Serum oxidized LDL is inversely associated with HDL2-cholesterol subclass in renal failure patients on hemodialysis.

BACKGROUND: Dyslipoproteinemia and oxidative modification of LDL (oxLDL) are common symptoms in patients suffering from chronic renal failure on hemodialysis (HD), and contribute to the development of oxidative stress. High-density lipoprotein cholesterol (HDL-C) protects against atherosclerosis by inhibiting the oxidation of lipoproteins and by supporting reverse cholesterol transport. This study intends to examine the association of oxLDL with HDL2 and HDL3 subclasses of HDL-C in HD patients, in order to elucidate whether oxidative stress influences HDL-C composition. METHODS: Thirty-four patients on HD and 21 age- and sex-matched controls were studied. HDL2 and HDL3-C subclasses were isolated from serum according to a single-step precipitation method following a homogenous HDL-C assay. oxLDL was measured by ELISA. RESULTS: In HD patients, oxLDL concentration was higher compared to the controls (1.40 +/- 0.47 vs. 0.21 +/- 0.05 mg/l, p = 0.017) and was significantly associated to total cholesterol (r = 0.480, p = 0.044), LDL-C (r = 0.544, p = 0.019), HDL-C (r = -0.589, p = 0.027) and C-reactive protein (r = 0.578, p = 0.024). Comparing HDL-C subclasses, only HDL2-C was negatively correlated to oxLDL levels (r = -0.565, p = 0.035). CONCLUSIONS: In HD patients, high serum levels of oxLDL are associated with low HDL2-C subclass levels. This might suggest that oxidative stress affects the HDL subclass more related to the protecting activity of HDL-C, contributing to atherosclerosis development.

Reactive oxygen metabolites: a link between oxidative stress and inflammation in patients on hemodialysis.

Oxidative stress plays a significant role in the development of inflammation in patients undergoing hemodialysis (HD). This study intends to evaluate the relationship between C-reactive protein (CRP) and the newly established marker of lipid peroxidation, d-ROMs (reactive oxygen metabolites), in comparison with different indicators of oxidative stress. Plasma total antioxidant capacity (TAC), lipid peroxidation products malonaldehyde (MDA) and 4-hydroxyalkenals, as well as d-ROMs, were determined in 24 patients before HD and in 21 normal controls (NC). It was found that HD patients had higher levels of d-ROMs than NC (p = 0.033). A highly significant positive correlation was observed between logCRP and d-ROMs concentrations (p < 0.0001, r = 0.85) in patients, but not in NC. The concentrations of TAC and MDA were not associated with CRP in HD or in NC individuals. It is concluded that d-ROMs concentration is a potent marker of oxidative injury that is strongly indicative of the inflammatory status in HD patients.

The platelet-activating factor acetylhydrolase of mouse platelets.

Platelet-activating factor (PAF) acetylhydrolases are a family of distinct enzymes with the common property of hydrolyzing and inactivating PAF. It has been shown that the structure and the biochemical behavior of these enzymes depend on their cellular origin. We studied the PAF acetylhydrolase activity in mouse platelets in order to investigate the unusual response of these platelets to PAF. We found that mouse platelets contain a PAF acetylhydrolase with an apparent Km value of 0.8 microM, suggesting a very high affinity for PAF. Contrary to other normal mammalian cells and tissues, mouse platelet PAF acetylhydrolase is almost equally distributed in the membranes and the cytosol and is characterized by an extreme sensitivity to heating. The enzyme requires the presence of dithioerythritol for maximal activity, it is affected by 5,5'-dithiobis(2-nitrobenzoic acid) and N-ethylmaleimide and it is strongly inhibited by phenylmethylsulfonylfluoride. We purified, to near homogeneity, the PAF acetylhydrolase from mouse platelet membranes and demonstrated that it is a protein relatively abundant in the membranes with an apparent molecular weight of 270 kDa. Electrophoretic analysis, under reducing conditions, revealed four bands and one duplet with molecular weights of 66, 55, 52, 49 and 62 kDa. respectively. Thus, PAF hydrolysis in mouse platelets is mediated by a PAF acetylhydrolase having biophysical and biochemical properties more intricate than those of the PAF acetylhydrolases found in other species.

GVHD-associated chronic kidney disease after allogeneic haematopoietic cell transplantation.

Chronic kidney disease (CKD) has been related to allogeneic haematopoietic cell transplantation (HCT) as a late effect caused by a variety of factors. We retrospectively evaluated the development of CKD in 230 patients, aged 34 (5-65) years, who had undergone allogeneic HCT for haematological disease, using sibling or unrelated donors and myeloablative or reduced conditioning regimens. Pre-HCT glomerular filtration rate (GFR) was within normal limits (108±28 mL/min/1.73 m(2)) in patients who did not develop CKD and 95±24 mL/min/1.73 m(2) in those with CKD postHCT, while the GFR 12 months post transplant declined to 104±26 and 69±19 mL/min/1.73 m(2), respectively. CKD incidence was 20.4%, with a median time of development of 6 (3-18) months post transplant. On multivariate analysis, risk factors for CKD were the presence of chronic GVHD (cGVHD; P=0.001), unrelated donor transplantation (P=0.008), post-transplant event of acute kidney injury (AKI) (P=0.002) and older age (P=0.002). In long-term survivors stable significant predictors for CKD were older age at transplantation, cGVHD and AKI. CKD did not influence non-relapse mortality. In our study, cGVHD emerges as an important cause of kidney injury in HCT survivors, regardless of administration of nephrotoxic agents.

Metabolism and effects on biliary lipid secretion of murocholic acid in the hamster.

The metabolism of murocholic acid (MC), a 6 beta-hydroxylated bile acid, was investigated after intravenous (i.v.), intraduodenal (i.d.) or intragastric (i.g.) administration to bile fistula hamsters. The effects on biliary cholesterol and phospholipid secretion were measured during intravenous infusions of increasing doses of [3H]MC. At an infusion rate of 0.1 or 1 mumol.min-1.kg-1, the hepatic uptake was effective. More than 90% of the dose was recovered in bile within 4 h. A bolus injection of 500 micrograms of [3H]MC in the duodenum led to a rapid and efficient biliary secretion of radioactivity. Increasing i.v. infused doses of MC had no effect on bile flow or biliary cholesterol output compared to the controls. Phospholipid secretion was significantly reduced (0.113 mumol.min-1.kg-1 versus 0.238 mumol.min-1.kg-1 in in controls per mumol.min-1.kg-1 of excreted bile acids) as MC progressively replaced the endogenous bile acid pool in bile. After i.v. and i.d. administration, MC was secreted in bile as glyco and tauro conjugates without additional hepatic hydroxylation, sulfation or glucuronidation. The i.g. ingestion of MC followed by the faecal analysis of metabolites showed the formation of hyodeoxycholic acid and 3 alpha-OH-6-oxo-5 beta-cholan-24-oic acid. An equivalent experiment with hyodeoxycholic acid gave MC and the same oxo bile acid. We concluded that MC is metabolized by the hamster liver as an endogenous bile acid, which undergoes intestinal bacterial transformation into a 6-oxo derivative and is then reduced into hyodeoxycholic acid. This process is completely reversible.(ABSTRACT TRUNCATED AT 250 WORDS)