A study of plasmalogen as an index of oxidative stress in patients with chronic renal failure. Evidence of increased oxidative stress in malnourished patients

BACKGROUND: The incidence of premature cardiovascular disease is high in patients with chronic renal failure (CRF). Free-radical-induced tissue damage is thought to play a major role in the pathogenesis of atherosclerosis and several reports indicate increased oxidative stress in patients with CRF. However, the cause of such stress in CRF is not exactly known. Plasmalogens, a group of phospholipids with a vinyl ether bond in the sn-1 position, are supposed to be sensitive markers of oxidative stress. METHODS: The fasting relative plasmalogen levels of erythrocyte membranes (DMA 16/C16:0 and DMA 18/C18:0), as well as of vitamin E and serum lipids, were determined in a cohort of 105 patients (mean age 51+/-2 years) with advanced CRF (creatinine clearance 9+/-1 ml/min) before starting dialysis treatment. Twenty-nine healthy controls (47+/-2 years) were also investigated. RESULTS: Significantly lower relative plasmalogen levels (DMA 16/C16:0 and DMA 18/C18:0) were found in erythrocytes of predialysis patients than in controls. When the patients were divided on the basis of subjective global assessment of nutritional status (SGA), the malnourished patients (SGA 2-4) had significantly (P<0.05) lower relative plasmalogen levels than the well-nourished predialysis patients (SGA 1). In the prospective part of the study, we found that a 12-month dialysis treatment in 38 patients was associated with significant increases in both erythrocyte DMA 16/C16:0 (P<0.001) and DMA18/C18:0 (P<0.05) ratios. CONCLUSION: The present results suggest that predialysis patients are exposed to an augmented oxidative stress which is partially reversed by 12 months of dialysis treatment. The present study also demonstrates lower relative plasmalogen levels in erythrocyte membranes in malnourished than in well-nourished predialysis patients. One could speculate that an increased oxidative stress may be a factor contributing to the high prevalence of cardiovascular disease documented in malnourished CRF patients.     

Protein and amino acid metabolism in chronic renal failure

We investigated the inhibitory effect of clarithromycin, a 14-membered ring macrolide antibiotic, on tumor-induced angiogenesis in vivo using a mouse dorsal air sac model. The inhibitory effect of clarithromycin was dose-dependent, and 100 mg/kg of clarithromycin administered intraperitoneally twice a day reduced the area of dense capillary network to about 30% that of the control. However, in concentrations up to 50 microM clarithromycin had no effect on lung cancer cells and human vascular endothelial cell growth, endothelial cell migration, or lung cancer cell production of the angiogenesis-inducing factors interleukin-8 and vascular endothelial growth factor. Clarithromycin in concentrations greater than 10 microM inhibited endothelial cell tube formation on Matrigel in a dose-dependent manner. These data suggest clarithromycin is a potent inhibitor of tumor-induced angiogenesis that exerts its effect by inhibiting endothelial cell tube formation, and may be a possible candidate for therapeutic application.     

Disturbances of oxidative metabolism in congestive heart failure. Possibility of pharmacologic protection

In 20 patients with congestive heart failure, a significant increase in malonyldialdehyde (MDA) plasma concentration, decrease in GSH-Px plasma activity and decrease in selenium (Se) concentration in plasma and whole blood were found. We discussed possibility of pharmacological protection in observed oxidative metabolism disturbances.     

Uric acid in chronic heart failure: a marker of chronic inflammation

BACKGROUND: Chronic heart failure is associated with hyperuricaemia and elevations in circulating markers of inflammation. Activation of xanthine oxidase, through free radical release, causes leukocyte and endothelial cell activation. Associations could therefore be expected between serum uric acid level, as a marker of increased xanthine oxidase activity, and markers of inflammation. We have explored these associations in patients with chronic heart failure, taking into account the hyperuricaemic effects of diuretic therapy and insulin resistance. METHODS AND RESULTS: Circulating uric acid and markers of inflammation were measured in 39 male patients with chronic heart failure and 16 healthy controls. All patients underwent a metabolic assessment, which provided a measure of insulin sensitivity (intravenous glucose tolerance tests and minimal modelling analysis). Compared to controls, patients with chronic heart failure had significantly higher levels of circulating uric acid, interleukin-6, soluble tumour necrosis factor receptor (sTNFR)-1, soluble intercellular adhesion molecule-1 (ICAM-1, all P<0.001), E-selectin and sTNFR2 (both P<0.05). In patients with chronic heart failure, serum uric acid concentrations correlated with circulating levels of sTNFR1 (r=0.74), interleukin-6 (r=0.66), sTNFR2 (r=0.63), TNFa (r=0.60) (all P<0.001), and ICAM-1 (r=0.41, P<0.01). In stepwise regression analyses, serum uric acid emerged as the strongest predictor of ICAM-1, interleukin-6, TNF, sTNFR1 and sTNFR2, independent of diuretic dose, age, body mass index, alcohol intake, serum creatinine, plasma insulin and glucose, and insulin sensitivity. CONCLUSIONS: Serum uric acid is strongly related to circulating markers of inflammation in patients with chronic heart failure. This is consistent with a role for increased xanthine oxidase activity in the inflammatory response in patients with chronic heart failure.     

Serum uric acid concentration and anticonvulsant therapy in childhood

In antiepileptic treated adults a decrease of serum uric acid concentration was reported. In contrast to these findings we did not find a general decrease of uric acid concentration in 233 studied epileptic children and juveniles treated with antiepileptic drugs. But we found a significant decrease of uric acid concentration in epileptic children and juveniles treated with carbamazepine in monotherapy as well as in combined treatment. Rather increased uric acid serum concentration were found in primidone and valproate monotherapy. In the studied age groups only carbamazepine seems to be able to diminish uric acid concentration. The underlying mechanisms are unknown.     

Serum lipids in chronic renal failure

The serum lipids and lipoprotein patterns in 100 adult patients with nonnephrotic chronic renal failure were analyzed retrospectively. Hypertriglyceridemia was found in 43% of these patients. Forty-nine of the 100 had a normal lipoprotein pattern, whereas 42 had type IV hyperlipoproteinemia. This abnormal lipoprotein pattern could not be correlated with the degree of renal impairment, the type of renal disease, or with the patient's age, sex, weight, or diet.     

Management of chronic heart failure

Throughout the last years the concept and methods of treatment of chronic heart failure have considerably changed. The objective of the treatment is not only the relief of the symptoms, but also prevention of the onset and progression of the disease. The emphasis of treatment aims to moderate the increased neuroendocrine activity and thus to prevent myocardial damage. This review summarizes our knowledge concerning the treatment of chronic heart failure due to left ventricular dysfunction. It is based on former American guidelines and especially on the guideline of the Task Force of the European Society of Cardiology. The treatment of systolic and diastolic dysfunction of left ventricle are separately discussed. Emphasis is laid on the non pharmacologic treatment of heart failure. The treatment with ACE-inhibitors, diuretics, betablockers, digitalis, calcium antagonists and other drugs as well as the invasive procedures are also discussed.     

Serum uric acid and cognitive function in community-dwelling older adults.

Among possible markers of age-related cognitive decline, uric acid (UA) is controversial because it has antioxidant properties but is increased in diseases that often lead to cognitive impairment. In this study of 96 elderly adults, participants with mildly elevated (but normal) serum UA were 2.7 to 5.9 times more likely to score in the lowest quartile of the sample on measures of processing speed, verbal memory, and working memory. Even after controlling for age, sex, race, education, diabetes, hypertension, smoking, and alcohol abuse, the multivariate-adjusted odds of poor verbal memory and working memory remained significant (ps     

Decrease in accessible thiols as an index of oxidative damage to membrane proteins

The effect of several oxidative agents (hydrogen peroxide, tert-butyl hydroperoxide, menadione, AAPH, peroxynitrite and ionizing radiation) on the ratio of weakly to strongly immobilized residues of erythrocyte membrane-bound maleimide-tempo spin label (h(w)/h(s) ratio) was studied in order to test the hypothesis that a decrease in the h(w)/h(s) ratio may be a general index of oxidative damage to membrane proteins. Most of the agents studied decreased though H2O2 almost did not affect and ionizing radiation increased the h(w)/h(s) ratio. In parallel, the ratio of DTNB accessible/DTNB inaccessible membrane protein-SH groups was determined from membrane-SH group measurements with the Ellman reagent in the absence and in the presence of sodium dodecyl sulfate. This ratio decreased in all cases studied and seems to be a more universal and easy to measure parameter to describe the oxidative damage to membrane proteins.     

Drug therapy of chronic heart failure

Prevention of disease leading to cardiac dysfunction, improvement of quality of life and reduction of mortality are the primary objectives in the treatment of chronic heart failure. The therapeutic possibilities are various, including general advices, pharmacological therapy and surgical interventions. Standard medical treatment of systolic cardiac dysfunction contains ACE inhibitors, diuretics and cardiac glycosides. Beta-blocking agents, oral anticoagulation and antiarhythmic drugs can be used in addition. A therapeutic management of chronic heart failure tailored to the individual patient has nowadays become available due to multiple treatment options.     

Increased oxidative stress in patients with congestive heart failure

OBJECTIVES: We sought to study the markers of lipid peroxidation and defenses against oxidative stress in patients with varying degrees of heart failure. BACKGROUND: Despite advances in other areas of cardiovascular disease, the morbidity and mortality from congestive heart failure (CHF) are increasing. Data mainly from animal models suggest that free radical injury may promote myocardial decompensation. However, there are no studies in humans correlating the severity of heart failure with increased free radical injury and antioxidants. METHODS: Fifty-eight patients with CHF and 19 control subjects were studied. In addition to complete clinical and echocardiographic evaluations, the prognosis of these patients was established by measuring the levels of soluble tumor necrosis factor-alpha receptors 1 and 2 (sTNF-R1 and sTNF-R2). Oxidative stress was evaluated by measuring plasma lipid peroxides (LPO), malondialdehyde (MDA), glutathione peroxidase (GSHPx) and vitamin E and C levels. RESULTS: The patients' age range, cause of heart failure and drug intake were comparable across the different classes of heart failure. Heart failure resulted in a significant increase in LPO (p < 0.005), MDA (p < 0.005), sTNF-R1 (p < 0.005) and sTNF-R2 (p < 0.005). There was a significant positive correlation between the clinical class of heart failure and LPO, MDA, sTNF-R1 and sTNF-R2 levels. There was an inverse correlation between GSHPx and LPO. With increased lipid peroxidation in patients with CHF, the levels of vitamin C decreased, but vitamin E levels were maintained. CONCLUSIONS: These data demonstrate a progressive increase in free radical injury and encroachment on antioxidant reserves with the evolution of heart failure; they also suggest that oxidative stress may be an important determinant of prognosis. The therapeutic benefit of administering antioxidant supplements to patients with CHF should be evaluated.     

Failing diuretics in severe chronic heart failure

Three patients with chronic heart failure, men aged 29, 78 and 69 years, developed severe dyspnoea and oedema in spite of reduced sodium and fluid intake and medication including furosemide. Heart failure may become 'resistant to diuretics' due to pharmacokinetic and pharmacodynamic causes. High-dose continuous intravenous administration of a loop diuretic may afford relief in such cases, if necessary in combination with a thiazide derivative, an ACE inhibitor, an inotropic agent or an extracorporal technique. Monitoring and correction of the state of hydration of a patient with chronic heart failure may improve the prognosis and the quality of life.     

The renin-angiotensin-aldosterone system in chronic heart failure

Renin-angiotensin-aldosterone system (RAAS) in patients with rheumatic valve defects clearly tends to activation which in its turn aggravate chronic heart failure (CHF). Plasma renin activity in CHF depends on the cause of the latter, humoral changes in rheumatic heart disease being the most considerable. At the same time activated RAAS was characteristic of patients with rhythm disorders. All this evidence an important role of morphological changes and affected intracardiac haemodynamics in development of humoral vicious circle.     

Tumor necrosis factor and steroid metabolism in chronic heart failure: possible relation to muscle wasting

OBJECTIVES: We sought to assess the possible relations between clinical severity of chronic heart failure and catabolic factors, specifically tumor necrosis factor (TNF), soluble TNF receptors 1 and 2 (sTNFR-1 and sTNFR-2), cortisol, testosterone and dehydroepiandrosterone (DHEA). BACKGROUND: Chronic heart failure is associated with loss of muscle bulk that may be related to alteration of the balance between catabolism and anabolism. METHODS: Sixty-three patients (average age +/- SD 60.4 +/- 11.3 years) with stable chronic heart failure and 20 control subjects aged 52.8 +/- 11.4 years were studied. We measured body mass index (BMI) and obtained maximal incremental exercise testing with metabolic gas exchange measurements and measurements of venous levels of TNF, sTNFR-1 and sTNFR-2, cortisol and DHEA. RESULTS: There was no difference in total TNF-alpha levels between patients and control subjects (9.76 +/- 8.59 vs. 6.84 +/- 2.7 pg/ml). sTNFR-1 (128.9 +/- 84.5 vs. 63.6 +/- 23.3 pg/ml, p < 0.003) and sTNFR-2 (250.1 +/- 109.5 vs. 187.9 +/- 92.2 pg/ml, p = 0.03) were higher in patients. DHEA was lower in patients (9.88 +/- 6.94 vs. 15.64 +/- 8.33 nmol/liter, p = 0.004). The ratio of log cortisol to log DHEA correlated with log TNF level (r = 0.50, p < 0.001 for the patients alone; r = 0.48, p < 0.001 for the group as a whole). Peak oxygen consumption correlated with both sTNFR-1 and sTNFR-2 (r = -0.51, p < 0.001 and r = -0.39, p < 0.001, respectively). There was a negative correlation between BMI and TNF levels (r = -0.43, p < 0.001 for the patients) and the cortisol/DHEA ratio (r = -0.32, p = 0.01 for the patients). CONCLUSIONS: There is an increase in TNF and its soluble receptors in chronic heart failure. This increase is associated with a rise in the cortisol/DHEA (catabolic/anabolic) ratio. These changes correlate with BMI and clinical severity of heart failure, suggesting a possible etiologic link.