Late acute liver allograft rejection; a study of its natural history and graft survival in the current era.

BACKGROUND: Late acute rejection (LAR) after liver transplantation is often associated with poor clinical outcomes. We reviewed our experience of managing LAR in the current era to determine its natural history. METHODS: A database of 970 consecutive adult liver transplants was reviewed retrospectively. LAR was defined as histologically proven acute cellular rejection occurring more than 90 days after transplantation. RESULTS: The incidence of LAR was 11%, with a mean time of 565 days (median, 311 days; range, 90-2922 days) after transplantation. The highest rates for LAR were in seronegative hepatitis (17%), primary biliary cirrhosis (16%), and primary sclerosing cholangitis (13%) with an odds ratio of 2.3, 2.1, and 1.8, respectively. Logistic regression showed that younger recipients, primary biliary cirrhosis, and previous graft loss were independent predictors of LAR (P<0.001). Mean trough whole blood tacrolimus levels were at their lowest levels 1 week before the diagnosis of rejection (5.5 ng/mL; SD, 2.6) compared with levels of 7.7 ng/mL 4 weeks before rejection, showing a clear temporal relation. Graft survival was worse in those with LAR (P<0.01), whereas the best graft survival was among early acute rejection cases (85% 10-year survival; P<0.01). Poor response to treatment correlated with the development of ductopenic rejection (r=0.3; P<0.01). Approximately half with early ductopenic rejection eventually died (n=15). CONCLUSION: LAR continues to provide a risk to patient and graft survival: understanding risk factors may allow an improvement in monitoring and early intervention and so prevent early graft loss.

Evaluation of clinical and safety outcomes associated with conversion from brand-name to generic tacrolimus in transplant recipients enrolled in an integrated health care system.

STUDY OBJECTIVE: To evaluate clinical and safety outcomes among transplant recipients whose tacrolimus was converted from the brand-name formulation to a generic formulation. DESIGN: Retrospective analysis. DATA SOURCE: Clinical databases and electronic records from a large, integrated health care system in California. PATIENTS: A total of 234 clinically stable, adult transplant recipients (renal, liver, and heart) whose tacrolimus was converted from the brand-name formulation to a generic formulation between October 1, 2010, and December 31, 2010, according to a physician-approved protocol. MEASUREMENTS AND MAIN RESULTS: For each patient, pre- and postconversion tacrolimus trough concentrations and serum creatinine concentrations were analyzed. Data were also collected on the percentage of patients who required dosage titration, drug cost savings, and rates of reversion to brand-name tacrolimus, biopsy-proved acute allograft rejections, and mortality. No significant differences were noted in mean ± SD pre- and postconversion tacrolimus trough levels (6.74 ± 1.61 vs 6.96 ± 2.31 ng/ml, p=0.137) or serum creatinine concentrations (1.33 ± 0.48 vs 1.36 ± 0.82 mg/dl, p=0.302). The mean ± SD percent change in tacrolimus trough concentration was 5.63 ± 32.95%. Thirty-six patients (15.4%) required dosage titration. Six patients (2.6%) reverted back to brand-name tacrolimus. No deaths or acute rejections occurred. Use of the generic product saved each patient an average of $45/month in drug acquisition cost and $26/prescription copayment. CONCLUSION: Clinical experience as well as research data show that use of generic tacrolimus results in trough concentrations that are comparable to the brand-name drug. Given the lack of adverse events reported and the cost savings recognized, conversion from brand-name tacrolimus to generic tacrolimus should be encouraged. Since dosage titration may be required, close therapeutic drug monitoring is recommended.

Factors that affect deceased donor liver transplantation rates in the United States in addition to the Model for End-stage Liver Disease score.

Under an ideal implementation of Model for End-Stage Liver Disease (MELD)-based liver allocation, the only factors that would predict deceased donor liver transplantation (DDLT) rates would be the MELD score, blood type, and donation service area (DSA). We aimed to determine whether additional factors are associated with DDLT rates in actual practice. Data from the Scientific Registry of Transplant Recipients for all adult candidates wait-listed between March 1, 2002 and December 31, 2008 (n = 57,503) were analyzed. Status 1 candidates were excluded. Cox regression was used to model covariate-adjusted DDLT rates, which were stratified by the DSA, blood type, liver-intestine policy, and allocation MELD score. Inactive time on the wait list was not modeled, so the computed DDLT hazard ratios (HRs) were interpreted as active wait-list candidates. Many factors, including the candidate's age, sex, diagnosis, hospitalization status, and height, prior DDLT, and combined listing for liver-kidney or liver-intestine transplantation, were significantly associated with DDLT rates. Factors associated with significantly lower covariate-adjusted DDLT rates were a higher serum creatinine level (HR = 0.92, P < 0.001), a higher bilirubin level (HR = 0.99, P = 0.001), and the receipt of dialysis (HR = 0.83, P < 0.001). Mild ascites (HR = 1.15, P < 0.001) and hepatic encephalopathy (grade 1 or 2, HR = 1.05, P = 0.02; grade 3 or 4, HR = 1.10, P = 0.01) were associated with significantly higher adjusted DDLT rates. In conclusion, adjusted DDLT rates for actively listed candidates are affected by many factors aside from those integral to the allocation system; these factors include the components of the MELD score itself as well as candidate factors that were considered but were deliberately omitted from the MELD score in order to keep it objective. These results raise the question whether additional candidate characteristics should be explicitly incorporated into the prioritization of wait-list candidates because such factors are already systematically affecting DDLT rates under the current allocation system.

Donor polymorphisms of toll-like receptor 4 associated with graft failure in liver transplant recipients.

There have been many reports showing significant associations between recipient genetic variants and allograft outcomes, including acute rejection and graft failure, but less is known about the contribution of the donor genotype. We analyzed 37 single-nucleotide polymorphisms (SNPs) within the toll-like receptor 4 (TLR4) gene from deceased donor liver allografts transplanted into 738 recipients to determine their effects on liver graft failure (LGF). Two SNPs exhibited a significant association with LGF after adjustments for donor race and recipient race and corrections for multiple test comparisons: rs11536865 [hazard ratio (HR) = 2.5, P = 0.0003] and rs5030717 (HR = 1.67, P = 0.0008). An additional SNP, rs913930, exhibited a significant association in Caucasian donors (HR = 1.62, P = 0.0006), and 2 SNPs exhibited a suggestive association in African American donors: rs11536865 (HR = 2.45, P = 0.002) and rs5030717 (HR = 2.32, P = 0.002). Additionally, the liver donor risk index (HR = 2.56, 95% confidence interval = 1.54-4.26, P = 0.0003) and the recipient hepatitis C virus (HCV) status (HR = 1.53, 95% confidence interval = 1.04-2.24, P = 0.032) increased the risk of all-cause LGF in a Cox proportional hazards model adjusted for recipient race. Donor polymorphisms in TLR4 could be important factors in modulating TLR4 activity and, therefore, affect the risk of graft loss. Additionally, there is a suggestion of an interaction between polymorphisms within TLR4 and the HCV status.

Cytomegalovirus infection: its incidence and management in cytomegalovirus-seropositive living related liver transplant recipients: a single-center experience.

It is believed that antiviral prophylaxis decreases the incidence of cytomegalovirus (CMV) reactivation and disease. There are few data regarding weekly assays for CMV DNA after transplantation and the subsequent management of CMV. Here we report a cohort of living related liver transplantation (LRLT) patients who were treated for invasive CMV disease or for CMV infections if they were receiving steroids for rejection. Patients who underwent liver transplantation at our center between September 2006 and August 2010 and were recipient-positive/donor-positive (R(+) /D(+) ) were prospectively included. Patients were tested for CMV DNA 3 weeks after transplantation. CMV DNA-positive patients underwent weekly DNA monitoring until there were 2 consecutive negative reports. Those who developed CMV disease or had rising DNA titers while they were on treatment for rejection were treated. A Cox regression analysis was performed for factors predicting survival. Two hundred sixty-six of the 306 R(+) /D(+) patients were CMV DNA-negative 3 weeks after transplantation, and 40 had detectable DNA. One of the DNA-negative patients developed CMV disease after treatment for rejection with methylprednisolone. Thirty patients had <500 copies/mL, and 10 had ≥500 copies/mL. Two of the 30 patients with DNA levels < 500 copies/mL developed CMV disease. Six of the 10 patients with DNA levels ≥500 copies/mL developed disease. CMV disease occurred in 9 of the 306 patients (2.9%). One patient received treatment for a rise in DNA titers while he was receiving steroids. There was a significant correlation between steroid administration for acute cellular rejection (ACR) and CMV reactivation (P = 0.003) and disease (P = 0.002). A multivariate analysis showed that CMV reactivation/disease did not predict survival. There was no difference in survival between CMV DNA-positive patients and CMV DNA-negative patients (P = 0.68). In conclusion, CMV reactivation is common after LRLT (13%), but the disease is rare (2.9%) without prophylaxis in CMV immunoglobulin G-positive recipients. The administration of steroids for ACR strongly correlates with CMV reactivation and disease. CMV reactivation and disease did not affect survival in our patient cohort.

Safety assessment of intraportal liver cell application in New Zealand white rabbits under GLP conditions.

Liver cell transplantation (LCT) is considered a new therapeutic strategy for the treatment of acute liver failure and inborn metabolic defects of the liver. Although minimally invasive, known safety risks of the method include portal vein thrombosis and pulmonary embolism. Since no systematic data on these potential side effects exist, we investigated the toxicological profile of repeated intraportal infusion of allogeneic liver cells in 30 rabbits under GLP conditions. Rabbit liver cells were administered once daily for 6 consecutive days at 3 different dose levels, followed by a 2-week recovery period. No test item-related mortality was observed. During cell infusion, clinical findings such as signs of apathy and hyperventilation, moderate elevations of liver enzymes ALT and AST and a slight decrease in AP were observed, all fully reversible. Cell therapy-related macroscopic and histological findings, especially in liver and lungs, were observed in animals of all dose groups. In conclusion, the liver and lungs were identified as potential toxicological target organs of intraportal allogeneic liver cell infusion. A NOAEL (no observed adverse effect level) was not defined because of findings observed also in the low-dose group. No unexpected reactions became apparent in this GLP study. Overall, LCT at total doses up to 12 % (2 % daily over 6 days) of the total liver cell count were tolerated in rabbits. Observed adverse effects are not considered critical for treatment in the intended patient populations provided that a thorough monitoring of safety relevant parameters is in place during the application procedure.

Infectious complications of acute and chronic liver disease.

Acute and chronic liver diseases are frequently complicated by infections, which result in increased morbidity and mortality and place an economic burden on health care systems. This review discusses the epidemiology and the impact on prognosis of infections in liver cirrhosis, nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, acute liver failure, and post-liver transplantation. Possible mechanisms for this increased susceptibility are innate immune dysfunction (Kupffer cells, neutrophils, monocytes), genetic predisposition, and intrinsic cellular defects. The causes for innate immune dysfunction may lie in increased gut permeability, the occurrence of endotoxemia, albumin and lipoprotein dysfunction, or toll-like receptor expression. From a clinical viewpoint this article discusses problems in diagnosing infection. Established (vaccination, antibiotic prophylaxis, antiviral prophylaxis, and nutrition) and experimental (probiotic) prophylactic strategies as well as established (antibiotics) and experimental (liver support, albumin, toll-like receptor antagonists) strategies are also reviewed.

The risk factors to predict acute rejection in liver transplantation.

PURPOSE: The aim of this study was to evaluate risk factors for an acute cellular rejection episode (ARE) among adult liver transplant (OLT) patients. MATERIALS AND METHODS: We retrospectively reviewed 110 consecutive patients who underwent OLT between May 2007 and December 2010. The diagnosis of ARE was based upon clinical and biochemical data; liver biopsy was only performed when clinical presentation was equivocal. We recorded donor and recipient characteristics, perioperative immune status, and postoperative laboratory data. Forty patients (36.4%) who suffered a clinical rejection episode and received pulsed or recycled steroid therapy (R group), were compared with 70 (63.6%) free of rejection (N group). RESULTS: The mean age of R recipients was 46.61±9.97 years, which was younger than the N group (51.86±8.37, P=.005). R group patients displayed a lower pre-OLT creatinine (P=.016) and higher alanine aminotransferase (P=.048). Cox regression model showed recipient age to be the only significant factor to predict ARE (odds ratio=1.071, P=.003). The cutpoint of age was 46 years by receiver operating characteristic analysis. Patients younger than 46 years showed higher initial CD8+ T-cell counts (P=.038). CONCLUSION: Recipient age was significantly associated with ARE; younger patients showed higher CD8+ lymphocyte counts than older patients. More aggressive immunosuppression should be considered for younger recipients to prevent ARE.

The assessment of GFR after orthotopic liver transplantation using cystatin C and creatinine-based equations.

The measurement of kidney function after orthotopic liver transplantation (OLT) is still a clinical challenge. Cystatin C (CysC) has been proposed as a more accurate marker of renal function than serum creatinine (sCr). The aim of this study was to evaluate sCr- and CysC-based equations including the Chronic kidney disease (CKD)-EPI to determine renal function in liver transplant recipients. CysC and sCr were measured in 49 patients 24 months after OLT. The glomerular filtration rate (GFR) was calculated using the MDRD 4, the Cockroft-Gault, Hoek, Larsson, and the CKD-EPI equations based on sCr and/or CysC. As reference method, inulin clearance (IC) was estimated. Bias, precision, and accuracy of each equation were assessed and compared with respect to IC. Forty-five percent had a GFR < 60 ml/min/1.73 m(2) according to the IC. The Larsson, the Hoek and the CKD-EPI-CysC formula identified the highest percentage of patients with CKD correctly (88%, 88%, and 84%, respectively). The sCr-based equations showed less bias than CysC-based formulas with a similar precision. All CysC-based equations were superior as compared with sCr-based equations in the assessment of renal function in patients with an IC < 60 ml/min/1.73 m(2).

Prophylaxis against de novo hepatitis B for liver transplantation utilizing hep B core (+) donors: does hepatitis B immunoglobulin provide a survival advantage?

Donor liver allografts with positive serology for hepatitis B core antibody [HBc (+)] have been increasingly used for liver transplantation. However, the optimal prophylactic regimen to prevent development of de novo hepatitis B has not been determined. To evaluate this, we screened United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research (STAR) registry data for adult recipients of HBc (+) organs who were HBsAg (-), and evaluated the effects of using prophylactic anti-viral therapies (HBIG and lamivudine) on patient and graft survival. Out of a total cohort of 958 patients transplanted since 2004, 61 received HBIG alone, 116 received lamivudine alone, 66 both, 509 neither and 206 were missing this information. Based on several multivariable Cox regression models, patients receiving HBIG therapy-only were observed to have a statistically significant (approximately 70%) reduction in risk of mortality compared with patients receiving lamivudine-only therapy [HR=0.29, 95% CI (0.10, 0.86), P=0.026], and a nonstatistically significant reduction in risk of graft failure. However, no graft failures were attributed to de novo hepatitis B, suggesting that any improved graft/patient survival possibly associated with HBIG therapy occurs independently of de novo hepatitis B virus (HBV) reduction. While this study cannot prove that HBIG therapy is protective for graft and patient survival after liver transplantation, these findings do highlight the need to further examine and study prophylactic use in recipients of HBc (+) donors.

Factors affecting outcomes of liver transplantation: an analysis of OPTN/UNOS database.

This was a historic cohort analysis based on 110,521 patients who underwent liver transplant between 1987 and July 2011 in the United States and were reported to the UNOS registry. In addition to univariate Kaplan-Meier survival analyses, we used cox proportional hazard analysis and multiple logistic regression analysis to evaluate hazard ratios adjusted for clinical factors. The overall 5- and 10-year patient survival rates were 81% and 72%, respectively, for 4,412 recipients of living donor livers and 73% and 59%, respectively, for 106,109 recipients of deceased donor livers. Multivariate analyses suggest that these differences are due to demographics, including patient age rather than differences due to the donor organs. Recipients of zero HLA-mismatched livers had significantly worst graft survival (HR 1.29, p = 0.02) compared with those given an HLA mismatched graft. This appears to be due in part to graft versus host disease. Among recipients who experienced GVHD, multivariate analysis revealed that zero mismatch of HLA-A (HR 2.75), zero mismatch of HLA-B (HR 4.79), recipient age > 65 (HR 2.57) and Asian recipient (HR 2.70) were significant risk factors for GVHD respectively.

Hyperimmune anti-HBs plasma as alternative to commercial immunoglobulins for prevention of HBV recurrence after liver transplantation.

BACKGROUND: Hepatitis B immune globulins (HBIG) in combination with nucleos(t)ide analogues (NA) are effectively used for the prevention of hepatitis B virus (HBV) recurrence after liver transplantation (LT). However, associated treatment costs for HBIG are exceedingly high. METHODS: Fresh frozen plasma obtained from blood donors with high anti-HBs levels (hyperimmune plasma, HIP) containing at least 4,500 IU anti-HBs was used as alternative treatment for HBV recurrence prophylaxis post-LT. RESULTS: Twenty-one HBV-related LT recipients received HIP starting at transplantation, followed by long-term combination treatment with NA. Mean follow-up time was 4.5 years (range 0.5-12.6) and each patient received on average 8.2 HIP per year (range 5.8-11.4). Anti-HBs terminal elimination kinetic after HIP administration was 20.6 days (range 13.8-30.9), which is comparable to values reported for commercial HBIG products. All 21 patients remained free of HBV recurrence during follow-up and no transfusion-transmitted infection or other serious complication was observed. Seven patients developed reversible mild transfusion reactions. The cost for one HIP unit was US$140; average yearly HBIG treatment cost was US$1,148 per patient, as compared to US$25,000-100,000 for treatment with commercial HBIG. CONCLUSION: The results of this study suggest that the use of HIP may be a useful and economical approach for the prevention of HBV recurrence post-LT if used in combination with NA. Additional prospective controlled studies in larger populations are needed to confirm these results.

Influenza vaccination coverage among adult solid organ transplant recipients at three health maintenance organizations, 1995-2005.

Annual immunization against influenza is recommended for solid organ transplant (SOT) recipients. We used Vaccine Safety Datalink data from 1995 to 2005 to assess influenza vaccination during the first full vaccination season (September-February) following transplant among 1800 kidney, liver, and heart transplant recipients at three health maintenance organizations. Overall, 52% of recipients were vaccinated. Older age at transplant (age 50-64 years, OR 1.81, 95% CI 1.43-2.30; age > or =65 years, OR 1.94, 95% CI 1.39-2.69), receiving vaccination in the full season pre-transplant (OR 4.54, 95% CI 3.67-5.60), and year of transplantation were significant predictors of post-transplant vaccination. Although vaccine coverage increased during study years, SOT recipients are under-immunized against influenza. Efforts to understand barriers to vaccination and increase education of physicians managing patients while awaiting and after receipt of transplant are needed.

Study of the factors affecting health-related quality of life in adolescents after liver transplantation.

The aim of the study was to identify factors affecting health-related quality of life (HRQL) in adolescents after liver transplantation. HRQL was measured using the CHQ-CF87 in 55 adolescents, aged 12-18 years. Factors associated with HRQL included allograft morbidity, psychological and family-related variables measured through standardized questionnaires. The domains of the CHQ-CF87 were reduced using factor analysis to give physical, psychological and social domains. Impacting factors were identified through stepwise, multiple regression analysis. Adolescents had significantly lower HRQL in every domain except for role/social-behavior and family cohesion compared to the general population. Adolescents experienced median 18 (range 4-31) symptoms related to immunosuppression, 40(75%) had one or more chronic illnesses related to immunosuppression and 12(22%) had a history of emotional difficulties. Self-esteem and emotional health were similar to the general population but behavior and aspects of family function were lower. Following regression analysis, the factors associated with HRQL were: age at transplant, secondary chronic illness, symptom distress, headaches, history of emotional difficulties, self-esteem and family conflict. These explained 57% of the variance in physical function, 61% of psychological function and 39% of social function. HRQL is significantly reduced in adolescents after transplantation, which could be related to immunosuppression and psychosocial factors.

Costs and efficacy of "on demand" low-dose immunoprophylaxis in HBV transplanted patients: experience in the Romanian program of liver transplantation.

BACKGROUND: HBV in liver transplant (LT) patients is associated with good outcomes and the challenges are primarily focused around optimizing prophylactic regimens with hepatitis B immune globulin (HBIG) and minimizing related costs. AIM: To identify recurrence rates in patients transplanted for HBV or HBV+HDV infection in whom a combined "on demand" low-dose HBIG was used, maintaining low anti-HBs titres (not below 50 IU/L). METHODS: Medical records of 42 patients transplanted for HBV or HBV+HDV induced cirrhosis between April 2000 and September 2007 at Fundeni Clinical Institute were analyzed. Patients received immunoprophylaxis with lamivudine and HBIG (10,000 IU within anhepatic phase and daily within the first postoperative week, followed by 2,500 IU on demand). HBV recurrence rates and survival during follow-up were evaluated using the Kaplan Meier method. RESULTS: HBV recurrence rate was 4.8% after a median of 1.8 years. Three year patient survival rate was 70%. None of the patients died due to liver failure related to HBV recurrence. Using our "on demand" low-dose administration of HBIG, the total mean cost for HBIG and lamivudine for patient per month of survival was 598.3 Eur. The projected monthly cost for the "ideal" schedule/patient was 2,017 Eur. CONCLUSION: Individualization of immunoprophylaxis after LT for HBV related disease according to the lowest protective anti-HBs titers in combination with lamivudine is probably the best approach for non-replicative pre-LT patients in terms of costs and efficacy.

Pharmacokinetic-pharmacodynamic assessment of tacrolimus in liver-transplant recipients during the early post-transplantation period.

During the early post-transplantation period, the limitations of monitoring current tacrolimus dose with classic pharmacokinetics (PK) have been demonstrated in liver-transplant recipients. Evaluation of the pharmacodynamics (PD) using calcineurin activity (CNA) has been proposed to optimize tacrolimus dosing. The aim of the present study was to determine the time of maximal inhibition of CNA, to explore the relation between exposure to tacrolimus and CNA, and to analyze its variability. Blood was drawn from 14 patients 0, 2, 3, 4, 6, and 9 hours after tacrolimus intake on post-transplantation days 8, 21, and 90 to measure blood tacrolimus concentrations using the EMIT 2000 assay and CNA in peripheral blood mononuclear cells. Tacrolimus and CNA data were obtained for 33 blood-sample collection sessions and analyzed using a population approach. Three models were built to describe tacrolimus PK, CNA kinetics, and the relationships between the area under the CNA-time curve (AUC12effCNA) and AUC12Tacrolimus or CminTacrolimus. Coagulation factor V and whole/split liver graft were identified as covariates influencing tacrolimus clearance. Indeed, apparent tacrolimus clearance rose by 14% when factor V increased by 10% and was threefold higher in patients with whole-liver grafts. The median maximal inhibition of CNA was reached 4 hours after tacrolimus intake on days 8, 21, and 90 and represented an 18% drop in CNA compared with activity at drug intake. The variability of the PK-PD relationship was minimal when using AUC12Tacrolimus. The large variability of the PD parameters (coefficient of variation was 89%) that linked AUC12effCNA to AUC12Tacrolimus indicates that monitoring tacrolimus concentrations may not be adequate to control CNA. Measuring CNA in peripheral blood mononuclear cells 4 hours after tacrolimus intake during the first 3 months after liver transplantation could be a means to improve tacrolimus monitoring and thereby avoid acute graft-rejection episodes.

Serial assessment of immune status by circulating CD8 effector T cell frequencies for posttransplant infectious complications.

To clarify the role of CD8+ effector T cells for infectious complications, 92 recipients were classified according to the hierarchical clustering of preoperative CD8+CD45 isoforms: Group I was naive, Group II was effector memory, and Group III was effector (E) T cell-dominant. The posttransplant infection rates progressively increased from 29% in Group I to 64.3% in Group III recipients. The posttransplant immune status was compared with the pretransplant status, based on the measure (% difference) and its graphical form (scatter plot). In Groups I and II, both approaches showed a strong upward deviation from pretransplant status upon posttransplant infection, indicating an enhanced clearance of pathogens. In Group III, in contrast, both approaches showed a clear downward deviation from preoperative status, indicating deficient cytotoxicity. The % E difference and scatter plot can be used as a useful indicator of a posttransplant infectious complication.

Steroid-free, tacrolimus-basiliximab immunosuppression in pediatric liver transplantation: clinical and pharmacoeconomic study in 50 children.

Corticosteroid-free immunosuppression (IS) may be potentially beneficial for transplanted patients, particularly children. The purpose of this study was to evaluate the efficacy and cost of such strategy in primary pediatric liver transplantation (LT). Fifty pediatric LT recipients were prospectively treated with a steroid-free, tacrolimus-basiliximab-based IS (group TB). A group of 34 children transplanted under a conventional tacrolimus-steroids regimen served as control series (group TS). Groups TB and TS were compared regarding patient and graft survival, rejection incidence, infectious complications, and growth, as well as cost of the transplant procedure. Patient and graft survivals at 3 years were 96% and 94% in group TB, versus 91% and 88% in group TS (P = 0.380 and P = 0.370, respectively). Rejection-free graft survival at 3 years was 72% in group TB, versus 41% in group TS (P = 0.007). Patients in group TB had significantly less viral infections than patients in group TS (P = 0.045). Height standard deviation score was significantly enhanced in children from group TB, when compared to group TS. Medical care costs were similar in both groups. Steroid avoidance together with basiliximab immunoprophylaxis was not harmful in terms of allograft acceptance, and even seemed to be beneficial in the long term.

Longitudinal assessment of cytomegalovirus (CMV)-specific immune responses in liver transplant recipients at high risk for late CMV disease.

Cytomegalovirus (CMV)-seronegative recipients (R(-)) of a liver transplant from CMV-positive donors (D(+)) are at high risk for developing late CMV disease after discontinuation of antiviral prophylaxis. Levels of viremia and CMV-specific interferon (IFN)- gamma -producing CD4(+) and IFN- gamma -producing CD8(+) T cell responses were prospectively measured from discontinuation of antiviral prophylaxis until 1 year after transplantation in 17 consecutive D(+)/R(-) patients. CMV loads of >1000 copies/mL were strongly associated with CMV disease in the 6 symptomatic patients. Despite immunosuppression, broadly diverse T cells specific for CMV lysate or peptide libraries spanning pp65 and immediate early (IE) 1 immunodominant CMV antigens developed in all patients. A vigorous CD8(+) T cell response to pp65 and IE1 antigens characterized the D(+)/R(-) cohort. Unexpectedly, none of these responses were predictive of CMV disease or viremia. No significant lymphopenia or functional impairment of CMV-specific T cells was detected in the symptomatic patients, whose morbidity was resolved after antiviral treatment while measurable CMV immunity was maintained during the 1-year observation period.

The incidence and management of acute and chronic rejection after living donor liver transplantation.

Living donor liver transplantation (LDLT) is a good alternative to cadaveric liver transplantation for end-stage liver disease. Herein we report the outcome of 132 LDLTs performed between 1999 and 2005, with special emphasis on the incidence and management of acute and chronic rejection. Among the LDLT population a first acute rejection episode (ARE) was clinically suspected in 24% and proven by liver biopsy in 11%. According to the Banff classification, 50% of AREs were grade 1, and 50%, grade 2. There was no grade 3 AREs. The first ARE occurred between 7 days and 23 months posttransplantation (mean 97 days, median 70 days). Ninety-seven percent (31/32) of the AREs occurred within the first year after transplantation and 3% (1/32) in the second year. Among the patients with ARE, 23% developed a second ARE between 4 and 11 months. A third ARE was detected in 8% of patients after month 18. All AREs responded to adjustment of immunosuppressive doses or steroid boluses. Chronic rejection (CR) was detected in 2%. In conclusion, the incidences of ARE and CR are consistent with the previously reported data. Acute and chronic rejections seem to be mild and easily manageable clinical conditions. Our results also showed a significant difference between clinically suspected and biopsy-proven ARE emphasizing the importance of indicated liver biopsies in the management of the LDLT population.