What is the role for mycophenolate mofetil in pediatric renal transplantation?

Mycophenolate mofetil (MMF) has gained considerable popularity in pediatric renal transplantation. This popularity is largely a result of data from three large trials of MMF in adult cadaveric transplant patients who demonstrated a decreased rate of acute rejection episodes when treated with cyclosporin A (CsA), prednisone, and MMF compared with those receiving CsA, prednisone, and azathioprine (AZA) or placebo. However, the ability of MMF to reduce acute rejection appears to be limited to the first month post-transplant, and its effectiveness with microemulsion CsA or tacrolimus-based regimens has not been proven. In addition, there are currently no data that convincingly demonstrate that this agent improves graft survival, patient survival, graft function or protects against chronic rejection. Finally, there may be an increased risk for severe cytomegalovirus (CMV) disease and lymphoproliferative disorder with central nervous system involvement in patients treated with MMF. These data call into question the role of MMF in current immunosuppressive regimens.     

Influence of external biliary drainage on cyclosporin A (Neoral®) absorption in a pediatric liver transplant recipient

We report on a patient who underwent a liver transplant 8 yr ago at the age of 2. The post-operative course and further follow-up were uneventful, maintaining immunosuppression with cyclosporin A (CsA) (Sandimmune) and prednisone; 1.5 yr ago, the patient was converted to Neoral. The mean +/- SD trough CsA level was 127 +/- 37.2 ng/mL, when the patient was maintained on a daily dose of 180 mg. Following an increase in gamma-GTP levels, a biliary-enteric anastomotic stricture was found. Dilatation was performed and a tube placed for external biliary drainage. Three days later the trough CsA level was at the limit of detection; consequently, the Neoral dose was increased to 480 mg/d. CsA concentration measured 5 days later reached 164 ng/mL. After restoring internal biliary drainage the dose was decreased to 180 mg/d and the CsA level was 142 ng/mL. Later on the CsA dose was further reduced to 160 mg/d (a third of the dose during external biliary drainage) and trough levels were maintained at 90-120 ng/mL. We suggest that CsA dose adjustment and continuous drug monitoring are necessary when bile flow is compromised, in order to prevent rejection of the transplanted liver.     

A comparative analysis of the use of mycophenolate mofetil in pediatric vs. adult renal allograft recipients

Mycophenolate mofetil (MMF) is a new immunosuppressive drug used in combination with cyclosporin A (CsA) or tacrolimus and prednisone to prevent rejection of renal allografts in both adult and pediatric recipients. It has been shown in several large studies that MMF significantly decreases the incidence of acute rejection in adults and has acceptable adverse effects. In this retrospective study, we compare the incidence of adverse events between pediatric and adult renal allograft recipients. Twenty-two children and 37 adult renal allograft recipients were included in the study. The initial dose of MMF was 1.5 g b.i.d. for the adult patients and ranged from 15 to 30 mg/kg/d for the pediatric patients. All patients received p.o. acyclovir as prophylaxis for cytomegalovirus (CMV). The two groups were similar regarding gender distribution and graft source. Acute rejections occurred in 10 of the 22 pediatric patients (45%) and in nine of the 37 adults (24%), p = NS. The incidence of infections was similar in both groups except for the occurrence of CMV (n = 5), which was seen only in adults. The incidence of GI symptoms was significantly higher in the pediatric population (54.5% vs. 21.6%; p = 0.02). Significant weight loss was seen more often in the smaller pediatric patients (weight < or = 15 kg) compared to the larger pediatric patients, 60% vs. 11.7%, p = 0.05. Among the patients who had significant GI symptoms 50% of the adults and 75% of the pediatric recipients required either dose reduction or, most commonly, discontinuation of the MMF. The need to discontinue MMF was significantly higher in the pediatric patients, especially in those that weighed less than 15 kg. We suggest the possibility that the optimum dose, dosing interval or preparation of MMF has not yet been established for pediatric patients. One should therefore monitor pediatric patients closely, especially the small ones, to avoid significant nutritional problems and other adverse GI events.     

Limited sampling model for area‐under‐the‐curve monitoring in pediatric patients receiving either Sandimmune® or Neoral® cyclosporin A oral formulations

Several limited sampling equations were tested to predict the area under the curve (AUC) of cyclosporin A (CsA) at steady state in 10 children with end-stage renal disease receiving oral CsA 2.5 mg/kg b.i.d. as two different formulations, namely Sandimmune and Neoral, according to a randomized crossover design with a one-month washout period. AUC was significantly correlated with CsA concentration at 5 h. The equation derived from this single concentration time point was able to adequately predict the AUC for Sandimmune but not for Neoral. The equation derived from CsA concentration data, measured at 2 and 12 h, significantly improved predictive performance in terms of bias and precision, allowing adequate AUC predictions in both formulations. CsA concentration at 2 h was also able to predict Cmax, while the concentration at 12 h corresponded to the trough value in a b.i.d. dosing scheme. Therefore, it is concluded that a limited sampling model including concentration data at 2 and 12 h allows the estimation of AUC, Cmax and trough levels, yielding a complete profile in patients exposed to CsA as Sandimmune or Neoral. Hence, this model can be used for therapeutic monitoring of CsA levels in pediatric patients being switched from one formulation to another.     

Mycophenolate mofetil – is it worth the cost? The in-favor opinion

Since its introduction, mycophenolate mofetil (MMF) has rapidly gained acceptance among renal transplant physicians. Three large multicenter studies have shown that MMF decreased the incidence of acute rejection episodes by 50%. While clinical data supporting the long-term benefits of MMF are not available, there is some experimental evidence which demonstrates that MMF may play a role in the prevention of chronic allograft rejection. Furthermore, MM F is a potent immunosuppressive agent, which could result in a reduction of the dose of cyclosporin A (CsA) required and subsequently reduce its associated toxicity. Despite the fact that MMF is six to seven times more expensive than azathioprine (AZA), its introduction into maintenance immunosuppressive protocols may not increase renal transplant charges during the first year after renal transplant as its cost can be offset by the reduced number of acute rejection episodes (ARE). The long-term societal impact of MMF will need to be evaluated as the data related to graft and patient survival, as well as chronic rejection, become available.     

Cyclosporine monitoring in the early post-transplant period in pediatric liver transplant recipients

Monitoring of CsA blood levels two h post-dose (C2) has shown a higher correlation to drug exposure than monitoring of trough levels (C0) at least in adults, but initial doses and target blood levels of CsA have yet to be established in pediatric transplant patients. The objectives of the study were to describe the pharmacokinetics of CsA administered by NGT in the first days after transplantation and the dose of Sandimmun Neoral required to achieve minimum therapeutic range blood levels. This study included 20 pediatric liver transplant recipients (mean age of 3.2 yr) treated with CsA administered by NGT from day one post-transplant until they were able to ingest oral medication. The study was continued until one yr of post-transplant follow-up. Eight h pharmacokinetic profiles were performed on days one, three, and five post-transplant to determine the minimum dose required to achieve the therapeutic range. All children received an initial dose of 15 mg/kg/day of CsA by NGT. Mean CsA doses administered on days one, three, and five were 16.8, 29.5, and 36.5 mg/kg/day, respectively. Mean C0 levels of 119, 310, and 337 ng/mL and mean C2 levels of 213, 753, and 888 ng/mL were obtained. No correlation was found between C0 and C2 levels and the AUC(0-8 h). Intravenous administration of CsA was required in 55% of patients. The biopsy-confirmed acute rejection rate was 45%, with graft and patient survival rates of 95 and 100%, respectively. CONCLUSIONS: Poor absorption of CsA in small children requires a considerable increase in dose. CsA exposure cannot be estimated by single C0 or C2 determinations in the early post-transplant period.     

Single-center experience with mycophenolate mofetil in pediatric renal transplant recipients

Mycophenolate mofetil (MMF), a potent and specific inhibitor of guanosine nucleotide synthesis, is a new immunosuppressive drug used to prevent rejection in transplant patients. Extensive data on its utility and efficacy exists in adult patients but there is limited experience in pediatrics. Twenty-four children (14 male, 10 female; 2-19 yr of age), eight of whom had received living-related donor (LRD) transplants and 16 of whom had received cadaveric donor (CD) transplants, have been treated with MMF in our institution since September 1996. MMF was administered for a duration ranging from 13 weeks to 38 months, at an average dose of 600 mg/m2 (range: 200-1,000 mg/dose) every 12 h, for a total experience of 304 patient months. MMF capsules were used in 16 patients and/or pediatric suspension in eight. Five patients were switched to MMF from azathioprine as a result of rejection episodes or inability to taper prednisone, between 5 weeks and 3.5 yr post-transplant. All patients received prednisone, cyclosporin A (CsA), and induction therapy with anti-lymphocyte globulin (19 patients), anti-thymocyte globulin (one patient) or daclizumab (four patients). In 12 patients started on MMF at the time of CD transplant, five (42%) had an acute rejection episode. In seven who received a LRD transplant, one (14%) had an acute rejection episode. No patients who were converted to MMF were treated for acute rejection following conversion to MMF. One LRD graft was lost at 19 days following injury to the donor artery at the time of retrieval. At the last follow-up, the average creatinine level was 93 micromol/L and average urea level was 8.6 mmol/L. One patient developed epigastric distress. Three patients developed diarrhea/abdominal pain requiring dose adjustment. Five episodes of leukopenia and one episode of thrombocytopenia required dose adjustment. Two patients developed symptomatic cytomegalovirus (CMV) infection, one while on acyclovir prophylaxis. No malignancy has been encountered to date. Hence, MMF can be administered safely to children with good effect and with an acceptable side-effect profile.     

Diltiazem retards the metabolism of oral prednisone with effects on T‐cell markers

The area under the time-plasma concentration curve (AUC) was measured for prednisolone (the major active metabolite of prednisone) after ingestion of 15 mg of prednisone (phase 1) and again after 3 d of oral diltiazem (180 mg/d) followed by the same dose of oral prednisone (phase 2) in eight normal adult patients. Diltiazem increased the prednisolone AUC by 21% (range 3-38%), from 1297 +/- 157 ng/h/mL to 1560 +/- 169 ng/h/mL (p = 0.001). This effect was associated with a greater decrease from baseline in CD3+ lymphocyte number at 4 h after prednisone ingestion (596 +/- 175 vs. 516 +/- 140, p = 0.05), a larger percentage decrease of circulating CD3+ lymphocytes at 8 h (43 +/- 19% vs. 53 +/- 19%, p = 0.04), and a decrease in the number of CD3+ CD8+ T cells at 4 h post-prednisone ingestion (279 +/- 81 vs. 236 +/- 51, p = 0.04). Diltiazem retards prednisolone metabolism and when used chronically with prednisone could conceivably, in some patients, enhance its immunologic and other clinical effects. Potentiation of prednisone side-effects by diltiazem may be of special interest in pediatric patients, and possible diltiazem-prednisone interactions merit study in this population.     

Introduction of mycophenolate mofetil and cyclosporin reduction in children with chronic transplant nephropathy

Chronic transplant nephropathy (CTN) is the most important cause of kidney graft dysfunction. Studies in adult populations have reported a beneficial effect of non-nephrotoxic mycophenolate mofetil (MMF) on graft function in this setting. However, few studies were reported in children in this setting. We therefore reviewed the charts/medical records of renal transplanted patients < 18 yr of age at a single center who had switched from azathioprine to MMF as a result of progressive loss in graft function, for which vascular, infectious, and urological causes were excluded. Serum creatinine (SCr) and calculated creatinine clearance were compared prior to and after MMF introduction. Thirteen patients (nine male/four female), followed-up for 59.3 +/- 35.4 months after transplantation, were analyzed. Age at MMF introduction was 14.2 +/- 3.6 yr. In 11 patients a previous biopsy had shown features of CTN and four patients also presented signs of chronic cyclosporin A (CsA) nephrotoxicity. MMF was started at a dose of 1211 +/- 351 mg/day, and the CsA dose was decreased from 6.69 +/- 3.15 mg/kg/day 6 months before MMF to 4.8 +/- 2.3 mg/kg/day at the time of MMF introduction. CsA was withdrawn in four patients. The median (25-75%) SCr value increased from 1.60 mg/dL (range 1.3 to 1.87 mg/dL) 6 months before MMF to 2.2 mg/dL (range 1.87-2.32 mg/dL) when MMF was introduced. Six months after introduction of MMF, the SCr level had decreased to 1.5 mg/dL (range 1.2-1.8 mg/dL) and remained stable until the last follow-up (17.5 +/- 9.2 months after MMF was started). A similar pattern occured with calculated SCr clearance. There were no acute rejections after changes in immunosuppression. The safety of MMF was also analyzed and in only one patient was the drug stopped as a result of intractable diarrhea. These findings suggest that MMF is sufficiently powerful to allow a decrease/withdrawal of CsA without the burden of acute rejection in a pediatric population with CTN.     

Passage from sandimmun to neoral in kidney transplantation in children]

BACKGROUND: The cyclosporine microemulsion formulation Neoral, which allows a better absorption and a more regular pharmacokinetic profile, is proposed for replacing the original formulation, Sandimmun. The present study reports the results of conversion from Sandimmun to Neoral in children with a kidney graft, a population for which information remains limited. METHODS AND PATIENTS: Twenty children, 2.5 to 10.5 years of age, who had a kidney graft with a stable renal function for between six months to five years (m = 2.6) were the subjects of this study. The patients were switched from Sandimmun to Neoral at the same dose, adjusted afterwards on a cyclosporine trough level. RESULTS: After six months, the mean dose decreased from 9.1 mg/kg/d to 8.4 mg/kg/d, i.e., 12.5%. After one year, the mean dose was 7 mg mg/kg/d, i.e., 28%. Of the 65% of patients who had a decreased dose, most of them had the highest dose of Sandimmun at the start. Mean serum creatininemia levels slightly increased from 85.6 to 89.5 mumol/L after six months (P = 0.03). None of the patients had a rejection crisis during the first six months under Neoral. Blood pressure did not change significantly, hirsutism improved in two cases but increased or appeared in two cases as well. Gingival hypertrophy increased or appeared in four cases. DISCUSSION: A decrease in the dose was decided on either to maintain the trough CsA blood level in the desired range or because of the appearance of a symptom suggesting a side effect of cyclosporine, especially the increase of creatinemia. The trough level did not appear to be the best index for adapting the dose. CONCLUSION: In stable pediatric kidney transplant recipients, the switch from Sandimmun to Neoral provided a reduction in drug dosage in 65% of cases without an increase in adverse events.     

Mycophenolate mofetil in pediatric heart transplant recipients: a single-center experience

Mycophenolate mofetil (MMF) is emerging as an effective agent for the treatment of both established rejection and primary rejection prophylaxis in solid-organ transplantation (Tx). However, little data is available on the use of MMF in the pediatric population. We therefore report on our experience with MMF in 21 pediatric heart transplant recipients. Data were obtained by retrospective chart review. Median age at time of review was 12.3 yr (range 11 months to 16.9 yr). Median age at Tx was 10.7 yr (range 55 days to 16.7 yr). MMF was started at a median of 4.3 months after Tx (range 1 day to 4.5 yr). At the time of MMF institution, all patients were concurrently on prednisone and azathioprine; 20 of these patients were also undergoing treatment with tacrolimus (median dose 0.18 mg/kg, range 0.03-0.64 mg/kg) and one with cyclo-sporin A (10 mg/kg). Azathioprine was discontinued at the time of commencing MMF. The average MMF dose was 40 +/- 14 mg/kg. The rationale for switching to MMF included rejection (International Society for Heart and Lung Transplantation [ISHLT] 3A/B), 66%; inability to wean steroids, 14%; ABO blood group donor-recipient mismatch, 10%; coronary artery disease (CAD), 5%; and side-effects of immuno-suppression, 5%. Of the patients switched for rejection, 93% demonstrated resolved or improving rejection. Both ABO donor-recipient mismatch patients were started on tacrolimus/MMF as primary therapy and had no significant episodes of rejection. Two patients had rejection classified as unchanged (one with CAD, one treated with addition of sirolimus prior to improvement). Corticosteroids were successfully discontinued in 28% of patients, and 20% are currently on a reduced dose. Fourteen per cent developed significant rejection while attempting to reduce the steroid dose. Steroid reduction has not yet been attempted in 38% of patients. The following side-effects were reported in 38% of the patients: diarrhea, 10%; gastrointestinal discomfort, 20%; and leukopenia, 20%. Dose reduction or temporary discontinuation was required in 63% of the patients who experienced side-effects (24% of the total number of patients). Opportunistic infections developed in 10% (cryptococcus, cytomegalovirus). Hence, MMF appears to be effective for treatment of rejection in the pediatric heart transplant population and has an acceptable side-effect profile. In addition, it may have a role in primary rejection prophylaxis and may facilitate a reduced steroid dosage or a steroid-free immunosuppression regimen.     

儿童肾移植术后的免疫抑制治疗

目的 探讨长期存活的儿童肾移植受者不同免疫抑制方案的有效性与安全性.方法 回顾性分析34例存活5年以上的儿童受者免疫抑制剂使用情况,按所使用的免疫抑制剂不同分为5组:A组:环孢素A+强的松;B组:环孢素A+硫唑嘌呤+强的松;C组:环孢素A+霉酚酸酯+强的松;D组:他克莫司+硫唑嘌呤+强的松;E组:他克莫司+霉酚酸酯+强的松.结果 术后按Kaplan-Meier法得出1、3、5年人/肾存活率分别为100%/97%、91%/87.8%、84.4%/80.9%.术后1、3、5年时肾存活的33例、30例和28例中,服用环孢素A者为16/33(48.5%)、18/30(60%)、15/28(53.6%),服用他克莫司者为17/33(51.5%)、12/30(40%)、13/28(46.4%);服用硫唑嘌呤者为7/33(21.2%)、7/30(23.3%)、9/28(32.1%),服用霉酚酸酯者为26/33(78.8%)、21/30(70%)、17/28(60.7%).移植1年后环孢素A血浓度谷值100～150 ng/ml,他克莫司血浓度1.5～3 ng/ml.各组不同时期的环孢素A和他克莫司剂量和浓度均无明显差异.霉酚酸酯剂量维持在10 mg·kg-1·d-1,强的松5～10 mg/d.服药不依从者占30%.移植肾丢失5例,原因分别为排异反应1例,移植肾带功能死亡4例(肺部感染和药物性肝功能损害各2例).并发症包括高血压(35.7%)、高血脂(28.6%)、感染(17.9%)、牙龈增生(14.3%)、多毛(10.7%)、糖尿病(3.6%).结论 环孢素A/他克莫司、霉酚酸酯、强的松三联免疫抑制治疗是儿童肾移植受者主要的抗排异方案,须定期监测血药浓度,个体化调整剂量.     

Mycophenolate mofetil in pediatric renal transplantation

The use of mycophenolate mofetil (MMF) in adult renal transplantation has been associated with significantly decreased incidence of acute rejection. However, limited data are available for children after renal transplantation. A total of 67 patients undergoing renal transplantation at the University of Alabama at Birmingham, AL, USA and Children's Hospital of Boston, MA, USA were enrolled into the Cooperative Clinical Trials in Pediatric Transplantation randomized controlled trial of induction with OKT3 vs. i.v. cyclosporin A (CsA) at the time of transplantation. The first 31 patients entered were begun on azathioprine (AZA), 2 mg/kg on the first post-operative day. The subsequent 36 patients were begun on MMF, 1000 mg/m2/d. Other maintenance immunosuppression included oral CsA and Prednisone. Biopsy confirmation was obtained for all suspected rejection episodes. Glomerular filtration rate (GFR) was calculated using the Schwartz formula. Data were analyzed using Kaplan Meier survival curves and compared using log-rank tests. At the time of analysis, 52 patients (mean age 10.1 +/- 5 yr) had completed at least 12 months and 15 others had completed at least 6 months of follow-up post-transplantation. Of these, there were 39 male/28 female; 48 white/15 black/4 other; 49 living donor/18 cadaver donor. There were no significant differences in the incidence of rejection episodes, number of rejection episodes, the GFR at 6 and 12 months, allograft, or patient survival between patients receiving MMF vs. AZA. We could demonstrate no significant differences in these outcomes based on sex, race or induction therapy, leading to the conclusion that pediatric patients treated under a consistent protocol in two institutions have no improvement in short-term allograft outcome with the addition of MMF therapy.     

儿童肾移植临床免疫抑制用药探讨

目的　探讨儿童肾移植免疫抑制治疗特点。方法　回顾性分析 31例儿童肾移植患者(男 18例,女 13例)的临床资料。根据起始免疫抑制方案不同,分为 3组:A组(环孢素A+硫唑嘌呤+泼尼松)7例;B组(环孢素A+霉酚酸酯 +泼尼松)17例;C组 (他克莫司 +霉酚酸酯 +泼尼松)7例。统计 3组免疫抑制药物调整及维持剂量、移植肾功能变化和术后并发症。结果　1年人 /肾存活率为100% /96.8%,3年人 /肾生存率为94.4% /88.9%。三组各观察点肌酐实测值差异无显著性意义 (P<0.05)。他克莫司组药物副作用小且能保持良好的肾功能。泼尼松调整幅度大、维持量小,与其他组差异有显著性意义(P<0.01)。结论　肾移植是儿童终末期肾病的有效治疗措施。遵循儿童个体差异的免疫抑制治疗是移植后预防排斥的重点。他克莫司、霉酚酸酯、泼尼松三联抗排斥治疗是儿童肾移植理想的免疫抑制治疗方案。     

泼尼松联合霉酚酸酯与环孢霉素A治疗儿童激素耐药型肾病综合征的疗效比较

目的 比较泼尼松联合霉酚酸酯(MMF)与环孢霉素A(CsA)治疗儿童激素耐药型肾病综合征(SRNS)的疗效。方法 收集2004年1月至2013年12月住院并采用泼尼松联合MMF或CsA治疗的164例SRNS患儿的临床资料,回顾性分析泼尼松联合MMF(简称MMF组;n=112)与泼尼松联合CsA(简称CsA组;n=52)治疗儿童SRNS的临床疗效。结果 CsA组治疗后1个月的缓解率为67.3%(35/52),高于MMF组(42.9%,48/112)(PPPP结论 泼尼松联合MMF或CsA治疗儿童SRNS疗效均较好且安全,治疗3个月内CsA优于MMF。     

儿童肾移植21例报告

目的 探讨肾移植对儿童终末期肾病(ESRD)的疗效及其手术处理、免疫抑制剂应用方法。方法 总结肾移植患儿的临床资料、植肾手术方法、免疫抑制剂应用和随访情况。结果 患儿术后早期平均肾功能恢复时间为5．6d。1、3、5年人／肾存活率分别为95、2％／95．2％、86．7％／73．3％,72．7％／63．6％。最长存活12年。其中1例发生超急性排斥反应,5例发生急性排斥反应,3例出现移植物功能延迟恢复,3例死亡。术后采用了免疫抑制治疗。术后主要并发症有：高血压(48％)、糖尿病(19％)、感染(19％)、药物性肝损害(14％)。结论 肾移植是治疗儿童：ESRD最为理想的方法。儿童可以适应成人肾脏的移植。术后免疫抑制治疗建议联合应用泼尼松 霉酚酸酯 他克莫司。     

Comparison of polyclonal induction agents in pediatric renal transplantation

Collective pediatric data suggest that anti-T-cell induction therapy with polyclonal antibodies improves the outcome of both short- and long-term renal allograft survival. Polyclonal agents, including thymoglobulin (Thy), a rabbit anti-thymocyte globulin; Minnesota (horse) anti-lymphoblast globulin (ALG); and ATGAM, a horse anti-thymocyte globulin (ATG), all suppress B and T cells. While no specific T-cell subset marker exists to measure the adequacy of immunosuppression with polyclonal induction, flow cytometric analysis has been used to evaluate the suppression of CD3, CD4, and CD8 cells. Thy is currently undergoing pediatric trials at our center, and we have utilized ATG and ALG in previous pediatric induction protocols. ALG (20 mg/kg/day) and ATG (15 mg/kg/day) were administered over 10 days, whereas Thy (2 mg/kg/day) was given over 5 days. All inductions were accompanied by preoperative intravenous solumedrol (10 mg/kg) followed by oral prednisone (2 mg/kg/day) with taper. Preoperative (1.5 mg/kg/day) and post-operative (2 mg/kg/day) azathioprine was administered to patients receiving ALG or ATG. Mycophenolate mofetil (MMF) (1200 mg/m2/day) was given to the patients receiving Thy. Post-operative cyclosporin A (CsA) (14 mg/kg/day) was started (for all groups) once renal function permitted (creatinine < 50% of baseline with brisk urine output) (trough goal 150-250 ng/mL via HPLC). Values for CD3, CD4, and CD8 T cells were determined by flow cytometry in 2-18-yr-old renal transplant recipients, comparing the polyclonal induction agent utilized [Thy (n = 8), mean age 9.7 +/- 2.3 yr; ATG (n = 13), mean age 10.1 +/- 4.1 yr; and ALG (n = 9), mean age 9.3 +/- 3.7 yr] over days 2-10 post-induction. Data were expressed as the average percentage of cells remaining relative to the baseline T-cell subsets (day 1 = 100%), because of the large age variation present in basal T-cell subset values. The flow cytometric data suggest that 5 days of Thy appears to give an equal or greater peripheral blood T-cell suppression by day 10 than a 10-day course of either ATG or ALG.     

Vesico‐ureteral reflux in pediatric kidney transplants: Clinical relevance to graft and patient outcome

From June 1985 to December 1998, 173 pediatric renal transplants were carried out in 170 patients at our center. From this pool, 73 patients (34 males and 39 females) with a follow-up of 48 months were examined. In all patients, ureteroneocystostomy was performed according to the Lich-Grégoire procedure. All patients were treated with cyclosporin A (CsA)-based immunosuppression, including prednisone and sometimes azathioprine (AZA). Six months after transplantation, voiding cystography (VCU) was performed in all patients and reflux was classified from Grade I to Grade IV. The patients were divided into two groups: those with reflux (Group A: 25 patients) and those without (Group B: 48 patients). Grade I reflux was found in four patients, Grade II in seven patients, Grade III in seven patients, and Grade IV in seven patients. All the patients with severe reflux (Grade IV) underwent a corrective surgical procedure. Both groups were examined for immunologic and non-immunologic risk factors and no significant differences were found. Analysis of patient and graft survival rates revealed no statistical differences (NS) between Groups A and B. Mean serum creatinine (mg/dL) was 1.06 +/- 0.28 and 1.12 +/- 0.41 at 4 yr in Groups A and B, respectively (NS). Mean calculated creatinine clearance (cCrC; ml/min) was 76.74 +/- 15.92 and 77.96 +/- 15.66 in Groups A and B, respectively (NS). The analysis was further extended by considering the grade of reflux (I to IV). Again, no significant differences in the above parameters emerged between the reflux sub-groups; only in the Grade IV sub-group was a slight decrease in cCrC detected, although this difference was not statistically significant when compared with the other sub-groups. In conclusion, vesico-ureteral reflux (VUR) does not seem to negatively affect graft function. However, as all severe reflux patients (Grade IV) were surgically corrected, no conclusions can be drawn with regard to the influence of Grade IV reflux on long-term graft function.     

Low-dose cyclosporin A microemulsion in children with severe atopic dermatitis: Clinical and immunological effects

Cyclosporin A (CsA) is an effective and well-tolerated treatment for severe childhood atopic dermatitis (AD). By starting at a low dose, the therapeutic safety should be further increased. The aim of this study was to evaluate low-dose CsA in childhood AD with respect to clinical outcome and modulation of T-cell dysregulation. In an open prospective study, 10 children (age: 22–106 months) with severe AD (mean objective SCORAD score > 40 on two baseline measurements at a minimum interval of 2 weeks) were treated with CsA solution for 8 weeks. All patients received a starting dose of 2.5 mg/kg/day, which was increased stepwise in non-responders to a maximum of dose of 5 mg/kg/day. Disease activity was monitored using the SCORAD index. The frequency of cytokine-producing peripheral blood T lymphocytes was analyzed by intracellular cytokine staining, and T-cell numbers were measured by fluorescence-activated cell sorter (FACS) analysis. Twenty healthy age-matched children were included as controls for the immunological data. Nine of the 10 patients had a SCORAD reduction of at least 35%. In seven patients this was achieved with low-dose CsA at 2.5 mg/kg/day (n = 4) and 3.5 mg kg/day (n = 3). Seven of the nine responders experienced no relapse within the 4-week follow-up period. At baseline the percentage of interleukin-4 (IL-4), IL-13, and human leucocyte antigen (HLA)-DR-positive CD3⁺ cells was higher in the patient group than in the controls. After CsA treatment there was a significant reduction in interferon-γ (IFN-γ), IL-2, IL-4, IL-13, and HLA-DR-positive CD3⁺ cells. Hence, in severe pediatric AD, CsA microemulsion, when started at a low dose (2.5 mg/kg/day), improves clinical measures of disease, reduces T-lymphocyte cytokine production, and regulates T-cell activation.     

吗替麦考酚酯治疗儿童难治性肾病综合征

目的：观察吗替麦考酚酯（MMF）分散片联合泼尼松治疗难治性肾病综合征（RNS）的疗效性及安全性。方法：采用前瞻性多中心对照方法，10个中心共142例患者入选。治疗组87例，对照组55例。治疗组以MMF分散片（每日30～40 mg/kg）联合泼尼松（每日0.5～1 mg/kg）治疗，服MMF 6个月后，如无效应者停药，有效者减量维持治疗6个月，维持剂量每日10～20 mg/kg；对照组以环磷酰胺（CTX）冲击，每2周连用2 d，每日10 mg/kg 联合泼尼松治疗，疗程3个月，随后第4，7，10个月的第1天分别给予CTX 500 mg/m2，静脉点滴1次。泼尼松服用2～3个月开始减量。定期检测尿蛋白、肝肾功能及药物副作用。观察随访期共1年。结果：MMF治疗组87例中58例获完全效应，16例部分效应，9例表现为早期效应，4例治疗失败，治疗总有效率95.4％，尿蛋白转阴67例（77％）；CTX组55例中35例获完全效应，9例部分效应，1例早期效应，10例治疗失败，治疗总有效率81.8％，尿蛋白转阴36例（65.4％）。两组尿蛋白转阴率统计学差异无显著性，有效率MMF治疗组较CTX组高，而且有统计学意义(P<0.01)。尿蛋白转阴天数、低蛋白血症恢复天数、尿量恢复时间、高脂血症、水肿消退时间等方面MMF明显优于CTX。MMF治疗组用药期间主要副作用有一过性转氨酶升高3例次、感染32例次、消化道症状11例次、月经紊乱、肌肉颤动各1例次；对照组发生转氨酶升高9例次、感染30例次、消化道症状15例次、血红蛋白降低4例次、白细胞降低2例次、脱发7例次。结论：结果表明，推荐MMF每日20～35 mg/kg联合泼尼松0.5～1 mg/kg治疗难治性肾病综合征，尿蛋白转阴率不劣于CTX，而且起效时间较CTX短，药物副作用少。