Long Term Management of Liver Transplant Rejection in Children

The current management of hepatic allograft rejection after liver transplantation in children requires effective baseline immunosuppression to prevent rejection and rapid diagnosis and treatment to manage acute rejection episodes. The subsequent impact on chronic rejection is dependent on the combination of adequate prevention and the treatment of acute rejection. Tacrolimus is a macrolide lactone that inhibits the signal transduction of interleukin-2 (IL-2) via calcineurin inhibition. Introduced in 1989, tacrolimus was first used in the salvage of refractory acute or chronic rejection under cyclosporin or to rescue patients with significant cyclosporin-related complications. The majority of paediatric transplant centres use a combination of steroids with tacrolimus as a basic immunosuppressant regimen following paediatric liver transplantation. This combination has allowed the acute cellular rejection-free rate to increase to between 30 and 60%, while lowering the rate of refractory rejection to less than 5%. Corticosteroid-resistant rejection is commonly treated with monoclonal (muromonab CD3) or polyclonal preparations. Although most episodes of acute cellular rejection occur during the first 6 weeks after liver transplant, the appearance of late acute liver allograft rejection must raise the question of noncompliance, especially in the adolescent population. Chronic rejection is becoming increasingly rare under tacrolimus-based immunosuppression. Tacrolimus is effective in reversing refractory acute cellular rejection or early chronic rejection in patients initially treated with cyclosporin-based regimens. Patients with a history of noncompliance as well as children with autoimmune liver disease are at risk of chronic rejection. Retransplantation therapy for chronic rejection has, fortunately, become more rare in the tacrolimus era with only 3% of retransplants being performed for this indication. Newer immunosuppressive agents are further modifying the long term management of liver allograft rejection. These include mycophenolate mofetil, rapamycin and IL-2 antibodies such as daclizumab. The development of these agents is allowing patient-specific immunosuppressive management to minimise rejection as well as the complications related to immunosuppression.     

Different in vitro proliferation and cytokine‐production inhibition of memory T‐cell subsets after calcineurin and mammalian target of rapamycin inhibitors treatment

Calcineurin inhibitors (CNI) and mammalian target of rapamycin inhibitors (mTORi) are the main immunosuppressants used for long‐term maintenance therapy in transplant recipients to avoid acute rejection episodes. Both groups of immunosuppressants have wide effects and are focused against the T cells, although different impacts on specific T‐cell subsets, such as regulatory T cells, have been demonstrated. A greater knowledge of the impact of immunosuppression on the cellular components involved in allograft rejection could facilitate decisions for individualized immunosuppression when an acute rejection event is suspected. Memory T cells have recently gained focus because they might induce a more potent response compared with naive cells. The impact of immunosuppressants on different memory T‐cell subsets remains unclear. In the present study, we have studied the specific impact of CNI (tacrolimus) and mTORi (rapamycin and everolimus) over memory and naive CD4⁺ T cells. To do so, we have analysed the proliferation, phenotypic changes and cytokine synthesis in vitro in the presence of these immunosuppressants. The present work shows a more potent effect of CNI on proliferation and cytokine production in naive and memory T cells. However, the mTORi permit the differentiation of naive T cells to the memory phenotype and allow the production of interleukin‐2. Taken together, our data show evidence to support the combined use of CNI and mTORi in transplant immunosuppression.     

Pancreas Transplantation for Diabetes Mellitus

Between 1966 and 1997, over 10 000 pancreas transplants were performed worldwide, 88% of these being simultaneous kidney-pancreas transplantations (SKPTs). The overall 1-year patient survival rate exceeds 90%, and the graft survival (complete insulin independence) rate is 80%. SKPT should be regarded as the treatment of choice in carefully selected patients with type 1 (insulin-dependent; IDDM) diabetes mellitus and advanced nephropathy, because of its ability to offer superior glycaemic control and an improved quality of life. Studies have shown that the addition of a pancreas transplant does not appear to jeopardise either the patient or the kidney transplant, as many centres report either similar or improved survival rates after SKPT compared with kidney transplantation alone. Indications for solitary pancreas transplantation are based on the presence of early, well defined diabetic complications or glucose hyperlability with poor quality of life. Improvements in quality of life and possible prevention of further morbidity associated with diabetes makes pancreas transplantation an important therapeutic option for selected diabetic patients. According to registry data from the United Network for Organ Sharing (UNOS) Registry, rejection accounts for 32% of graft failures in the first year after pancreas transplantation. Most pancreas transplant centres employ quadruple drug immunosuppression with antilymphocyte induction with either a monoclonal or polyclonal agent. Maintenance immunosuppression involves triple therapy, consisting of a calcineurin inhibitor (cyclosporin or tacrolimus), corticosteroids and an antimetabolite (azathioprine or mycophenolate mofetil). Before 1995, nearly all pancreas transplant recipients were managed with the original formulation of cyclosporin ('Sandimmun'). In the past 2 years, tacrolimus-based therapy has been used in approximately 20% of cases and a new microemulsion formulation of cyclosporin ('Neoral') has replaced the original formulation in contemporary post-transplant immunosuppression. In addition, mycophenolate mofetil is replacing azathioprine as part of the standard immunosuppressive regimen after pancreas transplantation. At present, a number of centres are conducting various trials with new drug combinations including either cyclosporin microemulsion or tacrolimus in combination with corticosteroids and mycophenolate mofetil with or without antibody induction therapy. The current array of new immunosuppressive agents is providing more effective control of rejection and permitting solitary pancreas transplantation to become an accepted treatment option in diabetic patients without advanced complications. Immunosuppressive strategies will continue to evolve to achieve effective control of rejection while minimising injury to the allograft and risk to the patient. In addition, new regimens must not only address the issue of specific drug toxicities but also long term economic, metabolic and quality-of-life outcomes.     

Tacrolimus in Heart Transplant Recipients

The development of cyclosporine was pivotal in allowing cardiac transplantation to become an accepted treatment for patients with end-stage heart disease. More recently, tacrolimus has become available as a useful alternative to cyclosporine, and has been successfully combined with either azathioprine or the newer anti-proliferative agents, mycophenolate mofetil or sirolimus. Numerous randomized clinical trials have demonstrated that tacrolimus is comparable to cyclosporine in terms of overall patient survival and at least equally effective in preventing acute rejection. In addition, tacrolimus has been particularly effective as a rescue treatment in cases where recurrent rejection has occurred with cyclosporine. The adverse effects of tacrolimus differ from those of cyclosporine, and the drug particularly shows an improved profile with respect to hypertension, dyslipidemia, and long-term renal function. These data have recently led to the regulatory approval of tacrolimus for primary immunosuppression in patients undergoing cardiac transplantation in the US.     

Impact and production of Non‐HLA‐specific antibodies in solid organ transplantation

Organ transplantation is an effective way to treat end‐stage organ disease. Extending the graft survival is one of the major goals in the modern era of organ transplantation. However, long‐term graft survival has not significantly improved in recent years despite the improvement of patient management and advancement of immunosuppression regimen. Antibody‐mediated rejection is a major obstacle for long‐term graft survival. Donor human leucocyte antigen (HLA)‐specific antibodies were initially identified as a major cause for antibody‐mediated rejection. Recently, with the development of solid‐phase‐based assay reagents, the contribution of non‐HLA antibodies in organ transplantation starts to be appreciated. Here, we review the role of most studied non‐HLA antibodies, including angiotensin II type 1 receptor (AT₁R), K‐α‐tubulin and vimentin antibodies, in the solid organ transplant, and discuss the possible mechanism by which these antibodies are stimulated.     

急性腹泻期间肾移植受者他克莫司血药浓度的变化

背景：长期以来器官移植工作者比较重视吗替麦考酚酯的肠道不良作用,而对他克莫司与腹泻的关系则未引起足够的关注。 目的：观察肾移植受者急性腹泻期间他克莫司的谷浓度变化及对腹泻的治疗效果。 方法：观察90例出现急性腹泻的肾移植受者,免疫抑制方案均为他克莫司+吗替麦考酚酯+泼尼松,检测围腹泻期间内他克莫司血药谷浓度及相关病原学指标,将浓度升高的72例患者中病原学检查阴性的48例患者分为2组,每组24例,一组在治疗过程中只减少他克莫司剂量,另一组同时减少他克莫司及吗替麦考酚酯剂量,观察对腹泻的治疗效果及他克莫司谷浓度升高持续时间。 结果与结论：两种方案对腹泻的治疗效果及他克莫司谷浓度升高持续时间差异均无显著性意义。腹泻是他克莫司浓度异常升高的重要因素,腹泻期间应适当减少他克莫司剂量及增加其血药浓度监测频率,以免增加他克莫司的不良反应;在治疗过程中没有必要同时减少吗替麦考酚酯剂量,以免增加排斥发应发生率。     

Comparison of long-term impact of immunosuppressants at therapeutic doses on hepatic function and histological changes in unilateral nephrectomized rats

Cyclosporine, tacrolimus and sirolimus are commonly used in renal transplant recipients to prevent rejection. Various adverse effects of these agents on the multiple organ system have been reported clinically. However, animal studies are necessary to determine and compare these effects on individual organ given the presence of multiple confounding factors and multi-pharmacy in clinical settings. In a physiologically and clinically relevant rat model of unilateral nephrectomy, the long-term impacts of commonly used immunosuppressants at doses equivalent to the therapeutic levels used for post-renal transplant patients on hepatic function and histological changes of the liver were examined. Cyclosporine induced significant hepatocellular injury, impairment of synthetic function of the liver, hyperbilirubinemia and cholestasis, and dyslipidemia accompanied by profound histological changes of hepatic structures on both light and electron microscopic examinations. On the other hand, neither tacrolimus nor sirolimus developed any hepatotoxic effects except for more remarkable dyslipidemia was observed in animals treated with sirolimus. Our study indicates that long-term administration of commonly used immunosuppressants has various impacts on biochemical parameters as well as histological alterations of the liver even at therapeutic levels. These data may therefore provide useful information for judicious selection of immunosuppressive agents based on different clinical settings.     

ABCB1基因多态性对肝移植后他克莫司用量的影响

背景：钙神经素抑制剂他克莫司被广泛用于移植后预防排斥反应的发生,但其治疗窗狭窄,且药代动力学个体差异较大。 目的：观察ABCB1基因多态性对肝移植患者移植后早期免疫抑制剂他克莫司的用量及C/D比值的影响。 方法：选择2008-01/2010-09-31在昆明市第一人民医院暨昆明医学院附属甘美医院肝胆外科接受原位肝移植患者67例,通过检测67例肝移植受者移植后不同时间他克莫司的血药浓度及其用量,并利用DNA直接测序检测受体ABCB1的基因多态性,分析肝移植后免疫抑制剂他克莫司的用量及其血药浓度与ABCB1基因多态性的关系。 结果与结论：肝移植后他克莫司的口服需药量在个体间存在很大差异,67例肝移植患者中,ABCB1不同位点的基因多态性分布不同,其中仅ABCB1 3435C>T基因多态性与他克莫司用量有关。提示ABCB1的基因多态性可能是患者肝移植后他克莫司药代动力学显著个体差异的重要因素,ABCB1 3435C>T野生型的患者需要更高剂量的他克莫司便可达到目标血药浓度水平,检测ABCB1的基因多态性可以优化肝移植后免疫抑制剂的个体化治疗方案。     

Immune and gene expression profiling during tacrolimus to everolimus conversion early after liver transplantation

Early elimination of tacrolimus in favor of everolimus can improve renal function in liver transplant recipients. However, as this approach increases the risk of acute rejection, it may benefit from predictive biomarkers guiding weaning. We enrolled 20 recipients on stable tacrolimus + everolimus to undergo tacrolimus withdrawal early post-liver transplant. Blood samples were collected at month 3 (withdrawal initiation), 4 (withdrawal completion), 4.5 and 6 (both everolimus alone). 15 patients did not reject and 5 had mild rejection responding to tacrolimus resumption. Before tacrolimus withdrawal, eventual rejecters had higher percentages of CD56⁺ NK cells and CD19⁺CD27⁺CD24⁺ memory B cells, and lower levels of T cells expressing the exhaustion marker PD-1. Over time, memory B cells, Ki-67⁺CD3⁺ (proliferating) cells and CD4⁺CD127^-CD25^HIGH FOXP3⁺ Tregs increased in rejecters. Tregs also increased in non-rejecters over time. The number of differentially expressed genes progressively increased in rejecters, particularly in mTOR, Eukaryotic Initiation Factor 2, and Neuroinflammation signaling pathways. There was no difference in anti-HLA antibodies between the groups. In summary, blood mononuclear cell and gene expression may predict successful vs. failed early tacrolimus withdrawal in liver transplant recipients. While needing validation, these preliminary findings highlight the potential for cellular and molecular biomarkers to guide decision-making during tacrolimus weaning.     

Current trends in renal transplant immunosuppression

Several new immunosuppressives have been introduced in renal transplantation during the past decade. Mycophenolate mofetil, tacrolimus, cyclosporine microemulsion, sirolimus, monoclonal and polyclonal antibodies have all contributed to decreasing the rate of acute rejection. However, a more intense immnuosuppression has resulted in an increased incidence of opportunistic infections and malignant diseases. The main cause of death in renal transplant recipients are cardiovascular diseases, and the majority of patients die with a functioning graft. Renal transplant recipients are at an increased risk of the development of cardiovascular diseases due to prolonged uremia and dialysis itself, combined with the proatherogenic effect of immunosuppressive drugs. Corticosteroids and calcineurin inhibitors are the main groups of drugs associated with an increased risk of atherosclerosis. The main challenge in the present and future treatment of transplanted patients is the establishment of an immunosuppressive protocol that will minimize or completely avoid proatherogenic immunosuppressives while preserving the low incidence of acute rejection.     

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。     

Corticosteroid Withdrawal after Renal Transplantation in the Cyclosporin Era

In an effort to eliminate the well-known adverse effects of long term corticosteroid therapy, a number of transplant centres have attempted to withdraw corticosteroids at various times following renal transplantation. Reported benefits of corticosteroid withdrawal in patients maintained on cyclosporin-based immunosuppressive regimens have included accelerated growth in children, improvements in hypertension, reductions in total cholesterol levels and improved glycaemic control for diabetic patients. However, results from single centres, and from meta-analyses of randomised prospective trials, suggest that corticosteroid-free immunosuppression is associated with an increased risk of acute allograft rejection when compared with treatment with corticosteroid-based regimens. In addition, some long term follow-up studies suggest that withdrawal of corticosteroids may increase the risk of chronic allograft dysfunction. In the cyclosporin era, the risks of corticosteroid withdrawal outweigh the benefits in a substantial minority of patients. A number of new immunosuppressants may prove to be more corticosteroid-sparing than cyclosporin, and promise to increase the safety of corticosteroid-free immunosuppression for renal transplant recipients.     

T helper subsets & regulatory T cells: rethinking the paradigm in the clinical context of solid organ transplantation

Recent years have witnessed remarkable expansion in the knowledge of how various immune/inflammatory cells and T helper (Th) cell subsets, including Th1, Th2, Th9, Th17, Th22, follicular T helper (Tfh) and Treg subpopulations, reciprocally regulate each other. This review highlights current understanding of the Th subsets paradigm, who are the old school players, who are the new kids on the block and how does each come to play in different clinical contexts in solid organ transplantation. The article commences with a brief overview of the development and characteristic cytokine profiles of individual members of the paradigm. However, the main focus of this review is on the current understanding of the Th subset paradigm, and how these unique subpopulations impact host responses towards solid organ allografts. More specifically, it will highlight the recent findings that implicate the paradigm in transplantation. The interplay among different subsets is discussed collectively in the clinical context of pretransplant immunological risk factors such as alloimmunization as well as post‐transplant immunological consequences such as rejection. Accumulating evidence suggests that Th17 cells play a role in the development of chronic allograft injury in transplantation of various organs. In vitro, tacrolimus suppressed Th1 and Th2 cells but not Th17 cells. Animal studies suggest that regulatory T cells (Treg)‐based therapies could be effective as mechanisms of long‐term drug‐free transplant tolerance in humans. Indeed, a dual role for TGF‐β and Foxp3 in induced tolerance has been proposed, in which TGF‐β stimulates Foxp3 expression and is associated with the induction of Treg‐facilitating acquisition of tolerance. Exploiting Th subsets' regulatory functions could potentially offer opportunities for immunological interventions in solid organ transplantation.     

Extensive human cytomegalovirus (HCMV) genomic DNA in the renal tubular epithelium early after renal transplantation: Relationship with HCMV DNAemia and long‐term graft function

Human cytomegalovirus (HCMV) infection is associated with a series of direct and indirect effects following renal transplantation. However, the presence of HCMV in the kidney and its relationship with acute rejection and long‐term graft function remain to be fully elucidated. Sixty‐two biopsies derived from 30 renal transplant recipients with signs of clinical rejection were analyzed for HCMV using a sensitive in situ DNA hybridization method. Biopsies were also subjected to staining with anti‐C4d antibodies and an anti‐caspase 3 antibody to detect humoral rejection and apoptosis, respectively. In 21 patients, serial serum creatinine levels over 5 years of follow‐up were analyzed. HCMV DNA was detected in biopsies from 21/30 (70%) of the patients and 32/62 (52%) of the individual biopsies. HCMV DNA was detected early after transplant and was localized to renal tubule epithelial cells but not associated with apoptosis. HCMV DNAemia developed within 2 weeks of detecting HCMV DNA in the biopsy in 53% of patients. Ninety percent of patients experiencing HCMV disease had HCMV DNA in their biopsy. HCMV DNA was equally distributed between patients with or without histological evidence of acute rejection and was detected more frequently in patients with peritubular C4d deposits. Creatinine levels at 12 months post‐transplant were significantly higher in patients with HCMV DNA and remained elevated over the 5 years of follow‐up. HCMV DNA is frequently detected in renal tubular epithelial cells early after renal transplantation, precedes DNAemia and is associated with poor long‐term graft function. J. Med. Virol. 82:85–93, 2010. © 2009 Wiley‐Liss, Inc.     

Immunosuppression for pancreas transplantation with an emphasis on antibody induction strategies: review and perspective

A review of recent literature was performed to identify trends and evaluate outcomes with respect to immunosuppression in pancreas transplantation (PTX). In the past decade, the majority of PTXs were performed with depleting antibody induction, particularly in the setting of either calcineurin inhibitor minimization, corticosteroid withdrawal or both. Maintenance immunosuppression consisted of predominantly tacrolimus (TAC)/mycophenolatemofetil, TAC/mycophenolic acid or TAC/sirolimus with or without corticosteroids. Depending on PTX category, donor and recipient risk factors, case mix and immunosuppressive regimen, the 1-year incidence of acute rejection has decreased to 5–20%. Current 1-year rates of immunological pancreas graft loss range between 1.8 and 6%. Depleting antibody induction and either TAC/mycophenolatemofetil or TAC/sirolimus maintenance therapy with early steroid withdrawal have become the mainstay of immunosuppression in PTX. However, the development of non-nephrotoxic, nondiabetogenic, and nongastrointestinal toxic regimens is highly desirable to improve quality of life in all solid organ transplant recipients.     

他克莫司和西罗莫司对行肝癌肝移植患者Foxp3+调节性T细胞产生及肝癌复发的影响

背景：通过促进调节性T细胞的产生及增强其功能的发挥已成为维持移植物免疫耐受的有效手段。 目的：探讨他克莫司和西罗莫司对行肝移植的肝癌患者Foxp3⁺调节性T细胞产生及肝癌复发的影响。 方法：纳入符合米兰标准的肝癌肝移植患者40例,随机分为西罗莫司组和他克莫司组,每组20例,移植后第2~12个月间每月抽取受试者外周血检测Foxp3⁺调节性T细胞,并行彩超和外周血检测甲胎蛋白,必要时肝穿刺活检观察排斥反应及肿瘤的复发情况。 结果与结论：流式细胞仪检测结果显示,西罗莫司组外周血Foxp3⁺调节性T细胞阳性率明显高于他克莫司组(P < 0.05),移植肝穿刺活检证实西罗莫司组排斥反应与他克莫司组差异无显著性意义(P > 0.05),而移植肝彩超、外周血甲胎蛋白检测及移植肝穿刺活检或手术亦证实在肝癌复发率方面西罗莫司组明显低于他克莫司组(P < 0.05)。说明西罗莫司在肝癌肝移植中对肿瘤复发的抑制作用方面优于他克莫司,且排斥反应较他克莫司并未增加,甚至有更好的免疫耐受效果。     

Basiliximab

Basiliximab (Simulect®) is a recombinant chimeric murine/human IgG1 monoclonal anti-interleukin-2 receptor antibody that is indicated for the prevention of acute organ rejection in adult and pediatric renal transplant recipients in combination with other immunosuppressive agents. Induction therapy with two doses (day 0 and day 4) of intravenous basiliximab as part of double- or triple-immunotherapy regimens in adult renal transplant recipients reduces acute rejection episodes without increasing the incidence of adverse events. Compared with rabbit-derived antithymocyte globulin (RATG), basiliximab is generally associated with similar efficacy in standard-risk patients, but reduced efficacy in high-risk patients. Initial results indicate that induction with basiliximab is associated with a higher rate of biopsy-proven acute rejection than alemtuzumab induction. Basiliximab is generally associated with a tolerability profile that is similar to that reported with placebo, and better than that reported with RATG. As with other induction agents, basiliximab has not demonstrated improved graft or patient survival over the long term (periods of up to 7 years). Basiliximab induction allows for reduced dosage of corticosteroids or calcineurin inhibitors, while maintaining adequate immunosuppression, thereby reducing the potential for adverse effects associated with these coadministered agents. Thus, basiliximab provides an effective, well tolerated option for the prophylaxis of acute renal transplant rejection.     

肾移植后急性排异反应12例

背景：同种异体肾移植后发生的急性排斥反应是移植肾功能减退和最终移植肾丧失的最主要原因之一。有效预防和早期发现与治疗急性排异反应是关系到肾脏移植患者能否长期存活的重要问题。 目的：总结肾移植后1个月内急性排异反应患者治疗过程中免疫抑制剂的应用体会。 方法：选择首次肾移植患者12例,移植后采用霉酚酸酯+环孢素A+甲泼尼龙三联预防排异反应。当肾移植后3~30 d内出现尿量减少、移植肾区胀痛不适、血肌酐升高、尿蛋白增加等不同临床表现,确诊为肾移植后急性排斥反应时,先选用甲强龙500 mg/d静脉滴注,连续3 d。然后改甲泼尼龙24 mg口服1次/d,每5~7 d递减4 mg,至8 mg/d维持。 结果与结论：12例患者成功逆转,其中6例甲强龙冲击疗法成功;不能逆转者选用抗胸腺细胞球蛋白或CD3治疗。4例经抗胸腺细胞球蛋白治疗患者中1例8h内尿量迅速增加,2例24 h内尿量迅速增加,1例72 h后尿量迅速增加;1例选用CD3治疗48 h内尿量迅速增加;1例将环孢素转换为他克莫司治疗,同时服用霉酚酸酯胶囊和甲泼尼龙片。经以上治疗12例患者肾功能逐渐恢复。提示肾移植后早期发现、早期诊断、及时治疗是急性排异反应成功逆转的关键。     

Tacrolimus in cardiac transplantation

The availability of effective immunosuppressive agents has allowed cardiac transplantation to become an accepted treatment for patients with end-stage heart disease. In recent years, tacrolimus has emerged as a useful alternative to cyclosporine, combined with either azathioprine or the newer antiproliferative agents, mycophenolate mofetil or sirolimus. A number of randomized clinical trials have shown tacrolimus to be comparable with cyclosporine regarding survival and the drug also demonstrates equivalent or improved prophylaxis against acute rejection. The adverse effects of tacrolimus differ from cyclosporine and the drug demonstrates a particularly improved profile with respect to hypertension and dyslipidemia. These data have recently led to regulatory approval of tacrolimus for primary immunosuppression in cardiac transplantation in the USA.     

Histologic findings in protocol biopsies of transplanted kidneys

Fourty eight patients with cadaveric kidney allografts treated by cyclosporin A (CSA) or tacrolimus (FK506) underwent protocol graft biopsies at 1, 3 and 12 months after transplantation, and 110 biopsy specimens were obtained. Histologic diagnosis was made according to the Banff scheme. The main cause of the graft instability at 1 and 3 months was acute clinical rejection, these biopsies showed all known histological patterns of tubulointersticial and vascular rejection. Acute tubular nephropathy was found in 13% and borderline changes or nephrotoxicity in 8.7% of instable grafts. Specifically, we focused on the occurRence of subclinical rejection and toxic reactions in stable renal allografts. Of these, 36.1% showed histological patterns of acute tubulointersticial and vascular rejection. The Banff score of subclinical rejection was significantly lower than in clinically apparent rejection. CSA and tacrolimus nephrotoxicity were seen in 14.2%, 19.5% and 27.2% of specimens at 1, 3 and 12 months, respectively. In over one half of the identified cases of nephrotoxicity neither increased level of immunosuppression nor features of allograft dysfunction were found. At 12 months, 45.5% of specimens showed mild chronic transplant nephropathy and 18.1% moderate chronic transplant nephropathy. Normal morphology was found in 36.4% of biopsies. We found a high prevalence of subclinical rejection and nephrotoxicity in the studied cohort. We conclude that protocol biopsy is a reliable method in the diagnosis of clinically silent, as well as clinically apparent, disorders of the transplanted kidney.