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Introduction Laparoscopy is becoming the standard approach in liver surgery. As the degree of difficulty varies greatly from core skills to advanced procedures, strategies for teaching young surgeons need to be reconsidered. We here aimed to design a skills curriculum for LLR. Methods Using the nominal group technique, 22 substeps of LLR were identified by 61 hepatobiliary surgeons. The raters were asked to rate (1) the difficulty of substeps and (2) the minimum number of times that the substep must be performed for mastery of the technique. According to the frequency of defined substeps, being estimated on the basis of high volume center experiences (n = 222 LLR; 1/2017-12/2018), the center's training capacity and defined goals for a 2-year fellowship were calculated. Results Ten surgical substeps (45%) are routinely performed and can thus be taught sufficiently at centers carrying out ≥50 LLR in 2 years. As the mobilization of the right liver lobe and the dissection of the hepatic artery or portal vein is performed in only 27% and 28% of all LLR, respectively, sufficient training can only be provided at centers with ≥100 LLRs in 2 years. Mastery of complex parenchymal dissection (19%) and hilar lymphadenectomy (8%) can only be achieved in center performing ≥200 LLR in 2 years. Conclusion We here suggest a stepwise approach for training of hepatobiliary fellows in LLR. Based on the estimated complexity of the substeps and the size of the center, not every substep can be learned within 2 years.

The paper evaluates the application of a mixed reality (MR) headmounted display (HMD) for the visualization of anatomical structures in complex visceral-surgical interventions. A workflow was developed and technical feasibility was evaluated.Medical images are still not seamlessly integrated into surgical interventions and, thus, remain separated from the surgical procedure.Surgeons need to cognitively relate 2-dimensional sectional images to the 3-dimensional (3D) during the actual intervention. MR applications simulate 3D images and reduce the offset between working space and visualization allowing for improved spatial-visual approximation of patient and image.The surgeon's field of vision was superimposed with a 3D-model of the patient's relevant liver structures displayed on a MR-HMD. This set-up was evaluated during open hepatic surgery.A suitable workflow for segmenting image masks and texture mapping of tumors, hepatic artery, portal vein, and the hepatic veins was developed. The 3D model was positioned above the surgical site. Anatomical reassurance was possible simply by looking up. Positioning in the room was stable without drift and minimal jittering. Users reported satisfactory comfort wearing the device without significant impairment of movement.MR technology has a high potential to improve the surgeon's action and perception in open visceral surgery by displaying 3D anatomical models close to the surgical site. Superimposing anatomical structures directly onto the organs within the surgical site remains challenging, as the abdominal organs undergo major deformations due to manipulation, respiratory motion, and the interaction with the surgical instruments during the intervention. A further application scenario would be intraoperative ultrasound examination displaying the image directly next to the transducer. Displays and sensor-technologies as well as biomechanical modeling and object-recognition algorithms will facilitate the application of MR-HMD in surgery in the near future.

Concepts to ameliorate the continued mismatch between demand for liver allografts and supply include the acceptance of allografts that meet extended donor criteria (ECD). ECD grafts are generally associated with an increased rate of complications such as early allograft dysfunction (EAD). The costs of liver transplantation for the health care system with respect to specific risk factors remain unclear and are subject to change. We analyzed 317 liver transplant recipients from 2013 to 2018 for outcome after liver transplantation and hospital costs in a German transplant center. In our study period, 1‐year survival after transplantation was 80.1% (95% confidence interval: 75.8%‐84.6%) and median hospital stay was 33 days (interquartile rage: 24), with mean hospital costs of €115,924 (SD €113,347). There was a positive correlation between costs and laboratory Model for End‐Stage Liver Disease score (rs = 0.48, P

Background and aim Hepatic encephalopathy (HE) is a frequent complication of cirrhosis, characterized by cognitive deficits that negatively impact patients' quality of life. The mild, minimal hepatic encephalopathy (mHE) can only be detected by psychometric tests and early mHE detection can prevent more severe complications or even survival times. Here, we aimed to investigate the feasibility and validity of the novel-developed electronic number connection test (eNCT), which is designed as a fast and easy-to-perform mHE patient self-test. Methods The eNCT design was inspired by the paper-pencil number connection test version A, showing 25 numbers on the screen (1-25), in a random order. The time required to tap on all digits in the correct order was measured. A total of 238 individuals (112 patients with liver cirrhosis) were enrolled in this study and eNCT times were compared with well-established paper-pencil tests. The Psychometric Hepatic Encephalopathy Score test battery was used to detect mHE and cut-off values for mHE detection by the eNCT were defined. Results Overall, cirrhotic patients showed significantly slower test completion times compared with control participants. The eNCT performance was inversely correlated with Psychometric Hepatic Encephalopathy Score test performance in cirrhotic patients, independent of the HE status. Thirty cirrhotic patients fulfilled the mHE criteria and receiver operating characteristic curve analysis showed high sensitivity (>82%) and specificity (>85%) for mHE detection. Finally, the eNCT showed excellent test-retest reliability (intraclass correlation coefficient=0.94). Conclusion The novel eNCT is a reliable HE self-test to monitor cognitive function and detect cognitive impairment in cirrhotic patients.

BACKGROUND Non-HLA alloantibodies and autoantibodies are involved in allograft rejection in kidney and heart transplantation. Their role in intestinal transplantation has not yet been described. We examined the development of antiangiotensin II type I receptor antibodies (anti-AT1R) and antiendothelin type A receptor antibodies associated with the clinical course and histopathological findings of intestinal transplantation recipients. METHODS Thirty-seven patients underwent intestinal or multivisceral transplantation. Non-HLA antibodies (non-HLAabs) were screened in 29 transplant recipients. Antibody-levels greater than 12 U/L were considered positive and were evaluated retrospectively regarding rejection episodes. RESULTS Twenty patients developed anti-AT1R and/or antiendothelin type A receptor antibodies (non-HLAabs group), 9 did not (control group). The non-HLAabs group had a higher rate of allograft rejection than controls (80% vs 55%), especially a higher rate of antibody-mediated rejections (55% vs 11%, P < 0.01) with detection of donor-specific anti-HLAabs. All rejection episodes in the non-HLAabs group appeared around the time of positive non-HLAabs detection. Five patients had acute cellular rejections at the time of non-HLAabs development, 4 had viral infections. CONCLUSIONS Our data suggest that antibody-mediated mechanisms targeting antigens beyond HLA may trigger and accelerate immune responses. Given the possibility of pharmacologic targeting of non-HLA receptors, future studies will focus on the explanation of mechanisms how non-HLAabs may enhance rejection and affect long-term allograft survival.

Background and aims The aim of this study was to investigate the clinical usefulness of the placement of a transanal drainage tube to prevent anastomotic leakage in colorectal anastomoses. Material and methods This single-center retrospective trial included all patients treated with surgery for benign or malign colorectal disease between January 2009 and December 2012. The transanal drainage tube was immediately placed after colorectal anastomosis until day five and was routinely used since 2010. Patients treated with a transanal drainage tube were compared with the control group. Statistical analysis was performed using Fisher's exact or Chi-square tests for group comparison and a linear regression model for multivariate analysis. Results This study included 242 patients (46% female; median age 63 years; range 18–93); 34% of the patients underwent a laparoscopic procedure, and 57% of the patients received a placement of a transanal drainage tube. Anastomotic leakage occurred in 19 patients (7.9%). Univariate analysis showed a higher rate of anastomotic leakage in patients with an ASA score 4 (p = 0.02) and a lower rate in patients with transanal drainage placement (3.6% vs. 13.6%; p = 0.007). The grading of the complication of anastomotic leakage was reduced with transanal drainage (e.g., Dindo ≧ 3b: 20.0% vs. 92.9%; p = 0.006), and the hospital stay was shortened (17.6 ± 12.5 vs. 22.1 ± 17.6 days; p = 0.02). Multivariate analysis revealed that transanal drainage was the only significant factor (HR = −2.90; −0.168 to −0.032; p = 0.007) affecting anastomotic leakage. Conclusions Placement of a transanal drainage tube in patients with colorectal anastomoses is a safe and simple technique to perform and reduces anastomotic leakage, the severity of the complication and hospital stay., Highlights • A transanal drainage tube as a mechanism to reduce anastomotic leakage is proposed. • Transanal drainage tube reduces anastomotic leakage 3.6% vs. 13.6% (p = 0.007). • Transanal drainage reduced the grade of complication (e.g., Dindo ≧ 3b: 20.0% vs. 92.9%; p = 0.006).

Objectives Pancreatoduodenectomy is feasible also in patients with locally advanced pancreatic adenocarcinoma (PA) nowadays. Data on risk and survival analysis of palliative pancreatic resections followed by gemcitabine-based chemotherapy (Cx) are limited. Methods Between 2000 and 2009, a total of 45 patients had primary cytoreductive surgery (cS) (pancreaticoduodenectomy or total pancreatectomy) followed by gemcitabine-based Cx (cS + Cx) for advanced PA. We matched 1:1 the cS + Cx group with 45 contemporaneous patients who primarily started palliative gemcitabine-based Cx for age, sex, performance status, and body mass index. Overall, survival was evaluated. Results Local R0 and R1 resection in metastatic patients was achieved in 27% and 27%, respectively. The R2 resection status without distant metastasis resulted in 33%, whereas 13% showed a local R2 status with additional metastasis (M1). Median overall survival was 10.4 months after cytoreductive pancreatic surgery and consecutive gemcitabine-based Cx versus 7.2 months after upfront gemcitabine-based Cx (P = 0.009). Median survival for R0/M1 patients was 14.4 months and 11.0 months for R2/M0 patients, whereas the median survival for R1/M1 and for R2/M1 patients was 7.3 months and 6.1 months, respectively. Conclusions Individual patients with advanced PA had a significantly longer overall survival after palliative pancreaticoduodenectomy followed by Cx than patients in a matched control group who underwent primarily palliative Cx.

PURPOSE OF REVIEW With a persisting organ shortage and constant high discard rates, there is an urgent need to optimize the outcome and allocation of marginal grafts. RECENT FINDINGS The Eurotransplant Senior Program was established as an 'old-for-old' allocation system emphasizing on the importance of keeping ischemic times short when utilizing marginal grafts. In addition to refined allocation systems, brief cold ischemic times, novel preservation techniques, a careful assessment of organ quality the utilization of dual kidney transplantation and donation after cardiac death kidneys from elderly donors may all help to increase the supply for renal transplantation. Moreover, age-adapted immunosuppression, improved patient selection and preparation for transplantation may help in improving outcomes when using marginal kidneys. SUMMARY There is a significant potential to increase the utilization of marginal grafts with reduced discard rates, an increased utilization of dual kidney transplantation and the application of novel preservation methods.

The diagnosis of acute cellular rejection (ACR) after liver transplantation is based on histological analysis of biopsies because noninvasive biomarkers for allograft rejection are not yet established for clinical routines. CD31, CD44, and chemokine (C-X-C motif) ligand (CXCL) 9 have previously been described as biomarkers for cross-organ allograft rejection. Here, we assessed the predictive and diagnostic value of these proteins as serum biomarkers for clinically significant ACR in the first 6 months after liver transplantation in a prospective study. The protein levels were measured in 94 patients immediately before transplantation, at postoperative days (PODs) 1, 3, 7, and 14 and when biopsies were performed during episodes of biochemical graft dysfunction. The CD44 serum protein levels were significantly lower at POD 1 in patients who experienced histologically proven ACR in the follow-up compared with patients without ACR (P 0.001). CXCL9 was significantly higher before transplantation (P = 0.049) and at POD 1 (P 0.001) in these patients. Low CD44 values (cutoff,200.5 ng/mL) or high CXCL9 values (cutoff,2.7 ng/mL) at POD 1 differentiated between rejection and no rejection with a sensitivity of 88% or 60% and a specificity of 61% or 79%, respectively. The combination of both biomarker cutoffs at POD 1 had a positive predictive value of 91% and a negative predictive value of 67% for clinically significant ACR. Moreover, CD44 was significantly lower at the time of ACR (P 0.001) and differentiated the rejection group from patients with graft dysfunction due to other reasons. Our results suggest that CD44 and CXCL9 may serve as predictive biomarkers to identify liver allograft recipients at risk for clinically significant ACR.

Background— Organ transplantation has seen an increased use of organs from older donors over the past decades in an attempt to meet the globally growing shortage of donor organs. However, inferior transplantation outcomes when older donor organs are used represent a growing challenge. Methods and Results— Here, we characterize the impact of donor age on solid-organ transplantation using a murine cardiac transplantation model. We found a compromised graft survival when older hearts were used. Shorter graft survival of older hearts was independent of organ age per se, because chimeric young or old organs repopulated with young passenger leukocytes showed comparable survival times. Transplantation of older organs triggered more potent alloimmune responses via intragraft CD11c + dendritic cells augmenting CD4 + and CD8 + T-cell proliferation and proinflammatory cytokine production, particularly that of interleukin-17A. Of note, depletion of donor CD11c + dendritic cells before engraftment, neutralization of interleukin-17A, or transplantation of older hearts into IL-17A −/− mice delayed rejection and reduced alloimmune responses to levels observed when young hearts were transplanted. Conclusions— These results demonstrate a critical role of old donor CD11c + dendritic cells in mounting age-dependent alloimmune responses with an augmented interleukin-17A response in recipient animals. Targeting interleukin-17A may serve as a novel therapeutic approach when older organs are transplanted.

Curative treatment of intrahepatic cholangiocarcinoma (ICC) and hilar cholangiocarcinoma (Klatskin tumors) is limited to surgical resection or orthotopic liver transplantation. However, not all patients benefit from a surgical approach and suffer from early tumor recurrence. Response to chemotherapy is generally poor and, until today, no targeted therapy could be established. Metastasis-associated in colon cancer 1 (MACC1) is a recently discovered regulator of the hepatocyte growth factor (HGF)/Met/mitogen-activated protein kinase pathway, which induces proliferation, migration, and invasion in cell culture, as well as metastasis in mice. MACC1 expression shows a significant correlation with Met expression in colon cancer tissue and is highly prognostic for occurrence of distant metastasis and survival in colon cancer patients. Thus, we aimed to measure the expression of MACC1, Met, and HGF messenger RNA in microdissected tumor tissue and corresponding normal liver tissue of 156 patients with Klatskin tumors (n = 76) and ICC (n = 80) using real-time quantitative reverse-transcriptase polymerase chain reaction. We used immunohistochemical staining to validate the results. MACC1 expression in tumor tissue of both tumor entities was significantly higher than in corresponding normal liver tissue (P

BACKGROUND The quest for less traumatic abdominal approaches is changing paradigms in times of minimally invasive surgery. While natural orifice translumenal endoscopic surgery remains experimental, the single-incision approach could be the future of gallbladder surgery. METHODS Prospectively collected data from 875 patients subjected to conventional single-incision laparoscopic cholecystectomy (SILC) or 4-port [laparoscopic cholecystectomy (LC)] were retrospectively analyzed and discussed with the current literature. RESULTS Between 2008 and 2011, 201 (23%) SILCs and 674 (77%) LCs were performed. Mean age was 51.7±17.5 years (SILC: 45.1 vs. LC: 53.7 y). Patients were predominantly female (SILC: 75.1% vs. LC: 56.5%). Preoperative body mass index was 27.4±9.1 (SILC: 26.4 vs. LC: 27.8; P

BACKGROUND The effect of cold ischemia (CI) in vascularized composite allotransplantation is unknown. We herein assess tissue-specific damage, acceptable CI time, and the effect of preservation solutions in a syngenic rat hindlimb transplant model. METHODS Lewis rat limbs were flushed and stored for 2, 10, or 30 hr CI in saline, histidine-tryptophan-ketoglutarate or University of Wisconsin preservation solution before transplantation. Morphologic alterations, inflammation, and damage of the individual tissues were analyzed on day 10 using histomorphology, confocal, light, and transmission-electron microscopy. RESULTS Two-hour CI led to mild inflammation of tissues on day 10, whereas 10-hr and 30-hr CI resulted in massive inflammation and tissue damage. Although muscle was mainly affected after prolonged CI (≥10 hr), nerve was affected in all CI groups. A perineural cell infiltrate, hypercellular appearance, pronounced vacuolization, and mucoid degeneration, appearing as Wallerian degeneration, were observed. Staining with propidium iodide and Syto 16 revealed a decrease in viable muscle cell nuclei in the anterior tibial muscle on day 10 in all groups, which was most pronounced in 10-hr and 30-hr CI animals. Transmission-electron microscopy indicated that a large number of mitochondria were degenerated in the 10-hr and 30-hr CI groups. Histidine-tryptophan-ketoglutarate preservation solution slightly decreased inflammation and tissue damage compared to University of Wisconsin-treated and saline-treated animals, especially in skin and muscle when CI times did not exceed 10 hr. CONCLUSION Severe inflammation and tissue damage are observed after prolonged CI in muscle and nerve. Ischemia times in vascularized composite allotransplantation should be kept as short as possible and certainly below 10 hr.

PURPOSE OF REVIEW In liver transplantation, the ischemia/reperfusion injury (IRI) is influenced by factors related to graft quality, organ procurement and the transplant procedure itself. However, in brain-dead donors, the process of death itself also thoroughly affects organ damage through breakdown of the autonomous nervous system and subsequent massive cytokine release. This review highlights the actual knowledge on these proinflammatory effects of brain death on IRI in liver transplantation. RECENT FINDINGS Brain death affects IRI either through hemodynamical or molecular effects with proinflammatory activation. Immunological effects are mainly mediated through Kupffer cell activation, leading to TNF-α and TLR4 amplification. Proinflammatory cytokines such as interleukin (IL)-6, IL-10, TNF-β and MIP-1α are released, together with activation of the innate immune system via natural killer cells and natural killer T cells, which promote organ damage and activation of fibrosis. Preprocurement treatment regimens attempt to hamper inflammatory response by the application of methylprednisolone or thymoglobulin to the donor. Selective P-selectin antagonism resulted in improved function in marginal liver grafts. Inhaled nitric oxide was found to reduce apoptosis in liver grafts. Other medications like the immunosuppressant tacrolimus produced conflicting results regarding organ protection. Furthermore, improved organ storage after procurement - such as machine perfusion - can diminish effects of IRI in a clinical setting. SUMMARY Brain death plays a fundamental role in the regulation of molecular markers triggering inflammation and IRI-related tissue damage in liver transplants. Although several treatment options have reached clinical application, to date, the effects of brain death during donor conditioning and organ procurement remain relevant for organ function and survival.

Acute-on-chronic liver failure (ACLF) is characterized by high short-term mortality. Liver transplantation (LT) is a potential therapy for patients who do not improve with supportive measures, but the efficacy of LT has not been shown. The aim of this study was to investigate the feasibility of LT and to determine the postoperative outcomes of patients with ACLF. All patients referred to our liver unit between 2002 and 2010 were registered in a database. The diagnosis of ACLF was made in accordance with the Asian Pacific Association for the Study of the Liver consensus. The post-LT outcomes were compared with the outcomes of a cohort of patients with chronic liver disease who underwent transplantation for other indications during the same period. One hundred forty four of 238 patients fulfilled the ACLF criteria. In an intention-to-treat analysis, the median transplant-free survival time was 48 days. Multiorgan failure was the most common cause of death. Ninety-four patients (65%) were evaluated for LT, 71 patients (49%) were listed, and 33 patients (23%) finally underwent deceased donor LT; this resulted in a wait-list mortality rate of 54%. Patients who developed infectious complications (particularly pneumonia and/or sepsis) and patients who received renal replacement therapy or mechanical ventilation were less likely to undergo LT. The 1- and 5-year survival rates of 87% and 82% were comparable to the rates for non-ACLF patients. In conclusion, this study shows that LT remains the only therapeutic option for the vast majority of patients with ACLF. However, LT was feasible in less than one fourth of the patients with a 5-year survival rate greater than 80%. Liver Transpl 19:879-886, 2013. © 2013 AASLD.

BACKGROUND Simultaneous pancreas-kidney (SPK) transplantation is widely accepted as an optimal therapeutic option for patients with type 1 diabetes mellitus (T1DM) and end-stage renal disease, but the indication for patients with type 2 diabetes mellitus (T2DM) is still controversially discussed. METHODS Twenty-one T2DM recipients of a first combined pancreas-kidney graft performed at our center during a 9-year period were retrospectively analyzed with regard to demographic characteristics; cardiovascular risk factors; surgical, immunological, and infectious complications; and patient and graft survivals and compared with T1DM recipients (n=195) and 32 T2DM patients who received a kidney transplant alone (KTA) during the same period. RESULTS Patient survival at 1 and 5 years was 96.9% and 91.6% for the T1DM group, 90.5% and 80.1% for the T2DM group, and 87.1% and 54.2% for the T2DM KTA group, respectively (P

There have been few detailed studies of viral kinetics after liver transplantation (LT), and conflicting data have been reported on viral loads and the severity of recurrent hepatitis C virus (HCV) disease. This long-term study aimed to examine (1) the impact of HCV RNA levels at specific points in time within the first year and (2) the influence of interleukin-28B (IL-28B) genotypes on patient outcomes and the severity of recurrent HCV disease. The viral loads were measured 2, 4, 12, 24, and 48 weeks after LT, and the recipient/donor IL-28B genotypes of 164 patients were determined. A Cox regression analysis showed that the viral load at week 2 was an independent negative predictor of recipient outcomes. A week 2 viral load ≥ 6.0 log10 IU/mL was significantly associated with reduced patient survival. After a mean follow-up of 6.5 years, 21 of 164 patients (12.8%) developed a cholestatic type of HCV recurrence and/or rapidly progressed to cirrhosis within 1 year. A multivariate binary regression analysis showed that HCV viremia at week 2 and a non-C/C recipient IL-28B genotype were independent risk factors for cholestatic recurrent HCV. No predictive factors could be found for the occurrence of recurrent liver cirrhosis 5 and 10 years after LT. Our study shows that the HCV RNA level at week 2 and the recipient IL-28B genotype are independent, statistically significant risk factors for post-LT cholestatic HCV, and it emphasizes the importance of viral load monitoring and IL-28B genotyping for identifying HCV recipients at risk for severe HCV recurrence. Liver Transpl 18:671–679, 2012. © 2012 AASLD.

Proteomics has emerged as a powerful tool in clinical biomarker research. In the field of transplantation, proteomics aims not only at developing noninvasive tools for immune monitoring and identifying biomarkers of allograft rejection but also to gain mechanistic insights into the pathophysiology of an alloimmune response and hence defining new therapeutic targets. A basic knowledge of proteomic technology is a prerequisite to appreciate the complex data generated and required for critical evaluation/interpretation of proteomic-driven studies. This review provides an overview of proteomic approaches and its underlying concepts and discusses the advantages, clinical implications, challenges, and limitations of this exciting modality in transplantation.

Background Kidney transplantation in the elderly is complicated by comorbidities and a higher incidence of death. The Eurotransplant Senior Program (ESP) has been established to allocate kidneys from older donors to the increasing number of older recipients. In this retrospective, single center data analysis, we compare the outcome of recipients older than 70 years with younger recipients transplanted under the ESP protocol. Methods Between 1999 and 2009, a total of 83 kidneys were transplanted under the ESP protocol in Innsbruck and 19 of the recipients were older than 70 years (mean, 72.7 years). Cold ischemia time was kept short in both groups by giving preference to regional donor organs. Results Patient survival at 1 and 5 years were 95% and 67% in the 70+ group and 94.4% and 82.6% in the 70- group. Graft survival was 95% and 52% at 1 and 5 years in the 70+ group and 94.4% and 79.0% in the 70- group. When censored for death, graft survival at year 1 and 5 were 100% and 82% in the 70+ group and 98.1% and 92.7% in the 70- group. The delayed graft function rate was high in both groups (36.8% and 41.1%, respectively). Morbidities were largely related to hemodynamic, oncologic, and infectious events. Cardiac failure was the major cause of death. Conclusion Relatively good results can be achieved with renal transplantation in patients older than 70 years under careful pretransplant evaluation and postoperative management of comorbidities.

Background. Organ shortage is responsible for high mortality rates of patients awaiting liver transplantation (LT). Domino transplantation has had reported success in patients with metabolic disorders. Primary hyperoxaluria type 1 (PH1) is a rare metabolic disorder. There are a few case reports that suggest that PH1 livers originating from donors that have undergone combined liver-kidney transplantation can be successfully used for domino transplantation. Methods. In the last decade, five patients received a domino liver transplant from patients with PH1 in the EUROTRANSPLANT region. In this study, we report the clinical course and outcome of these five patients who were received a domino graft transplant. Results. All patients, with the exception of one, suffered from multifocal hepatocellular carcinoma and underwent domino LT from patients undergoing combined liver-kidney transplantation for PH1. Within the first 4 weeks, all the domino recipients developed dialysis-dependent kidney failure despite good liver function. Four of the five patients died. The only survivor underwent retransplantation due to hepatic artery thrombosis. Twenty months after transplantation, this patient is doing well and has had no recurrence of hepatocellular carcinoma. Conclusion. Domino LT using donors with PH1 results in early renal failure and cannot be recommended for transplantation unless preventive strategies have been identified.

Background. Risk factors for delayed graft function (DGF) in pancreas transplantation (PTx) and its implications on graft survival are poorly defined. Methods. Eighty-seven consecutive first-time PTx for type I diabetes performed between January 2003 and December 2007 were retrospectively reviewed. DGF was defined as a reversible need for exogenous insulin beyond postoperative day 10 (DGF group [DGFG]). For statistical analysis, DGFG patients were compared with patients with immediate graft function (control group [CG]). Results. DGF occurred in 16 patients (18.6%). C-peptide levels and DGF were inversely correlated (r=0.24, P=0.03). In univariate analysis, donor cytomegalovirus (CMV)+ antibody status, and D+/R− CMV mismatch were significantly associated with DGF (81.3% vs. CG 52.1%, P=0.029; and 62.5% vs. CG 21.1%, P=0.002, respectively). Compared with University of Wisconsin solution, histidine tryptophan ketoglutarate-preserved grafts displayed higher DGF rates (37.5% vs. CG 12.7%, P=0.030), similar to female recipients (DGFG 68.8% vs. CG 35.2%, P=0.015). On multivariate analysis, a significantly higher DGF incidence was noted in female recipients (DGFG 68.8% vs. CG 35.2%; P=0.03) and in recipients with D+/R− CMV mismatch (DGFG 62.5% vs. CG 21.1%; P=0.03). With a median follow-up of 40.4 months (range 0.7–74.2), graft survival at 5 years did not differ between both groups (94.4% CG vs. 93.8% DGFG; P=0.791). Conclusion. This is the first study that identifies CMV mismatch (D+/R−) as an additional risk factor for DGF occurrence in PTx. In this particular cohort, DGF does not seem to affect graft survival.

Background De novo sirolimus in calcineurin inhibitor-free regimens, although potentially useful to improve early renal function, are complicated by various drug-related side effects. Methods We report a prospective open-label, multicenter, randomized trial to evaluate early conversion from a CsA-based to a sirolimus (SRL)-based regimen 10 to 24 days after renal transplantation. Of the 196 patients, 141 patients with a low-to-moderate immunological risk were eligible to be converted to SRL or to continue CsA. All patients received antithymocyte globulin-F single-bolus induction, mycophenolate mofetil, and steroids. Results The primary endpoint, renal function determined by S-creatinine and estimated glomerular filtration rate calculated by Nankivell formula at 12 months was significantly better in the SRL group (1.51+/-0.59 vs. 1.87+/-0.98 mg/dL or 64.5+/-25.2 vs. 53.4+/-18.0 mL/min/1.73 m). Patient survival, graft survival, and incidence of biopsy-proven acute rejection after conversion were not statistically different. Drug discontinuations were significantly higher in the SRL group (36.2% vs. 19.7%). Significantly, more patients in the SRL group reported acne, aphtous, and temporary hyperlipidemia, whereas cytomegalovirus viremia was significantly decreased (7.3% vs. 28.2%). Conclusions Early conversion to a calcineurin inhibitor-free regimen with SRL in combination with mycophenolate mofetil may be a useful strategy to improve renal function. The identification of appropriate candidates and safe management of SRL-related adverse events will be a key to avoid the high rate of dropouts, which currently limit the broad applicability of this protocol.

Objective: The biliary anastomosis is still one of the major causes for morbidity after orthotopic liver transplantation. The optimal method of reconstruction remains controversial. The aim of the study was to assess biliary complications after liver transplantation using a choledochocholedochostomy with or without a temporary T-tube. Background Data: Several reports have suggested that biliary reconstruction without T-tube is a safer method with a lower rate of biliary complications compared with T-tube insertion. Methods: A total of 194 recipients of deceased donor liver grafts were randomized. In group 1 the biliary reconstruction was performed by side-to-side choledochocholedochostomy with (n = 99) and in group 2 (n = 95) without a T-tube. The T-tube was removed after 6 weeks. Results: The overall biliary complication rate was significantly increased in group 2 (P < 0.0005). Biliary leaks occurred in 5 patients in group 1 and in 9 patients in group 2 (5.05% vs. 9.47%; P = 0.2756 ns). Anastomotic strictures of the bile duct were seen in 7 patients in group 1 and in 8 patients in group 2 (7.07% vs. 8.42%; P = 0.7923 ns). Two of the patients in group 1 and 5 patients in group 2 developed an ischemic type biliary lesion (2.02% vs. 5.26%; P = 0.2716 ns). The rate of reoperations was comparable in both groups. The rate of invasive interventions was higher in the group without T-tubes (9% vs. 18%, P = ns), as was the rate of cholangitis (5% vs. 11%. P = ns) and pancreatitis (4% vs. 14%, P = 0.0218). No complications after removal of the T-tube were observed. Conclusion: This study is a large prospective randomized trial to assess biliary complications that occur following liver transplantation, after anatomizing the bile duct with or without T-tubes. A significant increased rate of complications in the group without T-tube insertion was observed. In summary, our results indicate that the usage of T-tubes is safe and an excellent tool for the quality control of biliary anastomoses.

For patients with irresectable hilar cholangiocarcinoma, liver transplantation (LT) is currently being reassessed because of promising data for neoadjuvant radiochemotherapy. For increased radicality, hepatectomy in combination with pancreatic head resection [extended bile duct resection (EBDR)] was performed for irresectable hilar cholangiocarcinoma during our initial experience. EBDR and LT was performed in 16 patients between 1992 and 1998. No neoadjuvant or adjuvant treatment was performed. The Union Internationale Contre le Cancer stages were I (n = 6), IIA (5), IIB (3), and IV (2). To evaluate the suspected increase in surgical radicality, a matched pair analysis was performed with 8 patients undergoing LT for hilar cholangiocarcinoma without partial pancreatoduodenectomy. The 1-, 5-, and 10-year patient survival rates after EBDR were 63%, 38%, and 38%, respectively. Twelve patients died: 2 died because of postoperative complications, 8 died because of tumor recurrence, and 2 died while recurrence-free more than 10 years after transplantation. Among the 6 stage I patients, only 1 developed tumor recurrence, but 2 died because of postoperative complications. The following factors showed a trend toward inferior survival: distant metastases, positive lymph nodes, high carbohydrate antigen 19-9 levels, and preoperative percutaneous transhepatic cholangiodrainage. When all lymph node–negative patients were considered after the exclusion of perioperative deaths, 10-year survival was 56%. In conclusion, the overall long-term survival was relatively low in our inhomogeneous cohort but favorable in patients without metastases. However, because of the increased perioperative mortality, EBDR is not recommended as a standard procedure for hilar cholangiocarcinoma instead of LT alone. To further improve the results, other approaches such as (neo)adjuvant therapy have to be increasingly investigated. Liver Transpl 15:1499–1507, 2009. © 2009 AASLD.

BACKGROUND Although the incidence of early acute rejection could have been diminished in the past, the long-term renal allograft survival could not benefit from the introduction of more effective immunosuppressive regimens mainly aiming at cellular rejection mechanisms. The cause of chronic rejection is still discussed controversially. Here, we demonstrate to what extent human leukocyte antigen (HLA) antibodies (HLAab) posttransplant contribute to late graft outcome. METHODS A total of 1014 deceased kidney transplant recipients transplanted at the Charite hospital were monitored in a cross-sectional manner for the development of HLAab using Luminex Single Antigen beads. Patients with stable kidney function at a median of 5-years posttransplant were tested once for HLAab and monitored for 5.5 years after testing. RESULTS Thirty percent of recipients showed HLAab. Donor-specific antibodies (DSA) were found in 31% of antibody positive patients. The presence of DSA was associated with a significantly lower graft survival of 49% vs. 83% in the HLAab negative group (P< or =0.0001). Non-DSAs also had an adverse effect on graft survival (70% vs. 83%; P=0.0001). In a prospective analysis of 195 patients with repeatedly no detectable HLAab, the survival probability was 94% as opposed to 79% survival among patients who developed HLAab de novo after the first testing (P=0.05). CONCLUSIONS We confirmed that HLAab produced even late after transplantation are detrimental to graft outcome. DSA were proven to have a strong adverse impact on graft survival. The results indicate that a posttransplant HLAab monitoring routine could be appropriate to improve long-term results.

Background. Ischemia/reperfusion injury activates innate immunity, which in turn may prevent tolerance induction. We asked whether prolonged cold ischemia interferes with successful tolerance induction. Methods. Kidneys from Dark Agouti donors were grafted into binephrectomized Lewis rats after short (20 min) or prolonged (6 hr) cold ischemia. Tolerance was induced by nondepleting anti-CD4 monoclonal antibody RIB 5/2 (10 mg/kg for 5 days). Binephrectomized untreated and cytotoxic T-lymphocyte antigen (CTLA)-4Ig treated recipients served as controls. Animals were followed for 100 days. Adoptive transfer experiments into sublethally irradiated naive Lewis were performed at day 100. Animals received kidneys from Dark Agouti rats subsequently without further immunosuppression and were followed for an additional 20 days. Results. All RIB 5/2-treated recipients survived the first observation period independent of the cold ischemia time. Graft function, morphology, and transferred T-cell numbers were comparable in both groups. Twenty days after transfer amounts of intragraft and peripheral donor-derived cells were significantly reduced in recipients of the initially prolonged cold ischemia group associated with an attenuated immune response. Conclusions. Our results prove that an initially extended cold ischemia does not interfere with tolerance induced by RIB 5/2. Moreover, we conclude that a "tolerizing conditioning" achieved by prolonged cold ischemia during the tolerance-induction phase may reduce the immune response in recipients of an adoptive cell transfer.

BACKGROUND: The increasing age of organ donors and the transplantation of older recipients have become clinical practice. Age-adapted immunosuppressive protocols considering these changes are currently not established. This study analyzed the age-dependent immune response after human kidney transplantation. METHODS: One hundred renal allograft recipients were prospectively evaluated from 2004 to 2005. Patients older than 65 years of the European Senior Program receiving kidneys from donors older than 65 years were compared with recipients younger than 65 years receiving kidneys from donors younger than 65 years. Age-dependent modifications of the immune response were evaluated before transplantation and 7 days and 6 months after grafting by flow cytometry analysis of lymphocyte surface markers in peripheral blood. The cytokine pattern was determined by Cytometric Bead Array, T-cell alloreactivity by enzyme-linked immunospot analysis. RESULTS: There were no differences between the groups regarding patient survival, graft survival, and function at 6 months after transplantation. Before transplantation, 7 days and 6 months thereafter recipients older than 65 years demonstrated significantly elevated numbers of memory T-cells while counts for naive T-cells were significantly reduced. Numbers of activated cytotoxic cells were elevated with increasing age before and 7 days after transplantation. T-cell alloreactivity was more pronounced in older recipients at all time points. Seven days after transplantation tumor necrosis factor-alpha (TNF-alpha) levels were significantly higher, whereas TNF-alpha and interleukin-10 (IL-10) concentrations were significantly reduced after 6 months in older recipients. CONCLUSIONS: Our data demonstrate an initially pronounced immune response in elderly recipients receiving grafts from elderly donors. This observation supports the concept of a donor and recipient age-adapted immunosuppression.

To investigate potential beneficial effects of donor treatment with methylprednisolone on organ function and outcome after liver transplantation.It is proven experimentally and clinically that the brain death of the donor leads to increased levels of inflammatory cytokines and is followed by an intensified ischemia/reperfusion injury after organ transplantation. In experiments, donor treatment with steroids successfully diminished these effects and led to better organ function after transplantation.To investigate whether methylprednisolone treatment of the deceased donor is applicable to attenuate brain death-associated damage in clinical liver transplantation we conducted a prospective randomized treatment-versus-control study in 100 deceased donors. Donor treatment (n = 50) consisted of 250 mg methylprednisolone at the time of consent for organ donation and a subsequent infusion of 100 mg/h until recovery of organs. A liver biopsy was taken immediately after laparotomy and blood samples were obtained after brain death diagnosis and before organ recovery. Cytokines were assessed by real-time reverse transcriptase-polymerase chain reaction. Soluble serum cytokines were measured by cytometric bead array system.After methylprednisolone treatment, steroid plasma levels were significantly higher (P0.05), and a significant decrease in soluble interleukins, monocyte chemotactic protein-1, interleukin-2, interleukin-6, tumor necrosis factor-alpha, and inducible protein-10 was observed. Methylprednisolone treatment resulted in a significant downregulation of intercellular adhesion molecule-1, tumor necrosis factor-alpha, major histocompatibility complex class II, Fas-ligand, inducible protein-10, and CD68 intragraft mRNA expression. Significantly ameliorated ischemia/reperfusion injury in the posttransplant course was accompanied by a decreased incidence of acute rejection.Our present study verifies the protective effect of methylprednisolone treatment in deceased donor liver transplantation, suggesting it as a potential therapeutical approach.

Objective To assess the preoperative disease characteristics as well as the rate of postoperative complications, patient survival, and course of symptoms after liver resection or orthotopic liver transplantation (OLT) for Caroli disease (CD) or syndrome (CS). Summary background data The clinical course of monolobar or diffuse CD or CS is often characterized by multiple conservative treatment attempts and interventions with recurrent episodes of cholangitis and a serious reduction in quality of life. The role and effectiveness of surgical treatment is still not well defined. Patients and methods Between June 1989 and December 2002, we treated 44 consecutive patients with CD or CS who had failure of conservative treatment before and were referred for surgical intervention. Demographic and clinical data, operative procedures and related morbidity, course of symptoms, and long-term follow-up were reviewed. Four patients with palliative resection for cholangiocarcinoma and incidental diagnosis of CD were excluded from the analysis. Results Twenty-two women and 18 men had a median period of 26.5 months from onset of symptoms to surgical therapy. Their median age at therapy was 49 years and 80% of the patients had monolobar disease with a left-right ratio of 2.6 to 1. Thirty-three (82.5%) patients underwent liver resection, while 4 (10%) patients received OLT for diffuse disease. Biliodigestive anastomosis alone was performed in 3 (7.5%) patients with contraindications to OLT. Patients (37.5%) had minor postoperative complications, which were treated conservatively, while 2 (5%) transplanted patients had a reoperation due to intraperitoneal bleeding. After a median follow-up of 86.5 months, we observed a favorable patient and graft survival. Three deaths during follow-up were not related to treatment or disease complications. Follow-up of disease-related symptoms, biliary complications, and antibiotic treatment revealed a significant improvement. Conclusion Our data show that liver resection for monolobar CD or CS and OLT for diffuse manifestations can achieve excellent long-term patient survival with marked symptom relief. Because of life-threatening long-term complications such as biliary sepsis and development of cholangiocarcinoma, timely indication for surgical treatment is crucial.

Although it generally is accepted that renal hypoxia may occur in various situations after renal transplantation, direct evidence for such hypoxia is lacking, and possible implications on graft pathophysiology remain obscure. Hypoxia-inducible factors (HIF) are regulated at the protein level by oxygen-dependent enzymes and, hence, allow for tissue hypoxia detection. With the use of high-amplification HIF-1alpha immunohistochemistry in renal biopsies, hypoxia is shown at specific time points after transplantation with clinicohistologic correlations. Immediately after engraftment, in primarily functioning grafts, abundant HIF-1alpha is present and correlates with cold ischemic time >15 h and/or graft age >50 yr (P < 0.04). In contrast, a low HIF-1alpha score correlates with primary nonfunction, likely reflecting loss of oxygen consumption for tubular transport. Protocol biopsies at 2 wk show widespread HIF-1alpha induction, irrespective of histology. Beyond 3 mo, both protocol biopsies and indicated biopsies are virtually void of HIF-1alpha, with the only exception being clinical/subclinical rejection. HIF-derived transcriptional adaptation to hypoxia may counterbalance, at least partly, the negative impact of cold preservation and warm reflow injury. Transient hypoxia at 2 wk may be induced by hyperfiltration, hypertrophy, calcineurin inhibitor-induced toxicity, or a combination of these. Lack of detectable HIF-1alpha at 3 mo and beyond suggests that at this time point, graft oxygen homeostasis occurs. The strong correlation between hypoxia and clinical/subclinical rejection in long-term grafts suggests that hypoxia is involved in such graft dysfunction, and HIF-1alpha immunohistochemistry could enhance the specific diagnosis of acute rejection.

Background Nonspecific inflammatory damages occurring prior to organ transplantation reduce long-term graft survival. Here, we tested the beneficial effects of carbon monoxide (CO) induction by methylene chloride (MC). Methods Fischer-344 (F-344 Rat) or Dark Agouti (DA Rat) donor animals were either treated with MC four hours prior to organ removal or remained untreated. Kidneys were transplanted into Lewis (LEW) recipients. The low responder strain combination (F-344-->LEW) was studied for long-term graft changes. Dendritic cells (DCs) migration and early changes were followed in additional groups of a high responding donor/recipient strain combination (DA-->LEW). Native kidneys of uninephrectomized, age-matched normal animals served as controls. Results Following MC application COHb peaked within two hours in donor animals. Renal function and morphology improved significantly in renal allografts of CO induced donor animals and were comparable to native controls long-term (24 wks). Early after transplantation (24 hr) donor-derived DCs, CD4+ T-cells and alloreactive T-cells were significantly reduced following the engraftment of organs from treated donors. In addition, a trend towards a Th1/Th2 shift and a significant intragraft reduction of CD3 mRNA expression was observed. Conclusion Donor treatment for the induction of CO reduced graft immunogenicity and inhibited chronic allograft nephropathy.

BACKGROUND Acute rejection (aRx) has a major impact on the long-term outcome of renal allografts, and its diagnosis is contingent on the invasive procedure of allograft biopsy. New immunosuppressive protocols have reduced the incidence but have not abolished this problem. Moreover, aRx is now more frequently seen several weeks after transplantation in outpatients. A noninvasive diagnostic test for predicting aRx could improve the management and outcome. The recently described measurement of urinary mRNA expression offers a new noninvasive approach. METHODS In this study, the authors monitored the urinary mRNA expression (221 specimens from 26 patients) of various immune molecules by real-time reverse-transcriptase polymerase chain reaction for up to 3 months after kidney transplantation. Most of the patients received anti-interleukin (IL)-2 receptor monoclonal antibody induction and tacrolimus-based maintenance immunosuppression, which resulted in a low incidence of aRx. To verify the "rejection" markers, an additional nine samples of patients with aRx were analyzed. RESULTS Granulysin mRNA increase (vs. 95% confidence interval of 159 urine samples from nonrejecting patients) was detected during 11 of 14 aRx episodes, and follow-up studies showed its predictive value for delayed aRx episodes, even weeks before enhanced serum creatinine was observed. Granulysin induction was associated with enhanced regulated on activation normal T-cell expressed and secreted (RANTES) mRNA expression in 8 of 11 samples. Other cytotoxic effector molecules (granzyme B, perforin, FasL), cytokines (tumor necrosis factor-alpha, RANTES, IL-2, IL-10, interferon-gamma, transforming growth factor-beta), CD3, and CCR1 showed less specificity and sensitivity. CONCLUSIONS The authors' data illustrate that the noninvasive kinetic mRNA expression measurement of defined markers in urinary cells of renal allograft recipients allows the early noninvasive detection of ongoing aRx.

Purpose of reviewThe donor-associated risk factor of brain death is closely associated with ischemia and reperfusion injury. This article outlines the interference between brain death–induced graft alterations and conditions after reperfusion injury during the pretransplantation and early posttransp

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

Background. Grafts from so-called “marginal donors” are increasingly used for organ transplantation. The combination of reduced organ quality and additional inflammatory damages may be particularly detrimental in these grafts. In a previous study, we showed the beneficial effects on long-term graft outcome of “suboptimal” grafts by the induction of heme oxygenase-1. Here we tested the impact of short-term donor treatment with established immunosuppressants. Methods. Twelve-month-old Fischer 344 donor rats either were treated with prednisolone, mycophenolate mofetil, RAD, or FK506 24 hr and 1 hr before organ harvesting or remained untreated. Renal allografts were perfused with University of Wisconsin solution and kept at 4°C for an ischemic period of 2 hr. Morphologic, immunohistologic, and real time reverse transcriptase-polymerase chain reaction analyses for relevant markers were performed at serial intervals and at the end of the observation period (6 months). Results. All animals survived the observation period, although the ischemic time resulted in accelerated chronic graft dysfunction. Grafts from donors treated with prednisolone or FK506 demonstrated significantly improved graft function and structure by 6 months. Mononuclear infiltrates were significantly reduced by the end of the observation period, whereas intragraft mRNA levels of tumor necrosis factor-α and interleukin-10 were significantly altered during the early period after transplantation. Minor improvements in graft function and histologic alterations of suboptimal grafts were observed after pretreatment with mycophenolate mofetil and RAD. Conclusion. Donor treatment with approved immunosuppressants, in particular prednisolone or FK506, represents a novel therapeutic strategy of clinical relevance, most importantly when using grafts from marginal donors.

Today, the major problem in organ transplantation is not acute graft rejection but chronic graft deterioration. In addition to alloantigen-specific events, alloantigen independent factors like donor age, previous diseases, consequences of brain death, and perioperative events of ischemia/reperfusion injury have a major impact on long-term graft function. The induction of the stress protein heme oxygenase-1 (HO-1) protects cells from injury and apoptosis. Here, we tested the protective effects of HO-1 induction in a clinically relevant kidney transplant model. Induction of HO-1 expression following cobalt-protoporphyrin (CoPP) treatment in organ donors prolonged graft survival and long-term function remarkably following extended periods of ischemia. Positive effects were observed with both optimal and marginal grafts from old donor animals. Structural changes characteristic for chronic rejection, as well as graft infiltration by monocytes/macrophages and CD8+ T cells, were substantially reduced following HO-1 induction. Up-regulation of HO-1 expression before organ transplantation was also associated with reduced levels for tumor necrosis factor (TNF)-alpha mRNA, increased levels for interferon (IFN)-gamma, and bcl-x, and insignificant differences for CD25, interleukin (IL)-2, IL-4, IL-6, and IL-10 mRNA levels. The significant improvement of long-term graft function following induction of HO-1 expression in donor organs suggests that this strategy may be a novel clinical treatment option with particular relevance for transplantation of marginal organs.

BACKGROUND The lack of adequate numbers of kidneys for transplantation has stimulated interest in the use of organs from non-heart-beating donors (NHBDs). The short- and long-term effects of this risk factor on kidney isografts and allografts were examined with a rat model. METHODS NHBDs were killed by ether overdose. Kidney isografts (male Lewis rats [LEW]-->LEW) were transplanted orthotopically into bilaterally nephrectomized recipients 15, 30, 45, and 90 min after asystole to determine short-term survival patterns, which were compared to those of rats bearing kidneys from living donors (LDs, 0 min). Isografts and allografts (Fisher 344 rats-->LEW) from 45-min and 105-min NHBDs and from LD controls were placed in additional recipients in which contralateral native nephrectomy was performed on day 10 to allow the injured graft to recover from its ischemic insult. Serum creatinine, proteinuria, and graft morphology were assessed serially over a 24-week follow-up period. RESULTS Early survival and renal dysfunction of isografted rats correlated with the interval of donor cardiac arrest before transplantation. Long-term survival of recipients of kidneys from LDs and between 45-min and 105-min NHBDs was also significantly different (100% vs. 87% vs. 37% at 24 weeks, respectively, P