肾移植术后血清白细胞介素－6活性动态测定的临床意义

以血清白细胞介素－６（ＩＬ－６）依赖的７ＴＤ＿１细胞株－ＭＴＴ比色法测定人血清ＩＬ－６活性。确定国人ＩＬ－６活性正常值为６．７５±２．９８ｕ／ｍｌ，并于肾移植术后第一天明显升高（１６．４４±９．２０ｕ／ｍｌ），一周后下降并趋于稳定（８．１２±３．３６ｕ／ｍｌ）；急性排斥反应时明显升高（２４．３５±９．３７ｕ／ｍｌ）；排斥逆转或移植肾切除后再度下降（７．２３±４．７１ｕ／ｍｌ）。应用ＡＬＧ者ＩＬ－６释放增加，慢性排斥时无变化。ＩＬ－６活性是监测移植肾急性排斥反应的一个可靠生物学指标。     

Sequential interleukin 2 and interleukin 2 receptor levels distinguish rejection from cyclosporine toxicity in liver allograft recipients

Previous studies of renal transplant recipients have demonstrated that allograft rejection is accompanied by an increase in plasma and urinary levels of interleukin 2 and its soluble receptor before the development of clinical symptoms. After measuring interleukin 2 and interleukin 2 receptor levels in the plasma, bile, and urine of liver transplant recipients, we found that rejection is preceded by elevation of plasma and biliary levels of both substances, that cyclosporine toxicity did not affect either of these levels, and that urinary levels of the substances are unaffected in either condition. Levels of interleukin 2 and interleukin 2 receptors increased in bile earlier than in plasma, and interleukin 2 levels did not overlap among stable patients and those experiencing rejection, whereas levels of interleukin 2 receptors did. Serial measurements of interleukin 2 levels, particularly in the product of the transplanted organ, provide a reliable assessment of the immunologic status of the allograft.     

动态监测血清、尿液和肾组织液中SIL－2R水平在肾移植早期的应用价值

为了了解可溶性白介素２受体（ＳＩＬ－２Ｒ）在肾移植早期的应用价值，动态监测４０例肾移植患者血清、尿液及肾组织液中可溶性白介素２受体水平变化，发现术前透析患者血清ＳＩＬ－２Ｒ水平较正常人高，术后迅速下降。急性排斥（ＡＲ）发生时，ＳＩＬ－２Ｒ水平均有不同程度的升高，以肾组织液中升高最明显，比临床症状和血清肌酐出现早１～５天。在急性ＣｓＡ中毒发生时血清和肾组织液中ＳＩＬ－２Ｒ水平明显升高，而急性感染发生时只在血清中明显升高。结果表明：动态监测血清、尿液ＳＩＬ－２Ｒ水平有助于预测和早期诊断ＡＲ，同时行肾组织液及血清、尿液ＳＩＬ－２Ｒ水平测定能较好地诊断与鉴别诊断ＡＲ、急性ＣｓＡ中毒和感染     

Biliary interleukin 6 levels as indicators of hepatic allograft rejection in rats.

Interleukin 6 has recently been noted to be present during the rejection response to grafted organs. In this study, we investigated biliary and serum interleukin 6 levels following liver transplantation in rats. IL-6 levels in bile and serum of naive rats were below 0.6 U/ml and 0.5 +/- 0.2 U/ml (mean +/- SD), respectively. Both biliary and serum IL-6 levels showed high values (greater than 10.0 U/ml and greater than 1.6 U/ml, respectively) on the day after transplantation, which seemed to reflect the inflammatory status caused by the surgical stress. Later samplings showed that the kinetics of serum IL-6 differed among the animals without any definite feature related to graft rejection. In contrast, biliary IL-6 levels correlated well with the severity of the rejection response as determined histologically. Biliary IL-6 levels started to rise at the onset of the rejection response (6.6 +/- 0.6 U/ml), increased further with its progression (19.3 +/- 7.8 U/ml), and then finally fell in the terminal stage (less than 2.0 U/ml). Elevation of biliary IL-6 was observed at an early stage when abnormalities could be detected histologically but not in liver function tests and bile flow. Therefore, biliary IL-6 levels may be of value for the early diagnosis of rejection following liver transplantation.     

肾移植术后监测血清、尿液和肾组织液中肿瘤坏死因子的临床意义

为探讨肾移植术后肿瘤坏死因子（ＴＮＦα）在移植肾排斥反应（ＡＲ）诊断与鉴别诊断中的意义，采用液相竞争放射免疫法动态监测６０例肾移植患者术后血清、尿液及肾组织液中ＴＮＦα水平的变化。结果：ＡＲ组ＴＮＦα水平在血清、尿液及肾组织液中均显著升高，以肾组织液中升高最明显，比临床症状的出现早１～２天；ＣｓＡ肾中毒组ＴＮＦα水平轻度升高，但无统计学意义；急性肾小管环死（ＡＴＮ）组肾组织液及尿液中ＴＮＦα水平均显著升高；急性感染组仅血清中ＴＮＦα水平显著升高。结论：动态监测血清、尿液和肾组织液中ＴＮＦα水平能较好地早期诊断和鉴别诊断ＡＲ、急性感染、ＣｓＡ肾中毒和ＡＴＮ。     

Elevated biliary interleukin 5 as an indicator of liver allograft rejection

Interleukin 5 (IL-5) is a T cell-derived cytokine that acts as a potent and specific eosinophil differentiation factor in humans. During liver allograft rejection, intragraft IL-5 mRNA and eosinophilia have been observed. The objective of this study was to correlate the levels of IL-5 in bile and serum with eosinophilia and allograft rejection in paediatric liver recipients. IL-5 levels were determined by ELISA (enzyme-linked immunosorbent assay) in bile (n = 85) and serum (n = 106) and obtained prospectively from 15 patients during the first 3 weeks post-transplantation. Biliary and serum IL-5 levels were significantly elevated during allograft rejection compared to IL-5 levels when no rejection was apparent or during infectious complications. The highest IL-5 levels were measured in the bile during the early rejection period (3 days prior to biopsy-proven rejection). Fifteen of 16 rejection episodes were marked by increases in IL-5 as revealed by analysis of sequential samples from individual patients. In all patients with rejection, elevations in serum IL-5 were associated with elevations in peripheral eosinophil counts. These results indicate that IL-5 is produced in the liver and may be a useful and specific marker of allograft rejection. Furthermore, these findings provide further evidence for a pathway of liver allograft rejection mediated by IL-5 activated eosinophils.     

An increase in myeloid-related protein serum levels precedes acute renal allograft rejection

Upon interaction with activated endothelium, monocytes and neutrophils form complexes of myeloid-related protein 8 (MRP8) (S100A8) and MRP14 (S100A9), two members of the calcium-binding S100 family that are secreted during transendothelial migration. In a pilot study of 20 renal transplant recipients and a validation study of 36 renal transplant recipients, MRP8/14 serum levels were measured with an enzyme-linked immunosorbent assay for 28 d, associated with C-reactive protein and creatinine serum levels, and grouped according to biopsy-proven acute rejection. Serum levels of MRP8/14 but not C-reactive protein were significantly increased for several days during the first 2 wk for the acute rejection groups in both studies (P < 0.005, on day 6 after transplantation). As determined by using receiver operating characteristic curves, the optimal cutoff for 100% specificity and high sensitivity (67%) for acute rejection on day 6 after transplantation was calculated to be 4.2 microg/ml for MRP8/14 in the pilot study; this value was confirmed in the validation study. Positive MRP8/14 serum levels preceded acute rejection episodes by a median of 5 d. A 3-d course of intravenous methylprednisolone therapy reduced prerejection MRP8/14 serum levels from 5.7 microg/ml to 3.3 microg/ml (P < 0.05). All MRP8/14 serum levels were below the cutoff during urinary tract infections, delayed graft function, or cytomegalovirus infections, and these values did not differ significantly from control values. It is concluded that the MRP8/14 complex is a very early serum marker suitable for monitoring of acute rejection with high sensitivity and specificity.     

人巨细胞病毒感染对肾移植受者血清白细胞介素－6水平的影响

应用ＰＣＲ检测ＨＣＭＶ－ＤＮＡ，ＥＬＩＳＡ检测ＨＣＭＶ－ＩｇＭ、ＩｇＧ，诊断肾移植受者ＨＣＭＶ感染，６５例受者中ＨＣＭＶ感染者３９例，非感染者２６例。应用ＭＴＴ法检测受者血清ＩＬ－６生物活性，阐明了ＨＣＭＶ感染对肾移植受者血清ＩＬ－６水平的影响。结果表明：感染与非感染组间血清ＩＬ－６水平差异无显著性（Ｐ＞０．０５）；６例原发性感染者血清ＩＬ－６水平随感染时间延长呈增高及降低双相改变，表明慢性迁延性感染者血清ＩＬ－６水平降低。临床工作中监测ＨＣＭＶ感染的肾移植受者血清ＩＬ－６水平变化具有重要意义。     

预防预致敏受者尸体肾移植术后急性排斥反应的临床研究

目的 探讨HLA配型及新型免疫抑制剂治疗方案对预防致敏患者肾移植术后急性排斥反应的影响.方法 实验组选择46例术前致敏患者(术前PRA>10%),对照组选择同期705例未致敏患者(术前PRA<10%),实验组患者均采用诱导治疗(ATG 100 mg/d,5～7 d)+三联免疫抑制剂维持治疗方案(FK506+MMF+激素),比较两组间患者术后急性排斥反应发病率、移植肾功能延迟恢复比例、移植肾/患者一年存活率,同时分析HLA配型对移植肾急性排斥反应的影响.结果 实验组与对照组急性排斥反应的发病率分别为30.43%和19.57%(P<0.05);移植肾功能延迟恢复发病率分别为60.86%和11.87%(P<0.01).患者一年存活率分别为95.65%和98.44%,一年移植肾存活率分别为93.48%和96.88%;一年时平均血肌肝分别为130 mmol/dL和125 mmol/dL,差异无统计学意义.实验组患者HLA相配率(4.2)明显高于对照组患者(2.8)(P<0.05).实验组中HLA配型2-4错配的患者与0-2错配患者的急性排斥反应发病率有显著性差异,高度致敏患者(移植术前PRA>50%)急性排斥反应发病率较低度致敏患者(PRA 10%～20%)发病率高,移植术后PRA水平持续升高者更容易出现急性排斥反应.结论供、受者之间良好的HLA配型及采用新型免疫抑制药物治疗方案,对预防及减轻致敏患者移植术后急性排斥反应疗效确切.     

Comparison of serum neopterin levels and urinary neopterin excretion in renal allograft recipients

Determination of serum and urinary neopterin levels was performed daily in 30 patients undergoing kidney transplantation for treatment of end-stage renal failure. Neopterin serum levels were determined by RIA and urinary excretion by HPLC. In parallel, the same samples were tested for creatinine content. Results indicated a strong correlation between the clearance of neopterin and creatinine. This correlation was independent of the extent of functional impairment as well as of the different causes of renal insufficiency. As a consequence, a strong relationship between serum and urinary neopterin levels was only obtained when values were corrected for different renal function by dividing them by the creatinine levels. It thus appears that major attention has to be paid to the functional state of the kidney when studying neopterin serum and/or urine values. It also appears that under these prerequisites both methods of detection as well as both sample sources yield comparable results.     

Serum immunoreactive interleukin 1 in renal transplant recipients. Association of raised levels with graft rejection episodes

A solid-phase radioimmunoassay was used for monitoring serum interleukin 1 levels in 12 renal transplant recipients. From 10-fold to 20-fold elevations of interleukin 1 occurred in association with 10 of 12 graft rejection episodes. The interleukin 1 elevation preceded the clinical rejection diagnosis by an average of one day in transplant recipients with initially functioning grafts, and by two days in recipients with delayed onset of graft function. The results show that the release of interleukin 1 into the circulation is an early event in renal allograft rejection and demonstrate the potential utility of interleukin 1 antigenic assays in the early diagnosis of rejection.     

Prostaglandin as an effective antirejection therapy in rat renal allograft recipients

Because adenylate cyclase activators such as prostaglandin E1 elevate lymphocytic cyclic AMP and inhibit T cell proliferation and the effector function of cytotoxic T cells in vitro, we tested the efficacy of 15(S)-15-methyl prostaglandin E1, a prostaglandin derivative with a prolonged biologic half-life. Treatment with this agent resulted in a near complete protection of renal grafts from immunologic damage, despite withholding therapy until day 4 following transplantation.     

Effects of immediate switch from cyclosporine microemulsion to tacrolimus at first acute rejection in renal allograft recipients

BACKGROUND: A number of institutions have reported favorable results in renal transplant patients after conversion from cyclosporine (CsA) to tacrolimus at the time of acute rejection, but no prospective, controlled study has been performed to date. Here, we report the first randomized study comparing patients whose therapy was changed at a first episode of acute rejection to tacrolimus with those who were maintained on CsA microemulsion (ME). METHODS: This 3-month, prospective, open, multicenter, parallel-group study was conducted at 15 centers in seven European countries. In total, 119 renal graft recipients experiencing a first biopsy-proven acute rejection episode while receiving CsA-ME were randomized (1:1) to start tacrolimus-based therapy (n=61) or to continue CsA-ME-based therapy (n=58). RESULTS: Baseline characteristics were comparable for both groups. The initial rejection episode responded to steroid treatment in 93.4% (tacrolimus) and 63.8% (CsA-ME) (P=0.001), respectively. In patients at risk, the incidence of recurrent rejection events within 3 months was significantly lower with tacrolimus therapy (5/57, 8.8%) compared with CsA-ME therapy (15/44, 34.1%) (P=0.002). Patient and graft survival were similar in both study groups 3 months after randomization. The most frequently reported adverse events were increased serum creatinine (29.5% vs. 22.4%), hypertension (24.6% vs. 22.4%), and urinary tract infection (18.0% vs. 20.7%) for tacrolimus versus CsA-ME. Tremor was more common in tacrolimus treated-patients (17.4% vs. 2.1%, P=0.011). CONCLUSIONS: Early conversion to tacrolimus therapy benefited the resolution of acute rejection episodes and significantly reduced the risk of recurrent rejection compared with continuation of CsA-ME.     

Conversion from cyclosporine to azathioprine in renal allograft recipients

Fifty seven recipients of renal allografts initially treated with CsA and low-dose prednisone were switched to azathioprine and low-dose steroids. Ten had prolonged (greater than 28 days) allograft nonfunction after transplantation (group 1), 8 had ongoing, poorly controlled rejection (group 2), and 39 had stable functioning grafts (group 3). With a mean follow-up period of 5 +/- 3 months after conversion, 50 grafts remained functional including 6 of 10 in group 1, 6 of 8 in group 2, and 38 of 39 in group 3. Thirty-seven (65%) had improved function, 12 (21%) had stable function, and 8 (14%) experienced declining renal function. Three of these latter 8 patients required reinstitution of CsA therapy. There were 20 episodes of acute rejection in 18 patients; one graft lost function because of acute rejection unresponsive to therapy. Reasons for the 6 other graft losses were persistent primary nonfunction in 3 patients from group 1, untreated rejection in 2 patients who had multiple prior rejection episodes while on CsA, and chronic rejection in one patient. Although renal function has improved or stabilized in the majority (86%) of individuals changed to azathioprine therapy, there was substantial risk of acute rejection (32%) complicating this procedure. Patients most likely to benefit from conversion to azathioprine therapy are those with prolonged graft nonfunction after transplantation and those with serum creatinines greater than 2.0 mg/dl.