Asymmetric dimethylarginine in hemodialysis, hemodiafiltration, and peritoneal dialysis.

Artif Organs. 2010 May;34(5):420-5

Authors: Eiselt J, Rajdl D, Racek J, Siroká R, Trefil L, Opatrná S

Asymmetric dimethylarginine (ADMA) is a mediator of endothelial dysfunction. Production and elimination of ADMA may be affected by the type of renal replacement therapy used and oxidative stress. Plasma ADMA, advanced glycation end products (AGE), and homocysteine were assessed in 59 subjects: 20 hemodialysis (HD) patients, 19 patients undergoing peritoneal dialysis (PD), and 20 controls. Results were compared between the groups. The effect of 8 weeks of HD and high-volume predilution hemodiafiltration (HDF) was compared in a randomized study. HD patients showed higher ADMA (1.20 [0.90-1.39 micromol/L]) compared to controls (0.89 [0.77-0.98], P < 0.01), while ADMA in PD did not differ from controls (0.96 [0.88-1.28]). AGE and homocysteine were highest in HD, lower in PD (P < 0.01 vs. HD), and lowest in controls (P < 0.001 vs. HD and PD). PD patients had higher residual renal function than HD (P < 0.01). The decrease in ADMA at the end of HD (from 1.25 [0.97-1.33] to 0.66 [0.57-0.73], P < 0.001) was comparable to that of HDF. Switching from HD to HDF led to a decrease in predialysis homocysteine level in 8 weeks (P < 0.05), while ADMA and AGE did not change. Increased ADMA levels in patients undergoing HD, as compared to PD, may be caused by higher oxidative stress and lower residual renal function in HD. Other factors, such as diabetes and statin therapy, may also be at play. The decrease in ADMA at the end of HD and HDF is comparable. Switching from HD to HDF decreases in 8 weeks the predialysis levels of homocysteine without affecting ADMA.

PMID: 20633156 [PubMed - indexed for MEDLINE]

Cardiovascular parameters in rat model of chronic renal failure induced by subtotal nephrectomy.

Physiol Res. 2010;59 Suppl 1:S81-8

Authors: Svíglerová J, Kuncová J, Nalos L, Tonar Z, Rajdl D, Stengl M

Chronic renal failure (CRF) is associated with high incidence of cardiovascular complications. To clarify pathogenesis of CRF numerous animal models have been developed. The aim of our work was to describe methodology of subtotal surgical renal ablation in rat and to characterize some biochemical and cardiovascular parameters of this animal model. Male rats underwent 5/6 surgical nephrectomy or sham operations in two steps. The following parameters were measured on day 10 and in week 10 after the surgery: plasma concentrations of creatinine and urea, blood pressure, resting heart rate, chronotropic response to atropine and metipranol, heart ventricles weight, contraction parameters and action potential duration in the left ventricle. Increased serum concentrations of creatinine and urea, decreased creatinine clearance, polyuria and alteration of the remnant kidney tissue were found in CRF rats. Changes in cardiovascular parameters identified after subtotal nephrectomy resembled alterations of cardiovascular system in uremic patients and included hypertension, elevated resting heart rate, diminished parasympathetic cardiac tone, hypertrophy of the left ventricle associated with weakened force of contraction, prolonged contraction and relaxation and shortening of action potential duration. These data suggest that the present model can be a useful tool in the study of CRF and its cardiovascular complications.

PMID: 20626224 [PubMed - indexed for MEDLINE]

Parasympathetic regulation of heart rate in rats after 5/6 nephrectomy is impaired despite functionally intact cardiac vagal innervation.

Nephrol Dial Transplant. 2009 Aug;24(8):2362-70

Authors: Kuncová J, Svíglerová J, Kummer W, Rajdl D, Chottová-Dvoráková M, Tonar Z, Nalos L, Stengl M

BACKGROUND: Chronic renal failure is frequently associated with a high risk of sudden cardiac death due to dysfunction of the autonomic nervous system. The pathogenic mechanisms underlying the parasympathetic cardiac dysautonomia are not fully elucidated yet. METHODS: Chronic renal failure was induced in rats by 5/6 nephrectomy. Blood pressure, resting heart rate and plasma levels of creatinine, urea and asymmetric dimethylarginine (ADMA) were measured. To characterize the parasympathetic innervation of the heart, chronotropic responses to atropine, metipranolol and to vagal stimulation in the absence or presence of ADMA were investigated in vivo. In vitro, chronotropic and inotropic effects of carbachol and ADMA and mRNA expression of muscarinic M2 receptors, high affinity choline transporter (CHT1), vesicular acetylcholine transporter (VAChT) and choline acetyltransferase (ChAT) were assessed in the isolated cardiac tissues. RESULTS: In 5/6 nephrectomy rats, the resting heart rate was significantly higher and the parasympathetic tone, measured as the effect of atropine after administration of metipranolol was significantly lower than in control animals. Plasma ADMA levels were significantly elevated in the uraemic rats and significantly inversely correlated with the effect of atropine on the heart rate. No differences were revealed in the plasma norepinephrine concentrations, negative chronotropic responses to stimulation of the vagus nerves, chronotropic and inotropic responses to carbachol and the relative expression of M2 receptors, CHT1, VAChT and ChAT. CONCLUSION: The data suggest that cardioacceleration in chronic renal failure is caused by a diminished cardiac parasympathetic tone in the presence of a functionally intact intrinsic cardiac cholinergic signalling system.

PMID: 19321759 [PubMed - indexed for MEDLINE]

Effect of L-carnitine supplementation on secondary hyperparathyroidism and bone metabolism in hemodialyzed patients.

Calcif Tissue Int. 2007 Aug;81(2):99-106

Authors: Cibulka R, Racek J, Pikner R, Rajdl D, Trefil L, Vesela E, Studenovska M, Siroka R

The aim of our work was to test the influence of L-carnitine supplementation on secondary hyperparathyroidism and bone metabolism in hemodialyzed patients in a randomized study. Eighty-three chronically hemodialyzed patients were observed; 44 were supplemented with L-carnitine (15 mg/kg intravenously after each hemodialysis for 6 months), while 39 took placebo. Levels of free carnitine (CAR), calcium (Ca), inorganic phosphate (P), Ca x P product, parathormone (PTH), bone-specific alkaline phosphatase (b-ALP), osteocalcin (OC), and osteoprotegerin (OPG) were monitored. In comparison with pretreatment values, changes of some selected parameters occurred in the supplemented patients after 6 months (data are expressed as medians; NS, nonsignificant change): PTH, 186.0 vs. 135.5 ng/L (NS); b-ALP, 13.9 vs. 13.2 microg/L (P < 0.05); OC, 78.3 vs. 68.8 microg/L (NS); OPG, 144.0 vs. 182.0 ng/L (P < 0.05). In the controls, there were the following changes: PTH, 148.0 vs. 207.0 ng/L (NS); b-ALP, 15.2 vs. 13.2 microg/L (P < 0.05); OC, 62.7 vs. 79.8 microg/L (P < 0.05); OPG, 140.0 vs. 164.0 ng/L (NS). A significant correlation was found between CAR and OPG changes (r = 0.51, P < 0.001) in the supplemented patients. The supplementation led to a significant increase of serum OPG concentration. Nevertheless, we observed only nonsignificant tendencies to correction of secondary hyperparathyroidism and reduction of bone turnover in hemodialyzed patients supplemented with L-carnitine in contrast to controls. At this point, the use of L-carnitine does not seem to be justified.

PMID: 17622482 [PubMed - indexed for MEDLINE]

Asymmetric dimethylarginine--comparison of HPLC and ELISA methods.

J Chromatogr B Analyt Technol Biomed Life Sci. 2007 May 1;850(1-2):586-7

Authors: Siroká R, Trefil L, Rajdl D, Racek J, Cibulka R

PMID: 17197253 [PubMed - indexed for MEDLINE]

[Asymmetric dimethylarginine--a novel cardiovascular risk factor]

Vnitr Lek. 2006 Mar;52(3):249-55

Authors: Siroká R, Cibulka R, Rajdl D, Racek J

Understanding metabolism of nitric oxide (NO), signal molecule releasing from endothelial cells and influencing vascular tone, belongs to the most remarkable knowledge of last ten years. NO increases vascular tone, inhibits adhesion of monocytes and leukocytes to the vascular endothelium and reduces atherogenic process. Low NO level is one of pathogenic factors starting cardiovascular diseases. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of enzyme NO synthase, enzyme catalyzing NO production from arginine. This article gives a brief overview of contemporary state of the relation between ADMA and cardiovascular diseases. Increased ADMA levels are associated with reduced NO synthesis as assessed by impaired endothelium-dependent vasodilatation. In several prospective studies, ADMA evolved as a marker of cardiovascular risk. In the first chapters is described state of the art of biosynthesis, degradation and excretion of ADMA in connection with endothelial dysfunction, coronary artery disease, chronic heart failure, cardiovascular risk in haemodialysis patients, diabetes mellitus, hypertension, lipid metabolism disorders and intensive care unit treatment. Next chapters shortly summarize methods of ADMA detection and their applications. In conclusion clinical relevance of measurement of ADMA levels as a marker of endothelial dysfunction is discussed. Future research tasks of ADMA lead to prospective studies with different types of patients and also healthy population. Moreover ADMA is becoming a goal for pharmacotherapeutic intervention to improve endothelium-dependent vascular function in subjects with high ADMA levels.

PMID: 16722156 [PubMed - indexed for MEDLINE]

Brain natriuretic peptide and N-terminal proBNP in chronic haemodialysis patients.

Nephron Clin Pract. 2006;103(4):c162-72

Authors: Racek J, Králová H, Trefil L, Rajdl D, Eiselt J

BACKGROUND: Brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are released into circulation as a result of congestive heart failure (HF). As HF and water overload are frequent complications in haemodialysis (HD) patients, we decided to study the levels of BNP and NT-proBNP and their changes during HD. METHODS: BNP and NT-proBNP levels were determined in 94 HD patients before and after a regular 4-h HD. We followed changes in these peptides during HD depending on age, sex, HF (NYHA classification and left ventricular ejection fraction [LVEF]), duration on HD, presence of hypertension, coronary artery disease, type of membrane used for HD [low-flux (LFx) or high-flux (HFx)] and body mass change during HD. Furthermore, patients basic medication and creatinine levels and presence of diabetes mellitus were monitored. RESULTS: Respectively,94% and 100% of the patients had pre-dialysis concentrations of BNP and NT-proBNP above the cut-off values for HF. The marker levels correlated significantly both before and after HD (r = 0.903 and 0.888, respectively, p < 0.001). BNP levels significantly decreased (p < 0.0001), whereas NT-proBNP significantly increased (p < 0.0001) during HD on LFx membranes. HD on HFx membranes caused greater decrease of BNP (compared to LFx membranes, p < 0.001), but also a decrease of NT-proBNP (p < 0.001).We did not find any significant differences in marker levels for HF and non-HF patients (NYHA classification). However, both peptides reached higher levels in the group with LVEF < or = 50% (p < 0.001 for both peptides). Body mass change during HD negatively correlated only with the change of NT-proBNP (r = -0.27, p < 0.05). In the multiple regression model, the change of both peptides during HD was significantly influenced by membrane type (p = 0.003 for BNP and p = 0.001 for NT-proBNP). NT-proBNP change during HD was further significantly influenced by LVEF (p = 0.012), sex (p = 0.002) and duration on HD (p = 0.006). CONCLUSIONS: Both BNP and NT-proBNP levels were significantly increased in HD patients prior to dialysis. The change in concentrations of both peptides during HD is influenced by membrane type. HD probably triggers increased production of both peptides and this increase is emphasized by impaired LVEF. This fact can be clinically observed only on NT-proBNP levels, because BNP levels are biased by significant removal of this protein during HD.

PMID: 16645318 [PubMed - indexed for MEDLINE]

Influence of chromium-enriched yeast on blood glucose and insulin variables, blood lipids, and markers of oxidative stress in subjects with type 2 diabetes mellitus.

Biol Trace Elem Res. 2006 Mar;109(3):215-30

Authors: Racek J, Trefil L, Rajdl D, Mudrová V, Hunter D, Senft V

The aim of this study was to determine the effect of chromium (Cr)- enriched yeast on blood glucose and insulin variables, blood lipids, and blood markers of oxidative stress in persons with type 2 diabetes mellitus (median duration: 3.0 yr). Thirty-six subjects (9 men, 27 women; mean age: 61.3 yr; mean body mass index: 34.33 kg/m2) were supplemented with 400 microg Cr/d as Cr-enriched yeast (n = 19) or placebo (n = 17) for 12 wk in a randomized, double-blind study. The most interesting results were obtained by comparison of the change in the placebo group to the change in the Cr group. The Cr group showed a significantly greater increase in serum Cr compared to the placebo group (p < 0.05). Supplementation with Cr-enriched yeast was associated with a significant decrease in fasting serum glucose compared to placebo (p < 0.01). Blood markers of oxidative stress glutathione peroxidase activity and levels of reduced glutathione were essentially unchanged in the Cr group after 12 wk, but decreased significantly in the placebo group (p < 0.05, p < 0.01, respectively). Serum HbA1c and glycated protein (fructosamine) were essentially unchanged in the Cr group, whereas HbA1c tended to increase in the placebo group (from 6.94% to 7.11%). Fasting serum insulin decreased in both groups, with a greater tendency in the Cr group (-16.5% vs -9.5%). These data suggest that supplementation of well-controlled type 2 diabetics with Cr-enriched yeast is safe and can result in improvements in blood glucose variables and oxidative stress.

PMID: 16632892 [PubMed - indexed for MEDLINE]

Effect of white wine consumption on oxidative stress markers and homocysteine levels.

Physiol Res. 2007;56(2):203-12

Authors: Rajdl D, Racek J, Trefil L, Siala K

The aim of this study was to assess the influence of regular daily consumption of white wine on oxidative stress and cardiovascular risk markers. Forty-two healthy male volunteers consumed 375 ml of white wine daily. Each participant provided three venous blood samples (before wine consumption, following the wine consumption period and again a month later). Levels of superoxide dismutase, glutathione peroxidase, reduced glutathione, total antioxidant capacity, total cholesterol, HDL-cholesterol, apolipoprotein A I, apolipoprotein B, triglycerides, paraoxonase 1, C-reactive protein, homocysteine, thiobarbituric acid reactive substances (TBARS) and advanced oxidation protein products (AOPP) were measured. Immediately following the month of white wine consumption there was a significant increase in HDL-cholesterol (p<0.0001), paraoxonase 1 (p<0.001), glutathione peroxidase (p<0.001) and reduced glutathione (p<0.01) levels, a decrease in superoxide dismutase activities (p<0.0001), and a decrease in oxidation protein products (p<0.001) and TBARS (p<0.05) concentrations. However, there was also a clear increase in homocysteine (p<0.0001) after a month of white wine consumption. The results of our non-placebo controlled trial suggest that regular daily white wine consumption is associated not only with both antioxidative and antiatherogenic effects but also with a potentially proatherogenic increase of homocysteine concentrations.

PMID: 16555941 [PubMed - indexed for MEDLINE]

Asymmetric dimethylarginine, homocysteine and renal function--is there a relation?

Clin Chem Lab Med. 2005;43(10):1147-50

Authors: Siroká R, Trefil L, Rajdl D, Racek J, Rusnáková H, Cibulka R, Eiselt J, Filipovský J

The adverse effect of hyperhomocysteinemia on the vascular wall can be partially explained by increasing plasma concentration of asymmetric dimethylarginine (ADMA), a potent inhibitor of nitric oxide synthase. The aim of the study was to compare ADMA and homocysteine levels in three groups of subjects: blood donors with normal homocysteine concentration (group A), patients with hyperhomocysteinemia and normal kidney function (group B) and hemodialysis patients who are known to be hyperhomocysteinemic (group C). Concentrations of homocysteine (enzymatic method), ADMA (enzyme-linked immunoassay) and creatinine (Jaffe method) in EDTA plasma were measured. Plasma ADMA levels were significantly higher in both groups with hyperhomocysteinemia (1.60+/-0.56 micromol/L in group B, 1.81+/-0.57 micromol/L in group C) when compared with those in blood donors (0.82+/-0.29 micromol/L, p<0.001 in both cases). Significant positive correlations were found between concentrations of ADMA and homocysteine (r=0.42, p<0.0001), ADMA and creatinine (r=0.39 p<0.001), homocysteine and creatinine (r=0.69, p<0.0001), age and homocysteine (r=0.47, p<0.001), age and ADMA (r=0.57, p<0.001) and age and creatinine (r=0.37, p<0.001). Increased ADMA concentrations in hyperhomocysteinemic patients were confirmed, but multiple linear regression analysis showed that this significant correlation is only apparent due the dependence of both parameters on age.

PMID: 16197312 [PubMed - indexed for MEDLINE]

Markers of oxidative stress in diabetic mothers and their infants during delivery.

Physiol Res. 2005;54(4):429-36

Authors: Rajdl D, Racek J, Steinerová A, Novotný Z, Stozický F, Trefil L, Siala K

Oxidative stress is probably a pathophysiological process leading to disadvantageous outcomes in diabetic pregnancies. We aimed to map a complex of potential markers of oxidative stress in this condition. Diabetic mothers had significantly higher concentrations of thiobarbituric acid reactive substances in the plasma [TBARS] both before (p<0.0001) and after (p<0.001) delivery and also their newborns showed higher values of TBARS (p<0.0001) in comparison with the control group. Diabetic mothers also showed lower concentrations of reduced glutathione in erythrocytes [GSH] both before (p<0.05) and after (p<0.01) delivery and their infants also had lower levels of GSH (p<0.0001). We found a lower total antioxidative capacity of plasma [AOC] before delivery (p<0.05) in the diabetic group in comparison with the control group. Newborns of diabetic mothers had higher plasmatic concentrations of apolipoproteine B [apo B] (p<0.05), higher erythrocyte glutathione peroxidase [GPx] activity (p<0.05) and lower pH (p<0.001) in the umbilical cord blood, when compared with infants of control non-diabetic mothers. We conclude that pregestational and gestational diabetes mellitus represent increased oxidative stress for both mother and her infant. TBARS in plasma are a valuable marker of oxidative stress in this condition. Disruption of glutathione peroxidase/glutathione pattern can be involved in pathophysiology of enhanced oxidative stress in diabetic pregnancies.

PMID: 15588143 [PubMed - indexed for MEDLINE]

Significant increase in antibodies against oxidized LDL particles (IgoxLDL) in three-month old infants who received milk formula.

Atherosclerosis. 2004 Mar;173(1):147-8

Authors: Steinerová A, Korotvicka M, Racek J, Rajdl D, Trefil L, Stozický F, Rokyta Z

PMID: 15177136 [PubMed - indexed for MEDLINE]