效观察

目的：观察他克莫司用于治疗有症状的口腔扁平苔癣(OLP)的疗效。方法选取我院就诊OLP患者40例,局部应用他克莫司后了解用药后病损的症状,病变改善的时间,当前用药情况和副作用。结果40例患者中35例(87.5%)在局部应用他克莫司后症状有所改善,32(80%)例在使用后局部病变几近痊愈,3例(7.5%)认为病变没有变化,1(2.5%)人反应病变增多,1例(2.5%)反应症状加重,10(25%)人报告副作用与之前的报道一致(灼烧感,刺激疼,麻刺感等)。结论局部应用他克莫司对于OLP的治疗有效,大部分患者在用药1个月后感觉症状有所改善,但疗效不持久,停药后容易复发。     

他克莫司和环孢素A对肾移植后患者炎性细胞因子和血脂的影响

背景：环孢素A与他克莫司是肾移植后临床广泛应用的免疫抑制剂。 目的：观察他克莫司和环孢素A对肾移植后炎性细胞因子和血脂的影响。 方法：选择首次接受同种异体肾移植后患者112例,随机分为环孢素A组和他克莫司组,移植后分别给予环孢素A+吗替麦考酚酯+糖皮质激素三联疗法与他克莫司+吗替麦考酚酯+糖皮质激素三联疗法。 结果与结论：他克莫司组的1年人/肾存活率、治疗逆转率高于环孢素A组(P < 0.05),急性排斥反应发生率低于环孢素A组(P < 0.05);移植后1个月及1年的血清白细胞介素2,6,8和血糖水平高于移植前(P < 0.05),低于环孢素A组(P < 0.05),血清白细胞介素4,10低于移植前(P < 0.05),高于环孢素A组(P< 0.05);移植后1个月的血清总胆固醇、三酰甘油和低密度脂蛋白胆固醇高于移植前(P < 0.05),但低于环孢素A组(P < 0.05);移植后1年的血清总胆固醇和低密度脂蛋白胆固醇低于环孢素A组(P < 0.05)。说明他克莫司可通过抑制肾移植后炎性细胞因子释放,改善糖脂代谢等途径降低患者的排斥反应,提高肾移植的存活率。     

他克莫司血药浓度对肾脏移植病人血肌酐水平的影响

<正>目的:探讨他克莫司的血药浓度对肾脏移植病人血肌酐的影响。方法:选择本院行肾脏移植手术成功的68例患者,按照患者他克莫司的血药浓度将68例肾移植患者分为<5ng/ml组(n=23)、>20ng/ml组(n=18)和5～20ng/ml组(n=27),监测各组血肌酐(Scr)水平。另选40例同期健康体检者为对照组。结果:>20ng/ml组患者血肌酐水平(188.21±15.39μM)高于5～20ng/ml组(98.61±20.57μM)和<5ng/ml组(150.72±19.55μM),<5ng/ml组高于5～20ng/ml组,且高于对照组(74.04±15.92μM),差异有统计学意义(P<0.05或P<0.01)。结论:监测他克莫司的血药浓度并调整药物剂量对肾移植患者具有重要的临床意义。     

Erythropoiesis and erythropoietin levels in renal transplant recipients

Summary Moderately increased blood levels of endogenous erythropoietin (Epo) usually induce complete restoration of renal anemia after successful kidney transplantation. With good graft function erythropoiesis is maintained by normal Epo serum levels. Persistent anemia can be related to iron deficiency, low excretory graft function, and high dosage of immunosuppressive agents leading to marrow suppression or nephrotoxicity. Acute early rejection is associated with a fall in serum Epo and abrogation of reticulocytosis. About 15% of recipients fail to exhibit the normal feedback regulation and develop a mostly transient post-transplant erythrocytosis. Both an increased sensitivity of erythrocytic progenitors to Epo and inappropriate Epo secretion by the native kidneys may account for this overshooting reaction.Abbreviations Epo erythropoietin - rHuEpo recombinant human erythropoietin - RIA radioimmunoassay - ELISA enzyme-linked immunosorbent assay - RTx renal transplantation - CAPD continuous ambulatory peritoneal dialysis - PTE posttransplant erythrocytosis - Aza azathioprine - CsA cyclosporine A - ALG antilymphoblast globulin     

Cytomegalovirus infection in renal transplant recipients

Cytomegalovirus (CMV) belongs to the family of human herpes viruses. It is also known as the human herpes virus 5 (HHV-5). In immunocompromised host it becomes significant pathogen, causing the spectrum of different symptoms and affecting different tissues and organs. Epidemiologic forms of CMV infection include primary infection, reactivation or secondary infection, and superinfection or reinfection. CMV infection has direct and indirect effects. Direct effects occur at the time of highest viraemia with severe clinical presentation. To the contrast, indirect effects occur at the time of asymptomatic viraemia as the consequence of immunologic response. Indirect effects are mediated by cytokines, chemokines and growth factors. Diagnosis of CMV infection is based on virus detection in body fluids and tissues. There are several diagnostic methods for detection of CMV, and their use is primarily determined by the possibilities of the specific transplantation center. Regarding the risk of CMV infection, several categories of renal transplant recipients may be identified. The main factor for estimation of risk for development of CMV infection is donor and recipient serological status. The highest risk is associated with combination of CMV seropositive donor and CMV seronegative recipient (D+/R-). CMV infection was often fatal before introduction of potent antiviral drugs in therapeutic protocols. Contemporary treatment has significantly decreased mortality rate from the CMV infection. Several drugs are used for prevention and treatment of CMV infection: hyper immune gamma globulin, gancyclovir, valgancyclovir, valacyclovir and acyclovir, depending on the kind of treatment (prophylaxis or preemptive treatment). In the case of CMV disease, the best results may currently be achieved with the combination of hyper immune gamma globulin and intravenous gancyclovir.     

Cardiovascular pathology in renal transplant recipients

Various cardiovascular complications are among the major causes of mortality in renal transplant recipients. The authors examined the cardiovascular findings from necropsy of 18 renal transplant patients. All but three of the patients showed one or more pathological abnormalities. Five patients exhibited severe coronary arteriosclerosis with acute myocardial infarction with a history of myocardial infarction noted in four patients. In addition, one patient showed moderate and two showed mild coronary arteriosclerosis. Also prevalent were left ventricular (LV) hypertrophy (10/18), right ventricular (RV) hypertrophy (7/18), LV dilatation (4/18), RV dilatation (8/18), left atrial dilatation (3/18), and right atrial dilatation (6/18). Valvular abnormalities consisted of dilatations of mitral ring (1/18), pulmonic valve (2/18), and tricuspid valve (3/18). Pericarditis was found in two patients and aortic atherosclerosis in ten patients. Findings on routine chest roentgenograms and electrocardiograms did not always correspond with the anatomical findings noted on necropsy examination. The results demonstrate a marked increase in the incidence of various cardiac abnormalities in renal transplant recipients.     

Cutaneous complications in renal transplant recipients

Systematic review of the histologic characteristics of skin lesions biopsied and/or resected in a group of 580 renal transplant recipients collected over a 16-year period showed a total of 170 specimens from 120 patients. In this group there were 41 benign tumors, 22 infections, 35 inflammatory dermatoses, and 13 miscellaneous lesions. Fifty-nine lesions were malignant, and half of these were squamous cell carcinomas (SCCs). None were lethal or metastasized, although deeply invasive local recurrences and multiple lesions were common. Comparison with SCCs from a control group showed no clearcut differences with respect to level of invasion, grade, pattern, or presence of actinic change. Most of these lesions were found in sun-exposed areas, were associated with actinic changes, and with actinic keratoses. Problems in differentiating SCC from keratoacanthoma and the clinical implications of these difficulties are discussed in conjunction with a review of the literature.     

Arterial hypertension in renal transplant recipients

Arterial hypertension develops in up to 80% of renal transplant recipients. Uncontrolled hypertension induces left ventricular hypertrophy, heart failure and death, but also promotes deterioration of allograft function. Cadaveric transplantation, delayed graft function, renal artery stenosis, presence of native kidneys, increased body weight and therapy with calcineurin inhibitors and steroids have been associated with an increased incidence of hypertension after kidney transplantation. Cyclosporine increases both systemic and renal vascular resistance, enhances sympathetic activation, endothelin production and, possibly, decreases vascular relaxation by decreasing the generation of nitric oxide. Tacrolimus has less pronounced prohypertensive role after renal transplantation. Corticosteroids contribute to the development of hypertension, since their withdrawal results in a significant decrease of blood pressure in the majority of patients. Renal artery stenosis occurs in almost 12% of hypertensive renal transplant recipients. It is a correctable cause of hypertension, and for this reason should be investigated in all suspected patients. Doppler ultrasonography is used as the screening method that is highly sensitive and specific in the hands of a well-experienced investigator. However, dependence of the method on the experience of the investigator is its major drawback. Magnetic resonance angiography and spinal computed tomography angiography are useful noninvasive methods, but arteriography remains a method for establishing the definitive diagnosis. Percutaneous balloon angioplasty, with or without placement of the stent, is successful in the majority of patients, but with a high incidence of restenoses (20%). Surgery is indicated for stenoses that cannot be treated with angioplasty or that recur. Auto-transplantation of the kidney with complex stenoses of graft arteries is useful in selected cases. Posttransplant hypertension should be aggressively treated to prevent the development of end-organ damage. Every effort should be invested in reducing immunosuppression when appropriate, together with salt restriction and weight reduction. Calcium channel blockers have good antihypertensive properties accompanied with minimization of cyclosporine-induced renal vasoconstriction. Angiotensin-converting enzyme inhibitors (ACEi) should be used in patients with proteinuria. Renal function should be carefully monitored after their introduction since they may cause transitory deterioration of glomerular filtration and/or hyperkaliemia. ACEi can induce anemia in renal transplant recipients, side effect that is often used in the treatment of posttransplant erythrocytosis. All other antihypertensive drugs could be used, with minoxidil being the most potent one. Patients with resistant hypertension should be investigated for the presence of renal artery stenosis. After exclusion of rejection, renal artery stenosis and recurrent disease, in cases of severe hypertension, native kidneys laparoscopic nephrectomy should be considered.     

Gastrointestinal complications in renal transplant recipients

In a 16-year study, 101 gastrointestinal (GI) lesions (16 fatal) developed in 580 renal transplant recipients seen in the authors' institution. Lesions were seen at all levels of the GI tract, but colonic lesions were the most common (42 patients) and were fatal in 8. Segmental ischemic colitis was the single most common morphologic diagnosis (14 patients). Seven of these patients had an unusual syndrome that clinically, at surgery, and on gross examination resembled inflammatory bowel disease. Lesions were segmental; involved bowel was thickened and erythematous with creeping peritoneal fat. Histologically, mucosa adjacent to the frank necrosis showed simplification and striking epithelial atypia. Specific identifiable viral infections caused 28% of the GI complications in this series. This incidence is higher than that in other reported series. Most of these infections can be diagnosed from endoscopically obtained material. These findings have therapeutic implications.     

Neurological complications in renal transplant recipients

Renal transplantation is method of choice for treatment of patients with end-stage renal disease without contraindications for immunosuppressive therapy. Neurological complications occur frequently in renal transplant recipients. They may be the consequence of immunosuppressive treatment, but more often evolve as the consequence of previous disturbances which developed during the state of uraemia and treatment with dialysis. The most pronounced neurotoxic effect has calcineurin inhibitors tacrolimus and cyclosporine. The spectrum of neurological disturbances caused by calcineurin inhibitors range from very mild symptoms as paraesthesiae, tremor, headache or flushing, to severe changes that may cause lethal outcome. Peripheral neuropathies in renal transplant recipients may occur in the form of mononeuropathy or polyneuropathy. Cerebrovascular diseases are consequence of changes on blood vessels caused by uraemia, dialysis and side effects of immunosuppressive drugs. They cause death in 8% of renal transplant recipients. Central nervous system (CNS) infections usually occur during the first posttransplant year. Unclear symptomatology frequently postpones the diagnosis. Diagnostic evaluation should include magnetic resonance imaging for localization of the process, as well as lumbal puncture in cases without contraindications for the procedure, in order to determine the causative agent. Regarding the ominous prognosis of CNS infections in the immunocompromised host, only timely diagnosis may improve survival. The most common causative agents are Cryptococcus neoformans, Listeria monocytogenes and Aspergillus funigatus. Viral infections also occur, and are commonly caused by herpes virideae, varicella-zoster virus and papova virus. CNS infections clinically present as meningitis, progressive dementia or focal neurological defect. The most common primary brain tumors are B-cell lymphomas, but glioblastoma, hemangioblastoma, leiomyosarcoma or glioma may also occur. In cases of neurological posttransplant complications, optimal treatment should be guided by neurologist, nephrologist and infectologist, in some cases also by neurosurgeons.     

Pulmonary pathology in renal transplant recipients

Studies of the lungs have revealed multiple functional and histopathological abnormalities in patients with chronic renal failure, but data following renal transplantation are extremely limited. We examined postmortem data from 20 transplant patients and found pulmonary abnormalities in most patients. The number of pulmonary abnormalities noted in patients with poor transplantation, averaged 5.3 per patient. The corresponding number was significantly less (3.4 per patient) in the group with good transplant renal function, surviving more than one year after transplantation. Pulmonary calcification, fibrosis, and hemosiderosis were found in several patients in the former group but in none of the latter group. This observation suggests reversibility of these pulmonary abnormalities with successful renal transplantation.     

Characterization of cytomegalovirus isolates recovered during repeated infection in renal transplant recipients

The sources of cytomegalovirus (CMV) infection in seropositive renal transplant recipients include reactivation of latent endogenous virus in the recipient, reactivation of latent virus in donated kidney, or both. If infection occurs by either source, viruses isolated from the same recipient should be the same strain, whereas if it occurs by both sources, those from the same recipient should be different. In this study, we followed prospectively 25 seropositive recipients who predominantly received a kidney from a seropositive donor to determine whether CMV isolates recovered repeatedly from them are the same or different. During an average 10 month follow-up period, six (24%) patients had excreted the virus more than twice at any site and/or at different times. Restriction enzyme analysis of viral DNA prepared by the Hirt procedure revealed that three or four isolates obtained from each of five patients were same, whereas six isolates from one patient included three different strains. Five of six patients had clinical symptoms at the times when CMV was recovered. Three patients with acute rejection and one patient with hepatitis had been infected with one single strain, and all were successfully treated. One patient with fever and acute rejection had been infected with three different strains, and he failed to recover his renal function. These results suggest that most CMV infections in seropositive recipients may be caused by one single strain. However, multiple infections with different strains can also occur. Such infections are associated with more severe clinical disease.