Low-dose immunosuppression in a rat hind-limb transplantation model

Composite tissue allografts (CTAs) offer an alternative to conventional reconstructive methods. However, the toxicity of the drugs that are required to prevent rejection has prevented its widespread clinical application. The purpose of this study was to determine whether a low-dose, corticosteroid-free combination regimen of tacrolimus and mycophenolate mofetil (MMF) would prevent rejection in a rat hind-limb model, with minimal toxic side effects. Three groups were used in this study. In group I, Wistar Furth (WF) rats received a syngeneic WF hind-limb. In groups II and III, WF rats received an ACI hind-limb. The latter were treated with tacrolimus-MMF. Assessment for rejection, flow cytometry, and mixed lymphocyte reactions was performed. Biopsies were taken regularly and at the time of killing. Combination therapy with low-dose tacrolimus-MMF effectively prolonged CTA survival indefinitely, with minimal side effects. Toxicity associated with immunosuppressive drugs can be avoided in a low-dose combination corticosteroid-free regimen.     

他克莫司联合霉酚酸酯应用于胰肾联合移植的初步经验

目的 总结他克莫司(FK506)联合霉酚酸酯(MMF)应用于胰液膀胱引流式胰肾联合移植受者的初步经验. 方法 胰肾联合移植患者14例,术后应用FK506 0.07～0.15mg·kg-1·d-1加MMF 1.0～1.5 g/d加泼尼松25 mg/d三联免疫抑制治疗方案.采用微粒子酶免疫分析法每周测定口服FK506后全血峰谷浓度,依此调整剂量维持最初3个月内FK506全血浓度峰值10～20 μg/L,谷值5～15μg/L.并观察排斥反应的发生及药物的肝肾毒性. 结果 9例患者术后胰肾功能恢复良好,早期无排斥反应发生,血糖及肌酐水平恢复正常.随访18～70个月,平均34个月.存活1～3年者3例,3年～者1例,4年～者1例,>5年者4例,胰肾功能良好,血糖正常,均未使用降糖药.1例因超急性排斥反应术后第2天切除移植胰腺,随访2年肾功能良好.4例死亡,死因分别为术后急性右心功能衰竭、呼吸骤停、急性排斥反应及十二指肠瘘.胰肾联合移植术后各时期FK506全血峰、谷浓度差异均有统计学意义(P<0.05).术后共发生肾脏急性排斥反应4例次,肾毒性2例次,肝毒性1例次. 结论 FK506与MMF在药效上有协同作用,联合应用于胰肾联合移植具有良好的免疫抑制效果,能有效降低排斥反应发生率和提高移植物长期存活率.     

Mycophenolate mofetil added to immunosuppression after liver transplantation – first results

Mycophenolate mofetil (MMF) has been used successfully as an immunosuppressive agent after kidney and heart transplantation, but experience with MMF after liver transplantation is still limited. Between August 1995 and January 1996, we treated 20 patients with MMF after orthotopic liver transplantation in an open, prospective study. Five out of eight patients with acute rejection and one patient with early chronic rejection showed a complete response after MMF was added to the immunosuppression. Three patients with chronic rejection did not improve, one died, and two have stable graft function at present. In eight patients who suffered from toxicity, a reduction in the dosage of tacrolimus was attempted with simultaneous MMF therapy. One patient died due to multiple organ failure. Liver function improved completely in one other patient, and partially in three patients after adding MMF. In the remaining three patients, a reduced dosage of tacrolimus or cyclosporin, together with MMF, reduced toxicity, not significantly. In conclusion, MMF appears to be a safe and potentially useful adjuvant immunosuppressive agent for rescue and maintenance therapy. Received: 15 August 1996 Accepted: 6 December 1996     

Use of tacrolimus and mycophenolate mofetil as induction and maintenance in simultaneous pancreas‐kidney transplantation

Abstract Clinical trials using quadruple immunosuppression that include the combination of tacrolimus and mycophenolate mofetil have been shown to reduce the incidence of acute rejection episodes in simultaneous pancreas‐kidney (SPK) transplantation. In an attempt to obtain a low rejection rate without antibody induction therapy, we undertook a prospective study of combined tacrolimus and mycophenolate mofetil and steroids as primary immunosuppression for SPK transplantation. In this study, we analyzed 17 patients who received low‐dose intravenous tacrolimus as induction therapy. This was combined with oral tacrolimus, mycophenolate mofetil, and steroids as the primary immunosuppression regimen. There was a significant reduction of empirically and biopsy‐proven rejection with an incidence of 23 % (4 patients). Leukopenia, gastroparesis, and gastrointestinal side‐effects were the cause of discontinuation of mycophenolate mofetil, or low tacrolimus trough level in those patients who developed rejection. All rejection episodes were easy to treat, and none of them required antibody therapy. The combination of tacrolimus with mycophenolate mofetil without antibody induction therapy is effective in preventing early acute rejection. This combination is safe and effective as an alternative immunosuppressive regimen after SPK transplantation.     

慢性移植肾肾病患者使用他克莫司联合麦考酚吗乙酯替代环孢素为基础的免疫抑制剂方案的疗效分析

目的探讨应用以环孢素(cyclosporine,CsA)为基础免疫抑制剂的慢性移植肾肾病(chronic allograft nephropathy,CAN)患者转换为他克莫司(tacrolimus,FK506)联合麦考酚吗乙酯(mycophenolate mofetil,MMF)治疗的疗效及安全性。方法使用CsA为基础免疫抑制方案的CAN患者76例,转换为FK506+MMF,随访6个月,根据移植肾穿刺病理结果将患者分为伴有慢性排斥反应组(CR组,41例)和不伴有慢性排斥反应组(non-CR组,35例)。观察两组的疗效及不良反应。结果 CR组好转27例(66%),稳定9例(22%),无效5例(12%);non-CR组好转11例(31%),稳定15例(43%),无效9例(26%),CR组疗效优于non-CR组(P0.05)。CR组和non-CR组转换后,24h尿蛋白定量均有所降低,高血压和高脂血症的病例数有所减少,而且未出现继发性高血糖、严重感染等不良反应。结论 CAN患者使用FK506+MMF替代CsA为基础的免疫抑制剂方案是安全有效的。     

Pharmacokinetics of mycophenolate mofetil are influenced by concomitant immunosuppression

The recommended dosage for mycophenolate mofetil (MMF) in combination with cyclosporin (CyA) for pediatric kidney transplant recipients is 600 mg/m² twice daily (b.i.d.). We recently published pharmacokinetic (PK) profiles of MMF in combination with tacrolimus (FK506): in order to keep the mycophenolic acid (MPA) pre-dose trough concentration between 2 and 5 μg/ml and to avoid side effects, mean MMF doses were reduced to 300 mg/m² b.i.d.. In order to investigate whether this striking difference was due to alterations of MPA clearance by CyA or FK506, we analyzed PK profiles from 13 patients who received MMF without CyA or FK506, and compared these data with 14 patients who received a combination of MMF and FK506 and 15 patients who received MMF and CyA. Mean area under the curve (AUC) in all PK profiles was 61.9±23.8 μg×h/ml. Although the AUCs did not differ between the groups, the dose per square meter was significantly lower in patients receiving concomitant FK506 compared with CyA, and the dose-normalized AUC was significantly higher. The MMF doses were 1,158±301 mg/m² per day in the CyA group, 555±289 mg/m² per day in the tacrolimus group, and 866±401 mg/m² per day in the group without concomitant calcineurin inhibitor treatment. The apparent clearance of MPA is reduced in combination with tacrolimus. The reason for this remains unknown. There was a trend towards lower dose-normalized AUCs in the CyA group compared with the group without calcineurin inhibitor treatment. We conclude that concomitant medication alters the clearance of MPA. It is noteworthy that there was substantial interindividual variation, despite the rather marked differences between the groups, and therefore we recommend starting MMF in combination with CyA at a dose of 600 mg/m² b.i.d., in combination with tacrolimus at a dose of 300 mg/m² b.i.d., and without a calcineurin inhibitor at a dose of 500 mg/m² b.i.d., and adjusting doses using therapeutic drug monitoring of MPA. Received: 2 September 1998 / Revised: 7 January 1999 / Accepted: 7 January 1999     

Tacrolimus-based immunosuppression after liver transplantation: a randomised study comparing dual versus triple low-dose oral regimens

To evaluate the efficacy and safety of oral tacrolimus-based immunosuppressive induction therapy, 130 primary orthotopic liver transplant (OLT) recipients were randomised to treatment in an open, parallel-group, European multicentre trial. Following OLT, patients were immediately administered either tacrolimus (0.10 mg/kg) and prednisolone (dual therapy group) or tacrolimus (0.06 mg/kg) in conjunction with prednisolone and azathioprine (triple therapy group) both orally. Patient survival at 1 year was 79.4 % for the dual therapy group and 88.7 % for the triple therapy group (P = 0.194); 1-year graft survival rates were 76.5 % in the dual therapy group and 80.6 % in the group receiving triple therapy (P = 0.615). The frequencies of rejection (dual therapy 42.6 %, triple therapy 50.0 %; P = 0.482), infection, and other complications (renal, neurological and glucose metabolic disorders) were similar in both groups. Tacrolimus whole blood trough concentrations were detectable on days 1 and 2, respectively, in the dual and triple therapy treatment groups whilst median tacrolimus blood concentrations in the triple therapy group reached levels similar to those in the dual therapy group on postoperative day 11 following a steady increase in dose. After 1 year, 54.4 % of the patients randomised to dual therapy were receiving tacrolimus monotherapy and only 56.4 % of the patients randomised to triple therapy continued to receive azathioprine. In conclusion, oral tacrolimus-based immunosuppression is both potent and safe when administered as induction therapy after OLT. Treatment may commence at either 0.06 or 0.10 mg/kg per day, but doses may need to be increased to the latter value within the first 10 days to maintain effective immunosuppression. Received: 8 October 1996 Received after revision: 30 January 1997 Accepted: 17 February 1997     

World experience after more than a decade of clinical hand transplantation: update on the Polish program

It has been demonstrated over the past decade that the generally achieved functional outcomes of patients after hand transplantation (HTx) are better than those of equivalent replantations. However, HTx should be performed in specialized centers with Institutional Review Board-approved transplantation programs. In Poland such requirements are fulfilled by The Subdepartment of Replantation of Limbs of St. Jadwiga Hospital in Trzebnica. A main emphasis of this subdepartment is to make the very involved process of donor recruitment, recipient screening, surgery, and postoperative treatment fully transparent. This article summarizes the experience of this center with HTx over the past 5 years.     

Abbreviated mycophenolic acid AUC from C0, C1, C2, and C4 is preferable in children after renal transplantation on mycophenolate mofetil and tacrolimus therapy

In order to allow a similar algorithm to be used for both adults and children on tacrolimus-based and mycophenolate mofetil [MMF, a pro-drug for mycophenolic acid (MPA)]-based immunosuppression, a limited sampling technique from the trough level (C0) and the levels 30 min (C0.5) and 2 h (C2) after intake was to be developed from MPA area under the time–concentration curves (AUC). We retrospectively analyzed 49 full ten-point pharmacokinetic (PK) profiles from 29 pediatric patients on MMF and tacrolimus. We used stepwise multiple regression analysis to calculate limited sampling approaches. Agreement with the AUC was tested by means of Bland and Altman analysis. The correlation between AUC and pre-dose trough concentration was r²=0.5188 (P<0.0001) and between AUC and post-dose trough concentration r²=0.6924 (P<0.0001). The next best correlations were with 2 h (C2, r²=0.6711, P<0.0001), 4 h (C4, r²=0.6411, P<0.0001), 1.5 h (C1.5, r²=0.6344, P<0.0001), and 6 h (C6, r²=0.6219, P<0.0001). Three-point estimates at C0, C0.5, and C2 resulted in an acceptable correlation between predicted AUC and AUC from the full profile when we used the formula AUC = 10.01391+3.94791×C0+3.24253×C0.5+1.0108×C2, Pearsons r=0.8996, 95% confidence interval 0.8277–0.9424. However, even better results could be obtained when we used AUC = 8.217+3.163×C0+0.994×C1+1.334×C2+4.183×C4, Pearsons r=0.9456, 95% confidence interval 0.9051–0.9691. Bland and Altman analysis revealed good agreement between AUC predicted from C0, C0.5, and C2 and AUC from the full profile, but was inferior to the four-point approach. Also, the previously reported formula derived for adults was not usable in these patients. A special formula must be used for children. The AUC of MPA can be predicted by limited sampling including C0, C0.5, and C2, while an approach using C0, C1, C2, and C4 is preferable.     

Dosing of MMF in combination with tacrolimus for steroiD-resistant vascular rejection in pediatric renal allografts

Abstract SteroiD-resistant vascular rejection was treated in seven adolescent renal allograft recipients using the combination of mycopheno-late mofetil (MMF) and tacrolimus (FK506). Since there are no published pediatric dose recommendations for MMF using this combination, trough concentrations and pharmacokinetic profiles were used for therapeutic drug monitoring. In order to keep the mycophenolic acid (MPA) concentrations between 2–5 μg/ml, mean MMF doses were reduced from 600 to 250 mg/m² b. i. d. Apparent clearance of MPA decreased from 5 to 1 ml/min per kg within 2 weeks. Pharmacokinetic monitoring revealed substantial variability among patients of both MMF and FK506. The MPA dose ranged from 178 to 1008 mg/m² per day to achieve an area under the curve (AUC) of 59.9 μg × h/ml ± 10.5 SD (range 49–65 μg). FK506 dose ranged from 1.3 to 8.8 mg/m² per day to achieve an AUC of 116 ng × h/ml ± 27 SD (range 83–145). We recommend adjusting MMF doses using therapeutic drug monitoring.     

To what extent does the understanding of pharmacokinetics of mycophenolate mofetil influence its prescription

Within a short period, we have witnessed a dramatic increase in the use of mycophenolate mofetil (MMF) in pediatric renal transplantation, with the drug often replacing azathioprine in combination with calcineurin inhibitor therapy. When the drug was introduced, the manufacturer considered therapeutic drug monitoring (TDM) unnecessary. However, TDM studies revealed substantial inter- and intra-individual variability and drug interactions. There is a substantial drug interaction between MMF and cyclosporine, and lower doses are required in combination with tacrolimus (~500-800 mg/m(2) per day) than with cyclosporine (~1,200 mg/m(2) per day). Patients with autoimmune disease require an intermediate dose when receiving no concomitant calcineurin inhibitor (~900 mg/m(2) per day). It has been possible to detect drug interactions and to minimize adverse events only with TDM. This is especially important with increasing use of combination therapies. Pharmacodynamic monitoring (measuring the biological response to a drug) coupled with pharmacokinetics allow optimization of drug dosing, with maximum efficacy and minimal toxicity. More work is required to establish specific target ranges with the various drug combinations--especially for the pediatric population.     

Calcineurin inhibitor-free immunosuppression in kidney transplantation

The introduction of calcineurin inhibitors (CNI) revolutionized kidney transplantation (KTx). Exceptionally low acute rejection rates and excellent graft survival could be achieved with CNI-based (cyclosporine and tacrolimus) immunosuppressive protocols. However, despite short-term success, long-term graft attrition continues to be a significant problem, thus leaving clinicians looking for possible interventions. CNI nephrotoxicity is but one of numerous factors that may be contributing to long-term damage in transplant kidneys. Therefore, newer immunosuppressive agents such as mycophenolate mofetil and sirolimus (Rapa) have raised the possibility of withdrawing or avoiding CNIs altogether. Protocols exploring these options have gained greater attention over the last few years. Herein, we review studies addressing either CNI withdrawal or CNI avoidance strategies as well as discuss the risks versus benefits of these protocols. Given the accumulated experience to date, in our opinion, the use of CNIs as a part of immunosuppressive regimens remains the proven standard of care for renal transplant patients. The long-term safety and efficacy of CNI withdrawal and avoidance strategies need to be further validated in controlled clinical trials.     

霉酚酸酯治疗慢性移植物功能减退的多中心研究

目的　探讨霉酚酸酯 (MMF)治疗慢性移植物功能减退 (CAD)的疗效和安全性。方法　应用霉酚酸酯 (MMF)替换硫唑嘌呤 (Aza)或环磷酰胺 (CTX) ,并联合小剂量环孢素A(CsA)和泼尼松 (Pred )治疗 78例CAD患者的方案。平均随访 9.84个月 ,研究并分析该方案的效果和并发症。结果　应用MMF联合小剂量CsA和Pred治疗后 ,有 74例患者的血清肌酐 (SCr)下降 ,随访时与应用前比较 ,差异有显著性 (P <0 .0 5 ) ;治疗有效率达 94 .9% ;4例治疗无效。用MMF转换治疗后 ,尿蛋白减轻或消失 ,血压下降。贫血、腹泻等不良反应发生率为 33.3%。结论　MMF联合小剂量CsA和Pred治疗CAD是有效和安全的。贫血、腹泻是转换治疗的主要副作用。     

Mycophenolic acid trough levels after kidney transplantation in a cyclosporine‐free protocol

Abstract Twenty‐seven stable kidney transplant recipients treated with cyclosporine and prednisone were converted to mycophenolate mofetil (MMF) and prednisone 1 year after transplantation. After conversion the patients were treated with a standard daily dose of 1 g MMF b.i.d. and 10 mg prednisone for 4 months. Thereafter, two MMF dose reductions were performed with a 4‐month interval. Mycophenolic acid (MPA) trough levels were measured at regular intervals. A relation was found between MPA trough levels and MMF dose. The median MPA trough level for patients treated with 1 g MMF b. i. d. was 4.3 μg/ml (0.95‐15.5) and 3.0 μg/ml (0.73‐7.8) for patients treated with 750 mg b. i. d. (P = 0.0002). The MPA trough levels further decreased from 3.0 to 2.3 μg/ml (0.6‐6.63) in patients treated with 500 mg MMF b. i. d. (P = 0.01). Dose reduction of MMF from 1 g to 750 mg b.i.d. could be performed without acute rejections. A further dose reduction to 500 mg b.i.d. elicited 3 rejections. Patients experiencing an acute rejection had a median MPA trough level of 2.3 μg/ml (1.26‐3.38) compared to 3.8 μg/ml (1.48‐6.52) in patients without an acute rejection (P = 0.25). We conclude that there is a significant relation between MPA trough levels and MMF dose. MPA trough levels were not predictive of rejection in the present study.     

西罗莫司在肝移植术后免疫抑制中的效果及安全性

目的 探讨肝移植术后应用西罗莫司(SRL)的免疫抑制效果和安全性.方法 对21例以SRL作为免疫抑制维持治疗的肝移植受者进行了观察.其中术后直接应用SRL者6例(术前肾功能不全者2例、原发病为肿瘤者4例);因他克莫司(Tac)药物相关性因素替换为SRL者15例(Tac肾毒性4例、高度可疑Tae肝毒性8例、Tac用量过大仍不能达到预期血药浓度者3例).术后对21例受者平均随访25.4个月(6～42个月),评估SRL的临床免疫抑制效果及安全性.结果 随访期间,2例受者因药物副反应停药,药物耐受率为90.5%.发生急性排斥反应1例次,经治疗后痊愈,其余患者均获得良好的免疫抑制效果.Tac肾毒性患者肾功能改善3例;Tac肝毒性患者肝功能显著好转6例.结论 SRL作为受者肝移植术后的免疫抑制维持治疗是安全有效的.术后早期及时用SRL替换Tac可有效逆转后者所致的肝、肾毒性损害.     

吗替麦考酚酯治疗原发性肾病综合征的前瞻性多中心临床研究

目的观察吗替麦考酚酯(MMF)联合激素治疗原发性肾病综合征(PNS)的疗效及安全性。方法采用前瞻性多中心方法,9个中心共47例患者入选。其中初治患者16例,难治性患者31例。用MMF联合激素治疗。MMF起始剂量为1.0～2.0g/d,至少3个月后开始减量,至12个月时维持在0.75～1.0g/d。口服泼尼松起始剂量0.8～1.0mg·kg-1·d-1,根据疗效减量,至6个月时至少减至传统治疗剂量的50%或以下。定期监测蛋白尿等生化指标及副作用。随访期≥6个月。结果47例患者蛋白尿水平从治疗后第2周起明显下降,由治疗前(6.46±3.18)g/d降至治疗后6个月时的(1.45±2.47)g/d(P<0.01),31/47例达到缓解;治疗后12个月时为(0.96±4.17)g/d(P<0.01),23/26例达到缓解。平均缓解时间为(10.89±11.49)周。初治组与难治性NS组均有效(P<0.01),组间差异无显著性意义(P>0.05)。治疗前后Scr无明显改变(P>0.05),血清白蛋白显著上升(P<0.01),血胆固醇水平明显下降(P<0.05)。微小病变组中6个月时有6/8例已达缓解,治疗后12个月时有4/4例仍处于缓解。系膜增生性肾小球肾炎组中治疗后6个月时有8/10例已达缓解,治疗后12个月时有6/7例仍处于缓解。膜性肾病组中治疗后6个月时有4/10例已达缓解,治疗后12个月时有2/4例仍处于缓解。局灶节段性肾小球硬化组中治疗后6个     

Single centre experience with mycophenolate mofetil for refractory rejection in cadaveric renal transplantation

Ten patients with refractory rejection following renal transplantation were treated with mycophenolate mofetil (MMF) in an attempt to salvage the allografts. All cases of rejection were biopsy-proven. Seven of the patients had initially been on tacrolimus-based triple therapy and three were on cyclosporin-based regimens. Those on cyclosporin had been unsuccessfully converted to tacrolimus prior to receiving MMF. All patients had received at least one course of methylprednisolone pulse therapy and three had been given OKT3 prior to MMF. MMF was prescribed at a dose of 2000 mg per day in two divided doses and was given in addition to tacrolimus and prednisolone. Eight of the ten patients showed evidence of reversal of rejection, as indicated by improvement in renal function following commencement on MMF, whilst two patients experienced ongoing rejection and underwent graft nephrectomy. One of the patients successfully treated has since had his MMF discontinued due to gastrointestinal intolerance. We conclude that MMF is effective in salvaging renal allografts with resistant rejection and that it has an acceptable side-effect profile. Received: 30 September 1997 Received after revision: 2 December 1997 Accepted: 14 January 1998     

一种新的大鼠肺移植模型

目的　探讨建立更简单有效的大鼠肺移植模型。方法　采用袖套法进行肺动、静脉的吻合,采用内支架法进行支气管重建,建立大鼠原位左肺移植模型。结果　20 只大鼠移植后均存活10 d以上,胸片基本正常,阻断受者自体的右肺门前后血O2 分压和CO2 分压的差异无统计学意义(P>0.05)。结论　这种新的模型对于研究大鼠肺移植的相关问题,特别是供肺的保存问题,具有简单、经济、可靠的优点。