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.     

Vascular events after liver transplantation: a long-term follow-up study

Long‐term follow‐up studies on the impact of vascular events (VE) and risk factors of liver transplant recipients are scarce. In this study, 311 recipients of a first isolated liver transplant who survived at least 1 year were followed up from 1979 to 2002. The median follow‐up duration was 6.2 (range1–22.7) years. Overall median survival was 18.7 [95% confidence interval (CI): 15.5–20.1] years and this was significantly lower compared with age‐ and sex‐matched controls. Eleven (21%) of the patients had a vascular cause of death and VE were the third cause of death. VE occurred later compared with other causes of death (mean 10.3 years vs. 4.5 years, P < 0.0001, 95% CI: 2.7–8.9). Systolic hypertension, systolic blood pressure, smoking, renal failure, age, hypertriglyceridemia, serum total cholesterol levels and hypercholesterolemia at the 1‐year follow‐up visit were associated with the occurrence of VE, but renal failure and age at 1 year after transplantation were the only independent risk factors for vascular death (hazard ratio 0.06, 95% CI: 0.01–0.41 and hazard ratio 1.17, 95% CI: 1.02–1.34, respectively). Finally, it was shown that the adequate treatment of hypertension was associated with a significant reduced risk of vascular death. Therefore, vascular risk factors should be treated aggressively to prevent VE in the long term.     

肝移植术后持续高胆红素血症的诊治

目的 分析肝移植患者随访期间出现持续高胆红素血症的常见原因,总结诊治经验.方法 对2000年5月至2009年12月在北京大学人民医院肝胆外科接受肝移植手术并在门诊随访的527例患者的临床资料进行回顾性分析.结果 随访期间共有65例患者出现持续高胆红素血症,其病因分别为胆道并发症34例(52.3％),药物性肝损伤14例(21.5％),病毒性肝炎复发6例(9.2％),急性排斥反应4例(6.2％),十二指肠乳头炎性狭窄3例(4.6％),肝癌复发2例(3.1％),新发肿瘤和原因不明者各1例.通过保肝利胆药物治疗、调整或替换抗排斥药物、胆道镜取石和取栓、留置胆道引流和支撑管、以及再次进行外科手术后,65例患者中治愈或病情稳定者50例,死亡15例.结论 肝移植患者随访期间出现黄疸的病因多样而复杂,容易导致诊治的延误.弥漫性肝内胆道狭窄的治疗效果较差,药物性肝损伤并不少见且诊断困难,需引起重视.     

Steroid-free immunosuppression in renal transplantation: a long-term follow-up of 100 consecutive patients

BACKGROUND: Our goal in clinical renal transplantation is to establish a steroid-free immunosuppressive protocol that not only promotes long-term patient and graft survival, but also improves the overall well-being of the patients. METHODS: In a prospective, nonrandomized, clinical study 100 consecutive patients transplanted with first and second grafts were discharged from our center with functioning grafts 1996-1999 and followed for up to 4 1/2 years. Patients received steroid-free immunosuppression with an initial 10-day antithymocyte (ATG) induction and maintenance therapy with cyclosporine (CsA) and mycophenolate mofetil (MMF). No steroids were given. RESULTS: After an observation time of up to 4 1/2 years, 1-, 2-, 3-, and 4-year graft survivals of 97, 96, 90, and 82% were observed, with no correlation to HLA-matching, kidney disease, donor age or type, or number of transplants. Ninety-nine patients (1 died or peritonitis after returning to dialysis) were alive and well. Ninety grafts were functioning well, 9 patients returned to dialysis due to recurrence of hemolytic uremic syndrome, and glomerulonephritis in 2 and chronic rejection in 7 grafts after 7-36 months (3 due to non-compliance after 7-30 months). All 7 children below the age of 15 are alive, with well-functioning grafts, except 1 with recurrence of glomerulonephritis who returned to dialysis after 2 1/2 years. There were 13 acute rejections (13%), 10 early (first 3 months) (10%), and 3 late (6-42 months) (3%). All acute rejection episodes were successfully reversed. No lymphomas were observed. CONCLUSIONS: Our first-line, steroid-free immunosuppressive protocol allows initial graft function, provides a safe level of long-term graft survival and function with a very low rejection rate, gives an acceptable rate of side effects, and possesses the potential for lowering the incidence of chronic rejection over the long-term. Compared with protocols that discontinue steroids after the initial posttransplant period, a steroid-free protocol avoids the increased risk of infection, body disfigurement, and other steroid-induced side-effects in the early posttransplant period. It also avoids the long-term risks of steroid use and the increased risk of rejection when the steriods are withdrawn.     

Long-term outcome of immunosuppression withdrawal after liver transplantation

Eighteen liver transplant recipients were followed up for 10 years after a trial of immunosuppression withdrawal. Three groups were identified according to the early outcome of complete (group A, n = 5), partial (group B, n = 9), and unsuccessful (group C, n = 4) withdrawal of immunosuppression. The indications for liver transplantation (LT) (August 1983-December 1988) were as follows: primary biliary cirrhosis (n = 3), primary sclerosing cholangitis (n = 3), Budd-Chiari syndrome (n = 3), acute liver failure (n = 3), hepatitis C virus (HCV) cirrhosis (n = 1), HCV and autoimmune hepatitis (n = 1), HCV and alcohol-related cirrhosis (n = 1), HCV and hepatocellular carcinoma (HCC) (n = 1), cystic fibrosis (n = 1), and liver metastases from testicular teratoma (n = 1). Immunosuppression was based on cyclosporine. All patients experienced 1 or more complications of prolonged immunosuppression (median, 7 years; range, 5-11). Thirteen patients (72%) are alive at a median interval of 17 years (range, 16-21) after LT. Of the 5 patients in group A, 2 currently have normal graft function with no rejection episodes, and 3 have restarted immunosuppression following late low-grade acute rejection (n = 1), retransplantation for chronic rejection (n = 1), and kidney transplantation (n = 1). Of the 9 patients in group B, 5 died. The deaths were due to ruptured arterial pseudoaneurysm following retransplantation, HCC recurrence, cardiac failure, renal failure, and posttransplant lymphoma at 5, 7, 7, 14, and 17 years after LT, respectively. All 4 patients in group C are alive on a full immunosuppressive regimen. Long-term follow-up of 18 LT recipients withdrawn from immunosuppression has shown that at a median of 17 years 10% of patients remain off all immunosuppression.     

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     

Long-term immunosuppression after liver transplantation: are steroids necessary?

Steroid therapy was withdrawn in 85% of 152 orthotopic liver transplant recipients with grafts surviving for more than 3 months, and 87% of these remained steroid-free. Steroid therapy was restarted in 8% for reasons other than rejection. The most common was conversion of immunosuppression because of cyclosporine nephrotoxicity. The incidence of rejection after steroid withdrawal was low: 3.8% for chronic rejection (CR) and 4.5% for acute rejection. Only 3 grafts (1.9%) were lost because of CR. No risk factors have been identified for the development of CR after steroid withdrawal, but a protective role for azathioprine has been suggested.     

Steroid withdrawal after pediatric liver transplantation: a long-term follow-up study in 109 recipients

BACKGROUND: Steroids remain an important component of maintenance immunosuppression in liver transplantation, but when administered for a long period they may be associated with multiple severe side effects, particularly growth suppression in children. This study was conducted to clarify the balance of potential benefits and risks of steroid withdrawal (SW) in pediatric liver transplantation. METHODS: Between April 1984 and July 2000, 109 pediatric recipients with SW and at least 12 months of follow-up after SW were retrospectively reviewed and divided into three groups according to the type of anticalcineurin at SW: group I (cyclosporine, n=25), group II (cyclosporine microemulsion, n=25), and group III (tacrolimus, n=59). Steroids were withdrawn after a three-step reduction of steroid dosage (taper down to the substitution dose of 0.25 mg/kg/day, switch to alternate-day therapy, progressive SW). Patients were regularly followed up for clinical and biochemical monitoring. RESULTS: Median follow-up was 8.1 (range, 1.6-16.8) years. After SW, neither chronic rejection nor graft nor patient loss occurred. A trend toward lower anticalcineurin trough levels was observed in all groups. Glomerular filtration rate and fasting cholesterol were significantly better in group III (P<0.05). Median height z-score in all patients was -1.1 SD on alternate-day steroids versus -0.2 SD at the time of SW. Height z-score was slightly better in group III (NS). Early SW within 2 years after transplantation allowed a slightly better gain in growth. CONCLUSIONS: SW in pediatric liver transplantation is safe and may be beneficial to height outcome. Tacrolimus seems to offer several advantages in the long-term outcome.     

肝移植术后应用不含皮质激素的免疫抑制方案对糖代谢的影响

目的 探讨肝移植术后应用不含皮质激素的免疫抑制方案对受者糖代谢的影响.方法 回顾分析295例首次接受成人肝移植,且术后规律随访超过6个月受者的临床资料,将受者分研究组(153例)和对照组(142例),研究组受者采用他克莫司(Tac)+吗替麦考酚酯( MMF)的免疫抑制方案,对照组受者采用Tac+ MMF+皮质激素方案.分别于术前1周及术后第1、2、4、8、12、16、20和24周为观察时间点,检测两组受者的血糖水平变化,观察急性排斥反应及高血糖相关不良事件的发生情况.结果 两组间受者性别、年龄、体重等基本资料,尤其是术前空腹血糖水平和高血糖患者比例的差异均无统计学意义(P＞0.05).两组受者术后早期血糖水平均显著升高,术后1周时达到峰值,并随术后时间的延长呈逐渐下降的趋势.各时间点研究组的受者李腹血糖水平及高血糖患者比例均低于对照组,术后4周以后,与对照组比较,差异均有统计学意义(P＜0.05).研究组和对照组高血糖者的比例分别为52.9％和76.8％(P＜0.05),对照组术后发生高血糖的风险是研究组的2.94倍.随访期间,研究组和对照组的急性排斥反应发生率分别为8.50％ (13/153)和7.75％(11/142),两组比较,差异无统计学意义(P＞0.05).研究组受者出现组织愈合延迟、感染及高脂血症发生率亦低于对照组.结论 肝移植术后应用不含皮质激素的免疫抑制方案是安全的,并可降低术后发生糖尿病的风险,减少高血糖相关不良事件的发生率.     

Neurological recovery after liver transplantation: a prospective study of 22 patients

Abstract A group of 22 liver transplantation patients were examined pre- and postoperatively using clinical neurological, neurophysiological and neuroradiological methods. After the operation improvement was observed in neurological symptoms, and in neuropsychological and neuro-physiological test results. Our study shows that liver recipients have a high prevalence of nervous system dysfunction and that successful transplantation is followed by significant improvement.     

Sirolimus-based immunosuppression in liver transplantation for hepatocellular carcinoma: a meta-analysis

Sirolimus (SRL) is a novel immunosuppressant with antitumor properties. We performed a meta-analysis to determine whether SRL can improve patient survival and decrease the risks of tumor recurrence in patients with a pretransplant diagnosis of hepatocellular carcinoma (HCC). We searched databases for controlled clinical trials assessing the survival and oncological benefits of SRL for liver transplant recipients with pretransplant HCC. Five studies with a total of 2950 participants were included in this study. In comparison with SRL-free regimens, SRL-based regimens improved overall survival at 1 [odds ratio (OR) = 4.53, 95% confidence interval (95% CI) = 2.31-8.89], 3 (OR = 1.97, 95% CI = 1.29-3.00), and 5 years (OR = 2.47, 95% CI = 1.72-3.55). The pooled results showed that in comparison with SRL-free regimens, SRL-based regimens decreased tumor recurrence (OR = 0.42, 95% CI = 0.21-0.83). No significant differences in the frequencies of episodes of major posttransplant complications were observed between the groups. In conclusion, SRL is generally safe and prolongs patient survival in liver transplant recipients with pretransplant HCC.     

Long-term follow-up after liver transplantation for alcoholic liver disease under tacrolimus

BACKGROUND: Liver transplantation (LTx) for alcohol-related liver disease (ALD) is an accepted modality of treatment and is one of the most common indications for LTx in the United States. The present report examines the long-term patient survival, graft survival, rates of recidivism, and development of de novo cancers in this group, and compares these results with a contemporaneous group of patients who were transplanted for non-ALD indications. METHODS: Between August 1989 and December 1992, 185 adults received LTx for ALD (group I). During the same time interval, 649 adults received LTx for non-ALD (group II). The mean follow-up time was 94+/-10.7 months for group I vs. 92+/-11 months for group II. Kaplan-Meier survival estimates and the incidence of cancers using Surveillance Epidemiologic End Result data were compared in both groups. RESULTS: At 5 years after orthotopic LTx, the overall patient survival and graft survival for group I were 72.0% and 66.5% vs. 66.5% and 60.3% for group II, respectively. After 5 years, the patient survival and graft survival for the alcoholic group were significantly lower (P=0.001) compared to the non-alcoholic group. The rate of de novo oropharyngeal cancer and lung cancer was 25.5 times and 3.7 times higher, respectively, in ALD group compared with the general population matched for age, sex, and length of follow-up (P=0.001), whereas this was not higher in the non-ALD group. Prior pretransplant length of sobriety and alcohol rehabilitation was not associated with the rate of post-LTx rate of recidivism, which was 20%. Out of 79 deaths in group I, only 1 was attributed to recidivism and 3 to noncompliance with recidivism. The other deaths occurred from de novo cancer (n=13), posttransplant lymphoproliferative disorder (n=5), age-related complications (n=23), and other infection or miscellaneous causes (n=34). CONCLUSIONS: Patient and graft survival past 5 years after orthotopic LTx is significantly lower for ALD for a variety of reasons (P=0.001). The rate of upper airway malignances was significantly higher in ALD patients than for non-ALD post-LTx patients and the general public. Graft loss/death related to recidivism or chronic rejection was extremely low. More attention is needed for early diagnosis of de novo cancer and prevention of cardiorespiratory and cerebrovascular complications.