Immunosuppression in patients with grade 3 acute-on-chronic liver failure at transplantation: A practice analysis study.

Transplantation for patients with acute-on-chronic liver failure grade 3 (ACLF3) has encouraging results with 1-year-survival of 80-90%. These patients with multiple organ failure meet the conditions for serious alterations of drug metabolism and increased toxicity. The goal of this study was to identify immunosuppression-dependent factors that affect survival. This retrospective monocentric study was conducted in patients with ACLF3 consecutively transplanted between 2007 and 2019. The primary endpoint was 1-year survival. Secondary endpoints were overall survival, treated rejection, and surgical complications. Immunosuppression was evaluated as to type of immunosuppression, post-transplant introduction timing, trough levels, and trough level intra-patient variability (IPV). One hundred patients were included. Tacrolimus IPV < 40% (P = .019), absence of early tacrolimus overdose (P = .033), use of anti-IL2-receptor antibodies (P = .034), and early mycophenolic acid introduction (P = .038) predicted 1-year survival. Treated rejection was an independent predictor of survival (P = .001; HR 4.2 (CI 95%: 1.13-15.6)). Early everolimus introduction was neither associated with higher rejection rates nor with more surgical complications. Management of immunosuppression in ACLF3 critically ill patients undergoing liver transplantation is challenging. Occurrence and treatment of rejection impacts on survival. Early introduction of mTOR inhibitor seems safe and efficient in this situation.

Impact of real-time metabolomics in liver transplantation: Graft evaluation and donor-recipient matching.

BACKGROUND & AIMS: There is an emerging need to assess the metabolic state of liver allografts especially in the novel setting of machine perfusion preservation and donor in cardiac death (DCD) grafts. High-resolution magic-angle-spinning nuclear magnetic resonance (HR-MAS-NMR) could be a useful tool in this setting as it can extemporaneously provide untargeted metabolic profiling. The purpose of this study was to evaluate the potential value of HR-MAS-NMR metabolomic analysis of back-table biopsies for the prediction of early allograft dysfunction (EAD) and donor-recipient matching. METHOD: The metabolic profiles of back-table biopsies obtained by HR-MAS-NMR, were compared according to the presence of EAD using partial least squares discriminant analysis. Network analysis was used to identify metabolites which changed significantly. The profiles were compared to native livers to identify metabolites for donor-recipient matching. RESULTS: The metabolic profiles were significantly different in grafts that caused EAD compared to those that did not. The constructed model can be used to predict the graft outcome with excellent accuracy. The metabolites showing the most significant differences were lactate level >8.3 mmol/g and phosphocholine content >0.646 mmol/g, which were significantly associated with graft dysfunction with an excellent accuracy (AUROClactates = 0.906; AUROCphosphocholine = 0.816). Native livers from patients with sarcopenia had low lactate and glycerophosphocholine content. In patients with sarcopenia, the risk of EAD was significantly higher when transplanting a graft with a high-risk graft metabolic score. CONCLUSION: This study underlines the cost of metabolic adaptation, identifying lactate and choline-derived metabolites as predictors of poor graft function in both native livers and liver grafts. HR-MAS-NMR seems a valid technique to evaluate graft quality and the consequences of cold ischemia on the graft. It could be used to assess the efficiency of graft resuscitation on machine perfusion in future studies. LAY SUMMARY: Real-time metabolomic profiles of human grafts during back-table can accurately predict graft dysfunction. High lactate and phosphocholine content are highly predictive of graft dysfunction whereas low lactate and phosphocholine content characterize patients with sarcopenia. In these patients, the cost of metabolic adaptation may explain the poor outcomes.

Interleukin 6 at reperfusion: A potent predictor of hepatic and extrahepatic early complications after liver transplantation.

BACKGROUND AND AIMS: Ischemia-reperfusion injury impacts early liver graft function. Interleukin 6 (IL-6) as early as at reperfusion has shown to predict in-hospital complications, but its impact on vascular complications and long-term outcomes is not ascertained. METHODS: A retrospective study was conducted on all consecutive patients transplanted during a 6-year period to define significant early systemic inflammatory response (ESIR). The main end-point was 3-year graft survival. Significant ESIR was defined according to IL-6 level at reperfusion on an exploratory set of 121 patients and validated on an independent cohort (n = 153). RESULTS: Significant ESIR was defined as IL-6 at reperfusion >1000 ng/mL in the exploratory cohort. Three-year graft and overall survival were lower in patients with ESIR in the determination set (P = 0.001 and 0.045, respectively). This was confirmed in the validation set (P = 0.045 and 0.027). In patients with high cytolysis, IL-6 identified patients at risk for arterial thrombosis. The main determinants for IL-6 level were intragraft lactate level, cold ischemia time, and anhepatic phase duration (P = 0.005). IL-6 level independently predicted graft survival (P = 0.0003). CONCLUSIONS: IL-6 at reperfusion is a valid biomarker to predict long-term survival. Furthermore, it helps the interpretation of cytolysis in the prediction of early vascular complications.

Corticosteroid avoidance in adult kidney transplant recipients under rabbit anti-T-lymphocyte globulin, mycophenolate mofetil and delayed cyclosporine microemulsion introduction.

We conducted the first prospective, randomized, open-label multicenter study in low-immunologic risk adult recipients of primary cadaver kidney transplants receiving rabbit anti-T-lymphocyte globulin, mycophenolate mofetil, cyclosporine microemulsion introduced on day 5, with and without corticosteroids. Patients were randomly assigned according to age and cold ischemia time to receive corticosteroids for at least 6 months or no corticosteroids at all. The main efficacy evaluation criterion was acute rejection (including all treated episodes and those biopsy-confirmed) during the first year following transplantation. For this purpose, this report includes the actual results of the whole 12-month follow-up of all randomized patients. For efficacy analysis, 98 patients were evaluated in the Steroid avoidance group and 99 in the Steroid maintenance group. Taken as a whole, 81% of the patients (n = 159) never received anti-rejection treatment. From the 38 patients who received anti-rejection treatment, 25 (25.5%) were in the Steroid avoidance group and 13 (13.1%) in the Steroid maintenance group (P < 0.031), experiencing respectively 17 (17.3%) and 7 (7.1%) biopsy-proven first episodes of acute rejection (P < 0.031). Borderline changes (6 vs. 3) were not considered as biopsy-proven acute rejections. Onset of first rejection was significantly shorter in the Steroid avoidance group (P < 0.027). First-line anti-rejection treatment response, need for any rescue therapy, as well as histologic severity of rejection episodes did not statistically differ between the groups. One-year post-transplantation analysis showed no differences in delayed graft function, serum creatinine, creatinine clearance, 24-h proteinuria, as well as serious adverse events between the groups. De novo diabetes (P < 0.07) or dyslipidemia (P < 0.01) as well as newly diagnosed malignancies (P < 0.059) were however more frequently observed in the Steroid maintenance group. At the end of the first post-transplant year, 99% of patients in the Steroid avoidance group and 97% of patients in the Steroid maintenance group were respectively alive (P = 0.34), with respectively 95% and 93.2% of functioning kidney grafts (P = 0.62). Our results showed that total avoidance of corticosteroids from the day of transplantation was associated with a significantly increased number of clinically diagnosed and treated, and biopsy-proven acute rejections during the first year of transplantation. Nevertheless, overall outcome, 1-year patient and graft survival as well as renal function were similar, and the patients in the Steroid avoidance group exhibited a lower incidence of de novo dyslipidemia, diabetes mellitus and malignancies often associated with steroid treatment.

Lack of endothelial dysfunction in patients under tacrolimus after orthotopic liver transplantation.

BACKGROUND: Endothelial dysfunction is a significant cause of vascular and end-organ damage after solid organ transplantation. The aim of this study was to compare endothelial function in healthy controls and in patients who received tacrolimus for immunosuppression after orthotopic liver transplantation (OLT). METHODS: Eight OLT patients and eight age- and BMI-matched healthy subjects were included in the study. Apart from hemodynamic parameters, enzymatic liver function, fasting plasma glucose levels, creatinine, cholesterol, nitric oxide and endothelin-1 levels were measured. Flow-mediated dilatation (FMD) in the brachial artery was determined by bi-mode ultrasound. RESULTS: Systolic and diastolic blood pressure and heart rate were higher in OLT recipients compared with the control group, but remained within normal limits. Blood results did not differ significantly between the groups. Circulating nitric oxide (152.2 +/- 29.7 vs. 180.6 +/- 40.1 micromol/L) and endothelin-1 (20.5 +/- 1.0 vs. 18.9 +/- 1.3 pmol/L) values were similar, and the FMD was normal in both groups (10.29 +/- 0.89 vs. 9.86 +/- 2.43% in controls and OLT recipients, respectively). There was a significant positive correlation between plasma tacrolimus levels after OLT and FMD (r = 0.72, p < 0.05). CONCLUSION: As assessed by both laboratory and functional approaches, endothelial function was unaltered in patients taking tacrolimus after OLT. The positive correlation between tacrolimus plasma levels and FMD suggest that tacrolimus might have beneficial effects on endothelial function after OLT.

Impact of early remote organ dysfunction on long-term survival after liver transplantation.

BACKGROUND: Attention is focused on graft function although extrahepatic organ dysfunction often occurs. Renal failure, cardiovascular events and sepsis have individually shown a significant impact on short- and long-term outcomes. The aim of the study was to identify how extrahepatic organ dysfunction (EROD) and allograft dysfunction (EAD) may be associated and their relative impact on long-term survival. METHODS: A retrospective study was conducted in a unicentric cohort of 294 patients transplanted between 2009 and 2014. The composite endpoint EROD was defined as requirement during the hospitalization of de novo renal replacement therapy, reintubation/ventilation > 7 days or cardiovascular event. Donor and recipient characteristics were evaluated as predictive of EROD in uni- and multivariate analysis. Main endpoint was overall survival evaluated by Kaplan-Meier method. RESULTS: EROD occurred in 91 patients (31%) among whom 42 also experienced EAD (46%). Predicting factors associated with EROD were IL6 level (P = 0.002) and lab-MELD (P < 0.001). Only patients experiencing both EAD and EROD had a worse survival (P = 0.001). In patients without EAD, time to normalization of bilirubin and INR were longer in patients with EROD compared to those without EROD (P = 0.002 and P = 0.008 respectively). CONCLUSIONS: The composite endpoint described as early remote organ dysfunction could be used as a predictive factor after transplantation and should be included in future studies together with early allograft dysfunction. Identifying patients in whom EROD and EAD occur together or one after the other could help to better predict long-term outcomes.

Passive mesenterico-saphenous shunt: An alternative to portocaval anastomosis for tailored portal decompression during liver transplantation.

BACKGROUND: Temporary portocaval shunt has a positive impact on short-term outcomes after liver transplantation. An alternative to temporary portocaval shunt is a distal passive decompression through mesenterico-saphenous shunt. The purpose of this study was to compare outcomes of these two types of surgical portosystemic shunt and discuss their respective place during the anhepatic phase. METHODS: Patients transplanted with portal decompression during a 4-year period were included. Patients were compared according to two types of surgical decompression techniques: temporary portocaval shunt (n = 44) and mesenterico-saphenous shunt (n = 77). Spontaneous >5-mm portosystemic shunts were described as absent, nonpersistent, distal, or proximal. Intraoperative portal pressure variations and inhospital course were compared between the two groups, with special attention on the impact of competing spontaneous and surgical shunts. RESULTS: Mesenterico-saphenous shunt and temporary portocaval shunt showed a comparable hemodynamic efficiency, with no significant difference in terms of portal pressure variations. We found no significant difference in terms of reperfusion syndrome (P = .956), transfusion rate (P = .575), renal failure (P = .239) nor early allograft dysfunction (P = .976). There was a significantly higher risk of early allograft dysfunction when competing surgical and spontaneous shunts were used (P = .002) with a lesser hemodynamic efficiency (analysis of variance test; P = .04). CONCLUSION: Portacaval or mesenterico-saphenous shunts offer similar hemodynamic efficiency without impacting the outcomes after liver transplantation. Their respective place and the place of portal decompression should be discussed regarding the presence of portal thrombosis and pre-existing portosystemic shunts. Evaluation of the anatomy and the efficiency of these shunts may guide tailored portal decompression.

Circulating adrenomedullin is increased in relation with increased creatinine and atrial natriuretic peptide in liver-transplant recipients.

OBJECTIVES: Circulating adrenomedullin (ADM), a potent vasorelaxing and natriuretic peptide involved in cardiovascular homeostasis, is increased after cardiac and renal transplantation. ADM is also implicated in hemodynamic abnormalities during liver cirrhosis, but whether ADM is increased late after liver transplantation is unknown. PATIENTS: A total of 18 subjects--10 liver-transplant patients (Ltx) and 8 healthy subjects--were enrolled in the study. DESIGN AND MEASUREMENTS: After a 15-min rest period in supine position, heart rate and systemic blood pressure were determined in all subjects. Then, venous blood samples were obtained in order to simultaneously determine the cyclosporine through levels, the biological (cyclosporine, renal and hepatic functions) and hormonal (ADM and atrial natriuretic peptide (ANP)) characteristics of the Ltx. RESULTS: ADM (27.2+/-4.1 vs. 53.8+/-6.9 pmol/l, P=0.02), and ANP (5.9+/-0.9 vs. 12.8+/-1.4 pmol/l, P=0.001) were significantly increased in late, stable Ltx (35.4+/-9.6 months after transplantation). Furthermore, increased ADM correlated positively with elevated creatinine (r=0.76, P=0.01) and ANP (r=0.64, P=0.04) after liver transplantation. CONCLUSIONS: Liver-transplant patients exhibit a sustained increase in circulating ADM. Such an increase likely results from renal impairment associated with volume regulation abnormalities, suggesting a potential role for ADM in volume regulation after liver transplantation.

Candida albicans arteritis transmitted by preservation fluid after liver transplantation.

BACKGROUND: Fungal infections remain among the main causes of mortality in the chronically immunosuppressed liver transplant (LT) patient. Bacterial and fungal contamination of preservation fluid (PF), in which grafts are stored, represents a potential source of infection for recipients. CASE REPORT: A 54-year-old patient underwent LT for chronic alcoholic cirrhosis. Mycological culture of the liver PF was positive for Candida albicans. The patient received antimycotic prophylaxis for 4 weeks in absence of clinical and serological signs of infection. He was urgently readmitted 4 months later with hemobilia caused by an arterial pseudoaneurysm that was fistulized in the biliary anastomosis. After an unsuccessful embolization, arterial resection and reconstruction and a biliodigestive anastomosis were performed, with an uneventful postoperative course. Pathology found a mycotic arteritis of the graft artery. Mycotic culture of the arterial segment confirmed the presence of the same Candida albicans genotype previously isolated in the PF. CONCLUSIONS: Mycotic arteritis is one of the possible complications of yeast contamination of PF. Surgeons and physicians involved in the care of LT patients should be aware of this potentially lethal complication and adopt all the available means for early detection.

Pathologic response to non-surgical locoregional therapies as potential selection criteria for liver transplantation for hepatocellular carcinoma.

BACKGROUND: Preoperative locoregional treatments (PLT) are performed to avoid progression before liver transplantation for hepatocellular carcinoma (HCC). The objective of this study was to analyze the prognostic factors affecting the outcome in patients who received PLT. MATERIAL AND METHODS: A retrospective analysis of patients who underwent liver transplantation (LT) was performed. All patients who underwent PLT with confirmed pathological diagnosis of HCC were included. The rate of tumor necrosis (TN) was assessed by microscopic histological examination. RESULTS: From January 1997 to December 2010, PLT was performed in 154 patients ROC analysis individuated a TN cut-off value at 40%. Ninety-one patients (59.1%) of the patients presented TN>40%. At multivariate analysis, TN<40% (HR=1.76; p=0.04) and vascular invasion (VI) (HR=2.16; p<0.01) were associated with lower Overall Survival (OS). At multivariate analysis, TN<40% (HR=1.59; p=0.001) and VI (HR=2.51; p=0.001) were significant associated with lower Disease Free Survival (DFS). One, 3 and 5 years OS was 87.9%, 82.0% and 69.1% for patients with TN>40% and 82.5%, 64.2% and 53.2% for those with TN<40% (p=0.02). Tumour size <5 cm (p=0.02); age <55 years (p=0.02); absence of VI (p=0.02) and multiple procedures (p=0.04) were predictive factors for TN>40%. CONCLUSIONS: Response to preoperative locoregional treatment can be used as potential selection criteria for LT.

Liver transplantation for iatrogenic bile duct injuries sustained during cholecystectomy.

PURPOSE: The aim of this study was to report a single-center experience and review the literature on liver transplantation (LT) for iatrogenic bile duct injury (BDI) sustained during cholecystectomy. METHODS: A retrospective review of a prospectively maintained database of LT between 1990 and December 2012 was performed. For the same period, a review of the literature on LT for BDI was undertaken. RESULTS: Six patients, with a mean age of 55.3 years (range 52-65), referred at a mean interval of 206 months (range 96-384) from BDI underwent LT. All patients had class E Strasberg BDIs and were referred with end-stage liver disease after multiple previous attempts at BDI repairs. Mortality, morbidity, and retransplantation rates were 16.6, 50, and 16.6 %, respectively. Five patients were alive at a mean follow-up time of 80.4 ± 92 months. Fifty-eight patients listed or transplanted for BDI were identified and reviewed. Indications for LT included chronic or acute liver failure (22.4 %) and the delay between BDI and referral for LT ranged from 1 day to 180 months. Associated vascular injuries were present in 41.3 % of the patients, and 72.4 % of the patients had previous failed BDI repairs. The overall postoperative mortality was 34.4 %, and the morbidity ranged from 60 to 100 %. The overall 5-year survival reached 75 %. CONCLUSIONS: A long interval of time between BDI and referral to tertiary centers for repair, a high rate of associated vascular injuries, and multiple failed previous repair attempts characterize the clinical history of patients undergoing LT for BDI. Operative morbidity and mortality rates of LT in the setting of BDI are particularly high for patients with bilio-vascular injuries presenting with acute liver failure and for patients with chronic liver disease due to multiple previous repair attempts and recurrent preoperative biliary infection.

Successful liver transplantation for Rendu-Weber-Osler disease, a single centre experience.

UNLABELLED: BACKROUNDS/PURPOSE: Hereditary hemorrhagic telangiectasia or Rendu-Weber-Osler is an autosomal dominant inherited disorder characterized by arteriovenous malformations and telangiectasia that may affect the nose, skin, lungs, brain and gastrointestinal tract. Liver involvement of the disease has been described to be responsible of biliary tract necrosis, high cardiac output and portal hypertension, due to intra-hepatic vascular shunts. We aimed to present four cases of successful orthotopic liver transplantations in this indication performing our modified Piggy-back technique. PATIENTS AND METHODS: Between 2002 and 2008, four patients have been diagnosed for Rendu-Weber-Osler disease and underwent liver transplantation. Three of them suffered from high cardiac output with heart failure, two presented HBV infection and one patient suffered from renal failure requiring a liver-kidney transplantation. We performed our modified Piggy-back technique for liver implantation, which consists to clamp selectively the hepatic veins during the hepatectomy, without venous bypass, the retro-hepatic vena cava is preserved. RESULTS: No hemodynamic concerns disturbed the surgery and no massive transfusions were needed. The liver replacement corrected the cardiac insufficiency due to high cardiac output for the three patients. At present, the four patients are getting well. CONCLUSIONS: Despite new advances in immunotherapy for the medical treatment of Rendu-Weber-Osler disease, liver transplantation remains the curative option for hepatic based-hereditary hemorrhagic telangiectasia.

Biliary strictures after liver transplantation: is percutaneous treatment indicated?

BACKGROUND: Biliary complications are common after orthotopic liver transplantation. Our study's aim is to evaluate the efficacy of percutaneous treatment of biliary strictures after orthotopic liver transplantation (OLT). MATERIAL/METHODS: Sixty-five patients with biliary anastomotic strictures received percutaneous transhepatic balloon cholangioplasty (PTBC). Three dilatations were performed with a 2- to 4-week period between the procedures. Primary and secondary patency were evaluated, with a follow-up between 6 months and 6 years. RESULTS: PTBC successfully treated strictures in 52.3% (34/65) of cases. The normalization of clinical and biological features was noted at 2.3 months on average. Neither intercurrent episodes of sepsis nor a worsening of liver function were noted during the treatment; a significant complication was recorded in 8 patients. No patient needed surgery for the treatment of complications after PTBC. Factors related to a successful PTBC included older age at transplantation and single-site stricture. There were 7 recurrent strictures after PTBC, all successfully treated by nonsurgical procedures. The number of dilatations performed affected both the likelihood of success and the long-term risk of stricture recurrence. Of the 31 PTBC failures, 19 underwent subsequent surgical revision, 8 were treated endoscopically, and 4 were re-transplanted. Multifocal stenoses, central hepatic duct involvement, and intrahepatic localization resulted associated with treatment failure. CONCLUSIONS: PTBC should be considered as a first choice option for treatment of biliary strictures after liver transplantation as well as endoscopic treatment. For solitary extrahepatic strictures that fail PTBC and ERCP, surgical revision provides good results.

Frequent compartmentalization of hepatitis C virus with leukocyte-related amino acids in the setting of liver transplantation.

BACKGROUND: Nonrandom distribution of hepatitis C virus (HCV) quasispecies (compartmentalization between blood plasma and leukocytes) suggests the presence of HCV leukotropic variants. HCV compartmentalization in the setting of liver transplantation (LT) is poorly understood. To study HCV leukotropic variants, we investigated the evolution of HCV compartmentalization after immunosuppression in liver transplant recipients. METHODS: Plasma and peripheral blood mononuclear cell (PBMC) samples were collected from 5 liver transplant recipients before and after LT. We used clone sequencing to analyze the hypervariable region 1 (HVR1)-E2(384-419) region, which plays a key role in HCV entry and the induction of neutralizing responses, and assessed compartmentalization through phylogenetic analyses and Mantel's test. RESULTS: Compartmentalization was frequent in the LT setting. HCV quasispecies were more homogeneous after LT in both the plasma and PBMC compartments, with a significant decrease in quasispecies complexity (P = .003) and genetic distances (P = .004) after transplantation. Our analysis identified 8 PBMC-related amino acid residues in HVR1. CONCLUSIONS: HCV compartmentalization between plasma and PBMCs and the emergence of leukotropic variants could be potentiated by immunosuppression in liver transplant recipients. The identification of defined leukotropic variants may contribute to the understanding of virus-host interactions after transplantation.

The venous thrombosis of the pancreatic graft.

BACKGROUND AND AIMS: Venous thrombosis of the pancreatic graft is the main nonimmunological cause of the loss of transplants. It has a frequency between 0.8 to 20% according to literature. In this study our team tried to identify the risk factors related to the donor, the recipient including the surgical techniques involved. METHODS: The study was conducted in the Department of Transplant Surgery, University Hospital Strasbourg-Hautepierre. 37 patients, with type I diabetes who had been submitted to 7 transplantations of segmentary pancreas and 30 of total pancreas and kidney during 09.07.1992 and 14.08.2006 were included in the study. The surgery comprised the retroperitoneal placement of the pancreas and kidney and the anastomosis with the urinary bladder. RESULTS: In the immediate evolution we observed 4 thromboses (10.5%). All 4 thromboses were in the group of kidney and total pancreas transplantations. Two of these 4 patients were retransplanted and presented recurrence of thrombosis at 17 days and 1 year. CONCLUSIONS: To prevent thrombosis, it is necessary to perform surgery which avoids unnecessary handling and which ensures broad, tension free vascular anastomoses. The method of early monitoring by pulsed Doppler related to the biological data and the clinical state are suggestive to diagnose thrombosis. The venous thrombosis of the graft implies pancreatic explantation. Retransplantation in patients who have undergone thrombosis of the graft is possible only in well selected patients.

Early evolution of hepatitis C virus (HCV) quasispecies after liver transplant for HCV-related disease.

BACKGROUND: End-stage liver disease as a result of chronic hepatitis C virus (HCV) infection is the main indication for liver transplant (LT), but allografts are systematically infected with HCV soon after transplant. Viral quasispecies are poorly described during the early posttransplant period. METHODS: For 17 patients who received an LT for HCV disease, plasma viral quasispecies evolution was determined by sequence analysis of hypervariable region 1 of the E2 envelope gene before transplant (BT), after 7 days (D7), and after 1 month (M1). T helper (Th)1/Th2 cytokine levels were determined concomitantly. RESULTS: HCV quasispecies showed a significant decrease in amino acid diversity at D7 and M1, compared with BT (P<.05). A correlation was observed between low plasma tumor necrosis factor-alpha levels at D7 and decreased quasispecies amino acid complexity at the same date. Nucleic acid diversity was lower for genotype 1 than for genotype 3 infection (P<.05). The complexity and diversity of amino acids were lower in patients with hepatocellular carcinoma (HCC) BT than in those without HCC (P<.05). Conserved amino acid residues within quasispecies were shared by the whole cohort before and after LT. CONCLUSION: Viral structural and/or host immunological features could favor the emergence of fitter HCV strains after LT.

Cardiac diastolic dysfunction in renal-transplant recipients is associated with increased circulating Adrenomedullin.

BACKGROUND: Renal transplantation is an excellent therapeutic alternative for end-stage renal diseases. Nevertheless, the cardiac function is often impaired in renal-transplant patients (RTR) and importantly determines their prognosis. Adrenomedullin (ADM), a peptide involved in cardiovascular homeostasis, is believed to protect both cardiac and renal functions - by increasing local blood flows, attenuating the progression of vascular damage and remodelling and by reducing glomerular injury - and might be involved in renal-transplantation physiopathology. This work was performed to investigate whether an increase in circulating ADM might be related to RTR cardiac function. METHODS: Twenty-nine subjects, 19 RTR and 10 healthy subjects, participated in the study. After 15 min rest in supine position, heart rate and systemic blood pressure were measured together with cyclosporine through levels, creatinine and ADM. Systolic and diastolic cardiac functions were assessed, using Doppler echocardiography. RESULTS: Subjects were similar concerning age, weight, heart rate and blood pressure. Creatinine and ADM (53.8 +/- 6.9 vs. 27.2 +/- 4.1 pmol/L, p = 0.02) were significantly increased in RTR (73 +/- 10 months after transplantation). Cardiac systolic function was normal, but a reduced mitral E:A ratio was observed in RTR (0.90 +/- 0.06 vs. 1.38 +/- 0.10, p < 0.001), reflecting their impaired left ventricular relaxation. Such a ratio was negatively correlated with ADM (r = -0.55, p = 0.002). CONCLUSIONS: RTR present with an increased ADM is likely related to cardiac diastolic dysfunction. In view of its protective effect on the cardiovascular system, these data support further studies to better define the role and the therapeutic potential of ADM after renal transplantation.

Long-term survival in post-transplant lymphoproliferative disorders with a dose-adjusted ACVBP regimen.

Post-transplant lymphoproliferative disorders (PTLD) are severe complications after solid organ transplantation with no consensus on best treatment practice. Chemotherapy is a therapeutic option with a high response and a significant relapse rate leading to a low long-term tolerance rate. Currently, most centres use anthracycline-based drug combinations, such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone). We assessed the efficacy and safety of a dose-adjusted ACVBP (doxorubicin reduced to 50 mg/m(2), cyclophosphamide adjusted to renal function, vindesine, bleomycin, prednisone) regimen in patients failing to respond to a reduction in immunosuppressive therapy. Favourable responses were observed in 24 (73%) of the 33 treated patients. Fourteen (42%) patients died, mostly from PTLD progression. Actuarial survival was 60% at 5 years and 55% at 10 years. Survival prognostic factors were: number of involved sites (P = 0.007), clinical stage III/IV (P = 0.004), bulky tumour (P < 0.0001), B symptoms (P = 0.03), decreased serum albumin (P = 0.03) and poor performance status (P = 0.06). Both the international and the PTLD prognostic index were predictive for survival (P = 0.001 and P = 0.002, respectively). Overall 128 cycles were given. Grade 3 or 4 neutropenia was recorded after 26 (20%) chemotherapy cycles in 19 (58%) patients. Forty-one (32%) infections were recorded in 26 (79%) patients. This study demonstrated that an individual dose-adjustment of ACVBP regimen was manageable in PTLD patients and favourably impacted on long-term survival.

Early decrease in circulating dendritic cells number after liver transplantation could favor hepatitis C virus recurrence.

Cirrhosis and hepatocarcinoma related to hepatitis C virus (HCV) lead to more than 30% of liver transplantations. Host- and virus-related mechanisms, involved in the recurrence of HCV infection of the liver graft, are not yet well known. A weak CD4+ T-cell response was shown to be involved in the outcome of re-infection but whether dendritic cell numbers are modified in patients transplanted for HCV-related disease has never been evaluated. Eight transplanted patients for HCV-related disease and eight non-HCV-infected transplanted controls were included. Blood plasmacytoid dendritic cells and myeloid dendritic cells were quantified before transplantation, at day 7 and 1 month after transplantation. Plasma interferon (IFN)-alpha and interleukin (IL)-12 were concomitantly measured. The results showed a significant decrease in the relative (P < 0.0001) and absolute (P = 0.0002) values of blood plasmacytoid dendritic cells at day 7 after transplantation when compared to the values obtained before transplantation, increasing again 1 month later, in both HCV-infected patients and controls. The same tendency was observed for myeloid dendritic cell relative values (P = 0.0004) and plasma IL-12 (P < 0.05). IFN-alpha appeared to be less often detectable for HCV-infected patients. These results obtained on dendritic cell numbers could explain partially the early and systematic recurrence of HCV infection on the liver graft and contribute to better adapted therapeutic strategies.