Visual quality assessment of the liver graft by the transplanting surgeon predicts postreperfusion syndrome after liver transplantation: a retrospective cohort study.

BACKGROUND: The discrepancy between demand and supply for liver transplants (LT) has led to an increased transplantation of organs from extended criteria donors (ECD). METHODS: In this single center retrospective analysis of 122 cadaveric LT recipients, we investigated predictors of postreperfusion syndrome (PRS) including transplant liver quality categorized by both histological assessment of steatosis and subjective visual assessment by the transplanting surgeon using multivariable regression analysis. Furthermore, we describe the relevance of PRS during the intraoperative and postoperative course of LT recipients. RESULTS: 53.3% (n = 65) of the patients suffered from PRS. Risk factors for PRS were visually assessed organ quality of the liver grafts (acceptable: OR 12.2 [95% CI 2.43-61.59], P = 0.002; poor: OR 13.4 [95% CI 1.48-121.1], P = 0.02) as well as intraoperative norepinephrine dosage before reperfusion (OR 2.2 [95% CI 1.26-3.86] per 0.1 µg kg- 1 min- 1, P = 0.01). In contrast, histological assessment of the graft was not associated with PRS. LT recipients suffering from PRS were hemodynamically more instable after reperfusion compared to recipients not suffering from PRS. They had lower mean arterial pressures until the end of surgery (P < 0.001), received more epinephrine and norepinephrine before reperfusion (P = 0.02 and P < 0.001, respectively) as well as higher rates of continuous infusion of norepinephrine (P < 0.001) and vasopressin (P = 0.02) after reperfusion. Postoperative peak AST was significantly higher (P = 0.001) in LT recipients with PRS. LT recipients with intraoperative PRS had more postoperative adverse cardiac events (P = 0.05) and suffered more often from postoperative delirium (P = 0.04). CONCLUSIONS: Patients receiving ECD liver grafts are especially prone to PRS. Anesthesiologists should keep these newly described risk factors in mind when preparing for reperfusion in patients receiving high-risk organs.

Influence of Telomere Length in Hepatocytes on Liver Regeneration after Partial Hepatectomy in Rats.

BACKGROUND: The aim of this study was to investigate telomere length in hepatocytes as a biomarker for liver regeneration after partial hepatectomy (PH) in rats. MATERIALS AND METHODS: Sixty male Wistar rats underwent a 70% PH. One-month-old rats were assigned to group Y (n = 30) and 4-month-old rats were assigned to group O (n = 30). The rats were euthanized, and their livers were then harvested at postoperative day (POD) 1, 2, 3, 4, or 7. Telomere lengths and established parameters for liver regeneration (residual liver weight and levels of proliferating cell nuclear antigen [PCNA], Ki67, and interleukin [IL]-6) were measured. RESULTS: We observed a significant increase in residual liver weight in group Y compared to that in group O (p = 0.001). The levels of Ki67 (p = 0.016), PCNA (p < 0.0001), and IL-6 (p < 0.001) were significantly higher in group Y. Furthermore, the rats in group Y had significantly earlier peak values of Ki67 and PCNA. Telomeres were significantly longer at the time of PH in group Y (p = 0.001). We showed a correlation between telomere length at the day of PH and liver regeneration. Animals with longer telomeres at the time of PH had better liver regeneration (p = 0.015). In group Y, animals with increased liver regeneration (median cut-off: > 122%) did not show any significant difference in telomere length (p = 0.587) compared to rats with regular regeneration (< 122%). However, in the older animals, rats with increased regeneration had significantly longer telomeres (p = 0.019) than rats with regular regeneration. CONCLUSION: Telomere length in rat hepatocytes depends on age, and animals with long telomeres had earlier and better regeneration of healthy liver tissue than rats with short telomeres. Our data confirms that telomere length in rat hepatocytes could be used as a possible predictive marker for liver regeneration, and could help to identify older individuals with a high capacity for hepatic regeneration.

Elevated levels of circulating osteopontin are associated with a poor survival after resection of cholangiocarcinoma.

BACKGROUND & AIMS: Cholangiocarcinoma (CCA) represents a primary hepatic malignancy with incidence and mortality rising globally. Surgical treatment has remained the only potentially curative treatment option, but it is still unclear which patients benefit most from extended liver surgery, highlighting the need for new pre-operative stratification strategies. Osteopontin is a secreted extracellular glyco-phosphoprotein that has been associated with inflammation, metabolic disorders and cancer. Here, we examined the potential of circulating osteopontin serum levels as a diagnostic or prognostic biomarker in patients with CCA undergoing extended liver surgery. METHODS: Osteopontin expression levels were analysed in human and murine CCA tumour samples, using semi-quantitative reverse transcriptase PCR and immunohistochemistry. Osteopontin serum concentrations were measured by enzyme-linked immunosorbent assay in 107 patients with CCA undergoing elective tumour resection as well as 55 healthy controls. Results were correlated with clinical data. RESULTS: Correlating with an upregulation in CCA tumour cells and the tumour stroma, serum levels of osteopontin were elevated in patients with cholangiocarcinoma compared to healthy controls and patients with primary sclerosing cholangitis. Importantly, pre- and postoperative elevations of osteopontin showed a striking association with poor postoperative survival. CONCLUSIONS: Serum osteopontin concentrations represent a promising prognostic biomarker in patients resectable CCA which could help to guide preoperative treatment decisions and to identify patients that will particularly benefit from extended liver surgery. Lay summary: Extended liver surgery is the only potentially curative treatment for patients with cholangiocarcinoma (CCA/biliary cancer), but it is currently unclear which patients benefit most from surgery. Detecting serum levels of osteopontin - a specific secreted glycoprotein involved in multiple human diseases - in CCA patients might help to identify those patients that particularly benefit from tumour resection.

Comparative study of the effects of terlipressin versus splenectomy on liver regeneration after partial hepatectomy in rats.

BACKGROUND: Post-hepatectomy liver failure as a result of insufficient liver remnant is a feared complication in liver surgery. Efforts have been made to find new strategies to support liver regeneration. The aim of this study was to investigate the effects of terlipressin versus splenectomy on postoperative liver function and liver regeneration in rats undergoing 70% partial hepatectomy. METHODS: Seventy-two male Wistar rats were randomly assigned into three groups (n=24 in each group): 70% partial hepatectomy as control (PHC), 70% partial hepatectomy with splenectomy (PHS) or 70% partial hepatectomy with a micropump for terlipressin administration (PHT). Eight rats in each group were sacrificed on postoperative day (POD) 1, 3 and 7. To assess liver regeneration, immunohistochemical analysis of liver tissue using bromodeoxyuridine (BrdU) and Ki-67 labeling was performed. Portal venous pressure, serum concentrations of creatinine, urea, albumin, bilirubin and prothrombin time as well as liver-, body-weight and their ratio were determined on POD 1, 3 and 7. RESULTS: The liver-, body-weight and their ratio were not statistically different among the groups. On POD 1, 3 and 7 portal venous pressure in the intervention groups (PHT: 8.13±1.55, 10.38±1.30, 6.25±0.89 cmH2O and PHS: 7.50±0.93, 8.88±2.42, 5.75±1.04 cmH2O) was lower compared to the control group (PHC: 8.63±2.06, 10.50±2.45, 6.50±2.67 cmH2O). Hepatocyte proliferation in the intervention groups was delayed, especially after splenectomy on POD 1 (BrdU: PHS vs PHC, 20.85%±13.05% vs 28.11%±10.10%; Ki-67, 20.14%±14.10% vs 23.96%±11.69%). However, none of the differences were statistically significant. CONCLUSIONS: Neither the administration of terlipressin nor splenectomy improved liver regeneration after 70% partial hepatectomy in rats. Further studies assessing the regulation of portal venous pressure as well as extended hepatectomy animal models and liver function tests will help to further investigate mechanisms of liver regeneration.

Grade of donor liver microvesicular steatosis does not affect the postoperative outcome after liver transplantation.

BACKGROUND: The potential effect of graft steatosis on the postoperative liver function is discussed controversially. The present study aimed to evaluate the effect of the donor liver microvesicular steatosis on the postoperative outcome after liver transplantation. METHODS: Ninety-four patients undergoing liver transplantation at the University Hospital Aachen were included in this study. The patient cohort was divided into three groups according to the grade of microvesicular steatosis (MiS): MiS <30% (n=27), MiS 30%-60% (n=41) and MiS >60% (n=26). The outcomes after liver transplantation were evaluated, including the 30-day and 1-year patient and graft survival rates and the incidences of early allograft dysfunction (EAD) and primary nonfunction (PNF). RESULTS: The incidences of EAD and PNF did not differ significantly between the groups. We observed 5 cases of PNF, one occurred in the MiS <30% group and 4 in the MiS 30%-60% group. The 30-day and 1-year graft survivals did not differ significantly between groups. The 30-day patient survival rates were 100% in all groups. The 1-year patient survival rates were 94.4% in the MiS <30% group, 87.9% in the MiS 30%-60% group and 90.9% in the MiS >60% group. CONCLUSION: Microvesicular steatosis of donor livers has no negative effect on the postoperative outcome after liver transplantation.

Allocation procedure has no impact on patient and graft outcome after liver transplantation.

The aim of our study was to compare the postoperative outcome after liver transplantation (LT) in patients who received a donor liver via standard or rescue allocation (RA). Special emphasize was laid on the effect extended donor criteria might have on the outcome. One hundred and ten LTs have been performed at the University Hospital Aachen, Germany. A total of 49 patients were included in the standard allocation (SA) group and 53 patients in the RA group. The outcome of LT in both groups was evaluated by the length of stay on the intensive care unit (ICU), duration of hospitalization, 1-year patient survival, 1-year graft survival, incidence of primary nonfunction and major complications. Patients in group RA had a significant shorter ICU and overall hospital stay. The 1-year graft survival was 87.8% in group SA and 88.7% in group RA. The 1-year patient survival was 87.9% in group SA and 96.2% in group RA. The number of re-LT was 2% in group SA and 7.5% in group RA. Organs that were rejected for transplantation several times can successfully be transplanted through the RA procedure, thereby enlarging the donor pool without negative effects on the quality of LT.

A prospective cluster trial to increase antibiotic prescription quality in seven non-ICU wards.

Aim: To evaluate general shortcomings and faculty-specific pitfalls as well as to improve antibiotic prescription quality (ABQ) in non-ICU wards, we performed a prospective cluster trial. Methods: An infectious-disease (ID) consulting service performed a prospective investigation consisting of three 12-week phases with point prevalence evaluation conducted once per week (=36 evaluations in total) at seven non-ICU wards, followed by assessment of sustainability (weeks 37-48). Baseline evaluation (phase 1) defined multifaceted interventions by identifying the main shortcomings. Then, to distinguish intervention from time effects, the interventions were performed in four wards, and the 3 remaining wards served as controls; after assessing effects (phase 2), the same interventions were performed in the remaining wards to test the generalizability of the interventions (phase 3). The prolonged responses after all interventions were then analyzed in phase 4. ABQ was evaluated by at least two ID specialists who assessed the indication for therapy, the adherence to the hospital guidelines for empirical therapy, and the overall antibiotic prescription quality. Results: In phase 1, 406 of 659 (62%) patients cases were adequately treated with antibiotics; the main reason for inappropriate prescription was the lack of an indication (107/253; 42%). The antibiotic prescription quality (ABQ) significantly increased, reaching 86% in all wards after the focused interventions (502/584; nDf=3, ddf=1,697, F=6.9, p=0.0001). In phase 2 the effect was only seen in wards that already participated in interventions (248/347; 71%). No improvement was seen in wards that received interventions only after phase 2 (189/295; 64%). A given indication significantly increased from about 80% to more than 90% (p<.0001). No carryover effects were observed. Discussion: ABQ can be improved significantly by intervention bundles with apparent sustainable effects.

A 7-gene signature of the recipient predicts the progression of fibrosis after liver transplantation for hepatitis C virus infection.

Fibrosis recurrence after liver transplantation (LT) for hepatitis C virus (HCV) is a universal event and strongly determines a patient's prognosis. The recipient risk factors for fibrosis recurrence are still poorly defined. Here we assess a genetic risk score as a predictor of fibrosis after LT. The cirrhosis risk score (CRS), which comprises allele variants in 7 genes (adaptor-related protein complex 3 S2, aquaporin 2, antizyme inhibitor 1, degenerative spermatocyte homolog 1 lipid desaturase, syntaxin binding protein 5-like, toll-like receptor 4, and transient receptor potential cation channel M5), was calculated for 137 patients who underwent LT for HCV infection and experienced HCV reinfection of the graft. The patients were stratified into 3 CRS categories: <0.5, 0.5 to 0.7, and >0.7. All patients underwent protocol biopsy after LT (median follow-up = 5 years), and liver fibrosis was assessed according to the Desmet and Scheuer score. The data were analyzed with univariate and multivariate analyses. The results showed that the highest CRS category was strongly associated with the presence of F2 or F3 fibrosis in protocol biopsy samples 1, 3, and 5 years after LT (P = 0.006, P = 0.001, and P = 0.02, respectively). Overall, 75.0% of the patients with a CRS > 0.7 developed at least F2 fibrosis, whereas 51.5% developed F3 fibrosis during follow-up. The predictive value of the CRS for fibrosis progression was independent of known clinical risk factors, including the age of the donor, the sex of the recipient, and the occurrence of acute rejection. A Kaplan-Meier analysis confirmed the prognostic value of the CRS with respect to the recurrence of severe liver fibrosis in HCV-infected patients after LT (log rank = 6.23, P = 0.03). In conclusion, the genetic signature of the recipient predicts the likelihood of severe liver fibrosis in the graft after HCV recurrence. The CRS might help with early clinical decision making (eg, the selection of patients for antiviral therapy after LT).

Comparison of straight and Venaflo-type cuffed arteriovenous ePTFE grafts in an animal study.

BACKGROUND: The long-term prognosis of arteriovenous (AV) polytetrafluoroethylene (PTFE) hemodialysis grafts is dissatisfying. Responsible for the poor outcome is a stenosis of the venous anastomosis. This originates from both pseudointimal (PI) and neointimal hyperplasia (IH) development. Although cuffed grafts have a better short-term prognosis than straight grafts, the late results of both types are poor. This current study aimed to compare both arteriovenous straight and Venaflo-type (Bard, Tempe, Ariz) prostheses in an animal study with regard to patency, PI, and IH development. METHODS: Sixteen iliac arteriovenous expanded polytetrafluoroethylene (ePTFE) loops were inserted into 16 pigs. Animals were randomized into two groups. Group 1 animals received straight configured ePTFE grafts and group 2 animals received grafts with a Venaflo-type cuffed venous anastomosis. After insertion of the shunts and immediately before graft harvest, the shunt flows were measured. Six weeks after implantation, patency rates and development of pseudointima (PI) within the grafts were noted. The thickness of the venous intimal hyperplasia was measured using digital planimetry. RESULTS: Patency rates after 6 weeks were 25% for straight and 62% for Venaflo-type grafts. In both groups a significant decrease of the graft blood flow compared with the preoperative levels was observed, which was attributed to the marked development of pseudointima. The reduction in flow at graft harvest was greater in the straight ePTFE group (658 ± 68 vs 260 ± 42 mL/min, P < .05) than for the Venaflo-type grafts (770 ± 107 vs 661 ± 284 mL/min, P = ns), but the differences between the groups were statistically not significant. A marked pseudointima developed in the Venaflo cuff. The PI development was significantly higher in the graft hood (2.9 ± 0.6 mm) than in the heel (2.5 ± 0.4 mm, P < .05). In both groups, an intimal hyperplasia formed on the vein wall just opposite to the graft inflow. The intimal hyperplasia development was more pronounced in the straight configured shunts. CONCLUSIONS: The results of the present study confirm the inferior clinical results of ePTFE grafts used for hemodialysis access. Although the patency rates of cuffed grafts were superior, in both graft types a significant pseudointima leading to subtotal graft stenosis was observed in all grafts. Both straight and Venaflo-grafts. The Venaflo grafts have a slightly bettertype cuffed ePTFE grafts have major hemodynamic drawbacks that have to be addressed in future graft design efforts.

Fibroblast and vascular endothelial growth factor coating of decellularized vascular grafts stimulates undesired giant cells and graft encapsulation in a rat model.

Replacing an infected prosthesis with a bioimplant provides a hopeful alternative in septic vascular surgery. The objective of this study was to determine the effect of fibroblast endothelial growth factors (FGF) and vascular endothelial growth factors (VEGF) coating on a decellularized vascular graft in a rat model and the possible impact on recellularization processes. Rat aortas were decellularized, crosslinked with genipin, and coated with poly-(D, L) lactide containing either FGF or VEGF. Observation periods were 6 and 12 weeks. Surprisingly, we found moderate accumulation of giant cells around the grafts that contained poly-(D, L) lactide acid. FGF and VEGF grafts showed massive stimulation of giant cells and eosinophils leading to complete graft encapsulation (P < 0.05). Pseudointmal hyperplasia was significantly increased in the FGF group (P < 0.05). Both results can only be interpreted as very negative. We achieved a situation in diametric opposition to that which we had hoped for. These data demonstrate that the use of growth factors may produce harmful side effects.

In vitro testing of a newly developed arteriovenous double-outflow graft.

INTRODUCTION: The long-term prognosis of arteriovenous polytetrafluoroethylene (PTFE) hemodialysis grafts remains poor, causing significant morbidity and costs. The high failure rate is due to a stenosis development of the graft-vein anastomosis, consisting of two pathophysiologically separate and characteristic lesions emerging from two main mechanisms: development of intimal hyperplasia in the vein and pseudointima in the graft. We developed a new venous anastomotic graft design that combines a flow diffuser and flow division, thereby creating a double-channel graft (Bi-Flow graft) and tested it in vitro. METHODS: In vitro experiments have been performed using silastic models of six different anastomotic configurations (straight end-to-side, cuffed Venaflo-type, large and small diffuser, and large and small Bi-Flow) inserted into a pulsatile-flow circuit. The silastic models were created using a computerized numerical control design approach, varying only the venous anastomoses. Velocity fields and shear stresses were obtained using particle image velocimetry, and volumetric flow rates through the models were measured using an ultrasound flowmeter. RESULTS: The hooded graft configurations showed significantly lower shear forces than did the end-to-side anastomosis. The shear stresses in the straight end-to-side graft were as high as arterial wall stresses. Large separation areas were present in the hooded grafts, except for the small Bi-Flow graft, which showed only isolated separation zones near the baffle used to divide the flow. The double-channel grafts exhibited a parabolic flow profile consisting of laminar flow in the double-outflow portion of the model's laminar flow pattern through the venous anastomosis. A marked flow separation was present in the large Bi-Flow model. Volumetric flow measurements revealed an average flow increase of 21% through the small Bi-Flow graft, which was attributed to the optimization of flow dynamics and pattern within the venous anastomosis of the double-channel graft. CONCLUSION: The new arteriovenous Bi-Flow graft design addresses two major problems responsible for the development of venous stenosis of prosthetic hemodialysis grafts in vitro. The new graft design should be further investigated in animal studies.

Endovascular treatment of supra-celiac aortic pseudoaneurysms following liver transplantation.

The development of supra-celiac pseudoaneurysms following aorto-hepatic reconstruction during liver transplantation represents a major and surgically challenging complication. However, the use of endovascular stent grafts for the exclusion of aortic aneurysms is now a standard procedure with low morbidity and mortality. We demonstrate the successful endovascular repair of three cases of supra-celiac pseudoaneurysms, which developed after liver transplantation. A 40-yr-old woman, a 61-yr-old man, and a 45-yr-old woman underwent liver transplantation for end-stage liver disease. Between three months and five yr after the transplantation the patients developed large supra-celiac pseudoaneurysms leading to thrombosis of the hepatic artery and biliary complications. The stent graft implantation was uneventful, one endoleak Type I occluded spontaneously. There were no intervention-related complications. Unfortunately, one patient died one month after the procedure due to progressive liver failure and one died after five months due to multiple organ failure. One patient is still alive and in good condition.

Incidence of and risk factors for ischemic-type biliary lesions following orthotopic liver transplantation.

Ischemic-type biliary lesions (ITBL) account for a major part of patients' morbidity and mortality after orthotopic liver transplantation (OLT). The exact origin of this type of biliary complication remains unknown. This study retrospectively evaluated 1843 patients. Patients with primary sclerosing cholangitis were excluded from this study. The diagnosis of ITBL was established only when all other causes of destruction of the biliary tree were ruled out. Donor age (P = 0.028) and cold ischemic time (CIT) (P = 0.002) were found to be significant risk factors for the development of ITBL. Organs that were perfused with University of Wisconsin (UW) solution developed ITBL significantly more often than Histidine-Tryptophan-Ketoglutarate (HTK)-perfused organs (P = 0.036). The same applied to organs harvested externally and shipped to our center versus those that were procured locally by our harvest teams (P < 0.001). Pressure perfusion via the hepatic artery significantly reduced the risk of ITBL (P = 0.001). The only recipient factor that showed a significant influence was Child-Pugh score status C (P = 0.021). Immunologic factors had no significant impact on ITBL. The clinical consequences of this study for our institution have been the strict limitation of CIT to <10 h and the exclusive use of HTK solution. We further advocate that all organ procurement teams perform pressure perfusion on harvested organs.

Liver resection in the elderly: A retrospective cohort study of 460 patients - Feasible and safe.

INTRODUCTION: The aim of this study was to determine the influence of age on the early postoperative outcome after liver surgery. MATERIAL AND METHODS: Between January 2005 and July 2012 460 hepatic resections were performed in patients aged 60 years or younger and 70 years or older at the University Hospital Aachen and University Hospital Maastricht. The postoperative outcome of hepatic resection was evaluated by the time of intensive care unit (ICU) stay, length of hospital stay, appearance of postoperative complications and in-hospital mortality. RESULTS: The median postoperative hospital stay was 7 days in group ≤60 and 8 days in group ≥70 (p = 0.007). The median time of ICU stay was 1 day in both groups. There were no statistically significant differences according to liver related complications. In group ≥70, significantly more patients suffered from pneumonia (8% vs. 2% in group ≤60, p = 0.015). The overall mortality rate was 3.5%. CONCLUSION: Age alone should not be a contraindication for liver resection. However, elderly patients who develop pneumonia are at high risk for postoperative mortality. Therefore, factors such as short time of invasive ventilation, direct and intensive respiratory therapy and mobilization are of particular importance and should be focused on even more.

Bypass during Liver Transplantation: Anachronism or Revival? Liver Transplantation Using a Combined Venovenous/Portal Venous Bypass-Experiences with 163 Liver Transplants in a Newly Established Liver Transplantation Program.

Introduction. The venovenous/portal venous (VVP) bypass technique has generally become obsolete in liver transplantation (LT) today. We evaluated our experience with 163 consecutive LTs that used a VVP bypass. Patients and Methods. The liver transplant program was started in our center in 2010. LTs were performed using an extracorporal bypass device. Results. Mean operative time was 269 minutes and warm ischemic time 43 minutes. The median number of transfusion of packed cells and plasma was 7 and 14. There was no intraoperative death, and the 30-day mortality was 3%. Severe bypass-induced complications did not occur. Discussion. The introduction of a new LT program requires maximum safety measures for all of the parties involved. Both surgical and anaesthesiological management (reperfusion) can be controlled very reliably using a VVP bypass device. Particularly when using marginal grafts, this approach helps to minimise both surgical and anaesthesiological complications in terms of less volume overload, less use of vasopressive drugs, less myocardial injury, and better peripheral blood circulation. Conclusion. Based on our experiences while establishing a new liver transplantation program, we advocate the reappraisal of the extracorporeal VVP bypass.

Alterations of the immune response with increasing recipient age are associated with reduced long-term organ graft function of rat kidney allografts.

BACKGROUND: Clinically, an increasing number of older recipients are listed for transplantation. We examined recipient age-associated alterations of the immune response and their effects on graft function. METHODS: Three- and 18-month-old Lewis (LEW) rats received kidneys from 3- and 18-month-old Fischer 344 (F344) rats (1.5 mg/kg/d cyclosporine A for 10 days; n=6/group) and were observed for 180 days. In additional groups, double kidney transplantations were performed to determine the impact of nephron mass and recipient age on graft outcome. RESULTS: All young recipients but only 66% of old recipients survived the observation period. Increasing recipient age resulted in a significant decrease in renal allograft function (P<0.001), more advanced morphologic evidence of chronic allograft damage (P<0.001), and greater cellular infiltration (P<0.05) and major histocompatibility complex expression (P<0.01) within grafts. Additional in vitro studies examined age-related changes in the cellular immune response by enzyme-linked immunosorbent assay, fluorescence-activated cell sorter analysis, and alloreactive enzyme-linked immunospot: splenocytes from old LEW rats produced significantly more interleukin (IL)-2 (P<0.0001), IL-4 (P<0.05), interferon (IFN)-gamma (P<0.0001), and tumor necrosis factor-alpha (P<0.05). IFN-gamma-producing memory-type T cells were significantly elevated in older rats (P<0.0001). Moreover, they revealed significantly more alloreactive T cells directed against F344 (146 +/- 64.2 and 512 +/- 277/10(6) T cells; P<0.05). Double renal allografts from young donors into old recipients confirmed an independent effect of recipient age on the acceleration of chronic graft deterioration. CONCLUSIONS: The enhanced cellular immune responsiveness in elderly recipients was associated with advanced chronic graft injury. Clinically, older recipients may need a modified immunosuppression.

Mycophenolate mofetil monotherapy in liver transplantation: 5-year follow-up of a prospective randomized trial.

BACKGROUND: Calcineurin inhibitors (CNIs) play the key role in immunosuppressive protocols yet are often associated with numerous side effects. Renal insufficiency, hypertension, hyperglycemia, and increased risk of secondary malignancy are major problems in short- and long-term follow-up of liver transplant patients. Mycophenolate mofetil (MMF) has proved to be a potent immunosuppressive agent free of the CNI-associated side effects. PATIENTS AND METHODS: One hundred fifty patients who received liver transplantation at our institution (1998-2003) were prospectively randomized: 75 patients continued CNI standard therapy, 75 patients were switched to MMF monotherapy, and follow-up was 5 years. Incidence of rejection, renal complication, cardiovascular, neurological and gastrointestinal adverse effects, and diabetes and malignancy development was recorded. Graft biopsies were performed every 2 to 3 years. RESULTS: No significant difference regarding the incidence of acute rejection was detected. A trend to higher rejection frequency was apparent in the MMF monotherapy group. Chronic rejection was absent; organ and patient survival were identical in the two groups. No significant difference occurred concerning the incidence of cardiovascular, gastrointestinal or neurological adverse effects, or the development of malignancies. Renal function improved significantly in patients with renal insufficiency when patients treated with CNI were switched to MMF monotherapy. CONCLUSION: MMF monotherapy may serve as safe long-term immunosuppression after liver transplantation for a subgroup of patients. Especially for patients with renal insufficiency MMF offers immunosuppression without the risk of nephrotoxicity.

Polymer coating of porcine decellularized and cross-linked aortic grafts.

This article investigates a method of modifying and optimizing the biocompatibility of decellularized vascular bioimplants when treated with a specialized, drug eluting coating. For this purpose, we carried out aortic transplantations using a porcine model. Decellularized, cross-linked aortic grafts were coated with poly(D,L-lactide) (PDLLA). To this coating, we added the anticoagulant drug lepirudin which, following transplantation, would be linearly eluted. These aortic grafts are easily manipulated in surgery. It was shown that, as a result of the lepirudin-eluting coating, the rate of thrombogenesis was reduced and the patency rate was significantly improved. However, lumen-stenosing pseudointima developed in all of the transplants and was not effected by PDLLA coating. Furthermore, no evidence of recellularisation was documented. This trial demonstrates that polymer coating of decellularized tissue is possible. Neointimal hyperplasia and the absence of cellular repopulation mark the negative consequences of this concept.