Single-center experience with primary orthotopic liver transplantation with FK 506 immunosuppression.

OBJECTIVE: The efficacy for primary orthotopic liver transplantation of a new immunosuppressive agent, FK 506 (tacrolimus, Prograf, Fujisawa USA, Deerfield, IL), was determined. SUMMARY BACKGROUND DATA: After 3 years of preclinical research, a clinical trial of FK 506 for orthotopic liver transplantation was begun in February 1989, first as a rescue therapy for patients with intractable rejection with conventional immunosuppression, then as a primary drug. METHODS: Between August 1989 and December 1993, 1391 recipients (1188 adult and 203 pediatric) of primary liver allografts were treated with FK 506 from the outset. Results from these patients were analyzed and compared with those of 1212 historical control patients (971 adult and 241 pediatric) given cyclosporine-based immunosuppression. RESULTS: Actuarial survival at 4 years was 86.2% with FK 506 versus 65.5% with cyclosporine in the pediatric patients (p < 0.0000) and 71.4% versus 65.5% in the adults (p < 0.0005). The need for retransplantation was reduced significantly for FK 506 patients. Four-year graft survival was 77.0% with FK 506 versus 48.4% with cyclosporine in the pediatric patients (p < 0.0000), and 61.9% with FK 506 versus 51.4% with cyclosporine in the adult recipients (p < 0.0000). Regression analysis revealed that reduction in mortality or graft loss from uncontrollable rejection, sepsis, technical failure, and recurrent original liver disease were responsible for the improved results with FK 506 therapy. CONCLUSIONS: FK 506 is a potent and superior immunosuppressive agent for orthotopic liver transplantation.     

Long-term follow-up after recurrence of primary biliary cirrhosis after liver transplantation in 100 patients

Orthotopic liver transplantation (OLT) is the only effective curative therapy for end-stage primary biliary cirrhosis (PBC). Survival after OLT is excellent, although recent data have shown a recurrence rate of PBC of up to 32% after transplantation. The aim of this study is to investigate the course after disease recurrence, particularly with regard to liver function and survival in a long-term follow-up. Between April 1989 and April 2003, 1,553 liver transplantations were performed in 1,415 patients at the Charité, Virchow Clinic. Protocol liver biopsies were taken after one, three, five, seven, 10 and 13 yr. One hundred (7%) patients suffered from histologically proven PBC. Primary immunosuppression consisted of cyclosporine (n = 54) or tacrolimus (Tac) (n = 46). Immediately after OLT, all patients received ursodeoxycholic acid. Corticosteroids were withdrawn three to six months after OLT. The median age of the 85 women and 15 men was 55 yr (range 25-66 yr). The median follow-up after liver transplantation was 118 months (range 16-187 months) and after recurrence 30 months (range 4-79 months). Actuarial patient survival after five, 10 and 15 yr was 87, 84 and 82% respectively. Ten patients (10%) died after a median survival time of 32 months. Two of these patients developed organ dysfunction owing to recurrence of PBC. Histological recurrence was found in 14 patients (14%) after a median time of 61 months (range 36-122 months). Patients with Tac immunosuppression developed PBC recurrence more often (p < 0.05) and also earlier (p < 0.05). Fifty-seven patients developed an acute rejection and two patients a chronic rejection episode. Liver function did not alter within the first five yr after histologically proven PBC recurrence. Multivariate analysis of the investigated patients showed that the recipient's age and Tac immunosuppression were significant risk factors for PBC recurrence. Long-term follow-up of up to 15 yr after liver transplantation, owing to PBC, in addition to maintenance of liver function, shows excellent organ and patient survival rates. Although protocol liver biopsies revealed histological recurrence in 14 (14%) patients, only two patients developed graft dysfunction. Tac-treated patients showed more frequently and also earlier histologically proven PBC recurrence; however, in our population we could not observe an impact on graft dysfunction and patient's survival.     

Rescue therapy with tacrolimus (FK 506) in renal transplant recipients -a Scandinavian multicenter analysis

Abstract All renal allograft recipients ( n = 32) in Sweden and Norway who were converted from cy-closporin(CyA)-based immunosuppression to FK 506 (tacrolimus) between October 1992 and June 1995 were analyzed retrospectively. The reasons for conversion were acute refractory rejection ( n = 21), chronic rejection ( n = 4), and suspected CyA toxicity ( n = 6); one patient was converted for psychological reasons. The mean time from transplantation to conversion was 29 (range 1–243) weeks and there was a mean follow-up of 46 (2–143) weeks. Overall graft survival was 59 %, with graft survival 52 % in patients converted because of acute rejection, 50 % in patients converted because of chronic rejection, and 83 % in patients converted because of CyA toxicity. There was no significant correlation between preconversion serum creatinine and outcome. Seventy-two percent of the patients had significant side effects during FK 506 treatment, the most frequent ones being neurological and gastrointestinal symptoms. These improved after dose reduction. Two patients became overimmunosup-pressed and developed lymphoma. One patient died of the primary kidney disease, hemolytic uraemic syndrome. We conclude that FK 506 therapy is able to salvage kidneys with acute refractory rejection and that it is an alternative in patients with CyA toxicity. However, the risk of overimmunosuppression must be considered.     

Rescue therapy with tacrolimus (FK 506) in renal transplant recipients —a Scandinavian multicenter analysis

All renal allograft recipients (n = 32) in Sweden and Norway who were converted from cyclosporin(CyA)-based immunosuppression to FK 506 (tacrolimus) between October 1992 and June 1995 were analyzed retrospectively. The reasons for conversion were acute refractory rejection (n = 21), chronic rejection (n = 4), and suspected CyA toxicity (n = 6); one patient was converted for psychological reasons. The mean time from transplantation to conversion was 29 (range 1–243) weeks and there was a mean follow-up of 46 (2–143) weeks. Overall graft survival was 59%, with graft survival 52% in patients converted because of acute rejection, 50% in patients converted because of chronic rejection, and 83% in patients converted because of CyA toxicity. There was no significant correlation between preconversion serum creatinine and outcome. Seventy-two percent of the patients had significant side effects during FK 506 treatment, the most frequent ones being neurological and gastrointestinal symptoms. These improved after dose reduction. Two patients became overimmunosuppressed and developed lymphoma. One patient died of the primary kidney disease, hemolytic uraemic syndrome. We conclude that FK 506 therapy is able to salvage kidneys with acute refractory rejection and that it is an alternative in patients with CyA toxicity. However, the risk of overimmunosuppression must be considered.     

The effect of immunosuppressive regimens on the recurrence of primary biliary cirrhosis after liver transplantation

Recurrence of primary biliary cirrhosis (PBC) has been described in liver transplant recipients. Type of immunosuppression has been reported to influence the frequency of recurrence. The aim of this study is to evaluate the occurrence and pattern of recurrent PBC in our liver transplant recipients and determine any association of immunosuppressive agents with its recurrence. Patients who underwent orthotopic liver transplantation (OLT) for PBC were identified from the University of Chicago Liver Transplant Database. Recurrent PBC was diagnosed based on specific pathological criteria. Of 46 patients who underwent OLT for PBC between 1984 and 2000, a total of 7 patients (15%) were diagnosed with recurrent PBC at a median of 78 months (range, 27 to 120 months) after OLT. Forty-three percent of patients were administered cyclosporine, whereas 57% were administered tacrolimus before disease recurrence. Rates of recurrence were not different between patients maintained on cyclosporine therapy (16%) compared with those maintained on tacrolimus therapy (18%; P = 1.0). There also was no difference in frequency of rejection episodes or duration of corticosteroid therapy between those who did and did not have recurrent PBC. In conclusion, recurrent PBC developed in a small number of patients 2 years or longer after OLT. In our population, there was no difference in recurrence rates between those administered cyclosporine or tacrolimus for immunosuppression. (Liver Transpl 2003;9:733-736.)     

Adult liver transplantation and steroid-azathioprine withdrawal in cyclosporine (Sandimmun)-based immunosuppression – 5 year results of a prospective study

New immunosuppressants are said to be superior to cyclosporine due to their higher incidence of steroid sparing and to the reduced incidence of side-effects. From May 1992 to February 1995, 79 adults underwent primary liver transplantation using cyclosporine A (Sandimmun)-based triple drug immunosuppression. Nine patients who died early after liver transplantation due to reasons unrelated to immunological problems were excluded from this analysis. The long-term outcome of the remaining 70 patients was prospectively studied in relation to steroid and azathioprine withdrawal. They were re-evaluated 6-monthly in relation to liver and kidney function; cholesterolemia, infection, de novo diabetes mellitus and arterial hypertension, malignancy, ophthalmological and osteomuscular diseases. In case of rejection occurring during or after steroid tapering, patients were switched, by protocol, to tacrolimus therapy. Median follow-up was 81 months (range 60–96). Forty-four patients (62.8 %) were biopsied 5 years after transplant; 20 patients (28.6 %) were biopsied at a median follow-up of 32 months (range 7.8–47). Six patients (8.6 %) who refused biopsies more than 1 year after liver transplantation had normal liver values throughout the whole follow-up period. Five-year actual patient and graft survivals were 75 % and 65.8 %, respectively, for the whole group (n = 79) and 85.7 % and 74.3 % for the studied group (n = 70). Steroids could be withdrawn in all but two patients (97.1 %) at a median time of 7 months (range 3–42). Steroids were restarted in six patients (8.6 %) for extrahepatic reasons. Freedom from steroids was thus observed in 62 patients (88.6 %). Seven patients (10 %) had rejection after steroid tapering; six were switched to tacrolimus. Two patients (2.9 %) needed retransplantation because of acute and chronic rejection whilst still being on full immunosuppression. In total, three patients (4.3 %) had histological signs of chronic rejection during follow-up. At 5 years post-transplant, 66.6 % and 13.3 % of the 60 patients at risk were on cyclosporine and tacrolimus monotherapy, respectively; 93.3 % were steroid-free. Mean creatinine and cholesterol levels were 1.56 ± 1.3 mg/dl and 193.5 ± 56.6 mg/dl; incidences of de novo arterial hypertension, insulin dependent diabetes mellitus were 26.6 % and 13.3 %. Two patients (2.8 %) developed post-transplant lymphoproliferative disease, two (2.8 %) had skin cancer. Cyclosporine-based immunosuppression allows safe steroid withdrawal in most patients and cyclosporine monotherapy can be achieved in two-thirds without compromising graft and patient survival. Results of new immunosuppressive strategies should be approached with caution, especially when considering steroid sparing and the incidence of side-effects. Received: 12 July 2000 Revised: 15 December 2000 Accepted: 11 September 2001     

Canine whole pancreatic transplantation with exocrine drainage into the bladder

A canine model of whole pancreas transplantation with pancreaticocystostomy was studied for reproducibility and long-term graft function with oral cyclosporine. The feasibility of the operative technique was established in three dogs and the graft histology at 5 days was studied. Seven pancreatectomized dogs were transplanted without immunosuppression; acute rejection was evident at a median of 10 days (range: 7-12 days). Another 14 non-pancreatectomized dogs were given oral cyclosporine (25 mg/kg per day) resulting in prolonged graft survival (P less than 0.01) with a median (actuarial) survival of 91 days (range: 8-159 days); five dogs had vascular thrombosis or graft rejection and eight dogs died with functioning grafts. Early technical loss in two dogs (8.3%) was due to arterial thrombosis. It is concluded that the model of whole pancreas transplantation was reproducible in dogs, that long-term graft function can be achieved on oral cyclosporine, and that duct patency can be maintained. Graft infarction, either primary or due to rejection, continues to complicate this model of pancreas transplantation.     

Switching From Tacrolimus to Cyclosporine A to Prevent Primary Biliary Cirrhosis Recurrence After Living-Donor Liver Transplantation

Recurrence of primary biliary cirrhosis (PBC) after liver transplantation has been shown to negatively affect graft and patient survival. Recently, protective effects of cyclosporine A against PBC recurrence after liver transplantation have been reported. Participants were 4 patients who underwent living-donor liver transplantation (LDLT) for end-stage liver disease due to PBC. Tacrolimus was used for initial immunosuppression, and this was switched to cyclosporine A at least 3 months after liver transplantation. Targeted trough level of cyclosporine A was 20 times that of tacrolimus. We assessed liver and renal function, as well as antimitochondrial M2 antibody for recipients prior to LDLT, as well as before and after switching immunosuppressive agents. Patients were 1 man and 3 women, and they were ages 45 to 47 years at LDLT. Timing of switching from tacrolimus to cyclosporine A was 13, 3, 7, and 4 months respectively after liver transplantation, and all 4 patients have been on cyclosporine A without adverse effects at 20 to 46 months after transplantation. In 2 of 4 patients who had high titers of antimitochondrial M2 antibody before transplantation, antibody titer did not elevate after LDLT. In the other 2 patients without elevation of antimitochondrial M2 antibody, the titer did not turn positive. Switching from tacrolimus to cyclosporine A was possible without medical problems, and all patients exhibit no recurrence of PBC. Cyclosporine A may be useful for prevention of PBC recurrence after LDLT.     

Long-term results after conversion from cyclosporine to tacrolimus in pediatric liver transplantation for acute and chronic rejection

Tacrolimus is beneficial in liver transplantation for reversing steroid-resistant acute rejection, and for controlling the process of chronic rejection in allograft recipients receiving Cyclosporine- (CyA) based regimens. Very little is known about the long-term efficacy of tacrolimus in pediatric transplantation after conversion from CyA. Our study examines the long-term outcome after conversion to tacrolimus for acute or chronic rejection in pediatric liver transplant (LTx) recipients. METHOD: Seventy-three children (age < 18 years) receiving their primary LTx under CyA between August 1989 and April 1996 were converted to tacrolimus for ongoing acute rejection (n=22, group I) or chronic rejection (n=51, group II). Mean age at the time of conversion was 10.2+/-5.5 years with a mean interval from LTx to conversion of 3.5+/-2.9 (range 0.5-10.1 years). There were 33 boys and 40 girls. All patients were followed until June 1999. Mean follow-up was 97.3+/-17.4 months (range 62.4-118.9 months). RESULTS: Overall 5-year actual patient survival was 78.1% and 8-year actuarial survival was 74.6%. Patients converted to tacrolimus therapy to resolve acute rejection (group I) experience significantly better patient and graft survival at 5 and 8 years than those converted to resolve chronic rejection (group II). Eight-year patient survival and graft survival was 95.5 and 90.9% for group I compared to 74.6 and 53.5% for group II, respectively (long rank P=0.035 and 0.01, respectively). Nearly 75% of children were weaned off steroids after conversion. There was a marked improvement in hypertension, gum hyperplasia, hirsutism, and cushingoid appearance. One child in group I (4.5%) and four children in group II (7.8%) developed posttransplant lymphoproliferative disorder after conversion. There was an improvement in growth in children who were less than the age of 12 years at the time of conversion and who were weaned off steroids; more significantly girls responded more favorably than boys. CONCLUSION: The benefit of transplantation is maintained long-term after conversion to tacrolimus for acute or chronic rejection. The response rate was significantly better in group I as compared with group 11. Marked improvement in growth, hypertension, and reversal of the brutalizing effects of CyA was noted after conversion to tacrolimus. The results suggest that early conversion of pediatric liver transplant patients is warranted for the treatment of acute and chronic rejection, and for improvements in quality of life.     

Four-year follow-up of a prospective randomized trial of mycophenolate mofetil with cyclosporine microemulsion or tacrolimus following liver transplantation

BACKGROUND: This is a 4-yr follow-up of a trial using mycophenolate mofetil (MMF) induction in orthotopic liver transplantation (OLT). The goal of this study was to evaluate a multidrug approach that would reduce both early and long-term morbidity related to immunosuppression while maintaining an acceptable freedom from rejection. METHODS: This was a prospective, randomized, intent to treat study designed to compare the primary endpoints of rejection and infection, and secondary endpoints of liver function, renal function, bone marrow function, cardiovascular risk factors, and the recurrence of hepatitis C. Ninety-nine consecutive patients with end stage liver disease who underwent OLT were randomized to receive either cyclosporine microemulsion (N) (50 patients) or tacrolimus (FK) (49 patients) starting on postoperative day 2, with MMF and an identical steroid taper begun preoperatively. RESULTS: Ninety of 99 patients (N 46, FK 44) completed the 4-yr follow-up. The overall 4-yr patient and graft survivals were 93 and 89%, respectively. There was no significant difference in 4-yr patient (N 96% vs. FK 90%, p = ns) or graft (N, 90% vs. FK, 88%, p = ns) survival between groups. The 4-yr rejection rate was not significantly different in either arm (N = 34%, FK = 24%; p = 0.28). There were no differences in infection rates in either arm. The patients with hepatitis C had no differences in the viral titers or Knodell biopsy scores between groups. However, in the hepatitis C subgroup (37 patients), the FK patients had a significantly lower rejection rate (p = 0.0097) and a significantly lower clinically recurrent hepatitis C rate (p = 0.05) than the N patients. No difference was seen in the percent of patients weaned off of steroids after 4 yr (N 51%, FK 49%). There were no differences in the incidences of diabetes mellitus and hypertension. When renal dysfunction was analyzed, a significant difference in the number of patients whose creatinine had increased twofold since transplant was seen (N 63%, FK 38%, p = 0.04). CONCLUSIONS: Use of MMF induction and maintenance following OLT in conjunction with either N or FK and an identical steroid taper, resulted in an acceptable long-term incidence of rejection and infection, without an increase in long-term graft or patient morbidity.     

A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: evidence for improved allograft survival at five years

BACKGROUND: The 1-year results of the Phase III U.S. Multicenter Trial comparing tacrolimus (FK506)- and cyclosporine (CsA)-based immunosuppressive therapy in kidney transplantation revealed a significant reduction in the incidence and severity of acute rejection episodes among patients maintained on tacrolimus. The present report at 5 years of follow-up focuses on the long-term impact of tacrolimus treatment on kidney allograft outcome. METHODS: The study protocol permitted crossover of patients to the alternate treatment arm under stringent conditions. The effect of crossover on graft survival was analyzed. Cardiovascular risk factors and serious adverse events were also monitored over 5 years. RESULTS: Intent-to-treat analysis revealed equivalent patient and graft survival between treatment arms at 5 years of follow-up (79.1% vs. 81.4%; P=0.472 and 64.3% vs. 61.6%; P=0.558 among tacrolimus and CsA-treated patients, respectively). However, the rate of crossover was significantly higher among patients randomized to receive CsA-based therapy (27.5% vs. 9.3%; P<0.001). The incidence of treatment failure (43.8% vs. 56.3%; P=0.008) was significantly lower among tacrolimus-treated patients. Graft survival was significantly improved in the tacrolimus treatment arm when crossover due to rejection was counted as graft failure (63.8% vs. 53.8%; P=0.014). Tacrolimus therapy was also associated with a significantly reduced requirement for medications to control hypertension and hyperlipidemia. There was a substantial rate of reversal of tacrolimus-associated insulin dependence. CONCLUSION: Tacrolimus-based therapy resulted in significantly reduced risk of graft failure, without an increase in the incidence of adverse events associated with long-term immunosuppression.     

Incidence of BK with Tacrolimus Versus Cyclosporine and Impact of Preemptive Immunosuppression Reduction

Our purposes were to determine the incidence of BK viruria, viremia or nephropathy with tacrolimus (FK506) versus cyclosporine (CyA) and whether intensive monitoring and discontinuation of mycophenolate (MMF) or azathioprine (AZA), upon detection of BK viremia, could prevent BK nephropathy. We randomized 200 adult renal transplant recipients to FK506 (n = 134) or CyA (n = 66). Urine and blood were collected weekly for 16 weeks and at months 5, 6, 9 and 12 and analyzed for BK by polymerase chain reaction (PCR). By 1 year, 70 patients (35%) developed viruria and 23 (11.5%) viremia; neither were affected independently by FK506, CyA, MMF or AZA. Viruria was highest with FK506-MMF (46%) and lowest with CyA-MMF (13%), p = 0.005. Viruria >/= 9.5 log(10) copies/mL was associated with a 3-fold increased risk of viremia and a 13-fold increased risk of sustained viremia. After reduction of immunosuppression, viremia resolved in 95%, without increased acute rejection, allograft dysfunction or graft loss. No BK nephropathy was observed. Choice of calcineurin inhibitor or adjuvant immunosuppression, independently, did not affect BK viruria or viremia. Viruria was highest with FK506-MMF and lowest with CyA-MMF. Monitoring and preemptive withdrawal of immunosuppression were associated with resolution of viremia and absence of BK nephropathy without acute rejection or graft loss.     

Tacrolimus rescue in liver transplant patients with refractory rejection or intolerance or malabsorption of cyclosporine. The US Multicenter FK506 Liver Study Group.

Tacrolimus is an effective immunosuppressant in the rescue of liver allograft patients in whom conventional immunosuppression failed. Efficacy and safety were examined in a multicenter trial of liver transplant recipients converted to tacrolimus because of rejection despite cyclosporine (CyA) therapy or intolerance to CyA. Six hundred seventy-seven patients were enrolled onto the study; 475 patients for rejection, 197 patients for intolerance, and 5 patients treated compassionately. The mean daily dose of tacrolimus was less in the intolerance (Int) patients throughout the study: 0.22 versus 0.17 mg/kg at 1 week and 0.14 versus 0.11 mg/kg at 24 months in rejection (Rej) and Int patients, respectively. Mean blood levels paralleled dosing in both groups, but were greater in the Rej patients (10.7 v 8.3 ng/mL at 18 months). Kaplan-Meier estimates of patient and graft survival were similar in the two groups. Patient survival rates were 80.1% and 81.5%, and graft survival rates were 72.7% and 73.9% at 24 months in the Rej and Int patients, respectively. Most adverse events occurred with a similar incidence in the two groups. Those with a 4% or greater incidence were fever, viral hepatitis, and pneumonia. The incidence of sepsis, gastrointestinal hemorrhage, kidney failure, and convulsion was greater in the Int group. The incidence of abnormal liver function test results, hyperglycemia, headache, and abnormal kidney function was greater in the Rej group. Mean liver function test results decreased with time postrescue in both groups. Mean serum creatinine level increased from baseline to 18 months postrescue in both groups (1.44 to 1.51 mg/dL for Int patients, 1.14 to 1.48 mg/dL for Rej patients). We conclude tacrolimus is safe and effective rescue in liver transplant recipients with rejection or CyA intolerance.     

Primary immunosuppression with tacrolimus in kidney transplantation: three-year follow-up in a single center

INTRODUCTION: The 1-year results of the phase III US Multicenter Trial comparing tacrolimus- and cyclosporine (Sandimmun)-based immunosuppressive therapy in kidney transplantation revealed a significant reduction in the incidence and severity of acute rejection episodes among patients maintained on tacrolimus. This retrospective, nonrandomized, single-center study represented 3-year data for patient and graft survival and safety in the tacrolimus-treated patients. METHODS: Among 97 consecutive kidney transplant recipients 41 who received tacrolimus and 56 cyclosporine-based immunosuppression were followed for 3 years for patient and graft survivals and for the incidence of acute rejection episodes as well as serious adverse events. RESULTS: The 3-year patient and graft survival rates for tacrolimus and cyclosporine were similar (91.0% vs 90.2%, 96.5% vs 95.0%). However, the incidence of acute rejection episodes was significantly lower in the tacrolimus (17.1%) compared with the cyclosporine group (35.7%, P = .043). There was a higher incidence of headache, posttransplant diabetes, and alopecia reported in the tacrolimus group, whereas hypertension, hypercholesterolemia, and hirsutism were more frequent in the cyclosporine group. The incidences of hand tremor, hyperkalemia, and viral infections were comparable in both groups. Two patients in the tacrolimus group were converted to cyclosporine due to nephrotoxicity and posttransplant diabetes, respectively, whereas 12 patients in the cyclosporine group were converted to tacrolimus as rescue therapy for acute rejection (41.7%), gingival hyperplasia (33.3%), nephrotoxicity (8.3%), neurotoxicity (8.3%), and hirsutism (8.3%), respectively. CONCLUSION: The 3-year results of tacrolimus treatment show excellent efficacy and safety in kidney transplantation. Due to different side-effect profiles, it is necessary to develop individualized immunosuppressive strategies in kidney transplant recipients.     

Evaluation of renal grafts in patients with lupus nephritis as cause of end-stage renal disease

INTRODUCTION: Kidney transplantation is the best option in end-stage renal disease (ESRD). For many years patients affected with lupus nephritis have had poor graft results. However, this has been changing over recent years with the development of new immunosuppressive drugs and a better comprehension of the natural evolution of the entity. METHODS: We studied 20 patients with lupus nephritis who received 22 kidney grafts: 15 women and five men (n = 11) who were treated with cyclosporine or with tacrolimus (n = 11). Secondary immunosuppression included mycophenolate match (MMF) (n = 13) or azathioprine (n = 9). We analyzed human leukocyte antigen, cold ischemia time, acute tubular necrosis, creatinine, cholesterol, triglycerides, glucose, blood pressure, acute rejection episodes, immunosuppression, infections, disease recurrences, as well as graft and patient survival. RESULTS: After a mean cold ischemia time of 22 +/- 4 hours, nine patients displayed delayed graft function of an average duration 9 +/- 4 days. At 36 +/- 35 months nine grafts were lost: two due to acute rejection; five to chronic allograft nephropathy; and two to venous thrombosis. One patient died of hemorrhagic shock. There were five cytomegalovirus infections. Graft survival was dependent on the type of secondary immunosuppression, incidence of acute rejection episodes and occurrence of delayed graft function. CONCLUSIONS: We found no clinical recurrence of lupus nephritis after transplantation and a low incidence of complications, although there was a trend toward thrombosis. The presence of delayed graft function, episodes of acute rejection, and receiving azathioprine instead of MMF as secondary immunosuppression were associated with poorer graft survival.     

肝移植治疗原发性胆汁性肝硬化的远期效果观察

目的 观察肝移植治疗原发性胆汁性肝硬化(PBC)的远期效果.方法 对15例接受了肝移植的终末期PBC患者进行长期随访,中位随访时间为70个月(38～86个月),记录并总结随访期间患者的相关资料,分析肝移植术后患者的预后、新发疾病以及术后远期存活率.结果 15例PBC患者共接受原位肝移植16例次,其中1例因原发性移植肝无功能进行了2次肝移植.术后患者均采用环孢素A(或他克莫司)+霉酚酸酯+激素的三联免疫抑制方案,部分患者使用了熊去氧胆酸.术后2周时,患者肝功能指标基本恢复正常,乏力、皮肤瘙痒及黄疸等症状缓解,患者的生存质量明显改善.术后有4例患者出现新发疾病(26.7%),1例为乙型肝炎病毒感染,2例为自身免疫性肝炎,1例为结肠癌,经治疗后2例好转,2例治疗无效死亡.肝移植术后,患者无PBC复发,1、2和5年的存活率分别为100%、100%和86.7%.结论 肝移植可提高终末期PBC患者的生存质量和存活率,但一些少见的新发疾病对患者的远期存活率影响较大.     

Does race influence outcomes after primary liver transplantation? A 23-year experience with 2,700 patients

BACKGROUND: Data about the influence of race on survival after liver transplantation (LT) are limited and conflicting. This study was undertaken to evaluate longterm outcomes for LT in African-American (AA) recipients compared with recipients of other races and to determine factors responsible for any observed differences. STUDY DESIGN: This was a retrospective case series. Among 2,728 adult patients who underwent primary LT from 1984 to 2007, 1,566 (57%) were Caucasian, 761 (28%) were Hispanic, 290 (11%) were Asian, and 111 (4%) were AA. The primary immunosuppressive agent was cyclosporine from 1984 to 1993 (Era I, n=817) and tacrolimus from 1994 to 2007 (Era II, n=1922). RESULTS: In Era I, the 1-, 5- and 10-year patient and graft survival figures for AA and Asian recipients were considerably lower compared with Caucasian and Hispanic recipients. In Era II, patient and graft survival figures were comparable for all groups. Statistically significant independent predictors of diminished patient survival included LT in Era I; recipient or donor age greater than 55 years; and liver failure secondary to cryptogenic cirrhosis, malignancy, or hepatitis C. Predictors of graft failure included LT in Era I; recipient or donor age greater than 55 years; prolonged cold ischemia time; liver failure secondary to hepatitis C, cryptogenic cirrhosis, or malignancy; and acute rejection. Patient and graft survival were independent of race in both eras. CONCLUSIONS: This is the first study to demonstrate equivalent longterm results after LT for AA and other races. Modern immunosuppression with tacrolimus substantially lowered rejection rates and improved graft and patient survival after LT.     

Tacrolimus as secondary intervention vs. cyclosporine continuation in patients at risk for chronic renal allograft failure

BACKGROUND: Chronic renal allograft failure (CRAF) is the leading cause of graft loss post-renal transplantation. This study evaluated the efficacy and safety of tacrolimus as secondary intervention in cyclosporine-treated kidney transplantation patients with impaired allograft function as indicated by elevated serum creatinine (SCr) levels. METHODS: Patients receiving cyclosporine-based immunosuppression who had an elevated SCr at least 3 months post-renal transplantation were enrolled. Treatment allocation was 2:1 to switch to tacrolimus or continue cyclosporine. This analysis was performed after 2 yr; patients will be followed for an additional 3 yr. RESULTS: There were 186 enrolled and evaluable patients. On baseline biopsy, 90% of patients had chronic allograft nephropathy. Baseline median SCr was 2.5 mg/dL in both treatment groups. For patients with graft function at month 24, SCr had decreased to 2.3 mg/dL in the tacrolimus-treated patients and increased to 2.6 mg/dL in the cyclosporine-treated patients (p = 0.01). Acute rejection occurred in 4.8% of tacrolimus-treated patients and 5.0% of cyclosporine-treated patients during follow-up. Two-year allograft survival was comparable between groups (tacrolimus 69%, cyclosporine 67%; p = 0.70). Tacrolimus-treated patients had significantly lower cholesterol and low-density lipoprotein levels and also had fewer new-onset infections. Cardiac conditions developed in significantly fewer tacrolimus-treated patients (5.6%) than cyclosporine-treated patients (24.3%; p = 0.004). Glucose levels and the incidences of new-onset diabetes and new-onset hyperglycemia did not differ between treatment groups. CONCLUSIONS: Conversion from cyclosporine to tacrolimus results in improved renal function and lipid profiles, and significantly fewer cardiovascular events with no differences in the incidence of acute rejection or new-onset hyperglycemia.     

A prospective randomized trial comparing the efficacy of tacrolimus versus cyclosporine in black recipients of primary cadaveric renal transplants.

BACKGROUND: We performed a prospective randomized trial to compare the efficacy and safety of tacrolimus (FK506) versus cyclosporine (CSA) in black primary cadaveric renal transplant (CRT) recipients. METHODS: Between December 1994 and February 1997, 35 black primary CRT recipients were enrolled in this trial. All patients received 7 days of induction therapy with OKT3. Fourteen patients received FK506 and prednisone only. Twenty-one patients received CSA, azathioprine, and prednisone. The two groups were comparable in terms of age, gender, plasma renin activity, human leukocyte antigen mismatches, and cause of renal failure. RESULTS: Patient and graft survival were 12 of 14 (86%) for the FK506 group and 20 of 21 (95%) for the CSA group (P = 0.71). Three patients died owing to cardiac events with functioning grafts. Acute rejection was 2 of 14 (14%) for the FK506 and 8 of 21 (38%) for the CSA group (P = 0.25). Two other patients on CSA were converted to FK506 as rescue for OKT3-resistant rejection. Mean serum cholesterol at 1 year was 198 +/- 45 mg/dL for the FK506 group and 244 +/- 49 mg/dL for the CSA group (P = 0.03). Mean serum creatinine at 1 year was 1.39 +/- 0.38 mg/dL for the FK506 group and 1.94 +/- 0.64 mg/dL for the CSA group (P = 0.02). CONCLUSION: Patient and graft survival were similar in both groups at 1 year posttransplant. Although statistically not significant, the incidence of acute rejection was lower in the FK506 group. Furthermore, FK506-treated patients had significantly lower serum creatinine and cholesterol levels at 1 year posttransplant.     

Review of the clinical experience with a modified release form of tacrolimus [FK506E (MR4)] in transplantation

Abstract:  Non-compliance in solid transplantation recipients is a major factor in acute graft rejection, which influences patient survival. Nowadays, tacrolimus is one of the most widely used immunosuppressant agents together with cyclosporine following kidney and liver transplantation with a standardized twice-daily dosing regimen. To improve the patients' compliance to the prescribed immunosuppressive therapy, FK506E (MR4), a modified release (MR) oral dosage form of tacrolimus has been developed for a once-daily dosing regimen. This report reviews the most recent results of clinical trials with MR tacrolimus after kidney and liver transplantation.