Hemodialysis reduces inhibitory effect of plasma ultrafiltrate on LDL oxidation and subsequent endothelial reactions.

Oxidative modification of low-density lipoprotein (LDL) and its deleterious effect on endothelium is implicated in the pathogenesis of atherosclerosis. Endothelium responds to such an insult by upregulating the synthesis of heme oxygenase-1 (HO-1) and ferritin. Endothelial cell damage and dysfunction have been observed in patients with chronic kidney disease (CKD) on maintenance hemodialysis (HD). We studied the effect of low-molecular-weight components of uremic plasma on LDL oxidation and LDL-oxidation-provoked endothelial cell reactions, such as the induction of cytotoxicity and the upregulation of cell-protective HO-1 and ferritin. Plasma ultrafiltrate (molecular weight<5000 Da) from CKD patients on HD or when treated conservatively exhibited a pronounced inhibition on heme-mediated oxidative modification of LDL. Endothelial cell cytotoxicity provoked by LDL oxidation was also attenuated by plasma ultrafiltrate from CKD patients. During HD treatment, a dramatic drop occurred in the retardation of oxidative reactions, and a loss of endothelial cytoprotection exerted by plasma ultrafiltrate was noted. The upregulation of HO-1 and ferritin in response to oxidative stress of LDL was blunted by uremic plasma ultrafiltrate that was released by the end of HD. The decreased antioxidant capacity of ultrafiltrate after HD occurred as a consequence of the intradialytic removal of L-ascorbic acid, uric acid, bilirubin, 3-indoxyl sulfate, indoxyl-beta-D-glucuronide, p-cresol, and phenol. Intradialytic removal of L-ascorbic acid, uric acid, bilirubin, 3-indoxyl sulfate, indoxyl-beta-D-glucuronide, p-cresol, and phenol increases the risk of LDL oxidation and subsequent endothelial cell damage, which underlines the importance of activation of cytoprotective HO-1 and ferritin in endothelium.

Structure prerequisite for antioxidant activity of silybin in different biochemical systems in vitro.

Structural analogues (flavanone: 2-4 and flavone: 5 and 6, respectively) of silybin (1a) were synthesized and tested for inhibitory activity on O(2)(-) release and PKC translocation in PMA-stimulated neutrophils as well as xanthine oxidase activity in order to identify the molecular structures responsible for the antioxidant property of silybin. Concerning the prevention of hem-mediated oxidative modification of LDL by silybin, the hydroxyl radical scavenging activity of its structural analogues was also determined. We demonstrated that the basic skeleton of 1a (4) is responsible for its inhibitory activity on O(2)(-) release in PMA-stimulated neutrophils via inhibition of PKC translocation, since introduction of a double bound and hydroxyl groups at C-5 and C-7 position (5 and 6) did not result in further increase in inhibition of O(2)(-) release. It has been shown that the presence of the phenolic hydroxyl group at C-5 and C-7 of 1a is essential for the inhibition of xanthine oxidase activity. Moreover, introduction of a double bond into the C-ring of 2 and 3, resulting in flavone derivatives (5 and 6), markedly enhanced the antioxidant effect in all the tested systems. Finally, silybin (1a) and its flavon derivatives (5 and 6) directly scavenged hydroxyl radicals as well. On the basis of these results it might be concluded that different moiety of silybin is responsible for inhibition of overproduction of O(2)(-) in stimulated neutrophils, xanthine oxidase activity, and for prevention of hem-mediated oxidative modification of LDL.

Effect of silybin on phorbol myristate actetate-induced protein kinase C translocation, NADPH oxidase activity and apoptosis in human neutrophils.

Mechanism of the action of silybin (1) and its derivatives (2-4), possessing different lipid solubility in PMA-stimulated neutrophils was evaluated. Silybin (1) inhibited the calcium, phosphatidylserine- and diacylglycerol-dependent protein kinase C translocation and the NADPH oxidase activity in PMA-stimulated neutrophils and resulted in decreased apoptosis. Furthermore, silybin (1) inhibited xanthine oxidase activity and hem-mediated oxidative degradation of low-density lipoprotein, as well. Its derivatives (2-4), possessing different lipid-solubility, affected all the studied parameters. The lipid solubility of silybin (1) was enhanced by methylation (5'7'4''trimethylsilybin: 2), whereas a decrease in lipid-solubility by acetylation of compound 2 (5',7,'4"-trimethylsilybin-acetate: 3) or all the hydroxyl groups of silybin (peracetyl-silybin: 4) attenuated the antioxidant capacity by decreasing the inhibition in PKC translocation and NADPH oxidase activation. All the derivatives of silybin (2-4) showed no inhibition in cell free systems; e.g. did not alter the xanthine oxidase activity and the hem-mediated oxidative degradation of LDL. In conclusion, the antioxidant activity of (1) might be due to its ability to inhibit PKC translocation and NADPH oxidase activation in PMA-stimulated neutrophils. The increase of lipid solubility of silybin (1) supports its penetration through cell membrane and enhances its inhibitory effects. This structural modification of (1) might have pharmacological consequences.

Effects of intra-striatal GDNF on motor coordination and striatal electrophysiology in aged F344 rats.

The purpose of this study was to examine whether improvement in motor function could be demonstrated in old rats, and to see if GDNF affected post-synaptic DA function. Aged (20 month old) versus young rats were tested following GDNF treatment for postural control by using an inclined balance beam and a wire grip strength test. Rats were also examined electrophysiologically for spontaneous striatal cell firing rate alone and in the presence of DA receptor agonists, and histologically for the intensity of striatal TH staining, and number of DA containing nigral cells. Behavior was significantly improved in the aged animals who received central GDNF infusions, although the extent of improvement was less than what has been observed in 16-month-old rats. There was no effect of GDNF treatment in the aged animals on spontaneous firing rate in the striatum, or on the post synaptic response to locally applied D(1) and D(2) receptor family agonists. However, there was an effect of age alone on firing rate, and on the response to locally applied SKF 38393 and quinpirole. By using unbiased cell counting we observed no age-related decline in the number of TH positive cells in the substantia nigra. There was no effect of GDNF on the number of TH positive cells in the substantia nigra in either young or aged rats, although there were morphological improvements in DA neurons of the GDNF treated aged rats. These results replicate earlier studies showing an effect of age on striatal firing rate and dopamine receptor function, and suggest that the GDNF mediated improvement in behavior may be located other than post synaptically within the striatum.

The serum paraoxonase activity in patients with chronic renal failure and hyperlipidemia.

Human serum paraoxonase is physically associated with an apolipoprotein (Apo-A1) and clusterin-containing high-density lipoprotein (HDL) and prevents low-density lipoprotein from lipid peroxidation. The aim of our study was to determine whether paraoxonase activity or phenotype is altered in patients with chronic renal failure and in hyperlipidemic subjects without renal insufficiency and to compare the values with those of healthy controls. We investigated the serum paraoxonase activity and polymorphism in 119 hemodialyzed uremic patients, 107 patients with primary hyperlipoproteinemia, and in 110 healthy control subjects. The serum paraoxonase activity was significantly decreased both in hyperlipidemic (p < 0.01) and uremic patients (p < 0.001) as compared with controls. On comparison, the serum paraoxonase activity was significantly lower (p < 0.001) in uremic than in hyperlipoproteinemic patients. The HDL and Apo-A1 levels were as follows: uremic < hyperlipidemic < control. To assess whether the observed reduction in paraoxonase activity was due to HDL and Apo-A1 level decreases, we standardized the enzyme activity for HDL and Apo-A1 concentrations. We found that the standardized paraoxonase activity (paraoxonase/HDL ratio) was also lower in the uremic patients (103.3 +/- 69.5) as compared with hyperlipidemic patients (137.64 +/- 81.0) and controls (194.45 +/- 94.45). The standardized values for Apo-A1 showed a similar tendency: paraoxonase/Apo-A1 ratio in uremic patients 89.64 +/- 47.8, in hyperlipidemic patients 128.12 +/- 69.83, and in controls 161.40 +/- 47.35. The phenotypic distribution of paraoxonase (AA, AB, BB) did not change significantly in the patient groups. These results suggest that HDL concentration and phenotypic distribution of paraoxonase may not be the only determining factors, but that other as yet undetermined factors could be involved in the enzyme activity changes.

[Use of erythropoietin in pregnancy: review of the literature in connection with 2 cases]. / Erythropoietin alkalmazása terhességben: irodalmi áttekintés két eset kapcsán.

Recently a growing number of case reports has been published about successful pregnancy outcome of dialysed women on recombinant human erythropoietin therapy. During pregnancy the maternal demand for erythropoietin may undergo changes, with consideration of recombinant human erythropoietin therapy in the early stage of renal insufficiency, as is shown by our two reported cases. The use of recombinant human erythropoietin seems to be safe for the foetus: it does not cross the placental barrier, and therefore lacks any direct foetal effect. The treatment of anaemia with recombinant human erythropoietin carries benefits for both the mother and foetus. One of the most important preconditions for successful recombinant human erythropoietin therapy is adequate iron supplementation. Due to the increased risk of pregnancy induced hypertension or preeclampsia, there is a need for slow and gradual correction of anaemia, and an individually tailored target hematocrit. A close follow up of he patient by the obstetrical-nephrological team is essential, with the intensive monitoring of the fetuses. In some cases with normal renal function the stimulation of erythropoiesis with recombinant human erythropoietin may also be needed during the pregnancy.

[Interferon therapy in cryoglobulinemic membranoproliferative glomerulonephritis associated with hepatitis C virus infection]. / Interferon kezelés hepatitis-C vírusfertózéssel társult cryoglobulinaemiás membranoproliferatív glomerulonephritisben.

The authors report the case of a 38 year old man with horseshoe kidney who developed a severe nephroso-nephritis syndrome, caused by cryoglobulinemic membranoproliferative glomerulo-nephritis. A combination of steroid and cyclophosphamide treatment resulted in partial improvement, but was discontinued after 12 weeks due to adverse reactions, with a consequent early relapse. The 4 week course of cyclosporine monotherapy proved ineffective and signs of cryoglobulinemia appeared. The elevation of transaminase, manifested during the immunosuppressive therapy demonstrated the presence of underlying chronic C hepatitis. In the light of the liver biopsy result, interferon treatment was commenced at a dose of 3 million unit thrice weekly. After 4 months of interferon treatment the persistent nephrotic range proteinuria decreased to below 0.5 g/day. Four months later clinical signs of cryoglobulinemia disappeared, and after the 10th month of interferon treatment no cryoglobulin could be detected in the patient's sera. After one year, the interferon treatment was discontinued following a negative PCR result for HCV. However, one month later the proteinuria increased and the quantitative hepatitis C virus nucleic acid test in sera became positive again. Our case demonstrates that interferon therapy may be effective in the treatment of cryoglobulinemic glomerulonephritis responding poorly to the immunosuppressive therapy, though larger doses or longer periods of treatment may be required to prevent relapses.

Lipid abnormalities in uraemic patients on chronic haemodialysis.

Patients kept on haemodialysis because of chronic renal insufficiency were investigated for lipid profiles. The cholesterol level did not differ as compared to the age-matched control, while the triglyceride level was elevated. The correlation was found between the lipid parameters, period spent in dialysis programme and level of serum creatinine and urea. In renal failures of different origin the lipid levels are in relationship with the underlying disorders.

[Prevention of acute renal failure in rhabdomyolysis caused by alcohol and drug intoxication]. / A heveny veseelégtelenség megelözése alkohol- és gyógyszerintoxicatio indukálta rhabdomyolysisben.

Authors report a case of rhabdomyolysis occurring in a chronic alcoholic patient where they suspect in the development of rhabdomyolysis beside the effect of alcohol also a role of drug intoxication and muscle compression. They found sustained myoglobinaemia and myoglobinuria, while in this case beside the hypocalcemia during the initial phase of rhabdomyolysis normal parathyroid hormone level was found. Therefore in alcoholic intoxicated patients the measurement of creatine kinase is indicated. Beside total lactate dehydrogenase the determination of isoenzymes is in some cases helpful. In the presented case despite extensive rhabdomyolysis, acute renal failure was prevented by early volumen replacement therapy and use mannitol-sodium bicarbonate infusions. Authors discuss the possibility of the role of calcium blocking agent nifedipine in the prevention of rhabdomyolysis and acute renal failure.