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 Corticosteroids were withdrawn three to six months after OLT.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.     

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.     

Liver transplantation for primary biliary cirrhosis: influence of primary immunosuppression on survival

INTRODUCTION: Liver transplantation is the only established curative therapy for end-stage primary biliary cirrhosis (PBC). However, the influence of primary immunosuppression on long-term patient and graft survival is still controversial. PATIENTS AND METHODS: Among 1372 patients who underwent liver transplantation from April 1989 to January 2001, 95 (6.9%) suffered from PBC. The primary immunosuppression consisted of cyclosporine (CyA; n = 56) and tacrolimus (FK; n = 39). RESULTS: The median survival of all PBC patients at 5 years was 92% and at 10 years, 90%. There was no difference between the two primary immunosuppression agents. Seven patients died, including five in the cyclosporine group (median = 25 months) and two in the tacrolimus cohort (median = 37 months). One CyA patient group died due to PBC recurrence. Seven patients underwent retransplantation without any difference in primary immunosuppression (CyA 7%; FK 10%). Fifty patients developed an acute rejection episode (CyA 57%; FK 46%); 2 patients, chronic rejection (CyA 2%; FK 4%). Fifty-five patients developed AMA titers after liver transplantation (CyA 66%; FK 46%). Patients presented cyclosporine-based regimens showed significantly (P = .001) more side effects. CONCLUSION: Long-term follow-up after liver transplantation for PBC shows excellent organ and patient survival. The choice of the primary immunsuppressant had no significant influence on patient survival, PBC-related graft loss, or development of acute or chronic rejection episodes.     

Successful use of cyclosporine in a lung transplant recipient with tacrolimus-associated hemolytic uremic syndrome.

Hemolytic-uremic syndrome (HUS) is a rare, but well-described complication in organ transplant recipients maintained on cyclosporine immunosuppression. Tacrolimus is a newer agent with similar immunosuppressant efficacy. In cases of cyclosporine-related HUS in renal transplant recipients, tacrolimus has been used successfully without recurrence of HUS. Tacrolimus has been reported to cause HUS in renal and more recently in cardiac transplant patients. We report a case of HUS in a lung transplant recipient receiving tacrolimus who was subsequently converted to cyclosporine without recurrence of HUS.     

Clinical significance of recurrent primary biliary cirrhosis after liver transplantation

Abstract  Primary biliary cirrhosis (PBC) represents a classic indication for orthotopic liver transplantation (OLT); as an autoimmune disease, however, the existence and incidence of recurrent PBC is a matter of significant controversy. Between September 1988 and September 1994 a total of 544 OLTs was performed at our institution. Forty-nine patients (40 female) with a median age of 50.5 years and previous surgery in 36.4 %, received a liver graft for PBC. The mean serum bi-lirubin level was 8.9 mg/dl (range 0.7–29.7). Immunosuppression was commenced as a cyclosporine A-based quadruple therapy or with FK 506 and prednisolone. Protocol liver biopsies were taken at defined intervals posttransplant. Two patients died due to Legionella pneumonia and hypoxic brain damage 2 and 8 weeks after OLT, resulting in an actuarial 5-year survival rate of 95 % with 47/49 patients being alive compared to 83.5 % of all other liver recipients. Evidence of recurrence of PBC, as defined by elevated chole-static parameters and histological features of PBC, was found in four patients, another five patients showed only histological signs. Recurrence of PBC, which might compromise the long-term outcome after OLT, was suspected in 4/47 patients (8.5 %). This evidence of recurrent PBC is in conflict with findings of other groups that did not report recurrent PBC. OLT is still the optimal therapy for advanced PBC, with an excellent prognosis.     

Biliary stricture secondary to donor B-cell lymphoma after orthotopic liver transplantation

Biliary complications after orthotopic liver transplantation (OLT) lead to considerable morbidity and occasional mortality after surgery. Bile duct strictures secondary to localized lymphoproliferative disorder of the porta hepatis is rare, with only 12 cases reported in the English literature. Posttransplant lymphoproliferative disorder develops in up to 9% of liver allograft recipients. We describe 2 adult patients who developed Epstein-Barr virus-associated localized B-cell lymphoma of donor-tissue origin confined to the porta hepatis 3 and 5 months after OLT. Both patients were administered cyclosporine (CyA) and prednisone as primary immunosuppression. One patient was administered basiliximab as induction therapy. Neither patient had CyA trough levels greater than 250 ng/mL. Both patients were treated with a hepatojejunostomy, 75% reduction in immunosuppression therapy, and acyclovir. One patient had complete involution of the tumor, and the second patient had an 80% reduction of the tumor at the 2-year follow-up visit. This report illustrates the need to consider localized lymphoma post-OLT as a cause of obstructive jaundice even within the first 6 months after surgery. Aggressive reduction of immunosuppression in conjunction with acyclovir remains a highly effective therapy. (Liver Transpl 2001;7:62-67.)     

Living donor liver transplant recipients achieve relatively higher immunosuppressant blood levels than cadaveric recipients

Two recent brief reports suggest that recipients of living donor liver transplants achieve higher levels of immunosuppressive agents than cadaveric (CAD) liver transplant recipients administered the same dose. These results could have important implications regarding the dosing of immunosuppressives in living donor liver transplant recipients. We report our findings relative to immunosuppressive doses and levels in a cohort of 46 living donor liver transplant recipients. Immunosuppressive blood levels and doses were recorded weeks 1, 2, 3, and 4 and months 2, 3, 4, 5, and 6 for 46 living donor liver transplant recipients and 66 matched CAD liver transplant recipients who underwent transplantation between August 1997 and May 2001. The ratio of level to dose also was recorded at each interval. The mean overall cyclosporine A dose was similar in living donor liver transplant recipients (323 mg/d) compared with CAD recipients (344 mg/d; P = not significant [NS]). The mean overall tacrolimus dose was 15% lower in patients who underwent living donor liver transplantation (LDLT; 5.7 mg/d) than CAD transplantation (6.7 mg/d), although statistical significance was not achieved (P = .08). The mean overall cyclosporine A level was 18% higher in those undergoing LDLT (275 ng/mL) than CAD transplantation (234 ng/mL; P = .015). The mean overall tacrolimus level was the same in living donor liver transplant recipients (10.8 ng/mL) and CAD recipients (10.2 ng/mL; P = NS). The overall cyclosporine A level-dose ratio was 26% higher for those undergoing LDLT (0.83) than CAD transplantation (0.66; P = .01). The overall tacrolimus level-dose ratio was 26% higher for those undergoing LDLT (1.82) than CAD transplantation (1.44; P = .01). In conclusion, (1) living donor liver transplant recipients achieve higher blood levels of tacrolimus and cyclosporine A for a given dose compared with CAD recipients, and (2) this difference is observed up to 6 months after transplantation, when hepatic regeneration is completed. (Liver Transpl 2002;8:212-218.)     

Liver Transplantation for Primary Biliary Cirrhosis: Results of Aggressive Corticosteroid Withdrawal

IntroductionA subset of patients with primary biliary cirrhosis (PBC) may require long-term corticosteroid (CS) therapy following liver transplantation (OLT) due to concern over the possibility of recurrence. Our center has attempted to minimize CS use in all of our OLT recipients. In this study, we review our experience in this cohort to determine (1) patient outcome including PBC recurrence following transplantation and (2) the long-term requirement for CS use in PBC patients.MethodsFrom 1988 to 2006, 1102 OLTs were performed in 1032 adults at the University of Colorado, of which 70 patients (6.8%) with PBC received 74 allografts. Bivariate and multivariate analyses were used to evaluate predictors of CS withdrawal. Thirteen potential predictors of CS discontinuation were considered: age, gender, body mass index (BMI), race, type of graft (cadaveric or living donor [LD]), recurrence of PBC, warm ischemia time, and immunosuppressant.ResultsOverall survival at 5 years was 85%. The 1-, 5-, and 10-year recurrence-free survivals were 90%, 72%, and 54%, respectively. PBC recurred in 18 patients (25.7%). Of these, none received a second transplant due to disease recurrence. At the time of last follow-up, 73% of recipients were steroid free. Independent predictors of CS discontinuation are age (>54; P = .0059) and LD graft type (P = .0008). Conversely, cyclosporine (P = .0007), female gender (P = .0216), and BMI > 31 (P = .0306) were negatively associated with CS withdraw. Importantly, steroid discontinuation did not influence PBC recurrence.ConclusionsWhile long-term outcomes in PBC patients are favorable, disease recurrence can generally be managed medically without the need for a second transplant. Using an aggressive CS minimization approach, nearly three-quarters of the patients were CS free at the time of last follow-up. Increasing age and LD grafts were associated with successful CS withdraw. Conversely, cyclosporine use, female gender, and increasing BMI were associated with unsuccessful steroid discontinuation.     

Risk factors associated with cytomegalovirus-positive antigenemia in orthotopic liver transplant patients

The aim of the study was to investigate risk factors associated with cytomegalovirus (CMV)-positive antigenemia in orthotopic liver transplant (OLT) patients. Sixty-nine patients undergoing OLT during 2001 were retrospectively evaluated for CMV antigenemia during a follow-up of 6 months after transplantation for demographic variables, pretransplant donor and recipient CMV serologic status, etiology of liver disease, number of blood transfusions, and type of immunosuppression. Among the 69 patients who underwent 71 OLT in this period, 43 met study criteria. Mean age was 49.7 +/- 10.8 years and 60.5% were men. End-stage liver disease was the indication for liver transplant, except in one case. The most prevalent etiology of liver disease was hepatitis C and/or alcohol in 66% of the cases. CMV-positive status was recorded in 74% of donors and 95% of recipients. None of the CMV-negative recipients received a positive donor allograft. CMV-positive antigenemia was 84% with 12% having two episodes of infection. There was no correlation between CMV infection and age, gender, etiology of liver disease, or number of blood transfusions. However, all patients using cyclosporine had CMV-positive antigenemia compared with 61% using tacrolimus (P <.032). In this study, the incidence of CMV infection after OLT in adult patients was slightly higher than reported in literature. No risk factor was associated with CMV antigenemia; however, this study suggests a higher probability of CMV infection among patients treated with cyclosporine.     

Successful treatment of fibrosing cholestatic hepatitis after liver transplantation

Background

A minority of liver transplant (OLT) recipients with hepatitis C virus (HCV) develop fibrosing cholestatic hepatitis (FCH), a severe form of HCV recurrence associated with early graft failure and death. There are few reports of successful salvage strategies. In this retrospective study, we sought to determine the characteristics and outcomes for patients with FCH at our transplant center.

Methods

All cases of HCV-positive OLT recipients from July 2007 through July 2010 were reviewed. Patient demographics, donor characteristics, and the post-OLT clinical course were analyzed. Tacrolimus-based immunosuppression was used. FCH was treated by conversion to cyclosporine A (CsA) and aggressive treatment with pegylated interferon (IFN) alpha2A and ribavirin (RBV). Liver biopsies and HCV RNA were obtained frequently per protocol or for cause.

Results

The rate of FCH during the study period was 13.5% (5/37). Of the 5 patients with FCH (4 males, 4 Caucasian), mean age was 51 (± 4.8) years and the Model for End-Stage Liver Disease (MELD) score at listing was 26.6 (± 10). Three of the 5 received liver and kidney (L/K) transplants (60%); the rate of L/K transplant in non-FCH patients was 12.5%. HCV RNA levels ranged from 5 to 6.69 log IU/mL pre-OLT; none were on anti-HCV therapy at the time of OLT. Mean ischemic time was 385 (± 152) minutes; donor age was 34.4 (± 13.7) years. No CMV infections developed postoperatively. Time to histologic HCV recurrence was 2 (± 2.23) months (range, 1-6); FCH occurred at 2.2 (± 2.2) months. Patients were converted from tacrolimus to CsA and treated with IFN and RBV; 2 were changed to consensus IFN. HCV RNA increased post-OLT in all, but responded to therapy in 4 of 5. None of the L/K recipients experienced renal graft rejection during treatment. Four of 5 had clinical and histologic improvement; 1 progressed to cirrhosis with minimal inflammation. One-year patient survival after OLT in this group was 80%. Liver allograft rejection occurred in 60% at 4.7 (± 5.5) months and was treated by CsA and prednisone dosage adjustments. In this cohort of patients undergoing OLT for HCV, FCH occurred early after OLT but responded to aggressive management with conversion from tacrolimus to CsA and treatment with pegylated IFN or consensus IFN/RBV. There was a higher rate of combined L/K transplants in the FCH group compared with the non-FCH group. Liver allograft rejection occurred in 60% of cases, but responded to treatment in all; no renal graft rejection occurred in the 3 with L/K transplants while on IFN. One-year graft and patient survival was 80%.

Conclusion

Better survival with FCH is possible with early initiation of IFN/RBV therapy with close monitoring of biopsies and viral load, and conversion from tacrolimus to CsA. Treatment can be performed even in L/K transplantation recipients, although it is associated with a higher incidence of treatable liver allograft rejection.     

Liver transplantation for primary biliary cirrhosis: A long-term pathologic study

Although recurrent primary biliary cirrhosis (PBC) after liver transplantation (LT) has been reported, the full spectrum of changes and progression to fibrosis and cirrhosis is not yet established. We performed a detailed retrospective clinicopathologic analysis of 43 patients who underwent LT for PBC. Eight patients (18.6%) had definite recurrent PBC with florid duct lesions, 5 patients (11.6%) had recurrence with features of autoimmune liver disease, not otherwise specified (AILD-NOS), 7 patients (16.3%) had plasmacytosis only, 4 patients (9.3%) had chronic rejection, 18 patients (41.9%) have no recurrence at present, and 1 patient (2.3%) had acquired hepatitis C. Although definite diagnoses of PBC and AILD-NOS recurrences (n = 13) were made 1 month to 14 years (median, 4 years) post-LT, all patients had plasmacytosis in their earlier biopsy specimens. Also, these patients showed similar pre-LT and post-LT clinical features, with progressive fibrosis in 4 of 8 and 2 of 5 patients, respectively. Four of 13 patients with definite recurrence and 14 of 18 patients with no recurrence were administered azathioprine (AZA) as part of their post-LT therapy (P = .01). Six of 13 and 16 of 18 patients currently are alive, with median follow-ups of 11 and 5 years, respectively. No significant differences were seen with donor-recipient group A, group B, group O blood type, sex, or HLA mismatches; native liver histological characteristics; or tacrolimus-based therapy. In conclusion, recurrent autoimmune liver disease was seen in 30% of patients after LT for PBC and had features of PBC and/or AILD-NOS. Progression seen in 46% of patients was associated with late graft failure. Patients with no recurrent disease had shorter follow-up periods and more frequent immunosuppression, including AZA; some may still develop recurrence with longer follow-up. (Liver Transpl 2003;9:87-96.)     

Cyclosporine A Protects Against Primary Biliary Cirrhosis Recurrence After Liver Transplantation

Primary biliary cirrhosis (PBC) reoccurs in a proportion of patients following liver transplantation (LT). The aims of our study were to evaluate the risk factors associated with PBC recurrence and determine whether recurrent disease constitutes a negative predictor for survival. One hundred and eight patients receiving LT for end‐stage PBC were studied. Recurrent disease was diagnosed in 28 patients (26%). Probability of recurrent PBC at 5 years was 13% and 29% at 10 years with an overall incidence of 3.97 cases per 100 patient years. By univariate Cox analysis use of tacrolimus (HR 6.28, 95% CI, 2.44–16.11, p < 0.001) and mycophenolate mofetil (HR 5.21, 95% CI, 1.89–14.33, p = 0.001) were associated with higher risk of recurrence; whereas use of cyclosporine A (CsA) and azathioprine were associated with reduced risk of recurrence (HR 0.13, 95% CI 0.05–0.35, p < 0.001 and HR 0.27, 95% CI 0.11–0.64, p = 0.003, respectively). In the multivariate Cox analysis, only CsA was independently associated with protection against recurrence (HR 0.17, 95% CI 0.06–0.71, p = 0.02). Five‐year probability of survival was 83% and 96%, in patients without and with recurrence (log‐rank test, p = 0.3). Although PBC transplant recipients receiving CsA have a lower risk of disease recurrence, the development of recurrent PBC did not impact on long‐term patient 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.     

Repeated steroid pulse therapies in HCV-positive liver recipients: significant risk factor for HCV-related graft loss

BACKGROUND: The optimal immunosuppressive regimen for HCV-positive liver transplant recipients has not been established. Treatment for acute cellular rejection (ACR) with steroids is associated with increased viral replication and graft hepatitis. We retrospectively analyzed 232 patients after orthotopic liver transplantation (OLT) for HCV cirrhosis to determine the influence of methylprednisolone pulse therapy on long-term outcome after OLT. METHODS: Two hundred thirty-two liver transplants were performed in HCV-positive recipients between 1989 and 2001. Median follow-up was 4.4 years and median age of patients was 53 years (range 15 to 72 years). Immunosuppression consisted of tacrolimus (Tac) or cyclosporine (CyA) in different protocols. All rejection episodes were histologically proven. RESULTS: Twenty-eight of 232 (12.06%) graft losses were due to severe hepatitis C reinfection. Of 232 patients, 105 showed a minimum of one episode of ACR (45.25%). Of 232 patients, 71 (30.6%) received methylprednisolone pulse therapy once and 15 of 232 required OKT3 treatment for steroid-resistant rejection (6.4%). Of 232 patients, 19 (8.1%) required repeated steroid pulse therapy due to more than one episode of ACR. In patients with more than one episode of ACR, the risk of HCV-related graft loss was significantly enhanced (6/19, P < .05). The primary immunosuppression had no influence on the outcome in our data. CONCLUSION: Our data show that outcome of HCV-positive patients who require repeated steroid pulse therapy (RSPT) for ACR is significant worse than that in patients with a single pulse therapy. Therefore RSPT should be avoided in HCV-positive transplant recipients. New strategies to manage acute rejection are required for these patients.     

心脏移植后采用他克莫司替代环孢素A治疗的体会

目的 探讨心脏移植后因排斥反应或环孢素A(CsA)不良反应而将CsA替换为他克莫司(FK506)的临床效果.方法 6例原位心脏移植患者中,5例因发生严重排斥反应或排斥反应不能控制、1例因CsA的肝毒性,而将CsA替换为FK506,其它免疫抑制剂不变,转换时间为术后(167.8±166.7)d,FK506的用量为(6.0±1.4)mg/d,维持其血药浓度在(14.7±5.6) μg/L.心内膜心肌活检(EMB)联合超声心动图监测排斥反应.结果 随访(17.1±6.0)个月,6例患者全部存活,2例心功能下降者在换用FK506后心功能恢复正常.换用FK506前,排斥反应评分为(2.50±0.42)分,换用FK506后,排斥反应评分降至(0.60±0.39)分(P＜0.01).1例患者转换为FK506后3周,出现发热及胸腔积液,经抗结核治疗1周后好转,半年后停止抗结核治疗,患者至今存活1年;转换为FK506后,4例患者因血糖升高(其中2例转换前血糖即升高)需用胰岛素治疗;换用FK506后,CsA所致的多毛消失,牙龈增生减轻.结论 心脏移植后采用CsA进行免疫抑制治疗者,若反复发生排斥反应或出现不能耐受的CsA不良反应,可将CsA替换为FK506,临床效果明显.     

Conversion to cyclosporine provides valuable rescue therapy for living donor adult liver transplant patients intolerant to tacrolimus: A single-center experience at the University of Tokyo

Tacrolimus-based immunosuppression is currently accepted as mainstream therapy in many transplant centers worldwide due to its potent immunosuppressive activity compared to cyclosporine. A tacrolimus-based regimen has been successfully used for our living donor liver transplantation (LDLT) recipients. Adverse effects such as neurotoxicity, nephrotoxicity, and new-onset diabetes mellitus, however, have limited its clinical application. In deceased donor liver transplantation, cyclosporine rescue therapy is valuable for such complications, but few reports have described a strategy for conversion in LDLT. Herein, we present our experience of conversion from tacrolimus to cyclosporine therapy in adult LDLT recipients. Among 203 recipients, 37 patients (18%) required conversion, primarily for neurotoxicity (41%), diabetes mellitus (16%), hematopoietic disorder (16%), and gastrointestinal intolerance (11%). Primary adverse events resolved within 2 months after conversion in 35/37 (94%) of the patients. For LDLT recipients unable to maintain effective immunosuppression with tacrolimus, conversion to cyclosporine is an effective option.     

Influence of albumin supplementation on tacrolimus and cyclosporine therapy early after liver transplantation

Liver transplant recipients administered gelatin (GEL) rather than human albumin solution (HAS) can become profoundly hypoalbuminemic in the early postoperative period and often have hepatic dysfunction at this time. The combined effect of these two abnormalities could be an increase in the unbound (active) concentration of low-extraction highly albumin-bound drugs, such as tacrolimus (TAC). This may increase the efficacy and/or toxicity of such drugs. We prospectively compared the clinical outcome of 69 de novo liver transplant recipients randomized primarily to TAC or cyclosporine (CYA) and secondarily to HAS or GEL therapy during the first 14 days after liver transplantation. Antipyrine clearance on the 7th postoperative day was used as a measure of liver metabolic function. Serum albumin levels were significantly lower in both GEL arms than HAS arms during the first 14 days (P [lt ] .001). Although antipyrine clearance was similar in all four trial arms, it was intermediate between that found in historic healthy controls and patients with cirrhosis (P [lt ] .0001). Serum creatinine concentrations were significantly greater in the TAC plus GEL arm than the other three arms (P [lt ] .001). The linearized treated acute rejection rate was significantly greater in the TAC plus HAS arm than the other three arms (relative risk, 2.02; 95% confidence interval, 1.07 to 3.78; P = .03). These data indicate that excess nephrotoxicity can occur with TAC in liver transplant recipients with impaired hepatic metabolism who are administered GEL. In addition, supplementary albumin may reduce the efficacy of TAC in liver transplant recipients at a time when the risk for rejection is greatest. (Liver Transpl 2002;8:224-232.)     

Relationship between immunosuppression and osteoporosis in an outpatient liver transplant clinic

BACKGROUND: The aim of this study is to determine the relationship between immunosuppression, disease state, and osteoporosis in an outpatient liver transplant clinic. METHODS: All liver transplant recipients visiting an outpatient transplant clinic received bone density scanning with a dual-energy X-ray absorptiometry (DEXA) device of the calcaneal bone after completing a questionnaire assessing risk and medications currently being used. RESULTS: Of the 137 liver transplant (OLT) recipients completing questionnaires and receiving DEXA screening, patients with low bone density (n = 50) were older (56.6 +/- 12.7 years vs 50.2 +/- 10.1 years; P = .02) compared with normal density patients (n = 87) and were predominately female (64.0% vs 35.6%; P = .01). Based on disease state, patients with cholestatic liver failure had lower bone calcaneal area (17.3 +/- 1.3 cm2 vs 18.9 +/- 1.57 cm2; P < .01). Patients taking tacrolimus (n = 112), as compared with cyclosporine (n = 25), had a tendency toward fewer findings of low bone density (37.5% [42 of 112] vs 56.0% [14 of 25]; P = .08) but had more risk factors (3.1 +/- 1.2 vs 2.1 +/- 0.8; P = .001) and a higher prednisone dose (4.4 +/- 5.9 mg/d vs 2.1 +/- 3.8 mg/d; P = .026). For patients weaned from prednisone, the tacrolimus patients were less likely to have low bone density (36.2% vs 68.8%; P = .02). Mycophenolate mofetil did not influence bone density or area measured. CONCLUSIONS: After liver transplantation, patients taking cyclosporine were more likely to have low bone density compared with those taking tacrolimus.     

Everolimus-Based Immunosuppression in Patients With Hepatocellular Carcinoma at High Risk of Recurrence After Liver Transplantation: A Case Series

BackgroundLiver transplantation offers the most effective treatment in patients with hepatocellular carcinoma (HCC). However, transplant patients outside the Milan criteria have a high risk of tumor recurrence, which has been linked to standard immunosuppression regimens. Everolimus is a mammalian target of rapamycin inhibitor that has been used for immunosuppression, but its effect on recurrence and survival in HCC patients with a high risk of tumor recurrence has not been examined. We compared long-term survival and cumulative recurrence in high-risk patients receiving everolimus-based immunosuppression after liver transplantation for HCC with an historic control group.MethodsThe everolimus group comprised 21 patients receiving a liver transplant at our center from February 2005 to December 2010. The control group comprised 31 patients receiving a liver transplant from May 1994 to January 2005. All patients received cyclosporine or tacrolimus as initial post-transplant immunosuppression. Patients in the everolimus group switched to everolimus 2 weeks later.ResultsThere were no differences between the two groups in number of rejection episodes or of infectious or surgical complications. Five-year survival was 60.2% in the everolimus group and 32.3% in the control group (P = .05). Five-year cumulative recurrence rate was 61.3% in the control group and 41.3% in the everolimus group. Treatment with everolimus was identified as an independent predictor of longer survival (hazard ratio = 0.34; P = .02).ConclusionsPatients receiving liver transplantation for HCC with a high risk of tumor recurrence may well benefit from everolimus-based immunosuppression, with no added risks of rejection or other post-transplant complications.