两种免疫抑制方案在肾移植中应用的不良反应对比分析

目的 评价免疫抑制剂的不同组合在肾移植中应用的安全性。方法 回顾分析肾移植患者的临床资料，术后采用环孢素A(CsA)、硫唑嘌呤(Aza)及泼尼松(Pred)三联用药预防排斥反应者37例(Aza组)，采用CsA、霉酚酸酯(MMF)及Pred三联用药者35例(MMF组)。比较分析两个组用药后的药物不良反应。结果 在消化道反应、白细胞减少、全血细胞减少以及继发感染发生率等方面，MMF组与Aza组的差异无显著性(P＞0．05)，而肝功能损伤的发生率，Aza组明显高于MMF组(P＜0．05)。结论 在药物性肝损伤方面，以MMF、CsA及Pred组成的免疫抑制方案较CsA、Aza及Pred方案相对安全。     

Symptomatic cholelithiasis in pediatric renal transplant recipients

We report two cases of symptomatic cholelithiasis in pediatric renal transplant recipients immunosuppressed with cyclosporine (CsA), prednisone and azathioprine. CsA was present in the bile and in the cholesterol gallstones of one patient. The diagnosis of cholelithiasis was established in both cases by abdominal ultrasound examination.     

A randomised, prospective study on the conversion from cyclosporine-prednisone to cyclosporine-azathioprine at 6 months after renal transplantation

Abstract In a randomised prospective trial, we studied the effects of replacement of prednisone (Pred) by azathioprine (Aza), 6 months after transplantation, in stable renal allograft recipients on cyclosporine and prednisone (CsA+Pred). Out of 83 patients, 42 started treatment with CsA+Aza and 41 continued therapy with CsA+Pred. CsA was dosed to achieve a level of 150 ng/ml, the Aza dose was 3 mg/kg per day and the Pred dose was 0.15 mg/ kg per day. Eighteen months after randomisation, in the CsA+Aza group 18 of the 42 patients were effectively treated with CsA+Aza. In the main, anaemia, leuco- and thrombocytopenia, and hypocorticism necessitated the reintroduction of Pred in the remaining 24 patients. Compared to the continuation of CsA+Pred, conversion of Pred to Aza resulted in a reduced number of antihypertensive drugs needed, and in lower serum total, LDL and HDL cholesterol levels; the incidence of acute rejections and graft losses was no different. In conclusion, conversion of CsA+Pred to CsA+Aza is a safe option in renal transplant patients with contraindications to long-term corticosteroid treatment.     

Randomised open clinical trial of conversion from mycophenolate mofetil to azathioprine in cadaveric renal transplantation

Abstract Mycophenolate mofetil (MMF) is a powerful immunosuppressive drug with established efficacy and safety. The search for a less expensive immunosuppressive protocol has led to an open randomised clinical trial of conversion from MMF to azathioprine (Aza). A total of 28 renal allograft recipients treated with prednisone, cyclosporine, and MMF was randomised into two groups: converted (early conversion) and control (late conversion). Conversion from MMF to Aza was conducted at the end of the 4th post‐transplant month in the converted group and after the 12th month in the control. During the 20‐month observation period, biopsy‐proven acute rejection occurred more frequently in the converted than in the control group, although the difference was not statistically significant. Early conversion from MMF to Aza increased the risk of subsequent rejection in those patients who underwent at least one episode of acute rejection prior to conversion.     

Risk factors for chronic rejection in pediatric renal allograft recipients

To determine the risk factors predictive of graft loss from chronic rejection in pediatric renal allograft recipients, we reviewed the collaborative study database of the Société de Néphrologie Pédiatrique which registered 314 grafts from January 1987 to December 1991. Of the 289 grafts analyzed, 71 failed during follow-up, chronic rejection being the most common cause of graft loss (35%). The clinical features of the chronic rejection group (n = 25) were compared with those of the group without failure (n = 218). The variables tested by monovariate analysis were cyclosporine dose at 1 year, donor type, donor and recipient age, and acute rejection episodes. The incidence of graft loss due to chronic rejection was 4% (4/109) in patients who had no acute rejection and 16% (21/134) in those with at least one acute rejection episode (P = 0.002). Donor age (≤5 years) was a risk factor for chronic rejection (P = 0.024). Recipient age and donor type were not significantly different between the chronic rejection group and the control group. Using time-dependent covariates, the risk factors were an acute rejection episode (P = 0.003) and low cyclosporine doses at 1 year (P = 0.02). We conclude that acute rejection and low cyclosporine doses in these pediatric patients were risk factors for graft loss due to chronic rejection. Received 3 April 1995; received in revised form 28 December 1995; accepted 22 March 1996     

Cyclosporine in the treatment of azathioprine-induced red cell aplasia following renal transplantation

Azathioprine, a well-known immunosuppressive agent, is used extensively in renal transplantation. There have been several case reports of pure red cell aplasia induced by this drug following a successful kidney transplant. Previous management of azathioprine-induced red cell aplasia included reduction of azathioprine dose, or treatment with cyclophosphamide. We propose the substitution of cyclosporine for azathioprine, in this clinical setting. Not only does cyclosporine allow recovery of bone marrow function, but it maintains a level of immunosuppression which stabilizes renal function in the post-transplant patient.     

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。     

Improvement in long-term graft survival in cadaveric renal transplant recipients treated with mycophenolate mofetil

Though mycophenolate mofetil has markedly reduced the incidence of acute rejection in renal transplantation, a significant improvement in graft survival has been more difficult to demonstrate. This retrospective study compares an historical control group of 210 consecutive renal transplant patients, who had received ATG induction associated with cyclosporin, prednisolone and azathioprine, with 187 patients receiving mycophenolate instead of azathioprine. The incidence of acute rejection was decreased with mycophenolate. In rejection-free patients, the 3-year graft survival rates were equivalent. In contrast, graft survival at 3 years improved significantly for patients who experienced a rejection crisis and remained under the initial triple drug regimen with mycophenolate compared to the patients of the historical group who were kept on azathioprine after a rejection episode. In conclusion, mycophenolate mofetil is not only able to reduce the incidence of acute rejection but could also improve the prognostic significance of acute rejection crises.     

The impact of thiopurine S-methyltransferase polymorphisms on azathioprine dose 1 year after renal transplantation

Azathioprine metabolism is influenced by activity of the enzyme thiopurine S-methyltransferase (TPMT), which varies markedly between individuals. In this study we examined the influence of TPMT gene polymorphisms on azathioprine dose 1 year after renal transplantation. TPMT coding and promoter genotypes were determined using PCR-based assays. Azathioprine dose, white cell count, and intercurrent events throughout the first year after renal transplantation were ascertained from contemporaneous clinical notes. All patients analysed (n=172) received an initial azathioprine dose of 1.5 mg/kg per day. Twelve individuals with one variant TPMT coding allele were detected (*3A n=11, *3C n=1). Of these, 58% required azathioprine dose reduction because of leucopenia, compared to only 30% of homozygous wild-type patients (P=0.04). A significant correlation between the presence of 11 variable number tandem repeats (VNTRs) in the TPMT promoter and reduction in azathioprine dose was also identified (P=0.001). We concluded that when azathioprine is administered at an initial dose of 1.5 mg/kg per day, both coding and promoter TPMT polymorphisms influence the dose tolerated.     

Tuberculosis in renal transplant recipients: Rifampicin sparing treatment protocol

The reactivation of mycobacterium infection inrenal transplant recipients in developingcountries is a common therapeutic dilemma,especially in those patients receivingcyclosporin immunosuppression. The inclusion ofrifampicin in the antituberculosis protocolincreases the risk of precipitating acuteallograft rejection due to its interaction withcyclosporin and also increases the financialburden. We successfully treated 16 patients whodeveloped mycobacterial infection post renaltransplant with a rifampicin sparingantituberculosis drug regimen. Pyrexia ofunknown origin was the most common manifestationobserved and a therapeutic trial withantituberculosis drugs is justified. De novodiabetes mellitus appears to be an added riskfactor and increases the susceptibility tomycobacterial infection.     

Safe conversion from cyclosporine to azathioprine with improved renal function in pediatric renal transplantation

Although cyclosporine has improved allograft survival in renal transplant patients, problems with drug toxicity remain, raising the question whether cyclosporine should be stopped at some point post-transplant. However, the relative safety of converting from cyclosporine to another immunosuppressive agent, or simply stopping cyclosporine remains an issue of debate and has not been evaluated in children. We have developed a protocol to convert children, who are 6 months post-transplant and have stable kidney function, from cyclosporine and prednisone to azathioprine and prednisone. Eleven children have undergone conversion because of suspected/potential nephrotoxicity or because of other difficulties with cyclosporine (expense, hirsutism). These children were compared with a control group of 12 children who met all criteria for conversion at 6 months but remained on cyclosporine. Allograft survival was similar in both groups but the children converted from cyclosporine experienced an improvement in renal function as measured by calculated creatinine clearance. There were no episodes of rejection for a period of 4 months postconversion and all rejection episodes that developed subsequently occurred during or after the change from daily to alternate-day prednisone. We believe that conversion from cyclosporine to azathioprine can be accomplished safely in children with stable allograft function but long-term risks and benefits need further evaluation.     

肾移植慢性排斥的后期药物调整

对２７例术后６个月－８年７个月发生慢性排斥的肾移植患者进行治疗，２１例经治疗后血清肌酐明显下降，并稳定，６例病情有反复。比较不同时期的免疫抑制剂用量，发生稳定组在慢性排斥发生后１、３、６个月时环孢素Ａ、强的松、硫唑嘌呤的用量均明显高于治疗前，而不稳定组在上述时期的免疫抑制用量不高于或于治疗前。认为长期应用较大剂量的免疫抑制剂（尤其是环孢素Ａ）是维持慢性排斥治疗效果的关键，并应充分重视硫唑嘌呤的作用     

肾移植术后环孢素向硫唑嘌呤转换的临床研究

目的 观察肾移植木后环孢素向硫唑嘌呤转换的临床效果。方法 选择60例术后1年以上、肾功能稳定的肾移植受者进行免疫抑制剂从环孢素向唷唑嘌呤的转换。结果 60例病人平均血清肌酐在转换后1个月明显下降(148±58.5至132±86.9mmol/L,P<0.01),并在以后几年内继续下降,转换后6年时平均血清肌酐为112±39.8mmol/L。转换后平均血压也明显下降,并且抗高血压药物数量逐渐减少(P<0.01)。分别有9例(15％)和3例(6.7％)病人在转换后3个月内和3个月后发生急性排斥反应。转换后1年、5年人/肾存活率分别为95％/81.7％、86.7％/78.3％。5例(8.7％)病人因药物副作用和慢性排斥反应从硫唑嘌呤再转换为环孢素。结论 肾移植受者在术后一定时间将免疫抑制剂从环孢素转换为硫唑嘌呤是一种安全的免疫抑制方案,具有较好的移植肾长期存活。     

Cause of death in renal transplant patients: a comparison between azathioprine and ciclosporin

The results of renal transplantation have improved due to advances in immunosuppression techniques of preservation, and pre- and postoperative treatments; however, both morbidity and mortality remain serious problems. To decrease the morbidity and mortality rates we analyzed the causes of death after renal transplantation in our hospital. Between 1972 and 1999, we performed 364 renal transplantations, 257 of which were living-related and 107, cadaveric. There were 178 patients given azathioprine and 186 given ciclosporin. The survival rate of the patients on ciclosporin therapy was much better than that of those on azathioprine therapy. Of the total 364 renal transplant patients, 59 (16.2%) died, and 28 (47.5%) of these 59 deaths occurred within 1 year after renal transplantation. The causes of death were infection in 19 (32.2%) patients, gastrointestinal diseases in 16 (27.1%), cardiovascular diseases in 11 (18.6%), cerebrovascular diseases in 6 (10.2%), suicide in 3 (5.1%), and other causes in 4 (6.8%). These findings reinforce that early diagnosis and treatment are essential to decrease the morbidity and mortality rates assoiated with renal transplantation. Received: May 23, 2000 / Accepted: November 20, 2000     

The effect of acute rejection on long-term renal graft survival is mainly related to initial renal damage

Abstract It has been suggested that poor long-term prognosis of acute rejection is due to hyperfiltrationmediated injury secondary to the initial renal damage, rather than to ongoing immunological mechanisms. A total of 953 renal transplant recipients was reviewed to examine the effect of acute rejection episodes on graft function and survival; 40 % had no rejections, 45 % one, 12% two and 3% three. Rejection episodes adversely affected short- and long-term prognosis (5-year survival for no rejections, 62 %; one, 34 %; two, 26 %; three, 19 %, P <0.001) and creatinine clearance at one year (cl 1) (none, 56.7 ml/ min; one, 51.1; two, 52.9; three, 35.2, P < 0.01). This was mainly due to increased graft loss, but patient survival was also reduced (5-year survival for no rejections, 77 %; one, 76 %; two, 63 %; three, 53 %, P < 0.05). There was no overall effect of rejection number, independently of cl 1. However, subgroup analysis showed a detrimental effect of rejection number on grafts with high residual function, i.e. cl 1 > 60 ml/min (5-year graft survival none and one, 87 %; two and three, 71 %, P < 0.01). Late initial rejection episodes adversely affected prognosis (5-year survival 1–7 days, 34 %; 8–60, 31 %; 60–300, 21 %, P < 0.05) and residual graft function (cl 1 1–7 days, 56.2 ml/min; 8–60, 48.7; 60–300, 44.6, P < 0.01). In conclusion, the poor long-term prognostic effect of rejection episodes is mainly, but not entirely, related to initial graft destruction. Late (>2 months after transplantation) initial rejection is an important independent risk factor for graft loss.     

Pediatric renal transplantation in Laurence-Moon-Biedl syndrome

Two cases of renal transplantation in pediatric patients with Laurence-Moon-Biedl syndrome are reported. Immunosuppressive therapy consisted of cyclosporine, prednisone and azathioprine. Renal function has been good but both patients developed morbid obesity.     

尼卡地平对肾移植受者环孢素A血浓度的影响

目的：研究尼卡地平对肾移植受者血压和环孢素A（CaA)全血谷值浓度的影响。方法：试验组62例肾移植术后肾功能恢复正常的受者服用尼卡地平，服药前后作自身对照；23例受者服用硝苯地平作为对照组，以CsA全血谷值浓度、CsA剂量、肌酐、血压作为临床评价指标。结果：试验组受者服用尼卡地平后CsA血药浓度显著升高、血压下降并维持在正常范围，与服用尼卡地平前比较，差异均有显著性意义（P＜0．01），6个月后环孢素剂量A减少达34．2％，对血肌酐无明显影响。结论：尼卡地平用于肾移植术后能有效治疗和预防高血压，并可提高CsA血药浓度，减少CsA用量和费用，并不增加CsA的毒性反应。尼卡地平与CsA合用可节省费用。     

Association of fever,nasal congestion and rise in serum creatinine with azathioprine therapy

The association of fever, nasal congestion and reversible rise in serum creatinine in a patient receiving azathioprine is reported. An identical pattern of symptoms was induced after two rechallenges with azathioprine. The increases in serum creatinine were not associated with renal parenchymal abnormalities. This paper illustrates that in transplanted patients, fever and rises in serum creatinine are not only related to rejection or infection, but may also involve drug hypersensitivity.     

Are blood transfusions beneficial in the cyclosporine era?

In patients treated with conventional immunosuppression (azathioprine and prednisone) after renal transplantation, there is a beneficial effect of pre-transplant blood transfusions on graft survival; in patients treated with cyclosporine, this effect may be lost. In 66 children who received living-related donor transplants after donor-specific transfusions (DST) and were treated with azathioprine-prednisone in our center, 1- and 5-year graft survival rates were 99% and 77% respectively. These rates were similar to those reported for children who did not receive DST but were treated with cyclosporine in other centers. There were 634 adult and pediatric recipients of cadaver transplants in our center who were treated with cyclosporine and prednisone (non-sequential therapy,n=89) or antilymphoblast globulin, azathioprine preduisone, and cyclosporin (sequential therapy,n=545). When all patients were considered, graft survival rates were higher in transfused than in non-transfused patients at 3–5 years, but in the sequential therapy group, there were no differences in graft survival rates between transfused and non-transfused patients. The results suggest that transfusions do not improve cadaver graft survival in patients receiving optimal cyclosporine therapy and that equally good related donor graft survival can be achieved with DST and conventional immunosuppression or no DST and cyclosporine.     

肾移植超急性排斥反应13例次分析

报告１９７８年８月￣１９９４年１２月间共做尸体肾移植５７０例次，其中发生超急性排斥反应（ＨＡＲ）１１例１３例（１３例次），均经病理证实，发生率为２．３％。移植肾于术中或术后短期予以摘除。并结合临床资料对ＨＡＲ的发生机理、危险因素、鉴别诊断及预防等进行分析，认为ＨＡＲ的发生与受者体内的预存抗体有关，反复输血、多次妊娠、再次肾移植是ＨＡＲ的诱发因素，术前系统、准确的配型有助于减少ＨＡＲ的发生。