Renal allograft immunosuppression: II. A randomized trial of withdrawal of one drug in triple drug immunosuppression

Abstract. A prospective randomized study was conducted to evaluate the impact of four different conversion protocols on graft outcome in long-term follow-up. Between January 1986 and May 1987, 128 patients with first cadaveric kidney allografts were randomized at the time of transplantation to four treatment groups of 32 patients each, to be assigned 10 weeks post-transplantation. During the first 10 weeks, all patients received triple therapy with low-dose azathioprine (Aza), cyclosporin (CyA), and methylprednisolone (MP). After 10 weeks, one group continued with triple therapy (group A) while the three other groups received different combinations of two drugs, namely, Aza and CyA (group B), Aza and MP (group C), or CyA and MP (group D). Withdrawal of MP (group B) or especially of CyA (group C) was associated with 4/29 (14%) and 10/28 (36%) acute rejection episodes, respectively, for 60 days after conversion. All rejections were mild and reversible. There were no rejections after Aza withdrawal or in the group that continued on triple therapy during the corresponding time period. The most common reason for dropping out after withdrawal, for those patients who could not continue on the originally randomized medication, was azathioprine intolerance (n= 12). Five patients were switched back to triple therapy after CyA withdrawal due to rejection. Steroid intolerance was rare and CyA in low doses was very well tolerated. At 1 year there were no statistically significant differences in graft survival between groups A, B, C, and D-81 %, 88%, 88%, and 88%, respectively-or in patient survival-88%, 88%, 88%, and 97%, respectively. For those patients continuing with the originally randomized treatment protocol, there were no differences in patient or graft survival either, the means being 91% and 89%, respectively. The most common cause of death after withdrawal was cardiovascular in nature, and there were no more fatal infections under triple drug treatment than with double drug regimens. There were no statistically significant differences in mean serum creatinine values at 1 year. The median serum creatinine values for groups A, B, C, and D were 112, 132, 133, and 133 μmol/l, respectively. At 1 year the mean CyA dose in the groups that continued with CyA was 3. 5–4. 2 mg/kg per day and CyA concentrations were equal.     

外周血及移植肾内嗜酸性粒细胞变化的临床意义

为了解移植肾在急性排斥时外周血和移植肾内嗜酸性粒细胞（ＥＯ）变化的意义，动态观察３１例同种异体肾脏移植病人的外周血和移植肾内ＥＯ的变化。结果发现在急性排斥反应时，移植肾内ＥＯ数＞２％者占８０．９％，明显高于肾功能稳定时，Ｐ＜０．０１；重度排斥中血ＥＯ数＞４％者占８２．６％，明显高于肾功能稳定时和中度以下排斥者，Ｐ＜０．０１。结果认为，测定移植肾内的ＥＯ变化可以做为监测急性排斥反应的可靠指标，外周血中的ＥＯ明显增多常提示排斥反应较为严重。     

Transplantation of embryonic noradrenergic neurons in two models of adult rat spinal cord injury: ultrastructural immunocytochemical study

The synaptic connections established by grafted noradrenergic (NA) neurons into the lesioned adult rat spinal cord were analysed using immunocytochemistry at the electron microscopic level. An embryonic cell suspension of the locus coeruleus region from E-13 rat embryos was transplanted into the spinal cord following either: (1) spinal cord transection or (2), partial selective denervation by 6-hydroxy dopamine (6-OH DA). One month after grafting, the NA-neurons established, in the two models, an innervation pattern similar to that found in the intact spinal cord. In both models, the transplanted NA-immunoreactive neurons formed extensive synaptic contacts with dendrites, spines and perikarya. The proportion of axodendritic and axospinous contacts was inverse in the two models. The first model thus reproduced more closely the normal synaptic pattern prefering dendritic targets, which could correspond to a better integration of the graft. In the second model, a partially NA-denervated spinal cord, there existed a competition between residual intrinsic and grafted neuron-derived fibres, which presumably affects synaptogenesis. In conclusion, the present study illustrate the complexity of cell interations conducting to the formation of a specific circuitry. Recognition phenomenon are likely modulated by space constraints, which ultimately shape-up the geometry of synaptic contacts.     

Effects of Pyridoxalated Hemoglobin Polyoxyethylene Conjugate and Stroma-free Hemoglobin on Renal Vascular Responsiveness to Vasoactive Substances in Isolated Perfused Rat Kidney

Abstract: The effects of pyridoxalated hemoglobin polyoxyethylene conjugate (PHP) and stroma-free hemoglobin (SFH) on vascular responsiveness to various vasoactive substances were examined in isolated perfused rat kidneys. The kidneys isolated from rats were perfused with 6% PHP, 6% SFH, and 6% hydroxyethylstarch (HES) solution at a constant flow rate. Vascular responsiveness to acetylcholine (ACh), nitroglycerin (NG), norepinephrine (NE), and angiotensin-II (ANG-II) was examined by measuring the perfusion pressure (PP). Effects of inhibition of endothelium-derived relaxing factor (EDRF) by N^G-monomethyl L-arginine (L-NMMA) on NE-induced and ANG-II-induced renal vascular responses were examined. ACh and NG induced a dose-dependent decrease in perfusion pressure (PP) in all groups. NE and ANG-II induced an increase in PP in all groups, but NE-induced and ANG-II-induced responses in the PHP-perfused and SFH-perfused groups were significantly larger than those in the HES-perfused group. L-NMMA did not alter vascular responsiveness to NE and ANG-II. These results indicate that PHP and SFH do not inhibit EDRF induced by ACh, but hemoglobin moiety per se does augment the vascular responsiveness to NE and ANG-II in the isolated perfused rat kidney.     

胚胎脊髓细胞悬液植入急性成年大鼠损伤脊髓

目的：建立胚胎脊髓细胞悬液移植于脊髓损伤模型，以评价其治疗脊髓损伤的可能性。方法：４２只Ｗｉｓｔａｒ大鼠以改良Ａｌｅｎ法（５０ｇｃｍ）打击脊髓，３天后将孕１４天（Ｅ１４）ＦＳＣＳ２０μｌ植入损伤空腔，移植后２、４、６、８、１０、１２周，以光、电镜、免疫组织化学观察移植物存活、分化及其与宿主之间关系。结果：移植细胞逐渐长大。充满不规则空腔，宿主ＮＦ、５－ＨＴ、ＣＧＲＰ纤维分别出现于移植物，ＧＦＡＰ纤维于宿主移植物交界处适量存在。移植成神经细胞、成少突胶质细胞、成星形细胞的细胞器日渐完善，细胞功能活跃。复杂及多样突触与细胞连接，将上述细胞与神经纤维、胶质纤维、毛细血管网在三维空间内连接成一体，并与宿主紧密嵌合。结论：（１）成年大鼠脊髓损伤３天后植入ＦＳＣＳ可以存活。（２）移植物进入宿主后，出现再分布，继而器官样分化。（３）长、短传导束进入移植物，显示了移植物的桥作用。（４）成少突胶质细胞的神经营救作用。（５）移植区内出现多种突触，提示移植物中继作用的可能性。     

Comparison of FK-506 and cyclosporine regimens in pediatric renal transplantation

Clinical aspects of FK-506 or cyclosporine immunosuppression regimens were evaluated in 48 consecutive pediatric renal transplant recipients. Tapering and discontinuation of prednisone was employed only in children receiving FK-506 who experienced minor or no rejection episodes during the 1st posttransplant month. At 1 year follow-up, 17 of 22 (77%) of all children with functioning allografts were receiving no prednisone (n=13) or a mean dosage of 0.07 mg/kg per day (n=4). During the 1st month, acute cellular rejection was more common in the FK-506 group (0.58 vs. 0.21 rejections per patient,P<0.05) but allograft survival (92%) and renal function at 1 year posttransplant were identical in both groups. Compared with the cyclosporine regimen, FK-506 immunosuppression may be associated with a higher incidence of cytomegalovirus or reversible Epstein-Barr virus-induced lymphoproliferative disease. However, the FK-506 group had less hirsutism and gingival hypertrophy and required fewer antihypertensive medications independent of steroid use. Height standard deviation scores and weight-for-height index improved only in preadolescents receiving FK-506 but no prednisone (P<0.02 andP<0.05, respectively), but did not differ between children on FK-506 plus prednisone and those in the cyclosporine group. We conclude that the major advantages of FK-506 over cyclosporine immunosuppression are a reduced severity of hypertension and an improved cosmetic appearance which may improve long-term medical compliance. When used as monotherapy, FK-506 also shows promise in relieving the growth retardation associated with cyclosporine regimens that include prednisone.     

Pretransplant Exposure to Donor HLA-DR Antigen in Random Transfusion Units and the Development of Donor Antigen-Specific Hyporeactivity

Our previous studies have shown that the in vitro assay of donor antigen-specific hyporeactivity is a useful marker for identifying solid organ transplant recipients (kidney, lung and heart) at low risk for immunologic complications (i.e., late acute rejection episodes and chronic rejection). Donor antigen-specific hyporeactivity is defined as a significantly decreased post- vs. pretransplant proliferative response to donor antigens while response to third-party controls remains unchanged. We analyzed whether exposure to the same HLA-DR antigen pretransplant via random blood transfusion and posttransplant via the transplanted organ influenced the development of hyporeactivity. Thirty previously nontransfused recipients, each receiving two 150 ml pretransplant random blood transfusions, were assessed for hyporeactivity at 1 year posttransplant. Of the 12 recipients with pretransplant exposure to kidney HLA-DR via transfusions, 6 (50%) developed hyporesponsiveness; in contrast, of the 18 recipients who were not preexposed, only 3 (15%) exhibited this form of immunomodulation. Of interest, 2 of the 3 hyporesponsive recipients who were not preexposed, received units containing HLA-DR antigens previously shown to share crossreactive epitopes with the kidney HLA-DR. In conclusion, these results suggest a increased incidence in the development of hyporeactivity in patients receiving pretransplant transfusions which share an HLA-DR antigen with the transplanted kidney.     

人工肾的最新进展及临床应用

本介绍了人工肾的发展史、临床应用、选购和发展趋势。指出:随着高新技术和透析原理的发展，目前已从血液透析演变为血液净化，拓宽了其临床应用范围。采用组织工程、基因、细胞技术研制的生物人工肾，可望生产出易携带或可移植的生物人工肾，可完全替代肾功能，减少肾衰竭病人的死亡率，成为代肾发展史上的又一个里程碑。     

小鼠原位脂肪肝移植模型的建立

目的　建立了ob/ob小鼠脂肪肝移植模型 ,探讨保证建模成功的关键因素。方法　采用小鼠非动脉化肝移植技术 ,5～ 7周肥胖小鼠为供体 ,正常小鼠为受体 ,双袖套法行原位肝移植。受体肝组织行HE染色和油红O染色 ,血清ALT、AST水平检测采用常规生化分析法。结果非脂肪肝移植组 (lean to lean)受体长期存活率 (n =10 )为 70 % ,脂肪肝移植组 (ob/obtoagematchedlean)受体存活率为 0 (n =10 ) ,差异有显著性 (P <0 .0 5 )。脂肪肝移植给体积相当的正常小鼠 ,其短期存活率为 3 0 % (n =10 ) ,所有小鼠术后存活并苏醒 ,但均未超过 2 4h。脂肪肝移植受体ALT水平为 (62 85± 2 93 7)U /L ,AST为 (5 812± 2 942 )U /L ;而正常小鼠移植组ALT与AST水平分别为 (5 96± 114 )U /L ,(1796± 870 )U/L ,差异有显著性 (P <0 .0 5 ) ,组织学检测显示大量胆管中央凝固性坏死伴出血。结论　该模型的成功建立为我们提供了一种新的肝原发性肝无功能移植模型 ,为脂肪肝移植后脂肪肝细胞受损的机制研究奠定了基础。     

促红细胞生成素治疗透析前贫血临床分析

目的观察人类重组红细胞生成素(r-HuEPO)对透析前贫血的疗效,探讨早期治疗肾性贫血的意义.方法患者分两组,治疗组应用r-HuEPO皮下注射,补充叶酸、铁剂,给予饮食疗法、大黄散、控制血压等措施.对照组不用r-HuEPO治疗,其它措施相同.观察症状、HGB、HCT、SCr和血清钾、钠、氯水平.结果治疗组症状改善,生活质量提高;HGB、HCT明显升高,与对照组比较有显著性差异(P＜0.01).血清肌酐无明显升高.结论r-HuEPO能明显提高HGB、HCT水平,安全有效治疗透析前贫血,肾性贫血早期治疗值得重视和进一步探讨.