Sebastian Klammt

Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute‐on‐chronic liver failure: The RELIEF trial

Acute‐on‐chronic liver failure (ACLF) is a frequent cause of death in cirrhosis. Albumin dialysis with the molecular adsorbent recirculating system (MARS) decreases retained substances and improves hemodynamics and hepatic encephalopathy (HE). However, its survival impact is unknown. In all, 189 patients with ACLF were randomized either to MARS (n = 95) or to standard therapy (SMT) (n = 94). Ten patients (five per group) were excluded due to protocol violations. In addition, 23 patients (MARS: 19; SMT: 4) were excluded from per‐protocol (PP) analysis (PP population n = 156). Up to 10 6‐8‐hour MARS sessions were scheduled. The main endpoint was 28‐day ITT and PP survival. There were no significant differences at inclusion, although the proportion of patients with Model for Endstage Liver Disease (MELD) score over 20 points and with spontaneous bacterial peritonitis (SBP) as a precipitating event was almost significantly greater in the MARS group. The 28‐day survival was similar in the two groups in the ITT and PP populations (60.7% versus 58.9%; 60% versus 59.2% respectively). After adjusting for confounders, a significant beneficial effect of MARS on survival was not observed (odds ratio [OR]: 0.87, 95% confidence interval [CI] 0.44‐1.72). MELD score and HE at admission and the increase in serum bilirubin at day 4 were independent predictors of death. At day 4, a greater decrease in serum creatinine (P = 0.02) and bilirubin (P = 0.001) and a more frequent improvement in HE (from grade II‐IV to grade 0‐I; 62.5% versus 38.2%; P = 0.07) was observed in the MARS group. Severe adverse events were similar. Conclusion: At scheduled doses, a beneficial effect on survival of MARS therapy in patients with ACLF could not be demonstrated. However, MARS has an acceptable safety profile, has significant dialysis effect, and nonsignificantly improves severe HE. (HEPATOLOGY 2013)

Albumin Regeneration in Liver Support—Comparison of Different Methods

Abstract:  Albumin is the most abundant human plasma protein. Among many other functions it is an important transporter of hydrophobic internal and external substances such as intermediate and end products of metabolism and drugs. In liver failure the albumin binding capacity is decreased because of a disproportion between available albumin molecules caused by decreased hepatic synthesis and hydrophobic toxins because of decreased hepatic clearance. The resulting increase in plasma and tissue concentrations of these substances is associated with multiple organ dysfunctions frequently seen in severe liver failure. The scope of the present article is to compare different liver support strategies with regard to their ability to regenerate the patients albumin pool by removing albumin‐bound toxins. Most prominent technique in this group is the molecular adsorbent recirculating system (MARS). It will be compared with single pass albumin dialysis (SPAD), fractionated plasma separation and adsorption system (FPSA, Prometheus), and plasma perfusion/bilirubin adsorption with special regard to efficacy and selectivity.

Albumin dialysis MARS: knowledge from 10 years of clinical investigation.

A decade ago, albumin dialysis was introduced as a new extracorporeal detoxification method for patients with liver failure. Today, the molecular adsorbent recirculating system is the most frequently used type of albumin dialysis and most studied liver-support technique. Numerous preclinical and clinical studies demonstrated the importance of albumin as a scavenger for molecules with pathophysiological relevance in liver failure. Albumin dialysis enables the selective regeneration of albumin. The resulting increase of albumin binding capacity is paralleled by improvement of central and local hemodynamics and liver, brain, and kidney functions. The treatment can contribute to liver regeneration and prolongation of patient survival in the context of acute liver failure, decompensated chronic liver disease, and bridging of patients to liver transplantation. Proper patient selection is critical for clinical success. Aggressive treatment of infections and sepsis seems to be a decisive prerequisite for its safe and efficient use. Cautious anticoagulation with heparin is the common standard. Citrate use is recommended for patients prone to bleeding. Taken together, albumin dialysis represents a valuable therapeutic tool for the treatment of various types of liver failure. Ongoing and future studies will help define the optimal patient selection and technical process parameters such as session length and frequency of treatment.

Improvement of impaired albumin binding capacity in acute‐on‐chronic liver failure by albumin dialysis

Extracorporeal albumin dialysis (ECAD) enables the elimination of albumin bound substances and is used as artificial liver support system. Albumin binding function for the benzodiazepine binding site specific marker Dansylsarcosine was estimated in plasma samples of 22 patients with cirrhosis and hyperbilirubinaemia (ECAD: n = 12; control: n = 10) during a period of 30 days in a randomized controlled clinical ECAD trial. Albumin Binding Capacity (ABiC) at baseline was reduced to 31.8% (median; range 24%‐74%) and correlated to the severity of liver disease. Within two weeks a significant improvement of ABiC and a reduction of the albumin bound markers bilirubin and bile acids were observed in the ECAD group. During single treatments a significant decrease of albumin bound substances (bilirubin and bile acids) as well as an increase in ABiC was observed. In the control group, baseline ABiC was significantly lower in patients who died during study period (34.2% vs. 41.7%; P < 0.028), whereas no significant differences were observed for CHILD, coagulation factors, albumin, bile acids nor bilirubin. At baseline 13 patients had a severely impaired ABiC (<40%), improvement of ABiC was more frequent in the ECAD group (5/6) than in the SMT group (2/7). Reduced albumin binding function is present in decompensated liver failure and is related to severity and 30 day survival. ABiC can be improved by ECAD. The beneficial effect of this treatment may be related to the improvement of albumin binding function more than to the elimination of specific substances. Characterization of albumin function by the ABiC test may help to evaluate different liver support systems and other therapeutic measures. Liver Transpl 14:1333–1339,2008.

Albumin-binding capacity (ABiC) is reduced in patients with chronic kidney disease along with an accumulation of protein-bound uraemic toxins

BACKGROUND Albumin is an important transport protein for non-water-soluble protein-bound drugs and uraemic toxins. Its transport capacity is reduced in patients with advanced chronic kidney disease (CKD) and unbound fractions of uraemic toxins are related to complications of CKD. We investigated whether this reduction could be quantified and how it correlated with the stages of CKD. Albumin-binding capacity (ABiC) is a dye-based method that quantifies the remaining binding capacity of one major binding site (site II) of the albumin molecule. METHODS Blood samples from 104 CKD patients were incubated with a binding site-specific fluorescent marker and the amount of unbound marker was determined by means of fluorescence detection after filtration. Measurements in a pooled human plasma were used for reference. Glomerular filtration rate and serum indoxyl sulphate (IS) levels were also determined. RESULTS Impairment of renal function was associated with a reduction in ABiC (mean ± SD: 118 ± 12; 111 ± 11; 99 ± 8 and 79 ± 9% for Stages 1/2, 3, 4 and 5, respectively; P < 0.001) and an increase in IS (3.9 ± 1.1; 6.2 ± 3.2; 16.3 ± 14.9 and 56.1 ± 28.6 μmol/L for Stages 1/2, 3, 4 and 5, respectively; P < 0.001). In dialysis patients, ABiC was lower in those with urine outputs <500 mL/day than in those with preserved urine output (73.7 ± 6.0 versus 83.8 ± 8.5%; P < 0.001). CONCLUSION Impaired albumin function in CKD patients can be quantified, is related to severity of kidney disease and is associated with an accumulation of uraemic albumin-bound retention solutes.

Schistosoma mansoni: Schistosomicidal effect of mefloquine and primaquine in vitro

We investigated the effects of the anti-malarials mefloquine and primaquine against the juvenile and adult life stages of Schistosoma mansoniin vitro. Cercariae were incubated with 0.5 μg/ml, 1 μg/ml and 2 μg/ml mefloquine or primaquine and with 1 μg/ml praziquantel for 12h. Schistosomula, pre-adults and adults were incubated with 0.5 μg/ml, 1 μg/ml and 2 μg/ml mefloquine or primaquine and with 1 μg/ml praziquantel for 7 days. The viability status was classified as viable, damaged or dead and was checked every 3h for cercariae and every 12h for schistosomula, pre-adults and adults. Both, mefloquine and primaquine show time and dose-dependent schistosomicidal effects on the four life stages of S. mansoni. The promising in vitro effects on all stages of the blood fluke S. mansoni warrants further evaluation of both anti-malarials and their derivatives for their prophylactic and therapeutic values in early and late schistosomiasis in field trials.

High prevalence of Pneumocystis jirovecii colonization among patients with autoimmune inflammatory diseases and corticosteroid therapy

Background: Patients with autoimmune inflammatory diseases (AID) account for 13–36% of Pneumocystis pneumonia (PCP) cases in human immunodeficiency virus (HIV)-negative patients. Up to 88% of PCP cases in HIV-negative patients are associated with prior steroid treatment. Pulmonary colonization with Pneumocystis in HIV-negative patients is associated with corticosteroid therapy in up to 75% of cases. The aim of this study was to detect the prevalence and risk factors of pulmonary colonization with Pneumocystis jirovecii in patients with AID receiving corticosteroid therapy in comparison with healthy control persons. Methods: We investigated induced sputa of 102 patients with AID on current corticosteroid treatment and of 117 healthy controls for the presence of P. jirovecii using polymerase chain reaction (PCR). Results: Twenty-nine patients (28.5%) with AID were colonized with P. jirovecii compared to three healthy controls (2.6%) [p < 0.001, odds ratio (OR) 15.10, 95% confidence interval (CI) 4.43–51.38]. In patients with AID, age over 60 years was significantly associated with colonization (p = 0.015, OR 3.19, 95% CI 1.27–7.94). Multivariate analysis showed age to be independently associated with the colonization of P. jirovecii (95% CI 1.002–1.092). Neither duration nor dose of corticosteroid therapy nor immunosuppressive co-medication had a significant influence on P. jirovecii colonization. Conclusion: Patients with AID, especially those over 60 years of age, display a high prevalence of colonization with P. jirovecii. Clinicians should be aware of this and ensure that they consider the possibility of PCP when pulmonary symptoms arise in these patients.

Safety and immunogenicity of a trivalent single dose seasonal influenza vaccine containing pandemic A(H1N1) antigen in younger and elderly subjects: a phase III open-label single-arm study.

BACKGROUND During the pandemic of the 2009 A(H1N1) influenza virus strain, 20-40% of the population in some areas were infected. Infection with A(H1N1) may be mild, with an average case fatality rate below 0.25%, but severe disease is not limited to patients with underlying medical conditions. Since A(H1N1) is expected to continue to circulate it is included in the seasonal influenza vaccines for the 2010-2011 winter season. We investigated the immunogenicity and safety of a preservative-free non-adjuvanted seasonal trivalent influenza vaccine. METHODS We conducted a single center single-arm study involving 142 subjects (77 adults of 18-60 years and 65 subjects 61 years and above) to test the immunogenicity, safety, and tolerability of a trivalent split influenza vaccine. The vaccine contained 15μg of hemagglutinin of each of the virus strains recommended for the 2010-2011 northern hemisphere winter season (A/California/7/2009 (H1N1)-like strain; A/Perth/16/2009 (H3N2)-like strain; B/Brisbane/60/2008-like strain) in a non-adjuvanted preservative-free formulation. Antibody response to each antigen was measured by hemagglutination inhibition (HI) 21 days after immunization. Subject diary cards and additional telephone interviews were used to assess the safety profile. RESULTS By day 21 after the vaccination, seroconversion, or a 4-fold antibody increase in HI antibody titers, was detectable against A(H1N1) in 84% and 75% of younger and older adults, against A(H3N2) in 80% and 57%, and against the B influenza strain in 61% and 33%. HI antibody titers of 40 or more were observed against A(H1N1) in 99% and 90% of younger and older adults, against A(H3N2) in 100% and 90%, and against the B influenza strain in 91% and 78%. Pre-vaccination antibody titers were protective against A(H1N1), A(H3N2), and B in 26%, 44% and 33%, respectively of the adults below 61 years and in 27%, 54% and 44% of the subjects of 61 years and above. Local and systemic reactions were more common in younger than in older subjects and the most frequently reported reactions were pain at the injection site (36%), myalgia (24%), and fatigue (15%). Five percent elderly subjects and 1% of younger subjects had mild or moderate unsolicited adverse events such as prolonged ecchymosis or night sweats that resolved within 7 days after vaccination. CONCLUSIONS This single dose trivalent seasonal influenza vaccine generated protective antibodies to all three viral strains and had an acceptable safety profile in both younger and older adults (ClinicalTrials.gov identifier: NCT01147081).

Pneumocystis jirovecii colonization among renal transplant recipients

Renal transplant recipients are at risk of developing Pneumocystis pneumonia (PcP), especially in the first 2 years after transplantation, with a mortality rate of up to 50%. No data are available on pulmonary colonization with Pneumocystis jirovecii in renal transplant recipients. The aim of this study was to determine the prevalence of pulmonary colonization with Pneumocystis jirovecii in renal transplant recipients and to find related risk factors.

Clinical Trial to Evaluate the Safety and Immunogenicity of a Trivalent Surface Antigen Seasonal Influenza Vaccine Produced in Mammalian Cell Culture and Administered to Young and Elderly Adults with and without A(H1N1) Pre-Vaccination

Vaccination against influenza is an important means of reducing morbidity and mortality in subjects at risk. The prevalent viral strains responsible for seasonal epidemics usually change annually, but the WHO recommendations for the 2011/2012-season in the Northern hemisphere included the same antigens as for the previous season. We conducted a single-center, single-arm study involving 62 younger (18–60 years) and 64 older (>60 years) adults to test the immunogenicity, safety and tolerability of a trivalent surface antigen, inactivated influenza vaccine produced in mammalian cell-culture. The vaccine contained 15 µg hemagglutinin of each of the virus strains recommended for the 2011–2012 Northern hemisphere winter season (A/California/7/09 (H1N1)-; A/Perth/16/09 (H3N2)-; B/Brisbane/60/08-like strain) in a non-adjuvanted preservative-free formulation. Antibody response was measured by hemagglutination inhibition 21 days after immunization. Adverse events and safety were assessed using subject diary cards and telephone interviews. Seroconversion or a 4-fold antibody increase in antibody titers was detectable against A(H1N1) in 68% of both younger and older adults, against A(H3N2) in 53% and 27%, and against the B influenza strain in 35% and 17%. Antibody titers of 40 or more were observed against A(H1N1) in 87% and 90% of younger and older adults, against A(H3N2) in 98% and 98%, and against the B influenza strain in 93% and 90%. Pre-vaccination antibody titers were protective against A(H1N1), A(H3N2) and B in 38%, 58% and 58%, respectively, of younger and in 43%, 88% and 70% of older adults. Among subjects with previous A(H1N1) vaccination only 48% of younger and 47% of older adults had protective A(H1N1) antibodies at inclusion. Adverse reactions were generally mild. The most frequently reported reactions were pain at the injection site, myalgia and fatigue. The vaccine generated protective antibodies against all three viral strains and had an acceptable safety profile in both younger and older adults. Trial Registration ClinicalTrials.gov NCT01422512