Management of Portal Hypertension After Liver Transplantation.

INTRODUCTION: Post-transplantation portal hypertension has severe complications, such as esophageal varix bleeding, therapy refractory ascites, extreme splenomegaly, and graft dysfunction. The aim of our study was to analyze the effectiveness of the therapeutic strategies and how to visualize the procedure. METHODS: A retrospective study involving liver transplantation patients from the Semmelweis University Department of Transplantation and Surgery was performed between 2005 and 2015. The prevalence, etiology, and leading complications of the condition were determined. The applied interventions' effects on the patients' ascites volume, splenic volume, and the occurrence of variceal bleeding were determined. Mean portal blood flow velocity and congestion index values were calculated using Doppler ultrasonography. RESULTS: The prevalence of post-transplantation portal hypertension requiring intervention was 2.8%. The most common etiology of the disease was portal anastomotic stenosis. The most common complications were esophageal varix bleeding and therapy refractory ascites. The patients' ascites volume decreased significantly (2923.3 ± 1893.2 mL vs. 423.3 ± 634.3 mL; P < .05), their splenic volume decreased markedly. After the interventions, only one case of recurrent variceal bleeding was reported. The calculated Doppler parameters were altered in the opposite direction in cases of pre-hepatic versus intra- or post-hepatic portal hypertension. After the interventions, these parameters shifted towards the physiologic ranges. CONCLUSION: The interventions performed in our clinic were effective in most cases. The patients' ascites volume, splenic volume, and the prevalence of variceal bleeding decreased after the treatment. Doppler ultrasonography has proved to be a valuable imaging modality in the diagnosis and the follow-up of post-transplantation portal hypertension.

Examinations of Factors Influencing Survival of Liver Transplantation for Hepatocellular Carcinoma: A Single-Center Experience From Budapest.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Orthotopic liver transplantation (OLT) is the best therapy of choice for early, unresectable HCC. The Hungarian Liver Transplantation Program was launched in 1995 at the Department of Transplantation and Surgery, Semmelweis University, Budapest. From that time more than 60 patients underwent OLT for hepatic tumors, which in most cases were HCC. Our clinical examination was undertaken to analyze the possible influential factors of outcomes for our series of patients who received OLT for HCC. METHODS: We performed a review of all patients who underwent OLT for HCC at our department from 1996 to October 1, 2013. Disease extent was determined by preoperative computed tomography or magnetic resonance images. All explants were examined and categorized based on tumor number, size, distribution, HCC histologic grade, and vascular invasion. Patients with HCC were classified as having tumors either meeting Milan criteria, beyond Milan criteria but within UCSF criteria, or exceeding UCSF criteria. OLT was performed using standard techniques including orthotopic implantation with cross-clamp technique or with the piggyback technique. Postoperative immunosuppression included a triple drug regimen of calcineurin inhibitor (CNI), mycophenolate mofetil (MMF), and prednisone. mTOR inhibitors have been available since 2004. RESULTS: HCC most commonly occurs in the presence of cirrhosis as a result of longstanding chronic liver disease. Most of our patients who underwent OLT for HCC are 56 to 60 years old, and most also had underlying HCV cirrhosis. As of October 1, 2013, 21 of 49 (42.85%) patients had died after OLT for HCC. The main cause was the recurrence of the HCC in 38%, followed by sepsis in 33%, and HCV recurrence in 19%. One death each (4.7% of the total number of deaths) was caused by primary nonfunction of the graft, acute myocardial infarct, and de novo malignancy, respectively. Overall survival for the entire group at 1, 3, and 5 years after transplantation was 73.48%, 65.2%, and 50.08%, respectively. Using pretransplant imaging, 34 tumors (69.3%) were within Milan criteria, 8 (16.3%) were beyond Milan but within UCSF criteria, and 7 (14.3%) exceeded UCSF criteria. Based on explant pathology, 30 tumors (61.2%) were within Milan criteria, 7 (14,3%) were beyond Milan but within UCSF criteria, and 12 (24.3%) exceeded UCSF criteria. New onset, non-HCC malignant tumor developed in 2 cases (4%). There was no significant difference between the surgical techniques or the immunosuppressive strategies. Using the Cox analysis in our series, it can be seen that mortality was higher with tumors exceeding Milan criteria but within UCSF criteria compared with tumors within Milan criteria (Coef. = 0.5749 in Setting 1 and 0.1226 in Setting 2), and even higher with tumors beyond UCSF criteria compared with tumors within Milan criteria (Coef. = 0.7228 in Setting 1 and 0.1456 in Setting 2). Recurrence of the tumor causes higher mortality (Coef. = 1.709 in Setting 1 and 1.0256 in Setting 2). It seems that using an mTOR inhibitor has a beneficial impact on mortality (Coef. = -1.409 in Setting 1). Vascular invasion was associated with higher mortality (Coef. = 0.6581in Setting 1). Higher AFP levels correlated with higher mortality but not significantly (Coef. = 0.0002 in Setting 2). In our series, survival after OLT for HCC was best with tumors within Milan criteria comparing those exceeded Milan criteria (odds ratio = 4.000). CONCLUSION: According to our findings, the Milan criteria are still the safest criteria system; however, slightly expanded criteria do not have significantly worse results. Preoperative imaging methods sometimes show fewer or smaller tumors, and the explant histology reports the exact staging of HCC at the time of OLT. Histological examination especially of the lymphovascular invasion is mandatory to assess the estimated prognosis. Extremely high levels of AFP mean higher risk. HCC recurrence is an important factor on the outcome; therefore, continuous oncologic screening is mandatory. Immunosuppressant agents are chiefly responsible not just for higher risk of recurrence but for higher risk to develop de novo malignancies. Viral serology must be done periodically to catch HCV recurrence in time and begin adequate antiviral therapy. Potentially, mTOR inhibitors could be potent immunosuppressive agents after OLT for HCC due to this antiproliferative effect.

Analysis of Incretin Hormones After Orthotopic Liver Transplantation.

BACKGROUND: Several well-known risk factors play an important role in the development of new-onset diabetes mellitus after orthotopic liver transplantation (OLT). Immunosuppressant drugs and hepatitis C virus (HCV) infection have a direct effect on pancreatic beta cells resulting insulin hyposecretion. Steroids mainly cause peripheral insulin resistance. Although in type 2 diabetes mellitus the incretin-insulin axis is impaired and incretin hormones are advantageous targets of many antidiabetic drugs, the endocrinologic background of new-onset diabetes mellitus after transplantation (NODAT) is still not completely understood. METHODS: During the first postoperative year the oral glucose tolerance test (OGTT) was performed on 21 patients after OLT. Patients' glycemic metabolic status was determined according to the results of OGTT. The level of incretin hormones, namely glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), were measured with competitive enzyme-linked immunoassay reaction. RESULTS: Six patients had normal glucose tolerance (NGT), 9 had impaired glucose tolerance (IGT, serum glucose 7.8-11.0 mmol/L), and 6 were diagnosed with NODAT (serum glucose >11.1 mmol/L). Fasting insulin and c-peptide levels were higher if IGT/NODAT was found. Insulin secretion was not further stimulated after OGTT. GIP and GLP-1 levels did not differ significantly, not even after glucose load. HCV infection had not influenced the levels of incretin hormones [GLP-1 (0 min): 1.21 ± 0.27 vs 1.38 ± 0.65; P = ns; GLP-1 (120 min): 1.46 ± 0.61 vs 1.07 ± 0.58; P = ns; GIP (0 min): 2.55 ± 0.95 vs 1.99 ± 0.63; P = ns, GIP (120 min): 2.62 ± 0.6 vs 2.33 ± 0.77; P = ns]. CONCLUSION: The stimulation of insulin secretion in NODAT is limited. Incretin hormones are present independently from the current glycemic status. The use of dipeptidyl peptidase-4 inhibitors through their positive effect on the incretin-insulin axis can be beneficial in the therapy of NODAT after liver transplantation.

Exchange of best practices within the European Union: surgery standardization of abdominal organ retrieval.

Considering the growing organ demand worldwide, it is crucial to optimize organ retrieval and training of surgeons to reduce the risk of injury during the procedure and increase the quality of organs to be transplanted. In the Netherlands, a national complete trajectory from training of surgeons in procurement surgery to the quality assessment of the procured organs was implemented in 2010. This mandatory trajectory comprises training and certification modules: E-learning, training on the job, and a practical session. Thanks to the ACCORD (Achieving Comprehensive Coordination in Organ Donation) Joint Action coordinated by Spain and co-funded under the European Commission Health Programme, 3 twinning activities (led by France) were set to exchange best practices between countries. The Dutch trajectory is being adapted and implemented in Hungary as one of these twinning activities. The E-learning platform was modified, tested by a panel of Hungarian and UK surgeons, and was awarded in July 2013 by the European Accreditation Council for Continuing Medical Education of the European Union of Medical Specialists. As a pilot phase for future national training, 6 Hungarian surgeons from Semmelweis University are being trained; E-learning platform was fulfilled, and practical sessions, training-on-the-job activities, and evaluations of technical skills are ongoing. The first national practical session was recently organized in Budapest, and the new series of nationwide selected candidates completed the E-learning platform before the practical. There is great potential for sharing best practices and for direct transfer of expertise at the European level, and especially to export this standardized training in organ retrieval to other European countries and even broader. The final goal was to not only provide a national training to all countries lacking such a program but also to improve the quality and safety criteria of organs to be transplanted.

De novo Prograf versus de novo Advagraf: are trough level profile curves similar?

BACKGROUND: According to the clinical trials, Advagraf (ADV) has efficacy and safety profile similar to Prograf (PROG). The aim of this study was to compare the graft functions, dosages, and tacrolimus (TAC) trough level profile curves of patients on de novo PROG and ADV therapy. METHODS: The ADV group included 39 de novo renal cases who had received initial immunosuppression (IS) with once-daily TAC (1 × 0.2 mg/kg from day1 after transplantation). We compared them with a PROG group of 38 transplant patients who received equivalent IS with twice-daily TAC (2 × 0.1 mg/kg from day1). In both groups, the IS was combined with antimetabolites and steroids. The mean follow-up time was similar (13.5 ± 7 days) in both groups after renal transplantation until the emission of the patients from our clinic. RESULTS: TAC mean total daily dose was reduced and whole-blood trough levels decreased over the time in early postoperative days. Only on day 3 and day 4 after transplant, a significant higher adjustment in the ADV dosage was necessary to achieve sufficient TAC trough levels. The average TAC trough level profile curves were similar in PROG and ADV groups, but the individual curves were very different. Mainly in patients on ADV therapy, the initial concentrations were often >30 ng/mL, and in some cases on the 9th posttransplant day decreased to <5 ng/mL, then slowly increased into the required therapeutic range. CONCLUSIONS: The results demonstrate that patients after renal transplantation can be safely treated de novo with ADV. Setting the required therapeutic TAC blood levels may require more attention to avoid the "fluctuations" of trough level profile curve during the early postoperative period. Our data suggest that dose adjustment of ADV can be carried out more carefully compared with PROG on the basis of clinical symptoms and the value of TAC blood levels to avoid acute rejection and toxicity.

New-onset diabetes mellitus and the analysis of dipeptidyl-peptidase-4 after liver transplantation.

BACKGROUND: New-onset diabetes mellitus after transplantation (NODAT) is a common complication after orthotopic liver transplantation (OLT). The diabetogenic effect of hepatitis C virus (HCV) infection is well known. The aim of this study was to analyze the glucose homeostasis before and after OLT. The oral glucose tolerance test (OGTT) was carried out, and dipeptidyl-peptidase-4 (DPP-4) activity was measured. METHODS: The study period was from 2012 to 2014. We enrolled 49 non-diabetic patients from the waiting list (group A) and 21 patients after OLT (group B). Seven patients were monitored continuously both before and after OLT. According to our preoperative OGTT results, 13 patients in group A had newly diagnosed diabetes mellitus (group A/DM) and 11 had impaired glucose tolerance (group A/IGT). In 25 cases, normal glucose tolerance was diagnosed (group A/NGT). The calculated homeostasis model assessment insulin resistance (HOMA2-IR) values were both in group A/DM and-IGT higher compared with group A/NGT (2.42 ± 0.81 vs 2 ± 0.98 vs 1.28 ± 0.67; P = .001). In the case of HCV infection (n = 14; 29%) DM and IGT were more frequent. RESULTS: Six patients in group B had NODAT. In 9 cases, IGT and in 6 cases NGT was detected. In the case of HCV infection (n = 9; 43%), DPP-4 levels were higher compared with that in patients with all other indications for OLT (15.5 ± 5.2 vs 8.7 ± 3.5; P = .008). We evaluated the same individuals before and after OLT (n = 7), and a decrease in ß-cell function was noted. CONCLUSIONS: Preoperative OGTT is an important and easy investigation to rule out glucose imbalance before OLT. The HOMA2 calculation can also be useful both in preoperative and postoperative risk assessment. In our results, DPP-4 activity is not specific for the type of glucose homeostasis imbalance, but, in HCV infection, it is higher. DPP-4 inhibitors can be effective in the therapy of NODAT, especially in HCV-infected patients.

Retransplantations in the Hungarian liver transplant program.

Retransplantation of the liver (ReOLT), not infrequent consequence of transplantation, was analyzed from 512 patient records between 1995 and 2012. The 34 cases (33 secondary and 1 tertiary). Of ReOLT all employed cadaveric donor organs. The 34 reOLT were performed in 31 adults and 3 children. The original indication for OLT, among these patients was usually primary sclerosing cholangitis (PSC) and acute liver failure (ALF): there were no alcoholic liver disease (ALD) patients. The indication for early reOLT (within 3 months) was hepatic artery thrombosis while the late reOLTs beyond 3 months after primary transplantation was nonanastomotic biliary stenosis. The cumulative patient versus graft survivals were 61%, 52%, and 52% versus 61%, 52%, and 52% in contrast with primary OLT rates of 81%, 75%, and 70% versus 79%, 72%, and 61% respectively at (P = .03). In conclusion, our data suggested that the characteristics and number of early reOLTs did not change over time. However, the rate of late reOLTs increased. This can be explained by the increased rate of late onset biliary complications in spite of proper interventional radiological treatment. The second conclusion is that hepatitis C virus (HCV) recurrence did not become a main indication among late reOLT. Since a center policy states that patients with an early, cholestatic HCV recurrence are not referred for a secondary transplantation.

Technical risk factors for hepatic artery thrombosis after orthotopic liver transplantation: the Hungarian experience.

Hepatic artery thrombosis (HAT) significantly affects graft loss and mortality after orthotopic liver transplantation (OLT). The aim of this study was to analyze the risk factors of HAT in our program, with special regard to the personal-technical factor. We retrospectively analyzed the data of 500 adult liver transplant recipients between 1995 and 2011. Operations were performed by a certain group of surgeons, with standardized technique. The incidence rate of HAT decreased since 1995 from 12% to 7.8%. In accordance with the literature, HAT associated with acute rejection, polytransfusion, and the duration of the hepatectomy, arterial variations/reconstructions, tiny arteries, and furthermore, the timing of the anastomosis in Hungary. However we did not find an association with other parameters, like cytomegalovirus infection, and hepatocellular carcinoma as indication. We created a "difficulty index" that consists of the technical parameters. The difficulty index together with surgical experience (number of OLTs performed) had an outstanding association with HAT. In conclusion, the incidence and risk factors for HAT are similar to the results published by others. However, personal factors, such as experience, timing, given anatomy, and tiredness, might also play a significant role in the occurrence of HAT.

Biliary complications after orthotopic liver transplantation: the Hungarian experience.

Biliary complications (BC) significantly affect morbidity and mortality after orthotopic liver transplantation (OLT). The aim of this study was to analyze the incidence and types of biliary complications after OLT in Hungary. We retrospectively analyzed data of 471 adult liver transplant recipients between 1995 and 2011. Biliary complications occurred in 28% of patients. The most frequent BCs were bile duct stricture, stenosis (19%), biliary leakage (12%), and necrosis (BN: 6.4%). Biliary complications were associated with the incidence of acute rejection (51% vs 31%; P = .003), hepatic artery thrombosis (43% vs 11%; P < .001), and hepatic artery stenosis (26% vs 11%; P = .002). When cold ischemic time was longer than 12 hours, leakage (10% vs 3%; P = .043), ischemic type biliary lesion (20% vs 3.4%; P = .05), and BN (12% vs 3%; P = .067) were more often diagnosed post-OLT. Most of the biliary complications were treated by radiologic interventions (70%). Bile duct necrosis was associated with lower graft and patient survival. In conclusion, acute rejection, hepatic artery thrombosis/stenosis and cold ischemic time longer than 12 hours increase the incidence of BCs. Successful management of these risk factors can reduce the incidence of biliary complications and improve mortality.

Measurement and clinical significance of interleukin 28B in hepatitis C virus-infected liver transplant patients.

One-third of the liver transplantations are performed because of hepatitis C cirrhosis all over the world and also in Hungary. The recurrence rate is practically 100%, influencing graft and patient survivals; within 5 years cirrhosis develops again in 20% to 30% of cases. The therapy is pegylated interferon α-2a and α-2b plus ribavirin as for nontransplanted subjects with the goal to eradicate the virus and maintain graft function. In 25% to 45% of treated patients, it is possible to achieve a sustained virological response (SVR). The response is influenced by viral, donor, and recipient factors. We investigated the genotype of 68 liver recipients transplanted because of hepatitis C virus (HCV) infection between September 1998 and February 2011. We focused on the interleukin (IL) 28B gene locus single nucleotide polymorphism found on chromosome 19; the rs12979860 minor allele (homozygous [wild TT and CC], heterozygous [CT]) in relation to the interferon response. Ten percent of the patients belonged to the CC, 62% to the CT, and 28% to the TT group, and 83% of the CC group became negative or therapy is still ongoing. The CT genotype reached 15.4% SVR with ongoing treatment for most patients. In TT carriers showed a 23.5% SVR. Our patients formed a homogenous group regarding the surgical team, the therapy, and the HCV genotype. Ninety percent belonged to the possible "hard to treat" group. The 10% CC group gave the highest number of SVR and HCV polymerase chain reaction negativity upon antiviral therapy. Regarding our results, one has to take in consideration the small patient number and the fact that the cirrhotic patients were listed for transplantation where they could not be treated or became therapy-resistant. IL28B is just one predictive factor among others for successful posttransplant HCV therapy; further examinations are needed to fully understand its role.

Significance of mycophenolate monitoring in liver transplant recipients: toward the cut-off level.

Mycophenolate mofetil blocks the "de novo" -purine synthesis to reduce the incidence and severity of acute rejection episodes. There has been an increased interest in utility of monitoring mycophenolic acid (MPA) levels, however currently the MPA monitoring is not part of the protocol following liver transplantation. We assessed whether trough MPA monitoring could be advisable in liver transplant patients or not. For this reason MPA levels of 56 liver transplants were measured on 3, 5, 10, 14, 21, 30, 60, and 180 posttransplant days. The optimal cut-off of MPA level (≥1.73 mg/L) for all (56) and ≥1.34 mg/L for ciclosporin-treated- and ≥1.98 mg/L for the tacrolimus-treated transplants were calculated by statistical analysis to reduce the incidence of acute rejection. MPA concentrations of 3 days period before the day of clinical diagnosis acute rejection were well below the cut-off value. Only 3 (16%) out 19 patients with acute rejection had higher MPA levels than the cut-off value on the day of diagnosis of acute rejection. In conclusion, our data suggests that MPA predose level monitoring, especially in the early "filling phase" after transplantation, is applicable in liver allograft recipients given adjunctive MMF, protecting them from the ineffective immunosuppression.

The impact of Milan criteria on liver transplantation for hepatocellular carcinoma: first 15 years' experience of the Hungarian Liver Transplant Program.

In addition to hepatitis C, hepatocellular carcinoma. is a leading indication for orthotopic liver transplantation (OLT). The indications for OLT in HCC remains a topic of debate. The successful Milan criteria are still accepted as the gold standard to select candidates with a good chance for long-term survival. The Hungarian Liver Transplant Program launched in 1995 reached 45 OLT/year in 2010. Among 412 first OLTs, there were 49 cases of a malignant tumor, including 41 among which the indication was the tumor. Of the 412 patients, 154 (37.4%) were hepatitic C virus (HCV) positive, including 29 with HCC and 23 cases in which HCC was the indication itself. Half of the HCC patients were within the Milan criteria; 50% exceeded the criteria. We observed a solitary HCC in 36% of cases: 2 foci in 18%; 3 in 7%, 4 in 14%, and ≥5 in 25%. Only 12 patients underwent a "down-staging" treatment before OLT: 8 radiofrequency ablation (RFA) and 4 transarterial chemoembolization (TACE). Cumulative 1-, 3-, and 5-year patient survivals were 62%, 54%, and 43%, respectively in HCC/HCV-positive patients and they were 74%, 67%, and 61% among non-HCC HCV-positive subjects. The cumulative HCC patient survival rates of 64%, 64%, and 53% among Milan criteria were superior to those of 57%, 40%, and 27% among subjects exceeding the Milan criteria (P=.01). Pre-OLT "down-staging" treatment increased the 1-year patient survival from 64% to 70%; however, it did not affect the long-term results. Among items of the Milan criteria tumor size had less impact on outcomes then number of foci. The majority of cases who exceeded the Milan criteria had been transplanted before 2003. Our results suggested that the Milan criteria should be applied for the selection of candidates in order to promise good survival after OLT for HCC.

Liver transplantation for acute liver failure: the Hungarian experience.

Acute liver failure (ALF) counts for 9%-11% of activity in leading liver transplant programs. We have summarized the Hungarian Liver Transplant Program experience for ALF among 412 consecutive orthotopic liver transplantations (OLTs). All OLTs were performed without an extended international donor background. The proportion of ALF among the indications for OLT was lower (5.8% vs 9%) and early mortality higher than the European Liver Transplant Registry (1 year cumulative patients survival is 70% in ELTR vs 60% in the HU LT Program). The waiting time for a donor was longer than expected in the Eurotransplant community. Regarding postoperative complications, there was a higher incidence of initial poor function, bacterial infection, sepsis, and multiorgan failure. We conclude that ALF can be managed with reasonable results but requires an extended donor pool with an integrated international network to improve postoperative morbidity and mortality.

Relationship between hepatitis C virus recurrence and de novo diabetes after liver transplantation: the Hungarian experience.

De novo diabetes mellitus is a common complication after liver transplantation. It is strongly associated with hepatitis C virus (HCV) infection. We analyzed the relationship between HCV recurrence and de novo diabetes among the Hungarian liver transplant population. This retrospective study included cases from 1995 to 2009 on 310 whole liver transplantations. De novo diabetes was defined if the patient had a fasting plasma glucose ≥126 mg/dL permanently after the third month post liver transplantation, and/or required sustained antidiabetic therapy. De novo diabetes occured in 63 patients (20%). The cumulative patient survival rates at 1, 3, 5, and 8 years were 95%, 91%, 88%, and 88% in the control group, and 87%, 79%, 79%, and 64% in the de novo group, respectively (P=.011). The majority of the patients in the de novo group were HCV positive (66% vs 23%). Early virus recurrence within 5 months was associated with the development of diabetes (80% vs 20% non-diabetic controls; P=.017). The fibrosis (2.05 ± 1.5 vs 1 ± 1; P=.039) and Knodell scores (3.25 ± 2 vs 1.69 ± 1.2; P=.019) were higher among the de novo group after antiviral therapy. Rapid recurrence, more severe viremia, and fibrosis showed significant roles in the developement of de novo diabetes after liver transplantation.

Outcome of liver transplantation based on donor graft quality and recipient status.

BACKGROUND: Availability of suitable donor organs has always limited the number of liver transplantations performed. Use of marginal donor organs is an alternative to overcome organ shortage. OBJECTIVE: To analyze the effect of various combinations of donor organ quality and recipient status on the outcome of liver transplantation. MATERIALS AND METHODS: Data from 260 whole-liver transplantations performed between January 2003 and September 2009 were analyzed retrospectively. Study groups were established according to donor organ quality (marginal score 0-1 vs 2-5) and recipient status (Model for End-Stage Liver Disease [MELD] score <17 or >17). In patients at low risk, 102 received optimal grafts (good-to-good group [G/G], and 75 received marginal grafts (bad-to-good group [B/G]. In patients at high risk, 46 received optimal grafts (good-to-bad group [G/B], and 37 received marginal grafts (bad-to-bad group [B/B]. RESULTS: No differences were observed in cumulative patient and graft survival rates; however, total survival differed in the early period after transplantation, that is, within 1 year. There was a higher rate of overall postoperative complications including initial poor graft function, bleeding, infection, and kidney failure in group B/B compared with group G/B (25 of 37 patients [67.5%] vs 27 of 46 patients [59.0%]), group B/G (25 of 37 patients [68%] vs 39 of 75 patients [52%], and group G/G (25 of 37 patients [68%] vs 43 of 102 patients [42%]) (P = .04). Patients with a high MELD score (G/B and B/B) demonstrated increased risk of postoperative complications. Use of donor organs with marginal score of 2 or higher in patients with high MELD scores increased early patient mortality. CONCLUSION: In summary, patients with a high MELD score (G/B and B/B) are at an increased risk of post-OLT complications. In contrast, use of marginal grafts (B/G and B/B) increased the rate of hepatitis C virus recurrence and decreased the response rate to antiviral therapy. The combination of impaired donor grafts and recipients at high risk should be avoided.

Mitigation of cytokine storm by intraoperative use of renal replacement therapy during combined liver-kidney transplantation.

BACKGROUND: Combined liver-kidney transplantation (CLKT) is a widely used multiorgan transplantation with good graft survival rates. Previous studies have shown beneficial effects of renal replacement therapy in critically ill patients. This observation led us to use intraoperative continuous veno-venous hemofiltration (CVVH) during multiorgan transplantations. METHODS: We analyzed (CRP) inflammatory response parameters of tumor necrosis factor (TNF)alpha, interleukin(IL)-6, procalcitonin (PCT) and C-reactive protein (CRP) at various stages of the combined transplantations. RESULTS: All patients survived with well-functioning grafts. Mean +/- SD follow-up was 32.8 +/- 14.2 months. During the whole operation we used intraoperative CVVH starting at the beginning and continuing in the intensive care unit (ICU) afterward (mean +/- SD, 11.2 +/- 8.4 hours). Intraoperative TNFalpha, IL-6, CRP, and PCT were measured before surgery, during hepatectomy in the anhepatic phase, before and after liver reperfusion, exactly before kidney reperfusion, after kidney reperfusion, and upon arrival in the ICU. The wash-out of cytokines together with hemodynamic stability gave optimal circumstances for recovery of the transplanted organs. CONCLUSIONS: CVVH-based therapy offered stable intraoperative parameters, prevention of fluid overload, correction of metabolic disturbances, and wash-out of cytokines, which gave optimal circumstances for recovery of transplanted organs.

Factors in association with sepsis after liver transplantation: the Hungarian experience.

Sepsis is the major cause of patient death after orthotopic liver transplantation (OLT). To identify risk factors for sepsis, we analyzed all 199 primary OLTs performed between 1995 and 2004. Patients were divided into 2 groups according to whether they experienced sepsis after liver transplantation. Recipient, perioperative factors, and complications were subjected to univariate analyses. Statistically significant factors were exposed to multivariate analyses: Cox regression and Hosmer-Lemeshow test. Sepsis occurred in 45 (23%) patients. Recipient Child-Pugh score, preoperative broad spectrum antibiotic (meropenem) prophylaxis, intraoperative red blood cell transfusion, starch infusion, postoperative bleeding, hepatic artery thrombosis, and biliary leakage/necrosis were independent risk factors for sepsis. Our results agree with the international experience. A high amount of starch infusion and an extended use of broad spectrum antibiotics for prophylaxis adverse experiences in our center and have been removed from the protocol.

Mutation scanning of the p53 tumor suppressor gene in renal and liver transplant patients in Hungary.

INTRODUCTION: The increased incidence of malignancies among transplanted patients is well known. Abnormal function of the p53 tumor suppressor gene has been reported in more than half of all tumors. The aim of our study was to detect point mutations of p53 gene in transplanted patients because the presence of mutations may be a predictive factor for tumor development. An earlier diagnosis can help to develop new strategies for immunosuppressive therapies. METHODS: Three point mutations were chosen based on the literature: exon5-codon175, exon7-codon248, exon8-codon273. Genomic DNA from the plasma of 60 liver, 362 renal transplants, and 45 nontransplanted patients with different tumors and 20 suspected healthy patients were analyzed with a real-time PCR method using the Roche LightCycler. The mutations were evaluated by melting curve analysis. RESULTS: We elaborated a special protocol for scanning the above mentioned p53 point mutations, which were proved by sequencing as well. Among 487 patients, 486 showed a wild-type genotype. The only patient carrying a mutation at codon 273 (heterozygous) was a liver transplant patient, who developed pancreas carcinoma and had already died. CONCLUSION: Our data suggest that mutations of the targeted codons in leukocyte DNA seem to be rare, but a mutation could be lethal. The evaluated three point mutations of p53 gene were not predictive for tumor development.

Experimental vascular graft for liver transplantation.

Hepatic artery thrombosis is a major cause of graft failure in liver transplantation. Use of donor interponates are common, but results are controversial because of necrosis or thrombosis after rejection. Reperfusion injury, hypoxia and free radical production determinate the survival. The aim of the study was to create an 'ideal' arterial interponate. Autologous, tubular graft lined with mesothelial cells, prepared from the posterior rectus fascia sheath, was used for iliac artery replacement in eight mongrel dogs for six months under immunosuppression. Patency rate was followed by Doppler ultrasound. Eight grafts remained patent and another two are patent after one year. The patency rate was good (median Doppler flow: 370 cm/sec) and there was no necrosis, thrombosis or aneurysmatic formation. The grafts showed viable morphology with neoangiogenesis, appearance of elastin, smooth muscle and endothelial cells. Electron microscopy showed intact mitochondrial structures without signs of hypoxia. Tissue oxygenation was good in all cases with normal (< 30 ng/ml) myeloperoxidase production. In conclusion, this autologous graft presents good long-term patency rate. Viability, arterialisation and low thrombogenicity are prognostic factors indicating usability of the graft in the clinical practice without the risk of rejection. Further investigations such as cell cultures and standardisation are necessary.

[Qualitative and quantitative detection of hepatitis C virus RNA by PCR technique. Monitoring of viral copies after liver transplantation]. / Hepatitis C-vírus (HCV)-RNS kvalitatív és kvantitatív kimutatása PCR technikával. A HCV-RNS-kópiaszám monitorozása májtranszplantációt követóen.

The authors demonstrate the HCV nucleic acid amplification method is not wide-spread in Hungary yet. The HCV-RNA is usually detectable 2-4 weeks after infection independently the immunostate of the patients. The authors help to select the adequate measurement(s) in logical order when HCV infection is suspected. The benefit of the PCR method is emphasized. Monitoring of the HCV-RNA titer of the liver transplanted patients promotes to establish the fluctuation of HCV-RNA copies and the effectivity of therapy following transplantation. The detection of HCV-RNA by PCR method is a proof of an acute or chronic infection and rules out past infection. The quantitative PCR measurement is useful for determination of indication and control of efficacy of antiviral therapy.