Outcome of simultaneous liver-kidney transplantation in highly sensitized,crossmatch-positive patients

BACKGROUND: In simultaneous liver-kidney transplantation (SLKT), the liver has been described to protect the kidney from rejection, and acceptable results are possible despite a pretransplant positive crossmatch. At our center, 21 SLKT have been performed since 1993, 2 of them against a positive crossmatch. OBJECTIVES: In this study we retrospectively analyzed two cases of SLKT after positive pretransplant crossmatch. METHODS: Two highly sensitized women (30 and 52 years) with hepatic cirrhosis VHC on hemodialysis after a first KT failure were assessed. Pretransplant panel reactive antibodies (PRA) by complement dependent cytotoxicity NIH (CDC) were 81% and 99% respectively. Both patients received a SLKT. CM was performed at pretransplant and 24 and 48 hours posttransplant by CDC and by flow cytometry with double labeling with CD3-PE and antihuman IgG-FITC. Patients received ATG, cyclosporine, and prednisone therapy. RESULTS: CM was positive pretransplant by CDC and flow cytometry. At 48 hours, CDC became almost negative (10%-20% mortality) and flow cytometry became negative. One of the patients experienced an episode of acute rejection at 10 days posttransplant that resolved with steroid pulses. Both patients presently have working grafts 26 and 24 months posttransplant (Cr, 1.1 and 1.5 mg/dL; GOT, 34 and 14 IU/L; GTP, 29 and 12 IU/L; GGT, 9 and 66 IU/L). CONCLUSIONS: Our experience suggests that a positive crossmatch is not an absolute contraindication for SLKT. Good graft and patient survival rates are possible even among highly sensitized patients.     

Microbial aromatic acid metabolites formed in the gut account for a major fraction of the polyphenols excreted in urine of rats fed red wine polyphenols

The health effects of dietary polyphenols might be explained by both intact compounds and their metabolites formed either in the tissues or in the colon by the microflora. The quantitative importance and biological activities of the microbial metabolites have seldom been examined in vivo. We measured the microbial metabolites formed in four groups of rats (n = 8) fed for 8 d a diet supplemented with 0.12 g/100 g catechin, 0.25 or 0.50 g/100 g red wine powder containing proanthocyanidins, phenolic acids, flavanols, anthocyanins and flavonols or an unsupplemented diet. Fourteen aromatic acid metabolites were assayed in urine collected for 24 h by an HPLC-electrospray ionization (ESI)-mass spectrometry (MS)-MS method. The three main metabolites formed from the catechin diet were 3-hydroxyphenylpropionic acid, 3-hydroxybenzoic acid and 3-hydroxyhippuric acid. Their total urinary excretion accounted for 4.7 g/100 g of the catechin ingested and that of intact catechins for 45.3 g/100 g. For wine polyphenols, the same microbial metabolites as observed for the catechin diet were identified in urine along with hippuric, p-coumaric, vanillic, 4-hydroxybenzoic and 3-hydroxyphenylacetic acids. All together, these aromatic acids accounted for 9.2 g/100 g of the total wine polyphenols ingested and intact catechins for only 1.2 g/100 g. The higher excretion of aromatic acids by rats fed wine polyphenols is likely due to their poor absorption in the proximal part of the gut. Some of the microbial metabolites still bear a reducing phenolic group and should also prevent oxidative stress in inner tissues. More attention should be given in the future to these microbial metabolites and their biological properties to help explain the health effects of polyphenols that are not easily absorbed through the gut barrier.     

Effect of MG132 on proteasome activity and prooxidant/antioxidant status of rat liver subjected to ischemia/reperfusion injury.

Aim: Previous studies have shown that proteasome inhibitors exerted protective effects against ischemia/reperfusion injury (IRI) of brain, heart, kidney and intestine. The aim of the present study was to investigate: (i) whether the proteasome inhibitor MG132 protects rat liver against IRI; and (ii) whether MG132 modulates prooxidant/antioxidant status of rat liver subjected to warm IRI. Methods: The left lateral and medial lobes (approximately 70% of the total liver volume) of livers of male Wistar rats were subjected to 30-min ischemia followed by 60-min reperfusion. Lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels were measured in the plasma. Proteasome chymotryptic-like (ChT-L) activity, levels of thiobarbituric acid-reactive substances (TBARS), protein carbonyls (PC) and glutathione (GSH), as well as superoxidase dismutase (SOD), catalase (CAT), glutathionine peroxidase and glutathionine reductase activities were measured in liver fractions. Results: Thirty-min ischemia followed by 60-min reperfusion increased liver TBARS and PC, CAT and SOD activities, but decreased GSH level. Ischemia/reperfusion-induced oxidative stress was exacerbated in mitochondria, indicating that these organelles are the preferential target of IRI. Plasma LDH and AST levels were decreased by MG132 during both ischemia and reperfusion, while ALT values were decreased only after 30 min of reperfusion. MG132 did not significantly affect liver TBARS and GSH levels, but it increased PC and decreased ChT-L activity; the activities of CAT and SOD were also decreased. Conclusions: MG132 exerts a protective effect during the early phase of reperfusion and it modulates prooxidant/antioxidant status of rat liver subjected to warm IRI.     

Localization of blood proteins thrombospondin1 and ADAMTS13 to cerebral corpora amylacea

Corpora amylacea (CA) have long been described in aging brains and in patients with neurodegenerative conditions, but their origins have been debated. It has been proposed that CA represent collections of nervous system breakdown products that accumulate within astrocytic cytoplasm. In support of this, studies have shown that CA include glycosylated material, ubiquitin, and an assortment of proteins derived from neuronal cytoplasm. On the other hand, many of these proteins are not specifically localized to neurons or astrocytes; some components of CA, such as complement proteins, are most abundantly expressed outside the central nervous system. The characteristic predilection for CA to accumulate near vessels and ependyma suggests that proteins extravasated from blood or transudated from CSF may form a component of these structures. In this study, we report the immunohistochemical localization of blood and platelet proteins thrombospondin1 and ADAMTS13 in CA from aged individuals and patients with vascular dementia. Thrombospondin1 localized to neurons, but was most prominently localized to CA. An independent serum and platelet expressed protein, ADAMTS13, was found in CA in the same brain regions. In vitro analysis shows that thrombospondin1 and ADAMTS13 form complexes together in cells and in direct protein binding assays. We speculate that CA could result from a conglomeration of interacting proteins from degenerating neurons and from extravasated blood elements released after transient breakdown of the blood–brain barrier.     

Clinical predictors of early second event in patients with clinically isolated syndrome

This study aimed to determine the predictors of increased risk of a second demyelinating event within the first year of an initial demyelinating event (IDE) suggestive of early multiple sclerosis (MS). Patients with MS or clinically isolated syndrome (CIS) seen at the UCSF MS Center within one year of the IDE were studied. Univariate and multivariate Cox models were used to analyze predictors of having a second event within 1 year of the IDE. Of 330 patients with MS/CIS, 111 had a second event within 1 year. Non-white race/ethnicity (HR = 2.39, 95% CI [1.58, 3.60], p < 0.0001) and younger age (HR for each 10-year decrease in age = 1.51, 95% CI [1.28, 1.80], p < 0.0001) were strongly associated with an increased risk of having a second event within one year of onset. Having a lower number of functional systems affected by the IDE was also associated with an increased risk of early second event (HR for every one less FS involved = 1.31, 95% CI [1.06, 1.61], p = 0.011). These results were similar after adjusting for treatment of the IDE with steroids and disease-modifying therapy. Non-white race/ethnicity, younger age, and a lower number of FS affected by the IDE are associated with a substantially increased hazard ratio for a second demyelinating event within 1 year. Since early relapse is predictive of worse long-term outcome, identifying and treating such patients after the IDE may be of benefit to them.