Glutathione antioxidant system as a marker of oxidative stress in chronic renal failure.

A profound imbalance between oxidants and antioxidants has been suggested in uremic patients on maintenance hemodialysis. However, the respective influence of uremia and dialysis procedure has not been evaluated. Circulating levels of copper-zinc superoxide dismutase (CuZn SOD), glutathione peroxidase (GSH-Px), and reductase (GSSG-Rd), total GSH and GSSG were determined in a large cohort of 233 uremic patients including 185 undialyzed patients with mild to severe chronic renal failure, and 48 patients treated by peritoneal dialysis or hemodialysis. Compared to controls, erythrocyte GSH-Px and GSSG-Rd activities were significantly increased at the mild stage of chronic uremia (p < .001), whereas erythrocyte CuZn SOD activity was unchanged, total level of GSH and plasma GSH-Px activity were significantly decreased, and GSSG level and GSSG-Rd activity were unchanged. Positive Spearman rank correlations were observed between creatinine clearance and plasma levels of GSH-Px (r = .65, p < .001), selenium (r = .47, p < .001), and GSH (r = .41, p < .001). Alterations in antioxidant systems gradually increased with the degree of renal failure, further rose in patients on peritoneal dialysis and culminated in hemodialysis patients in whom an almost complete abolishment of GSH-Px activity was observed. In conclusion, such disturbances in antioxidant systems that occur from the early stage of chronic uremia and are exacerbated by dialysis provide additional evidence for a resulting oxidative stress that could contribute to the development of accelerated atherosclerosis and other long-term complications in uremic patients.

Prognostic relevance of a scoring system based on clinical and biological parameters in early chronic lymphocytic leukemia.

INTRODUCTION: Among patients with indolent form of B-cell chronic lymphocytic leukemia, some of them will progress into more advanced stages. To better define this subpopulation of patients, we attempted to define some parameters capable of predicting a pejorative clinical outcome. MATERIALS AND METHODS: Eighty-eight previously untreated patients with B-cell chronic lymphocytic leukemia in Binet stage A were analysed to study the prognostic value of simple serological variables: soluble CD23 (sCD23), beta2 microglobulin (beta2m), lactate-dehydrogenase activities and albumin level. Results were compared to other conventional clinical and biological parameters by univariate and multivariate statistical analysis. RESULTS: Our data show that: (1) among those studied, sCD23 >50 u/ml was the only serological significant parameter clearly correlated with disease progression and (2) stage A" patients (hemoglobin level between 100 and 120 g/l and/or lymphocytosis >30.10(9)/l), axillary lymph nodes and hypogammaglobulinemia were found to be other variables associated with a pejorative outcome. These four variables enabled the establishment of a scoring system, capable of predicting disease progression since 66% of the patients with a score < or =2 are going to evolve into advanced stages vs 12% with a score <2. Furthermore, the time to progression is shortened when the score is increasing. CONCLUSION: Our findings show the prognostic relevance of a scoring system including sCD23 level. This score could be taken into account in the treatment strategy of B-cell chronic lymphocytic leukemia.

Correction of selenium deficiency in hemodialyzed patients.

Selenium is an essential trace element important for glutathione peroxidase activity. Selenium deficiency has been found in association with skeletal and cardiac myopathy and may increase the risk for cardiovascular diseases and for cancer. We studied 39 hemodialysis patients and 15 control subjects. Plasma selenium, plasma glutathione peroxidase activity and erythrocyte glutathione peroxidase activity were lower than in controls (38 +/- 14 vs. 88 +/- 17 micrograms/liter (P less than 0.01); 153 +/- 32 vs. 334 +/- 41 IU/liter (P less than 0.01), 19 +/- 4 vs. 26 +/- 4 IU/g Hb (P less than 0.01), respectively). Plasma selenium and plasma glutathione peroxidase activity were strongly correlated with duration of dialysis. There was no correlation between plasma selenium and protein or calorie intakes. Plasma selenium was lower in patients dialyzed with highly permeable membranes (P less than 0.01). The total muscle mass, assessed by anthropometry, was lower in the patients who had the lowest plasma selenium (P less than 0.01) and plasma glutathione peroxidase activity (P less than 0.05). Interventricular septum hypertrophy, documented by echocardiography, was greater in patients with the lowest plasma selenium and plasma glutathione peroxidase activity (P less than 0.01). Twenty hemodialysis patients had oral supplementation of 500 micrograms/day of sodium selenite for three months, and then, 200 micrograms/day for the next three months. Plasma selenium increased as early as the first week and reached a plateau similar to the control levels after three weeks. Plasma glutathione peroxidase activity increased after two months but remained below controls. Erythrocyte glutathione peroxidase activity reached a higher value than controls after one month.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal effects of S10036 in man.

The renal hemodynamic and tubular effects of S10036 (fotemustine) were evaluated in seven patients with advanced malignancy. Initial evaluation carried out prior to treatment and repeated 1 day after the first fotemustine infusion and 7 days after the second included clinical, haematological parameters, liver-function tests, and determination of the glomerular filtration rate, renal blood flow and enzymuria. The glomerular filtration rate was 108 +/- 3.7 ml/min before treatment and remained stable after the first (117 +/- 5 ml/min) and second (124 +/- 6 ml/min) fotemustine infusions. Renal blood flow and urinary beta 2-microglobulin and N'-acetylglucosaminidase excretion were also not modified by fotemustine administration. We conclude that fotemustine does not acutely alter renal haemodynamics, nor does it have direct tubular toxicity.

Comparison of serum copper determination by colorimetric and atomic absorption spectrometric methods in seven different laboratories. The S.F.B.C. (Société Française de Biologie Clinique) Trace Element Group.

An interlaboratory collaborative trial was conducted on the determination of serum copper using two different methods, based on colorimetry (test combination Copper, Boehringer Mannheim, Mannheim, Germany) and flame atomic absorption spectrometry (FAAS). The general performance of the colorimetric method was below that of FAAS, except for sensitivity and linear range, as assessed by detection limit (0.44 versus 1.32 mumol/L) and upper limit of linearity (150 versus 50 mumol/L). The range of the between-run CVs and the recovery of standard additions were, respectively, 2.3-11.9% and 92-127% for the colorimetric method and 1.1-6.0% and 93-101% for the FAAS method. Interferences were minimal with both methods. The two techniques correlated satisfactorily (the correlation coefficients ranged from 0.945-0.970 among laboratories) but the colorimetric assay exhibited slightly higher results than the FAAS method. Each method was transferable among laboratories.

Consequences of the diabetic status on the oxidant/antioxidant balance.

It has been shown that elevated extra- and intra-cellular glucose concentrations result in an oxidative stress, which is defined as an imbalance between prooxidants and antioxidants. Several mechanisms seem to be involved in the genesis of this oxidative stress, which has been reported both in experimental diabetes in animals and in type 1 and type 2 diabetic patients: glucose autoxidation, protein glycation and formation of advanced glycation endproducts, and the polyol pathway. Reciprocally, oxidative stress is involved in the origin of type 1 diabetes, especially via the apoptosis of pancreatic beta-cells, as well as insulin resistance in type 2 diabetes. Glucose control plays an important role in the prooxidant/antioxidant balance. Macromolecules such as molecules of extracellular matrix, lipoproteins and deoxyribonucleic acid are also damaged by free radicals in diabetes mellitus. A supplementation with antioxidants has been proposed as a complementary treatment, and some antidiabetic agents may by themselves have antioxidant properties independently of their role on glucose control. The aim of this paper was to review the consequences of the diabetic status on the oxidant/antioxidant balance.

Effects of nifedipine on cisplatinum-induced nephrotoxicity in rats.

The effects of calcium channel blockade with nifedipine (N) on cis-diammine dichloroplatinum II (CDDP)-induced nephrotoxicity were tested in male Sprague-Dawley rats. Renal function was evaluated before and five days after CDDP administration (5 mg/kg). The rats were treated with various doses of N (0.1; 0.3; 0.6 mg/kg/day) 2 days before CDDP administration and throughout the study. The severity of CDDP-induced acute renal failure was markedly modified in N-treated animals according to the daily dosage of N. At 0.3 and 0.6 mg/kg BW/day, N enhanced CDDP nephrotoxicity. Serum creatinine was 637 +/- 45 and 611 +/- 71 mumoles/liter, respectively, 5 days after CDDP administration (vs. 313 +/- 24 mumoles in animals treated with CDDP alone; p less than 0.05). In these animals the plasma potassium level was significantly elevated at day 7 when compared with CDDP-treated and control rats. In contrast, at the dose of 0.1 mg/kg BW/day N attenuated CDDP nephrotoxicity with a serum creatinine of 214 +/- 35 mumoles at the end of the study. The pathologic changes were also more severe in the groups receiving 0.3 and 0.6 mg/kg of nifedipine. We postulate that at the higher doses (0.3 and 0.6 mg/kg) the systemic hemodynamic effects of nifedipine may override the potentially beneficial intrarenal effect which may account for the favorable results recorded with a dosage of 0.1 mg/kg.

Duocart biofiltration: a new method of hemodialysis.

DuoCart biofiltration (DCB) is a new hemodialysis method using a dialysate with only sodium chloride and bicarbonate obtained from two separate powder cartridges (BiCart and SelectCart, Gambro, Sweden). The ionic complement is directly reinfused in postdilution mode, using one 2 L bag of a specially designed sterile solution. The adaptation of the quantity of these infused substances to their removal through the dialysis membrane is made possible by repeated measurements of ionic dialysance (D), which are automatically performed every 30 min by the Diascan module, systematically available on the Integra dialysis monitor (Hospal, Italy), and by subsequent modification of the infusion rate (Q(R)). An appropriate kinetic model was used to determine the composition of the reinfusion solution (mM: 57 K, 47 Ca, 14.5 Mg, 180 Cl), the conductivity dialysate (set at 14.8 mS/cm) and the ratio Q(R)/D (set at 1/28). This ratio is kept constant by updating Q(R) after each measurement of D. The implementation of this technique requires an Integra dialysis monitor equipped with a two-powder-cartridge dialysate generation system. Fifteen dialysis sessions were performed (duration: 213+/-38 min; blood flow: 238+/-26 ml/min; ultrafiltration rate: 16+/-6 ml/min). The per-dialytic changes of ion plasma concentrations were monitored and found to be within the predicted range. The results substantiate the feasibility of this new hemodialysis method that presents several advantages: dialysate concentrates are in powder form, an alkaline and acetate-free dialysate is used with superior dialysate biocompatibility, no precipitation of Ca and Mg carbonate occurs in the dialysate circuit, the supply of calcium and potassium is easily adapted to individual patients' needs by change in the composition of the reinfusion solution, and a calcium-free dialysate that facilitates citrate anticoagulation is used.

[Neuropathologic and toxicologic study of 12 cases of bismuth encephalopathy]. / Etude neuropathologique et toxicologique de douze cas d'encéphalopathie bismuthique (EB).

Examination of twelve cases of bismuth encephalopathy showed a constantand marked elevation of the bismuth levels in autopsy cerebral tissue (ranging from 2-8 mg/kg to 25 mg/kg). These values were found to be much higher than the last-measured Bismuth venous blood values. In every case, periveinular lymphocytic infiltration and abundant intra-cytoplasmic lipofuscin were seen. The microanalysis with Castaing's electrode revealed the presence of focal areas of bismuth in the leptomeningeal spaces. The significance of the lesions is not fully established and it will undergo further investigations.

[Estimation of aluminium in biological fluids by atomic absorption spectrophotometry in a graphite oven (author's transl)]. / Dosage de l'aluminium dans les liquides biologiques par spectrophotométrie d'absorption atomique en four graphite.

The possibilities of use of a graphite oven type HGA 74 (Perkin Elmer) for the estimation of aluminium in biological fluids by atomic absorption spectrophotometry are described, with a special study of the stages of drying, mineralisation, atomisation, flow of inert gas, requirement for correction of non-specific absorption, etc. Under fixed experimental conditions, the limit of sensitivity (absorption 1%) was 2.28.10.(-11) grams and the linearity was good up to 100 microgram/l. This method of analysis by direct treatment of the samples required only small volumes of the latter and reduces the risk of contamination.

[Determination of trace elements by an assay using flameless atomic absorption spectrometry]. / Mise au point d'un dosage d'élément trace par absorption atomique électrothermique.

The authors review the keys parameters of flameless atomic absorption spectrometry trace element determination in biological medium. Contamination during sample collection and analysis are discussed. Treatments of sample are indicated. The different graphite furnaces are reviewed. Interferences and background correction are discussed. Reference samples are quoted.

[Concentration of zinc, copper, selenium and aluminium in nutritive solutions for parenteral administration]. / Concentration de Zn, Cu, Se et Al dans des solutés nutritifs utilisés par voie parentérale.

Total parenteral nutrition (TNP) therapy is widely used. However the quantitative requirements or the toxicity of trace elements in parenteral solutions are difficult to assess. This paper deals with a study performed by the Trace Element Commission of the Société Française de Biologie Clinique. Trace metals (zinc, copper, selenium and aluminium) which are mainly involved in TPN solutions are analyzed in 12 different parenteral nutrition solutions commercially available. This multicentric assay (5 different sites of analysis) shows that a slight pollution can be noted for nearly all the solutions examined. But at this level (10 mumol/l for the most concentrated solution), the zinc intake cannot induce any toxicity. For copper and selenium the results indicated a negligible pollution. Small-volume solutions added with zinc, copper and selenium are correctly supplemented. As regard aluminium pollution, 4 solutions among 12 contain non negligible amounts of aluminium. The consequences of this TPN overload especially for young infants, indicate that the struggle against this pollution has to be strengthened.

[Nutritional biological markers of deficiencies of zinc, copper and selenium]. / Marqueurs biologiques nutritionnels des carences en zinc, cuivre et sélénium.

Direct and indirect indices used for the assessment of copper, zinc or selenium status in humans are reviewed. Variations, advantages and disadvantages are discussed. Despite the numerous indices, none of them provide a satisfactory assessment of the nutritional status for these trace elements. The best indices are probably serum zinc and alkaline phosphatase for the assessment of zinc status, serum selenium for the assessment of selenium status and possibly erythrocyte Cu-Zn superoxide dismutase for the assessment of copper status.

[Glycosylated plasma proteins in chronic renal failure]. / Protéines glyquées plasmatiques dans l'insuffisance rénale chronique.

In chronic renal failure HbA1c values and plasma fructosamine concentrations are difficult to interpret owing to anaemia (for HbA1c) and analytical interferences (for fructosamine test). Plasma proteins glycation was measured more specifically by affinity chromatography. Glycated albumin, glycated immunoglobulins G and glycated proteins were determined in 30 control patients, 30 diabetics and 28 patients with chronic renal failure divided into 17 non diabetics and 11 diabetics. Glycated albumin, glycated IgG and glycated total proteins were not modified by chronic renal failure in non diabetic patients on the contrary of HbA1c and fructosamine test.

[Interlaboratory tests: completion of a method of aluminum assay in serum by electrothermal atomic absorption spectrometry]. / Essais interlaboratoires: mise au point d'une méthode de dosage de l'aluminium dans le sérum par spectrométrie d'absorption atomique électrothermique.

After carrying out a prior analysis of published literature, the members of the SFBC trace-elements study group present an interlaboratory trial on the measurement of aluminum in serum using electrothermal atomic absorption spectrometry. The means of measurement chosen, following methods reliability criteria, was the use of a standard addition calibration of the samples diluted 1/5 in nitric acid 0.02 mol.l-1. Standard addition calibration was performed on two serums and gives acceptable results. Measurements are preferably carried out in 'tantalised' graphite tubes or pyrolytic tubes with platforms. However, when using graphite tubes, their quality must be checked because measurements can be seriously affected by poor quality tubes.

[Value of plasma fructosamine in non-diabetic and diabetic chronic renal failure]. / Valeur de la fructosamine plasmatique chez les insuffisants rénaux chroniques non diabétiques et diabétiques.

Plasma fructosamine concentrations were measured in non-diabetic and diabetic patients with chronic renal failure divided into two three groups: patients without dialysis, under haemodialysis and under continuous ambulatory peritoneal dialysis. In non-diabetic patients plasma fructosamine values were consistently higher than in a control population (2.26 +/- 0.26 mmol/l), being 2.38 +/- 0.35 mmol/l in patients without dialysis, 2.57 +/- 0.33 mmol/l in patients under peritoneal dialysis and 2.67 +/- 0.31 mmol/l in patients under haemodialysis. In diabetic patients, plasma fructosamine values were increased, being equal to, or higher than 3 mmol/l; these values were almost identical with those obtained in populations of diabetics without renal pathology. Considering that Hb Alc values are difficult to interpret in chronic renal failure owing to anaemia and to the analytical problems raised by haemoglobin carbamylation, the fructosamine test may well be a reliable marker for the monitoring of diabetes in patients with chronically impaired renal function.

[Oxidative stress in 29 HIV seropositive patients. Two-year results of a double-blind trial of diethyldithiocarbamate versus placebo]. / Stress oxydatif chez 29 sujets séropositifs. Résultats à 2 ans d'une étude en double insu diéthyldithiocarbamate versus placebo.

Among 29 seropositive subjects who had participated in the HIV 87 therapeutic trial (Mérieux laboratories), the oxidative stress was evaluated at 24 months in 16 treated with diethyldithiocarbamate (dithiocarb) and in 13 who had received the placebo. No significant difference was found between these two groups, whereas the existence of an oxidative stress has been confirmed in seropositive subjects compared with controls.

[Correction of selenium deficiency in patients with renal failure undergoing hemodialysis]. / Correction du déficit en sélénium chez des insuffisants rénaux hémodialysés.

Plasma selenium levels (p Se) as well as glutathione peroxidase activity in plasma (p GPx) and in erythrocytes (e GPx) were measured in 39 haemodialysis patients. Glutathione peroxidase is a selenium-dependent enzyme which protects cells against oxidation. The mean level values obtained were significantly lower in patients than in controls: p Se: 38 +/- 14 versus 88 +/- 17 micrograms/l; p GPx: 15 +/- 32 versus 334 +/- 41 IU/l; e GPx: 19 +/- 4 versus 26 +/- 4 IU/g Hb. These values were found to correlate significantly with the duration of dialysis and with the type of membrane utilized. The total muscular mass was significantly smaller in patients with the lowest p Se or p GPx values. At echocardiography, septal hypertrophy correlated with both p Se and p GPx. Twenty patients were supplemented with sodium selenite administered orally at the end of each haemodialysis session during 6 months. After this period, muscular mass and septal hypertrophy were decreased and the echocardiographic contractility parameters were improved, albeit not significantly.

[The plasma antioxidant status and trace elements in patients with familial hypercholesterolemia treated with LDL-apheresis]. / Statut plasmatique en antioxydants et en oligoéléments de patients atteints d'hypercholestérolémie familiale traités par LDL-aphérèse.

Oxidation of low density lipoprotein is involved in the pathogenesis of atherosclerosis. Epidemiological studies suggest a negative correlation between the occurrence of cardiovascular diseases and blood concentrations of lipophilic antioxidants such as vitamin A and E and beta-carotene. Trace elements such as selenium, zinc and copper are involved in the activity of antioxidant enzymes: glutathione peroxidase and superoxide dismutase. The aim of this work was to determine the antioxidant and trace elements status of patients with very severe hypercholesterolemia and who were treated by dextran sulphate low density lipoprotein apheresis, in comparison with two control populations: one constituted by normocholesterolemic subjects and the other by hypercholesterolemic patients before treatment. Our results showed that, as compared with normocholesterolemic subjects, patients treated by LDL-apheresis were not deficient in vitamin E, beta-carotene and copper but had low plasma levels of selenium, zinc and vitamin A. The low selenium and vitamin A levels were due to the treatment by LDL-apheresis by itself, while the hypercholesterolemia of these patients might have provoked the low plasma levels of zinc. This study pointed out the interest of a supplement of selenium, zinc and vitamin A in patients treated by LDL-apheresis.