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2. LPS-induced downregulation of MRP2 and BSEP in human liver is due to a posttranscriptional process

Author

Elferink, Marieke G.L., Olinga, Peter, Draaisma, Annelies L., Merema, Marjolijn T., Faber, Klaas Nico, Slooff, Maarten J.H., Meijer, Dirk K.F., and Groothuis, Geny M.M.

Subjects
Cytokines -- Research, Liver -- Research, Biological sciences
Abstract

LPS-induced downregulation of MRP2 and BSEP in human liver is due to a posttranscriptional process. Am J Physiol Gastrointest Liver Physiol 287: G1008-G1016, 2004. First published June 17, 2004; doi: 10.1152/ajpgi.00071.2004.--Endotoxin-induced cholestasis in rodents is caused by hepatic downregulation of transporters, including the basolateral [Na.sup.+]-dependent taurocholate transporter (ntcp) and the canalicular bile salt export pump (bsep) and multidrug resistance-associated protein 2 (mrp2). Details about the regulation of the human transporter proteins during this process are lacking. We used precision-cut human and rat liver slices to study the regulation of transporter expression during LPS-induced cholestasis. We investigated the effect of LPS on nitrate/nitrite and cytokine production in relation to the expression of inducible nitric oxide synthase, NTCP, BSEP, and MRP2 both at the level of mRNA with RT-PCR and protein using immunofluorescence microscopy. In liver slices from both species, LPS-induced expression of inducible nitric oxide synthase was detected within 1-3 h and remained increased over 24 h. In rat liver slices, this was accompanied by a significant decrease of rat ntcp and mrp2 mRNA levels, whereas bsep levels were not affected. These results are in line with previous in vivo studies and validate our liver slice technique. In LPS-treated human liver slices, NTCP mRNA was downregulated and showed an inverse correlation with the amounts of TNF-[alpha] and Il-1[beta] produced. In contrast, MRP2 and BSEP mRNA levels were not affected under these conditions. However, after 24-h LPS challenge, both proteins were virtually absent in human liver slices, whereas marker proteins remained detectable. In conclusion, we show that posttranscriptional mechanisms play a more prominent role in LPS-induced regulation of human MRP2 and BSEP compared with the rat transporter proteins. human liver slices; endotoxin-induced cholestasis, transporter expression; cytokines; immunofluorescence microscopy

Published
2004

29. Does the meld system provide equal access to liver transplantation for patients with different ABO blood groups?

Author

IJtsma, Alexander J.C., Hilst, Christian S., Nijkamp, Danielle M., Bottema, Jan T., Fidler, Vaclav, Porte, Robert J., and Slooff, Maarten J.H.

Subjects
LIVER transplantation, ALLOCATION of organs, tissues, etc., BLOOD grouping & crossmatching, ORGAN donors, TRANSPLANTATION of organs, tissues, etc., PATIENTS
Abstract

This study investigates the relationship between blood group and waiting time until transplantation or death on the waiting list. All patients listed for liver transplantation in the Netherlands between 15 December 2006 and 31 December 2012, were included. Study variables were gender, age, year of listing, diagnosis, previous transplantations, blood group, urgency, and MELD score. Using a competing risks analysis, separate cumulative incidence curves were constructed for death on the waiting list and transplantation and used to evaluate outcomes.In 517 listings, the mean death rate per 100 patient-years was 10.4. A total of 375 (72.5% of all listings) were transplanted. Of all transplantations, 352 (93.9%) were ABO-identical and 23 (6.1%) ABO-compatible. The 5-year cumulative incidence of death was 11.2% ( SE 1.4%), and of transplantation 72.5% ( SE 2.0%). Patient blood group had no multivariate significant impact on the hazard of dying on the waiting list nor on transplantation. Age, MELD score, and urgency status were significantly related to the death on the waiting list and transplantation. More recent listing had higher probability of being transplanted. In the MELD era, patient blood group status does not have a significant impact on liver transplant waiting list mortality nor on waiting time for transplantation. [ABSTRACT FROM AUTHOR]

Published
2016
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30. The price of donation after cardiac death in liver transplantation: a prospective cost-effectiveness study.

Author

Hilst, Christian S., IJtsma, Alexander J.C., Bottema, Jan T., Hoek, Bart, Dubbeld, Jeroen, Metselaar, Herold J., Kazemier, Geert, den Berg, Aad P., Porte, Robert J., and Slooff, Maarten J.H.

Subjects
LIVER transplantation, ORGAN donors, BRAIN death, COST effectiveness, SURGICAL complications, ORGAN donation
Abstract

This study aims to perform a detailed prospective observational multicenter cost-effectiveness study by comparing liver transplantations with Donation after Brain Death ( DBD) and Donation after Cardiac Death ( DCD) grafts. All liver transplantations in the three Dutch liver transplant centers between 2004 and 2009 were included with 1-year follow-up. Primary outcome parameter was cost per life year after transplantation. Secondary outcome parameters were 1-year patient and graft survival, complications, and patient-level costs. From 382 recipients that underwent 423 liver transplantations, 293 were primarily transplanted with DBD and 89 with DCD organs. Baseline characteristics were not different between both groups. The Donor Risk Index was significantly different as were cold and warm ischemic time. Ward stay was significantly longer in DCD transplantations. Patient and graft survival were not significantly different. Patients receiving DCD organs had more and more severe complications. The cost per life year for DBD was € 88 913 compared to € 112 376 for DCD. This difference was statistically significant. DCD livers have more and more severe complications, more reinterventions and consequently higher costs than DBD livers. However, patient and graft survival was not different in this study. Reimbursement should be differentiated to better accommodate DCD transplantations. [ABSTRACT FROM AUTHOR]

Published
2013
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36. Genogrouping and Incidence of Virulence Factors of Enterococcus faecalis in Liver Transplant Patients Differ from Blood Culture and Fecal Isolates.

Author

Waar, Karola, Muscholl-Silberhorn, Albrecht B., Willems, Rob J.L., Slooff, Maarten J.H., Harmsen, Hermie J.M., and Degener, John E.

Subjects
ENTEROCOCCUS faecalis, LIVER transplantation, PATIENTS
Abstract

Enterococcus faecalis is a leading cause of infections in liver transplant patients. This study reviewed the incidence of virulence factors such as hemolysin, gelatinase, aggregation substances (asa1 and asa373), or the enterococcal surface protein (Esp) in isolates from liver transplant patients. In total, 133 isolates from liver transplant patients were compared with 47 isolates from feces of healthy volunteers and 66 isolates from blood cultures. Amplified fragment length polymorphism (AFLP) analysis indicates that the isolates from different clinical subgroups can be divided into genogroups with an AFLP similarity of >80% and different virulence factors. Hemolysin and asa1 might be associated with infection, as they are more frequent in isolates from blood cultures and transplant patients. Esp might be associated with colonization and spread, because it is more frequent in isolates from feces of healthy volunteers and transplant patients. An epidemic esp gene--positive strain among liver transplant patients supports this hypothesis. [ABSTRACT FROM AUTHOR]

Published
2002
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