Calcineurin inhibitors-related posterior reversible encephalopathy syndrome in liver transplant recipients: Three case reports and review of literature

BACKGROUND Posterior reversible encephalopathy syndrome(PRES),characterized by acute neurological deterioration and extensive white matter lesions on T2-fluid attenuated inversion recovery magnetic resonance imaging(MRI),is increasingly associated with calcineurin inhibitors(CNI)-related neurotoxicity.Prompt diagnosis is crucial,as early intervention,including the modification or discontinuation of CNI therapy,strict blood pressure management,corticosteroid treatment,and supportive care can significantly improve patient outcomes and prognosis.The growing clinical recognition of CNI-related PRES underscores the importance of identifying and managing this condition in patients presenting with acute neurological symptoms.CASE SUMMARY This report describes three cases of liver transplant recipients who developed PRES.The first case involves a 60-year-old woman who experienced seizures,aphasia,and hemiplegia on postoperative day(POD)9,with MRI revealing ischemic foci followed by extensive white matter lesions.After replacing tacrolimus,her symptoms improved,and no significant MRI abnormalities were observed after three years of follow-up.The second case concerns a 54-year-old woman with autoimmune hepatitis who developed headaches,seizures,and extensive white matter demyelination on MRI on POD24.Following the switch to rapamycin and the initiation of corticosteroids,her symptoms resolved,and she was discharged on POD95.The third case details a 60-year-old woman with hepatocellular carcinoma who developed PRES,evidenced by brain MRI abnormal-ities on POD11.Transitioning to rapamycin and corticosteroid therapy led to her full recovery,and she was discharged on POD22.These cases highlight the critical importance of early diagnosis,CNI modification,and stringent management in improving outcomes for liver transplant recipients with CNI related PRES.CONCLUSION Clinical manifestations,combined with characteristic MRI findings,are crucial in diagnosing PRES among organ transplant recipients.However,when standard treatments are ineffective or MRI results are atypical,alternative diagnoses should be taken into considered.

Treatment of young patients with lupus nephritis using calcineurin inhibitors

Recent advances in the management of lupus nephritis, together with earlier renal biopsy and selective use of aggressive immunosuppressive therapy, have contribut-ed to a favorable outcome in children and adolescents with systemic lupus erythematosus （SLE）. Neverthe-less, we believe that a more effective and less toxic treatment is needed to attain an optimal control of the activity of lupus nephritis. Recent published papers and our experiences regarding treatment of young patients with lupus nephritis using calcineurin inhibitors are re-viewed. Although it has been reported that intermittent monthly pulses of intravenous cyclophosphamide （IVCY） are effective for preserving renal function in adult pa-tients, CPA is a potent immunosuppressive agent thatinduces severe toxicity, including myelo- and gonadal toxicity, and increases the risk of secondary malig-nancy. Thus, treatment for controlling lupus nephritis activity, especially in children and adolescents, remains challenging. Cyclosporine A （CsA） and tacrolimus （Tac） are T-cell-specific calcineurin inhibitors that prevent the activation of helper T cells, thereby inhibiting thetranscription of the early activation genes of interleu-kin （IL）-2 and suppressing T cell-induced activation of tumor necrosis factor-α, IL-1β and IL-6. Therefore, both drugs, which we believe may be less cytotoxic, are attractive therapeutic options for young patients with lupus nephritis. Recently, a multidrug regimen of prednisolone （PDN）, Tac, and mycophenolate mofetile （MMF） has been found effective and relatively safe in adult lupus nephritis. Since the mechanisms of action of MMF and Tac are probably complementary, multidrug therapy for lupus nephritis may be useful. We propose as an alternative to IVCY, a multidrug therapy with mizoribine, which acts very similarly to MMF, and Tac, which has a different mode of action, combined with PDN for pediatric-onset lupus nephritis. We also believe that a multidrug therapy including CsA and Tac may bean attractive option for young patients with SLE and lupus nephritis

Microproteinuria for detecting calcineurin inhibitor-related nephrotoxicity after liver transplantation

AIM： To investigate whether microproteinuria could be used as an early and sensitive indicator to detect calcineurin inhibitor （CNI）-related nephrotoxicity after liver transplantation.METHODS： All liver transplant recipients with normal serum creatinine （SCr） and detectable microproteinuria at baseline were included in this study. The renal function was monitored by the blood clearance of 99mTc-diethylenetriaminepentaacetic acid every 6 mo. Microproteinuria, SCr and blood urea nitrogen （BUN） were measured at entry and at subsequent follow-up visits. The patients were divided into different groups according to the mean values of glomerular filtration rate （GFR） at the follow-up time points： Group 1, GFR decreased from baseline by 0%-10%; Group 2, GFR decreased from baseline by 11%-20%; Group 3, GFR decreased from baseline by 21%-40%; Group 4, GFR decreased from baseline by 〉 40% and/or SCr was increasing.RESULTS： A total of 143 patients were enrolled into this study （23 females and 120 males）. The mean follow-up was 32 mo （range 16-36 mo）. Downward trends in renal function over time were observed in the study groups. SCr and BUN increased significantly only in Group 4 patients （P 〈 0.001）. β2-microglobulin （β2m） and al-microglobulin （αlm） significantly increased with the subtle change of renal function in recipients who were exposed to CNI-based immunosuppression regimens. The reductions in GFR were closely correlated with elevated cclm （P = -0.728, P 〈 0.001） and β2m （r2 = -0.787, P 〈 0.001）.CONCLUSION： β2m and α1m could be useful as early and sensitive indicators of CNI-induced nephrotoxicity.

Calcineurin Inhibitor Use and Myoclonus Association. Is There a Clinical Implication?

Background: Calcineurin Inhibitors (CNIs) play a pivotal role in anti rejection therapy for transplant patients. Neurotoxicity is a known side effect that usually manifests as encephalopathy but myoclonus has also been described. Perioperative myoclonus as a manifestation of neurotoxicity, has not been well studied. Methods: We retrospectively reviewed data from 842,762 patients from the Nationwide Inpatient Sample (NIS) database from January 2011 to December 2014. Of those records we compared 56,423 patients requiring CNIs and undergoing Heart Transplant (HT) with 786,339 patients undergoing Coronary Artery Bypass Graft (CABG) surgery as controls. The objective was to study the rates of myoclonus in patients undergoing cardiac surgery, especially those requiring CNIs, and study the outcome of those patients with myoclonus. The NIS database from January 2011 to December 2014 was the source for the analysis. Patients with underlying epilepsy or hypo-ischemic encephalopathy based on ICD-9-CM codes were excluded from the study. Results: A total of 147 patients (0.26%) were found to have myoclonus in the HT group versus 338 patients (0.04%) in the CABG group, p < 0.0001. No differences in the demographics were seen except for kidney disease which was higher in the HT group. The difference remained statistically significant after adjusting for confounders. Patients with myoclonus in both groups were more likely to have acute kidney injury and have a prolonged length of stay. Only patients with myoclonus in the CABG group had higher rates of discharge disposition to a nursing home and higher rates of in-Hospital mortality. A trend towards higher in-Hospital mortality was found in patients with myoclonus in the HT group. Conclusion: In this study we have compared the rate of myoclonus found in HT patients versus CABG patients. We have identified calcineurin inhibitors as potentially contributing to myoclonus due to its neurotoxic effects. The study also suggests that other disease processes like renal failure may also have an impact on the rate of myoclonus even in the absence of calcineurin inhibitors. Higher rates of myoclonus were seen in patients undergoing HT when compared to patients undergoing CABG, suggesting that CNIs may increase the risk for myoclonus. Myoclonus may be a clinical indicator of patient overall health including a more permeable blood brain barrier. In-Hospital mortality was higher in patients with myoclonus undergoing CABG and a trend towards significance in the HT group suggesting that it may be a marker of poor prognosis. More studies are needed to corroborate our findings.

Calcineurin inhibitor sparing strategies in renal transplantation, part one: Late sparing strategies

Kidney transplantation improves quality of life and reduces the risk of mortality. A majority of the success of kidney transplantation is attributable to the calcineurin inhibitors(CNIs), cyclosporine and tacrolimus, and their ability to reduce acute rejection rates. However, longterm graft survival rates have not improved over time, and although controversial, evidence does suggest a role of chronic CNI toxicity in this failure to improve outcomes. Consequently, there is interest in reducing or removing CNIs from immunosuppressive regimens in an attempt to improve outcomes. Several strategies exist to spare calcineurin inhibitors, including use of agents such as mycophenolate mofetil(MMF), mycophenolate sodium(MPS), sirolimus, everolimus or belatacept to facilitate late calcineurin inhibitor withdrawal, beyond 6 mo post-transplant; or using these agents to plan early withdrawal within 6 mo; or to avoid the CNIs all together using CNI-free regimens. Although numerous reviews have been written on this topic, practice varies significantly between centers. This review organizes thedata based on patient characteristics(i.e., the baseline immunosuppressive regimen) as a means to aid the practicing clinician in caring for their patients, by matching up their situation with the relevant literature. The current review, the first in a series of two, examines the potential of immunosuppressive agents to facilitate late CNI withdrawal beyond 6 mo post-transplant, and has demonstrated that the strongest evidence resides with MMF/MPS. MMF or MPS can be successfully introduced/maintained to facilitate late CNI withdrawal and improve renal function in the setting of graft deterioration, albeit with an increased risk of acute rejection and infection. Additional benefits may include improved blood pressure, lipid profile and serum glucose.Sirolimus has less data directly comparing CNI withdrawal to an active CNI-containing regimen, but modest improvement in short-term renal function is possible, with an increased risk of proteinuria, especially in the setting of baseline renal dysfunction and/or proteinuria. Renal outcomes may be improved when sirolimus is used in combination with MMF. Although data with everolimus is less robust, results appear similar to those observed with sirolimus.

Is it time to give up with calcineurin inhibitors in kidney transplantation?

Calcineurin inhibitors(CNIs) represent today a cornerstone for the maintenance immunosuppressive treatment in solid organ transplantation. Nevertheless, several attempts have been made either to minimize their dosage or to avoid CNIs at all because these drugs have the severe side effect of chronic nephrotoxicity. This issue represents a frontier for renal transplantation. The principal problem is to understanding whether the poor outcome over the long-term may be ascribed to CNIs nephrotoxicity or to the inability of these drugs to control the acute and chronic rejection B cells mediated. The authors analyze extensively all the international trials attempting to withdraw, minimize or avoid the use of CNIs. Few trials undertaken in low risk patients with an early conversion from CNIs to proliferation signal inhibitors were successful, but the vast majority of trials failed to improve CNIs side effects. To date the use of a new drug, a co-stimulation blocker, seems promising in avoiding CNIs with similar efficacy, better glomerular filtration rate and an improved metabolic profile. Moreover the use of this drug is not associated with the development of donorspecific anti-human leukocyte antigen antibodies. Thispoint has a particular relevance, because the failure of CNIs to realize good outcomes in renal transplantation has recently ascribed to their inability to control the acute and chronic rejections B-cell mediated. This paper analyzes all the recent studies that have been done on this issue that represents the real frontier that should be overcome to realize better results over the long-term after transplantation.

Conversion from Calcineurin Inhibitors to Sirolimus Maintenance Therapy in Renal Allograft Recipients with Risk Factors

Background: The efficacy and safety of conversion treatment with sirolimus in renal transplant recipients using the calcineurin inhibitor (CNI) with one or more risk factors was evaluated. Methods: Ninety-three renal transplant recipients were prospectively enrolled. CNIs(CsA and FK506) as main immunosuppressant were converted to SRL immunosuppressant protocol. Rapid conversion with si-rolimus was performed in all patients. The CNI withdrawal was in 2 weeks. At 4 hours after oral administration of cyclosporin A or tacrolimus, the patients took sirolimus. Initial dose of sirolimus was 6 mg, and repeated maintenance dose is 1.0 - 2.0 mg/d. The first concentration of sirolimus was detected at 5 - 7 days after first oral administration, and the target concentration was 6 - 10 μg/L. Results: The symptoms were markedly improved in patients with CNI induced renal toxicity and CNI induced liver toxicity, and the concentration of sirolimus were maintained at (5.1 ± 1.2) μg/L. Serum creatinine levels decreased from (297.72 ± 150.28) μmol/L to (123.76 ± 44.2) μmol/L, and the liver function were recovery in 24 (92.3%) patients. 9 patients with high glucose returned to normal, and 2 patients were improved. Serum creatinine levels decreased more than 25% of primary level in 17 patients, and the effective rate was 51.5%. 10 patients with tumor were appeared 6 - 43 months after renal transplantation, no recurrence was found in 8 of them and 2 patients were dead. Acute rejections were occurred in 3 patients at 6 months after conversion treatment. The complications were included hyperlipidemia and proteinuria. 3 patients were dead, 6 patients returned to dialysis treatment, and 2 patients were removal of grafts. At 3 years after conversion treatment, the survival rates of patients and grafts were 90.9% and 75.8%, respectively. Conclusion: The conversion treatment with SRL and MMF may be a better option for the renal transplant recipients using the CNI with risk factors appeared.

Calcineurin inhibitors and nephrotoxicity in children

Background Calcineurin inhibitors(CNIs)are commonly given to transplant recipients of kidneys and other solid organs and to patients with immune disorders,such as steroid-resistant nephrotic syndrome,steroid-dependent nephrotic syndrome,and frequent relapse nephrotic syndrome.Although CNIs remain the most effective available immunosuppressant agent,there is clinical concern regarding possible long-term nephrotoxicity.This concern is especially significant in children who have a longer life expectancy and greater growth rate.Data sources In this review,we analyzed the literatures to identify original articles that examined use of CNIs in children who received organ transplantation and nephropathy to assess the available evidence of their nephrotoxicity.PubMed,Elsevier,and Tompson ISI Web of Knowledge were searched for identifying relevant papers.Results Clinical research supports the presence of CNI-related nephrotoxicity.However,some researchers have questioned the prevalence and seriousness of chronic CNIs nephrotoxicity,especially because the pathological lesions typically associ-ated with long-term CNI use are nonspecific.Many researchers have focused on early markers of CNI nephrotoxicity,and the methods that may help prevent and manage nephrotoxicity.Conclusions Future research should focus on investigating early markers of CNI nephrotoxicity and strategies for improved immunosuppressant therapy,and developing alternative treatments.CNI-mediated nephrotoxicity should always be taken seriously in clinic.

A randomized controlled trial to evaluate efficacy and safety of early conversion to a low-dose calcineurin inhibitor combined with sirolimus in renal transplant patients

Background:The calcineurin inhibitor(CNI)-based immune maintenance regimen that is commonly used after renal transplantation has greatly improved early graft survival after transplantation;however,the long-term prognosis of grafts has not been significantly improved.The nephrotoxicity of CNI drugs is one of the main risk factors for the poor long-term prognosis of grafts.Sirolimus(SRL)has been employed as an immunosuppressant in clinical practice for over 20 years and has been found to have no nephrotoxic effects on grafts.Presently,the regimen and timing of SRL application after renal transplantation vary,and clinical data are scarce.Multicenter prospective randomized controlled studies are particularly rare.This study aims to investigate the effects of early conversion to a low-dose CNI combined with SRL on the long-term prognosis of renal transplantation.Methods:Patients who receive four weeks of a standard regimen with CNI+mycophenolic acid(MPA)+glucocorticoid after renal transplantation in multiple transplant centers across China will be included in this study.At week 5,after the operation,patients in the experimental group will receive an additional administration of SRL,a reduction in the CNI drug doses,withdrawal of MPA medication,and maintenance of glucocorticoids.In addition,patients in the control group will receive the maintained standard of care.The patients’vital signs,routine blood tests,routine urine tests,blood biochemistry,serum creatinine,BK virus(BKV)/cytomegalovirus(CMV),and trough concentrations of CNI drugs and SRL at the baseline and weeks 12,24,36,48,72,and 104 after conversion will be recorded.Patient survival,graft survival,and estimated glomerular filtration rate will be calculated,and concomitant medications and adverse events will also be recorded.Conclusion:The study data will be utilized to evaluate the efficacy and safety of early conversion to low-dose CNIs combined with SRL in renal transplant patients.

Systemic meta-analysis assessing the short term applicability of early conversion to mammalian target of rapamycin inhibitors in kidney transplant

AIM To consolidate the present evidence of effectiveness in renal functioning and graft survival following early introduction of mammalian target of rapamycin(m TOR) inhibitors with or without calcineurin inhibitors(CNIs) in renal transplant recipients.METHODS We analysed the current literature following PROSPERO approval describing the role of immunosuppressive agent, m TOR inhibitors as an alternative to CNI within six months of renal transplant by searching the Pub Med, EMBASE, Cochrane, Crossref, and Scopus using Me SH terms. RESULTS Six articles of early withdrawal of CNI and introduction of m TOR-inhibitors within six months of renal transplantation were sought. Glomerular filtration rate(GFR) and serum creatinine were significantly better in m TOR inhibitor group with equivalent survival at 12 mo, even though Biopsy Proven Acute rejection was significantly higher in m TOR-inhibitor group. CONCLUSION The evidence reviewed in this meta-analysis suggests that early introduction m TOR-inhibitors substantial CNI minimization. The m TOR inhibitors such as everolimus and sirolimus, due to their complementary mechanism of action and favourable nephrotoxicity profile; better glomerular filtration, lower serum creatinine with equivalent survival. Having said that, due to the higher rejection rate, may influence the use of these regimens to patients with moderate to high immunological risk patients.

HIV阳性实体器官移植受者的免疫抑制药物管理

联合抗逆转录病毒治疗(cART)的应用显著提高了人类免疫缺陷病毒(HIV)感染者的预期寿命。但病毒感染和cART药物的不良反应使患者更容易发生器官衰竭。针对HIV感染者的终末期器官衰竭患者,实体器官移植成为一种标准的治疗方案。然而,在HIV阳性实体器官移植受者中,存在移植物排斥反应发生增多、感染风险升高、药物毒性以及cART治疗和免疫抑制药之间的药物相互作用等诸多问题,管理HIV阳性实体器官移植受者具有极大的挑战性。因此,本文就免疫诱导治疗、钙调磷酸酶抑制剂、哺乳动物雷帕霉素靶蛋白抑制剂及其他免疫抑制药在HIV阳性实体器官移植受者中的应用进行综述,旨在为未来HIV阳性实体器官移植受者的免疫抑制管理提供参考。

肾移植受者免疫抑制方案的优化

随着手术技术的成熟与发展,以及围手术期管理水平的提高,肾移植手术成功率显著提高。但由于供受者在遗传性与抗原性上存在的明显差异,会导致肾移植术后发生排斥反应,影响移植物的存活。免疫抑制是治疗排斥反应的重要手段,对减少排斥反应发生,提高移植物存活率具有重要意义。但免疫抑制药在减少排斥反应的同时会引起感染、心血管疾病、肿瘤等并发症,严重影响患者的生活质量,甚至可能导致患者死亡。合理地选择免疫抑制药,不断优化受者免疫抑制方案,对改善受者和移植肾的存活具有重要意义。因此,本文就器官移植发展史、免疫诱导治疗、免疫维持治疗进行评述,探讨肾移植受者免疫抑制方案优化取得的进展,以期为改善肾移植预后提供参考。

钙调磷酸酶抑制剂预防经内镜逆行胰胆管造影术后胰腺炎的研究进展

急性胰腺炎是经内镜逆行胰胆管造影(ERCP)术后最常见的不良事件,尽管使用了多种预防性措施,其仍是临床面临的一个棘手问题。近年来,钙调磷酸酶在胰腺炎发病机制中的作用受到关注,其特异性抑制剂为ERCP术后胰腺炎的预防提供了新的很有前景的方向。本文就近年来钙调磷酸酶及其抑制剂与ERCP术后胰腺炎预防相关的基础和临床研究进展作一综述,以期为后续研究提供更多思路。

低镁血症与肾移植:免疫影响及感染风险的研究进展

镁作为细胞内含量丰富且具有广泛作用的阳离子,在免疫功能方面发挥着积极的作用,备受关注。在多种因素的影响下,如使用钙调磷酸酶抑制剂等,肾移植术后低镁血症的发生并不罕见。感染是肾移植术后常见的并发症,也是导致肾移植受者死亡的常见原因之一。近年来的临床研究表明,肾移植术后低镁血症与移植后感染风险密切相关。在肾移植受者中关注并监测镁浓度可能有助于预防感染的发生,改善受者及移植物预后。因此,本文就镁与免疫反应、肾移植术后低镁血症发生的原因及肾移植术后低镁血症与感染的相关研究进展进行综述,以期为肾移植术后感染的预防与治疗提供参考。

移植后糖尿病危险因素研究进展

实体器官移植极大地延长了终末期疾病患者的生存时间,但器官移植受者术后需要长期服用免疫抑制药,会导致移植后糖尿病(PTDM)的发生风险增加,从而使感染、心血管疾病和死亡的风险升高。近年来,随着PTDM诊断标准的不断完善,临床医师对其认识越来越深入,与2型糖尿病相比,PTDM在病理生理特征和临床进展上存在着明显差异,需采用不同的治疗策略。及早识别器官移植受者的危险因素,早期诊断和干预对于改善受者的生活质量,延长移植物的存活时间以及降低受者病死率具有重要意义。因此,本文就PTDM的诊断、发生情况及危险因素做一综述,以期为临床医师早期识别并干预PTDM提供参考。

新型钙调神经磷酸酶抑制药伏环孢素临床研究进展

伏环孢素是一种口服新型钙调神经磷酸酶抑制药,是环孢素A的衍生物,主要用于治疗自身免疫性疾病,如银屑病、非感染性葡萄膜炎和器官移植后排斥反应。2021年1月,基于两个Ⅱ期和Ⅲ期临床试验的积极结果,FDA批准伏环孢素与标准治疗方案联合用于治疗成人活动性狼疮肾炎。目前,也有研究在探索伏环孢素用于新型冠状病毒感染的肾移植患者。本文对伏环孢素的作用机制、药动学和药效学、用法用量、联合用药和疾病中应用进行归纳总结,为其临床用药提供参考。

西罗莫司用于治疗肝癌肝移植术后肿瘤复发患者的疗效分析

目的探讨原发性肝细胞癌(肝癌)肝移植术后肿瘤复发患者在减少钙调磷酸酶抑制剂(他克莫司或环孢素)剂量并联用西罗莫司的临床疗效。方法 24例复发患者随机分为两组:研究组12例,确诊复发后即将钙调磷酸酶抑制剂减量并联合应用西罗莫司(3mg/d,连用3d后改为1.5mg/d,按血药谷浓度4～8ng/ml调整用量)治疗;对照组12例,继续原免疫抑制方案。比较两组患者的带瘤生存时间、排斥反应及其他不良反应发生情况。结果 两组患者的带瘤生存时间分别为3～37个月(中位数17个月)和1～50个月(中位数4个月),两组比较差异有统计学意义(P<0.05)。研究组1例患者发生急性排斥反应,增加他克莫司用量排斥反应得以控制,对照组无患者发生排斥反应,两组排斥反应发生率比较差异无统计学意义(P>0.05)。研究组高脂血症发生率较高(50%),两组患者的其他不良反应发生率差异无统计学意义(P>0.05)。结论 西罗莫司能显著延长肝癌肝移植术后肿瘤复发患者的带瘤生存时间,并不增加排斥反应发生率,为肝移植术后肿瘤复发的治疗提供了一种新的选择。

激素、钙调磷酸酶抑制剂和吗替麦考酚酯三联用药治疗激素耐药型肾病综合征患儿的疗效和安全性

背景少数病初即表现为激素耐药型的儿童原发性肾病综合征,临床治疗较困难,对于无明确遗传因素证据患儿,临床多采用激素联合一种或多种免疫抑制剂进行治疗,但目前尚无统一的药物添加原则或规范的治疗方案。目的观察激素联合钙调磷酸酶抑制剂、吗替麦考酚酯对初治激素耐药型肾病综合征患儿的治疗效果和安全性。设计回顾性非随机对照研究。方法纳入2014年1月至2020年12月北京大学第一医院儿科收治的初治激素耐药型肾病综合征患儿,除外遗传因素后,分为A组(激素+钙调磷酸酶抑制剂+吗替麦考酚酯三联治疗,三种药按先后顺序依次添加)、B组(激素+钙调磷酸酶抑制剂+吗替麦考酚酯三联治疗,激素联合钙调磷酸酶抑制剂治疗3个月以上无效,改为激素联合吗替麦考酚酯治疗3个月以上仍无效,最后三者联用)、C组(钙调磷酸酶抑制剂+吗替麦考酚酯治疗,因类固醇性糖尿病或青光眼停用激素)和D组(激素+钙调磷酸酶抑制剂+美罗华),比较各组的治疗效果。主要观察指标尿蛋白转阴时间、尿蛋白阴性时间百分比、平均复发次数。结果39例患儿纳入分析,A、B、C、D组分别为16、8、3、12例。A、B、C、D组尿蛋白转阴率分别为75.0%(12/16)、75.0%(6/8)、100%(3/3)和75.0%(9/12),组间比较差异无统计学意义(P>0.05)。A、D组平均尿蛋白转阴时间低于B、C组,尿蛋白阴性时间百分比高于B、C组,差异均有统计学意义(P<0.05)。A和D组间平均尿蛋白转阴时间和尿蛋白阴性时间百分比差异均无统计学意义(P>0.05)。各组患儿用药期间未报告药物相关不良反应。结论对于少数原发性激素耐药型肾病综合征患儿,激素联合钙调磷酸酶抑制剂、吗替麦考酚酯三联治疗有较好的效果。

雷帕霉素治疗肾移植术后慢性移植物肾病疗效的初步观察

目的探讨雷帕霉素对肾移植术后慢性移植物肾病(CAN)的疗效和安全性。方法回顾性分析2002年3月起在本中心随访的31例CAN患者的临床资料,比较从钙神经蛋白抑制剂(CNI)为主的方案转换成SRL为主的方案前后的血清肌酐值(Cr)变化,统计用药相关的不良反应。结果15名患者达到主要终点即恢复规律透析,8人肾功能改善,8人肾功能维持。其中高Cr0组(Cr0≥3mg/dl,n=12)有9人恢复透析,两人肾功能改善;低Cr0组(Cr0<3mg/dl,n=19)中5人恢复透析,8人肾功能维持,6人肾功能改善;两亚组间有显著差异(P=0.003)。14人到达次要终点即停用SRL,其中5人因感染停用SRL,最终4人恢复透析,1人死于感染;9人因不良反应停用SRL改用其他免疫抑制剂,后4人恢复透析,2人肾功能维持,3人肾功能改善。高脂血症(51.6%)、白细胞减少(41.9%)、口腔溃疡(29.0%)和肝功能损害(16.1%)是本研究中SRL常见的不良反应。严重不良事件共13人次,包括脑出血死亡2例、感染死亡3例和需要住院治疗的肺部和泌尿道感染共8人次。结论CNI转换为SRL对部分CAN患者有效,在基线肌酐水平低于3mg/L的患者尤其明显;但SRL的应用必需注意高脂血症和白细胞减少等不良反应及其相关的脑血管意外和感染。

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孢素（CsA）或他克莫司（FK506）＋麦考酚吗乙酯（MMF）＋肾上腺皮质激素（激素）调整为西罗莫司＋MMF＋激素,观察用西罗莫司替代CNI后受者的排斥反应、肺部感染发生率,药物替换后1、3、6个月受者血清肌酐（Scr）水平及其他不良反应发生情况。结果出现CNI药物肾毒性的受者药物转换前及转换后1、3、6个月Scr分别为（190±27）μmol/L、（166±32）μmol/L、（145±46）μmol/L和（110±56）μmol/L,与替换前比较,替换后1、3、6个月受者Scr水平均明显降低（均为P〈0.05）。出现CAN的受者药物替换前及替换后1、3、6个月Scr水平分别为（175±43）μmol/L、（171±38）μmol/L、（180±40）μmol/L和（185±62）μmol/L,替换后1、3、6个月患者Scr水平和替换前比较差异均无统计学意义（均为P〉0.05）。硬化率〈30%的10例受者中有6例Scr水平较替换前下降25%;硬化率30%~50%的3例受者中,仅1例Scr水平较替换前下降25%,余2例肾功能无改善。替换治疗期间所有受者均未发生排斥反应及肺部感染,人、肾存活均率为100%。结论西罗莫司替换CNI治疗肾毒性效果良好,治疗CAN欠佳,其疗效主要取决于开始替换治疗的早晚和肾小球硬化程度。