Significant prolongation of renal allograft survival by delayed combination therapy of FK778 with tacrolimus in nonhuman primates

BACKGROUND: Malononitrilamide 715 (FK778) is a new class of low-molecular-weight immunosuppressant that is a derivative of the active metabolite of leflunomide, A77 1726. In this study, the authors evaluated the combined effect of FK778 with tacrolimus in prevention of renal allograft rejection in Vervet monkeys. METHODS: Male Vervet monkeys were obtained from Caribbean Primates Ltd. Donor and recipient monkeys were from different breeding colonies. Eleven groups (n>or=4 per group) were involved in this study. FK778 and tacrolimus were administered orally for 60 days according to protocol. RESULTS: Naive controls rejected renal grafts, with a median survival time (MST) of 8.0 days in group 1. When recipient monkeys were treated with tacrolimus 1.0 mg/kg/day in group 2 or FK778 2.5 mg/kg/day in group 3, the MST was 16.0 days (P=0.001) and 11.0 days (P=0.266), respectively. Combination therapy of these two agents at the same doses immediately after transplantation resulted in an MST of 25.0 days (P=0.016) in group 4. When tacrolimus was initiated immediately after transplantation and FK778 treatment was delayed until day 7 after surgery in group 5, recipient survivals were significantly prolonged to 38.0 days (P=0.02). These results were repeatable when FK778 5.0 mg/kg/day (9.0 days, P=0.544 in group 6) was combined with tacrolimus 1.0 mg/kg/day immediately after transplantation (8.0 days, P=0.339) in group 7, or when FK778 was delayed 7 days (60.0 days, P=0.002) in group 8. Furthermore, it was also repeatable when FK778 10 mg/kg/day was combined with tacrolimus 1.0 mg/kg/day with a 7-day delay. CONCLUSIONS: A significant prolongation of renal allograft survival was produced when FK778 administration was delayed by 7 days combined with tacrolimus in Vervet monkeys.     

Anti-TNF-alpha therapy for acute rejection in intestinal transplantation

INTRODUCTION: We present our experience with infliximab rescue therapy for steroid- and OKT3-resistant rejection after intestinal transplantation (ITx). METHODS: Twelve ITx and one multivisceral transplant recipients were immunosuppressed with tacrolimus, rapamycin, daclizumab, steroids (n = 10) or tacrolimus, campath, and steroids (n = 3). RESULTS: In two patients, severe acute rejection did not resolve despite steroid bolus therapy plus 5 to 10 days of OKT3 treatment. Signs of moderate rejection persisted in the distal portions of the grafts. Treatment with infliximab, a chimeric anti-TNF-alpha antibody (four infusions of 3 mg/kg body weight), induced a complete remission of histological and clinical signs of rejection. Two further patients with steroid-resistant rejection received two courses of infliximab (3 mg/kg body weight) as antirejection therapy. All rejection episodes resolved completely. CONCLUSIONS: Infliximab effectively treats steroid and OKT3 resistant acute rejection episodes of intestinal transplantations.     

Control of antidonor antibody production with tacrolimus and mycophenolate mofetil in renal allograft recipients with chronic rejection

BACKGROUND: In renal transplantation, chronic rejection is a major cause of late allograft loss. Recent studies indicate that a subset of chronic rejection is associated with anti-HLA donor specific antibodies (DSA) and complement C4d deposition in peritubular capillaries (PTC). Since rescue therapy with tacrolimus and mycophenolate mofetil has been found to limit antidonor B-cell responses in recipients with acute humoral rejection, we sought to determine whether a similar immunosuppressive regimen might be effective in patients with 'chronic humoral rejection'. METHODS: Four renal allograft recipients with 'chronic humoral rejection' were prospectively identified. The diagnosis was based on: (1) progressive rise in serum creatinine over 12 months; (2) typical pathologic features by light microscopy (transplant arteriopathy and glomerulopathy); (3) widespread C4d deposits in PTC by immunofluorescence; (4) detection of 'de novo' DSA at the time of biopsy. Maintenance immunosuppression was CsA, prednisone and azathioprine (n=3) or prednisone and azathioprine (n=1). Rescue therapy with tacrolimus and mycophenolate mofetil was initiated in all patients, 12 hr after cyclosporine and azathioprine discontinuation. RESULTS: At diagnosis, the mean serum creatinine was 3.9 mg/dl (range: 3.3 to 5.4 mg/dl). DSA was an IgG directed against HLA class II (n=3) or class I (n=2), that is one patient had both anti-HLA class I and class II antibodies. Pretreatment antibody titers varied between 1:8 and 1:128. Rescue therapy was associated with a rapid and sustained decrease in antibody titers. In two patients, DSA became undetectable after 9 months and a repeat biopsy performed after 12 months revealed a decrease in C4d deposition in PTC. CONCLUSION: These results suggest that a decrease in DSA production can be induced in renal allograft recipients with 'chronic humoral rejection' by using an immunosuppressive regimen that combines tacrolimus and mycophenolate mofetil. Limitation of antidonor antibody synthesis may be important for the treatment or the prevention of chronic rejection in organ transplantation.     

Conversion of renal transplant recipients from cyclosporin to low-dose tacrolimus for refractory rejection

Abstract Twenty-five patients with refractory rejection following renal transplantation were converted from cyclosporin to tacrolimus in an attempt to salvage the allografts. All patients had received two or three pulses of methylprednisolone, 6 had OKT3, 14 had antithymocyte globulin (ATG) and 2 had both OKT3 and ATG prior to conversion. The median time from transplantation to conversion to tacrolimus was 32 days (range 12–322). Patients underwent a simple switch from cyclosporin- to tacrolimusbased therapy with tacrolimus administered at a median dose of 0.15 mg/kg per day. Doses were adjusted according to clinical response and trough blood levels. Twenty-one of the 25 patients (84 %) with refractory rejection showed evidence of reversal of rejection as indicated by a significant reduction in serum creatinine (Student's paired t -test, P < 0.05) following conversion to tacrolimus. None of these patients had further episodes of rejection. Three patients had ongoing rejection and returned to dialysis, and 1 patient showed deteriorating renal function associated with a cytomegalovirus infection. Of 18 patients currently on tacrolimus, 15 have improved renal function and 3 have shown no further deterioration. We conclude that low-dose tacrolimus appears to be effective in salvaging renal allografts with resistant rejection.     

Basiliximab-chimeric anti-IL2-R monoclonal antibody in pediatric liver transplantation: comparative study

Basiliximab is a monoclonal antibody that binds to the alpha subunit (CD(25)) of the interleukin-2 receptor of activated T lymphocytes. The advantage of basiliximab in organ transplantation is the reduce possibility to calcineurin inhibitor dosages to avoid nephrotoxicity. Basiliximab has significantly reduced the incidence of acute rejection (AR) in renal transplant recipients; however, the results are uncertain in liver transplantation (LT). The objective of this investigation was to assess the effect of basiliximab to prevent AR in the first 6 months after pediatric LT. From March 2000 to October 2001, 32 recipients of a primary orthotopic cadaveric or living donor LT were given basiliximab by intravenous bolus injection on the day of transplantation (day 0) and on day 4. Four children who received one dose were excluded from the study. The rate and the intensity of AR episodes, the incidence of chronic rejection, serum creatinine level, incidence of infections, adverse side effects, and daily oral dosage of cyclosporine (Neoral) to maintain the target blood level of 850 to 1000 mg/dL at C2, 2 hours after the administration, were analyzed in the remaining 28 recipients. Results were compared to those obtained from a matched historical group (n = 28) of similar age, weight, and hepatic diseases distribution. None of the analyzed parameters was statistically significant (P >.05) except for the daily oral dose of cyclosporine (7 to 13 mg/kg/dose, P <.05). In our series, the addition of basiliximab to the immunosuppressive therapy did not reduce the incidence of AR in pediatric LT.     

The influence of mycophenolate mofetil versus azathioprine and mycophenolic acid pharmacokinetics on the incidence of acute rejection and infectious complications after renal transplantation

PURPOSE: The present retrospective study investigated the influence of mycophenolate mofetil (MMF) instead of azathioprine (AZA) as part of tacrolimus-based immunosuppression. Mycophenolic acid (MPA) pharmacokinetic (PK) parameters were used for associations with the incidence of acute rejection (AR) episodes and infectious complications after renal transplantation. METHODS: The 66 consecutive renal transplant recipients reported herein excluded ABO-incompatible transplants or cytomegalovirus (CMV)-seronegative recipients. The immunosuppressive regimen consisted of tacrolimus, steroids, and AZA 1-2 mg/kg/d in 22 patients (between February 1998 and December 2000) or MMF 2 g/d in 44 patients (since January 2001). CMV infection was defined as positive CMV-antigenemia. MPA PK was studied on day 28 after transplantation in 21 recipients. RESULTS: AR occurred in 13.6% of patients in the MMF group compared with 18.2% in the AZA group. The viral infection (CMV, varicella zoster virus, adenovirus hemorrhagic cystitis, and malignancy related to Epstein-Barr [EB] virus) rate was 22.7% in the MMF group and 0% in the AZA group (P = .015). There were no bacterial or fungal infections observed in the 2 groups. MMF dose per body weight was significantly lower among patients with AR than those without AR (25.1 vs 35.6 mg/kg; P = .026). There were no differences in MPA PK parameters between patients with and without viral infections. CONCLUSIONS: Patients treated with MMF required less treatment for AR, however, there were no significant differences. MMF dose per body weight may play an important role in the occurrence of AR. Although virus infections occurred in recipients treated with MMF, MPA PK did not influence the infectious complications after renal transplantation.     

Anti‐C1s monoclonal antibody BIVV009 in late antibody‐mediated kidney allograft rejection—results from a first‐in‐patient phase 1 trial

The classical pathway (CP) of complement may contribute to the pathogenesis of antibody‐mediated rejection (ABMR). Selective CP blockade may be a promising strategy to counteract rejection. The objective of this first‐in‐patient phase 1b trial was to evaluate the safety/tolerability and CP‐blocking potential of 4 weekly doses (60 mg/kg) of the anti‐C1s antibody BIVV009 in complement‐mediated disorders. Here we describe the results in a cohort of 10 stable kidney transplant recipients (median of 4.3 years posttransplantation) with late active ABMR and features of CP activation, such as capillary C4d or complement‐fixing donor‐specific antibodies (DSA). During 7 weeks follow‐up, no severe adverse events were reported, and BIVV009 profoundly inhibited overall and DSA‐triggered CP activation in serum. Five of 8 C4d‐positive recipients turned C4d‐negative in 5‐week follow‐up biopsies, while another 2 recipients showed a substantial decrease in C4d scores. There was, however, no change in microcirculation inflammation, gene expression patterns, DSA levels, or kidney function. In conclusion, we demonstrate that BIVV009 effectively blocks alloantibody‐triggered CP activation, even though short‐course treatment had no effect on indices of activity in late ABMR. This initial trial provides a valuable basis for future studies designed to clarify the therapeutic value of CP blockade in transplantation. ClinicalTrials.gov NCT#02502903.     

Value of monitoring circulating donor‐reactive memory B cells to characterize antibody‐mediated rejection after kidney transplantation

Antibody‐mediated rejection (ABMR) is defined by specific histopathological lesions and evidence of circulating donor‐specific antibodies (DSA). Although DSA are not always detectable, monitoring donor‐reactive memory B cells (mBC) could identify patients at risk of developing ABMR. Peripheral donor‐reactive mBC using a novel HLA B cell ELISpot assay, serum DSA, and numbers of different B cell subsets were assessed in 175 consecutive kidney transplants undergoing either for‐cause or 6‐ and 24‐month surveillance biopsies for their association with main histological lesions of ABMR and impact on allograft outcome. In 85 incident for‐cause biopsies, high frequencies of donor‐reactive mBC were detected in all 16 (100%) acute ABMR/DSA+ and most chronic ABMR, with or without DSA (24/30[80%] and 21/29[72.4%], respectively). In a longitudinal cohort of 90 nonsensitized patients, a progressively higher expansion of donor‐reactive mBC than de novo DSA was observed at 6 and 24 months (8.8% vs 7.7% and 15.5% vs 11.1%, respectively) and accurately identified patients with ongoing subclinical ABMR (area under the curve = 0.917 and area under the curve = 0.809, respectively). An unsupervised hierarchical cluster analysis revealed a strong association between donor‐reactive mBC with main fundamental allograft lesions associated with ABMR and conferred a significant deleterious impact on graft outcome. Monitoring donor‐reactive mBC may be useful to further characterize humoral rejection after kidney transplantation.     

Development of posttransplant antidonor HLA antibodies is associated with acute humoral rejection and early graft dysfunction

BACKGROUND: The goal of this study was to determine whether the production of posttransplant antibodies directed against donor HLA mismatches (donor specific antibody; DSA) is associated with renal allograft rejection and early graft dysfunction. METHODS: Forty-nine adult renal allograft recipients with increased risk of rejection were enrolled during the period of October 2001 through May 2003 and were prospectively monitored for the development of anti-HLA antibodies. RESULTS: Of 49 patients, eight (16.3 %) patients were diagnosed with acute humoral rejection (AHR) and 11/49 (22.4%) patients were diagnosed with acute cellular rejection (ACR). A strong association between pretransplant HLA sensitization and AHR was found (P=0.005). Of the eight patients diagnosed with AHR, the majority developed DSA before or concomitant with episodes of rejection (P<0.001). Only 3 of 41 patients (7.3%) without AHR developed DSA. The pathogenic role of alloantibodies was further substantiated by analyzing their association with graft function as measured by serum creatinine levels. The average serum creatinine after the third month posttransplantation in DSA producers was 2.24+/-1.01 mg/dL, while in non-DSA patients the average serum creatinine was 1.41+/-0.37 mg/dL (P<0.01). CONCLUSION: This study reveals a strong association between the production of DSA, AHR, and early graft dysfunction. Our findings indicate that prospective monitoring for anti-HLA antibodies following transplantation is a useful test for the diagnosis and classification of AHR for identifying patients at risk of early graft dysfunction.     

The effect of acute rejection and cyclosporin A-treatment on induction of platelet-derived growth factor and its receptors during the development of chronic rat renal allograft rejection

BACKGROUND: In the development of chronic kidney allograft rejection acute rejection (AR) is the single most important risk factor. Although Cyclosporin A (CsA) medication has decreased the incidence of AR, chronic rejection (CR) is still the major reason for late allograft loss. Platelet-derived growth factor (PDGF) is a major mitogen mediating mesenchymal cell proliferation in CR. We have investigated the impact of AR and different doses of CsA on the expression of PDGF ligands and receptors in the development of CR. METHODS: Kidney transplantations were performed from DA to WF rats and syngenic controls were done from DA to DA rats. Two groups of allografts were treated daily with CsA either at low dose (1.5 mg/kg) or high dose (5 mg/kg). Third group of allografts was treated with CsA 5 mg/kg/day for 1 week and then left untreated until the development of AR. AR episodes were treated with CsA 5 mg/kg/day. Grafts were harvested 3 months after transplantation for histology and immunohistochemistry (PDGF-AA, -BB and PDGFR-alpha, -beta). RESULTS: In syngenic grafts no histological signs of CR were seen and the expression of PDGF ligands and receptors remained almost nonexistent. AR episodes increased the chronic rejection changes. High-dose CsA-treatment ameliorated inflammation compared to low-dose CsA-treatment, although it failed to inhibit the development of chronic changes. More fibrosis was even seen in high-dose than in low-dose CsA-treated grafts. CR in each allograft group was associated with induction of all PDGF ligands and receptors (P<0.05 compared with syngenic controls) in interstitial inflammatory cells, capillary endothelium, and arterial smooth muscle cells. In the group with AR episodes the expression was further increased. CONCLUSIONS: Our results demonstrate that CsA treatment cannot inhibit the expression of PDGF ligands and receptors in the development of chronic kidney allograft rejection and that AR episodes induce even more PDGF and its receptors in the graft indicating a link between AR and subsequent development of CR.     

A chronic renal rejection model with a fully MHC-mismatched rat strain combination under immunosuppressive therapy

BackgroundThe Fischer-to-Lewis (LEW) rat model of kidney transplantation is a widely accepted and well-characterized model of chronic rejection. In contrast to transplantation in a clinical setting, however, the absence of treatment with immunosuppressants and only minor mismatch of major histocompatibility complexes (MHCs) are critical discrepancies. Here, we established a rat model of chronic rejection using fully MHC-mismatched strains in which kidney disease progresses even under immunosuppressive therapy.MethodsLEW (RT1^l) rats were used as donors and Brown Norway (BN, RT1ⁿ) rats as recipients. Intramuscular administration of 0.1 mg/kg of tacrolimus was initiated on the day of transplantation. Post-transplantation, this dose was maintained until Day 9, suspended until Day 28 and then resumed from Day 29. Renal function, histopathology, and levels of donor-specific antibody (DSA) and several biomarkers of renal injury were assessed.ResultsOn Day 91 post-transplantation, recipients received tacrolimus treatment with short-term suspension exhibited reduced renal function and changes in histology. Those were characteristics of chronic rejection including glomerulosclerosis, interstitial fibrosis, and tubular atrophy in human transplantation recipients. Urinary protein excretion increased in a linear fashion, and elevated levels of several biomarkers of renal injury and DSA were observed even under administration of an immunosuppressant.ConclusionsWe established an allograft rejection model with impaired renal function and typical histopathological changes of chronic rejection in fully MHC-mismatched rats by controlling administration of an immunosuppressant. These findings suggest that this model more accurately reflects transplantation in a clinical setting than existing models and enables the evaluation of therapeutic agents.     

Results and complications of 50 laparoscopic nephrectomies for live donor renal transplantation

Living donors represent 30% of kidneys for renal transplantation. Laparoscopic nephrectomy is the best surgical procedure due to its clear advantages: low morbidity, less blood transfusion requirements, and shorter donor hospitalization. From March 2002 to August 2004, we performed 50 laparoscopic nephrectomies for transplantation to recipients who were prescribed tacrolimus (0.1 mg/kg bid), mycophenolate mofetil (1 gr bid), and prednisone (0.5-1 mg/kg per day PO from 48 hours before transplantation). Mean surgery time was 170 minutes (120-260); warm ischemia time, 3.1 minutes (1.5-10); and cold ischemia time, 1.27 hours (0.85-4). Mean bleeding was 270 cc (100-900), and mean donor hospitalization was 5.5 days (3-9). Four cases required conversion of the laparoscopic procedure to open surgery because of bleeding. Seventy-two hours posttransplantation, the mean plasma creatinine was 170 micromol/L. None of the patients suffered delayed graft function. Eighteen percent experienced acute rejection episodes. Donor and recipient survivals were 100% at 1 year, and graft survival, 94% (kidney losses were due to acute rejection, severe acute pancreatitis, and surgical complications).     

Effects of mycophenolate mofetil on donor-specific antibody formation in renal transplantation

BACKGROUND: Mycophenolate mofetil (MMF) is a routinely used immunosuppressive agent that selectively blocks T- and B-lymphocyte proliferation. The present study was designed to investigate the effects of this drug on human leukocyte(HLA) antibody production in general and donor-specific antibody (DSA) formation in particular in 154 recipients of renal allografts. PATIENTS AND METHODS: Renal allograft recipients were subdivided into three groups. Group 1 patients (n = 60) had received MMF since transplantation in combination with either cyclosporin A or tacrolimus and steroids. Group 2 patients (n = 29) had received an MMF-free immunosuppressive regimen initially followed by addition of MMF some time later. Group 3 patients (n = 65) had received no MMF. Cyclosporin A or tacrolimus in combination with azathioprine and/or steroids were used for immunosuppression. DSA were demonstrated by enzyme-linked immunosorbent assay (ELISA) for detection of panel-reactive antibodies of HLA class I and II specificity. RESULTS: The HLA antibodies were found in 16.7%, 27.6% and 30.8% of transplant recipients in groups 1, 2 and 3, respectively. DSA were found in 8.3%, 17.2% and 20.0%, and non-DSA in 10.0%, 20.7% and 24.6%, of patients in groups 1, 2 and 3, respectively. CONCLUSION: The MMF reduces anti-HLA class I and II antibody production and consequently DSA production in renal allograft recipients. Our data indicate this effect to be more pronounced in patients given MMF immediately after transplantation than in those in whom MMF is introduced some time later. The presence of DSA in the serum of renal allograft recipients is associated with poorer graft function (higher serum creatinine and more rejection episodes).     

肾移植术后中远期急性排斥反应临床研究

目的探讨肾移植术后中远期移植肾急性排斥反应(AR)发生影响因素及移植肾生存情况。 方法回顾性分析浙江大学医学院附属第一医院肾脏病中心2018年1月至2019年12月因血清肌酐水平升高而接受移植肾病理活检并确诊移植肾AR受者临床资料,共纳入43例受者,其中急性抗体排斥反应组17例,急性T细胞排斥反应组26例;同时纳入同期(2周内)肾移植且移植肾功能正常的39例受者为对照组。正态分布计量资料比较采用配对t检验或单因素方差分析。计数资料比较采用χ²检验或Fisher确切概率法。采用Kaplan-Meier进行生存分析,并采用log-rank进行比较。P<0.05为差异有统计学意义。 结果急性抗体排斥反应组HLA-A错配2个比例(4/17)高于对照组(1/39),差异有统计学意义(P＝0.026)。急性抗体排斥反应组和急性T细胞排斥反应组AR发生时和末次血清肌酐和估算肾小球滤过率(eGFR)均高于AR发生前(P均<0.05);急性抗体排斥反应组和急性T细胞排斥反应组AR发生时和末次血清肌酐和eGFR均高于对照组(P均<0.05);急性抗体排斥反应组进入慢性肾脏病(CKD)-4期受者比例低于急性T细胞排斥反应组(χ²＝5.73,P<0.05);急性T细胞排斥反应组进入CKD-4期受者比例以及急性抗体排斥反应组移植肾失功比例均高于对照组(χ²＝17.727和9.882,P均<0.05)。AR发生时急性抗体排斥反应组和急性T细胞排斥反应组受者均接受PRA检测,前者PRA-Ⅰ和PRA-Ⅱ阳性比例分别为41.2%(7/17)和88.2%(15/17),均高于后者[11.5%(3/26)和26.9%(7/26)],差异均有统计学意义(P＝0.042,P<0.001)。急性抗体排斥反应组、急性T细胞排斥反应组及对照组术后分别有13、24和38例受者应用他克莫司。发生AR时,急性抗体排斥反应组他克莫司血药浓度[(3.72±0.76)ng/mL]与急性T细胞排斥反应组[(3.37±0.86)ng/mL]均低于对照组[(5.73±1.25)ng/mL],差异均有统计学意义(P均<0.05);急性抗体排斥反应组与急性T细胞排斥反应组他克莫司血药浓度均低于发生AR前[(6.27±1.18)和(6.33±1.63)ng/mL],差异均有统计学意义(t＝7.120和6.216,P均<0.05)。急性抗体排斥反应组4例受者应用以环孢素为基础的免疫抑制方案,其中3例术后33、36和55个月环孢素血浓度分别为112.4、138.3和7.0 ng/mL,均低于要求血药浓度。急性T细胞排斥反应组2例应用环孢素受者术后16和177个月环孢素血药浓度分别为43.2和24.6 ng/mL,均低于要求血药浓度。随访至2021年6月30日,急性抗体排斥反应组移植肾生存率低于对照组(χ²＝8.738,P<0.05)。 结论HLA-A位点错配及他克莫司低血药浓度是肾移植术后中远期诱发AR的重要原因。急性抗体介导排斥反应是移植肾生存重要影响因素。     

Efficacy of tacrolimus in the treatment of refractory rejection in heart and lung transplant recipients.

BACKGROUND: Refractory acute cellular rejection may occur despite triple-drug immunosuppression (cyclosporine A, steroids, azathioprine/mycophenolate mofetil). The purpose of this study was to determine the efficacy of tacrolimus rescue therapy in patients maintained on cyclosporine-based immunosuppression (CBI). METHODS: Between December 1993 and October 1996, 208 patients underwent thoracic organ transplantation at the Hospital of the University of Wisconsin at Madison. One hundred forty-nine patients underwent heart replacement; 59 underwent lung transplantation. One hundred thirty-nine of the heart transplant cohort received CBI preceded by induction therapy with OKT3. Forty-six of the lung transplant cohort received CBI without induction cytolytic therapy. Refractory rejection was defined as failure to respond to high-dose steroids (500 mg to 1 g IV methylprednisolone for 3 days) and/or monoclonal antibody therapy (OKT3, 5 to 10 mg IV/day for 7 to 14 days). In patients with refractory rejection, cyclosporine was replaced with tacrolimus. RESULTS: Overall, 16% (30/185) of patients receiving CBI experienced refractory rejection. Thirty-one episodes of grade IIIa or greater rejection occurred in 11% (15/139) of heart transplant recipients. Twenty episodes of grade II to IV rejection occurred in 33% (15/46) of lung transplant recipients. After tacrolimus rescue therapy, 93% (14/15) of patients in the heart transplant group converted to grade II or less rejection. Refractory rejection was reversed in 73% (11/15) of the lung transplant group. Reversal was documented at biopsy in all (8/8) lung recipients in whom it had been histologically identified. FEV1 values of 3 additional patients stabilized. CONCLUSIONS: The incidence of refractory rejection in thoracic organ transplant recipients on CBI is significant. Reversal of refractory rejection follows rescue immunotherapy with tacrolimus.     

The experience of administration of 15-deoxyspergualin on rejection in kidney transplant recipients]

We report here the favorable results of clinical application of 15-deoxyspergualin (DSG) as a rescue therapy for rejection episodes in kidney transplant recipients. DSG was discovered in Japan and was proved to be a novel immunosuppressant in various animal transplantation models. The immunosuppressive mechanism of DSG is unclear yet, but its point of action is supposed to be in the early immuno response to allogeneic stimulation without the regulation of cytokine production. We performed the administration of DSG in fifteen patients, who had rejection episodes, with a dosage of 3 mg/kg/day or 5 mg/kg/day for five days by drip infusion. In the group of recipients who had rejection episodes within six months after kidney transplantation, DSG proved effective on six out of seven acute rejection episodes and induced favorable remission. And in the group of recipients who had rejection episodes after six months since kidney transplantation, DSG proved effective on all of ten rejection episodes. There was not a difference of effectiveness in respect to the dosage of DSG. The side effect of DSG treatment was mainly leukopenia but in most cases these leukopenia was remitted just under careful observation. Some patients complained the sense of abdominal discomfort. But so far, we did not encounter serious or critical side effects and complications during all the time of progression. Another benefit was that DSG was able to reverse the rejection episode even in the patient who had already treated with anti lymphocyte globulin and/or anti CD3 monoclonal antibody OKT3. We concluded that the administration of DSG as a rescue therapy was not accompanied by the serious side effects and was most effective against acute rejection after kidney transplantation.     

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.     

小肠移植术后排斥反应的诊断与治疗四例报告

目的 总结小肠移植术后排斥反应的诊断和治疗体会.方法 4例患者小肠移植术后均采用阿来佐单抗诱导及单用他克莫司(Tac)的无激素维持方案,术后前3个月血Tac浓度维持在10～15μg/L,术后4个月开始减少至5～10 μg/L,术后7个月开始减少至5/μg/L.术后采用临床症状观察、移植肠内镜观察及移植肠黏膜活检等方法监测排斥反应.排斥反应的诊断和分级则依据2003年国际小肠移植会议上确立的小肠移植急性排斥反应的病理学诊断标准.当发生IND级至轻度排斥反应时,提高血Tac浓度至15/μg/L并联合短程小剂量激素治疗,如排斥反应控制不理想,则应用大剂量激素冲击治疗;当发生中度排斥反应时,则提高血Tac浓度至15μg/L并联合大剂量激素冲击治疗.同时积极预防全身感染,停止肠内营养使肠道彻底休息.结果 4例患者术后共发生排斥反应9次,术后3个月内3例发生IND级至轻度排斥反应4次,术后3～6个月2例发生IND级至轻度排斥反应3次,术后7～12个月2例发生中度排斥反应2次.发生的9次排斥反应经治疗后均得到很好控制,移植肠功能恢复良好.IND级或轻度排斥反应的恢复时间为2～8d(平均4.8 d),中度排斥反应为15d.4例患者中有2例的存活时间已超过1年,1例为术后8个月余,1例为术后4个月,目前均在顺利康复中.结论 移植肠黏膜活组织病理学检查仍然是诊断排斥反应的金标准.提高血Tac浓度及联合应用激素治疗可成功逆转小肠移植排斥反应.