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.

Regional citrate anticoagulation in patients with liver failure supported by a molecular adsorbent recirculating system.

OBJECTIVE: Regional citrate anticoagulation has emerged as a promising method in critically ill patients at high risk of bleeding. However, in patients with liver failure, citrate accumulation may lead to acid-base and electrolyte imbalances, notably of calcium. The aim of this study was to evaluate the feasibility and safety of regional citrate anticoagulation during liver support using a molecular adsorbent recirculating system as well as its effects on electrolyte and acid-base balance in patients with liver failure. DESIGN: Prospective observational study. SETTING: University hospital. PATIENTS: Twenty critically ill patients supported by molecular adsorbent recirculating system resulting from liver failure between January 2007 and May 2009. MEASUREMENTS AND MAIN RESULTS: The median duration of molecular adsorbent recirculating system treatment was 20 hrs (interquartile range, 18-22 hrs). Two of 77 molecular adsorbent recirculating system treatments (2%) were prematurely discontinued as a result of filter clotting and bleeding, respectively. The median citrate infusion rate, necessary to maintain the postfilter ionized calcium between 0.2 and 0.4 mmol/L, was 3.1 mmol/L (interquartile range, 2.3-4 mmol/L) blood flow. The median calcium chloride substitution rate was 0.9 mmol/L (0.3-1.7 mmol/L) dialysate. Total serum calcium remained stable during molecular adsorbent recirculating system treatments. There was a statistically significant increase of the ratio of total calcium to systemic ionized calcium (2.04 ± 0.32 mmol/L to 2.17 ± 0.35; p = .01), which reflected citrate accumulation resulting from liver failure. Under close monitoring, no clinically relevant electrolytes or acid-base disorders were observed. CONCLUSIONS: Our results suggest that regional citrate anticoagulation is a safe and feasible method to maintain adequate circuit lifespan without increasing the risk of hemorrhagic complications while maintaining a normal acid-base as well as electrolyte balance in patients with liver failure supported by molecular adsorbent recirculating system.

Up-regulation of interleukin 33 and soluble ST2 serum levels in liver failure.

BACKGROUND: IL-33, a member of the IL-1 family, induces the production of pro-inflammatory and Th2-associated cytokines and may also serve as an 'alarmin' similar to HMGB1. Soluble ST2 has been implicated as a decoy receptor, to attenuate Th2 inflammatory responses. The relevance of both molecules in hepatic failure is unknown. MATERIALS AND METHODS: The trial was a prospective preliminary study in a university hospital surgical ICU; 11 patients with acute liver failure (ALF) and 12 patients with acute-on-chronic liver failure (ACLF), who were admitted to the ICU; 14 patients with chronic hepatic failure (CHF) awaiting liver transplantation; 13 healthy individuals served as controls. IL-33 and soluble ST2 concentrations were determined by enzyme linked immunosorbent assay (ELISA). RESULTS: The concentration of IL-33 and soluble ST2 was significantly higher in ALF, ACLF, and CHF patients compared with the controls. Soluble ST2 serum concentration was significantly elevated in ALF and ACLF compared with CHF; moreover, soluble ST2 was significantly higher in CHF compared with healthy controls. IL-33 and soluble ST2 serum levels correlated significantly (r = 0.6117, P < 0.0001). Moreover, there was a correlation between IL-33 serum levels and alanine aminotransferase (ALT) activity in CHF, ALF, and ACLF patients (r = 0.4321, P = 0.0171). CONCLUSION: Our data provide evidence for elevated levels of IL-33 and soluble ST2 in liver failure, which could a sign of immune hyperactivation, and/or a mechanism to down-regulate inflammation. Especially, soluble ST2 maybe useful to discern acute from chronic hepatic failure or to monitor the course and the severity of the disease.

MCP-1 and MIP3-alpha serum levels in acute liver failure and molecular adsorbent recirculating system (MARS) treatment: a pilot study.

OBJECTIVE: The CC chemokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-3 alpha (MIP3-alpha) may be involved in the pathogenesis of acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). In ALF and ACLF, the molecular adsorbent recirculating system (MARS) has been used to support liver function. Enhancement of MCP-1, as seen in other extracorporeal support systems such as haemodialysis, might thus have mitigated the beneficial effects of the MARS system in acute hepatic failure. MATERIAL AND METHODS: Serum concentrations of MCP-1 and MIP3-alpha were measured in 10 patients with ALF or ACLF treated with MARS. Thirteen patients suffering from chronic hepatic failure (CHF) and 15 healthy individuals served as controls. RESULTS: Baseline MCP-1 serum concentrations were significantly increased in ALF and ACLF patients as compared to patients with CHF (p=0.0027 and p=0.0046, respectively) and controls (p=0.0006 and p=0.0012, respectively). MIP3-alpha serum concentrations were also significantly enhanced in the ALF and ACLF groups as compared with those in CHF patients (p=0.0002 and p=0.0003, respectively) and controls (p<0.0001 and p<0.0001, respectively). Moreover, MIP3-alpha levels were significantly increased in CHF patients as compared to controls (p=0.0002). MCP-1 and MIP3-alpha concentrations did not change significantly during MARS treatment in ALF and ACLF patients. CONCLUSIONS: The CC chemokines MCP-1 and MIP3-alpha are increased in ALF and ACLF patients. MARS had no effect on MCP-1 and MIP3-alpha serum concentrations in patients with ALF and ACLF, and yielded no evidence of any harmful effects of the increase of these potentially hepatocidal chemokines.

Combination of extended donor criteria and changes in the Model for End-Stage Liver Disease score predict patient survival and primary dysfunction in liver transplantation: a retrospective analysis.

BACKGROUND: The purpose of this study was to analyze the impact of extended donor criteria (EDC) and of changes in the Model for End-Stage Liver Disease (MELD) score while waiting for liver-transplantation (Delta-MELD) on patient survival and initial graft function. METHODS: We included 386 consecutive patients with end-stage liver disease who underwent orthotopic liver transplantation at the Medical University Vienna between 1997 and 2003. Primary outcome was patient survival and secondary outcome was initial graft function. EDC included: age >60 years, >4 days intensive medical care, cold ischemia time >10 hr, need for noradrenalin >0.2 microg/kg/min or doputamin >6 microg/kg/min, a donor peak serum sodium >155 mEq/L, a donor serum creatinine >1.2 mg/100 mL, and a body mass index >30. RESULTS: Delta-MELD was significantly higher in the nonsurvivor population (P=0.01) and EDC showed a significant influence on initial graft function (P=0.01). Worsening in either Delta-MELD or the presence of at least two EDC was not associated with an increased risk of primary graft dysfunction and death. Worsening in Delta-MELD and the presence of at least two EDC was significantly associated with primary graft dysfunction (P=0.01) and death (P=0.008). CONCLUSION: The combination of a liver recipient with worsening Delta-MELD and a potential donor with at least two EDC should be avoided.

Genetic detection of lymph node micrometastases: a selection criterion for liver transplantation in patients with liver metastases after colorectal cancer.

BACKGROUND: Liver transplantation for nonresectable liver metastases from colorectal cancer was abandoned in 1994 on account of high recurrence rates. The aim of this study was to investigate whether the genetic detection of micrometastases in histologically negative lymph nodes of the primary colon cancer could be applied to select patients for liver transplantation. METHODS: We analyzed 21 patients with colorectal cancer who had undergone liver transplantation between 1983 and 1994 for liver metastases. Eleven patients were histologically lymph node negative at the time of surgery; ten patients with lymph node metastases served as control group. DNA sequencing was used to screen tumor material for p53 and K-ras mutations. Mutant allele-specific amplification (MASA) was then used to search for micrometastases in DNA from regional lymph nodes of the primary colorectal cancer. RESULTS: p53 and K-ras mutations were detected in 12 (57%) and 3 (14%) of 21 patients in the colorectal cancer, respectively. The mutations were confirmed in the corresponding liver metastases. Of 11 patients with histologically negative lymph nodes, nine were eligible for MASA due to presence of p53 or K-ras mutation. MASA revealed six of nine patients to be genetically positive for micrometastases. Three patients were both genetically and histologically negative. These three patients showed a significantly longer overall survival (P = 0.011) of 4, 5, and 20 years, respectively. CONCLUSIONS: We conclude that the genetic detection of micrometastases by MASA could be a powerful prognostic indicator for selecting patients with colorectal liver metastases who could benefit from liver transplantation.

Molecular adsorbent recirculating system and hemostasis in patients at high risk of bleeding: an observational study.

INTRODUCTION: Liver failure is associated with reduced synthesis of clotting factors, consumptive coagulopathy, and platelet dysfunction. The aim of the study was to evaluate the effects of liver support using a molecular adsorbent recirculating system (MARS) on the coagulation system in patients at high risk of bleeding. METHODS: We studied 61 MARS treatments in 33 patients with acute liver failure (n = 15), acute-on-chronic liver failure (n = 8), sepsis (n = 5), liver graft dysfunction (n = 3), and cholestasis (n = 2). Standard coagulation tests, standard thromboelastography (TEG), and heparinase-modified and abciximab-fab-modified TEG were performed immediately before and 30 minutes after commencement of MARS, and after the end of MARS treatment. Prostaglandin I2 was administered extracorporeally to all patients; 17 patients additionally received unfractioned heparin. RESULTS: Three moderate bleeding complications in three patients, requiring three to four units of packed red blood cells, were observed. All were sufficiently managed without interrupting MARS treatment. Although there was a significant decrease in platelet counts (median, 9 G/l; range, -40 to 145 G/l) and fibrinogen concentration (median, 15 mg/dl; range, -119 to 185 mg/dl) with a consecutive increase in thrombin time, the platelet function, as assessed by abciximab-fab-modified TEG, remained stable. MARS did not enhance fibrinolysis. CONCLUSION: MARS treatment appears to be well tolerated during marked coagulopathy due to liver failure. Although MARS leads to a further decrease in platelet count and fibrinogen concentration, platelet function, measured as the contribution of the platelets to the clot firmness in TEG, remains stable. According to TEG-based results, MARS does not enhance fibrinolysis.

Iced versus room temperature injectate for assessment of cardiac output, intrathoracic blood volume, and extravascular lung water by single transpulmonary thermodilution.

PURPOSE: To assess the accuracy of iced versus room (RT) temperature single transpulmonary thermodilution (STPD) measurements for cardiac output, intra-thoracic blood, volume and extravascular lung water. MATERIALS AND METHODS: We studied 15 critically ill patients in a surgical intensive care unit with sepsis/septic shock (n = 8), pancreatitis (n = 2), acute liver failure (n = 2), orthotopic liver transplantation (n = 2) and lung resection (n = 1). All patients were sedated and mechanically ventilated. A 4-French femoral arterial catheter was inserted into each patient and connected to the pulse contour computer system (PiCCO). The pulse contour computer was then consecutively calibrated by triplicate STPD with 20 mL of RT and iced saline solution. The measurements with RT injectate were performed with a special in-line sensor adapted for measurement with RT injectate. All measurements were completed in less than 10 min. RESULTS: A total of 144 measurements were carried out. Linear regression analysis revealed good correlation between the two methods [r = 0.95; r = 0.91 and r = 0.97 for iced v RT cardiac index (CI), intrathoracic blood volume index (ITBVI) and extravascular lung water index (ELWI) respectively]. The bias +/- 2 * standard deviation of difference was -0.2 +/- 0.7 L/min/m2 for CIIT v CIRT; -4,9 +/- 194 mL/m2 for ITBVIIT v ITBVIRT and -0.535 +/- 1,5 mL/kg for ELWIIT v ELWIRT. CIRT and ELWIRT were measured slightly higher compared to IT injectate (P <.05). CONCLUSIONS: CI, ITBVI, and ELWI assessed by STPD with RT injectate are well correlated with measurements by iced injectates. According to our results room temperature injectates can be used in critically ill patients for assessment of CI, ITBVI and ELWI, which is more convenient for both the patients and medical staff and is also less expensive.

Bilateral lung transplantation with intra- and postoperatively prolonged ECMO support in patients with pulmonary hypertension.

OBJECTIVE: Lung transplantation for pulmonary hypertension (PH) is usually performed on cardiopulmonary bypass, with the disadvantage of full systemic anticoagulation, uncontrolled allograft reperfusion and aggressive ventilation. These factors can be avoided with intra- and postoperatively prolonged extracorporeal membrane oxygenator (ECMO) support. PATIENTS AND METHODS: Between February 1999 and March 2001, 17 consecutive patients with PH (systolic pulmonary artery pressure >70 mmHg) of different etiologies underwent bilateral lung transplantation (BLTX). There were 11 females and six males in the age range from 7 to 50 years (mean age, 28.4+/-12.9 years). Six patients were preoperatively hospitalized, four in the intensive care unit (ICU), one was on ECMO for 3 weeks pretransplantation, and one was resuscitated and bridged with ECMO for 1 week until transplantation. Femoral venoarterial ECMO support with heparin-coated circuits was set up after induction of anesthesia and discontinued at the end of surgery (n=3) or extended for 12 h median into the postoperative period (n=14). Postoperative ventilation pressure was kept below 25 mmHg. Allograft function at 2 h after discontinuation of ECMO, outcome and adverse events were monitored in all patients. Mean follow up time was 18+/-11.4 months. RESULTS: The perioperative mortality was 5.9% (n=1). Arterial oxygen pressure measured 2 h after weaning from ECMO, and under standard mechanical ventilation with a peak pressure of 25 mmHg and inspired oxygen fraction of 0.4, was 157+/-28 mmHg. The mean pulmonary artery pressures were reduced to 29+/-3,4 from 66+/-15 mmHg before transplantation. Postoperative complications included rethoracotomy due to bleeding (n=4) and temporary left ventricular failure (n=4). Median ICU stay was 12 days. Incidence of rejection within the first 100 days was 0.4 per patient. CONCLUSION: BLTX with intraoperative and postoperatively prolonged ECMO support provides excellent initial organ function due to optimal controlled reperfusion and non-aggressive ventilation. This results in improved outcome even in advanced forms of PH.

Liver support in fulminant liver failure after hemorrhagic shock.

Acute liver failure (ALF) is a rare clinical syndrome associated with a mortality of up to 80% and its management remains an interdisciplinary challenge. Despite recent improvements in intensive care management, the mortality of patients with ALF remains high and is related to complications such as cerebral edema, sepsis and multiple organ failure. Emergency orthotopic liver transplantation (OLT) is currently the only effective treatment for those patients who are unlikely to recover spontaneously. Nevertheless, OLT is not always possible because of the shortage of the organs and/or complications related to ALF. Newly introduced liver-assist devices can temporarily support the patient's liver until native liver recovers or can serve as a bridging device until a liver graft is available. The support devices use both cell-based and non-cell-based techniques. One of the latest non-cell-based extracorporeal hepatic support devices, the molecular adsorbent recycling system (MARS), is based on the concept of albumin dialysis. MARS utilises selective hemodiafiltration with countercurrent albumin dialysis aiming to selectively remove both water-soluble and albumin-bound toxins of the low and middle molecular-weight range. We report on a young patient who presented with clinical symptoms of ischemic hepatitis and multi-organ failure (APACHE II score 38-->predicted postoperative mortality 87%) due to prolonged hemorrhagic shock. OLT was contraindicated because of history of pancreas cancer with metastases. It was necessary to use aggressive conservative therapy and an extracorporeal liver-assist device until liver regeneration began and hemodynamic conditions were stable. The patient underwent five treatments with MARS. During the treatment, there were improvements of hemodynamics, respiratory function, acid-base disturbances and laboratory parameters. The plasma disappearance rate of indocyanine green, a parameter of dynamic liver function, improved during MARS treatment. Although repeated neurological examination predicted diffuse brain damage (brain oedema, decreased cerebral blood flow), the patient recovered without any neurological deficits. The patient survived and was discharged from the hospital in good condition. In this case MARS treatment was successful in supporting the patient through the most critical period of ALF.

Septic shock secondary to ß-hemolytic streptococcus-induced necrotizing fasciitis treated with a novel cytokine adsorption therapy.

INTRODUCTION: Numerous animal studies and preliminary data from a clinical trial in septic patients demonstrated that a decrease in blood cytokine levels using an extracorporeal cytokine filter (CytoSorb) can effectively attenuate the inflammatory response during sepsis and possibly improve outcomes. METHODS: A 60-year-old female was admitted to hospital due to a forearm fracture. After surgical wound care by osteosynthesis the patient developed surgical wound infection which progressed to necrotizing fasciitis. All diagnostic criteria for SIRS were evident with additional proven infection from ß-hemolytic streptococcus. On admission to the ICU, the patient presented a full picture of multiple organ dysfunction syndrome due to septic shock including kidney failure, lung failure as well as thrombocytopenia, metabolic acidosis, and arterial hypotension. RESULTS: After one day on mechanical ventilation and an IL-6 level of 70,000 pg/ml the patient was treated with CytoSorb therapy over a period of four days, resulting in a significant reduction of IL-6 to 66 pg/ml and an overall improvement of the patient's condition. Despite the necessity of enucleation, the patient was successfully stabilized until control of the surgical infectious source was achieved. Importantly, treatment was safe and well-tolerated, without any adverse events. CONCLUSIONS: This is the first report of the clinical application of CytoSorb hemoadsorption in combination with a CRRT in a patient with septic shock. CytoSorb as described was able to significantly reduce IL-6 plasma levels and decrease vasopressor need while no adverse and device-related events occurred. CytoSorb seems to be an interesting and safe extracorporeal therapy to stabilize and bridge septic patients to surgery or recovery.

Transesophageal echocardiography during orthotopic liver transplantation in patients with esophagoastric varices.

BACKGROUND: Hemodynamic monitoring using transesophageal echocardiography (TEE) in patients with signs of portal hypertension undergoing orthotopic liver transplantation (OLT) carries potential risk of esophageal and gastric variceal hemorrhage. The aim of our retrospective analysis was to evaluate the safety of intraoperative TEE monitoring during OLT in patients with esophagogastric varices. METHODS: A retrospective analysis of 396 liver transplant recipients was performed at the Medical University of Vienna monitored by TEE during OLT between 2003 and 2010. RESULTS: Varices were documented by esophagogastroduodenoscopy in 287 (72.5%) of 396 analyzed patients: 130 (32.8%) varices grade I (<5 mm under insufflation) and 157 (39.6%) varices grade II (>5 mm under insufflation). Red spot signs were identified in 40 patients (10.1%). Most varices (82.2%) were documented in the esophagus, 4.2% in the stomach, and 13.6% in both (esophagus and stomach). Only one major bleeding occurred, and it was only in a case of one patient with an esophageal varix, which was treated with a balloon tamponade during OLT. Although patients with varices demonstrated a significantly longer prothrombin time and lower platelet count, there was no significant difference in the requirement for blood products among patients with and without varices. CONCLUSIONS: TEE is a relatively safe method for monitoring cardiac performance with a low incidence of major hemorrhagic complications in patients with documented esophagogastric varices undergoing OLT.

HSP27 and HSP70 serum and urine levels in patients suffering from chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a condition associated with inflammation and high levels of uremic toxins and reactive oxygen species. As a counterregulation to systemic stress heat shock proteins (HSP) are increased expressed to minimize cell death and preserve cell integrity by inhibiting apoptotic pathways. The aim of this study was to determine HSP27 and HSP70 concentrations in sera and urine of patients suffering from CKD. METHODS: Concentrations of HSP27 and HSP70 in urine and serum were determined in 119 patients with CKD stages 1 to 5 and 23 healthy volunteers by using ELISA technique. RESULTS: HSP27 serum levels were significantly elevated in patients suffering from CKD stages 3 to 5 as well as fractional HSP27 excretion in stages 2-5 versus healthy controls. Absolute HSP70 urinary values were significantly elevated in stages 4 and 5 and fractional HSP70 excretion was increased in stage 5 compared to controls. Moreover, ROC curve analysis showed the potential of urine and especially serum HSP levels to identify various stages of CKD. CONCLUSION: We provide evidence for elevated HSP27 concentrations in serum and urine and increased HSP70 excretion levels in patients suffering from CKD. Moreover, our results show that HSP levels might offer potential to examine the stages of CKD as well as the disease course which could further promote individually adjusted treatment planning.

A surge of flu-associated adult respiratory distress syndrome in an Austrian tertiary care hospital during the 2009/2010 Influenza A H1N1v pandemic.

We report on 17 patients with influenza A H1N1v-associated Adult Respiratory Distress Syndrome who were admitted to the intensive care unit (ICU) between June 11th 2009 and August 10th 2010 (f/m: 8/9; age: median 39 (IQR 29-54) years; SAPS II: 35 (29-48)). Body mass index was 26 (24-35), 24% were overweight and 29% obese. The Charlson Comorbidity Index was 1 (0-2) and all but one patient had comorbid conditions. The median time between onset of the first symptom and admission to the ICU was 5 days (range 0-14). None of the patients had received vaccination against H1N1v. Nine patients received oseltamivir, only two of them within 48 hours of symptom onset. All patients developed severe ARDS (PaO(2)/FiO(2)-Ratio 60 (55-92); lung injury score 3.8 (3.3-4.0)), were mechanically ventilated and on vasopressor support. Fourteen patients received corticosteroids, 7 patients underwent hemofiltration, and 10 patients needed extracorporeal membrane-oxygenation (ECMO; 8 patients veno-venous, 2 patients veno-arterial), three patients Interventional Lung Assist (ILA) and two patients pump driven extracorporeal low-flow CO(2)-elimination (ECCO(2)-R). Seven of 17 patients (41%) died in the ICU (4 patients due to bleeding, 3 patients due to multi-organ failure), while all other patients survived the hospital (59%). ECMO mortality was 50%. The median ICU length-of-stay was 26 (19-44) vs. 21 (17-25) days (survivors vs. nonsurvivors), days on the ventilator were 18 (14-35) vs. 20 (17-24), and ECMO duration was 10 (8-25) vs. 13 (11-16) days, respectively (all p = n.s.). Compared to a control group of 241 adult intensive care unit patients without H1N1v, length of stay in the ICU, rate of mechanical ventilation, days on the ventilator, and TISS 28 scores were significantly higher in patients with H1N1v. The ICU survival tended to be higher in control patients (79 vs. 59%; p = 0.06). Patients with H1N1v admitted to either of our ICUs were young, overproportionally obese and almost all with existing comorbidities. All patients developed severe ARDS, which could only be treated with extracorporeal gas exchange in an unexpectedly high proportion. Patients with H1N1v had more complicated courses compared to control patients.

Increased total cytokeratin-18 serum and urine levels in chronic kidney disease.

BACKGROUND: Increased cell death in chronic kidney disease (CKD) by either necrosis or apoptosis has been confirmed by a variety of studies. Possible sources are an inadequate persistent inflammation and ischemia as a consequence of CKD or caused by the underlying renal disease. Detection of total or caspase cleaved cytokeratin 18 (CK-18) is a novel and elegant method to determine necrosis or apoptosis of epithelial cells in the patients' sera and urine. METHODS: 120 patients with CKD stages 1 to 5 were included in the study. Twenty healthy volunteers served as controls. Total and caspase cleaved CK-18 urine and serum concentrations were determined by ELISA. RESULTS: The concentration of serum total CK-18 was significantly higher in CKD stages 3-5 as compared to the healthy controls. Urinary total CK-18 excretion was increased in patients with CKD 5 compared to controls. A significant correlation between urine total CK18 and urine protein and albumin levels was found. Moreover, ROC curve analysis showed the potential of serum and especially urine total CK-18 levels to predict various CKD stages. CONCLUSIONS: We provide evidence for increased total CK-18 serum and urine levels in CKD patients, possibly indicating that epithelial cell necrosis is prevalent in CKD.

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.

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.

Caspase-cleaved cytokeratin 18 and 20 S proteasome in liver degeneration.

Apoptosis of epithelial hepatocytes plays a pivotal role in acute as well as in chronic liver diseases. The cleavage of cytokeratin-18 (CK-18) by caspases is an early event in the apoptotic process. We therefore sought to investigate serum levels of CK-18 and 20S proteasome in patients with liver cirrhosis, primary graft dysfunction (PDF), and acute liver failure (ALF), and in healthy volunteers. Enzyme-linked immunosorbent assay (ELISA) was utilized to measure the concentration of M30, a fragment of CK-18 cleaved at Asp396 (M30 neoantigen), and the concentration of 20S proteasome. Serum levels of the CK-18 neoepitope M30 were significantly increased in ALF, primary graft dysfunction, and liver cirrhosis vs. healthy controls (1,993.6+/-124.7 U/L, 2,238.1+/-235.9 U/L, and 673.6+/-86.5 U/L vs. 66.8+/-29.1 U/L, respectively, P<0.001). Similar results were detected with the evaluation of 20S proteasome (124,014.5+/-13,235.6 ng/mL, 76,993.2+/-15,720.1 ng/mL, and 2,395.9+/-1,098.2 ng/mL vs. 1,074.5+/-259.4 ng/mL, respectively; P<0.001). Detection of CK-18 neoepitope M30 and 20S proteasome may represent a novel marker of tracing apoptotic epithelium, respectively mirroring degenerative liver processes in affected patient population.

Is MELD score sufficient to predict not only death on waiting list, but also post-transplant survival?

Model for end-stage liver disease (MELD) score has emerged as a useful tool in predicting mortality in patients awaiting liver transplantation. There is still, however, discussion as to whether further parameters could improve the sensitivity and specificity of the MELD score. From 1997 to 2003, 621 adult patients with end-stage liver disease were listed for orthotopic liver transplantation (OLT). Patients suffering from hepatoma were excluded from analysis (113 patients). The MELD score was investigated at the time of listing (MELD ON) and of coming off the list (MELD OFF). Patients who died while on the waiting list showed a significant increase in their MELD score during the waiting time (MELD ON: 21 +/- 7 vs. MELD OFF: 28 +/- 9) as well as a significantly higher MELD ON compared with patients who were transplanted (MELD ON: 16 +/- 5 vs. MELD OFF: 17 +/- 7) or removed from the waiting list (MELD ON: 16 +/- 6 vs. MELD OFF: 12 +/- 3). Multivariate analysis identified MELD ON, ascites and recurrent infection as independent risk factors for death on the waiting list (P < 0.01). MELD score was not identified as a predictor for the post-transplant survival rate. MELD score is a strong predictor for death on the waiting list, but refractory ascites and recurrent infection are independent risk factors, too.