免疫吸附联合他克莫司和霉酚酸酯逆转肾移植后急性体液性排斥反应

目的探讨免疫吸附(IA)联合他克莫司(FK506)和霉酚酸酯(MMF)治疗C4d阳性的急性体液性排斥反应(AHR)的临床效果。方法1999年4月至2003年6月间行同种异体尸肾移植490例,其中9例受者发生AHR,其诊断均依据Banff 97标准,Banff分级为Ⅱ级5例,Ⅲ级4例。患者发生AHR后均采用免疫吸附联合FK506 MMF 激素治疗,同时辅以连续性血液净化。治疗前、后行移植肾活检,分别进行病理观察、免疫荧光和免疫组织化学检测,同时检测患者血清HLA、免疫球蛋白水平以及肝、肾功能。结果治疗后,9例AHR患者中有8例得到逆转;1例治疗无效,转而采用血液透析治疗。患者的HLA-Ⅰ、Ⅱ水平较治疗前明显下降,分别为(5.9±2.9)%和(2.2±0.6)%;血清总的免疫球蛋白水平也明显降低;患者移植肾肾小管周围毛细血管C4d沉积强度较治疗前明显减轻,其中5例患者C4d转阴;肾小球浸润细胞明显减少,肾小管炎症减轻,间质浸润细胞减少,血管炎减轻。患者在接受免疫吸附治疗过程中均未出现严重并发症。结论免疫吸附联合FK506 MMF可有效地逆转C4d阳性的急性体液性排斥反应。     

C4d-positive acute humoral renal allograft rejection: rescue therapy by immunoadsorption in combination with tacrolimus and mycophenolate mofetil

OBJECTIVE: We investigated the efficacy of immunoadsorption (IA) in combination with tacrolimus (FK506) and mycophenolate mofetil (MMF) rescue therapy for C4d-positive acute humoral rejection (AHR) of renal transplants. METHODS: Six of 185 cadaveric renal allograft recipients developed AHR at a mean of 4.8 +/- 0.8 days after the operation. C4d deposits were observed in peritubular capillaries (PTC) with accumulation of granulocytes. IA with staphylococcal protein A and FK506-MMF combination therapy were administered. RESULTS: After treatment with IA for 6.3 +/- 1.03 sessions combined with FK506 (0.14 to 0.16 mg.kg(-1).d(-1)) and MMF (1.5 g/d) therapy, renal function recovered in all the patients. The mean duration of treatment to a serum creatinine decrease was 14 +/- 2.9 days. The pre-IA panel reactive antibody reactivity (PRA) peaked at 50.2% +/- 6.1%, and was significantly reduced to 8.3% +/- 2.9% after IA. In four of six patients repeat allograft biopsy revealed a remission of AHR. With a mean follow-up of 18.8 +/- 5.46 months, patient and allograft survival are 100% and renal function remains stable with a mean serum creatinine of 1.2 +/- 0.22 mg/dL. CONCLUSION: The optimal treatment for alloantibody-mediated AHR remains uncertain. Our findings suggest that a therapeutic approach combining IA and FK506-MMF rescue improves the outcome of AHR.     

C4d-positive acute humoral renal allograft rejection: effective treatment by immunoadsorption.

There is increasing evidence for an important pathogenetic role of alloantibodies in acute renal allograft rejection. Acute humoral rejection (AHR) has been reported to be associated with a poor transplant survival. Although treatment modalities for cellular rejection are fairly well established, the optimal treatment for AHR remains undefined. Ten of 352 kidney allograft recipients transplanted at the authors' institution between November 1998 and September 2000 were diagnosed as having AHR, supported by severe graft dysfunction, C4d deposits in peritubular capillaries (PTC), and accumulation of granulocytes in PTC. AHR was diagnosed 18.9 +/- 17.5 d posttransplantation. All patients were subjected to immunoadsorption (IA) with protein A (median number of treatment sessions, 9; range, 3 to 17). Seven recipients with additional signs of cellular rejection (according to the Banff classification) received also antithymocyte globulin. In nine of ten patients, AHR was associated with an increase in panel reactive antibody reactivity. A pathogenetic role of alloantibodies was further supported by a positive posttransplant cytotoxic crossmatch in all tested recipients (n = 4). In nine of ten recipients, renal function recovered after initiation of anti-humoral therapy. One patient lost his graft shortly after initiation of specific therapy. Another recipient with partial reversal of AHR returned to dialysis 8 mo after transplantation. Mean serum creatinine in functioning grafts was 2.2 +/- 1.2 mg/dl after the last IA session (n = 9) and 1.5 +/- 0.5 mg/dl after a follow-up of 14.2 +/- 7.1 mo (n = 8). In conclusion, this study suggests that AHR, characterized by severe graft dysfunction, C4d staining, and peritubular granulocytes, can be effectively treated by timely IA. In the majority of patients, IA treatment can restore excellent graft function over a prolonged time period.     

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.     

C4d as a significant predictor for humoral rejection in renal allografts

OBJECTIVE: To determine the diagnostic and clinical significance of C4d accumulation in renal allografts followed by acute rejection. METHODS: A total of 158 graft biopsies performed from December 1997 to December 2002 were classified, according to the Banff-97 criteria, into hyperacute rejection (HAR, three cases), acute vascular rejection (AVR, 27), acute cellular rejection (ACR, 24), borderline rejection (BR, 38), acute tubular necrosis (ATN, five), stable graft function (SGF, 30) and baseline kidney (31). Immunohistochemical technique was used to determine the C4d deposition level. RESULTS: The percentages of C4d positive in HAR, AVR, ACR, BR, ATN, SGF and baseline kidney groups were 100% (3/3), 77.8% (21/27), 37.5% (9/24), 23.7% (9/38), 0% (0/5), 3.3% (1/30), 0% (0/31), respectively. In acute rejection patients, the peak serum creatinine (sCr) level in C4d(ptc)-positive group (41 cases) was 334.82 +/- 238.37 micromol/L, with that of C4d(ptc)-negative group (47 cases) being 220.20 +/- 176.94 micromol/L (p < 0.01). After treatment, the trough sCr level in C4d(ptc)-positive group and C4d(ptc)-negative group were 176.87 +/- 111.80 and 121.75 +/- 34.59 micromol/L (p < 0.01), respectively. In each AVR, ACR and BR subgroups, the peak sCr level, the trough sCr level, after 3 or 6 months of AR, the sCr level in C4d(ptc)-positive subgroup was higher than that of C4d(ptc)-negative subgroup. There were more resistance against steroid therapy [65.9% (27/41) vs. 36.2% (17/47), p = 0.005] and a higher rate of graft loss [29.3% (12/41) vs. 6.4% (3/47), p = 0.001] in C4d(ptc)-positive group than those of C4d(ptc)-negative group. In each C4d(ptc)-positive subgroup of AVR, ACR and BR the complete reversion was 57.1, 56 and 66.7%, respectively, it is almost same. CONCLUSION: The C4d deposition level is of great value in diagnosis of acute rejection caused by humoral immune components. It is a significant predictor of graft survival and will be of great help when treating acute rejection.     

Tacrolimus combined with mycophenolate mofetil can effectively reverse C4d-positive steroid-resistant acute rejection in Chinese renal allograft recipients.

BACKGROUND: Tacrolimus (TAC) combined with mycophenolate mofetil (MMF) has been suggested to play a critical role in the reversal of C4d-positive acute humoral rejection (AHR) in renal transplantation, but the efficacy of using only TAC-MMF without immunoadsorption or plasmapheresis has not been investigated. On the other hand, Chinese recipients of renal grafts usually need lower doses of immunosuppressants, and their optimal treatment for acute humoral rejection has not been established. METHODS: Since 1999, we have used TAC-MMF to treat steroid-resistant acute rejection (AR). C4d staining was retrospectively performed in 32 patients with steroid-resistant AR, and the treatments of 19 patients with C4d-positive steroid-resistant AR were investigated. RESULTS: Thirteen of 19 patients received TAC-MMF treatment only; 11 episodes of rejection in them were reversed (7 completely, 4 partially) and only 2 recipients lost their graft. Another 6 patients received immunoadsorption also. One of them failed to respond and lost her graft. Four of 5 patients treated with immunoadsorption and TAC-MMF recovered (3 completely, 1 partially), but 3 of them had severe pneumonia, a complication rate statistically higher than in patients treated with only TAC-MMF (P<0.05). AR occurring during the first two weeks after transplantation had a statistically better outcome than that occurring later (P = 0.003). CONCLUSION: Our study suggests that the combination of TAC and MMF is a potentially safe and economic treatment for most Chinese renal allograft recipients with C4d-positive steroid-resistant AR, especially for rejections developing within the first two weeks after transplantation.     

Rescue therapy by immunoadsorption in combination with tacrolimus and mycophenolate mofetil for C4d-positive acute humoral renal allograft rejection

The aim of this study was to investigate the efficacy of immunoadsorption (IA) in combination with tacrolimus (TAC; 0.14 to 0.16 mg/kg/d) and mycophenolate mofetil (MMF; 1.5 to 2.0 g/d) rescue therapy for C4d-positive acute humoral rejection in nine cadaveric renal allograft recipients. Initial Panel reactive antibody (PRA-I and PRA-II levels were as high as 28.8% ± 16.2% and 15.3% ± 8.9%, IA therapy significantly decreased PRA-I and PRA-II levels to 5.9% ± 2.9% and 2.2% ± 0.6%, respectively. Total serum immunoglobulin levels were markedly decreased. Repeated allograft renal biopsy in nine patients revealed remission of acute humoral rejection (AHR), and the deposition of C4d disappeared and reduced. With a mean follow-up of 29.4 ± 5.4 months, patient and allograft survivals were 100%, and renal function remained stable with a mean serum creatinine of 1.1 ± 0.3 mg/dL. Our findings suggested that a therapeutic approach combining IA and TAC and MMF rescue improved the outcomes of AHR.     

Tacrolimus rescue therapy for children with acute renal transplant rejection

Seventeen children with renal transplants (11 living-related, age 2–18 years) were converted from cyclosporine to tacrolimus because of acute rejection that failed to respond to high-dose corticosteroids. Resistance to corticosteroids was confirmed by renal biopsy in 14 patients, and assumed in 3 patients because of failure of serum creatinine to improve to baseline values. Four patients were also treated with OKT3, and 15 children had been receiving mycophenolate maintenance therapy prior to conversion to tacrolimus. Rejection occurred at 2–174 weeks post transplant (mean 52 weeks). Actuarial 1- and 2-year graft survival was 87% and 78%. Three children progressed to end-stage renal disease after 4, 12, and 13 months of tacrolimus. The remaining 14 children have functioning allografts after 20–168 weeks of treatment (mean 80 weeks). All 14 children exhibit stable or improved renal function: serum creatinine 1.1±0.7 mg/dl versus 2.0±0.9 mg/dl prior to tacrolimus. In conclusion, tacrolimus was effective therapy for both early and late acute rejection in children who failed to respond to high-dose corticosteroids. No significant short-term adverse effects were encountered. Received: 29 August 2000 / Revised: 31 July 2001 / Accepted: 31 July 2001     

Late developing C4d-positive humoral renal allograft rejection associated with withdrawal of mycophenolate mofetil

In renal transplantation, C4d-positive acute humoral rejection (AHR) usually develops in the early stage posttransplantation. It is clear C4d can be detected late after the operation, when it is associated with chronic renal allograft rejection. We report a case of a renal allograft recipient who experienced C4d-positive acute renal allograft rejection associated with withdrawal of mycophenolate mofetil (MMF) at 10 months after transplantation. This 21-year-old single male patient received his first cadaveric renal allograft under immunosuppression with cyclosporine, MMF, and prednisolone. The serum creatinine recovered to the normal range within 4 days. A protocol biopsy performed at 1 month after transplantation revealed no signs of rejection. The graft function was stable until 10 months postoperation, when MMF was converted to mizoribin. Three days later a biopsy showed a C4d-positive rejection. Patient had no response to the MMF combined with tacrolimus and steroid bolus therapy, which generally improves 85% of AHR among Chinese. He finally returned to dialysis. Our report suggested that C4d positive AHR may occur late after transplantation. MMF is important to suppress the body's humoral response to allograft; when MMF was converted to a weaker immunosuppressant, the dose of the other immunosuppressants (cyclosporine for example) must be adjusted properly.     

急性细胞性排斥伴补体裂解片断C4d沉积对移植肾预后的影响

探讨急性细胞性排斥伴肾小管周围毛细血管补体裂解片断(C4d)沉积对移植肾预后的影响.方法 经病理证实的急性细胞性排斥肾移植患者 145 例,根据病理表现有否肾小管周围毛细血管C4d沉积,将其分为细胞性排斥+C4d阳性组(C4d阳性组)64例,单纯细胞性排斥组(C4d阴性组)81例.比较两组术前一般情况、排斥反应发病情况、抗排斥治疗、移植肾失功率及移植肾存活率.结果两组的术前一般情况比较差异无统计学意义(P>0.05).C4d阳性组的急性细胞性排斥反应发生时间明显早于C4d阴性组,比较差异有统计学意义(P<0.05).两组Banff 分型Ⅰ型与Ⅱ型比例差异有统计学意义(P<0.01).随访期间C4d阳性组有22例(34%)移植肾失功,明显高于C4d阴性组的11例(14%),比较差异有统计学意义(P<0.01).Kaplan-Meier法分析发现C4d阳性组的移植肾存活率明显低于C4d阴性组(P<0.01),移植肾的5年生存率分别为51%、79%.结论 急性细胞性排斥反应伴肾小管周围毛细血管C4d沉积的肾移植患者,术后较早发生排斥反应,抗排斥治疗效果较差,移植肾存活率低.     

Potential value of high-dose mizoribine as rescue therapy for ongoing acute humoral rejection

Mizoribine (MZ) inhibits the proliferation of lymphocytes selectively via inhibition of inosine monophosphate dehydrogenase, like mycophenolate mofetil (MMF). The clinical dosage of MZ (2-5 mg/kg) is much lower than that of MMF (20-60 mg/kg). The purpose of this study was to examine whether high-dose MZ would be effective for treatment of acute humoral rejection. Renal transplantation was performed in a different pig strain combination. Group 1 (n = 2) received no treatment. Group 2 (n = 4) received cyclosporine microemulsion (6 mg/kg) and prednisolone (0.1 mg/kg) as baseline immunosuppression. Groups 3 (n = 4), 4 (n = 4) and 5 (n = 4) were additionally treated with MZ for rescue therapy, 30, 10 and 3 mg/kg, respectively, immediately after rejection was observed. All pigs developed acute vascular rejection between days 4 and 8. Complete reversal of acute rejection including reduction of elevated serum creatinine, suppression of anti-donor antibody production and pathological finding, was obtained in 3/4 (group 3), 1/4 (group 4) and 0/4 (group 5). Rescue with high-dose MZ (30 mg/kg) reversed ongoing acute humoral rejection. Such a high dose of MZ was tolerable for pigs. However, leukocytopenia was observed when MZ trough level was maintained over 10 mug/ml. Treatment with high-dose MZ would be applicable to a clinical trial, if blood level is carefully monitored.     

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。     

Impact of rituximab therapy for treatment of acute humoral rejection

Abstract: Introduction: Antibody mediated rejection (AMR) is associated with a greater incidence of allograft loss because traditional approaches ‐ pulse steroid or anti‐lymphocyte antibodies are usually ineffective. This retrospective analysis documented the benefit of rituximab administration in addition to plasmapheresis (PP). Methods: We retrospectively reviewed the data from 54 kidney transplant patients treated for AMR between 2001 and 2006, including 26 patients who received PP plus rituximab (Group A), versus 28 subjects who underwent PP without rituximab (Group B). Only patients whose serum IgG levels were below normal values received intravenous gamma globulin (IVIG). In addition to clinical and demographic variables we evaluated graft/patient survivals at two years post‐diagnosis, Banff classification of rejections, serum creatinine and calculated GFR values at baseline, rejection, resolution as well as three, six, 12 and 24 months thereafter. Results: The demographic features of the cohorts showed no significant differences. The two‐year graft survival for patients treated with rituximab plus PP was 90%, significantly better than 60% in the PP cohort (p = 0.005). Upon multivariate analysis administration of rituximab was the most significant factor (≥ 0.009); whereas, IVIG also produced a useful effect (p = 0.05). Neither the mean (≥ 0.42) nor the slope (p = 0.25) of GFR values showed a significant difference among salvaged kidneys over 24 months after completion of AMR treatment. The rates and types of infectious complications at three and six months did not show significant differences or impact on graft survival. Conclusion: Addition of rituximab improved the outcomes of PP treatment of antibody mediated rejection episodes.     

FK 506 rescue therapy for intractable liver allograft rejection

Abstract Intractable liver allograft rejection remains an important cause of graft loss. In this Present study, we evaluated the role of oral FK 506 in 30 rejection episodes resistant to conventional cyclosporin-based triple immunosuppression in a series of 28 patients. Rejection was reversed in 11 (91.7%) of 12 patients for intractable acute rejection and in 10 (58.8%) of 17 patients for chronic rejection. A progressive decline in serum bilirubin was observed within 14 days in those successfully salvaged and a serum bilirubin of less than 200 μmol/1 at the time of FK 506 conversion in the chronic rejection subgroup was found to be good predictor of response (specificity 100%, sensitivity 60%). New onset diabetes mellitus (29%) and reversible renal impairment (32%) were the commonest adverse events observed. Eleven (52%) of the responding patients successfully discontinued corticosteroid medication and are currently on FK 506 monotherapy. FK 506 therapy has a significant impact in the control of both intractable acute and chronic allograft rejection with an acceptable toxicity profile.     

他克莫司、霉酚酸酯和血浆置换联合应用治疗肾移植术后急性体液性排斥反应

目的　探讨他克莫司 (FK5 0 6 )、霉酚酸酯和血浆置换联合应用治疗急性体液性排斥反应的效果。方法　 6例肾移植后发生急性体液性排斥反应的患者 ,术后采用环孢素A、霉酚酸酯和激素行免疫抑制治疗 ,发生急性体液性排斥反应时经甲泼尼龙和抗胸腺细胞球蛋白治疗无效 ,行血浆置换 4～ 6次 ,并给予FK5 0 6 (0 .2mg·kg-1·d-1)及霉酚酸酯 (由 2 g/d加至 3g/d)治疗。 结果　经 4～ 6次血浆置换和FK5 0 6、霉酚酸酯治疗 ,排斥反应得到逆转 ,6例患者肾功能均恢复良好 ,随诊 3～ 18个月 ,患者的血肌酐水平为 (12 5 .2± 2 6 .5 ) μmol/L。 结论　FK5 0 6、霉酚酸酯和血浆置换联合应用能有效地逆转急性体液性排斥反应     

The increasing importance of chronic rejection as a cause of renal allograft failure

A consequence of reducing early graft failure due to acute rejection has been that more patients are at risk of chronic rejection, something which has become an increasingly important cause of graft loss. We examine the graft survival rates and reasons for failure in our unit from 1981 to 1986. Patients were divided into two series according to treatment of acute rejection episodes. From 1983 onwards, by treating acute vascular (poor prognosis) episodes with antilymphocyte globulin (ALG), we have significantly improved the 6-month actuarial graft survival rate. However, the percentage of total graft failure due to chronic rejection in this second series has significantly increased. The need for greater understanding of the aetiology of chronic rejection, together with its present unsatisfactory treatment, is discussed.     

The increasing importance of chronic rejection as a cause of renal allograft failure

Abstract. A consequence of reducing early graft failure due to acute rejection has been that more patients are at risk of chronic rejection, something which has become an increasingly important cause of graft loss. We examine the graft survival rates and reasons for failure in our unit from 1981 to 1986. Patients were divided into two series according to treatment of acute rejection episodes. From 1983 onwards, by treating acute vascular (poor prognosis) episodes with antilymphocyte globulin (ALG), we have significantly improved the 6-month actuarial graft survival rate. However, the percentage of total graft failure due to chronic rejection in this second series has significantly increased. The need for greater understanding of the aetiology of chronic rejection, together with its present unsatisfactory treatment, is discussed.     

Sirolimus-based rescue therapy after rejection in liver transplantation

Abstract:  Steroid-resistant acute rejection (SR-AR) and ductopenic rejection (DR) after liver transplantation are infrequent, but difficult to manage. We performed a retrospective review of patients with SR-AR or DR treated with sirolimus-based therapy. Since 2002, we have treated five patients with SR-AR and eight patients with DR. All patients had associated renal insufficiency. Six patients showed no response, of whom five died and one was retransplanted. In six cases, rejection was resolved after changing, while one improved. Therefore, the total response rate was 54%. Ten of 13 patients (77%) suffered some type of adverse event. Ten of these (77%) suffered a hematologic event. Four patients (31%) had infection. Only two patients had to discontinue treatment. Univariate analysis showed that pre-conversion bilirubin was lower in responders (Bilirubin: R: 210 ± 205 vs. NoR: 554 ± 159 μmol/L; p = 0.07 and Creatinine clearance higher: R: 37 ± 11 vs. NoR: 25   ±   11 mL/min; p = 0.09). Sirolimus trough levels one month after switching were higher in responders (R: 11 ± 1.8 vs. NoR: 7.5 ± 3.3 ng/mL; p = 0.03). We conclude that a dual therapy regimen of tacrolimus and sirolimus can achieve a high response rate as a rescue therapy for SR-AR and DR, provided it is begun as soon as possible.