ADMA levels correlate with proteinuria, secondary amyloidosis, and endothelial dysfunction

Asymmetric dimethyl-arginine (ADMA), a residue of the proteolysis of arginine-methylated proteins, is a potent inhibitor of nitric oxide synthesis. The increased protein turnover that accompanies proteinuric secondary amyloidosis may increase circulating levels of ADMA, and this may contribute to endothelial dysfunction. We performed a cross-sectional study of 121 nondiabetic proteinuric patients with normal GFR (including 39 patients with nephrotic-range proteinuria and secondary amyloidosis) and 50 age-, sex-, and BMI-matched healthy controls. The proteinuric patients had higher levels of serum ADMA, symmetric dimethyl-arginine (SDMA), high-sensitivity C-reactive protein (hsCRP), and insulin resistance (homeostasis model assessment index) than controls. Compared with controls, brachial artery flow-mediated dilatation (FMD), serum L-Arginine, and the L-Arginine/ADMA ratio were significantly lower among proteinuric patients, suggesting greater endothelial dysfunction. When patients with secondary amyloidosis were compared with patients with glomerulonephritis who had similar levels of proteinuria, those with amyloidosis had higher ADMA and SDMA levels and lower L-Arginine/ADMA ratios and FMD measurements (P < 0.001 for all). Finally, even after adjusting for confounders, ADMA level correlated with both proteinuria and the presence of secondary amyloidosis, and was an independent predictor of FMD. We propose that ADMA synthesis may be increased in chronic kidney disease, especially in secondary amyloidosis, and this may explain part of the mechanism by which proteinuria increases cardiovascular morbidity and mortality.     

Endothelial functions improve with decrease in asymmetric dimethylarginine (ADMA) levels after renal transplantation

BACKGROUND: Chronic kidney disease (CKD) is associated with increased cardiovascular events. The relationships between the markers of inflammation and endothelial dysfunction were investigated both before and after living donor kidney transplantation. METHODS: Twenty-seven renal transplant patients were studied. Eleven patients (six male, five female) were on cyclosporine A, whereas 16 patients (nine male, seven female) were treated with tacrolimus based regimes. Twenty-seven subjects (12 males, 15 females) were studied as controls. Plasma adiponectin, high sensitive C reactive protein (hsCRP), Asymetric dimethyl arginine (ADMA) levels were studied before transplantation and on days 1, 3, 7, 14, and 28. The brachial artery flow mediated dilatation (FMD) was studied before transplantation and on the 28th day. RESULTS: Serum hsCRP and ADMA levels decreased significantly from the first posttransplantation day on each measurement (P<0.001 for all) while the decrement of plasma adiponectin started in the third day (P<0.001 for all). The FMD was lower in the patients than the control group (P<0.001) and improved significantly in the 28th day of transplantation (P<0.001). CONCLUSIONS: The results indicate that ADMA is associated with FMD in CKD both before and after kidney transplantation. Endothelial functions improve at the very beginning of the posttransplantation period with accompanying reduction in ADMA and hsCRP levels.     

Methylated arginine derivatives in children and adolescents with chronic kidney disease

Asymmetric dimethylarginine (ADMA), a methylated L: -arginine (Arg) derivative is associated with endothelial dysfunction, vasoconstriction, and hypertension in animals and humans. We examined the relationship between these derivatives, estimated glomerular filtration rate (eGFR), and awake (AW) and asleep (AS) blood pressure (BP) load in children and adolescents (n = 28) with stage 2-3 chronic kidney disease (CKD) and in matched intra-familial controls (n = 10). Plasma L: -Arg, ADMA, and symmetric dimethylarginine (SDMA) levels were measured by high-performance liquid chromatography-tandem mass spectrometry. Subjects wore a 24-hr ambulatory BP monitor with BP load >95th percentile. ADMA, SDMA/ADMA ratio and SDMA were 38-200% higher in CKD patients while L: -Arg/ADMA and L: -Arg/SDMA ratios and the L: -Arg level were 11-64% lower. The eGFR explained 42-60% of L: -Arg/SDMA, SDMA/ADMA, and SDMA variability (n = 38). Using linear regression, SDMA and SDMA/ADMA separately explained 15-38% of AW and AS systolic (S) BP and diastolic (D) BP load variability (p < 0.001-0.022). Using multivariate stepwise regression with eGFR held constant, SDMA/ADMA was a significant independent variable for AW DBP load (p = 0.03). In conclusion, BP load and a disproportionate elevation of SDMA are seen in children and adolescents with stage 2-3 (mild-moderate) CKD. SDMA is a strong marker for reduced eGFR and serves as a moderate but significant indicator of 24-hr BP load variability.     

Effect of renin–angiotensin–aldosterone system (RAAS) blockade on visfatin levels in diabetic nephropathy

Aim: Plasma visfatin levels are elevated in diabetic nephropathy in parallel to the severity of proteinuria and glomerular filtration rate. The aim of this study was to find out whether the renin–angiotensin–aldosterone system (RAAS) blockage has any effect on the plasma visfatin levels. Methods: Thirty‐two patients with diabetic proteinuria (>500 mg/day) with a normal glomerular filtration rate (GFR) and 33 healthy subjects were enrolled. Patients were treated with ramipril 5 mg daily for 2 months. Proteinuria, GFR, high‐sensitivity C‐reactive protein (hsCRP), visfatin, flow‐mediated dilatation (FMD) and homeostasis model assessment of insulin resistance (HOMA‐IR) index measurements were performed both before and after the treatment. Results: The plasma visfatin, and hsCRP levels of the patients were significantly higher and the FMD was significantly lower (P < 0.001 for all). The visfatin levels were significantly correlated to FMD, systolic and diastolic blood pressures, proteinuria, eGFR, HOMA‐IR and hsCRP. Ramipril treatment resulted in a significant decrease in plasma visfatin, proteinuria, hsCRP, HOMA‐IR and increase in FMD (P < 0.001) in patients (P < 0.001 for all). Conclusion: The present study suggests that plasma visfatin levels are related to the endothelial functions, inflammation and the severity of proteinuria in diabetic nephropathy. Treatment with ramipril causes a significant decrease in visfatin levels along with the improvement of proteinuria, endothelial dysfunction and inflammatory state in diabetic nephropathy.     

Net renal extraction of asymmetrical (ADMA) and symmetrical (SDMA) dimethylarginine in fasting humans.

BACKGROUND: Recently, the potential importance of dimethylarginines as endogenously produced inhibitors of nitric oxide synthase has become clearer. Interestingly, elevated levels have been reported in patients with vascular disease, but especially in patients suffering end-stage renal disease. Although the kidney obviously seems to play a key role in the elimination of dimethylarginines, clear insight into the renal handling of these compounds is lacking. Thus, our aim was to investigate the renal extraction of dimethylarginines. METHODS: Plasma concentrations of dimethylarginines were determined in both arterial and renal venous blood in 20 fasting patients with normal renal function. Renal extraction was calculated as the arteriovenous concentration difference divided by the arterial concentration times 100%. RESULTS: A significant renal extraction was found for both dimethylarginines. Renal extraction was significantly higher for asymmetrical dimethylarginine (ADMA) when compared with symmetrical dimethylarginine (SDMA) (16.2 vs 10.5% respectively, P=0.001). In addition, arterial SDMA concentration, but not ADMA concentration, significantly correlated with arterial creatinine concentration. CONCLUSIONS: In healthy humans, the kidney contributes to the regulation of plasma levels of dimethylarginines, since both ADMA and SDMA were significantly extracted from the arterial supply. Interestingly, a higher renal extraction of ADMA was found when compared to SDMA extraction, which strongly suggests the presence of an additional catabolic pathway for ADMA in the kidney.     

Adiponectin level is reduced and inversely correlated with the degree of proteinuria in type 2 diabetic patients

AIMS: Adiponectin seems to be an important modulator for metabolic and vascular diseases. We aimed to measure plasma adiponectin levels in type 2 diabetic patients and investigate any association with the severity of proteinuria. METHODS: 80 patients (mean age, 46.9 +/- 5.1 years; body mass index (BMI), 25.8 +/- 1.98 kg/m2) and 47 healthy volunteers (mean age, 46.1 +/- 5.5 years; BMI 26.74 +/- 2.23 kg/m2) were included. Plasma adiponectin concentration, insulin levels, homeostasis model assessment (HOMA) indices, calculated glomerular filtration rate (GFR), high sensitive C reactive protein (hsCRP) and biochemistry panel were determined in all subjects. The association between adiponectin concentration and proteinuria was evaluated. Additionally, the relationship between adiponectin and hsCRP and calculated GFR were also investigated. RESULTS: Adiponectin levels in patients were significantly lower than those of controls (n = 80; 8.76 +/- 4.50 microg/ml for patients, n = 47; 24.27 +/- 5.59 microg/ml for controls, p < 0.001). Plasma adiponectin levels in patients with proteinuria were significantly lower than those without proteinuria (n = 43; 6.81 +/- 2.82 microg/ml for proteinuria, n = 37; 11.98 +/- 3.32 microg/ml for no proteinuria, p < 0.001). There was a significant negative correlation between plasma adiponectin concentrations and the degree of proteinuria (r = -0.433, p < 0.001). There were also significant negative correlations between adiponectin concentrations and insulin levels as well as HOMA index in the patient group (r = -0.322, p = 0.004; r = -0.301, p = 0.032). Additionally there was a significant negative correlation between adiponectin and hsCRP levels in the patient group (r = -0.872, p < 0.001). CONCLUSION: The results show that adiponectin is lower in patients with type 2 diabetes and the levels are negatively correlated with the severity of proteinuria.     

Handling of asymmetrical dimethylarginine and symmetrical dimethylarginine by the rat kidney under basal conditions and during endotoxaemia.

BACKGROUND: Asymmetrical dimethylarginine (ADMA) is capable of inhibiting nitric oxide synthase enzymes, whereas symmetrical dimethylarginine (SDMA) competes with arginine transport. The potential role of inflammation in the metabolism of ADMA has been elucidated in an in vitro model using tumour necrosis factor-alpha, resulting in a decreased activity of the ADMA-degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH). The kidney probably plays a crucial role in the metabolism of ADMA by both urinary excretion and degradation by DDAH. We aimed to further elucidate the role of the kidney in a rat model under basal conditions and during endotoxaemia. METHODS: Twenty-five male Wistar rats weighing 275-300 g were used for this study. The combination of arteriovenous concentration differences and kidney blood flow allowed calculation of net organ fluxes. Blood flow was measured using radiolabelled microspheres according to the reference sample method. Concentrations of ADMA, SDMA and arginine were measured by high-performance liquid chromatography. RESULTS: The kidney showed net uptake of both ADMA and SDMA and fractional extraction rates were 35% and 31%, respectively. Endotoxaemia resulted in a lower systemic ADMA concentration (P = 0.01), which was not explained by an increased net renal uptake. Systemic SDMA concentrations increased during endotoxaemia (P = 0.007), which was accompanied by increased creatinine concentrations. CONCLUSIONS: The rat kidney plays a crucial role in the regulation of concentrations of dimethylarginines, as both ADMA and SDMA were eliminated from the systemic circulation in substantial amounts. Furthermore, evidence for the role of endotoxaemia in the metabolism of dimethylarginines was obtained as plasma levels of ADMA were significantly lower in endotoxaemic rats.     

Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and L-arginine in patients with arteriogenic and non-arteriogenic erectile dysfunction

The plasma concentration of asymmetrical dimethylarginine (ADMA), an inhibitor of nitric oxide synthase, has been linked to endothelial dysfunction. We investigated the relation between ADMA, symmetric dimethylarginine (SDMA) and L-arginine concentrations and erectile dysfunction. We compared plasma levels of ADMA, SDMA and L-arginine in 61 men in good health with erectile dysfunction of arteriogenic and non-arteriogenic origin. Diagnosis of erectile dysfunction was based on the International Index of Erectile Function Score and its aetiology was classified with penile echo-colour-Doppler in basal condition and after intracavernous injection of prostaglandin E1. The ADMA and SDMA concentrations were significantly higher in men with arteriogenic erectile dysfunction compared with those with erectile dysfunction of non-arteriogenic origin (p??0.05) nor between each of the two erectile dysfunction subgroups and controls (p?>?0.05). The L-arginine/ADMA and the L-arginine/SDMA ratios in arteriogenic erectile dysfunction subgroups were significantly lower than both in controls (p??0.05). We conclude that ADMA and SDMA concentrations are significantly higher and L-arginine/ADMA ratio lower in patients who have arteriogenic erectile dysfunction compared with both patients with non-arteriogenic erectile dysfunction and controls. The negative correlation between ADMA and severity of erectile dysfunction is present only in patients with arteriogenic erectile dysfunction. This study supports the importance to always distinguish arteriogenic from non-arteriogenic erectile dysfunction patients to study the complicate erectogenic mechanisms that lead to erectile dysfunction and also to provide potential therapeutic agents for patients with arteriogenic erectile dysfunction.     

The changes in serum leptin,body fat mass and insulin resistance after renal transplantation

BACKGROUND: In this prospective-controlled study, we aimed to investigate the effect of changes in insulin resistance and anthropometrical parameters on serum leptin levels (SLL) after renal transplantation (Tx). PATIENTS AND METHODS: Thirty-four patients (M/F: 19/15, mean age: 29 +/- 9 yr) and 30 age and sex-matched healthy controls (C) were included. Body weight, subscapular, suprailiac, periumbilical, biceps and triceps skinfold thicknesses, neck, wrist, hip and waist circumferences, as well as body mass index and body fat mass were measured as anthropometrical parameters. In order to measure the serum glucose, insulin and SLL, blood samples were obtained before and 1 wk, 1 and 6 months after Tx. Homeostasis Model Assessment (HOMA) values were calculated as an index of insulin resistance. RESULTS: Serum leptin levels (SLL) of the patients at pre-Tx were significantly higher than C (21.5 +/- 3.5 vs. 7.8 +/- 0.9 ng/mL, p = 0.002) and decreased at first week after Tx (from 21.5 +/- 3.5 to 8.4 +/- 1.5 ng/mL, p < 0.001). Thereafter, it gradually increased to 12.8 +/- 2.1 ng/mL in the first month and to 14.4 +/- 2.1 ng/mL in the sixth month after Tx. Serum leptin levels at sixth month were significantly higher than C (p = 0.005). Serum insulin and HOMA values changed similar to SLL after Tx. Correlations between SLL and HOMA persisted during the study period [pre-Tx (r: 0.40) and at first (r: 0.38) and sixth (r: 0.47) months]. In linear regression analysis, HOMA and fat mass were found as independent variables for predicting SLL at the sixth month after Tx. CONCLUSION: Serum leptin levels dramatically decreased immediately after Tx and significantly correlated with serum insulin levels and HOMA during the entire study. Increase in SLL at sixth months was probably because of increase in fat mass, insulin resistance and steroid use in renal transplant recipients.     

Endothelial dysfunction in type-2 diabetics with early diabetic nephropathy is associated with low circulating adiponectin.

BACKGROUND: Type-2 diabetes and diabetic kidney disease have additive effects on cardiovascular risk. Furthermore, the degree of proteinuria is an independent predictor of mortality in this patient group. We hypothesized that altered kidney clearance and/or metabolism of vasoactive peptides occurring during proteinuria could link early diabetic nephropathy to cardio vascular disease (CVD). METHODS: We performed a cross-sectional study of 85 incident patients (51 +/- 5 years, 49 males) with type-2 diabetes and 38 age- and sex-matched controls. We further divided patients by the presence of minor (<500 mg/day; n = 40) or severe (>/=500 mg/day; n = 45) proteinuria. Clinical and anthropometric data, along with ultrasonographic flow-mediated dilatation (FMD) of the brachial artery and carotid intima-media thicknesses (CIMT), were recorded in each group. Circulating NAMPT/visfatin, adiponectin (normalized to BMI), AHSG/fetuin-A and hsCRP levels were also measured using commercial ELISA. RESULTS: Plasma NAMPT/visfatin, CIMT, HOMA index and hsCRP levels were all significantly higher in diabetics than in control subjects, and all but CIMT correlated with proteinuria (rho = 0.46; P < 0.001, rho = 0.54; P > 0.05, rho = 0.32; P = 0.003, rho = 0.76; P < 0.001, respectively). FMD, adiponectin and AHSG/fetuin-A levels were significantly lower, and negatively correlated with proteinuria (rho = -0.54; P < 0.001, rho = -0.56; P < 0.001, rho = -0.48; P < 0.001, respectively). In a multivariate regression analysis, the degrees of proteinuria (r(2) = -0.32, P = 0.04) and plasma levels of NAMPT/visfatin (r(2) = -0.33, P = 0.006) were independently related to FMD. CONCLUSIONS: The present study suggests that the presence of proteinuria, regardless of the degree of renal function impairment, is an important predictor of endothelial dysfunction in early diabetic nephropathy and that it is associated with altered circulating levels of NAMPT/visfatin and adiponectin.     

Effects of amlodipine and valsartan on oxidative stress and plasma methylarginines in end-stage renal disease patients on hemodialysis

Patients with end-stage renal disease (ESRD) receiving hemodialysis (HD) treatment have a markedly shortened life expectancy in large part owing to cardiovascular disease (CVD), not explained by established risk factors. We tested the hypothesis that therapy with valsartan, an angiotensin receptor blocker and amlodipine, an antioxidant calcium channel blocker will reduce oxidative stress and the plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase. We confirmed that compared with age- and gender-matched healthy controls, ESRD patients have excessive oxidative stress and arginine methylation as indexed by elevated plasma levels of oxidation products of lipids (13-hydroxyoctadecadienoic acid (13-HODE)), thiols (oxidized:reduced glutathione, oxidized glutathione (GSSG):GSH), proteins, and nucleic acids, and the methylation products ADMA and symmetric dimethylarginine (SDMA). We undertook a double blind, crossover study of equi-antihypertensive treatment with amlodipine and valsartan for 6 weeks each to test our hypothesis. Both treatments significantly reduced GSSG:GSH, 8-hydroxy 2-deoxyguanosine, ADMA, and SDMA levels and amlodipine reduced 13-HODE. We conclude that hypertensive patients with ESRD receiving HD have evidence of extensive oxidation of lipids, thiols, proteins, and nucleic acids and methylation of arginine that could contribute to CVD. Many of these changes can be reduced by short-term treatment with amlodipine and valsartan.     

PROGRESS IN UREMIC TOXIN RESEARCH: Asymmetric Dimethylarginine and Symmetric Dimethylarginine: Axis of Evil or Useful Alliance?

Almost 40 years ago, in 1970, Kakimoto and Akazawa were the first to isolate and describe N‐N, N‐G‐ and N‐G,N′‐G‐dimethyl‐arginine from human urine. Today, these substances are known as asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). In their detailed and meticulous publication, Kakimoto and Akazawa speculated about these two compounds: “They may have functional importance in proteins in which they are formed. If they are excreted into the urine as metabolites of body proteins, amounts of these substances in human urine may reflect methylation rate of body proteins and their turnover rates and determination of these substances might be important for the study of various pathological states.” The following decades proved them to be right. ADMA, the most potent endogenous nitric oxide synthase (NOS) inhibitor was first found to be elevated in hemodialysis patients. It has been shown to correlate with traditional and nontraditional cardiovascular risk factors. ADMA is also a strong predictor of cardiovascular events and death in both patients with chronic kidney disease (CKD, stage 2–5) and in the general population. Moreover, ADMA predicts the progression of CKD. SDMA, the structural isomer of ADMA, has been shown to be an excellent marker of renal function in human and animal studies. There is emerging evidence that SDMA might also be involved in inflammation and atherosclerosis although it is only thought to be a (weak) indirect inhibitor of NOS. There is burgeoning evidence that these two substances may indeed damage normal physiological functions, or interfere with physiological defense mechanisms in CKD, play a role in the progression of renal disease, induce uremic symptoms, and may even contribute to dialysis‐related complications. Hence these compounds are considered uremic toxins. This review summarizes our current concept how these two compounds might play a crucial part in the pathophysiology of uremia, either alone or in their combination. We also allude to the potential physiological role these substances might have.     

Asymmetric dimethyl-arginine (ADMA) response to inflammation in acute infections.

BACKGROUND AND METHODS: The endogenous inhibitor of nitric oxide synthase (NOs) asymmetrical dimethyl-arginine (ADMA) has been implicated as a possible modulator of inducible NOs during acute inflammation. We examined the evolution in the plasma concentration of ADMA measured at the clinical outset of acute inflammation and after its resolution in a series of 17 patients with acute bacterial infections. RESULTS: During the acute phase of inflammation/infection, patients displayed very high levels of C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin and nitrotyrosine. Simultaneous plasma ADMA concentration was similar to that in healthy subjects while symmetric dimethyl-arginine (SDMA) levels were substantially increased and directly related with creatinine. When infection resolved, ADMA rose from 0.62 +/- 0.23 to 0.80 +/- 0.18 micromol/l (+29%, P = 0.01) while SDMA remained unmodified. ADMA changes were independent on concomitant risk factor changes and inversely related with baseline systolic and diastolic pressure. Changes in the ADMA/SDMA ratio were compatible with the hypothesis that inflammatory cytokines activate ADMA degradation. CONCLUSIONS: Resolution of acute inflammation is characterized by an increase in the plasma concentration of ADMA. The results imply that ADMA suppression may actually serve to stimulate NO synthesis or that in this situation plasma ADMA levels may not reflect the inhibitory potential of this methylarginine at the cellular level.     

Roles of Insulin,Age, and Asymmetric Dimethylarginine on Nitric Oxide Synthesis In Vivo

We tested the effects of insulin on production of nitrous oxide (NO)-related substances (nitrites and nitrates [NOx]) after ¹⁵N-arginine intravenous infusion and on asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) concentrations in conditions reportedly associated with altered NO availability, i.e., aging, hypertension, hypercholesterolemia, and type 2 diabetes mellitus (T2DM). A total of 26 male subjects (age 23–71 years, BMI 23–33 kg/m²), some of whom were affected by mixed pathologic features, were enrolled. NOx fractional synthesis rate (FSR) was lower in elderly (P < 0.015) and T2DM subjects (P < 0.03) than in matched control subjects. Hyperinsulinemia generally increased both NOx FSR and absolute synthesis rate (ASR) and reduced NOx, ADMA, and SDMA concentrations. Insulin sensitivity was impaired only in T2DM. With use of simple linear regression analysis across all subjects, age was inversely correlated with both NOx FSR (R² = 0.23, P < 0.015) and ASR (R² = 0.21, P < 0.02). NOx FSR inversely correlated with both ADMA and SDMA. With use of multiple regression analysis and various models, NOx FSR remained inversely associated with age and ADMA, whereas ASR was inversely associated with age and diabetes. No association with insulin sensitivity was found. We conclude that whole-body NOx production is decreased in aging and T2DM. Age, ADMA concentration, and T2DM, but not insulin resistance, appear as negative regulators of whole-body NOx production.Nitric oxide (NO) is a molecule with key functions in the cardiovascular, immune, and nervous systems (1). NO production is modified during physical exercise (2) and is altered in aging (3), diabetes (4,5), hypertension (6,7), and hypercholesterolemia (8,9). The understanding of the pathophysiological mechanism(s) underlying the altered NO metabolism in these diseases is important also for the development of therapeutic interventions aimed at improving vascular function.NO is synthesized from the guanidine group of arginine via the enzyme family NO synthases (NOS), which include three isoforms (10). One of these, the constitutive endothelial NOS (eNOS) enzyme, is stimulated by hormones (insulin and estrogens), physical exercise, and cofactors such as tetrahydrobiopterin (10). Conversely, it is inhibited by the endogenous methylarginines asymmetric dimethylarginine (ADMA), l-monomethylarginine (LMMA), and symmetric dimethylarginine (SDMA) (11,12). ADMA and LMMA inhibit both eNOS and arginine cellular transport, whereas SDMA inhibits arginine transport (11,12). Dimethylarginines are increasingly recognized as important markers or factors of endothelial dysfunction and cardiovascular disease (11). ADMA concentration is increased in diabetes, hypertension, hypercholesterolemia, and aging (11,13).Insulin is an important regulator of NO production, and insulin resistance is frequently associated with endothelial dysfunction (14). Insulin mediates both glucose entry into insulin-sensitive tissues and NO production via stimulation of protein kinase B/Akt (15), translocation of GLUT4 on cell membrane, and stimulation of eNOS (16). Since in insulin-resistant states insulin signaling is altered at the Akt level (17), any pathway downstream of Akt (including glucose metabolism and NOS activity) should be concomitantly affected. Furthermore, in many insulin-resistant states, ADMA levels are increased, too (18), and they may thus interfere with the insulin signaling on NOS activity and NO production.The relative roles of insulin sensitivity and of ADMA and SDMA concentrations, as well as of other potential interfering factors such as age, on NO production in vivo have never been comprehensively investigated. Therefore, this study was designed to measure whole-body insulin sensitivity (i.e., the insulin-stimulated glucose disposal), ADMA and SDMA concentrations, and basal and insulin-stimulated NO production (19) in human subjects over a wide range of insulin sensitivity and age either healthy or affected by hypertension, hypercholesterolemia, or type 2 diabetes mellitus (T2DM). NO production was determined by a precursor product, isotope dilution technique (5). A key target of this study was also to examine the possible correlates between production of nitrites and nitrates (NOx) and ADMA, SDMA, insulin sensitivity, and age.     

Gender differences in oxidative and nitrosative stress parameters in kidney transplant patients on tacrolimus-based immunosuppression

Background

Cardiovascular (CV) morbidity and mortality rates are still higher after kidney transplantation than in general population. It is known that oxidative and nitrosative stress may contribute to the progress of CV disease in a post-transplant period, but still gender aspect has not been elucidated completely. The aim of this study was to analyze the gender differences in the oxidative and nitrosative stress parameters, as well as asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels among kidney transplant patients on tacrolimus-based immunosuppression.

Methods

Our research included 35 patients (20 men and 15 women) with renal transplant and 25 healthy volunteers. Patients were on chronic immunosuppressive regimen, which included tacrolimus, mycophenolate mofetil and prednisone. In order to estimate oxidative and nitrosative stress, we determined plasma levels of thiobarbituric acid-reactive substances (TBARS), activity of catalase (CAT), levels of total (protein and non-protein) sulfhydryl (SH) groups, advanced oxidation protein products (AOPP), ADMA and SDMA, as well as nitrite/nitrate (NOx) ratio.

Results

TBARS, CAT and SH in plasma were significantly higher in male patients than in female patients (p < 0.05, p < 0.01 and p < 0.05, respectively). There were no gender-dependent differences in AOPP, ADMA, SDMA and NOx in kidney transplant patients. Correlation analysis, Pearson and Spearman, showed significant correlations between tested oxidative and nitrosative stress parameters in male kidney transplant patients. Alternatively, in female patients, there were no significant correlations between tested parameters.

Conclusion

Our findings show that men might be more prone to oxidative damage than women. ADMA, the proven marker of CV morbidity and mortality, may be more significant in male kidney transplant patients concerning oxidative stress control of its level and function.     

Role of asymmetric dimethylarginine in the progression of carotid atherosclerosis in renal transplant patients

Backgrounds/Aims

Atherosclerotic cardiovascular diseases are among the major causes of mortality in renal transplant (RT) patients. Oxidative stress plays an important role in the pathogenesis of atherosclerosis. In this study, we investigated the role of asymmetric dimethylarginine (ADMA) along with oxidized LDL (oxLDL) and antioxidized LDL (anti-oxLDL) on the extent and progression of atherosclerosis measured by carotid artery intima-media thickness (CA-IMT) in RT patients.

Methods

One hundred and eighty renal transplant patients were studied. Baseline and 25th month CA-IMT were determined by B-mode Doppler ultrasonography. ADMA, oxLDL and anti-oxLDL were measured by commercially available ELISA.

Results

The mean age of the patients was 41 ± 9 years. The mean CA-IMT at baseline was 0.61 ± 0.15 mm. Age, cardiovascular disease and diabetes history, proteinuria and triglyceride levels were positively correlated, whereas HDL and albumin were negatively correlated with baseline CA-IMT. Ninety-two patients underwent a second CA-IMT measurement at a mean follow-up of 25th months. The mean second CA-IMT was 0.68 ± 0.18 mm. Serum ADMA levels, HCV positivity and albumin levels were predictors for CA-IMT progression in the multivariate analysis that included age, HCV positivity ADMA, albumin, glucose and proteinuria. OxLDL and anti-oxLDL were not associated with both CA-IMT presence and progression.

Conclusion

Serum ADMA levels predict progression of atherosclerosis in RT patients.     

The effect of icodextrin and glucose-containing solutions on insulin resistance in CAPD patients

PURPOSE: Peritoneal dialysis patients have particular risks with respect to their lipid status and hyperinsulinemia. The aim of this study was to investigate the relation between insulin resistance and the type of the peritoneal dialysis solution. MATERIALS: 41 randomly selected non-diabetic patient cohort who were already under treatment with continuous ambulatory peritoneal dialysis (CAPD) and 10 healthy controls participated in the study. 24 of the 41 patients were using 3 standard 1.36% glucose solutions during the day and 1 hypertonic solution with 2.27% glucose dwell during the night (glucose group: mean age 45.54 +/- 16.67 years and median CAPD duration 16.5 months). The remaining 17 patients were using 3 standard 1.36% glucose solutions during the day and 1 icodextrin dwell during the night for 8-10 hours (icodextrin group: mean age 47.47 +/- 13.15 years, median duration of icodextrin use 6 months (range 2-20 months), and median CAPD duration 30 months). Insulin resistance (IR) was calculated according to the homeostasis model assesment (HOMA) formula: HOMA-IR = fasting glucose (mmol/l) x fasting insulin (microU/1/22.5. The HOMA cutoff point for diagnosis of insulin resistance was established with receiver-operating characteristic (ROC) curves. The patients were called HOMA-IR(+) if their HOMA scores were higher than cutoff value. RESULTS: There were no significant differences between age, BMI, triglyceride, total and high-density lipoprotein (HDL) cholesterol, iron and ferritin, alanine aminotransferase, fibrinogen, intact parathyroid hormone, magnesium, hemoglobin and hematocrit levels of the 2 groups. The mean glucose levels of the groups were not different but fasting insulin levels and HOMA scores of the icodextrin group were significantly lower than the glucose group (10.15 +/- 6.87 vs. 18.11 +/- 13.15, p = 0.028, and 2.28 +/- 1.67 vs. 4.26 +/- 3.27, p = 0.027, respectively). The ratio of patients with low HOMA scores (cutoff = 2.511) were significantly higher in the icodextrin group than in the glucose group (71% vs 38%, p = 0.037). Other than fasting insulin and glucose levels, significantly positive correlation was found between HOMA score and BMI in both groups. With regression analysis, we found that the main parameters effecting HOMA score were BMI (p = 0.008) and triglyceride (p = 0.029) in the glucose group, but no parameters were found to affect HOMA score in icodextrin group. CONCLUSION: These results suggest that insulin resistance is reduced in peritoneal dialysis patients using icodextrin-based dialysis fluid instead of glucose-based dialysis fluid.     

Total nitric oxide production is low in patients with chronic renal disease

BACKGROUND: A deficiency of the endogenous vasodilator nitric oxide (NO) has been implicated as a potential cause of hypertension in chronic renal disease (CRD) patients. This study was conducted to determine whether 24-hour NOX (NO2 and NO3) excretion (a qualitative index of total NO production) is reduced in patients with CRD. METHODS: Measurements were made in 13 CRD patients and 9 normotensive healthy controls after 48 hours on a controlled low-NOX diet. Urine was collected over the second 24-hour period for analysis of 24-hour NOX, and cGMP and blood drawn at the completion. Plasma levels of arginine (the substrate for endogenous renal NO synthesis), citrulline (substrate for renal arginine synthesis), and the endogenous NO synthesis inhibitor asymmetrical dimethylarginine (ADMA) and its inert isomer and symmetrical dimethylarginine (SDMA) were also determined. RESULTS: Systolic blood pressure was higher in CRD patients (12 of whom were already on antihypertensive therapy) than in controls (P < 0.05). Twenty-four-hour urinary NOX excretion was low in CRD patients compared with controls despite similar dietary NO intake, suggesting that net endogenous NO production is decreased in renal disease. In contrast, the 24-hour urinary cGMP did not correlate with UNOXV. Plasma citrulline was increased in CRD patients, possibly reflecting reduced conversion of citrulline to arginine. Plasma arginine was not different, and plasma ADMA levels were elevated in CRD versus controls, changes that would tend to lower NO synthase. CONCLUSION: These results suggest that NO production is low in CRD patients and may contribute to hypertension and disease progression in CRD.     

Circulating endothelial nitric oxide synthase inhibitory factor in some patients with chronic renal disease

BACKGROUND: Chronic renal disease (CRD) is associated with hypertension and reduced synthesis of nitric oxide (NO). Here, we investigated whether there is a circulating endothelial NO synthase (eNOS) inhibitory factor(s) in some patients with CRD that might directly influence endothelial NOS. METHODS: Human dermal microvascular endothelial cells (HDMECs) were incubated for six hours with 20% plasma from subjects with normal renal function (PCr = 0.8 +/- 0.2 mg%), and patients with moderate renal insufficiency of various causes (PCr = 4.0 +/- 1.5 mg%) and impact on NOS activity, transport of L-arginine, and abundance of eNOS protein were measured. Plasma concentrations of asymmetric and symmetric dimethyl L-arginine (ADMA and SDMA) were also measured. RESULTS: There was no effect of any human plasma on L-arginine transport. The NOS activity was variable in CRD patients and fell into two subgroups: CRD I, individual values similar to control, and CRD II, individual values lower than control mean. The effect of CRD plasma on NOS activity in cultured cells was not related to the primary disease, but was predicted by plasma ADMA levels since plasma ADMA was elevated in CRD II versus both control and CRD I. Blood urea nitrogen and creatinine levels were uniformly elevated in CRD plasma. The abundance of eNOS protein was unaffected by plasma. CONCLUSION: High plasma levels of ADMA in CRD patients are independent of reduced renal clearance, suggesting an alteration in ADMA synthesis and/or degradation. High ADMA is a marker and is partly responsible for the inhibition of eNOS activity in cultured cells and may also result in reduced eNOS activity in vivo, with consequent hypertension.     

Impact of vitamin E on plasma asymmetric dimethylarginine (ADMA) in chronic kidney disease (CKD): a pilot study.

BACKGROUND: Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase and a proposed cardiovascular risk factor, is elevated in chronic kidney disease (CKD). Pharmacological strategies that lower plasma concentration of ADMA may be expected to increase nitric oxide (NO.) bioavailability and potentially limit atherosclerosis. We hypothesized that the antioxidant alpha-tocopherol (vitamin E) reduces ADMA levels in CKD. METHODS: An open-label pilot interventional study using 800 IU of vitamin E was undertaken in eight stable out-patients with non-diabetic CKD (creatinine clearance <30 ml/min/1.73 m(2)) and six healthy controls, with the objective of measuring plasma ADMA levels at baseline and after 8 weeks of treatment. Plasma ADMA, symmetric dimethylarginine (SDMA) and alpha-tocopherol concentrations were determined at study entry and exit using high-performance liquid chromatography, while plasma total F2-isoprostanes, an index of oxidative stress, were measured using a commercially available enzyme-linked immunosorbent assay kit. RESULTS: ADMA and SDMA concentrations were significantly higher in the plasma of patients compared with that of controls (P 相似文献