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ABSTRACT: Although increased oxidative stress and inflammation are highly prevalent in chronic kidney disease (CKD), few studies have investigated whether oral antioxidant therapy can alter markers of inflammation or oxidative stress in patients with CKD. The purpose of this study was to investigate whether a combination of mixed tocopherols and alpha lipoic acid (ALA) would alter biomarkers of oxidative stress and inflammation in subjects with stage 3 to 4 CKD.
This was a prospective, randomized, double-blind, placebo-controlled pilot trial. In all, 62 subjects were enrolled and were randomly assigned to receive a combination of mixed tocopherols 666 IU/day, in addition to ALA 600 mg/day, or their matching placebos for a total of 8 weeks. Plasma F(2)-isoprostane and protein thiol concentration were measured as biomarkers of oxidative stress, and C-reactive protein and interleukin-6 concentration as biomarkers of systemic inflammation.
There were no significant differences in demographics, diabetic status, or estimated glomerular filtration rate between study treatment and placebo groups at baseline. Of the 62 randomized subjects, 58 (93%) completed the study protocol. After 2 months of treatment, there were no significant changes in the concentrations of F(2)-isoprostanes, protein thiols, C-reactive protein, and interleukin-6 with respect to treatment with mixed tocopherols and ALA as compared with matching placebos, whether analyzed as intention to treat or as treated. Diabetic status and baseline body mass index did not influence the results.
Combination of oral mixed tocopherols and ALA treatment for 2 months does not influence biomarkers of oxidative stress and inflammation in patients with stage 3 to 4 CKD.
Journal of Renal Nutrition 12/2010; 21(3):211-8. · 1.57 Impact Factor
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ABSTRACT: Increased cardiovascular risk in hemodialysis patients may be related to augmented oxidative stress and inflammation, for which no proven beneficial therapies are available.
We examined the effects of gamma tocopherol and docosahexaenoic acid (DHA) administration on inflammation and oxidative stress markers in hemodialysis patients in a randomized, double-blinded, placebo-controlled, clinical trial. Active treatment consisted of capsules containing gamma tocopherol (308 mg) and DHA (800 mg).
Outpatient dialysis center.
Seventy maintenance hemodialysis patients.
Plasma concentrations of interleukin-6 (IL-6) and protein carbonyl content were determined by enzyme-linked immunosorbant assay. C-reactive protein was measured by nephelometry. The F(2) isoprostanes were measured by gas chromatography-mass spectrometry. Erythrocyte DHA content was measured by gas chromatography.
Sixty-three patients were enrolled, and 57 completed the study. No serious adverse events were attributed to either active treatment or placebo. In the treatment group, but not in the placebo group, there were significant decreases in IL-6 (21.4 +/- 3.5 to 16.8 +/- 3.7 pg/mL), white blood cell (WBC) count (7.4 +/- 0.3 to 6.9 +/- 0.4 10(3)/microL), and neutrophil fraction of WBCs (4.8 +/- 0.3 to 4.4 +/- 0.3 10(3)/microL), at P < .05 for all. There were no significant changes in plasma concentrations of CRP, F(2) isoprostanes, or carbonyls in either group.
Thus, gamma tocopherol and DHA are well-tolerated and reduce selected biomarkers of inflammation in hemodialysis patients. Larger randomized, clinical trials will be required to determine if gamma tocopherol and DHA can reduce cardiovascular complications in hemodialysis patients.
Journal of Renal Nutrition 09/2007; 17(5):296-304. · 1.57 Impact Factor
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ABSTRACT: The uremic syndrome remains poorly understood despite the widespread availability of dialysis for almost four decades. To date, assessment of the biologic activity of uremic toxins has focused primarily on in vitro effects, rather than on specific biochemical pathways or enzymatic activity in vivo. The activity of cytochrome P450 (CYP) 3A4, the most important enzyme in human drug metabolism, is decreased in uremia. The purpose of this study was to assess the effect of hemodialysis and hence varying concentrations of uremic toxins on CYP3A4 activity using the 14C-erythromycin breath test and the traditional phenotypic trait measure, 20-min 14CO2 flux. CYP3A4 activity increased by 27% postdialysis (P = 0.002 compared with predialysis) and was significantly inversely related to plasma blood urea nitrogen concentration (rs= -0.50, P = 0.012), but not to several middle molecules. This is the first study in humans characterizing uremia as a state in which hepatic CYP3A4 activity is acutely improved by hemodialysis.
Journal of the American Society of Nephrology 10/2006; 17(9):2363-7. · 9.66 Impact Factor
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Mona Boaz,
Luigi Iuliano,
Jonathan Himmelfarb,
Zipora Matas,
Fausta Micheletta, Ellen McMonagle,
Victoria Friedman,
Silvia Natoli,
Gabriella Gvirtz,
Alexander Biro,
Shmuel Smetana,
Gideon Sabo,
Uzi Gafter,
Talia Weinstein
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ABSTRACT: Oxysterols are markers of oxidative stress, levels of which have not yet been reported in hemodialysis (HD) patients. This study was designed to compare levels of the oxysterols 7-ketocholesterol (7KC) and 7beta-hydroxycholesterol (7betaOH) between a cohort of HD patients and healthy controls.
This nested cross-sectional study reflects baseline (pre-intervention) values for markers of oxidative stress, inflammation and nutrition status in the 160-member vitamin E and carotid intima media thickness progression in end-stage renal disease (VIPER) cohort (age 64.1 +/- 8.8, 33.5% female). Age- and sex-matched healthy volunteers served as controls. Plasma oxysterols 7KC and 7betaOH were determined by isotope dilution gas chromatography/mass spectrometry.
Despite higher plasma alpha-tocopherol levels in HD patients than controls (36.0 +/- 9.3 vs. 31.8 +/- 8.4 micromol/l, p = 0.007), 7KC levels (9.8 +/- 6.9 vs. 5.9 +/- 2.8 nmol/mmol cholesterol, p < 0.0001) and 7betaOH levels (8.7 +/- 4.3 vs. 2.7 +/- 1.6 nmol/mmol cholesterol, p < 0.0001) were higher in HD patients. The oxysterol 7betaOH was significantly, inversely associated with prealbumin (r = -0.18, p = 0.03), though neither oxysterol was significantly associated with any other marker of oxidative stress, inflammation or nutrition status and did not discriminate for CVD in HD patients.
Elevated levels of the oxysterols 7KC and 7betaOH indicate that HD patients are in a state of oxidative stress compared to healthy controls. However, oxysterols 7KC and 7betaOH did not appear to contribute additional information about oxidative stress among HD patients.
Nephron Clinical Practice 01/2005; 100(4):c111-9. · 2.04 Impact Factor
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ABSTRACT: Patients with acute renal failure (ARF) experience a high mortality rate. Dysregulated inflammation and altered metabolism may increase oxidative stress in ARF patients. Thirty-eight patients who met the Program to Improve Care in Acute Renal Disease (PICARD) Study inclusion criteria underwent plasma protein oxidation and plasma cytokine measurements. For comparison, similar measurements were also performed in 21 critically ill patients without ARF, 28 patients with ESRD, and 49 healthy subjects. Plasma protein thiol oxidation was measured by spectrophotometry. Plasma protein carbonyl content and cytokine concentrations were measured by ELISA. Plasma protein thiol oxidation and carbonyl content were markedly different in ARF patients compared with healthy subjects, ESRD patients, and critically ill patients (P < 0.001 in all cases). There were significant but less marked differences in plasma protein oxidation between ESRD patients and critically ill patients compared with healthy subjects. Plasma protein thiol oxidation in ARF patients improved with dialysis (P < 0.001); however, there was significant plasma oxidant reaccumulation during the interdialytic period (P < 0.001) not due to rebound equilibration of compartmentalized solutes. Plasma proinflammatory cytokine levels were significantly higher (P < 0.05) in ARF patients and critically ill patients than in healthy subjects. Plasma protein oxidation is markedly increased in ARF patients compared with healthy subjects, ESRD patients, and critically ill patients. Increased oxidative stress may be an important target for nutritional and pharmacologic therapy in ARF patients.
Journal of the American Society of Nephrology 10/2004; 15(9):2449-56. · 9.66 Impact Factor
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ABSTRACT: Chronic inflammation and oxidative stress are highly prevalent in patients with chronic kidney disease and end-stage renal disease (ESRD). These conditions contribute to high mortality rates associated with cardiovascular disease, the leading cause of death in this patient population. To our knowledge, no prospective studies have examined how initiation of maintenance hemodialysis (MHD) affects biomarkers of inflammation and oxidative stress status.
This was a prospective cohort study evaluating time-dependent changes in C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-10 (IL-10), and protein carbonyl content before and after initiation of MHD over a 12-month period. Fifty incident hemodialysis patients [57.6 +/- 17.2 years, 60% male, 38% Caucasians, 32% insulin-dependent diabetes mellitus (IDDM) were studied, with 50 healthy subjects for comparison. The study variables were assessed before the initial outpatient hemodialysis treatment, and every 3 months thereafter for 12 months.
At baseline, CRP, IL-6, and carbonyl content levels were significantly higher in MHD patients compared with healthy subjects (P < 0.001 for each). After initiation of MHD, there were no significant changes in any of the study variables. Patients who initiated MHD with the highest levels of all the study variables had a significant decrease over the next year, but the variables were still higher than normal at the end of the 12-month study period.
Our data show that initiation of MHD does not have significant influence on plasma concentrations of CRP, IL-6, and IL-10, as well as plasma protein carbonyl content. These findings suggest that MHD is ineffective in controlling inflammation and oxidative stress in uremia.
Kidney International 07/2004; 65(6):2371-9. · 6.61 Impact Factor
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ABSTRACT: The prevalence of increased oxidative stress and acute-phase inflammation in patients with chronic kidney disease (CKD) has not been thoroughly investigated.
Biomarkers of oxidative stress and acute-phase inflammation were measured in a cohort of 60 patients with stage 3-5 CKD compared to a healthy subject cohort. Levels of oxidative stress and inflammation were also compared to estimated glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) formula.
All biomarkers of oxidative stress (plasma protein carbonyl group content, plasma free F2-isoprostane content, plasma protein reduced thiol content) and all markers of inflammation [C-reactive protein (CRP), interleukin-6 (IL-6)] differed significantly between CKD patients and healthy subjects. There was no significant relationship between estimated GFR and any oxidative stress or inflammation biomarker. CRP levels were higher in patients with known coronary vascular disease (CVD) and in patients not taking angiotensin II inhibitors. Plasma IL-6 levels were significantly higher in patients with known coronary vascular disease and lower in patients taking statins. Biomarkers of oxidative stress were significantly higher in patients with diabetes and hypercholesterolemia.
There is evidence of increased oxidative stress and acute-phase inflammation in patients with stage 3-5 chronic kidney disease compared to healthy subjects that does not closely correlate with estimates of GFR. Among CKD patients, inflammatory biomarkers correlate with known CVD and inversely correlate with the use of angiotensin II inhibitors and statins. A further increase in oxidative stress was noted in diabetic and hypercholesterolemic patients. Inflammation and oxidative stress may contribute to cardiovascular risk in CKD patients.
Kidney International 04/2004; 65(3):1009-16. · 6.61 Impact Factor
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ABSTRACT: Hypoalbuminemia is a powerful predictor of cardiovascular mortality in maintenance hemodialysis patients. Increased biomarkers of acute-phase inflammation and oxidative stress are highly prevalent and also correlate with cardiovascular morbidity and mortality. The extent to which hypoalbuminemia, biomarkers of inflammation, and biomarkers of oxidative stress are linked in this patient population is unknown. We hypothesized that a high proportion of hypoalbuminemic hemodialysis patients also would manifest increased levels of biomarkers of inflammation and oxidative stress.
We surveyed 600 maintenance hemodialysis patients and identified 18 severely hypoalbuminemic patients (serum albumin level < 3.2 g/dL [32 g/L]) without recent infection or hospitalization. We then identified 18 age-, race-, sex-, and diabetes-matched normoalbuminemic hemodialysis patients, as well as 18 age-, race-, sex-, and diabetes-matched healthy subjects, for cohort comparison. Measurements of plasma interleukin-6 (IL-6) levels, plasma protein reduced thiol content, plasma protein carbonyl content, and plasma free F2-isoprostane levels, as well as serum concentrations of C-reactive protein (CRP) and prealbumin, were performed for study purposes.
Levels of serum CRP, IL-6, plasma protein thiol oxidation, and protein carbonyl formation were significantly elevated in both hypoalbuminemic and normoalbuminemic hemodialysis patients compared with healthy subjects and also were significantly different in hypoalbuminemic maintenance dialysis patients compared with normoalbuminemic hemodialysis patients. Prealbumin levels were significantly lower in hypoalbuminemic hemodialysis patients than in other groups.
There is a high prevalence of inflammation and oxidative stress in the maintenance hemodialysis population. Levels of inflammatory and oxidative stress biomarkers are increased further in hypoalbuminemic compared with normoalbuminemic dialysis patients. Hypoalbuminemia, acute-phase inflammation, and oxidative stress may act synergistically to increase cardiovascular morbidity and mortality risk in maintenance hemodialysis patients.
American Journal of Kidney Diseases 09/2003; 42(2):286-94. · 5.43 Impact Factor
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ABSTRACT: The metabolism of alpha and gamma tocopherol, the major components of vitamin E, have not been studied in uremic patients. The major pathway of tocopherol metabolism is via phytyl side chain oxidation, leaving carboxyethyl-hydroxychromans (CEHC) as metabolites. Alpha and gamma CEHC are water soluble, renally excreted, with known potent anti-inflammatory and antioxidative properties.
We examined serum alpha and gamma tocopherol and respective CEHC concentrations in 15 healthy subjects and 15 chronic hemodialysis patients.
Serum alpha tocopherol levels were similar in hemodialysis patients (12.03 +/- 1.34 microg/mL) and healthy subjects (11.21 +/- 0.20 microg/mL), while serum gamma tocopherol levels were significantly greater in hemodialysis patients (3.17 +/- 0.37 microg/mL) compared to healthy subjects (1.08 +/- 0.06 microg/mL, P < 0.0001). Serum alpha and gamma CEHC levels were tenfold and sixfold higher in hemodialysis patients compared to healthy subjects, respectively (both P < 0.0001). Serum alpha and gamma tocopherol levels and CEHC metabolites were also measured after supplementation of alpha- or gamma-enriched mixed tocopherols in both hemodialysis patients and healthy subjects. Tocopherol administration resulted in modest or nonsignificant changes in serum tocopherol concentrations, while markedly increasing serum CEHC concentrations in both healthy subjects and hemodialysis patients. Hemodialysis resulted in no change in the serum alpha or gamma tocopherol concentrations while decreasing serum alpha CEHC and gamma CEHC levels by 63% and 53%, respectively (both P = 0.001 versus predialysis). Fourteen-day administration of gamma-enriched but not alpha tocopherols lowered median C-reactive protein (CRP) significantly in hemodialysis patients (4.4 to 2.1 mg/L, P < 0.02).
First, serum alpha and gamma CEHC accumulate in uremic patients compared to healthy subjects; second, supplementation with tocopherols dramatically increases serum CEHC levels in both healthy subjects and hemodialysis patients; and, finally, CEHC accumulation may mediate anti-inflammatory and antioxidative effects of tocopherols in hemodialysis patients.
Kidney International 09/2003; 64(3):978-91. · 6.61 Impact Factor
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ABSTRACT: Alpha and gamma tocopherol metabolism in healthy subjects and patients with end-stage renal disease.Background The metabolism of alpha and gamma tocopherol, the major components of vitamin E, have not been studied in uremic patients. The major pathway of tocopherol metabolism is via phytyl side chain oxidation, leaving carboxyethyl-hydroxychromans (CEHC) as metabolites. Alpha and gamma CEHC are water soluble, renally excreted, with known potent anti-inflammatory and antioxidative properties.
Kidney International 08/2003; 64(3):978-991. · 6.61 Impact Factor
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ABSTRACT: Plasma aminothiols, including homocysteine, cysteine, and glutathione, function as an important extracellular redox system. We examined the plasma aminothiol concentration and redox status in ten chronic hemodialysis patients compared to ten age-matched healthy subjects.
Plasma levels of reduced, free oxidized, and protein-bound homocysteine, cysteine, cysteinylglycine, and glutathione were determined using high-pressure liquid chromatography (HPLC).
Total plasma homocysteine, cysteine, and cysteinylglycine levels were significantly elevated in hemodialysis patients before dialysis compared to healthy subjects. Total plasma concentration of cysteine and homocysteine significantly decreased after hemodialysis. The ratio of free oxidized to free reduced homocysteine, cysteine, cysteinylglycine, and glutathione were each significantly elevated before dialysis compared to healthy subjects, and decreased significantly by the end of dialysis. The free oxidized to reduced ratio of cysteine and homocysteine were also significantly correlated with total plasma concentrations.
Plasma aminothiols are excessively oxidized in uremia, while the hemodialysis procedure is restorative of redox status. Oxidized aminothiols are candidate uremic toxins.
Kidney International 03/2002; 61(2):705-16. · 6.61 Impact Factor
