Protective role of tauroursodeoxycholate during harvesting and cold storage of human liver: a pilot study in transplant recipients

BACKGROUND: Ischemia-reperfusion injury is a major cause of early graft dysfunction after liver transplantation. Tauroursodeoxycholic acid (TUDCA), a natural amidated hydrophilic bile salt, protects from cholestasis and hepatocellular damage in a variety of experimental models, as well as from ischemia-reperfusion injury. We investigated in the human liver transplantation setting the effect of the addition of TUDCA at time of liver harvesting and cold storage on the intra- and postoperative enzyme release and liver histopathology at the end of cold storage, at reperfusion, and 7 days after transplantation. METHODS: Eighteen patients undergoing elective liver transplantation were studied, including 6 serving as controls. In six patients, TUDCA was added to the University of Wisconsin solution used during harvesting and cold storage, to reach final concentrations of 2 mM. In three of these patients, TUDCA (3 g) was infused in the portal vein of the donor before organ explantation; in the other three cases, TUDCA was given through both routes. RESULTS: The use of TUDCA did not cause adverse events. The release of aspartate aminotransferase in the inferior vena cava blood during liver flushing was significantly lower (P=0.05) in TUDCA-treated than in control grafts, as were cytolytic enzyme levels in peripheral blood during the first postoperative week (P<0.02). At electron microscopy, an overt endothelial damage (cytoplasmic vacuolization, cell leakage, and destruction with exposure of hepatocytes to the sinusoidal lumen) was invariably found in control grafts, both at reperfusion and at day 7 after transplant. These features were significantly ameliorated by TUDCA (P<0.001). Several ultrastructural cytoplasmic abnormalities of hepatocytes were seen. Among these, damage to mitochondria matrix and crystae was significantly reduced in TUDCA-treated versus control grafts (P<0.01). Mild to severe damage of bile canaliculi was a constant feature in control biopsies, with dilatation of canalicular lumen and loss of microvilli. Both these abnormalities were markedly ameliorated (P<0.001 by TUDCA). The best preservation was observed when TUDCA was given through both routes. CONCLUSIONS: The use of TUDCA during harvesting and cold storage of human liver is associated with significant protection from ischemia-reperfusion injury. The clinical significance of this findings must be studied.     

Cardiovascular morbidity and obesity in adult liver transplant recipients

There is a direct relationship between the grade of obesity and mortality based on the increased cardiovascular diseases, cancer, etc. However, the results of studies in renal and liver allograft recipients relating obesity to morbidity and mortality are contradictory. A retrospective cohort study of 170 patients transplanted between March 1987 and July 1997 showed obesity to be identified in 77 (45.3%) patients. During the mean follow-up of 5 years posttransplantation, 16 (9.4%) patients experienced cardiovascular complications, including 10 patients with ischemic cardiac syndromes (five acute infarctions and five angina), five patients with acute cerebrovascular accidents, and one patient with intermittent lower limbs claudication. The prevalence of obesity at 1, 3, 5, 7, and 9 years after transplantation was 58.2%, 56.9%, 60.3%, 59.5%, and 66.4%, respectively. Compared with the baseline value, the BMI was increased at 1 year posttransplantation (25.78), a significant difference. No significant differences were found between the mean BMI values of patients with and without cardiovascular diseases, or overweight and morbidly obese patients compared to the normal weight population. Among liver transplant recipients, obesity was a frequent complication after transplantation, but it was not clearly associated with increased morbidity and mortality secondary to cardiovascular disease.     

Reduction of cyclosporine following the introduction of everolimus in maintenance heart transplant recipients: a pilot study

Data are scarce concerning the calcineurin inhibitor dose reduction required following introduction of everolimus in maintenance heart transplant recipients to maintain stable renal function. In a 48-week, multicenter, single-arm pilot study in heart transplant patients >12 months post-transplant, everolimus was started at 1.5 mg/day (subsequently adjusted to target C ₀ 5–10 ng/ml). Mycophenolate mofetil or azathioprine was discontinued on the same day and cyclosporine (CsA) dose was reduced by 25%, with a further 25% reduction each time calculated glomerular filtration rate (cGFR) decreased to <75% of baseline. Of 36 patients enrolled, 25 were receiving everolimus at week 48. From baseline to week 48, there was a mean decrease of 44.5%, 50.9% and 44.6% in CsA dose, C ₀ and C ₂, respectively. Mean cGFR was 68.9 ± 14.5 ml/min at baseline and 61.6 ± 11.5 ml/min at week 48 ( P  = 0.018). The prespecified criterion for stable renal function was met, i.e. a mean decrease ≤25% of cGFR from baseline. Two patients experienced biopsy-proven acute rejection Grade 3A (5.6%). Between baseline and week 48, there were significant increases in total cholesterol, LDL-cholesterol and triglycerides, and small but significant elevations in liver enzymes. This 1-year pilot study suggests that CsA dose reduction of ca. 40% after initiation of everolimus was associated with a decrease in cGFR, however, based on the prespecified criteria stable renal function was attained.     

Community-based weight management in long-term heart transplant recipients: a pilot study

BACKGROUND: Heart transplant recipients often suffer from obesity, dyslipidemia, and hypertension thought to be related to triple-drug immunosuppression and poor adherence to diet and exercise. A lifestyle intervention that allows recipients to attend a community-based weight management program may improve health outcomes. OBJECTIVE: To determine (1) the effects of attending a community-based weight management program on weight, systolic and diastolic blood pressure, and the lipid profile; and (2) the feasibility of a community-based program for weight management. METHODS: Twenty-one patients (81% male; age 57 years, 99.7 months since transplantation) participated in a randomized clinical trial and received either weight management counseling (control) or a 6-month scholarship to a structured commercial program (treatment). Using simple analysis of covariance models, group differences were assessed and reported as marginal means. RESULTS: At baseline, there were no demographic differences between groups. There were no differences in outcome variables except weight (control, 102.1 kg vs treatment, 98.3 kg; P= .05). After 6 months, significant differences were found in weight (control, 100.5 kg vs treatment, 95.6 kg; P= .047) and high-density lipoprotein cholesterol (control, 40.6 mg/dL vs treatment, 49.1 mg/dL; P= .044). A marginally significant difference was found in systolic blood pressure (control, 138 mm Hg vs treatment, 121 mm Hg; P= .07). A decrease in diastolic blood pressure (6 mm Hg) was attributed to treatment effect (P = .16). No differences were noted in total cholesterol, triglycerides, or low-density lipoprotein cholesterol. CONCLUSIONS: The structured commercial program appears to be an effective, feasible alternative to usual care. Findings need to be confirmed in future research with a larger sample.     

Persistent fatigue in liver transplant recipients: a two-year follow-up study

Background:  Fatigue after liver transplantation (LTx) is a major problem that is associated with lower daily functioning and health-related quality of life (HRQoL). This study aimed to assess changes over time in fatigue following LTx. We also examined daily functioning and HRQoL changes over time and assessed the influence of fatigue and changes in fatigue on daily functioning and HRQoL. We determined whether sleep quality, anxiety, and depression were associated with fatigue.
Methods:  We identified 70 LTx recipients who had previously participated in a cross-sectional study and reassessed them after two yr to determine changes in level of fatigue, daily functioning, and HRQoL. We also assessed sleep quality, anxiety, and depression after two yr.
Results:  Level of fatigue and level of daily functioning were unchanged at follow-up. HRQoL domains remained stable or worsened. Fatigue was a significant predictor of daily functioning and all HRQoL domains (p < 0.01). Change in fatigue was a significant predictor of daily functioning and the HRQoL domains of "physical functioning,""vitality," and "pain" (p < 0.05). Sleep quality, anxiety, and depression were associated with fatigue severity (r = 0.35 to r = 0.60, p < 0.05).
Conclusion:  This longitudinal study shows that fatigue is a chronic problem after LTx and that daily functioning and HRQoL do not improve over time. This study supports the need for intervention programs to address fatigue after LTx.     

Antifungal prophylaxis in liver transplant recipients: a randomized placebo-controlled study

The aim of this study was to evaluate the efficacy of two antifungal prophylaxis regimens in liver transplant recipients. One hundred and twenty-nine consecutive recipients were randomized to receive sequential treatment with intravenous liposomal amphotericin B + oral itraconazole, intravenous fluconazole + oral itraconazole, or intravenous and oral placebo. Frequency and incidence of mycotic colonization, local and systemic infection of mycotic origin, causes of death, and possible risk factors for mycotic infection were evaluated. The incidence of mycotic colonization was higher in the placebo group ( P<0.01), but there was no significant difference in the incidence of infection between the three groups. Pre-transplant colonization, severity of liver disease, and graft rejection were all risk factors for the development of fungal infection. The routine use of antifungal prophylaxis for all liver transplant recipients does not seem to be justified.     

Graft outcomes following diagnosis of post‐transplant lymphoproliferative disease in pediatric kidney recipients: a retrospective study

Data related to graft outcomes following post‐transplant lymphoproliferative disease (PTLD) in pediatric kidney transplantation are scarce. Data were analyzed retrospectively from 12 children (eight boys) for 3 years after diagnosis of PTLD, with a loss of follow‐up after 2 years in two of 12. In all cases, intensity of immunosuppressive therapy was reduced, which switched from calcineurin inhibitor to a mammalian target of rapamycin (mTOR) inhibitor in ten cases. Nine children were treated with six doses of rituximab according to the PED‐PTLD‐2005 protocol, with additional treatment in one child as per protocol. One patient received EuroNet‐PHL C1. In four patients, donor‐specific antibodies were detected after PTLD diagnosis at 3, 4, 5 and 7 years, respectively. One patient developed chronic antibody‐mediated rejection (cAMR) 12 years after diagnosis, losing the graft 1 year later. Three patients with recurrence of the original disease also lost their grafts, one at the time of diagnosis of PTLD, and two after 4 years. Range‐based analysis of variance showed that there was no decrease in estimated GFR at 1, 2, or 3 years after diagnosis of PTLD (P = 0.978). In conclusion, treatment of PTLD with reduced immunosuppression is safe and efficient. This may be due to B‐cell‐depleting therapy of PTLD with rituximab.     

Gastrointestinal complications in liver transplant recipients: MITOS study

INTRODUCTION: Liver transplant recipients frequently suffer gastrointestinal (GI) complications but their prevalence and their influence on quality of life remain unknown. OBJECTIVE: The objective of this study was to asses the prevalence, impact on quality of life, and management of GI complications in liver transplant recipients. PATIENTS AND METHODS: This was an epidemiologic, cross-sectional, multicenter study. Four hundred seventeen liver recipients were recruited in 14 centers. A questionnaire was filled for every patient. RESULTS: The median age of the patients was 55 years. The median time since transplantation was 4.1 +/- 4 years. Whereas 19.2% presented some GI disease before transplantation, 49.4% showed this type of complication after transplantation. Diarrhea was the most prevalent GI complication, and anorexia was the GI disorder that affected patients daily activities the most frequently. GI complications were more frequent among female patients, subjects with pretransplantation hiatal hernia, and those readmitted after transplantation. Of the patients with GI complications, 70.9% received pharmacological treatment (89.7% with gastric protectors). Immunosuppressive therapy was also modified because of GI complications. Immunosuppressive drug dose was reduced in 18.1%, transiently stopped in 3.4%, and definitively stopped in 3.4% of cases. The drug most frequently changed was mycophenolate mofetil: dose reduction, 23.6%; transient withdrawal, 5.7%; and definitive withdrawal, 6.6%. CONCLUSIONS: The prevalence of GI complications in the liver transplant population was approximately 50%. GI complications showed a significant impact on the quality of life of the patients. They were related to female gender, to pretransplantation GI pathology, and posttransplantation hospital admission. These complications were frequently managed with pharmacological therapy or with changes in immunosuppressive therapy.     

Surgical site infection in living-donor liver transplant recipients: a prospective study

BACKGROUND: Infection is a constant threat for the living-donor liver transplantation (LDLT) recipients, although little information is available on the occurrence of infection in such patients. METHODS: One hundred and thirteen consecutive LDLT recipients were prospectively followed for the presence of surgical site infections (SSIs) defined by CDC from April 2001 to March 2002. Risk factors for SSIs were evaluated by univariate and multivariate analysis. RESULTS: Of the 113 LDLT recipients, 42 (37%) developed 57 episodes of SSIs (21 intraabdominal abscess, 20 peritonitis, 8 cholangitis, and 9 wound). Of the 57 episodes, 29 (51%) had secondary bacteremia in 19 patients. Causative pathogens, including 17 episodes of polymicrobial infections, were 37 gram-positive cocci (17 Staphylococcus aureus, 16 Enterococcus spp., and 4 others), 40 gram-negative rods (25 Enterobacteriaceae, 13 Pseudomonas aeruginosa, and 4 others), and 2 Candida albicans. Univariate analysis revealed that ABO incompatibility and repeat surgery were associated with the development of SSIs. Also, univariate analysis revealed that adult recipients, ABO incompatibility, total operation duration, repeat surgery, and NNIS risk index were associated with secondary bacteremia. Multivariate analysis revealed that ABO incompatibility (OR: 14.0; 95% CI, 2.52-77.2) and repeat surgery (OR: 9.29; 95% CI, 2.00-43.1) were independently associated with secondary bacteremia. Eleven of the 42 cases (26%) who developed SSIs died. Of these 11 cases, 5 (45%) developed secondary bacteremia within 30 days before death. CONCLUSION: SSIs occurred in 37% of LDLT recipients. ABO incompatibility and repeat surgery increased the risk of developing SSIs with secondary bacteremia, which correlated with poor prognosis.     

肝移植受者手术决策困境的质性研究

目的 探索肝移植受者手术决策过程中面临的困境,为促进医患共同参与肝移植手术决策提供参考.方法 采用目的 抽样法选取15例行肝移植术的受者进行深入访谈,采用Colaizzi七步法分析访谈资料.结果 肝移植受者手术决策困境包括3个主题:决策情境特殊,受者参与决策机会受限;决策内容复杂,受者参与决策过程艰难;决策主体消极,参与决策意愿及能力不足(健康信念缺乏;自我负担感沉重,过度依赖他人;手术决策相关信息缺乏).结论 肝移植受者手术决策过程中受到决策情境、决策内容及决策主体多方面因素共同影响.护士应指导肝移植受者及家属加强症状管理、辅导其参与共同决策并协助其提升健康素养,以保障受者临床决策参与权.     

Consequences of vancomycin-resistant Enterococcus in liver transplant recipients: a matched control study

BACKGROUND: Liver transplant recipients are at high risk for multi-drug resistant infections because of broad-spectrum antibiotic and immunosuppression. This study evaluates the clinical and financial impact of vancomycin resistant Enterococcus (VRE) in liver transplant recipients. METHODS: Liver transplant recipients with VRE from 1995 to 2002 were identified and matched (age, gender, UNOS status, liver disease and transplant date) to controls. Demographics, clinical factors, co-infections, antibiotic use, length of stay, abdominal surgeries, biliary complications, survival and resource utilization were compared with matched controls. RESULTS: Nineteen patients were found to have 28 VRE infections via evaluation of microbiologic culture results of all liver transplant patients in the transplant registry. Thirty-eight non-VRE patients served as matched controls. The four most common sites VRE was cultured from included blood (35%), peritoneal fluid (35%), bile (20%), and urine (12%). Median time from transplant to infection was 48 d (range of 4-348). No significant differences in demographics were observed. The VRE group had a higher incidence of prior antibiotic use than the non-VRE group (95% vs. 34%; p < 0.05). The VRE group also experienced more abdominal surgery (20/19 vs. 3/38; p = 0.029), biliary complications (9/19 vs. 9/38; p = 0.018) and a longer length of stay (42.5 vs. 21.7 d; p = .005). Survival in the VRE group was lower (52% vs. 82%; p = 0.048). Six of the 19 VRE patients were treated with linezolid for eight infection episodes, and four of six patients survived. Eight patients were treated with quinupristin/dalfopristin for nine infections, and two of eight survived. Increased cost of care was observed in the VRE group. Laboratory costs were higher in the VRE group (6500 dollars vs. 1750; p = 0.02) as well. CONCLUSION: VRE was associated with prior antibiotic use, multiple abdominal surgeries, biliary complications and resulted in decreased survival compared to non-VRE control patients. VRE patients also utilized more hospital resources. Linezolid showed a trend toward improved survival.     

肾移植受者新型冠状病毒肺炎的流行病学特征：单中心回顾性研究

目的  探讨肾移植受者新型冠状病毒肺炎（新冠肺炎）的流行病学特征,分析新型冠状病毒（新冠病毒）感染重型/危重型的危险因素及保护因素。 方法  回顾性分析感染新冠病毒的468例肾移植受者的临床资料,按感染严重程度分为新冠病毒感染轻型受者（439例）和新冠肺炎组（29例）。将439例新冠病毒感染轻型受者按性别、年龄、移植时间与新冠肺炎组以3∶1进行随机配比的87例受者分为新冠病毒感染轻型组。将29例新冠肺炎组受者分为新冠肺炎中型组（21例）及新冠肺炎重型/危重型组（8例）。收集受者一般资料,分析肾移植受者新冠病毒感染的危险因素及保护因素。 结果  新冠肺炎组受者合并症种类2～3种的比例高于新冠病毒感染轻型组,新冠肺炎组受者采用他克莫司（Tac）+咪唑立宾+糖皮质激素免疫抑制方案的比例低于新冠病毒感染轻型组,差异均有统计学意义（均为P<0.05）。29例新冠肺炎组肾移植受者患新冠肺炎后白细胞、淋巴细胞绝对值、嗜酸性粒细胞绝对值、总T细胞绝对值、CD4⁺T细胞绝对值、CD8⁺T细胞绝对值及血尿酸较患新冠肺炎前明显下降,铁蛋白水平升高,差异均有统计学意义（均为P<0.05）。与新冠肺炎中型组比较,重型/危重型组受者低氧血症的比例更高,采用Tac/环孢素（CsA）+霉酚酸酯+糖皮质激素免疫抑制方案的受者比例更高,接种2～3针新型冠状病毒疫苗（新冠疫苗）者比例更少,差异均有统计学意义（均为P<0.05）。 结论  肾移植受者合并症多、使用含霉酚酸酯的免疫抑制方案是新冠病毒感染的危险因素,接种新冠疫苗、使用含咪唑立宾的免疫抑制方案可能是降低新冠病毒感染率的保护因素,炎症因子水平与新冠肺炎的严重程度相关。     

Cardiovascular mortality among liver transplant recipients with nonalcoholic steatohepatitis in the United States—a retrospective study

Nonalcoholic steatohepatitis (NASH) has become an increasingly important indication for liver transplantation (LT), and there has been a particular concern of excessive cardiovascular‐related mortality in this group. Using the United Network for Organ Sharing‐Standard Transplant Analysis and Research (UNOS STAR) dataset, we reviewed data on 56,995 adult transplants (January 2002 through June 2013). A total of 3,170 NASH liver‐only recipients were identified and were matched with 3,012 non‐NASH HCV+ and 3,159 non‐NASH HCV? controls [matched 1:1 based on gender, age at LT (±3 years), and MELD score (±3)]. Cox regression analysis revealed significantly lower hazard of all‐cause (HR 0.669; P < 0.0001) and cardiovascular‐related mortality (HR 0.648; P < 0.0001) in the NASH compared to the non‐NASH group after adjusting for diabetes, BMI, and race. Relative to the non‐NASH HCV‐positive group, NASH group has lower hazard of all‐cause (HR 0.539; P < 0.0001) and cardiovascular‐related mortality (HR 0.491; P < 0001). A lower hazard of all‐cause mortality (HR 0.844; P = 0.0094) was also observed in NASH patients compared to non‐NASH HCV‐negative group, but cardiovascular mortality was similar (HR 0.892; P = 0.3276). LT recipients with NASH have either lower or similar risk of all‐cause and cardiovascular‐related mortality compared to its non‐NASH counterparts after adjusting for diabetes, BMI, and race.     

A pilot study on the characteristics of circulating T follicular helper cells in liver transplant recipients

Circulating CD4⁺ CXCR5⁺ T follicular helper cells (cTfh) have been demonstrated to be involved in B cell-mediated systemic autoimmune diseases and alloreactive responses following kidney transplantation; however, whether cTfh cells are involved in alloreactive responses after liver transplantation (LT) remains unclear. Our present study aimed to investigate the characteristics of cTfh, as well as CXCR3⁺ CCR6⁻ Tfh1, CXCR3⁻ CCR6⁻ Tfh2, and CXCR3⁻ CCR6⁺ Tfh17 subsets in liver allograft recipients. A total of 30 liver transplant recipients were enrolled in this study. The frequencies of cTfh, Tfh1, Tfh2, and Tfh17 subsets, and interleukin (IL)-21-producing Tfh cells in the circulating blood were analyzed by flow cytometry. The capacity of cTfh cells to help B cells differentiate into plasmablasts was determined one day before and one month after LT. The results revealed that the frequency of cTfh cells remained unaltered before and after LT. However, the frequency of the cTfh subsets (e.g., Tfh1 and Tfh2 cells) and B cells were reduced one month after LT. Functionally, the capacity of Tfh cells to produce IL-21 was reduced one month after LT. In addition, cTfh cells exhibited the capacity to help B cells differentiate into plasmablasts in an IL-21-dependent manner in vitro, which was reduced after LT, despite the unaltered production of IgM and IgG by plasmablasts. Thus, our data suggest that cTfh cells may be involved in alloreactive responses following LT via helping B cells differentiate into plasmablasts and plasma cells.     

Relationship between postoperative erythromycin breath test and early morbidity in liver transplant recipients

BACKGROUND: Interindividual variability in dosage requirements of the calcineurin inhibitor immunosuppressive agents cyclosporine and tacrolimus after liver transplantation may result from differences in the CYP3A activity of the liver graft. Early postoperative erythromycin breath test (ERMBT) is an in vivo measure of graft CYP3A activity. This study evaluates the usefulness of an early postoperative ERMBT in predicting early morbidity in liver transplant recipients. METHODS: In 26 liver transplant recipients, ERMBT was performed within 2 hr after transplantation. Main end points were the occurrence of cyclosporine and tacrolimus nephrotoxicity, episodes of early graft rejection, early graft function, and graft survival. RESULTS: Cyclosporine and tacrolimus nephrotoxicity were associated with low postoperative ERMBT values (mean 0.63%+/-0.25% 14C/hr vs. 1.35%+/-0.84% 14C/hr, P=0.02). No significant association between early graft rejection and ERMBT values was demonstrated. There was a significant inverse correlation between postoperative ERMBT values and the time to normalization of international normalized ratio as a measure of early graft function (r=-0.78, P<0.001). Graft loss was associated with low postoperative ERMBT values (0.21%+/-0.15% 14C/hr vs. 1.09%+/-0.72% 14C/hr, P=0.002). CONCLUSION: An early postoperative ERMBT may be useful in predicting the development of cyclosporine and tacrolimus nephrotoxicity, severe graft dysfunction, or even graft loss in liver transplant recipients when calcineurin inhibitors are administered according to protocols. Whether ERMBT results may be used to individualize dosage of calcineurin inhibitors needs to be explored.     

Possible therapeutic effect of lipid supplementation on neurological complications in liver transplant recipients

Neurological complications (NCs) represent a serious problem following liver transplantation and may develop either because of various peri-operative factors or the toxicity of immunosuppression. Although the causality assessment of NCs can be particularly difficult in the setting of organ transplantation, calcineurin inhibitors (CNIs) might influence NCs to a certain extent, regardless of the etiology. Therefore, minimizing the influence of CNIs could be a reasonable strategy for alleviating NCs. Based on our hypothesis that lipid supplementation prevents lipophilic CNIs from crossing the blood-brain barrier, soybean oil was administered to five liver transplant patients with NCs. In all of these patients, the neurological symptoms improved without discontinuing or reducing the dose of CNIs. Thus, lipid supplementation might be able to reduce the adverse neurological effects of CNIs.