移植肾急性排斥反应新认识

急性排斥反应是影响肾移植长期预后的重要因素。在新型免疫抑制剂应用下,急性排斥反应具有表现不典型、难治性排斥反应比例高等特点。本文从发生急性排斥反应高危因素的术前筛查与处理、急性排斥反应早期诊断方法以及对急性排斥反应的干预和免疫抑制药物合理应用、移植后感染预防等方面,综合浙江大学医学院附属第一医院肾脏病中心的临床研究结果,探讨发生急性排斥反应的高危因素、诊断和防控措施,以提高肾移植后长期存活率。     

急性体液性排斥反应对移植肾预后的影响

目的 探讨急性体液性排斥反应对移植肾预后的影响.方法 共有1098例接受首次尸体肾移植的受者纳入研究.所有受者术后均采用以他克莫司或环孢素A为基础的三联免疫抑制方案,当发生排斥反应时,采用甲泼尼龙冲击治疗,疗效较差者则联合应用莫罗单抗-CD3或丙种球蛋白或行血浆置换进行治疗.术后1年内经病理检查证实,有53例受者发生急性体液性排斥反应(急性体液性排斥反应组),109例发生急性细胞性排斥反应(急性细胞性排斥反应组),其余936例受者术后1年内肾功能稳定(对照组).分析和比较3组受者性别、年龄、术前淋巴毒、HLA抗原错配数、群体反应性抗体(PRA)水平及供肾冷/热缺血时间等冈素间的差异,比较3组受者术后移植肾功能丧失情况及移植肾存活率,分析完全逆转的急性体液性排斥反应与细胞性排斥反应对移植肾预后的影响.结果 3组受者在性别、年龄、术前淋巴细胞毒性试验、供肾冷缺血时间及术后随访时间等方面比较,差异均无统计学意义(P＜0.05).急性体液性排斥反应组和急性细胞性排斥反应组受者在术前HLA抗原错配数、PRA水平及供肾热缺血时间等方面均明显高于对照组,与对照组比较,差异均有统计学意义(P＜0.05).随访期间,急性体液性排斥反应组受者移植肾功能丧失的发生率为27.4%(14/53),明显高于急性细胞性排斥反应组的7.3%(8/109)和对照组的2.2%(21/936),3组间差异均有统计学意义(P＜0.01).通过kaplan-meier生存分析发现,急性体液性排斥反应组受者的移植肾存活率明显低于急性细胞性排斥反应组和对照组(P＜0.01).剔除发生排斥反应后未逆转者,3组间移植肾存活率的比较,差异均无统计学意义(P＞0.05).结论 急性体液性排斥反应明显影响移植肾存活,但完全逆转的急性体液排斥反应并不影响移植肾的预后.     

Infection-associated cellular activation accelerates chronic renal allograft rejection in rats

The etiology of chronic rejection is unknown, although acute rejection, viral infection, and initial graft ischemia have been implicated. To test the effects of infections on the process of chronic rejection, we simulated bacterial infection by the administration of the endotoxin lipopolysaccharide (LPS), a potent activator of various cell types in an established rat model of chronic rejection. Lewis recipients of Fisher 344 kidneys were treated with a single dose of LPS or vehicle 8 weeks following transplantation and grafts were examined at various time points. In the chronically rejecting controls leukocytic infiltration and the expression of cytokines peaked at 16 weeks. In LPS-treated hosts, leukocyte infiltration and cytokine expression peaked at 12 weeks. By 16 weeks, glomeruli in LPS-treated recipients had become far more sclerotic than those in controls, mimicking the changes observed in controls at 24 weeks. We conclude that infections may play an important role in the development of chronic rejection.     

供者年龄与肾移植慢性排斥反应关系的实验研究

目的 探讨供者的年龄对大鼠同种异体肾移植慢性排斥反应的影响。方法 分别采用3、12、18个月龄的F－344大鼠肾移植给6个月大小的LEW受鼠,以自体肾移植作为对照组,术后检测各组的肾功能和免疫组化的改变,并进行移植肾的组织学观察。结果 18个月龄供肾移植组术后24h尿蛋白含量、移植肾肾小球硬化程度及纤维化程度均较3个月龄及12个月龄组严重,差异有显著性（P＜0.01）;18个月龄的供肾移植组移植肾组织中ED1^＋单核／巨噬细胞、CD4^＋T淋巴细胞及CD8^ 细胞毒性／抑制性T淋巴细胞明显高于3个月龄供肾组,差异有显著性（P＜0.01）。结论 供者的年龄越大,术后移植肾的肾小球硬化及间质纤维化就出现越早,且越严重。     

骨化三醇和氨基胍联合应用减轻大鼠肾移植急性排斥反应

目的探讨骨化三醇和氨基胍(AG)联合应用对大鼠肾移植急性排斥反应的作用。方法选取清洁级近交系健康雄性Wistar大鼠和SD大鼠为供、受者。实验随机分为5组,每组10只。Ⅰ组为同基因对照组:Wistar大鼠肾脏移植给Wistar大鼠,术前和术后不做任何处理;其余各组均为异基因移植,Wistar大鼠肾脏移植给SD大鼠,Ⅱ组为排斥对照组:术前和术后不做任何处理;Ⅲ组为氨基胍治疗组:手术当日开始腹腔注射氨基胍200mg/kg,2次/d,至实验结束;Ⅳ组为骨化三醇治疗组:术前1d开始腹腔注射骨化三醇1μg·kg-1·d-1,至实验结束;Ⅴ组为联合治疗组:氨基胍和骨化三醇联合应用,给药方案同Ⅲ、Ⅳ组。观察各组受者生存期和移植后5d肾组织病理学变化,检测血清肌酐、尿素氮、钙、磷以及γ干扰素(IFNγ)含量。结果Ⅰ～Ⅴ组受者存活时间分别为(9.1±1.9)d、(5.3±0.8)d、(9.7±2.1)d、(8.6±1.6)d和(12.9±3.4)d。Ⅴ组较Ⅱ～Ⅳ组生存期延长,差异有统计学意义(P<0.05)。Ⅲ、Ⅳ组受者存活期、移植肾排斥反应程度、肾功能及血清IFNγ表达水平较Ⅱ组明显改善或降低(P<0.01),Ⅴ组又较Ⅲ、Ⅳ效果更佳(P<0.05)。结论同种异体原位肾移植后联合应用用骨化三醇和氨基胍治疗可有效预防急性排斥反应,二者有明显的协同作用。     

IL-2R 在急性细胞性排异反应的同种异体尸体移植肾组织中的检测及意义

为探讨白介素－２受体（ＩＬ－２Ｒ，即ＣＤ２５）在同种异体肾移植急性细胞性排异（ＡＣＲ）临床诊断的作用，着重观察移植肾发生（ＡＣＲ）和无ＡＣＲ时，其间质浸润细胞中ＩＬ－２Ｒ阳性细胞数的变化，及其与间质浸润的淋巴细胞的关系。作者选择同期行异体肾移植，且无并发症患者１７例，采用ＰＡＰ四层免疫酶标法，检测移植肾组织中间质浸润细胞中ＩＬ－２Ｒ阳性细胞数的变化。结果显示：无ＡＣＲ的肾组织中，ＩＬ－２Ｒ阳性细胞仅轻度增加，当移植肾出现ＡＣＲ时，ＩＬ－２Ｒ阳性细胞数的增加十分显著，并与间质浸润的ＣＤ８密切相关。作者认为ＩＬ－２Ｒ对于ＡＣＲ的诊断及鉴别诊断具有一定的临床应用价值。     

移植肾急性排斥反应新认识（附视频）

急性排斥反应是影响肾移植长期预后的重要因素。在新型免疫抑制剂应用下,急性排斥反应具有表现不典型、难治性排斥反应比例高等特点。本文从发生急性排斥反应高危因素的术前筛查与处理、急性排斥反应早期诊断方法以及对急性排斥反应的干预和免疫抑制药物合理应用、移植后感染预防等方面,综合浙江大学医学院附属第一医院肾脏病中心的临床研究结果,探讨发生急性排斥反应的高危因素、诊断和防控措施,以提高肾移植后长期存活率。     

用补体裂解片断C4d监测大鼠移植肾慢性排斥反应

目的探讨补体裂解片断C4d在监测大鼠肾移植后慢性排斥反应中的作用与意义。方法以封闭群Wistar大鼠为供者,SD大鼠为受者,建立大鼠肾移植模型。将42只受者随机平均分为2组,A组在肾移植术后10d内给予小剂量环孢素A(5mg·kg-1·d-1)治疗;B组除使用环孢素A外,另给予霉酚酸酯10mg·kg-1·d-1灌胃。术后第3、5和10周观察各组移植肾形态变化及移植肾组织中C4d沉积情况。结果从术后第3周起,A组开始出现轻微慢性排斥反应的病理改变,并随着时间的推移逐渐明显。B组于术后第5周开始出现慢性排斥反应的病理改变,程度轻于A组。术后第3周A组即出现明显C4d沉积,至第10周时沉积已较广泛。B组也有C4d沉积,但沉积程度较A组同时段轻(P<0.05)。结论移植肾组织中C4d的沉积早于慢性排斥反应的病理改变,可作为预测慢性排斥反应的有效指标。     

雌激素预防大鼠同种肾移植慢性排斥反应的实验研究

目的 探讨雌激素对移植肾慢性排斥反应的影响。方法 以Fisher大鼠作供者,雌性Lewis大鼠作受者进行同种肾移植,为排除排卵周期及相应的内源性性激素变化的影响,肾移植均在非排卵期进行,后治疗组大鼠隔日给予25μg/kg雌二醇皮下注射。移植后16周作肾功能、移植肾组织学及免疫组化检测,测定肾组织中转化生长因子及β－机动蛋白mRNA的表达。结果 与对照组比较,移植后治疗组24d尿蛋白持续保持较低的水平（P＜0.01）,血清肌酐水平降低（P＜0.01）,肌酐清除率升高（P＜0.01）,移植肾组织管内膜增厚、肾小球硬化和间质纤维化程度减轻（P均＜0.01）,淋巴细胞和单核／巨噬细胞浸润减少（P＜0.01）,细胞间粘附分子（ICAM－1）、转化生长因子（TGF－β1）的mRNA表达减少（P均＜0.01）。结论 雌激素对移植肾功能有保护作用,其机理与影响上述细胞因子在移植肾的表达有关,提示雌激素可能为一类潜在的抗慢性排斥反应药物。     

一剂赛尼哌对肾移植急性排斥反应的预防作用

目的 探讨1剂赛尼哌在预防同种异体肾移植急性排斥反应中的作用。方法 回顾性分析50例应用1剂赛尼哌的肾移植患者资料，同期30例未应用赛尼哌患者作为对照，随访6个月。分析比较2组患者急性排斥反应、移植肾功能、感染及赛尼哌不良反应发生情况。结果 赛尼哌组发生急性排斥反应13例（26％），对照组为17例（57％），差异有统计学意义（P〈0．05），2组患者药物不良作用方面、血液系统损害、肝功能损害、感染发生率及人／肾存活率差异无统计学意义（P〉0．05）。结论 联合应用1剂赛尼哌免疫抑制方案可以降低肾移植急性排斥反应发生率，改善移植肾功能，不良反应轻。     

小剂量FK778预防大鼠移植肾的慢性排斥反应

目的研究小剂量FK778对大鼠移植肾慢性排斥反应的预防作用。方法应用显微外科技术制作大鼠移植肾慢性排斥反应模型；将肾移植后的大鼠分为两组。治疗组：将FK778溶解在羧甲基纤维素溶液中，行灌胃治疗，自术后第1天开始，每天1次，剂量为5mg·kg^-1·d^-1，治疗至肾移植后24周。对照组：用单纯羧甲基纤维素溶液对大鼠行灌胃治疗，每天1次，直至移植后24周。移植后每4周测定1次24h尿蛋白含量，第24周时处死大鼠，对移植肾行组织学、免疫组织化学及实时定量逆转录聚合酶链（RT-PCR）检测。结果治疗组大鼠24h尿蛋白含量、肾组织病理损害程度、淋巴细胞和单核／巨噬细胞浸润程度与对照组比较均显著减低，肾组织生长因子TGF-β、PDGF-B基因的表达也显著减少。结论小剂量FK778能预防大鼠移植肾慢性排斥反应。     

Antibodies against mesangial cells in a rat model of chronic renal allograft rejection.

BACKGROUND: Chronic renal allograft rejection (CR) is the leading cause of late renal transplant failure. The histological lesions of CR may comprise glomerular basement membrane (GBM) duplications and mesangiolysis. Its pathogenesis is not yet completely understood, although lately humoral responses have been suggested to be important. Recently, we identified antibody responses directed against GBM antigens in the Fischer (F344) to Lewis (LEW) renal transplantation model. Immunofluorescent studies in this model also suggested deposition of antibodies on mesangial cells. Therefore, we hypothesized that antibodies were not only directed at GBM antigens but also to mesangial cell antigens. METHODS: F344 to LEW renal transplantations were performed and sera were collected. Pre- and post-transplantation sera were tested for antibody binding to donor rat mesangial cells (RMCs) cultured from F344 kidneys. Anti-mesangial cell antibodies were compared with anti-GBM antibodies measured in the same sera. RESULTS: Post-transplant sera of F344 to LEW renal transplantations, but not LEW to F344, bound to F344 RMC in a dose-dependent manner. Whereas antibodies reactive with RMCs were not present before transplantation, all rats with CR developed antibodies. The antibodies were predominantly of the IgG1 isotype. Antibody binding to RMCs correlated with binding to F344 GBM. Pre-incubation with RMCs partially inhibited GBM binding, and RMC binding was inhibited by GBM. Antibody binding to RMCs did not result in complement activation or cell lysis. CONCLUSION: LEW recipients of F344 grafts produce antibodies reactive with F344 RMCs. The antigens involved are similar to or at least share antigenic epitopes with antigens recognized in the GBM.     

移植肾急性排斥反应的免疫表型

目的阐明移植肾急性排斥反应的发生机制。方法发生严重急性排斥反应的１６例移植肾行免疫组化染色,其中６例行免疫胶体金电镜观察。结果移植肾组织中主要免疫活性细胞为Ｔ细胞,动脉壁及肾小管细胞间的Ｔ细胞均为ＣＤ８细胞。结论移植肾急性排斥反应主要是由Ｔ淋巴细胞尤其是ＣＤ８细胞介导的一种免疫损伤。     

一种大鼠肾移植模型的建立

目的　建立大鼠异体肾移植模型。方法　用SD大鼠作为供体和受体 ,采用原位低温灌注 ,原位修剪 ,移植肾放置左侧 ,血管直接吻合 ,输尿管带膀胱瓣与膀胱吻合。结果　经过 6个多月近 80次的实验 ,克服了移植物灌注、血管吻合、膀胱吻合等技术难关 ,建立了稳定实用的肾移植动物模型。手术成功率为 85 %左右 ,受体存活可达 3 0d。结论　此模型可以在一般的实验室条件下开展 ,有较高的成功率 ,符合肾移植实验研究的需要。     

肾移植术后的巨细胞病毒感染及其对急性排斥反应的影响

目的 探讨肾移植受者术后活动性巨细胞病毒（ＣＭＶ）感染的发生率、感染的原因以及ＣＭＶ感染对急性排斥反应的影响。方法 检测１８７例肾移植受者和供者术前血清抗－ＣＭＶ抗体;受者术后定期检测体内ＣＭＶ ＤＮＡ、对ＣＭＶ ＤＮＡ阳性的部分患者给予抗ＣＭＶ治疗,并比较各组排斥反应的发生率。结果 无论是供者还是受者,术前如血清抗－ＣＭＶ抗体阳性,受者术后发生活动性ＣＭＶ感染者明显增多,这些患者急性排斥反应的发     

OKT3治疗移植肾难治性排斥反应

为了解ＯＫＴ３对移植肾难治性排斥反应的治疗效果，１９９３年１月至１９９６年６月，我们对４４例肾移植术后移植肾难治性排斥反应（其中加速性排斥反应７例，急性排斥反应３７例）应用ＯＫＴ３治疗。结果：６例加速性排斥反应及３１例急性排斥反应逆转，总逆转率为８４．６％。２５例对ＯＫＴ３治疗产生迅速反应，平均逆转时间为７±４天，１２例发生延迟性反应，平均逆转时间为３４±３天（Ｐ＜０．０１）。作者认为：ＯＫＴ３治疗难治性排斥反应效果显著。巨细胞病毒感染及细胞因子释放综合征是ＯＫＴ３治疗的主要副作用。患者对ＯＫＴ３治疗的延迟性反应与细胞因子释放综合征及排斥损害有关。产生低滴度抗ＯＫＴ３抗体的患者可再次接受ＯＫＴ３治疗。     

肾移植术后急性体液性排斥反应的治疗

目的 总结肾移植术后急性体液性排斥反应中针对HLA抗体的检测和处理经验.方法 肾移植受者15例,术前行HLA分型、交叉配型和群体反应性抗体(PRA)的检测,术后采用他克莫司(或环孢素A)、霉酚酸酯和糖皮质激素预防排斥反应.15例于肾移植后1～14 d发生抗体介导的急性排斥反应(AMR),采用抗胸腺细胞球蛋白(100 mg/d,使用5 d)治疗,或将环孢素A转换为他克莫司,当PRA明显升高,且血清中出现供者特异性HLA抗体时,即行血浆置换(PP),共行1～5次,每次PP后静脉输注免疫球蛋白(IVIG)100～150 mg/kg,最后1次PP后给予WIG 200～500mg/kg.结果 术后出现抗供者特异性HLA Ⅰ类抗体者9例,抗HLAⅡ类抗体者4例,同时出现抗Ⅰ、Ⅱ类抗体者2例.14例的AMR逆转,1例术后发生移植肾功能恢复延迟,彩色多普勒超声波显示移植肾血流灌注差,于术后第10天切除移植肾.并行二行肾移植.2例AMR后并发急性肾小管坏死,透析后移植肾功能恢复正常.抗排斥反应治疗期间患者均未发生严重感染.随访12～52个月,1例因慢性移植肾肾病恢复血液透析治疗,1例死于心血管疾病,其余患者移植肾功能稳定.结论 将ATG、PP和IVIG联合应用能有效逆转AMR.     

急性体液性排斥反应对移植肾预后的影响

Objective To explore the effect of acute humoral rejection on kidney graft survival.Methods 1098 patients received cadaveric renal transplant from January 2002 to December 2008 in our center. All patients were given triple immunosuppressants including tacrolimus or cyclosporine.According to patients who experienced biopsy-proved humoral rejection and cellular rejection within one year post-transplant, there were 53 cases in humoral rejection group, 109 in cellular rejection group (including 63 patients with borderline change), and 936 in normal group. Patients who experienced acute rejection received mythyl-prednisolone pulse, or received anti-CD3 antibody/plasma exchange/globulin. Clinical characteristics before operation including sex, age, HLA mismatch, panel reactive antibody, cold/warm ischemic time, graft loss rate and graft survival were compared among three groups. The effect of completely reversed cellular rejection and humoral rejection on graft survival was analyzed. Results There was no significant difference in sex, age and cold ischemic time among three groups, but there was significant difference in warm ischemic time, level of PRA and HLA mismatch between cellular rejection group or humor rejection group and normal group (P＜0. 05). During a follow-up period, the incidence of graft loss in humoral rejection group was 27.4 %, significantly higher than 7.3 % in cellular rejection group and 2.2 % in normal group, P＜0. 001. Kaplan-Meier analysis revealed the survival rate of grafts in humoral rejection group was significantly lower than in cellular rejection group and normal group (P＜0.001 ). After patients with irreversible rejection were excluded,there was no significant difference in the survival rate of grafts among the three groups.Conclusion Patients with acute humoral rejection survived with inferior graft outcome,but completely reversible rejection showed no effect on the graft survival.     

Development of injury in a rat model of chronic renal allograft rejection: effect of dietary protein restriction

Non-allogeneic factors such as increased nephron “workload” may contribute to chronic renal allograft rejection. Reducing dietary protein from 20 % to 8 % was tested in a model of chronic rejection: Dark Agouti kidney to Albino Surgery recipient, “tolerised” by previous donor blood transfusions. Survival, weight gain, serum creatinine concentration and creatinine clearance were similar for both groups at all times. Urinary protein was significantly (P < 0.05) lower in the low-protein (LP) group 1 month after transplantation. After 3 and 6 months, both groups demonstrated mild chronic rejection. After 6 months, tubular atrophy was significantly (P < 0.05) less in the LP group and interstitial fibrosis was marginally reduced. Glomerular hypertrophy, glomerular sclerosis, tubular dilatation, leucocyte infiltration, adhesion molecule expression and TGF-β ₁ mRNA expression were similarly increased in both groups. Thus, reducing dietary protein to 8 % lowered urinary protein, but did not significantly affect the development of chronic rejection in renal allografts beyond affording a degree of protection from tubulointerstitial damage. Received: 17 June 1998 Accepted: 23 September 1998     

HLA致敏原性错配对肾移植受者急性排斥反应发生率的影响

目的：探讨供受者HLA致敏原性错配(IM)对肾移植受者急性排斥反应发生率的影响。方法：回顾性分析196例首次肾移植受者IM对肾移植术后肾功能的恢复时间及1年内排斥反应发生率情况。结果：IM对肾移植术后肾功能恢复时间无明显影响；IM患者1年内急性排斥率明显增加；各类位点IM对肾移植术后急性排斥反应的影响进行比较，A位点影响不大，B位点与急性排斥反应有关，DR位点IM可致急性排斥反应明显增加。结论：在临床采用氨基酸残基配型标准判断组织配型的同时，IM不容忽视，HLA-B位点IM与肾移植术后急性排斥反应相关，HLA-DR位点IM明显影响肾移植术后排斥反应发生率。