No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Serum and Erythrocyte Tocopherol in Uremic Patients: Effect of Hemodialysis versus Peritoneal Dialysis
Abstract
alpha-Tocopherol is transferred from serum to erythrocytes by high-density lipoproteins (HDL). We have studied total serum, HDL and erythrocyte tocopherol concentration in uremic patients on hemodialysis (HD; n = 18) and continuous ambulatory peritoneal dialysis (CAPD; n = 14), and the relationship between HDL and erythrocyte tocopherol content. Serum and erythrocyte tocopherol were determined by high-performance liquid chromatography. Serum tocopherol levels were higher in CAPD patients (p < 0.05) than in control (n = 30) and HD groups. Erythrocyte tocopherol was lower in HD patients than in the controls but there were no differences between CAPD patients and the control group. Bioavailable tocopherol was found to be normal in both HD and CAPD patients. HDL-tocopherol was lower in both HD and CAPD groups, but probably enough to reach a normal level of tocopherol in erythrocytes, as has been demonstrated in CAPD patients. So, although a defect in the transfer of tocopherol to red blood cells is possible, some other causes could influence it too, as a greater antioxidant consumption in HD patients.
... In HD patients serum vitamin E is in the normal range 12,16,21 or lower 12,19,22 compared with healthy subjects, and ER tocopherol is decreased in HD patients. 12,14,19,23 Erythrocyte tocopherol deficiency in HD patients could be caused by an insufficiency of vitamin E transfer from plasma high-density lipoprotein fractions to erythrocytes because it is known that vitamin E is transferred from serum to erythrocytes by high-density lipoprotein. 24 Some other causes could influence it too, such as a greater antioxidant consumption in these patients. ...
... 24 Some other causes could influence it too, such as a greater antioxidant consumption in these patients. 23 The aim of the study was to investigate the influence of the vitamin E-coated cellulose membrane dialyzer on markers of oxidative stress and antioxidant defense parameters in HD patients during the 3-month study. The present study is the continuation of the previous short-term study (3 wk) in which we compared the influence of vitamin E-coated dialyzers with conventional dialyzers and with peroral supplementation of vitamin E on MDA and antioxidant defense parameters in HD patients. ...
... The erythrocyte vitamin E level was decreased in uremic patients on chronic hemodialysis 12,14,19,23 in contrast to the results of Paul et al, 5 who found the RBC vitamin E level to be in the normal range. According to the literature, long-term treatment by EPO in chronic renal failure patients led to the increase of ER vitamin E level to the normal range. ...
Atherosclerotic cardiovascular disease is the most frequent cause of death in patients with end-stage renal disease who have undergone dialysis treatment. Oxidative stress, increased lipid peroxidation, and impaired function of antioxidant systems may contribute to the accelerated development of atherosclerosis in chronic renal failure patients during renal replacement therapy. The aim of this study was to investigate the influence of a vitamin E-coated dialyzer on antioxidant defense parameters in hemodialysis (HD) patients. In 14 HD patients, hemodialysis was performed using a vitamin E-coated dialyzer (Terumo CL-E15NL; Terumo Corporation, Tokyo, Japan) during a 3-month study. In these patients, erythrocyte (ER) antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPX), glutathione reductase (GR) and catalase (CAT), plasma total antioxidant capacity (TAC), RBC glutathione (GSH), plasma malondialdehyde (MDA), plasma, and RBC vitamin E were investigated. Each parameter was measured at the beginning of the study, after the 1st, 2nd, and 3rd month of the study, and 10 weeks after the interruption of the use of vitamin E-coated dialyzer. All HD patients were treated by erythropoietin (EPO) and received vitamin C 50 mg/d, pyridoxine 20 mg/d, and folic acid 5 mg/wk during the entire study. The 3-month treatment with the vitamin E-coated dialyzer led to a significant decrease of plasma MDA level (from 2.85 +/- 0.44 to 2.25 +/- 0.37 micromol/L) and to an increase of plasma TAC, RBC, GSH, and the vitamin E levels both in plasma (from 25.9 +/- 2.8 to 33.6 +/- 3.8 micromol/L) and in the RBCs (from 6.7 +/- 0.8 to 7.4 +/- 0.7 micromol/L) by 30% and 10.5%, respectively. Ten-week interruption of the use of the vitamin E-coated dialyzer led to near initial values of MDA (2.90 +/- 0.28 micromol/L), plasma (28.6 +/- 3.5 micromol/L), and RBC (6.9 +/- 0.7 micromol/L) vitamin E and of other investigated parameters. Statistical analysis of results was performed by conventional methods and analysis of variance. The findings of the current study confirm the beneficial effect of the vitamin E-coated dialyzer against oxidative stress in HD patients.
... Malondialdehyde (MDA) as a product of lipid peroxidation was increased in uremic patients [1,3,13,14,15,16,17,18], indicating accelerated lipid peroxidation is a consequence of multiply pathogenetic factors [15]. ...
... Alpha-tocopherol (vitamin E) is a liposoluble vitamin placed on cell membranes and its main function is to protect polyunsaturated fatty acids against oxidative aggression, thus preserving their integrity [16]. In HD patients the levels of erythrocyte vitamin E are lower than in CAPD patients or in the healthy subjects. ...
... Our finding is similar to the data of Galli et al. [12]. Six-week short term oral administration of vitamin E to CAPD patients did not lead to the increase of enzymatic and non enzymatic markers of antioxidant defence system, with the exception of vitamin E. The erythrocyte vitamin E level was decreased in HD patients [12,14,16,33], in contrast to the results of Paul et al. [5], who found its value in normal range. According to Nenov et al. [33] the long-term treatment of EPO in HD patients led to the increase of erythrocyte vitamin E level to the normal range. ...
Oxidative stress, increased lipid peroxidation, and impaired function of antioxidant system may contribute to the accelerated development of atherosclerosis in chronic renal failure patients during renal replacement therapy. The aim of the study was to investigate the influence of oral vitamin E (400 mg/day) in 14 patients who underwent continuous ambulatory peritoneal dialysis (CAPD) and effects of the vitamin E-coated dialyzer in 14 haemodialysis patients on several antioxidant biochemical parameters. Six-week treatment with oral vitamin E in CAPD patients and three-month treatment using vitamin E-coated dialyzer in haemodialysis patients led to the significant decrease of plasma malondialdehyde, to the increase of plasma vitamin E and to the increase of erythrocyte vitamin E in haemodialysis patients. No significant changes of erythrocyte antioxidant enzyme--superoxide dismutase, glutathione peroxidase and catalase were found during the both types of antioxidant therapy. At the end of the third month of haemodialysis study the significant increase of erythrocyte glutathione in haemodialysis patients was found, but that value was significantly lower as normal range. Six-week interruption of the administration of oral vitamin E in CAPD patients led to the significant decrease of erythrocyte superoxide dismutase and plasma vitamin E. Ten-week interruption of the use of vitamin E-coated dialyzer led to the significant increase of plasma malondialdehyde and to the decrease of plasma and erythrocyte vitamin E in haemodialysis patients, near to the values at the beginning of the study. Our study confirmed the beneficial effect of oral administration of vitamin E and the use of vitamin E-coated dialyzer against oxidative stress in CAPD and haemodialysis patients.
... Each parameter was determined at the beginning of the study and at the end of each period. Six CAPD patients were treated by erythropoietin (EPO) In hemodialyzed patients the levels of red blood cell tocopherol are lower than in CAPD patients or in the healthy subjects (4,7,8). Erythrocyte tocopherol deficiency in hemodialyzed patients could be due to an insufficiency of vitamin E transfer from plasma HDL fractions to erythrocytes, since it is known that vitamin E is transferred from serum to erythrocyte by HDL. ...
... Erythrocyte tocopherol deficiency in hemodialyzed patients could be due to an insufficiency of vitamin E transfer from plasma HDL fractions to erythrocytes, since it is known that vitamin E is transferred from serum to erythrocyte by HDL. Some other causes could influence it too, such as a greater antioxidant consumption in these patients (4). Vitamin E reduces susceptibility of LDL to oxidation in patients with chronic renal failure but the benefit appears to be greater in patients on CAPD (1). ...
Oxidative stress, increased lipid peroxidation and decreased activity of antioxidant systems may contribute to the accelerated development of atherosclerosis in chronic renal failure patients during renal replacement therapy. The aim of the study was to investigate the influence of vitamin E (400 mg/day) on some antioxidant defense parameters in CAPD patients. In fourteen CAPD patients, erythrocyte antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT), the concentration of plasma malondialdehyde (MDA), vitamin A, vitamin C and vitamin E were investigated. The study was divided into two periods. Each period lasted six weeks. In the first period patients received orally vitamin E 400 mg/day, in the second period they did not receive vitamin E or other antioxidant drugs. Each parameter was determined at the beginning of the study and at the end of each period. Six CAPD patients were treated by erythropoietin (EPO) and received orally pyridoxine 20 mg/day and the others without EPO treatment received pyridoxine 5 mg/day. Six-week treatment by vitamin E (400 mg/day) led to the significant increase of serum vitamin E (from 33.6±9.0 to 49.3±15.5 μmol/L) and to the significant decrease of MDA (from 2.62±0.5 to 2.36±0.4 μmol/L). The mean values of erythrocyte enzymes were in or under the lower margin of normal range and were not influenced by vitamin E in CAPD patients.
The results of our study showed that orally administered vitamin E is a very important antioxidant agent for CAPD patients.
... Several studies showed that concentrations of various antioxidants (such as vitamins A+C+E, TAC, Zn, Cu, and Se) in serum and erythrocytes and even platelets and antioxidant activity (SOD, CAT, and GPx) are significantly suppressed in HD patients compared to PD patients [52,[58][59][60][70][71][72][73], while only two studies reported similar serum antioxidant status in both dialysis modalities [63,64]. ...
Peritoneal dialysis (PD) patients manifest excessive oxidative stress (OS) compared to the general population and predialysis chronic kidney disease patients, mainly due to the composition of the PD solution (high-glucose content, low pH, elevated osmolality, increased lactate concentration and glucose degradation products). However, PD could be considered a more biocompatible form of dialysis compared to hemodialysis (HD), since several studies showed that the latter results in an excess accumulation of oxidative products and loss of antioxidants. OS in PD is tightly linked with chronic inflammation, atherogenesis, peritoneal fibrosis, and loss of residual renal function. Although exogenous supplementation of antioxidants, such as vitamins E and C, N-acetylcysteine, and carotenoids, in some cases showed potential beneficial effects in PD patients, relevant recommendations have not been yet adopted in everyday clinical practice.
... S"ha observat com l"activitat dels antioxidants interns com la superòxid dismutassa o la glutation oxidassa es troba disminuïda en pacients dialitzats [46,61]. A més, els antioxidants externs, tant els hidrofílics (vitamina C) com els liposolubles (vitamina E) s"han trobat disminuïts en la urèmia [62][63][64][65][66]. L"oxidació de les lipoproteïnes junt amb una disminució en la capacitat antioxidant en pacients trasplantats semblen jugar un paper clau en la inducció de l"aterogènesi en el pacient trasplantat [71]. ...
... Since the efficiency of vitamin E to protect uremic LDL against oxidation appears to be diminished, relatively high doses of the vitamin are likely to be required to obtain that protection [63]. In another recent study, serum vitamin E was not different between hemodialysis patients and healthy subjects, although the content of tocopherol in red blood cells and in HDL was lower in the dialysis patients [127]. ...
Kidney International aims to inform the renal researcher and practicing nephrologists on all aspects of renal research. Clinical and basic renal research, commentaries, The Renal Consult, Nephrology sans Frontieres, minireviews, reviews, Nephrology Images, Journal Club. Published weekly online and twice a month in print.
... In agreement with the results of earlier studies [43][44][45], we did not find any significant changes in the basal plasma levels of either ·-tocopherol or ·-tocopherol/total lipid between normal controls and hemodialysis patients. In addition, both ·-tocopherol or ·-tocopherol/total lipid levels of smokers and nonsmokers who were on hemodial-ysis were similar. ...
Background/aim:
Cardiovascular disease is the major cause of mortality in dialysis patients, accounting for about 40% of deaths in most large registries. Oxidative stress has been strongly implicated in the pathogenesis of these events. As end-stage renal disease is a state of elevated free radical activity, the aim of the present study was to investigate the negative impact of smoking in 57 male hemodialysis patients.
Methods:
The patients, who were 20-85 years of age (mean age 51.0 +/- 14 years), had been on hemodialysis for at least 6 months before participating in this study. Fasting blood sampling for serum lipid, albumin, urate and lipophilic antioxidants such as tocopherols, carotenes, ascorbate and lipid peroxides was performed.
Results:
The plasma malondialdehyde (MDA) concentration was significantly higher in hemodialysis patients who smoked compared to hemodialysis patients who were nonsmokers (1.92 +/- 0.52 vs. 1.59 +/- 0.42 nmol/ml, p = 0.006). No association was found between levels of MDA in smokers and parameters such as body mass index, serum cholesterol, serum triglycerides and smoking index. There were no significant differences in the plasma levels of uric acid, alpha-tocopherol, gamma-tocopherol, delta-tocopherol, alpha-carotene, beta-carotene and retinol between the two groups. A significantly lower level of plasma ascorbate was observed in hemodialysis patients who smoked compared to the nonsmoking hemodialysis patients or healthy controls (4.59 +/- 4.0 vs. 9.57 +/- 4.0 and 10.16 +/- 4.6 microg/ml, p < 0.05). Moreover, in smokers, the plasma levels of ascorbate were negatively correlated with the levels of plasma MDA (r = -0.43, p < 0.001) of each patient. Partial correlation analysis of the plasma levels of the measured antioxidants and the smoking index revealed a negative correlation between the plasma levels of lipid-normalized lycopene and the smoking index (r = -0.53, p < 0.05).
Conclusion:
Our data suggest that cigarette smoking further increases plasma-circulating products of lipid peroxidation, which are already increased in nonsmoking hemodialysis patients as compared to matched healthy controls. The lower plasma levels of ascorbate in hemodialysis patients who smoke suggest that these patients may be more susceptible to oxidative tissue damage caused by smoking.
... Several antioxidant defence mechanisms also seem to be altered in HD patients: reduction in CuuZn superoxide dismutase (SOD) activity in erythrocytes [2] and decreased activity in plasma glutathione peroxidase (GSH-Px)121314 . Furthermore, hydrophilic and lipophilic antioxidant vitamins are altered in uraemia: vitamin E (vit E) levels in erythrocytes and mononuclear cells is low despite normal plasma levels151617; a dramatic depletion of vitamin C (vit C) is also observed [18– 20]. Vit E, a well-known peroxyl scavenger could prevent lipid peroxidation but its antioxidant function has been demonstrated to depend on the presence of vit C or ascorbic acid. ...
Enhanced oxidative stress in haemodialysis (HD) patients may be considered as a risk factor for accelerated atherosclerosis. Reduced antioxidant defences include impairment in enzyme activities and decreased plasma levels of hydrophilic vitamin C (vit C), and cellular levels of lipophilic vitamin E (vit E).
We investigated plasma levels of vit C in 19 patients undergoing regular haemodiafiltration (HDF) (mean age 62+/-7 years) and in 1846 healthy elderly subjects (HS) (mean age 69+/-5 years). The contribution of convection and diffusion was determined using paired filtration dialysis (PFD), a modified HDF technique which physically separates convective from diffusive fluxes. Blood samples were collected before and after the HDF session; in addition at 60 min of HDF, samples were drawn from arterial lines (AL) and venous lines (VL), dialysate (D) and ultrafiltrate (UF). Blood levels of total vit C were determined using an HPLC fluorescence method. Markers of oxidative stress were also assessed in both populations as follows: levels of malondialdehyde (MDA) were determined by fluorometric assay, measurements of advanced oxidation protein products (AOPP) and glutathione peroxidase (GSH-Px) activity were performed by spectrophotometric assay, and plasma vit E content was obtained by an HPLC procedure.
A significant reduction in plasma vit C level was observed in HDF patients when compared with HS (1.6+/-1.4 microg/ml in HDF vs 6.6+/-3.7 microg/ml in HS; P<0.01). The HDF session was associated with a dramatic reduction in vit C levels (1.87+/-1.57 microg/ml before HDF and 0.98+/-0.68 microg/ml after HDF); at 60 min of HDF, concentrations were as follows: AL=1.35+/-1.27 microg/ml; VL=0.37+/-0.31 microg/ml, D=0.40+/-0.34 microg/ml, UF=1.24+/-1.18 microg/ml; corresponding to a diffusive flux of 271 microg/min and a convective flux of 126 microg/min. Total loss of vit C could be assessed at 66 mg/session (8--230 mg/session). According to this loss of vit C, presence of an oxidative stress was demonstrated in HD population as shown by a significant increase in MDA (1.66+/-0.27 microM in HD vs 0.89+/-0.25 microM in HS; P<0.01) and AOPP (77.5+/-29.3 microM in HD vs 23.5+/-13.2 microM in HS; P<0.01) levels, and a decrease in GSH-Px activity (259.2+/-106.3 U/l in HD vs 661.2+/-92.2 U/l in HS; P<0.01). No change in plasma vit E between both populations (30.7+/-9.1 microM in HD vs 35.3+/-7.34 microM in HS) was observed.
These results suggest that HDF with highly permeable membranes is associated with a significant loss of vit C. Diffusive transport is responsible for two-thirds whereas convective phenomenon accounts for only one-third of this loss.
... Therefore, changes occur in water-and-fat-soluble vitamin levels, such as that of vitamin E. Altered vitamin E levels have also been detected in uremic patients. Some authors have found increased plasma vitamin E levels in HD patients (30,31), and in PD patients (32). In some studies, a low plasma vitamin E level in nondialyzed children (33) and in nondialyzed adult patients with CKD was observed (34). ...
Several medications have been tested with the aim of decreasing oxidative stress and erythrocyte osmotic fragility in patients on dialysis. The aim of the present study was to assess the influence of vitamin E therapy on oxidative stress and erythrocyte osmotic fragility in patients on hemodialysis (HD) and peritoneal dialysis (PD).
This was a placebo-controlled study. The study was performed on 34 HD patients, 13 PD patients and 22 healthy volunteers with a mean age of 45.57 +/- 8.54 years. HD patients were divided into 2 groups: treatment (n=19) and control (n=15). Vitamin E was administered, 300 mg/day, to the HD treatment group and PD patients for 20 weeks. Lipid peroxidation, antioxidant condition and erythrocyte osmotic fragility (EOF) were examined before and after treatment.
Before the treatment, the levels of EOF (p<0.001) and malondialdehyde (MDA) (p<0.001) were significantly lower, and erythrocyte superoxide dismutase (SOD) (p=0.001) and vitamin E levels (p<0.001) were significantly higher in the healthy group than PD and HD groups. Serum vitamin E increased from 0.93 +/- 0.16 to 1.09 +/- 0.14 mg/dL (p=0.001), EOF decreased from 0.49% +/- 0.03% to 0.42% +/- 0.04% NaCl (p<0.001), and plasma MDA values decreased from 2.77 +/- 0.87 to 2.20 +/- 0.767 nmol/mL (p=0.018) in the HD treatment group after vitamin E treatment. Levels of EOF decreased from 0.51% +/- 0.09% to 0.43% +/- 0.03% NaCl in the PD treatment group after vitamin E treatment (p=0.021).
Vitamin E therapy is effective in decreasing the levels of EOF in patients on HD and PD, and it is also effective in decreasing lipid peroxidation in patients on HD.
People with advanced chronic kidney disease (CKD) or end-stage kidney disease (ESKD) commonly have altered metabolism or actions of many vitamins and abnormal vitamin function. Vitamin intake is frequently reduced at all CKD stages. The following are among the disorders or key findings concerning vitamins commonly encountered found in people with advanced CKD or ESKD. Plasma vitamin A is usually elevated, and even relatively small vitamin A supplements may cause toxicity. The potential benefits of supplemental vitamin E have not been confirmed. Vitamin K may have an important role in preventing vascular calcification, and clinical trials examining this potential benefit are being conducted. There is an increased dietary need for vitamin B6, in the form of pyridoxine hydrochloride, of about 5 mg/d for advanced CKD and chronic peritoneal dialysis patients and 10 mg/d for maintenance hemodialysis patients. Vitamin C intake is often low, and without vitamin C supplements, deficiency is not uncommon because of a low intake with potassium-restricted diets and because it is readily removed during the dialysis procedure. Folate supplements are effective for decreasing plasma homocysteine levels, but several randomized controlled clinical trials did not demonstrate a reduction in adverse cardiovascular events or mortality with large doses of either folic acid or combinations of folic acid, pyridoxine HCl, and vitamin B12. Vitamin B1 status should be assessed in CKD or ESKD patients who present with atypical neurologic symptoms. Niacin, in large doses, appears to effectively inhibit intestinal phosphate absorption but often causes unpleasant symptoms. Except for vitamins A and E, there is an increased risk of deficiency of other vitamins, such as riboflavin, biotin, and pantothenic acid, in both CKD and chronic dialysis patients, especially in those suffering from protein–energy wasting. It is suggested, even in the absence of a strong evidence base, that multivitamin supplements should commonly be used in advanced CKD and ESKD patients to prevent vitamin deficiencies.
Vitamin nutriture has been extensively studied in the wide spectrum of renal disease from the nephrotic syndrome to chonic dialysis therapy. Regain of interest has been recently provided by the observational data from DOPPS reporting better outcome in dialysis patients under vitamin supplementation. In this chapter vitamin structure and functions are reminded. The role of kidney disease and renal failure on vitamin intake and metabolism, and the risk of deficiency in these conditions are reviewed. Recent data question previous concepts and trigger renewed interest, like as the relationship between retinol plasma level and outcome in hemodialysis patients, the disappointing effects of vitamin E supplementation, the role of vitamin K in bone mineral metabolism, the use of niacin as a phosphate binder, and the influence of vitamin C and B6 on oxalate metabolism in renal failure. Moreover the latest trials burying the hope of improving outcomes from homocystein-lowering therapy with multivitamins are discussed. Guidelines issued during the last decade regarding vitamin supplementation are reported and reviewed.
Oxidative stress can produce profound alterations to cellular membrane lipids, impairing cell metabolism and viability. This phenomenon, previously observed in haemodialysis patients, has been proposed as a significant factor in regard to haemodialysis-related shortened red blood cells (RBC) survival. In the present study, several parameters associated with oxidative stress were evaluated in a group of haemodialysis patients either receiving erythropoietin therapy (n = 12, mean erythropoietin dose 88 +/- 24 U/kg/week) or not receiving such therapy (n = 30), and in 38 controls. Malonyldialdehyde (MDA, nmol/ml), an end-product of lipid peroxidation, and RBC antioxidant systems were measured, including RBC alpha-tocopherol (RBC vitamin E, mg/l), RBC glutathione (GSH, nmol/mgHb), and RBC superoxide dismutase activity (SOD, U/mgHb). Plasma vitamin E concentrations were also evaluated. Finally, oral vitamin E supplementation (500 mg daily), an exogenous antioxidant, was administered for 6 months to seven patients from the dialysis group receiving erythropoietin while oxidative parameters were repeatedly evaluated and erythropoietin requirements monitored, in order to appreciate the therapeutic relevance of an antioxidant supplementation. An elevation of serum MDA was observed in all haemodialysis patients and a significant decrease in RBC vitamin E, despite normal serum vitamin E levels. Furthermore, the reduction in RBC vitamin E was more important in patients treated with erythropoietin. Vitamin E supplementation resulted in a significant increase in RBC vitamin E (from 0.3 +/- 0.1 to 1.2 +/- 0.2 mg/l of pellet) and a reduction in erythropoietin dose (from 93 +/- 24 to 74 +/- 26 U/kg/week) while maintaining stable haemoglobin concentrations. These results suggest that the oxidative stress could be one of the resistance factors to erythropoietin response in haemodialysis and that vitamin E supplementation could have a sparing effect on erythropoietin dosage requirement.
Because of concern that United States (US) chronic hemodialysis patients are at high risk for the development of vitamin deficiencies, the great majority of such patients are routinely supplemented with a multivitamin. This policy is supported by major US dialysis providers and nonprofit organizations. Yet routine multivitamin supplementation expands hemodialysis patients' already large pill burden, probably accounts for many millions of dollars in annual costs, and in light of previous reports may even carry with it the possibility of increased risk of adverse outcomes. An analysis of the benefits of routine multivitamin supplementation in US patients is therefore in order. We performed a systematic review of the medical literature between 1970 and 2014 using the Ovid MEDLINE database to address this question. We conclude that there is insufficient evidence to support routine multivitamin use and recommend that the decision to supplement be made on an individual basis.
Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
Aging “baby boomers” are ushering in the new millennium. Indeed, the fastest growing segment of the population in this nation is older adults (Fig. 1). In the year 1900, approximately 1 in every 25 persons in the United States was 65 years old or older. In the year 2000, 1 in 5 Americans will be 65 or older. This demographic transition has enormous consequences for the society at large. It calls for significant research attention to the major biologic, social, and psychological challenges of aging.
Objective: To determine the dietary intake of vitamins, minerals and trace elements in a chronic hemodialysis population.Setting: University-owned chronic hemodialysis center.Patients: Twenty-five patients dialyzed with cellulose acetate or cellulose membranes. The average KtV was 1.18 ± .12, the mean caloric intake was 1656 ± 538 kcal/d and the mean protein intake was 61.1 ± 17.2 g/d (.86 ± .22 g/kg/ideal body wt).Data source: Nine-day food record histories.Results: The mean daily intake of most water-soluble vitamins was less than the recommended daily allowance (RDA), with the most deficient intakes observed for vitamin B6 (64% of RDA) and riboflavin (84% of RDA). Only mean vitamin B12 intake was greater than the RDA. For the fat soluble vitamins the mean intake of both vitamins A and E was less than the RDA (63% and 73%, respectively). Mean iron intake was 101% of the RDA, whereas mean zinc intake was only 60% of the RDA. Intake of folic acid was greater in our patients compared with previous studies in Australian, Danish, and British patients. In addition, intake of thiamine and vitamins B6 and C was higher, and intake of niacin was lower in our patients compared with Australian patients.Conclusion: There is marked variability in the intake of vitamins and minerals in chronic hemodialysis patients. Careful attention should be paid to regional and national differences in dietary intake of vitamins, trace elements, and minerals in hemodialysis patients.
The aim of this study was to evaluate the antioxidant supplementation effect on antioxidant system in hemodialysis patients.
The study group consisted of 38 patients undergoing hemodialysis and 72 healthy subjects. The patients orally received combination
of vitamins C (250mg/time) and E (200IU/time) three times per week for 2months. Both, enzymatic antioxidants [superoxide
dismutase (SOD) and glutathione peroxidase (GPx)] activities and non-enzymatic (vitamins E and C) levels and malondialdehyde
(MDA) concentrations as lipid peroxidation product in patients were measured before and after supplementation compared with
control group. The levels of antioxidants (vitamin E, C and SOD) (P<0.0001) and GPx (P<0.05) were significantly enhanced and MDA concentrations declined (P<0.0001) during the supplementation period. The study demonstrates that combined supplementation of vitamins C and E can
noticeablyaffect antioxidant status and protect against oxidative stress caused during hemodialysis.
KeywordsHemodialysis-Combined supplementation-Vitamin C-Vitamin E-Oxidative stress
About 12-15 % of hemodialysis patients have a poor response to recombinant human erythropoietin (rHuEPO). The aim of this prospective study was to examine the influence of oxidative stress and vitamin E supplementation on rHuEPO responsiveness in chronic hemodialysis patients. Sixty-five hemodialysis patients treated with rHuEPO were studied. Those with iron deficiency, blood loss, malignancy, vitamin B12 and folate deficiency, severe hyperparathyroidism, liver cirrhosis, and congestive heart failure were excluded. Twenty-one healthy volunteers served as a control group. Malondialdehyde, carbonyl proteins, erythrocyte superoxide dismutase (SOD), ceruloplasmin, and serum antioxidant capacity were measured. Values of SOD > 150 U/ml were considered as normal. Patients with SOD < 150 U/ml were divided in two groups: group A (n = 11): treated with vitamin E 400 mg/day (600 IU/day) for 8 weeks; group B (n = 13): not treated. A third, group C consisted of patients with normal SOD. rHuEPO doses (U/kg/week) were recorded. rHuEPO responsiveness index was calculated as rHuEPO U/week/hematocrit. A poor response was defined as a rHuEPO responsiveness index >200. SOD positively correlated with hemoglobin (p = 0.0018, R = 0.337) and negatively with rHuEPO responsiveness index (p = 0.0122, R = 0.319). Vitamin E-treated patients from group A exhibited significantly increased hemoglobin levels as compared to initial values (10.5 ± 0.3 vs. 8.6±0.4, p = 0.002). In comparison with group B, the vitamin E-treated patients displayed a higher hemoglobin (10.5 ± 0.3 vs. 9.4 ± 0.3, p = 0.04), had a lower rHuEPO dose (85.7 ± 7.4 vs. 136.8 ± 13.8, p = 0.025), and a significantly improved rHuEPO responsiveness (rHuEPO responsiveness index 177.9 ± 28.6 vs. 314.1 ± 34.0, p = 0.006). Patients from group A significantly improved their rHuEPO responsiveness after vitamin E therapy as compared to baseline (rHuEPO responsiveness index 177.9 ± 28.6 vs. 271.7 ± 30.3, p = 0.034). We conclude that lower values of SOD correlate with lower hemoglobin, higher rHuEPO dose and poor response to rHuEPO in chronic hemodialysis patients. Vitamin E supplementation significantly improves rHuEPO responsiveness, increases hemoglobin level, and decreases rHuEPO dose.
Uremic patients undergoing hemodialysis (HD) are considered to face an elevated risk for atherosclerosis and cancer. This has been attributed in part to an increased oxidative stress. In this pilot study, oxidative cell damage in blood of HD-patients was compared to those of controls: total DNA damage (basic and specific oxidative DNA damage), modulation of glutathione levels (total and oxidized glutathione) and of lipid peroxidation were monitored via the Comet assay (with and without FPG), a kinetic photometric assay and HPLC quantification of plasma malondialdehyde (MDA), respectively. In some samples, leukocytes were analysed for malondialdehyde-deoxyguanosine-adducts (M1dG) with an immunoslot blot technique. HD-patients (n=21) showed a significant increase of total DNA damage (p<10(-12)), compared to controls (n=12). In a subset of patients and controls, GSSG levels and M1dG, however, only increased slightly, while tGSH and MDA levels did not differ. The influence of different low flux HD-membranes was tested in a pilot study with nine patients consecutively dialysed on three membrane types for four weeks each. In addition to the individual disposition of the patient, the dialyser membrane had a significant impact on oxidative stress. Total DNA damage was found to be almost identical for polysulfone and vitamin E coated cellulosic membranes, whereas a slight, but significant increase was observed with cellulose-diacetate (p<0.001). In patients receiving iron infusion during HD, MDA-formation (n=11) and total DNA damage (n=10) were additionally increased (p<0.005). Our results show an increased oxidative damage in HD-patients, compared to healthy volunteers. Significant influences were found for the dialyser membrane type and iron infusion.
Lipid peroxidation, measured by malonyldialdehyde (MDA) and vitamin E in red blood cells (RBC) and plasma, was investigated in 25 hemodialysis (HD) patients before and after 6 months rhEPO therapy. RBC-MDA was significantly elevated, but plasma MDA was in the reference range. After recombinant human erythropoietin (rhEPO) treatment, the MDA level was significantly decreased in both compartments. Marked vitamin E deficiency was established in RBC as well as in plasma. rhEPO therapy restored vitamin E levels in both compartments. Our data suggest a possible positive rhEPO-antioxidant effect in HD patients.
Recent data suggest that treatment with n-3 fatty acids could enhance the susceptibility of plasma low-density-lipoprotein (LDL) to oxidation. Twelve hypertriacylglycerolemic, hemodialyzed patients were treated with 2.5 g n-3 fatty acids/d for 2 mo. Treatment was then withdrawn for 2 mo (washout phase). Plasma total cholesterol and LDL cholesterol increased significantly (9% and 28%) and plasma triacylglycerols decreased significantly after the n-3 phase compared with baseline and washout values. LDL susceptibility to oxidation was tested by oxidation of LDL particles with 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH). No significant changes were observed for the lag phase and the peroxidation rate. The vitamin E content of LDL also did not change significantly. The results thus suggest that a daily dosage of 2.5 g n-3 fatty acids does not enhance LDL susceptibility to oxidation, while retaining its hypotriacylglycerolemic effect.
Oxidative stress can produce profound alterations to cellular membrane lipids, impairing cell metabolism and viability. This phenomenon, previously observed in haemodialysis patients, has been proposed as a significant factor in regard to haemodialysis-related shortened red blood cells (RBC) survival. In the present study, several parameters associated with oxidative stress were evaluated in a group of haemodialysis patients either receiving erythropoietin therapy (n = 12, mean erythropoietin dose 88 +/- 24 U/kg/week) or not receiving such therapy (n = 30), and in 38 controls. Malonyldialdehyde (MDA, nmol/ml), an end-product of lipid peroxidation, and RBC antioxidant systems were measured, including RBC alpha-tocopherol (RBC vitamin E, mg/l), RBC glutathione (GSH, nmol/mgHb), and RBC superoxide dismutase activity (SOD, U/mgHb). Plasma vitamin E concentrations were also evaluated. Finally, oral vitamin E supplementation (500 mg daily), an exogenous antioxidant, was administered for 6 months to seven patients from the dialysis group receiving erythropoietin while oxidative parameters were repeatedly evaluated and erythropoietin requirements monitored, in order to appreciate the therapeutic relevance of an antioxidant supplementation. An elevation of serum MDA was observed in all haemodialysis patients and a significant decrease in RBC vitamin E, despite normal serum vitamin E levels. Furthermore, the reduction in RBC vitamin E was more important in patients treated with erythropoietin. Vitamin E supplementation resulted in a significant increase in RBC vitamin E (from 0.3 +/- 0.1 to 1.2 +/- 0.2 mg/l of pellet) and a reduction in erythropoietin dose (from 93 +/- 24 to 74 +/- 26 U/kg/week) while maintaining stable haemoglobin concentrations. These results suggest that the oxidative stress could be one of the resistance factors to erythropoietin response in haemodialysis and that vitamin E supplementation could have a sparing effect on erythropoietin dosage requirement.
The present study was designed to test the biocompatibility of a new vitamin E-modified multi-layer membrane (CL-E filter), as well as its ability to protect against oxygen free radicals during hemodialysis (HD).
We investigated, both in vitro and in vivo, the bioreactivity of the filter with respect to the blood antioxidants and its ability to prevent lipoperoxidation. The effects on the leukocyte respiratory burst were also studied. Cuprammonium rayon was used as a comparison material (CL-S filter).
The in vitro results demonstrated that, under controlled conditions, CL-E is able to preserve blood antioxidants, and particularly vitamin E, from the spontaneous consumption observed in the incubation with CL-S filters and in control incubations. In accordance with this observation, the rate of the oxidative demolition of lipids either in plasma and red blood cells (RBC) or from rat brain homogenate decreased after the exposure to CL-E filters in comparison with the CL-S filter. Moreover, in the absence of any significant cytotoxic effects due to both the types of material studied, the production of oxygen free radicals and nitric oxide (NO) by leukocytes was higher after their in vitro exposure to CL-S, but was quite similar to that of the control leukocytes after exposure to CL-E. In vivo, a one-month treatment with the CL-E filter increased plasma vitamin E by 84.3% with respect to treatment with CL-S; this gain slightly decreased to 68.9% when CL-E treatment was prolonged to three months. In the RBC, vitamin E was found to have increased by 76.7% and 113.4% at one and three months, respectively. Plasma glutathione (GSH) levels determined at three months were significantly increased from 0.10 +/- 0.02 to 0.33 +/- 0.12 mumol/ml, while the erythrocyte GSH was only slightly increased. The leukocyte function estimated as responsiveness to soluble chemical stimuli in CL-S-treated patients was significantly improved both qualitatively and quantitatively after CL-E treatment. The presence of an increased number of mononuclear cells undergoing programmed cell death (apoptosis) in CL-S-treated patients (18.8 +/- 1.7% vs. a control value of 6.5 +/- 2.3%) as well as the apoptogenic effect of their plasma in vitro on U937 cells was significantly corrected after CL-E treatment (mean decrease in apoptotic mononuclear cells at 24 hours of culture, 25.5% and 27.1% at 1 and 3 months, respectively). The anti-apoptogenic effect of CL-E treatment showed a close dependence on the increase in vitamin E in the blood cell compartment.
This study suggests that this vitamin E-modified membrane can be considered a highly biocompatible material, the antioxidant properties of which can exert a site-specific and timely scavenging function against oxygen free radicals in synergy with a hypostimulatory action on the PMN respiratory burst.
The efficacy of combined therapy with recombinant human erythropoietin (rhEPO) and vitamin E versus rhEPO alone in the treatment of anemia was examined in children (n = 10, aged 15.2 +/- 3.2 years) on chronic hemodialysis at the restart of rhEPO therapy after a 4-week interval. The results confirmed that rhEPO induced oxidative stress of the red blood cells as observed during the first rhEPO therapy. Vitamin E (15 mg/kg per day per os) was introduced after 2 weeks of rhEPO monotherapy, when the signs of acute oxidative stress appeared. The level of oxidized glutathione (GSSG) increased from 8.9 +/- 3.1 to 26.7 +/- 5.7 nmol/g hemoglobin (Hb) by that time. After 2 weeks of simultaneous vitamin E treatment, there was a significant difference in GSSG values compared with rhEPO monotherapy (10.1 +/- 3.9 vs. 56.7 +/- 15.8 nmol/g Hb, P < 0.001). A considerable decrease was observed in the previously high ratio of GSSG/reduced glutathione (GSH), an indicator of oxidative stress, and the level of carboxyhemoglobin, indicating hemolysis. A significant increase in Hb and hematocrit (P < 0.01) was achieved within 2 weeks of starting the combined therapy, while similar results occurred only at the 8th and 5th weeks without vitamin E. Antioxidant vitamin E supplementation improved the therapeutic effect of rhEPO in patients with chronic renal failure on hemodialysis.
Renal failure patients require vitamin replacement therapy that addresses the specialized needs of renal failure. Four factors including restricted diet, uremic toxins, drug-nutrient interactions, and in ESRD, the dialysis process, affect the normal absorption, retention and activity of necessary micronutrients which support all aspects of carbohydrate, protein, lipid and nucleic acid metabolism. Studies have shown that the typical renal failure diet is low in B vitamins, that uremic factors affect folate and pyridoxine activities and that many B vitamins are lost on dialysis at a rate greater than are lost with normal urinary excretion. In addition, retention of vitamin A or inappropriately high supplementation of vitamin C may cause toxicities which exacerbate existing pathologies. Further, emerging research suggests some vitamins such as folic acid and pyridoxine, if provided in higher than normal amounts, may have an impact on reducing the risk of some aspects of renal cardiovascular disease. It is therefore important to supplement some vitamins, and use restraint in the supplementation of others. It is clear that renal failure patients, including predialysis, ESRD and transplant patients need specialized supplementation that meets the requirements of disease and its management.
Atherosclerotic cardiovascular disease is the leading cause of death in patients with end stage renal disease (ESRD) who have undergone dialysis treatment. The oxidation of low density lipoprotein (LDL) appears to be a crucial step in the pathogenesis of atherosclerosis. The increased oxidative stress and attendant increased oxidizability of lipoproteins, such as LDL could contribute to the accelerated atherosclerosis in dialysis patients. Since alpha-tocopherol (AT) is the major antioxidant in LDL, the aim of the present study was to test the effectiveness of RRR-AT supplementation (800 I.U. per day) for 12 weeks on the susceptibility of LDL to oxidation. The study subjects comprised patients with chronic renal failure on hemodialysis (HD), peritoneal dialysis (PD), and age and sex matched controls (C). Plasma fatty acids, lipoproteins and AT levels were measured in these subjects before and after supplementation. Also, LDL AT and oxidizability was studied. LDL was isolated by ultracentrifugation at baseline and after 12 weeks of supplementation, and subjected to a 5-h time course of copper catalyzed oxidation. Oxidation was measured by the formation of conjugated dienes (CD) and lipid peroxides (LP). Supplementation with AT did not alter the plasma lipid or lipoprotein profile of these subjects. Plasma lipid-standardized AT and LDL AT concentrations were not different among the groups at baseline. AT supplementation significantly increased plasma lipid-standardized AT (C=150%, HD=149%, PD=217%, P<0.001) and LDL AT concentrations (C=94%, HD=94%, PD=135%, P<0.003). AT enrichment of LDL resulted in a significant prolongation in conjugated diene lag phase in all groups (C=34%, HD=21%, PD=54%, P<0.02). Lipid peroxide lag phase was also increased significantly in C (27%,) and PD (40%) groups after AT supplementation (P<0.01). There was a significant positive correlation between plasma lipid standardized AT and lag phase (r=0. 54, P=0.0003). Overall, AT decreased the susceptibility of LDL to oxidation in patients with chronic renal failure but the benefit appears to be greater in patients on PD. Therefore, AT supplementation may also provide a measure of protection against CAD in patients with chronic renal failure on dialysis therapy.
Intravenous iron (Fe) and recombinant human erythropoietin (rHuEPO) are routine treatments in the management of anemia in patients with chronic renal failure. We investigated the oxidative stress acutely induced by these therapies and whether pretreatment with oral melatonin (MEL) would have a beneficial effect. Nine patients (four women) were studied within 1 month of entering a chronic hemodialysis program in the interdialytic period. Plasma malondialdehyde (MDA), red blood cell glutathione (GSH), and catalase (CAT) activity were measured in blood samples obtained before (baseline) and 1, 3, and 24 hours after the administration of Fe (100 mg of Fe saccharate intravenously over 1 hour) or rHuEPO (4,000 U intravenously). One hour before these treatments, patients were administered a single oral dose of MEL (0.3 mg/kg) or placebo. Each patient was studied on four occasions, corresponding to studies performed using either placebo or MEL in association with intravenous Fe and rHuEPO administration. Baseline data showed increased oxidative stress in patients with end-stage renal failure. Increments in oxidative stress induced by Fe were more pronounced at the end of the administration: MDA, baseline, 0.74 ± 0.09 nmol/mL; 1 hour, 1.50 ± 0.28 nmol/mL (P < 0.001); GSH, baseline, 2.51 ± 0.34 nmol/mg of hemoglobin (Hb); 1 hour, 1.66 ± 0.01 nmol/mg Hb (P < 0.001); and CAT activity, baseline, 27.0 ± 5.7 κ/mg Hb; 1 hour, 23.3 ± 4.2 κ/mg Hb (P < 0.001). rHuEPO-induced increments in oxidative stress were more pronounced (P < 0.001) at 3 hours (MDA, 1.24 ± 0.34 nmol/mL; GSH, 1.52 ± 0.23 nmol/mg Hb; CAT activity, 18.0 ± 3.1 κ/mg Hb). MEL administration prevented the changes induced by Fe and rHuEPO and had no adverse side effects. These studies show that intravenous Fe and rHuEPO in doses commonly used to treat anemia in chronic hemodialysis patients acutely generate significant oxidative stress. Oral MEL prevents such oxidative stress and may be of clinical use.
This study focuses on the extent of oxidative DNA damage in peripheral blood leukocytes of chronic peritoneal dialysis (CPD) patients. 8-Hydroxy 2'-deoxyguanosine (8-OHdG) contents in peripheral leukocyte DNA were measured by an HPLC-electrochemical detection method in 24 age- and sex-matched healthy subjects, 22 nondialyzed patients with advanced renal failure, and 42 CPD patients. Mean 8-OHdG content was the highest in CPD patients, followed by the nondialyzed patients, and then by the healthy subjects (19.4 versus 11.9 versus 8.3/10(6) dG; ANOVA P < 0.001). In nondialyzed subjects, peripheral leukocyte 8-OHdG contents inversely correlated with renal creatinine clearance (r = -0.772; P < 0.001). Deficiency of blood antioxidants in CPD and nondialyzed patients was expressed by the lower plasma levels of ascorbate, cholesterol-standardized alpha-tocopherol and whole-blood reduced glutathione, and the higher levels of whole-blood oxidized glutathione as compared with healthy subjects (ANOVA P < 0.05). Mean serum ferritin and iron levels and transferrin saturation were higher in the CPD patients than those in the nondialyzed patients and controls (ANOVA P < 0.05). Flow cytometric analyses of intracellular reactive oxygen species production of peripheral leukocytes showed that spontaneous production by granulocytes, as well as phorbol-12-myristate-13-acetate (PMA)-induced production by granulocytes, lymphocytes and monocytes, were the highest from CPD patients, followed by nondialyzed patients, and then by the healthy subjects (ANOVA P < 0.05). Forward stepwise multiple regression disclosed that uremia, PD treatment, spontaneous and PMA-induced reactive oxygen species production in leukocytes, and serum iron were the independent determinants of peripheral leukocyte 8-OHdG content (R(2) = 0.769; P < 0.001). In conclusion, profound increased 8-OHdG levels in peripheral leukocyte DNA occur in the course of chronic renal failure, gradually increase with its progression, and are further exacerbated by PD treatment.
Background/aim:
Oxidative damage has been suggested to play a key role in accelerated atherosclerosis and to be involved in cardiovascular disease (CVD) of dialyzed patients who are at risk of increased oxidative stress. The purpose of the present study was to examine the relationship between the severity of CVD and some markers of oxidative stress and antioxidant activity in our hemodialyzed (HD) and peritoneal dialysis (PD) patients.
Methods:
Plasma reactive oxygen metabolites, malondialdehyde and 4-hydroxynonenal (MDA-4HNE), thiols, alpha-tocopherol, and total antioxidant status (TAS) were measured in 55 HD and in 16 PD patients. CVD was considered as the result of variably combined cardiac, cerebral, and vascular pathologies which were scored and grouped in a single CVD index and analyzed with respect to the markers of the oxidative status. 16 normal subjects served as controls.
Results:
All patients showed evidence of increased oxidative stress which was more severe in HD than in PD patients and which was exacerbated by HD. When cardiac, cerebral, and vascular diseases were analyzed separately, plasma MDA-4HNE and TAS were significantly higher in more severely affected HD patients, but not in PD patients. In HD patients the CVD index was directly correlated with both MDA-4HNE and TAS (r = 0.42, p < 0.01; r = 0.39, p < 0.01) and inversely correlated with alpha-tocopherol (r = -0.32, p < 0.05). MDA-4HNE and TAS were directly correlated in HD patients and inversely correlated in control subjects.
Conclusions:
Our data show that, in spite of increased antioxidant defense, there is a relationship between the degree of lipid peroxidation and the severity of CVD in HD patients. Moreover, these data underscore the utility of MDA-4HNE, alpha-tocopherol, and TAS in the evaluation of cardiovascular disease.
Although the role of reactive oxygen species (ROS) in chronic renal failure (CRF) is not definitely demonstrated, a consistent number of observations has provided evidence for the presence of oxidative stress in uremic patients undergoing maintenance dialysis. In order to investigate this hypothesis further and to understand the role of antioxidant supplementation, peripheral blood lymphocytes were taken from 36 dialysis patients before and after Vitamin E supplementation in a dosage of 600 mg per day (2x300 mg) for 14 weeks and examined in the alkaline Comet assay for DNA strand breakage. The results were also compared with those of 36 controls with comparable age, sex, and smoking habits, and with no history of renal disease. The DNA breakage observed in the lymphocytes of patients before Vitamin E supplementation was significantly higher than in the controls (P<0.001) but a clear protective effect of Vitamin E supplementation were observed after 14 weeks of therapy.
This study investigated the supplementation with vitamin C or/and E on the antioxidant system in hemodialysis patients. Thirty-eight hemodialysis patients (27 males and 11 females) with the average of 60 years old were divided into four groups: placebo (400 mg starch/time), vitamin C (400 mg/time)-, vitamin E (400 mg d,l- alpha-tocopheryl acetate/time)-, and vitamin C (400 mg/time) + E (400 mg d,l- alpha-tocopheryl acetate/time)-supplemented groups for 6-week supplementation. The patients orally received three capsules of placebo or antioxidant(s) three times a week after finishing hemodialysis. Thirty-six healthy subjects (22 males and 14 females) with the average of 58 years old were recruited as the control group. Hemodialysis patients significantly decreased plasma vitamin C by 32%, erythrocyte glutathione by 26%, and plasma total antioxidant status by 9%, but increased plasma lipid peroxide levels by 102% compared with the control group at the baseline. The levels of plasma vitamin C and total antioxidant status significantly decreased by 24% and 18%, respectively, from the post-dialysate compared with those from the pre-dialysate. At week 6, vitamin C + E-supplemented group significantly increased plasma vitamin C and E, erythrocyte glutathione, and plasma antioxidant status, and inhibited plasma lipid peroxides compared with placebo group. Additionally, vitamin C + E-supplemented group had higher plasma vitamin C, vitamin E, and total antioxidant status, and lower plasma lipid peroxides than placebo group even at least 2 weeks after the termination of the supplements. Therefore, antioxidant vitamin supplements could improve antioxidant status and decrease lipid peroxides of hemodialysis patients.
We reported earlier that production of Cu/Zn-superoxide dismutase (SOD) increases markedly in hemodialysis patients but not in non-dialyzed chronic renal failure (CRF) patients. In this study, we compared the antioxidant effects of oral vitamin E supplementation (VE-PO) and vitamin E coating of a dialyzer (VE-BMD) by measuring increased Cu/Zn-SOD in hemodialysis patients.
31 hemodialysis patients were divided into two groups: 16 hemodialysis patients underwent usual dialysis with vitamin E supplementation 600 mg/day while 15 others were dialyzed using vitamin E-coated membrane for 6 months. Total plasma SOD activity was determined by NBT method, plasma Cu/Zn-SOD contents by ELISA and Cu/Zn-SOD mRNA in leukocytes by RT-PCR.
VE-PO and VE-BMD showed almost comparable effects on Cu/Zn-SOD contents and its mRNA levels in hemodialysis patients. VE-PO resulted in a progressive decrease of Cu/Zn-SOD content (p < 0.001). A comparable progressive decrease was observed also in VE-BMD (p < 0.0001). Both VE-PO and VE-BMD resulted in a progressive decrease of Cu/Zn-SOD mRNA (p < 0.01), which reached the level of non-dialyzed CRF patients.
During the past decade, hemodialysis (HD)-induced inflammation has been linked to the development of long-term morbidity in end-stage renal disease (ESRD) patients on regular renal replacement therapy. Because interleukins and anaphylatoxins produced during HD sessions are potent activators for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, an example of an enzyme that is responsible for overproduction of reactive oxygen species (ROS), this may constitute a link between leukocyte activation and cell or organ toxicity. Oxidative stress, which results from an imbalance between oxidant production and antioxidant defense mechanisms, has been documented in ESRD patients using lipid and/or protein oxidative markers.
Characterization of HD-induced oxidative stress has included identification of potential activators for NADPH oxidase. Uremia per se could prime phagocyte oxidative burst. HD, far from improving the oxidative status, results in an enhancement of ROS owing to hemoincompatibility of the dialysis system, hemoreactivity of the membrane, and trace amounts of endotoxins in the dialysate. In addition, the HD process is associated with an impairment in antioxidant mechanisms. The resulting oxidative stress has been implicated in long-term complications including anemia, amyloidosis, accelerated atherosclerosis, and malnutrition. Prevention of oxidative stress in HD might focus on improving the hemocompatibility of the dialysis system, supplementation of deficient patients with antioxidants, and modulation of NADPH oxidase by pharmacologic approaches.
In a prospective study of 5,004 women in Guernsey, plasma samples were collected and stored. Retinol, beta-carotene and vitamin E levels were later measured in the samples from 39 women who subsequently developed breast cancer and from 78 controls who did not develop cancer. Plasma retinol levels were not related to the risk of breast cancer, mean levels among cases and controls being 485 micrograms l-1 and 479 micrograms l-1 respectively. Plasma vitamin E levels showed a clear association, low levels being associated with a significantly higher risk of cancer. The mean vitamin E levels among cases and controls were 4.7 mg l-1 and 6.0 mg l-1 respectively (P less than 0.025), and the risk of breast cancer in women with vitamin E levels in the lowest quintile was about 5-times higher than the risk for women with levels in the highest quintile (P less than 0.01). beta-carotene levels showed a tendency to be lower in women who developed cancer than in controls (36 micrograms l-1 among cases compared with 50 micrograms l-1 among controls) but the difference was not statistically significant.
Quenching of singlet molecular oxygen () by α-tocopherol (I) involves the hydroxy function of the chromanol ring of I. In phosphatidylcholine (PC) uni- and multilamellar vesicles this structural element of I is localized at the interface polar headgroup/hydrophobic core. A dielectric constant of ϵ ∼ 25 was determined for this special region of the PC bilayer. The ratio kQ/kR of rate constants of quenching processes (kQ) and irreversible reactions (kR) of I with increases with decreasing polarity of the solvent. In ethanolic solutions where ϵ = 25.5, kQ/kR is about 40. Extrapolation of these results to phospholipid bilayers suggests that at the nearness of the ester carbonyl oxygen of the PC fatty acid moieties, α-tocopherol can deactivate approximately 40 molecules before being destroyed. It is concluded that in vivo, one may expect to find a higher kQ/kR ratio if the chromanol ring of I hides within the more hydrophobic interiors of the membrane surface peptides.
Recently, we have demonstrated that hemodialysis (HD) patients have higher serum and lower erythrocyte concentrations of vitamin E than controls. It is known that transfer of vitamin E from serum to erythrocyte is mostly due to high-density lipoproteins (HDL). For a better definition of the pattern of distribution of vitamin E in HD patients, we have dosed the amount of vitamin bound to serum HDL fraction. In 8 patients and in 8 healthy controls, we have determined the concentration of serum erythrocyte and HDL-bound vitamin E. The latest was obtained on an ultracentrifuged HDL fraction. HDL fractions from HD patients have been found to contain larger amounts of vitamin E than controls. The previously described higher serum and lower erythrocyte concentrations of vitamin E in HD patients have been confirmed in the study. The deficit of vitamin E in the membranes of erythrocytes from HD patients has been shown to be the result of increased consumption of the vitamin in the erythrocyte membranes, where it represents the major antioxidant agent. However, the finding of increased amounts of vitamin bound to HDL in HD patients suggests that the transfer of the vitamin to the erythrocyte membranes may also be defective.
A neutral polymer precipitation procedure for fractionation of human plasma lipoproteins is described. The method was also tested preliminarily for fractionation of rat plasma lipoproteins. Polyethylene glycol-6000 (PEG-6000) at a concentration of about 12% and at pH 7.9 precipitated human plasma very low density (VLDL) and low-density (LDL) lipoproteins completely. Precipitation was independent of time and temperature. VLDL and LDL could not be precipitated separately. Polyethylene glycol-6000 precipitation can be used for rapid determination of high-density (HDL) lipids and of the ratio of HDL to LDL lipids.
The responses of plasma tocopherols to dietary tocopherols were studied for 21 human subjects. Ten male and 11 female human subjects, aged 40 to 60, were fed 25% fat calorie diets for 40 days followed by a second 40 day feeding period of 35% fat calorie diets. The average α tocopherol content of the 25% fat calorie 2,000 kcal diets as analyzed was 7.6 mg and of the 35% fat calorie 2,800 kcal diets was 12.9 mg. Plasma tocopherol concentrations were determined at the beginning of the study and again at the termination of each of the two 40 day dietary periods. Average plasma tocopherols for females for these 3 samplings in order were 8.9, 7.6, and 9.4 μg α tocopherol/g of plasma and 1.0, 0.6, and 0.7 μg γ tocopherol/g of plasma. Average plasma tocopherol values for the same samplings for males were 6.3, 5.3, and 7.0 μg α tocopherol/g of plasma and 0.8, 0.6, and 0.8 μg γ tocopherol/g of plasma. For females, correlations were significant between plasma α tocopherol and total cholesterol for all 3 samplings and between plasma α tocopherol and triglyceride at the end of the second dietary period. For males, correlations were significant between plasma α tocopherol and triglyceride at the end of both dietary periods, but not at the prestudy sampling.
The relation of lipoprotein tocopherol levels to red blood cell (RBC) tocopherol was investigated in 81 healthy children, comprising 44 males and 37 females, using a new technique for separation of individual lipoprotein fractions. 1. In children there were no age and sex differences in tocopherol contents among individual lipoprotein fractions. The tocopherol content of high density lipoprotein (HDL) was slightly higher than that of low density lipoprotein (LDL), but this difference was not statistically significant. 2. The tocopherol content of HDL fractions was closely correlated with RBC tocopherol concentration, but there was no relationship in tocopherol levels between RBC and LDL and between RBC and very low density lipoprotein (VLDL). 3. There were no age and sex differences in contents of total cholesterol (T-ch), triglycerides (TG), phospholipids (PL), total lipids, HDL-cholesterol, LDL or VLDL in children.
In eight study populations in which the medians of total plasma cholesterol did not differ significantly (mean 5.8 mM, p greater than 0.05) and therefore did not correlate with the IHD mortality (r2 = 0.05), the median of absolute plasma level of vitamin E (alpha-tocopherol) was inversely related to the IHD mortality (r2 = 0.55; p = 0.003). Vitamin A behaved similarly (r2 = 0.51; p = 0.046). The absolute levels of vitamins E and A together with cholesterol predicted (by multiple regression analysis) the IHD mortality of these eight populations fairly well (r2 = 0.81; p = 0.06). Considering all 12 study populations analyzed thus far, total plasma cholesterol correlated with the IHD mortality directly as expected (r2 = 0.51; p less than 0.01), but the median of the plasma alpha-tocopherol individually standardized for cholesterol and triglycerides (220 mg/dL + 110 mg/dL, respectively) maintained a strong inverse association with the IHD mortality (r2 = 0.49; p = 0.01). In the partial regression analysis, lipid-standardized vitamin E exhibited an even stronger inverse correlation with IHD mortality (r2 = 0.69; p less than 0.001). Again, vitamin A behaved similarly to vitamin E, that is, after lipid-standardization of individuals (r2 = 0.33; p = 0.07), as well as in the cholesterol-independent partial regression analysis (r2 = 0.74; p less than 0.001). Both vitamins may act singularly, for after lipid-standardization they vary de facto independently (rs = 0.012) in individuals. The combination of vitamins E and A as obtained by multiple partial regression predicted the actual IHD mortality to a large extent (r2 = 0.89; p less than 0.001), whereas the three-variable prediction model, with the median of total cholesterol and of individually lipid-standardized vitamins E and A, fit the actual IHD mortality of these 12 populations almost completely (r2 = 0.94; p less than 0.001). In conclusion, the plasma status of vitamins E and A are important, hitherto underrated risk factors of IHD, which may act independently, but can, if combined, predict at least 53% of the cross-cultural differences of IHD mortality. After inclusion of total cholesterol into a multivariate model, up to 94% of the IHD mortality can be predicted. The present epidemiological data are in agreement with the hypothesis that these vitamins have physiological functions in the protection of lipoproteins against peroxidation and atherogenic apo-B modifications, respectively, but that does not exclude additional beneficial effects of vitamin E and A in the arterial wall.
The present study was undertaken to clarify the low erythrocyte (RBC) alpha-tocopherol (TOC) concentrations in patients on maintenance hemodialysis (HD) using in vivo and in vitro experiments. 15 age-matched male controls and HD patients were evaluated. The experimental designs and the results were as follows: 1) Changes in fasting stage; TOC levels of plasma, high density lipoproteins (HDL) and RBC, especially RBC, were lower in HD-patients than in controls. The ratio of RBC to plasma and HDL showed more significant changes between HD-patients and controls. In controls, RBC-TOC was noted to have a positive correlation with HDL-TOC and a negative correlation with non HDL-(plasma--HDL)-TOC, whereas a reverse correlation was observed in HD-patients. 2) In vivo experiments: Each 7 of HD-patients and controls were orally given TOC 600 mg after meal at early morning; the blood was sampled at 0, 3, 6, 10 and 24 hr. Poor increase of RBC-TOC in HD-patients was observed. In contrast, HDL-TOC was significantly higher at all measurement times than in controls. The change of plasma-TOC was similar to that of non HDL-TOC. 3) In vitro experiment:RBC from patients or controls showing various concentrations of RBC-TOC and plasma from controls were incubated at 37 degrees C or 4 degrees C. The inactivated plasma from controls was prepared by incubation at 56 degrees C, 30 min or by supplement of 2 mM parachloromerucuric benzonic sulfonate. The ratio of RBC and plasma was at 2:3 close to physiological conditions. No difference between patient and control RBCs as an acceptor of TOC and no appreciable transfer of TOC between RBC to plasma at 4 degrees C were observed. When RBC-TOC was low, transfer volume of TOC from plasma to RBC was increased and TOC was supplied from mainly non HDL fractions; in contrast, when it was high, the main source of TOC was due to the transfer from HDL fractions which was reduced when lecithin: cholesterol acyltransferase (LCAT) reaction was inhibited. From above in vivo and in vitro studies, it was concluded that low levels of RBC-TOC in HD-patients may be due to an insufficiency of TOC transfer from HDL fractions affected by low LCAT activity.
Comparison of lipid, lipoprotein and apolipoprotein levels was made between 3 groups: continuous ambulatory peritoneal dialysis patients (n = 5); haemodialysis patients (n = 15) and normals (n = 31). Continuous ambulatory peritoneal dialysis (CAPD) patients showed significantly elevated total cholesterol, low density lipoprotein (LDL)-cholesterol and apolipoprotein B (apo B) levels compared with haemodialysis and normal groups. Both CAPD and haemodialysis (HD) showed reduced levels of high density lipoprotein (HDL)-cholesterol and apolipoprotein A-I (apo A-I). Measurement of apo A-I and apo B in dialysate during a 6 h CAPD session indicated significant losses of apo A-I to dialysate with negligible losses of apo B. Grossly elevated apo B and reduced apo A-I indicates that CAPD patients are at increased risk of coronary heart disease and that their risk is probably greater than for haemodialysis patients.
Premature coronary artery disease is believed to be a major cause of death in patients undergoing long-term haemodialysis. We investigated the effects of chronic maintenance haemodialysis on lipid, lipoprotein and apolipoprotein levels of 42 black patients with chronic renal failure and compared them with those of 40 age- and sex-matched black controls to determine the changes in the lipoprotein profile and their possible contributions to increased risk of coronary heart disease in these patients. There were increases in triglyceride levels and in total/high density lipoprotein cholesterol ratios and decreases in high density lipoprotein cholesterol, in LDL cholesterol, in apolipoprotein AI and in apolipoprotein AII in haemodialysis patients in comparison to controls. No significant differences were observed in any of the lipid, lipoprotein and apolipoprotein levels between male and female patients and between patients receiving anti-hypertensive therapy and those who were not. Our findings suggest that haemodialysis and/or events associated with maintenance dialysis may contribute to unfavourable variations in lipoprotein metabolism and, in turn, the increased mortality from coronary artery disease in this patient population.
We have recently described that in the erythrocytes from uremic patients on chronic hemodialysis, the pentose-phosphate shunt is defective, the membrane concentrations of malonyldialdehyde, resulting from peroxidation of polyunsaturated fatty acids in the membranes themselves, are increased, and the concentrations of vitamin E, an antioxidizing agent, are reduced. In the present study we have analyzed these same metabolic aspects in a group of uremic patients in continuous ambulatory peritoneal dialysis. We have found normal function of the pentose-phosphate shunt, slightly elevated concentrations of malonyldialdehyde compared to controls, but definitely lower than in chronic hemodialysis patients, and higher tocopherol concentrations than in both controls and chronic hemodialysis patients.
Plasma vitamin E levels and the ascorbate cyanide test were assessed in 15 chronic hemodialysis (HD) patients (group A) exposed to persistently elevated chloramine levels in the dialysis water. The vitamin E levels in these patients, who had evidence of oxidant induced hemolytic anemia, were compared to 15 chronic HD patients exposed to low chloramine levels (group B) and 17 controls (group C). Vitamin E levels were found to be significantly lower in group A than in either groups B or C (p less than 0.001). Within group A, levels were lower in those patients who had a positive ascorbate cyanide test (p less than 0.05). Upon removal of chloramines from the dialysis water, vitamin E levels in group A were no longer significantly different from those found in groups B or C.
In these studies on the human hematopoietic system, it has been found that tocopherol levels in plasma and erythrocytes vary by a factor of approximately ten, depending upon the quantity of tocopherol ingested. The level of tocopherol in plasma largely determines the tocopherol level in the red blood cells. The distribution of vitamin E in plasma lipoproteins appears to be variable in normal human subjects, and this variability is further increased by the ingestion of large amounts of the vitamin. Both normal and tocopherol deficient red blood cells take up vitamin E from tocopherol rich plasma lipoproteins, and the relative ability to effect this transfer is HDL > LDL > VLDL plus chylomicrons. The same relative ability of lipoprotein fractions to accept tocopherol was observed when the incubation experiments were carried out with tocopherol rich erythrocytes and normal plasma lipoprotein fractions.
All the factors studied that affect the total lipid content of the serum lipoproteins influence the levels of α tocopherol in the serum at a given level of α tocopherol intake. Thus there is a tendency for the serum α tocopherol to rise and fall in proportion to the amounts of cholesterol, phospholipid, and triglycerides present in the serum. Physiological, pharmacological, genetic, and dietary factors that change the level of the serum lipids produce a concomitant change in the level of α tocopherol in the serum. This makes previous conclusions on the state of tocopherol nutrition from serum tocopherol levels inadequate, except in those cases where the level of blood lipids was in the medium range. It is suggested that serum tocopherol be related to serum total lipids, and that all future records of serum tocopherol levels also record the level of serum total lipids, simultaneously: for example, 0.62/630 mg, which means 0.62 mg tocopherol and 630 mg total lipids in 100 ml of serum. Examination of data from children and adults on tocopherol deficient diets produced a ratio of less than 0.8 mg serum tocopherol to 1 g total lipids, if the data on serum cholesterol levels are extrapolated. All subjects supplemented with tocopherol and practically all of 76 St. Louis University Hospital patients, taken at random, had a ratio of above 0.8. It is noteworthy that data from newborn full term infants who had low levels of tocopherol in their serum produced a ratio of 0.8 or slightly higher; this indicates that sufficient tocopherol can cross the placenta when the mother's tocopherol intake is adequate. All adult subjects who in a previous study had been fed a low tocopherol diet for several years had tocopherol:total lipid ratios of less than 0.8. After supplementation with tocopherol, all these subjects had tocopherol:total lipid ratios of above 0.8. Since the tocopherols in the blood are only a tiny part of the total tocopherols in the body, additional studies are required to relate tissue tocopherol to vitamin E nutrition. The concept that changes in serum lipid levels can change α tocopherol levels may also be applicable to other fat soluble vitamins and to fat soluble pharmacological products.
Some metabolic alterations of the pentose-phosphate shunt can increase susceptibility to red blood cell (RBC) lipid peroxidation in uraemic patients on maintenance haemodialysis. We investigated this phenomenon in 19 uraemic patients undergoing chronic haemodialysis by determining RBC malonyldialdehyde (MDA), a secondary product of lipid peroxidation and plasma and RBC tocopherols, which are powerful antioxidants. Evidence of RBC membrane lipid peroxidation was demonstrated by an increase of RBC MDA. RBC tocopherols were significantly decreased because of enhanced antioxidant activity. No significant variations of these parameters were found before and after dialysis.
The detection and measurement of lipid oxidation in biological systems and some biologic effects of this oxidation are reviewed. The role of lipid oxidation in the process of photocarcinogenesis and the protective effect of antioxidants against this process also are discussed. The mechanism of such protection is unknown and studies directed at elucidating the mechanism of antioxidant effect in photocarcinogenesis and in some other pathological conditons believed to involve lipid oxidation are needed. In addition to this, epoxidation of lipids observed in monolayer studies requires further investigation, particularly in the presence of some other unsaturated molecules. The possible significance of such a study--particularly in the presence of polycyclic aromatic hydrocarbon carcinogens, where formation of epoxides is generally accepted as active intermediates--is also discussed. In addition, present knowledge on the role of lipid peroxides in the destruction of proteins and biomembranes, in chemically induced toxicity and in generation of singlet oxygen is presented.