A randomized trial of thymoglobulin vs. alemtuzumab (with lower dose maintenance immunosuppression) vs. daclizumab in renal transplantation at 24 months of follow-up

Abstract: Introduction:  A long-term prospective randomized trial evaluating alemtuzumab, a humanized anti-CD52 monoclonal antibody, in a predominantly non-Caucasian population has yet to be reported.
Methods:  Ninety deceased donor (DD) first renal transplant recipients were randomized into three different antibody induction groups: group A, thymoglobulin (Thymo); group B, alemtuzumab; group C, daclizumab (Dac). In groups A and C, the target trough levels of tacrolimus were 8–10 ng/mL, mycophenolate mofetil (MMF) 1 g administered twice daily, and maintenance methylprednisolone. In group B, target tacrolimus trough levels were 4–7 ng/mL, 500 mg MMF administered twice-daily, without methylprednisolone. African-Americans and Hispanics comprised more than 50% in each group.
Results:  A minimum follow-up of 27 months showed no overall group differences in patient or graft survival (p   = 0.89 and 0.66), but a trend towards worse death-censored graft survival in group B (p   = 0.05). Acute rejection rates were not significantly different: six (20%), seven (23%), and seven (23%) in groups A, B, and C, respectively. The incidence of chronic allograft nephropathy was higher in group B than in A and C (p   = 0.008). The mean calculated creatinine clearance at 24 months was 81.1 ± 5.5, 64.4 ± 4.5, and 80.7 ± 5.7 in groups A, B, and C, respectively (p   = 0.01 for B vs. average of A and C).
Conclusion:  In this randomized 27-month minimum follow-up trial of predominantly non-Caucasian DD renal transplant recipients with alemtuzumab induction, lower maintenance tacrolimus, MMF, and steroid avoidance appear less effective than either Thymo or Dac with higher maintenance immunosuppression.     

Drug immunosuppression therapy for adult heart transplantation. Part 2: clinical applications and results

This review describes the clinical application of classical immunosuppressive drugs as well as that of more recent drugs. All current immunosuppressive drugs target T-cell activation, and cytokine production and clonal expansion, or both. Immunosuppressive protocols can be broadly divided into induction therapy, maintenance immunosuppression, and treatment of acute rejection episodes.     

Long-term results of pediatric heart transplantation.

OBJECTIVE: We retrospectively reviewed 104 consecutive patients who underwent orthotopic heart transplantation between November 1989 and February 2004. PATIENTS AND METHODS: From November 1989 to February 2004, the total number of heart transplantations were 1,340 cases at our institute. One hundred four (7.8%) of these 1,340 patients were pediatrics. Average age was 6.2 years, ranging from 4 months to 16 years. The cause of heart disease before transplantation was: idiopathic dilated cardiomyopathy (DCM) in 74 patients (71%), and congenital heart disease (CHD) in 30 (29%). RESULTS: Hospital mortality rate was 14.4% (15 patients). Late complications were rejection in 23 (22.1%), infection in 11 (10.6%), gingival hyperplasia in 28 (26.9%), hypertention in 22 (21.1%), coronary artery disease (CAD) in 12 (12.5%), graft failure in 11(10.5%), and malignancy in 2 (1.9%). Late mortality occurred in 11 (10.6%) patients. Causes of death were sudden death in 2 (1.9%), CAD in 3 (2.8%), graft failure in 1 (1.0%), acute rejection in 4 (4.6%), and infection in 1 (1.0%). Actuarial survival rates in pediatrics at 1, 5, 10 years were 82%, 80%, and 78%, respectively. On the other hand, actuarial survival rates in adults at 1, 5, 10 years were 78%, 75%, 59%, respectively. CONCLUSION: Heart transplantation for pediatrics is an effective therapy with acceptable morbidity and mortality. The long-term survival results in pediatrics are comparable to those of adult heart transplantations. However, the actuarial survival rate in pediatrics after 10 years is significantly better than in adults' cases. Renal function in pediatric heart transplantation recipients treated with cyclosporine remains stable during long-term follow-up.     

Randomized prospective trial of pylorus-preserving vs. classic duodenopancreatectomy (whipple procedure): Initial clinical results

During the past decades, the classic Whipple resection (cWhipple) and the pylorus-preserving Whipple (ppWhipple) operation have been advanced for the resection of cancer of the pancreatic head. However, no definitive answer exists as to whether the more conservative ppWhipple operation indeed equalizes the short- and long-term results of the cWhipple procedure. Therefore we conducted a randomized prospective trial in a nonselected series of consecutive patients. Demographics, diagnostic, intraoperative, and histologic findings (tumor type and tumor stage of these patients) as well as postoperative mortality, morbidity, and follow-up after discharge were analyzed. For statistical evaluation Kruskal-Wallis and chisquare tests were used where appropriate. Survival was analyzed according to Kaplan-Meier curves, and differences were examined using the log-rank test. From June 1996 to April 1999, a total of 114 patients with suspected pancreatic or periampullary tumors were prospectively randomized to undergo either a cWhipple or a ppWhipple (intention to treat) operation. Based on the inclusion and exclusion criteria, 77 of these patients were included in the final analysis. Forty had a cWhipple and 37 had a ppWhipple resection. There were no differences with regard to age, sex distribution, ASA classification, histologic classification, UICC stage, length of stay in the intensive care unit, and length of hospital stay. The ppWhipple group had a significantly shorter operative time, reduced blood loss, and fewer blood transfusions. There was no difference in mortality, but the cWhipple group showed a significantly higher total morbidity. The incidence of delayed gastric emptying was identical in both groups. For long-term follow-up, a total of 61 patients with histologically proven pancreatic or periampullary carcinoma were analyzed. There were no differences in tumor recurrence or in long-term survival at a median follow-up of 1.1 years (range 0.1 to 2.9 years). Our initial results demonstrate that the cWhipple and ppWhipple operations are equally radical. However, ppWhipple may be the procedure of choice for the treatment of pancreatic and periampullary cancer.     

Corticosteroid-free immunosuppression in pediatric liver transplantation: safety and efficacy after a short-term follow-up

BACKGROUND: We report our results with the use of corticosteroid-free immunosuppression after pediatric liver transplantation, evaluating the efficiency and safety of this protocol in the early posttransplantation period. PATIENTS AND METHODS: From July 2003 to October 2005, 34 liver transplantations were performed in 32 pediatric patients (19 boys, 13 girls) at our institution. Recipient median age was 5 years (range, 0.2-14 years), and median body weight was 10 kg (range, 4-49 kg). Twenty-seven patients received a graft from in situ split liver transplantation, 5 a whole graft. Twenty-nine children (90%) received an immunosuppressive therapy based on methylprednisolone IV bolus at reperfusion (10 mg/kg) plus tacrolimus given at an initial dose of 0.08 mg/kg/d and then adjusted to obtain whole blood trough levels of 10 to 15 ng/mL during the first 3 months and 5 to 10 ng/mL after the 3rd month; basiliximab was given on postoperative days 0 and 4. Biopsy-proven acute rejection episodes were treated by methylprednisone IV boluses. RESULTS: After a median follow-up of 9 months (range, 1-27 months), the overall patient survival rate was 84% and graft survival rate was 79%. Three children (9%) died after their transplantations. Three (9%) experienced episodes of biopsy-proven acute rejection, always treated with IV steroid boluses. Mean RAI score was 4. One patient experienced PTLD that resolved with temporary reduction of immunosuppression. Cytomegalovirus infection rate was 14%. Sepsis occurred in 2 cases (6%). CONCLUSIONS: Initial results with a steroid-free immunosuppressive protocol are encouraging, with low rates of acute rejection and infectious complications as in steroid-based protocols.     

Growth and pubertal development following pediatric heart transplantation: a 15-year experience at Ste-Justine Hospital.

BACKGROUND: Thirty-one children and adolescents have undergone allograft heart transplantation at Ste-Justine Hospital from July 1984 to August 1996. Twenty-five patients were followed prospectively more than 3 years to document their growth and pubertal development. METHODS: Parameters surveyed were clinical (height, weight, pubertal staging, and bone age) and biochemical (luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, estradiol, dehydroepiandrosterone sulphate (DHEAS), IGF-1, and fasting insulin). RESULTS: At surgery, there were 18 boys and 7 girls aged 11 months to 17 years (median 13 years); 14 had congenital heart defects (CHDs) and 11 had a cardiomyopathy (CM). Immunosuppressive therapy included cyclosporine, azathioprine, and prednisone. Eighteen patients were still growing (15 boys, 3 girls): 8 had a retarded bone age and 6 with CHD had severe growth failure. Following surgery, most patients maintained their height within one sodium dodecyl sulfate (SDS) score of that initially observed. Patients reaching their target heights do so mainly in the lower range. Three patients not reaching target height had a CHD. Weight was greatest 1 year postoperatively (113 +/- 27% ideal body weight) with normalization at 2 years (100 +/- 18%). Of the 13 prepubertal patients, menarche occurred at age 12 in 1 girl, while 3 boys began puberty at age 12 years. In both sexes, serum levels of gonadotropins and IGF-1 increased during puberty, moderate hyperinsulinism was observed, and DHEAS levels decreased. CONCLUSIONS: Our results indicate that children and adolescents grow normally following cardiac transplantation and that they attain their target height despite a lack of catch-up growth. They gain weight significantly in the first postoperative year with normalization of their weight at 2 years. Furthermore, the clinical and biochemical indices of puberty are overall within the norms. However, the severity of growth delay at the time of transplantation inherent to the cardiac pathology has a major impact on adult height.     

Glucose metabolism in the first 3 years after renal transplantation in patients receiving tacrolimus versus cyclosporine-based immunosuppression.

The long-term effects of tacrolimus and cyclosporine on pancreatic islet cell function in renal transplant recipients are unclear. Therefore, a prospective, randomized, longitudinal study was performed that compared glucose metabolism in adult kidney allograft recipients on tacrolimus versus cyclosporine-based immunosuppression. Twenty-three white renal allograft recipients, randomized for either therapy with cyclosporine or tacrolimus, underwent intravenous glucose tolerance tests 6 times during the first 3 yr after transplantation. Concomitant therapy (low-dose steroids and azathioprine) was the same in both groups. Insulin sensitivity index (kG), insulin resistance (insulin/glucose ratio and homeostasis model assessment), and C-peptide and insulin secretion were calculated. Trough levels of tacrolimus and cyclosporine were measured. The occurrence of posttransplantation diabetes mellitus was prospectively monitored. Statistical analysis was performed by ANOVA for repeated measures, and parametric and nonparametric tests were also performed. Although only one patient treated with cyclosporine developed posttransplantation diabetes mellitus, kG levels were below normal in up to one-third of both patients who received tacrolimus and cyclosporine. The only significant difference between patients who received tacrolimus and those who received cyclosporine was in pancreatic secretion capacity at week 3 after transplantation, when the increment of C-peptide secretion was 57% lower and the increment of insulin secretion was 48% lower for patients receiving tacrolimus. In both groups, from week 3 to month 6, there was a tendency toward an increase in kG, despite a significant increase in fasting glucose and insulin resistance calculated by homeostasis model assessment. After month 6, there were no significant changes in any of the parameters of glucose metabolism, indicating that long-term use of either tacrolimus or cyclosporine does not cause chronic, cumulative pancreatic toxicity.     

Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6 months

BACKGROUND: This is the first report of a randomized, multicenter, clinical trial comparing the combination of sirolimus or mycophenolate mofetil (MMF) with tacrolimus-based immunosuppression in kidney transplantation. Results at 6 months of follow-up are presented. METHODS: Before transplantation, patients were randomized to receive tacrolimus plus corticosteroids with sirolimus (n=185) or MMF (n=176). The primary endpoint of the study was the incidence of biopsy-confirmed acute rejection. Patient and graft survival, renal function, and composite endpoints also were evaluated. Safety was assessed by monitoring laboratory parameters and adverse events. RESULTS: By 6 months of follow-up, the incidence of biopsy-confirmed acute rejection was similar in both treatment groups (13.0% tacrolimus+sirolimus vs. 11.4% tacrolimus+MMF; P=0.64 log-rank). Patient survival (97.3% tacrolimus+sirolimus vs. 97.7% tacrolimus+MMF) and graft survival (93.0% tacrolimus+sirolimus vs. 95.5% tacrolimus+MMF) were equivalent (P=0.53, overall survival log-rank). There was a significantly higher incidence of study drug discontinuation in patients receiving sirolimus (21.1% vs. 10.8%; P=0.008). Renal function was significantly better in the MMF-treatment group (serum creatinine 1.44+/-0.45 mg/dL vs. 1.77+/-1.42 mg/dL; P=0.018). Hyperlipidemia was significantly more prevalent in the sirolimus-treatment group. Diastolic blood pressure was significantly higher in sirolimus-treated patients. There were significantly more leukopenia and gastrointestinal adverse events in the MMF-treatment group. The incidence of posttransplant diabetes mellitus was 7.6% in the sirolimus group and 7.7% in the MMF group. CONCLUSION: Tacrolimus is equally effective in renal transplantation when combined with sirolimus or MMF. The tacrolimus-MMF combination may be superior in terms of improved renal function and improved cardiovascular risk factors including hyperlipidemia and hypertension.     

Sirolimus immunosuppression in pediatric heart transplant recipients: a single-center experience.

BACKGROUND: Sirolimus has been used in heart transplant recipients for treatment of rejection, alternative immunosuppression (IS) and promotion of regression and prevention of graft vasculopathy (coronary artery disease [CAD]). This study reports on our center's experience with 16 children who underwent heart transplantation. METHODS: Data were obtained by retrospective review. RESULTS: Median age at time of review was 12.3 years (n = 16, 5.1 to 18.0 years; 9 boys, 7 girls), and at time of transplant 7.5 years (6 months to 18.0 years). Median time of sirolimus introduction was 2.7 years (1 month to 8.2 years) post-transplant. Fifteen patients were on steroids, 10 on tacrolimus (FK) and mycophenolate mofetil (MMF), 5 on FK and 1 on MMF with no calcineurin inhibitors (CNIs). The average dose of sirolimus was 0.25 mg/kg or 7.0 mg/m(2) to maintain a target level of 5 to 15 mug/liter. Sirolimus was started for CAD in 6 patients (38%), rejection in 5 (31%), and in 5 with combinations of CNI intolerance, CAD, renal dysfunction and rejection. All 6 who received sirolimus for rejection (International Society for Heart and Lung Transplantation [ISHLT] Grade 3A) showed improvement on follow-up biopsies. Two of 3 who received sirolimus for renal dysfunction showed improvement (glomerular filtration rate [GFR] 43 to 67 and 32 to 106 ml/min per 1.73 m(2), respectively). Side effects included hyperlipidemia (38%), abdominal pain (31%), mouth ulcers (26%), anemia or neutropenia (12.5%), persistent pericardial effusion (6%) and interstitial lung disease (6%). Sirolimus therapy was discontinued in 3 patients due to side effects. CONCLUSIONS: In this study sirolimus was found to be a valuable IS agent for the management of rejection, significant renal dysfunction and CNI side effects. These results support the need for prospective studies of the role of sirolimus in primary rejection prophylaxis, primary CAD prophylaxis and CAD regression. There also exists a need to establish an adverse event profile for this drug.     

半月板移植的早期临床疗效分析

目的 报告一组同种异体半月板移植病例的早期临床疗效.方法 2006年6月至2008年7月连续完成19例手术,18例入选本组.年龄21～52岁,平均38岁;男9例,女9例;外侧半月板11例,内侧7例.其中合并前十字韧带损伤7例,合并多发韧带损伤2例,合并胫骨平台骨折1例.适应证为半月板缺损,关节软骨Ⅲ度以下或局限性Ⅳ度损伤,关节力线正常,韧带正常,韧带同期或分期重建者.手术技术:2例外侧半月板采用骨桥技术,16例采用骨栓技术.采用四种技术缝合移植物的周边部分.韧带受损者同期或分期进行重建手术和半月板移植手术.结果 所有患者均得到16～41个月的随访,平均26个月.18例手术探奁结果显示移植半月板完整或基本完整者16例(89%),失效2例(11%,行切除术).有1例患者出现术后关节粘连,行关节镜下松解手术.1例术后1年出现半月板囊肿.18例中的15例接受了主观评估,Lysholm评分由术前的平均67分(62～77分)增加至术后的85分(72～100分).IKDC评分由术前的B级6例、C级9例,改善至术后的A级2例,B级12例,C级1例.VAS疼痛评分由术前的平均6.2分(5～7分)减少到术后的2.1分(0～4分)(满分10分).结论 本组18例关节镜下同种半月板移植手术的早期临床主、客观结果满意,术后1～3年的存活率89%.