Interleukin-2 receptor antagonists for pediatric liver transplant recipients: a systematic review and meta-analysis of controlled studies.

IL-2RA are frequently used as induction therapy in liver transplant recipients to decrease the risk of AR while allowing the reduction of concomitant immunosuppression. The exact association with the use of IL-2RA, however, is uncertain. We performed a systematic literature search for relevant studies. Random effects models were used to assess the incidence of AR, steroid-resistant rejection, graft loss, patient death, and adverse drug reaction, with or without IL-2RA. Six studies (two randomized and four non-randomized) met the eligibility criteria. Acute rejection at six months or later favored the use of IL-2RA significantly (RR 0.38; 95% CI 0.22-0.66, p = 0.0005). Although not statistically significant, IL-2RA showed a substantial reduction of the risk of steroid-resistant rejection (RR 0.32; CI 0.19-1.03, p = 0.0594). Graft loss and patient death showed a reductive tendency through the use of IL-2RA. The use of IL-2RA is safe and is associated with a statistically significantly lower incidence of AR after transplantation and substantial reduction of steroid-resistant rejection, graft loss, and patient death.

Erythropoietin rs1617640 G allele associates with an attenuated rise of serum erythropoietin and a marked decline of hemoglobin in hepatitis C patients undergoing antiviral therapy.

BACKGROUND: A decline in hemoglobin (Hb) concentration during antiviral therapy in chronic hepatitis C (CHC) is a serious side effect. It may compel to dose reduction or even termination of antiviral treatment. The activation of erythropoietin (EPO) synthesis as a physiological response to anemia and its relation to a genetic variation within the EPO gene has not been evaluated yet. METHODS: Data of 348 CHC patients were reviewed retrospectively. Samples were genotyped for EPO rs1617640 and inosine triphosphatase (ITPA) rs1127354. Serum EPO concentrations were determined before and during therapy. Primary endpoints were set as Hb decline >3 g/dl at weeks 4 and 12. RESULTS: EPO rs1617640 G homozygotes showed a significantly lower rise of serum EPO level over time than T allele carriers (p < 0.001). The cumulative frequency of a significant Hb reduction added up to 40%. Multivariate analysis revealed that besides age, ribavirin starting dose and baseline Hb also EPO rs1617640 G homozygosity associates with Hb reduction at week 4 (p = 0.025) and 12 (p = 0.029), while ITPA C homozygotes are at risk for Hb decline particularly early during treatment. Furthermore, EPO rs1617640 G homozygotes were more frequently in need for blood transfusion, epoetin-α supplementation, or ribavirin dose reduction (p < 0.001). CONCLUSIONS: Our data suggest that EPO rs1617640 genotype, the rise of serum EPO concentration as well as ITPA rs1127354 genotype are promising parameters to evaluate the Hb decline during antiviral therapy. A rational adjustment of therapy with epoetin-α supplementation might prevent serious adverse events or the need to terminate treatment.

Treatment of chronic HCV genotype 1 infection with telaprevir: a Bayesian mixed treatment comparison of fixed-length and response-guided treatment regimens in treatment-naïve and -experienced patients.

BACKGROUND: Telaprevir (TVR) has been approved for response-guided-therapy (RGT) of chronic hepatitis C (HCV) genotype-1-infection in treatment-naïve and -experienced patients. In RGT-regimens patients that did not achieve extended rapid-virological-response (eRVR) within the first 4-12 weeks undergo treatment for 48-weeks, whereas in fixed-length-treatment (FLT) patients are treated for a fixed-duration regardless of their RVR. METHODS: This systematic review and Bayesian mixed-treatment-comparison (MTC) aimed to compare the efficacy and safety of standard-therapy with pegylated-interferon-α/ribavirin (Peg-IFN-α/RBV (48 weeks), group A), FLT with TVR, Peg-IFN-α/RBV for 12 weeks with a long (+36 weeks, group B) or short (+12 weeks, group C) tail of Peg-IFN-α/RBV treatment, and RGT with 12 weeks of TVR, Peg-IFN-α/RBV followed by 12 weeks of Peg-IFN-α/RBV (group D) or no therapy (group E). RESULTS: We identified seven randomized controlled trials including 3505 patients. Compared to standard-treatment (group A), treatment-naïve patients allocated to groups B, C, and D were significantly more likely to achieve sustained-virological-response (SVR, odds ratios (OR): B vs. A 3.5 (credibility interval [CrI] 2.2-5.4), C vs. A 3.0 (CrI 1.8-4.9), D vs. A 3.4 (CrI 2.5-4.6)). Treatment-experienced patients achieved increased SVR rates when they were treated in group B (OR: 8.2 (CrI 5.0-13.5)), C (OR 7.0 (CrI 3.9-12.8)), or simulated group D (OR 8.2 (CrI 4.3-15.3)). Patients treated with short RGT (simulated group E) did also have a significant improvement when they were treatment-experienced (simulated OR 3.6 (CrI 1.6-8.2)), whereas the effect was not significant in treatment-naïve patients (OR E vs. A 1.6 (CrI 0.9-2.7)). CONCLUSION: Long FLT and RGT regimens are useful treatment options for HCV-genotype-1 in both treatment-naïve and -experienced patients. A short 24-weeks FLT regimen does not seem to be inferior and should further be evaluated in clinical trials to reduce side effects and costs of treatment.

Vitamin D status and serum ferritin concentration in chronic hepatitis C virus type 1 infection.

The circulating 25-hydroxylated form of vitamin D(3), 25(OH)D, and serum ferritin concentrations have been described to be associated with disease progression in chronic hepatitis C. Both parameters also have been assessed with regard to treatment outcome, however, with divergent results. This study examined both the pre- and posttreatment serum concentrations of 25(OH)D and ferritin in 191 patients infected chronically with hepatitis C virus (HCV) type 1 with regard to liver inflammatory activity (grading), disease progression in terms of fibrosis (staging) and an antiviral treatment outcome. Mean pretreatment serum 25(OH)D and ferritin concentrations were 18 ± 10 ng/ml and 280 ± 225 µg/L, respectively. Multivariate analysis revealed lower pretreatment serum 25(OH)D and higher ferritin concentrations to be significantly related to both severity of inflammatory activity and of fibrotic alterations. Pretreatment serum ferritin concentration, furthermore, unlike 25(OH)D concentration, was found to be associated with a sustained virological response by uni- and multivariate analyses. A sustained virological response was featured by a significant increase in serum 25(OH)D levels (18 ± 10 ng/ml vs. 22 ± 11 ng/ml; P < 0.01), a reduction of serum ferritin concentration (191 ± 156 µg/L vs. 103 ± 63 µg/L; P < 0.001) and a normalization of serum alanine aminotransferase (ALT) and γ-glutamyl-transferase (γ-GT) activities. Taken together, decreased 25(OH)D and increased ferritin serum levels indicate the severity of hepatic inflammation and fibrosis in patients infected chronically with HCV type 1. Elevated ferritin, furthermore, was found to be an independent predictor for standard IFN-based therapy responsiveness.

Ten years survival with excellent outcome after living donor liver transplantation from 70 years old donor for primary hepatic neuroendocrine carcinoma: Case report.

BACKGROUND: Primary hepatic carcinoid tumors (PHCT) are rare entities; they are even rarer than extrahepatic neuroendocrine gastrointestinal tumors with only about 95 cases reported in the literature. An extrahepatic primary tumor must be excluded to confirm the diagnosis of PHCT. CASE PRESENTATION: We report a case of a 42-year-old male patient with a primary hepatic neuroendocrine carcinoma, who successfully underwent living donor liver transplantation from his 70 years old mother with 10 years follow-up. Both donor and recipient are still alive and in the good health. CONCLUSION: Living liver donation from elderly donors for the patients with irresectable neuroendocrine liver malignancies can be as safe as deceased donation or liver donation from young donors (age < 50). Living donation from elderly donors might significantly expand the donor pool for patients with liver neuroendocrine tumors (NET) and potentially reduce waiting list mortality. Especially young patients with irresectable NET can benefit from this option. However, case-control studies are needed to verify the advantage of living liver transplantation (LDLT) for the patients with irresectable liver NET and to define selection criteria for these patients.

Ultra-rapid virological response, young age, low γ-GT/ALT-ratio, and absence of steatosis identify a subgroup of HCV Genotype 3 patients who achieve SVR with IFN-α(2a) monotherapy.

BACKGROUND AND AIMS: The standard treatment regimen for chronic HCV genotype 3 (HCV-G3) hepatitis consists of PEGylated interferon-α (IFN-α) and ribavirin at varying doses ranging from 400 to 1,200 mg and results in response rates of 80%. However, this therapy has substantial side-effects including anemia, is teratogenic, and costly. To reduce the side-effects of therapy, the role of monotherapy consisting of only IFN-α was investigated. METHODS: A retrospective analysis of individual therapy courses of HCV-G3-infected patients who were treated with IFN-α(2a) monotherapy or a combination therapy with attention to the treatment outcome and the presence of IL28B rs12979860 and IL28B rs8099917 single-nucleotide polymorphism genotypes was performed. Conventional prognostic features in each case were assessed as well. RESULTS: In the study, 15/30 (50%) of patients treated with IFN-α(2a) monotherapy and 32/36 (89%) treated with combination therapy achieved a sustained virological response (SVR). In addition, 7/11 (64%) of those treated initially with monotherapy and subsequently with combination therapy achieved an SVR. An "ultra-rapid" virological response occurring within 2 weeks of initiation of therapy (p = 0.005), young age (<40; p < 0.001) and low initial γ-GT/ALT-ratio (p = 0.03) were associated with a SVR to IFN-α(2a) monotherapy. An SVR in those treated with combination therapy was found to be associated with a rapid virological response (RVR) (p = 0.03). The absence of histologic steatosis was associated with SVR in all patient groups (p = 0.01). Therapy duration (24 vs. 48 weeks) did not affect the SVR in either group. As expected, combination therapy resulted in more hematological side-effects than did monotherapy. CONCLUSIONS: An "ultra-rapid" virological response, young age, low initial γ-GT/ALT-ratio and absence of steatosis were each associated with an SVR in those receiving IFN-α(2a) monotherapy. Therefore, monotherapy in these patients should still be discussed independently of the existence of the IL28B polymorphisms.

Liver transplantation in patients with liver cirrhosis and active pneumonia: an observational study.

Patients with chronic liver disease are at high risk for severe infection because of increased bacterial translocation and immune suppression associated with liver dysfunction. Patients presenting with severe pneumonia and acute decompensation of cirrhosis are generally not considered for liver transplantation because it is unknown if these patients can recover from infection while under immunosuppression. We performed an observational study where patients with cirrhosis of the liver remained on the waiting list, although suffering from active pneumonia. Nine patients were included, but only six patients improved under goal-directed therapy and subsequently underwent liver transplantation. All six patients recovered quickly from infection; five patients recovered without sequelae and one patient died because of late complications. We propose that in patients with chronic liver disease and active pneumonia transplantation is a treatment option that should not hastily be abandoned.

Dental care and oral health in solid organ transplant recipients: a single center cross-sectional study and survey of German transplant centers.

Aim of this study was to collect information about oral health of patients before and after SOT as well as information about center-based recommendations for dental care. In a single center cross-sectional study, the oral situation of 20 patients before and 20 after SOT were examined including dental (DMF-T), periodontal (PSR(®)/PSI), and oral hygiene findings (modified QHI). In a second project, a survey among 50 transplant centers in Germany was questioned regarding their recommendations for dental care of SOT recipients. Patients before and after SOT showed similar quality of dental findings (DMF-T), but worse compared to the general population. In addition, most patients in both groups showed pronounced periodontal treatment need (PSR(®)/PSI score 3 or 4). Oral hygiene findings (modified QHI) after SOT were significantly worse than in patients on the waiting list (P = 0.032). In a second project, the questionnaire was returned by 28 of 50 centers. Interpretation of data showed that 89% carry out a dental examination before SOT and 67% contacted the patients' dentists. After SOT, 83% of the transplant centers recommend antibiotic cover before dental measures. The results of our study revealed lacks in the dental care of SOT recipients. Consistent recommendations regarding the dental care of patients before and after SOT should be determined.

Interleukin 2 receptor antagonists for liver transplant recipients: a systematic review and meta-analysis of controlled studies.

UNLABELLED: Interleukin 2 receptor antagonists (IL-2Ra) are frequently used as induction therapy in liver transplant recipients to decrease the risk of acute rejection while allowing the reduction of concomitant immunosuppression. We conducted a systematic review of prospective, controlled studies to test the hypothesis that the use of IL-2Ra is associated with a decrease in acute rejection and/or a decrease in the side effects of concomitant medication. We performed a search of all major databases and secondary sources from inception to December 2010. Random effects models were used to assess the incidence of acute rejection, graft loss, patient death, and adverse side effects, with or without IL-2Ra. Subgroup analysis and meta-regression were used to explore differences in effect and sources of heterogeneity. Eighteen studies (13 randomized and 5 nonrandomized) met the inclusion and exclusion criteria. Acute rejection at 12 months or later favored the use of IL-2Ra (relative risk [RR] 0.83; 95% confidence interval [CI] 0.76-0.94) and steroid-resistant rejection was also less frequent in patients receiving IL-2Ra (RR 0.66; CI 0.48-0.91). Graft loss and patient death did not differ significantly between treatments. Patients who received IL-2Ra in addition to reduced or delayed calcineurin inhibitors had better renal function (mean difference of estimated glomerular filtration rate: 6.29 mL/min; CI 1.66-10.91) and a lower incidence of renal dysfunction (RR 0.46; CI 0.27-0.78). The use of IL-2Ra was also associated with a lower incidence of posttransplant diabetes mellitus, whereas the incidence of other adverse events was similar. CONCLUSION: The use of IL-2Ra is associated with a lower incidence of acute rejection after transplantation. Concomitant immunosuppression can be reduced, avoiding long-term side effects of immunosuppression.

Posterior cavoplasty: a new approach to avoid venous outflow obstruction and symptoms for small-for-size syndrome in right lobe living donor liver transplantation.

PURPOSE: A common and serious problem after living donor liver transplantation (LDLT) of small grafts is small-for-size syndrome (SFSS). Although hyperdynamic portal inflow and portal hypertension are cornerstones in the development of SFSS, inadequate outflow may aggravate SFSS. Therefore, enlargement of the portal outflow tract by incision of the anterior rim of the orifice of the right hepatic vein (RHV) has been advocated for right lobe LDLT. But backwards tilt of a small graft into a large abdominal cavity may lead to a choking of the otherwise large anastomosis and thus we propose posterior enlargement of the orifice of the RHV. METHOD: In this test-of-concept study, we evaluated portal vein pressure (PVP), clinical parameters, and laboratory measurements in 22 patients that underwent right lobe LDLT and either received standard end-to-end anastomosis of the RHV or posterior cavoplasty. RESULTS: In patients that underwent posterior cavoplasty, we observed significantly lower PVP and less hyperbilirubinemia. There was a non-significant trend to lower incidence of SFSS. Other laboratory measurements and clinical parameters were not significantly different. CONCLUSION: We recommend posterior cavoplasty for enlargement of the hepatic venous outflow tract in right lobe LDLT as a method to avoid portal hypertension, hyperbilirubinemia, and possibly SFSS, especially in patients that receive small grafts.

Tissue damage with different surgical techniques in a porcine model of liver resection: implications for living-donor liver transplantation?

BACKGROUND/PURPOSE: For living-donor liver transplantation (LDLT) it is of paramount importance to preserve as much viable liver tissue as possible to avoid postoperative complications in the donor and recipient. The depth of tissue damage caused by common surgical techniques for liver resection has not been studied so far. METHODS: Here we compared the depth of tissue damage and the immunohistochemical expression of heat shock protein (HSP) 70, a marker for tissue damage, in a porcine model of liver resection, to assess the effect of different surgical techniques, i.e., blunt dissection (BD), and dissection with an ultrasound aspirator (UA), an ultrasound scalpel (US), or a water-jet (WJ). RESULTS: Analysis with linear mixed effects models (LME) showed significantly less tissue damage with BD and UA than with US and WJ (joint p value <0.001). Damage also increased within 6 h after surgery (p value = 0.004). Semiquantitative evaluation of HSP 70 showed increased expression after resection with US compared to all other resection methods (p value <0.001), indicating increased tissue damage with this method. CONCLUSION: We suggest that in cases of liver resection for LDLT surgeons should reevaluate using US and WJ because of possible excessive tissue damage compared to BD and UA. Overall we advocate the use of BD as it requires no special equipment and, hence, has considerably higher cost-effectiveness without compromising tissue preservation and clinical outcome and is readily available even in low-tech environments.

A therapeutic exploratory study to determine the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation: CILT.

BACKGROUND: Immunosuppression with calcineurin inhibitors (CNI) increases the risk of renal dysfunction after orthotopic liver transplantation (OLT). Controlled trials have shown improvement of renal function in patients that received delayed and/or reduced-dose CNI after OLT. Delaying immunosuppression with CNI in combination with induction therapy does not increase the risk of acute rejection but reduces the incidence of acute renal dysfunction. Based on this clinical data this study protocol was designed to assess the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation. METHODS/DESIGN: A prospective therapeutic exploratory, non-placebo controlled, two stage monocenter trial in a total of 29 liver transplant patients was designed to assess the safety and efficacy of de-novo CNI-free immunosuppression with basiliximab, mycophenolate sodium, prednisolone and everolimus. The primary endpoint is the rate of steroid resistant rejections. Secondary endpoints are the incidence of acute rejection, kidney function (assessed by incidence and duration of renal replacement therapy, incidence of chronic renal failure, and measurement glomerular filtration rate), liver allograft function (assessed by measurement of AST, ALT, total bilirubin, AP, GGT), treatment failure, (i. e., re-introduction of CNI), incidence of adverse events, and mortality up to one year after OLT. DISCUSSION: This prospective, two-stage, single-group pilot study represents an intermediate element of the research chain. If the data of the phase II study corroborates safety of de-novo CNI-free immunosuppressive regimen this should be confirmed in a randomized, prospective, controlled double-blinded clinical trial. The exploratory data from this trial may then also facilitate the design (e. g. sample size calculation) of this phase III trial. TRIAL REGISTRATION NUMBER: NCT00890253 (clinicaltrials.gov).

Acute paranoid psychosis as sole clinical presentation of hepatic artery thrombosis after living donor liver transplantation.

BACKGROUND: Hepatic artery thrombosis is a devastating complication after orthotopic liver transplantation often requiring revascularization or re-transplantation. It is associated with considerably increased morbidity and mortality. Acute cognitive dysfunction such as delirium or acute psychosis may occur after major surgery and may be associated with the advent of surgical complications. CASE PRESENTATION: Here we describe a case of hepatic artery thrombosis after living-donor liver transplantation which was not preceded by signs of liver failure but rather by an episode of acute psychosis. After re-transplantation the patient recovered without sequelae. CONCLUSION: This case highlights the need to remain cautious when psychiatric disorders occur in patients after liver transplantation. The diagnostic procedures should not be restricted to medical or neurological causes of psychosis alone but should also focus vascular complications related to orthotopic liver transplantation.

Fourteen-year survival of a renal graft reused 2 years after initial transplantation: a case report.

We report on the successful regrafting of a transplanted kidney. The donor kidney was first transplanted into a 32-year-old patient with renal atrophy. More than 2 years later, he suffered from severe grand mal seizure with brain edema and the patient met the criteria for brain death. The well-functioning graft was recovered and subsequently transplanted into a 66-year-old woman with chronic glomerular nephritis. Neither the first nor the second recipient experienced any acute rejection. To date, more than 14 years later, she is in good health with excellent graft function. This case report implies that excellent long-term graft function is viable in a graft reused 2 years after the initial transplantation.

Adult Living Donor Liver Transplantation with ABO-Incompatible Grafts: A German Single Center Experience.

Adult living donor liver transplantations (ALDLTs) across the ABO blood group barrier have been reported in Asia, North Americas, and Europe, but not yet in Germany. Several strategies have been established to overcome the detrimental effects that are attached with such a disparity between donor and host, but no gold standard has yet emerged. Here, we present the first experiences with three ABO-incompatible adult living donor liver transplantations in Germany applying different immunosuppressive strategies. Four patient-donor couples were considered for ABO-incompatible ALDLT. In these patients, resident ABO blood group antibodies (isoagglutinins) were depleted by plasmapheresis or immunoadsorption and replenishment was inhibited by splenectomy and/or B-cell-targeted immunosuppression. Despite different treatments ALDLT could safely be performed in three patients and all patients had good initial graft function without signs for antibody-mediated rejection (AMR). Two patients had long-term graft survival with stable graft function. We thus propose the feasibility of ABO-incompatible ALDLT with these protocols and advocate further expansion of ABO incompatible ALDLT in multicenter trials to improve efficacy and safety.