Georg Györi

Short-term induction therapy with anti-thymocyte globulin and delayed use of calcineurin inhibitors in orthotopic liver transplantation.

The appropriate time point for starting immunosuppressive treatment with calcineurin inhibitors after orthotopic liver transplantation (OLT) has been a subject of debate. The aim of the study was to analyze the effects of anti‐thymocyte globulin (ATG) induction therapy on rejection, renal function, infection, tumor rate, and survival. We retrospectively analyzed 391 patients after OLT who had either received calcineurin inhibitors immediately after OLT (n = 129) or after an initial short‐term Thymoglobulin induction therapy (n = 262). The 1‐year acute rejection rate was 14.5% vs. 31.8% in favor of ATG (P = 0.0008). Rejection grades and the need for treatment also differed significantly (7.3% vs. 23.3%; P = 0.001). Serum creatinine at transplantation was similar in both groups (1.14 mg/dL vs.1.18 mg/dL; P = NS). Postoperative hemofiltration was less frequently seen after induction therapy (P < 0.05). Reduced renal function at 1 year was commonly observed, but serum creatinine (1.26 mg/dL vs. 1.37mg/dL; P = 0.015) and glomerular filtration rate (81 mL/min vs. 75 mL/min; P = 0.02) were far better in the ATG group. Undesired side effects occurred at a similar rate in both groups. Five‐year patient survival was also similar in the 2 groups (70.1% and 74.3%; P > 0.05). Short‐term ATG induction therapy with delayed administration of calcineurin inhibitors led to a more favorable rejection rate and an improved clinical course in case of a rejection episode. It has beneficial effects on renal function immediately after OLT as well as later, and no additional harmful effects. Liver Transpl 13:1039–1044, 2007.

Dynamic changes in MELD score not only predict survival on the waiting list but also overall survival after liver transplantation

The predictive value of MELD score for post‐transplant survival has been under constant debate since its implementation in 2001. Aim of this study was to assess the impact of alterations in MELD score throughout waiting time (WT) on post‐transplant survival. A single‐centre retrospective analysis of 1125 consecutive patients listed for liver transplantation between 1997 and 2009 was performed. The impact of MELD score and dynamic changes in MELD score (DeltaMELD), as well as age, sex, year of listing and WT were evaluated on waiting list mortality and post‐transplant survival. In this cohort, 539 (60%) patients were transplanted, 223 (25%) died on list and 142 (15%) were removed from the waiting list during WT. One‐, three‐ and five‐year survival after liver transplantation were 83%, 78% and 76% respectively. DeltaMELD as a continuous variable proved to be the only significant risk factor for overall survival after liver transplantation (hazard ratio (HR): 1.06, 95% confidence interval (CI) 1.02–1.1, P = 0.013). The highest risk of post‐transplant death could be defined for patients with a DeltaMELD > 10 (HR: 4.87, 95% CI 2.09–11.35, P < 0.0001). In addition, DeltaMELD as well as MELD at listing showed a significant impact on waiting list mortality. DeltaMELD may provide an easy evaluation tool to identify patients on the liver transplant waiting list with a high mortality risk after transplantation in the current setting. Temporarily withholding and re‐evaluating these patients might improve overall outcome after liver transplantation.

Short-term versus long-term induction therapy with antithymocyte globulin in orthotopic liver transplantation.

T‐cell depletion is an essential aspect of clinical immunosuppression. The aim of the present study was to compare the efficacy of two dosage regimens in this setting. We retrospectively compared 246 patients (group 1) who received a 10‐day antithymocyte globulin (ATG) induction protocol with 226 patients (group 2) who received a 3‐day protocol. The 6‐month rejection rate was 22.3% in group 1 and 12.7% in group 2 (P = 0.03). The sub‐analysis showed a higher rejection rate in patients with cholestatic disease (P = 0.01), who were more numerous in group 1. This resulted in an overall difference between the groups. Rates of de novo malignancies and recurrent hepatocellular carcinoma were identical. Viral infection rates were 16% and 18%, respectively (P > 0.5). The rates of bacterial and fungal infection were also similar (37% vs. 42%, P > 0.1). However, infection and ATG administration are independent risk factors for survival. A lower rate of fatal infection was observed in group 2 (P = 0.01), while the 10‐day ATG regimen had a detrimental effect on patients who had infection (P < 0.0001). Our results strongly support the application of 3‐day ATG induction therapy regimen after orthotopic liver transplantation, as it is associated with the same rejection rate as long‐term ATG induction therapy, without the negative survival effect of the latter due to lethal infection.

Effect of Hemodialysis Before Transplant Surgery on Renal Allograft Function—A Pair of Randomized Controlled Trials

Background. Hemodialysis immediately before kidney transplant surgery has been suggested to adversely affect early graft function. On the other hand, considering its profound antiinflammatory effects, a beneficial impact of regional citrate anticoagulation on the evolution of graft function can be speculated. We sought to assess the clinical impact of preoperative hemodialysis and dialysis anticoagulation in two related randomized trials. Methods Eligible kidney transplant candidates with a serum potassium less than or equal to 5.0 mEq/L were randomized to receive dialysis or no dialysis before deceased donor transplantation. Patients with a potassium more than 5.0 mEq/L were randomized to receive dialysis with heparin or citrate anticoagulation. The primary endpoint was the estimated glomerular filtration rate (eGFR) at posttransplant day 5. Results The first comparison (56 vs. 54 patients) revealed no effect of dialysis on eGFR at day 5 (primary endpoint, 12 [interquartile range 5–36] vs. 13 [5–37] mL/min/1.73 m2, P=0.98), rates of delayed graft function (22% vs. 27%, P=0.66), cellular rejection (20% vs. 24%, P=0.65), and C4d-positive dysfunction (2% vs. 9%, P=0.11) or 1-year death-censored graft survival (89% vs. 91%, P=0.51). Comparing citrate with heparin anticoagulation (44 vs. 66 patients), no differences in eGFR at day 5 (17 [8–31] vs. 14 [6–38] ml/min/1.73 m2, P=0.57), delayed graft function (21% vs. 30%, P=0.28), cellular rejection (23% vs. 33%, P=0.29), and graft survival (90% vs. 88%, P=0.44) were found. For citrate anticoagulation, less C4d-positive rejection episodes (P=0.08) and higher 1-year eGFR levels (P=0.03) were observed. Conclusion Pretransplant hemodialysis and anticoagulation may not affect early graft function in a meaningful way.

Good outcome after liver transplantation for ALD without a 6 months abstinence rule prior to transplantation including post‐transplant CDT monitoring for alcohol relapse assessment – a retrospective study

Alcoholic liver disease (ALD) is the second most common indication for liver transplantation (LT). The utility of fixed intervals of abstinence prior to listing is still a matter of discussion. Furthermore, post‐LT long‐term observation is challenging, and biomarkers as carbohydrate‐deficient transferrin (CDT) may help to identify alcohol relapse. We retrospectively analyzed data from patients receiving LT for ALD from 1996 to 2012. A defined period of alcohol abstinence prior to listing was not a precondition, and abstinence was evaluated using structured psychological interviews. A total of 382 patients received LT for ALD as main (n = 290) or secondary (n = 92) indication; median follow‐up was 73 months (0–213). One‐ and five‐year patient survival and graft survival rates were 82% and 69%, and 80% and 67%, respectively. A total of 62 patients (16%) experienced alcohol relapse. Alcohol relapse did not have a statistically significant effect on patient survival (P = 0.10). Post‐transplant CDT measurements showed a sensitivity and specificity of 84% and 85%, respectively. In conclusion, this large single‐center analysis showed good post‐transplant long‐term results in patients with ALD when applying structured psychological interviews before listing. Relapse rates were lower than those reported in the literature despite using a strict definition of alcohol relapse. Furthermore, post‐LT CDT measurement proved to be a useful supplementary tool for detecting alcohol relapse.

The value of protecting the longitudinal staple line with invaginating sutures during esophageal reconstruction by gastric tube pull-up.

Background: Radical surgery with lymphadenectomy offers the best chance of curing esophageal cancer, but it carries considerable risks. Generally, the resected esophagus is replaced with a gastric tube. Rupture of the gastric tube staple line is a rare but serious surgical complication. One unresolved issue is whether oversewing of the longitudinal gastric staple line is necessary to avoid staple line rupture or insufficiency. Patients and Methods: Between 2000 and February 2008, 199 patients underwent esophageal resection for cancer or perforation at the Vienna General Hospital, Medical University of Vienna. Data were collected prospectively. Of these patients, 151 (75.9%) underwent reconstruction by pulling up a gastric tube. These comprised the study population. In 83 patients (55.0%) the longitudinal gastric staple line was not oversewn (group A). In 68 patients (45.0%) the staple line was reinforced by invaginating sutures (group B). Results: The mean age of the patients was 62.0 ± 10.6 years (median: 63.1 years). Males comprised 75.5% of the population. Adenocarcinoma was diagnosed in 77 patients (51.0%), 63 patients (41.7%) suffered from a squamous cell carcinoma, 10 patients (6.6%) had esophageal perforation, and in 1 patient (0.7%) a gastrointestinal stromal tumor was diagnosed. In group A, a leak within the staple line was observed in 4 of 83 patients (4.9%). No leak was found in group B (p = 0.09). Major surgical complications included anastomotic leakage (21 patients; 13.9%), gastric tip necrosis (3 patients; 2%), postoperative ileus (3 patients; 2.0%) and chylothorax (7 patients; 4.6%). Two major intraoperative complications (1.3%) were splenic injury and aortic bleeding. Conclusion: A remarkable but not statistically significant difference was found regarding staple line rupture between study groups. However, all leaks were seen in patients without a staple line suture.

A Greater Proportion of Liver Transplant Candidates Have Colorectal Neoplasia Than in the Healthy Screening Population

BACKGROUND & AIMS Various types of liver disease are associated with an increased prevalence of colorectal adenomas. We investigated whether cirrhosis is a risk factor for colorectal neoplasia by analyzing colonoscopy findings from 2 cohorts of patients awaiting liver transplantation. METHODS We performed a retrospective analysis to compare findings from colorectal cancer screenings of 567 adult patients with cirrhosis placed on the waitlist for liver transplantation with those from controls (matched for age, sex, body mass index, smoking, and diabetes). Rates of adenoma and advanced adenoma detection were adjusted owing to differences in rates of polypectomies performed in the 2 cohorts. RESULTS Adenomas were detected in a significantly higher percentage of patients with cirrhosis (29.3%) than in controls (21.5%) (P = .0057; relative risk [RR], 1.36; 95% confidence interval [CI], 1.09-1.69); and patients with cirrhosis had a higher rate of advanced adenoma detection than controls (13.9% vs 7.7%; P = .0015; relative risk, 1.82; 95% CI, 1.25-2.64). A greater percentage of patients with alcoholic cirrhosis had neoplasias (34.3%) than controls (25.3%; P = .0350; RR, 1.36), and rates of advanced adenoma detection were 16.7% vs 10.2% (P = .0409; RR, 1.63). Adenomas were detected in 27.8% of patients with viral cirrhosis vs 15.9% of controls (P = .0061; RR, 1.74), with rates of advanced adenoma detection of 13.6% vs 5.0% (P = .0041; RR, 2.73). Similar proportions of patients with cirrhosis of other etiologies and controls were found to have colorectal neoplasias. CONCLUSIONS Based on a retrospective analysis of colonoscopy findings from patients awaiting liver transplantation, those with alcoholic or viral cirrhosis are at higher risk of developing colorectal neoplasia and should be considered for earlier colonoscopy examination.

Non‐persistent effect of short‐term bisphosphonate treatment in preventing fractures after liver transplantation

Bone disease is one of the most common complications after transplantation, affecting many transplant patients; some of them have recurrent fractures. We recently showed that high-dose zoledronic acid (ZOL) prevents bone fractures after orthotopic liver transplantation (OLT) [1]. The anti-re-absorptive action of ZOL became evident after 6 months, resulting in a beneficial outcome on bone matrix mineralization [2]. Renal function was not affected by bisphosphonate therapy. This study was carried out to determine whether a high-dose bisphosphonate treatment within the first 12 months exerted long-term beneficial effects on bone mineralization and turnover, preventing fractures. For this purpose, all subjects received conventional X-ray, bone mineral density (BMD) measurements and determination of serologic markers of bone turnover 3 years after transplantation. The long-term consequence of this treatment is yet to be investigated. Baseline characteristics, cumulative steroid dose, creatinine values and liver function parameters did not differ significantly. A total of 96 patients underwent randomization (49 patients in the control (CON) group and 47 in the ZOL group) at the beginning of the trial and 29 patients were analysed in the CON and 28 in the ZOL group after 36 months of engraftment. The ZOL and CON groups did not differ significantly in major baseline characteristics (Table 1). Three new fractures at 12 months after OLT occurred in the ZOL group (total numbers over 36 months: n = 7), these ‘late’ fractures were asymptomatic and detected by X-ray: no further fractures could be seen after 12 months in the CON group (total numbers over 36 months: n = 11). Two patients with ‘late’ fractures had a normal BMD after 12 months. The third patient had osteopenia at the lumbar spine after 1 year of transplantation. All fractures were vertebral fractures. No clinical sign or biochemical parameter could be detected to predict these late fractures. The preventive effect of bisphosphonate treatment after engraftment for fractures was not sustained from 12 months to 3 years (P = 0.076) (Fig. 1). BMD of the femoral neck and lumbar spine increased significantly in both groups (P < 0.001) from the time of transplantation until the third year after OLT. The increase in BMD t-scores of the lumbar spine in the same time interval also reached statistical significance in both groups (P = 0.006). No statistically significant differences could be detected in BMD t-scores of the femoral neck in both groups 36 months after OLT (P = 0.125). Osteoprotegerin, C-telopeptide, calcitonin, iPTH, osteocalcin and bone specific alkaline phosphatase were not significantly different at 12 and 36 months after OLT between both groups. Accordingly, adequate conversion of 25OHVitD to bioactive 1,25 (OH)-VitD occurred within 12 months in both groups and continued to be sufficient in the following years. Serum calcium and phosphate levels were similar in both groups at every time point (Table 2). One patient suffered from osteonecrosis of the jaw 25 months after OLT and 13 months after the last ZOL infusion. CON-, but not ZOL, -treated patients lost bone mineral density at femoral neck in the first 6 months. From the sixth month onwards, femoral neck BMD increased in both groups, being statistically higher at 3 years than at 12 months. The BMD of the lumbar spine increased in the ZOL the CON group in the first 12 months without a statistically significant difference between the groups. After 1 year, the BMD of lumbar spine increased and was statistically higher at 3 years than that at 12 months. This effect is most likely driven by the fact that the corticosteroid doses are significantly higher early after transplantation than doses used for the maintenance of immunosuppression after the first year. Millonig et al. [3] used a study protocol involving alendronate in combination with calcium/VitD to prevent bone loss after OLT. The study was not powered to assess fractures. In this trial, patients were stratified by BMD before transplantation and patients with osteopenia or osteoporosis received alendronate after OLT. Similar to like their results, we found that patients who received bisphosphonate did not experience significant bone loss in the lumbar spine in the early phase after OLT. We could even demonstrate a significant increase of BMD in femo-

Endoscopic versus surgical management of biliary complications – Outcome analysis after 1188 orthotopic liver transplantations

BACKGROUND AND AIM After liver transplantation, the endoscopic approach has become the standard treatment modality for biliary complications. Aim of this study was to compare primary endoscopic with primary surgical management. PATIENTS AND METHODS A retrospective review on 1188 consecutive liver transplant patients between 1989 and 2009 was performed. Management strategies (endoscopic, surgical or combined approach) were evaluated for treatment success as well as patient survival. RESULTS Biliary complications after liver transplantation were diagnosed in 211 (18%) patients. Initial endoscopic approach (N=162, 77%) was successful in 97 of 162 (60%) patients. In 80% of patients, success was achieved within a median of four ERCPs. Sixty-one patients (38%) were referred to surgery after non-successful ERCP. Initial surgical approach was performed in 49/211 patients (23%) with successful management in 38/49 (78%) of patients. Patients presenting with intraluminal objects needed a significantly higher number of ERCPs to reach treatment success (median 3 versus 2 interventions, p=0.001) but had an equal endoscopic success rate (p=0.427). Patients with successful endoscopic treatment showed lower mortality compared to patients with primary surgical treatment (p=0.029). CONCLUSIONS Endoscopic management should be considered as the primary approach for biliary complications after liver transplantation.

Impact of dynamic changes in MELD score on survival after liver transplantation – a Eurotransplant registry analysis

With restricted numbers of available organs, futility in liver transplantation has to be avoided. The concept of dynamic changes in MELD score (DeltaMELD) has previously been shown to be a simple tool to identify patients with the greatest risk of death after transplantation. Aim was to validate this concept with the Eurotransplant (ET) database.