Antilymphocyte globulins versus OKT3 as prophylactic treatment in highly sensitized renal transplant recipients

Abstract Monoclonal antibodies were proposed as an effective prophylactic immunosuppressive treatment in highly sensitized patients (HSP). In this study we compared the results obtained in HSP treated with OKT3 or antilymphocyte globulins (ALG). From January 1989 to January 1993, 38 transplantations were performed in patients with high panel reactive antibodies (PRA>50%). The group comprised 22 women and 16 men, mean age 45 ± 2 (23–67) years; ten were second grafts and two were third grafts. Peak PR A was ≥ 80% in 24 sensitized patients and 50–80% in 14 sensitized patients. Patients were randomly assigned to either prophylactic OKT3 ( n = 15) or ALG ( n = 23). Oral cyclosporin A (10 mg/kg) was started at day 8 in the OKT3 group and when the serum creatinine level decreased to 200 μymol/l in the ALG group. OKT3 was systematically withdrawn on day 10 but ALG was stopped only when total blood cyclosporin A concentration reached 150–200 ng/ml. In both groups, azathioprine (150 mg/day) and prednisolone were given. During the first months, 6/15 grafts were lost in the OKT3 group (three hyperacute rejections, one renal vein thrombosis, one steroid-resistant rejection, one death); in the ALG group 4/23 grafts were lost (one hyperacute rejection, two steroid-resistant rejections, one death). Side effects were significantly more frequent in the OKT3 group than in the ALG group. After 12 months of follow up, the graft survival was 71% (27/38) and did not significantly differ (log-rank test, NS) between the OKT3 (60%, 9/15) and the ALG group (78%, 18/23). We conclude that the use of the monoclonal antibody OKT3 as a prophylactic agent in HSP does not improve the early graft survival when compared with prophylactic ALG. Polyclonal antibodies, which react with many epitopes and are much better tolerated seem to offer a good strategy for induction therapy in this population.     

Thromboembolic complications in renal allograft recipients. A report from the prospective randomized study of cyclosporine versus azathioprine-antilymphocyte globulin

The incidence of arterial and venous thromboembolic complications was compared in 224 renal allograft recipients who were prospectively randomized and stratified by risk to treatment with either cyclosporine-prednisone (CsA-P) (n = 117) or azathioprine-prednisone-antilymphocyte globulin (AZA-P-ALG) (n = 107). Thirteen CsA patients (11%) had 22 thromboembolic events, while 19 AZA patients (18%) had 24 events (P = 0.22). There was no significant difference between the 2 regimens in the number of patients with each type of venous or arterial event or in the number of patients with multiple or lethal events. The incidence of "minor" complications (all except myocardial infarction and stroke) in the related donor subgroup (n = 85) and the overall incidence of thromboembolism in the diabetic subgroup (n = 125) were both significantly higher in AZA-treated patients (P = 0.008 and 0.045, respectively). Thus, CsA immunosuppression does not appear to be a risk factor for thromboembolic disease, and it may in fact lower the incidence of thromboembolism in diabetic renal allograft recipients.     

全身淋巴照射联合ATG在致敏患者肾移植及逆转AMR中的应用

目的 探讨全身淋巴照射联合抗胸腺细胞球蛋白(ATG)用于高致敏患者肾移植脱敏治疗及移植后抗体介导的排斥反应(AMR)治疗的效果.方法 回顾性分析2009-2011年间13例肾移植受者的资料,其中2例为术前致敏患者,均接受全身淋巴照射+血浆置换+低剂量静脉注射丙种球蛋白(IVIG)+ ATG的脱敏方案;11例为经移植肾穿刺病理检查诊断的AMR,7例接受全身淋巴照射+血浆置换+低剂量IVIG+ ATG的治疗方案,4例接受全身淋巴照射+MG+ ATG的治疗方案.结果 术前脱敏治疗2例均治疗成功,并接受活体供肾移植,术后随访1年未出现病理证实的急性排斥反应,术后B淋巴细胞数量呈持续抑制趋势,随访期间未超过脱敏治疗前水平,术后各时间点调节性T淋巴细胞(Treg细胞)百分率较脱敏治疗前明显升高.术后AMR患者中,10例治疗后排斥反应成功逆转,1例因治疗失败行移植肾切除.治疗成功的AMR患者外周血B淋巴细胞比例及绝对数呈持续抑制趋势,Treg细胞百分率较治疗前明显升高,治疗后1年行移植肾程序性活检均未发现AMR.结论 全身淋巴照射联合ATG用于高致敏患者的脱敏治疗及肾移植受者AMR治疗,具有较好的临床效果,其机制可能与诱导Treg细胞的产生有关.     

The effect of HLA mismatch on highly sensitized renal allograft recipients

Paramesh AS, Zhang R, Baber J, Yau CL, Slakey DP, Killackey MT, Ren Q, Sullivan K, Heneghan J, Florman SS. The effect of HLA mismatch on highly sensitized renal allograft recipients.
Clin Transplant 2010: 24: E247–E252. © 2010 John Wiley & Sons A/S. Abstract: Introduction: We examined the effects of increasing human leukocyte antigen (HLA) mismatches (MM) on long‐term graft outcomes in patients transplanted with a panel reactive antibody (PRA) >80% over a 10‐yr period. Methods: A total of 142 recipients were divided into three groups based on the number of HLA MM with their allograft (0–2, 3–4 and 5–6 MM; Groups I, II and III). All patients received the same immunosuppression protocol. Results: The higher MM groups had a higher incidence of rejection (4.4% vs. 11.4% vs. 31.3%, p < 0.01). A multivariate analysis showed that rejection was the only significant variable affecting graft loss (OR = 7.45, p = 0.01). There was a trend toward more CMV infection and worse graft function with higher MM. Kaplan–Meier five‐yr graft survival estimates were 100% vs. 81% vs. 74% for Groups I, II and III, respectively (p = 0.14). Conclusions: In patients with PRA levels >80%, a higher HLA MM is associated with higher incidence of acute rejection. Acute rejection was the only significant variable affecting graft loss. We found a trend toward more CMV infections and worse graft outcomes with higher MM. Closer HLA matching and immunologic monitoring needs to be considered to improve graft outcomes among sensitized recipients.     

Contributions and clinical significance of IgM and autoantibodies in highly sensitized renal allograft recipients

The contributions of auto and IgM antibodies in the levels of serologic reactivities of 30 highly sensitized patients were assessed by autologous T cell crossmatches at 4 degrees C and 22 degrees C and dithiothreitol (DTT) reduction of IgM antibodies. The range of panel reactivities of sera from these patients was 30-100%, median 55%. A monthly screen of these sera against a 30-member T cell panel was performed with and without addition of DTT (final concentration = 0.005 M). The results were divided into 3 groups. Group 1 consisted of 17 sera whose PRA values did not change following the DTT treatment. Also none of these sera had autoantibodies, suggesting that these sera contained DTT-resistant (IgG) antibodies, most likely directed against allogeneic targets. Group 2 consisted of 10 sera whose PRA values declined substantially (20-42%) following the DTT treatment, but only 1 serum derived from a patient with systemic lupus erythematosus had autoantibodies. These results suggested that although these sera contained IgM and IgG antibodies, these antibodies were most likely directed at allogeneic target structures with only one exception. Group 3 consisted of 3 sera that became completely unreactive to panel lymphocytes following the DTT treatment. All 3 sera had autoantibodies that were also removed with DTT, suggesting that these sera contained predominantly IgM antibodies directed at autologous target cells. All 3 patients from whom these sera were derived received successful kidney transplants across donor-specific positive T cell crossmatches that became negative following the DTT treatment. We conclude that although 13 out of 30 patients have IgM antibodies, only a small subset of these patients have autoantibodies. Renal transplantation in the presence of auto/IgM antibodies may be safe.     

术前预处理及组织配型对高度致敏患者移植肾功能的影响

目的：探讨术前预处理及组织配型对高度致敏患者移植肾功能的影响。方法：对38例高度致敏患者(高敏组)肾移植术前进行预处理及组织配型,观察患者术后移植肾功能延迟(DGF)、排斥反应的发生和血肌酐(SCr)水平的变化。结果：高敏组术后发生超急性排斥反应(HAR)2例;其加速性排斥反应(ACR)、急性排斥反应(AR)以及DGF发生率均高于非高敏组受者,1年移植肾存活率则较低。高敏组中组织配型良好的受者较配型欠佳者AR发生率及术后1年SCr水平较低;术前预防性使用赛尼哌可降低术后的AR发生率。结论：预处理降低高度致敏患者群体反应性抗体(PRA),使患者易于配型成功,良好的组织配型和使用赛尼哌可降低术后AR的发生,均有助于移植肾功能的恢复。     

A prospective study of hepatitis C viremia in renal allograft recipients

In an attempt to study the impact of HCV viremia on renal transplant clinical course and outcome, we prospectively followed 133 HBsAg-negative end stage renal disease (ESRD) patients, in whom HCV-RNA-PCR results were available, from the pre- to post-transplant period. Eighty (60%) ESRD patients tested PCR-positive, of these, 12 (15%) were anti-HCV negative by second generation ELISA. The viremic patients had a longer time on dialysis (p < 0.001), received more blood units (p < 0.001) and had a higher frequency of pre-transplantation liver disease (p < 0.001). Further, 41% of PCR-positive patients gave a history of antischistosomal treatment compared with 23% of PCR-negative ones (p = 0.048). Recipients with and without HCV viremia were followed for a mean of 31.8 +/- 5.8 (range 6-42) months and 29.8 +/- 9 (range 6-41) months respectively, p = 0.14. While the prevalence of HCV viremia increased from 60 to 64% at the last follow-up, the anti-HCV seroprevalence decreased from 63 to 61%. PCR-positive patients had higher rates of both acute (p = 0.005) and chronic (p < 0.001) liver disease after transplantation compared with PCR-negative patients. However, none of our HCV RNA positive recipients developed a fulminant liver disease or hepatic failure until the last follow-up. Stepwise logistic regression analysis identified pre-transplant liver disease (Odds ratio = 2.4; p = 0.07) and a cumulative corticosteroid dose in excess of 15 g at the last follow-up (Odds ratio = 3; p = 0.03) as independent predictors of post-transplant hepatic dysfunction in PCR-positive patients. Azathioprine was discontinued due to hepatic dysfunction in a significantly (p = 0.005) higher proportion of viremic patients compared with the non-viremic ones. There were no significant differences between PCR-positive and -negative patients in terms of frequencies and individual causes of graft and patient losses. Our results demonstrate that HCV infection is extremely prevalent in Egyptian hemodialysis patients and is responsible for most hepatic dysfunctions after transplantation. Although HCV viremia did not negatively affect graft or patient outcome until 31 months post-transplantation, the authors would recommend that a viremic patient should have a liver biopsy before transplantation and be immunosuppressed with caution post-transplantation. A longer follow-up may be required to exclude increased rates of HCV-induced hepatic mortalities. Copyright Copyright 1999 S. Karger AG, Basel     

Results of the Minnesota randomized prospective trial of cyclosporine versus azathioprine-antilymphocyte globulin for immunosuppression in renal allograft recipients

Between September 26, 1980 and June 8, 1984, 246 splenectomized, transfused renal allograft recipients were randomized to treatment with either cyclosporine (CsA)-prednisone (n = 131) or azathioprine (Aza)-prednisone-antilymphocyte globulin (n = 115). On December 31, 1984, actuarial patient survival rates at three years were 89% in the CsA group and 90% in the Aza group, and the corresponding graft survival rates were 82% and 79% (statistically insignificant differences). The results were also compared separately in diabetic and nondiabetic patients and in recipients of related and cadaver donor grafts; only in the subgroup of diabetic recipients of cadaver kidneys were the differences in graft survival rates significantly different between CsA- and Aza-treated patients. The incidence of posttransplant acute tubular necrosis was similar in CsA- and Aza-treated patients (33% v 27%), but the duration was significantly longer in CsA- than in Aza-treated recipients (15.7 +/- 18.4 v 7.7 +/- 3.0 days). Rejection episodes and infections (particularly CMV) occurred significantly less frequently in CsA- than in Aza-treated patients. Mean serum creatinine levels were significantly higher in CsA- than in Aza-treated recipients (2.0 +/- 0.6 v 1.5 +/- 0.5 mg/dl). Treatment of hypertension and hyperkalemia was required significantly more frequently in the CsA-treated patients than in the Aza-treated patients. Initial mean hospitalization time was significantly shorter in the CsA group than in the Aza group (15.6 +/- 9.5 v 19.8 +/- 10.7 days). In the CsA group, 19% of the patients were switched to Aza and 35% had Aza added to their regimen with a concomitant lowering of the CsA dose because of nephrotoxicity. The results of our randomized trial are at variance with those of others in that the graft survival rates in our trial were not different between CsA and Aza-treated patients, primarily because our conventionally-treated patients had a higher graft survival rate than in the other trials. The advantages of CsA (fewer rejection episodes, fewer infections, shorter hospitalization) outweigh the disadvantages (higher serum creatinine, more hypertension), and thus we believe it should be used in most renal allograft recipients, perhaps in combination with Aza so that a lower dose of CsA can be used and the side effects minimized--a regimen that we are currently evaluating.     

肾移植术后撤除环孢素A的观察和体会

目的 总结肾移植术后因某些原因而撤除环孢素Ａ（ＣｓＡ）的经验教训,并对其可行性及安全性进行评价。方法 总结２０例术后撤除ＣｓＡ的肾移植患者的有关资料。结果 ２０例患者在撤除ＣｓＡ并同时调整其它免疫抑制剂剂量后,其肾功能、肝功能及白细胞计数等与撤药前比较,差异均无显著性;与周期常规治疗者比较,两组肾功能的差异也无显著性。结论 在调整其它免疫抑制剂剂量的前提下,逐步减少ＣｓＡ的用量并最终撤除ＣｓＡ,可     

Interaction between cyclosporine and fluconazole in renal allograft recipients

To determine the effect of fluconazole on cyclosporine concentrations, we used a randomized, double-blind, placebo-controlled study design to evaluate 16 stable renal transplant recipients receiving a constant cyclosporine dose. The two groups of patients were given identical capsules of either placebo or fluconazole 200 mg daily for 14 days. Compliance with the protocol was ensured by watching each patient take all the drug doses. Frequent whole-blood cyclosporine trough concentrations, measured by high-performance liquid chromatography, and two area under the blood concentration time curves were determined before and after 14 days of fluconazole or placebo. The results show that cyclosporine trough concentrations, in patients given fluconazole, increased from a mean +/- SD of 27 +/- 16 to 58 +/- 28 ng/ml (P = 0.001) while patients given placebo did not change--35 +/- 26 vs. 37 +/- 35 ng/ml (P = 0.7). Mean cyclosporine AUC increased in the fluconazole patients from 2167 +/- 1039 to 3989 +/- 1675 ng.hr/ml (P = 0.02) while the placebo patients did not change, 3089 +/- 2439 vs. 2954 +/- 2216 ng.hr/ml (P = 0.9). The pre- and post-treatment cyclosporine AUC difference (day 16 minus day 2) for fluconazole vs. placebo was 1822 +/- 1083 vs. -134 +/- 831 ng.hr/ml (P = 0.001). Mean cyclosporine clearance decreased an average of 55% in the fluconazole patients from 1.2 +/- 0.5 to 0.7 +/- 0.4 ml/hr.kg (P = 0.03); the placebo patients did not change--1.4 +/- 1.1 vs. 1.7 +/- 2.3 ml/hr.kg (P = 0.07). During the study period, serum creatinine concentrations did not increase after fluconazole vs. placebo treatment; they were 1.4 +/- 0.3 vs. 1.3 +/- 0.3 mg% (P = 0.8) initially, and 1.4 +/- 0.2 vs. 1.3 +/- 0.3 mg% (P = 0.5) after 14 days. This study indicates that fluconazole 200 mg daily can slowly increase cyclosporine concentrations over two weeks of therapy, approximately doubling the cyclosporine trough concentrations. The management of this interaction requires prospective planning for adjustments in the cyclosporine dosage, guided by cyclosporine concentrations, while transplant recipients are receiving fluconazole.     

Sequential therapy--a prospective randomized trial of MALG versus OKT3 for prophylactic immunosuppression in cadaver renal allograft recipients.

We prospectively studied the use of prophylactic Minnesota antilymphocyte globulin vs. OKT3 in kidney transplant recipients. Between 7/1/87 and 9/1/90, 138 adult kidney and 35 kidney-pancreas recipients were randomized after stratification for age (18-49 vs. greater than or equal to 50), diabetes (diabetic vs. nondiabetic), transplant number (1 vs. greater than 1) and, for retransplants, the length of survival of the first graft (less than 1 year vs. greater than or equal to 1 year), and then randomized to receive 7 days of either MALG (20 mg/kg/day) or OKT3 (5 mg/day). Immunosuppression was otherwise identical in both groups; prednisone and azathioprine started on the day of surgery, and cyclosporine started on postoperative day 6. Minimum follow-up was 9 months. There was no difference in one- and two-year actuarial patient or graft survival rates, incidence of rejection, or serum creatinine level. MALG was associated with a higher incidence of cytomegalovirus; it was statistically significant in the subgroup of CMV seronegative recipients of kidneys from seropositive donors (P less than .05). OKT3 was more expensive and was associated with significantly more side effects: fever (P less than .0001), dyspnea (P = .04), and acute respiratory distress syndrome (ARDS) (P = .02).     

高致敏肾移植供受者的HLA配型研究

目的　探讨人类白细胞抗原 (HLA)配型在高致敏受者肾脏移植中的临床意义。　方法　对 18例高致敏受者采用酶联免疫吸附法 (ELISA)检测体内预存的群体反应性抗体 (PRA IgG)水平及其特异性 ;采用补体依赖性细胞毒试验 (CDC)和微量序列特异性引物聚合酶链反应 (Micro PCR SSP)技术进行HLA I类和II类分型。　结果　 18例高度致敏受者的PRA IgG水平为 40 %～ 96 % ,平均 5 6 % ;供受者之间按传统的HLA A、B、DR抗原错配 (MM )原则 ,0～ 1MM者 5例 (2 8% ) ,2～3MM者 13例 (72 % ) ,而按交叉反应组 (CREGs)错配原则 ,0～ 1MM者 11例 (6 1% ) ,增加了 33 % ,而2～ 3MM者仅 7例 (39% ) ;肾移植术后仅 4例发生急性排斥反应 ,排斥发生率为 2 2 % ,经OKT3 治疗后逆转。　结论　CREGs配型可显著提高供受者的HLA配合率 ,良好的HLA配型对减少高致敏受者肾移植的排斥反应、提高移植物存活率具有重要临床意义     

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.     

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.     

Five-year results of renal transplantation in highly sensitized recipients

Abstract  A special program for the priority allocation of cadaver donor kidneys to highly sensitized patients was initiated 10 years ago. During the period from 1985 to 1994, 329 transplants were performed at 35 transplant centers. Five-year graft survival rates were: 59 ± 4 % for 156 first grafts, 52 ± 5 % for 133 second grafts, and 18 ± 7 % for 40 third or fourth grafts. The success rates of first and second grafts were comparable with the corresponding success rates of first and second cadaver transplants in non-sensitized recipients reported to the Collaborative Transplant Study. There was a highly significant impact of HLA matching on graft survival. Among first and second grafts, 35 transplants with no mismatches for HLA-B+DR had a 76 ± 8 % success rate at 5 years, compared with a 55 ± 4 % rate for 208 grafts with one or two mismatches and a 37 ± 8 % rate for 46 grafts with three or four mismatches (weighted regression P < 0.001).